Mendelian Inheritance in Man/MIM.ISO/source/omim.txt

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*RECORD*
*FIELD* NO
100050
*FIELD* TI
100050 AARSKOG SYNDROME
SHAWL SCROTUM, INCLUDED;;
HYPERTELORISM, INCLUDED
*FIELD* TX
Grier et al. (1983) reported father and 2 sons with typical Aarskog
syndrome, including short stature, hypertelorism, and shawl scrotum.
They tabulated the findings in 82 previous cases. X-linked recessive
inheritance has been repeatedly suggested (see 305400). The family
reported by Welch (1974) had affected males in 3 consecutive
generations. Thus, there is either genetic heterogeneity or this is an
autosomal dominant with strong sex-influence and possibly ascertainment
bias resulting from use of the shawl scrotum as a main criterion.
Stretchable skin was present in the cases of Grier et al. (1983). Teebi
et al. (1993) reported the case of an affected mother and 4 sons
(including a pair of monozygotic twins) by 2 different husbands. They
suggested that the manifestations were as severe in the mother as in the
sons and that this suggested autosomal dominant inheritance. Actually,
the mother seemed less severely affected, compatible with X-linked
inheritance.

*FIELD* RF
1. Grier, R. E.; Farrington, F. H.; Kendig, R.; Mamunes, P.: Autosomal
dominant inheritance of the Aarskog syndrome. Am. J. Med. Genet. 15:
39-46, 1983.

2. Teebi, A. S.; Rucquoi, J. K.; Meyn, M. S.: Aarskog syndrome: report
of a family with review and discussion of nosology. Am. J. Med.
Genet. 46: 501-509, 1993.

3. Welch, J. P.: Elucidation of a 'new' pleiotropic connective tissue
disorder. Birth Defects Orig. Art. Ser. X(10): 138-146, 1974.

*FIELD* CS

Growth:
   Mild to moderate short stature

Head:
   Normocephaly

Hair:
   Widow's peak

Facies:
   Maxillary hypoplasia;
   Broad nasal bridge;
   Anteverted nostrils;
   Long philtrum;
   Broad upper lip;
   Curved linear dimple below the lower lip

Eyes:
   Hypertelorism;
   Ptosis;
   Down-slanted palpebral fissures;
   Ophthalmoplegia;
   Strabismus;
   Hyperopic astigmatism;
   Large cornea

Ears:
   Floppy ears;
   Lop-ears

Mouth:
   Cleft lip/palate

GU:
   Shawl scrotum;
   Saddle-bag scrotum;
   Cryptorchidism

Limbs:
   Brachydactyly;
   Digital contractures;
   Clinodactyly;
   Mild syndactyly;
   Transverse palmar crease;
   Lymphedema of the feet

Joints:
   Ligamentous laxity;
   Osteochondritis dissecans;
   Proximal finger joint hyperextensibility;
   Flexed distal finger joints;
   Genu recurvatum;
   Flat feet

Skin:
   Stretchable skin

Spine:
   Cervical spine hypermobility;
   Odontoid anomaly

Heme:
   Macrocytic anemia;
   Hemochromatosis

GI:
   Hepatomegaly;
   Portal cirrhosis;
   Imperforate anus;
   Rectoperineal fistula

Pulmonary:
   Interstitial pulmonary disease

Thorax:
   Sternal deformity

Inheritance:
   Sex-influenced autosomal dominant form;
   also X-linked form

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
carol: 7/7/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
100070
*FIELD* TI
100070 ABDOMINAL AORTIC ANEURYSM
AORTIC ANEURYSM, ABDOMINAL;;
ANEURYSM, ABDOMINAL AORTIC
*FIELD* TX
Tilson and Seashore (1984) reported 50 families in which abdominal
aortic aneurysm had occurred in 2 or more first-degree relatives, mainly
males. In 29 families, multiple sibs (up to 4) were affected; in 2
families, 3 generations were affected; and in 15 families, persons in 2
generations were affected. Three complex pedigrees were observed: one in
which both parents and 3 sons were affected; one in which a man and his
paternal uncle were affected; and one in which a man and his father and
maternal great-uncle were affected. In the 'one-generation' families,
there were 3 with only females affected, including a set of identical
twins. The authors concluded that if a single gene is responsible, it is
likely to be autosomal but that a multigenic mechanism cannot be
excluded. Clifton (1977) reported 3 affected brothers. In North
Carolina, Johnson et al. (1985) found that white males have a frequency
of abdominal aortic aneurysm about 3 times that in black males, black
females, or white females; all 3 of the latter groups had about
comparable frequencies. Frequency was ascertained by a survey of
autopsies and a survey of abdominal computed tomographic scans in
subjects over the age of 50 years. Johansen and Koepsell (1986) compared
the family histories of 250 patients with abdominal aortic aneurysm with
those of 250 control subjects. Among the control subjects, 2.4% reported
a first-degree relative with an aneurysm, compared with 19.2% of the
patients with abdominal aortic aneurysm. This was taken to represent an
estimated 11.6-fold increase in abdominal aortic aneurysm risk among
persons with an affected first-degree relative. The authors suggested
that noninvasive screening to detect early abdominal aortic aneurysm may
be warranted in the relatives of affected persons. Borkett-Jones et al.
(1988) brought to 4 the number of reported sets of identical twins
concordant for abdominal aortic aneurysm. In a 9-year prospective study
of 542 consecutive patients undergoing operation for abdominal aortic
aneurysm, Darling et al. (1989) found that 82 (15.1%) had a first-degree
relative with an aneurysm as compared to 9 (1.8%) of the control group
of 500 patients of similar age and sex without aneurysmal disease.
Patients with familial abdominal aortic aneurysm were more likely to be
women (35% vs 14%), and men with familial abdominal aortic aneurysm
tended to be about 5 years younger than the women. No significant
difference was found between the patients with nonfamilial and familial
abdominal aortic aneurysms in anatomic extent, multiplicity, associated
occlusive disease, or blood type. The risk of rupture was strongly
correlated with familial disease and the presence of a female member
with aneurysm (63% vs 37%). Darling et al. (1989) suggested the term
'black widow syndrome' because of the grim significance of the presence
of an affected female in the family. Abdominal aortic aneurysm is, of
course, a common disorder; by ultrasound screening, Collin et al. (1988)
found an abdominal aortic aneurysm in 5.4% of men aged 65 to 74, and in
2.3% of men in this age group the aneurysm was 4 cm or more in diameter.
On the basis of a study of first-degree relatives of 91 probands,
Majumder et al. (1991) rejected the nongenetic model and concluded that
the most parsimonious genetic model was that susceptibility to abdominal
aortic aneurysm is determined by a recessive gene at an autosomal
diallelic major locus. Loosemore et al. (1988) described 2 brothers with
abdominal aortic aneurysm at ages 58 and 62 years, whose father died of
ruptured abdominal aortic aneurysm at the age of 72 years. Four other
sibs died of myocardial infarction at ages 47 to 61 years. Fitzgerald et
al. (1995) assessed the incidence of abdominal aortic aneurysm (AAA) in
the siblings of 120 patients known to have AAA. Twelve percent of the
siblings were found to have an aneurysm, including 22% of male siblings
but only 3% of female siblings. Male siblings with hypertension were
more likely to have AAA.

Ward (1992) looked for association of dilated peripheral arteries with
aortic aneurysmal disease by measuring the diameters of the common
femoral, popliteal, brachial, common carotid, internal carotid, and
external carotid arteries by color-flow duplex scan in 30 control
subjects and 36 patients with aortic aneurysm matched for age, sex,
smoking habits, and hypertension. Mean peripheral artery diameter was
significantly greater in patients with aortic aneurysms than in controls
at all measurement sites. Peripheral artery dilatation was identified at
sites that are seldom, if ever, involved in atherosclerosis. Ward (1992)
concluded that there is a generalized dilating diathesis in aortic
aneurysmal disease that may be unrelated to atherosclerosis.

Loosemore et al. (1988) suggested that a deficiency of type III collagen
might be the basis for the aneurysm formation. The proportion of type
III collagen in forearm skin biopsies was cited as accurately reflective
of the proportion in the aorta and was said to have been low in the
brothers. Kontusaari et al. (1989) and Kontusaari et al. (1990)
incriminated mutation in the COL3A1 gene (120180.0004) in the causation
of familial aortic aneurysms. See review of Kuivaniemi et al. (1991).
Tromp et al. (1993) carried out detailed DNA sequencing of the
triple-helical domain of type III procollagen on cDNA prepared from 54
patients with aortic aneurysms. In the case of 43 patients, at least 1
additional blood relative had aneurysms. The 43 males and 11 females
originated from 50 different families and 5 different nationalities.
Only one amino acid substitution likely to have functional significance,
a gly136-to-arg mutation, was found (see 120180.0018). Results indicated
that mutations in type III procollagen are the cause of only about 2% of
aortic aneurysms.

As part of a review of abdominal aortic aneurysm as a multifactorial
process, Henney (1993) reviewed family studies and the molecular
genetics. In a review focused on surgical aspects, Ernst (1993)
commented that 'there is little support for atherosclerosis as the
unitary cause...several factors appear to have an important role,
including familial clustering...'

Through questionnaire and telephone inquiries, Verloes et al. (1995)
collected family data on 324 probands with abdominal aortic aneurysm and
determined multigenerational pedigrees on 313 families, including 39
with multiple affected patients. There were 276 sporadic cases (264 men;
12 women); 81 cases belonged to multiplex pedigrees (76 men; 5 women).
The familial male cases showed a significantly earlier age at rupture
and a greater rupture rate as compared with sporadic male cases, as well
as a tendency (p less than 0.05) towards earlier age of diagnosis.
Relative risk for male sibs of a male patient was 18. Segregation
analysis with the mixed model gave single gene effect with dominant
inheritance as the most likely explanation for the familial occurrence.
The frequency of the morbid allele was 1:250, and its age-related
penetrance was not higher than 0.4.

Baird et al. (1995) collected information from 126 probands with
abdominal aortic aneurysm and 100 controls (cataract surgery patients)
concerning AAA. Of 427 sibs of probands, 19 (4.4%) had probable or
definite AAA, compared with 5 (1.1%) of 451 sibs of controls. The
lifetime cumulative risks of AAA at age 83 were 11.7% and 7.5%,
respectively. The risk of AAA began at an earlier age and increased more
rapidly for probands' sibs than for controls' sibs. The risk comparison,
based on the results of ultrasound screening of 54 geographically
accessible sibs probands and the 100 controls, showed a similar pattern.
AAA on ultrasound was found in 10 sibs of probands, or 19%, compared to
8% of controls.

*FIELD* SA
Gatalica et al. (1992); Norrgard et al. (1985); Norrgard et al. (1984)
*FIELD* RF
1. Baird, P. A.; Sadovnick, A. D.; Yee, I. M. L.; Cole, C. W.; Cole,
L.: Sibling risks of abdominal aortic aneurysm. Lancet 346: 601-604,
1995.

2. Borkett-Jones, H. J.; Stewart, G.; Chilvers, A. S.: Abdominal
aortic aneurysms in identical twins. J. Roy. Soc. Med. 81: 471-472,
1988.

3. Clifton, M. A.: Familial abdominal aortic aneurysms. Brit. J.
Surg. 64: 765-766, 1977.

4. Collin, J.; Araujo, L.; Walton, J.; Lindsell, D.: Oxford screening
programme for abdominal aortic aneurysm in men aged 65 to 74 years. Lancet II:
613-615, 1988.

5. Darling, R. C., III; Brewster, D. C.; Darling, R. C.; LaMuraglia,
G. M.; Moncure, A. C.; Cambria, R. P.; Abbott, W. M.: Are familial
abdominal aortic aneurysms different?. J. Vasc. Surg. 10: 39-43,
1989.

6. Ernst, C. B.: Abdominal aortic aneurysm. New Eng. J. Med. 328:
1167-1172, 1993.

7. Fitzgerald, P.; Ramsbottom, D.; Burke, P.; Grace, P.; McAnen, O.;
Croke, D. T.; Collins, P.; Johnson, A.; Bouchier-Hayes, D.: Abdominal
aortic aneurysm in the Irish population. Br. J. Surg. 82: 483-486,
1995.

8. Gatalica, Z.; Gibas, Z.; Martinez-Hernandez, A.: Dissecting aortic
aneurysm as a complication of generalized fibromuscular dysplasia. Hum.
Path. 23: 586-588, 1992.

9. Henney, A. M.: Abdominal aortic aneurysm: molecular genetics. Lancet 341:
216-217, 1993.

10. Johansen, K.; Koepsell, T.: Familial tendency for abdominal aortic
aneurysms. J.A.M.A. 256: 1934-1936, 1986.

11. Johnson, G., Jr.; Avery, A.; McDougal, E. G.; Burnham, S. J.;
Keagy, B. A.: Aneurysms of the abdominal aorta: incidence in blacks
and whites in North Carolina. Arch. Surg. 120: 1138-1140, 1985.

12. Kontusaari, S.; Kuivaniemi, H.; Tromp, G.; Grimwood, R.; Prockop,
D. J.: A single base mutation in the type III procollagen gene (COL3A1)
on chromosome 2q that causes familial aneurysms. (Abstract) Cytogenet.
Cell Genet. 51: 1024-1025, 1989.

13. Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Romanic, A. M.; Prockop,
D. J.: A mutation in the gene for type III procollagen (COL3A1) in
a family with aortic aneurysms. J. Clin. Invest. 86: 1465-1473,
1990.

14. Kuivaniemi, H.; Tromp, G.; Prockop, D. J.: Genetic causes of
aortic aneurysms: unlearning at least part of what the textbooks say. J.
Clin. Invest. 88: 1441-1444, 1991.

15. Loosemore, T. M.; Child, A. H.; Dormandy, J. A.: Familial abdominal
aortic aneurysms. J. Roy. Soc. Med. 81: 472-473, 1988.

16. Majumder, P. P.; St. Jean, P. L.; Ferrell, R. E.; Webster, M.
W.; Steed, D. L.: On the inheritance of abdominal aortic aneurysm. Am.
J. Hum. Genet. 48: 164-170, 1991.

17. Norrgard, O.; Angquist, K.-A.; Johnson, O.: Familial aortic aneurysms:
serum concentrations of triglyceride, cholesterol, HDL-cholesterol
and (VLDL + LDL)-cholesterol. Brit. J. Surg. 72: 113-116, 1985.

18. Norrgard, O.; Rais, O.; Angquist, K. A.: Familial occurrence
of abdominal aortic aneurysms. Surgery 95: 650-656, 1984.

19. Tilson, M. D.; Seashore, M. R.: Fifty families with abdominal
aortic aneurysms in two or more first-order relatives. Am. J. Surg. 147:
551-553, 1984.

20. Tromp, G.; Wu, Y.; Prockop, D. J.; Madhatheri, S. L.; Kleinert,
C.; Earley, J. J.; Zhuang, J.; Norrgard, O.; Darling, R. C.; Abbott,
W. M.; Cole, C. W.; Jaakkola, P.; Ryynanen, M.; Pearce, W. H.; Yao,
J. S. T.; Majamaa, K.; Smullens, S. N.; Gatalica, Z.; Ferrell, R.
E.; Jimenez, S. A.; Jackson, C. E.; Michels, V. V.; Kaye, M.; Kuivaniemi,
H.: Sequencing of cDNA from 50 unrelated patients reveals that mutations
in the triple-helical domain of type III procollagen are an infrequent
cause of aortic aneurysms. J. Clin. Invest. 91: 2539-2545, 1993.

21. Verloes, A.; Sakalihasan, N.; Koulischer, L.; Limet, R.: Aneurysms
of the abdominal aorta: familial and genetic aspects in three hundred
thirteen pedigrees. J. Vas. Surg. 21: 646-655, 1995.

22. Ward, A. S.: Aortic aneurysmal disease: a generalized dilating
diathesis?. Arch. Surg. 127: 990-991, 1992.

*FIELD* CS

Vascular:
   Abdominal aortic aneurysm;
   Generalized dilating diathesis

Misc:
   Estimated 11.6-fold increase among persons with an affected first-degree
   relative

Inheritance:
   Autosomal dominant vs. recessive at an autosomal major locus or multifactorial;
   COL3A1 gene (120180.0004) mutations cause about 2%

*FIELD* CN
Clair A. Francomano - updated: 5/12/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/02/1996
terry: 10/24/1995
mark: 7/11/1995
warfield: 4/6/1994
mimadm: 3/11/1994
carol: 7/13/1993

*RECORD*
*FIELD* NO
100100
*FIELD* TI
100100 ABDOMINAL MUSCLES, ABSENCE OF, WITH URINARY TRACT ABNORMALITY AND
CRYPTORCHIDISM
PRUNE BELLY SYNDROME
*FIELD* TX
This condition was first described by Frolich (1839). The appellation
'prune belly syndrome' is descriptive because the intestinal pattern is
evident through the thin, lax, protruding abdominal wall in the infant
(Osler, 1901). (Osler did not use the term 'prune belly.' His article on
this subject and one 'on a family form of recurring epistaxis,
associated with multiple telangiectases of the skin and mucous
membranes'--see 187300--appeared successively in the November 1901 issue
of the Johns Hopkins Hospital Bulletin. Osler wrote: 'In the summer of
1897 a case of remarkable distension of the abdomen was admitted to the
wards, with greatly distended bladder, and on my return in September,
Dr. Futcher, knowing that I would be interested in it, sent for the
child.') The full syndrome probably occurs only in males (Williams and
Burkholder, 1967). Multiple cases (of the full syndrome) in families
have rarely been reported, and the mode of inheritance, indeed whether
this is a mendelian condition, is still unclear. Autosomal recessive
inheritance is suggested by some reports. In Lebanon, where the rate of
consanguinity is high, Afifi et al. (1972) described an affected
offspring of first-cousin parents. Garlinger and Ott (1974) described 2
affected brothers in 1 family and 2 affected male cousins in a second,
and found 3 other reports of affected sibs, 2 of affected cousins and 1
of concordant male twins. In the first family the parents were
nonconsanguineous. In the second family the affected boys' mothers were
half-sisters; they had different maternal grandmothers. If this is an
X-linked recessive, multiple affected brothers should be observed. If
the disorder is due to fresh dominant mutation in each case, the
male-limitation would be unexpected but not impossible. In British
Columbia, Baird and MacDonald (1981) found a frequency of 1 in 29,231
live births. This malformation syndrome is similar to Poland syndrome
(173800) in being rather consistently reproduced in many cases but
having no clearly demonstrable mendelian basis. A possibly related
syndrome was described in a single patient by Texter and Murphy (1968).
The triad consisted of absence of the right testis, kidney, and rectus
abdominis muscle. King and Prescott (1978) presented evidence to support
the suggestion that the maldevelopment of the abdominal musculature and
abdominal laxity are secondary phenomena, the primary event being marked
distension of the abdomen in the fetal period because of obstruction of
the urinary tract. Likewise, Pagon et al. (1979) suggested that the
abdominal muscle deficiency is secondary to fetal abdominal distension
of various causes, most often perhaps, urethral obstruction with
enlarged bladder. 'Prune belly' occurs, in the main, as a consequence of
posterior urethral valves; thus the predominance as a male-limited
multifactorial trait. Gaboardi et al. (1982) reported 2 brothers and a
sister with prune belly syndrome with bilateral hydronephrosis,
megaureter and megabladder, but no urethral stenosis. A better prognosis
than is usually thought to obtain was suggested by the series of 19
patients reported by Burke et al. (1969). Greskovich and Nyberg (1988)
gave a review in which they stated incorrectly that the term prune belly
syndrome was coined by Osler.

*FIELD* SA
Burton and Dillard (1984); Harley et al. (1972); Lee  (1977); Monie
and Monie (1979); Riccardi and Grum (1977); Roberts  (1956); Welch
and Kearney (1974); Woodhouse et al. (1982)
*FIELD* RF
1. Afifi, A. K.; Rebeiz, J.; Mire, J.; Andonian, S. J.; Der Kaloustian,
V. M.: The myopathology of the prune belly syndrome. J. Neurol.
Sci. 15: 153-166, 1972.

2. Baird, P. A.; MacDonald, E. C.: An epidemologic study of congenital
malformations of the anterior abdominal wall in more than half a million
consecutive live births. Am. J. Hum. Genet. 33: 470-478, 1981.

3. Burke, E. C.; Shin, M. H.; Kelalis, P. P.: Prune belly syndrome:
clinical findings and survival. Am. J. Dis. Child. 117: 668-671,
1969.

4. Burton, B. K.; Dillard, R. G.: Prune belly syndrome: observations
supporting the hypothesis of abdominal overdistention. Am. J. Med.
Genet. 17: 669-672, 1984.

5. Frolich, F.: Der Mangel der Muskeln, insbesondere der Seitenbauchmuskeln.
Dissertation: Wurzburg (pub.)  1839.

6. Gaboardi, F.; Sterpa, A.; Thiebat, E.; Cornali, R.; Manfredi, M.;
Bianchi, C.; Giacomoni, M. A.; Bertagnoli, L.: Prune-belly syndrome:
report of three siblings. Helv. Paediat. Acta 37: 283-288, 1982.

7. Garlinger, P.; Ott, J.: Prune belly syndrome: possible genetic
implications. Birth Defects Orig. Art. Ser. X(8): 173-180, 1974.

8. Greskovich, F. J., III; Nyberg, L. M., Jr.: The prune belly syndrome:
a review of its etiology, defects, treatment and prognosis. J. Urol. 140:
707-712, 1988.

9. Harley, L. M.; Chen, Y.; Rattner, W. H.: Prune belly syndrome. J.
Urol. 108: 174-176, 1972.

10. King, C. R.; Prescott, G.: Pathogenesis of the prune-belly anomaly. J.
Pediat. 93: 273-274, 1978.

11. Lee, S. M.: Prune-belly syndrome in a 54-year-old man. J.A.M.A. 237:
2216-2217, 1977.

12. Monie, I. W.; Monie, B. J.: Prune-belly syndrome and fetal ascites. Teratology 19:
111-117, 1979.

13. Osler, W.: Congenital absence of the abdominal muscles with distended
and hypertrophied urinary bladder. Bull. Johns Hopkins Hosp. 12:
331-333, 1901.

14. Pagon, R. A.; Smith, D. W.; Shepard, T. H.: Urethral obstruction
malformation complex: a cause of abdominal deficiency and the 'prune
belly.'. J. Pediat. 94: 900-906, 1979.

15. Riccardi, V. M.; Grum, C. M.: The prune belly anomaly: heterogeneity
and superficial X-linkage mimicry. J. Med. Genet. 14: 266-270, 1977.

16. Roberts, P.: Congenital absence of the abdominal muscles with
associated abnormalities of the genito-urinary tract. Arch. Dis.
Child. 31: 236-239, 1956.

17. Texter, J. H.; Murphy, G. P.: The right-sided syndrome: congenital
absence of the right testis, kidney and rectus: urologic diagnosis
and treatment. Johns Hopkins Med. J. 122: 224-228, 1968.

18. Welch, K. J.; Kearney, G. P.: Abdominal musculature deficiency
syndrome: prune belly. J. Urol. 111: 693-700, 1974.

19. Williams, D. I.; Burkholder, G. V.: The prune belly syndrome. J.
Urol. 98: 244-251, 1967.

20. Woodhouse, C. R. J.; Ransley, P. G.; Innes-Williams, D.: Prune
belly syndrome--report of 47 cases. Arch. Dis. Child. 57: 856-859,
1982.

*FIELD* CS

Abdomen:
   Absent abdominal musculature;
   Visible intestinal pattern;
   Thin, lax, protruding abdominal wall

Skin:
   Wrinkled abdominal skin

GU:
   Distended bladder;
   Fetal urinary tract obstruction;
   Posterior urethral valves;
   Hydronephrosis;
   Hydroureter;
   Cryptorchidism

GI:
   Imperforate anus

Thorax:
   Flared ribs;
   Pectus excavatum/carinatum

Limbs:
   Club foot

Joints:
   Congenital hip dislocation

Misc:
   Oligohydramnios

Cardiac:
   Congenital heart defect;
   Patent ductus arteriosus

Inheritance:
   ? Autosomal dominant;
   Autosomal recessive suggested by some reports

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/13/1997
terry: 2/13/1997
carol: 7/12/1996
mimadm: 4/18/1994
carol: 2/13/1994
carol: 8/25/1992
supermim: 3/16/1992
carol: 9/4/1990

*RECORD*
*FIELD* NO
100200
*FIELD* TI
100200 ABDUCENS PALSY
*FIELD* TX
This is a form of hereditary strabismus. Affected persons in 2 or more
generations have been reported (Chavasse, 1938; Francois, 1961). Nuclear
aplasia has been found in some cases (Phillips et al., 1932). Abducens
palsy also occurs as part of the Moebius syndrome (157900).

*FIELD* RF
1. Chavasse, F. B.: The ocular palsies. Trans. Ophthal. Soc. U.K. 58:
493 only, 1938.

2. Francois, J.: Heredity in Ophthalmology.  St. Louis: C. V. Mosby
(pub.)  1961. Pp. 280 only.

3. Phillips, W. H.; Dirion, J. K.; Graves, G. O.: Congenital bilateral
palsy of abducens. Arch. Ophthal. 8: 355-364, 1932.

*FIELD* CS

Eyes:
   Abducens palsy;
   Strabismus

Neuro:
   Abducens nucleus aplasia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/15/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
100300
*FIELD* TI
*100300 ABSENCE DEFECT OF LIMBS, SCALP, AND SKULL
ADAMS-OLIVER SYNDROME;;
CONGENITAL SCALP DEFECTS WITH DISTAL LIMB REDUCTION ANOMALIES
*FIELD* TX
The proband described by Adams and Oliver (1945) had absence of the
lower extremities below the mid-calf region and absence of all digits
and some of the metacarpals of the right hand; a denuded ulcerated area
on the vertex of the scalp present at birth; and a bony defect of the
skull underlying the scalp defect. The skin and skull lesions were
similar to those of aplasia cutis congenita (107600, 207700). The
proband had 4 unaffected brothers and a sister and brother with
identical defects of limb, scalp and skull. The father was born with
absence of toes 2-5 on the left foot, with short terminal phalanges of
all fingers, and with a scalp defect. The father was 1 of 10 children of
whom 3 others had defects of the extremities. The father's father was
said to have had short fingers. The proband's parents were not related.
In a family described by Scribanu and Temtamy (1975), variable
expressivity and reduced penetrance were evident; cutis marmorata was
striking in the proband, a 3-year-old male. Toriello et al. (1988) also
described cutis marmorata telangiectatica congenita (CMTC; 219250) in a
child with the Adams-Oliver syndrome. The mother also had CMTC without
the other features of the Adams-Oliver syndrome. These vascular changes
in the skin may indicate that the features of Adams-Oliver syndrome are
'vascular disruption sequences.' The family reported by Bonafede and
Beighton (1979) added substantial support to dominant inheritance, with
one instance of male-to-male transmission. Kuster et al. (1988)
described 10 cases, 7 of them in 2 families and 3 sporadic cases. They
found 11 families and 19 sporadic cases reported in the literature. They
suggested that the important differential diagnoses are the syndrome of
scalp defect and postaxial polydactyly (181250), the amniotic band
sequence (which is usually nonmendelian), and the Bart type of
epidermolysis bullosa dystrophica (132000). Koiffmann et al. (1988)
recorded an experience which suggested autosomal recessive inheritance
of a disorder identical to the autosomal dominant form. Their patient
had the congenital scalp defect with hypoplastic fingers and toes. The
parents were unaffected first cousins. Among 7 sibs, 3 sisters and 2
brothers were normal, whereas 2 brothers born with the same scalp defect
died as a consequence of bleeding from this abnormal area. Sybert (1989)
concluded that 'most, if not all, instances of isolated ACC of the scalp
are the result of an autosomal dominant gene, that ACC of the body wall
+ limb defects is an extremely heterogeneous group among which there may
be inherited disorders of all Mendelian types as well as sporadic and
nongenetic causes, and that ACC limited to the scalp in association with
limb defects is most often inherited as an autosomal dominant.' Sybert
(1985) and Frieden (1986) gave comprehensive reviews. Jaeggi et al.
(1990) reported an affected mother and child as well as a third sporadic
case. They discussed the probable pathogenesis of the disorder by
vascular disruption as suggested by Toriello et al. (1988). Cutis
marmorata and dilated scalp veins further point to a vascular disorder.
Jaeggi et al. (1990) stated that among the 31 reported patients with the
full syndrome, major hemorrhage from the scalp defect occurred in 10,
with 2 fatalities. Local infection was noted in 7 babies, with 1 case of
fatal meningitis. Only 30% of the patients had surgical treatment of
their scalp defects by skin grafting. Der Kaloustian et al. (1991)
described 2 families having members affected with the Poland anomalad
and the Adams-Oliver syndrome. They hypothesized that the Poland
anomalad and the Adams-Oliver syndrome result from the interruption of
early embryonic blood supply in the subclavian arteries, and that the
gene predisposing to this interruption follows an autosomal dominant
pattern of inheritance. Hoyme et al. (1992) reported that 2 additional
individuals in family 2 of Der Kaloustian et al. (1991) had the Poland
sequence with no findings suggesting Adams-Oliver syndrome. Whitley and
Gorlin (1991) provided a follow-up on the family studied by Adams and
Oliver (1945); the gene had been transmitted to a member of a fourth
generation. They found reports of 81 cases in 32 families with
approximately equal distribution between males and females. Vertical
transmission in at least 8 families was consistent with autosomal
dominant inheritance. Despite large defects of the cranium, central
nervous system abnormalities have not been found in this disorder and
intellectual development appears to be normal. On the basis of the case
of a 10-year-old male, Chitayat et al. (1992) suggested that acrania is
a severe form of aplasia cutis congenita and is within the spectrum of
Adams-Oliver syndrome. In acrania, the flat bones of the cranial vault
are absent, whereas the bones at the base of the skull are normal. The
patient was a sporadic case. Bamforth et al. (1994) found this syndrome
in a mother and her 3 children with variable scalp defects and limb
defects. Other anomalies included congenital heart disease,
microcephaly, epilepsy, mental retardation, arrhinencephaly,
hydrocephaly, anatomic bronchial anomalies, and renal anomalies. The 3
children were by 2 different fathers.

Zapata et al. (1995) reported 2 patients with Adams-Oliver syndrome and
congenital cardiac malformations. A literature review demonstrated that
13.4% of individuals with this syndrome have congenital heart anomalies.

*FIELD* SA
Burton et al. (1976); Fryns  (1987); McMurray et al. (1977)
*FIELD* RF
1. Adams, F. H.; Oliver, C. P.: Hereditary deformities in man due
to arrested development. J. Hered. 36: 3-7, 1945.

2. Bamforth, J. S.; Kaurah, P.; Byrne, J.; Ferreira, P.: Adams Oliver
syndrome: a family with extreme variability in clinical expression.
Am. J. Med. Genet. 49: 393-396, 1994.

3. Bonafede, R. P.; Beighton, P.: Autosomal dominant inheritance
of scalp defects with ectrodactyly. Am. J. Med. Genet. 3: 35-41,
1979.

4. Burton, B. K.; Hauser, L.; Nadler, H. L.: Congenital scalp defects
with distal limb anomalies: report of a family. J. Med. Genet. 13:
466-468, 1976.

5. Chitayat, D.; Meunier, C.; Hodgkinson, K. A.; Robb, L.; Azouz,
M.: Acrania: a manifestation of the Adams-Oliver syndrome. Am.
J. Med. Genet. 44: 562-566, 1992.

6. Der Kaloustian, V. M.; Hoyme, H. E.; Hogg, H.; Entin, M. A.; Guttmacher,
A. E.: Possible common pathogenetic mechanisms for Poland sequence
and Adams-Oliver syndrome. Am. J. Med. Genet. 38: 69-73, 1991.

7. Frieden, I.: Aplasia cutis congenita: a clinical review and proposal
for classification. J. Am. Acad. Derm. 14: 646-660, 1986.

8. Fryns, J. P.: Congenital scalp defects with distal limb reduction
anomalies. J. Med. Genet. 24: 493-496, 1987.

9. Hoyme, H. E.; Entin, M. A.; Der Kaloustian, V. M.; Hogg, H.; Guttmacher,
A. E.: Possible common pathogenetic mechanisms for Poland sequence
and Adams-Oliver syndrome: an additional clinical observation.  (Letter) Am.
J. Med. Genet. 42: 398-399, 1992.

10. Jaeggi, E.; Kind, C.; Morger, R.: Congenital scalp and skull
defects with terminal transverse limb anomalies (Adams-Oliver syndrome):
report of three additional cases. Europ. J. Pediat. 149: 565-566,
1990.

11. Koiffmann, C. P.; Wajntal, A.; Huyke, B. J.; Castro, R. M.: Congenital
scalp skull defects with distal limb anomalies (Adams-Oliver syndrome--McKusick
10030): further suggestion of autosomal recessive inheritance. Am.
J. Med. Genet. 29: 263-268, 1988.

12. Kuster, W.; Lenz, W.; Kaariainen, H.; Majewski, F.: Congenital
scalp defects with distal limb anomalies (Adams-Oliver syndrome):
report of ten cases and review of the literature. Am. J. Med. Genet. 31:
99-115, 1988.

13. McMurray, B. R.; Martin, L. W.; Dignan, P. S. J.; Fogelson, M.
H.: Hereditary aplasia cutis congenita and associated defects: three
instances in one family and a survey of reported cases. Clin. Pediat. 16:
610-614, 1977.

14. Scribanu, N.; Temtamy, S. A.: Syndrome of aplasia cutis congenita
with terminal transverse defects of limbs. J. Pediat. 87: 79-82,
1975.

15. Sybert, V. P.: Aplasia cutis congenita: a report of 12 new families
and review of the literature. Pediat. Derm. 3: 1-14, 1985.

16. Sybert, V. P.: Congenital scalp defects with distal limb anomalies
(Adams-Oliver Syndrome--McKusick 10030): further suggestion of autosomal
recessive inheritance.  (Letter) Am. J. Med. Genet. 32: 266-267,
1989.

17. Toriello, H. V.; Graff, R. G.; Florentine, M. F.; Lacina, S.;
Moore, W. D.: Scalp and limb defects with cutis marmorata telangiectatica
congenita: Adams-Oliver syndrome?. Am. J. Med. Genet. 29: 269-276,
1988.

18. Whitley, C. B.; Gorlin, R. J.: Adams-Oliver syndrome revisited.
Am. J. Med. Genet. 40: 319-326, 1991.

19. Zapata, H. H.; Sletten, L. J.; Pierpont, M. E. M.: Congenital
cardiac malformations in Adams-Oliver syndrome. Clin. Genet. 47:
80-84, 1995.

*FIELD* CS

Limbs:
   Absent lower leg below mid-calf;
   Absent fingers;
   Absent metacarpals;
   Absent toes;
   Short finger terminal phalanges

Skin:
   Congenital scalp defect;
   Cutis marmorata;
   Dilated scalp veins

Skull:
   Skull defect underlying scalp defect

Heme:
   Hemorrhage from scalp defect

Misc:
   Scalp defect local infection;
   Fatal meningitis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 6/8/1995
mimadm: 3/11/1994
carol: 3/7/1994
carol: 12/18/1992
supermim: 3/16/1992
carol: 2/27/1992

*RECORD*
*FIELD* NO
100500
*FIELD* TI
*100500 ACANTHOCYTOSIS WITH NEUROLOGIC DISORDER
NEUROACANTHOCYTOSIS;;
CHOREOACANTHOCYTOSIS;;
LEVINE-CRITCHLEY SYNDROME
*FIELD* TX
In addition to the form of acanthocytosis that accompanies
abetalipoproteinemia (200100), Critchley et al. (1967) described an
adult form of acanthocytosis associated with neurologic abnormalities
and apparently normal serum lipoproteins. The neurologic manifestations
resembled those of the Gilles de la Tourette syndrome (137580) or
Huntington disease (143100). Five of 10 sibs had neurologic
manifestations. A niece had acanthocytes and a neurologic disorder
suggesting Friedreich ataxia. The same disorder was probably reported by
Estes et al. (1967) in a family in which 15 persons in 3 generations had
some degree of neuronal impairment and 9 of these had acanthocytosis.
Levine et al. (1968) concluded that the predominant neurologic
involvement is neuronal.

Critchley et al. (1970) reported a single case from England, a woman who
showed self-mutilation of the tongue, lips and cheeks. Another family
was reported by Aminoff (1972). Wasting of girdle and proximal limb
muscles, absent tendon reflexes, and disturbance of bladder function
were other features.

Bird et al. (1978) described a family in which 3 offspring (2 males, 1
female) of unaffected consanguineous parents had a progressive
neurologic disorder characterized primarily by chorea, which led to
death in the fourth or fifth decades. No malabsorption or abnormalities
of serum beta-lipoprotein were found, but erythrocyte acanthocytosis was
present. At postmortem examination, marked neuronal loss and gliosis of
the caudate and putamen were demonstrated. The disorder in this family
seems to have been recessive, whereas that in the family of Estes et al.
(1967) and Levine et al. (1968) was seemingly dominant. Thus,
heterogeneity may exist in the category of neurologic disease and
acanthocytosis. Vance et al. (1987) reviewed the literature and
concluded that out of 9 families in which there were 2 or more affected
members, 2 were probably autosomal dominant and 7 were autosomal
recessive (see 200150).

In a patient with acanthocytosis and degeneration of the basal ganglia,
Copeland et al. (1982) found an abnormally high level of a protein in
the 100,000 MW range on 2-D O'Farrell gel electrophoresis of red cell
membranes. This patient was from the family reported by Bird et al.
(1978) (Motulsky, 1982).

In 3 patients with neuroacanthocytosis, Rinne et al. (1994) demonstrated
reduced neuronal density in the substantia nigra. As in Parkinson
disease, the ventral lateral region was most severely affected, but with
a slightly more diffuse distribution.

Kartsounis and Hardie (1996) reviewed the clinical features of 19
previously reported cases of neuroacanthocytosis and found that the most
consistent neurologic findings were impairment of frontal lobe function
and psychiatric morbidity, in a pattern suggesting subcortical dementia.

Sakai et al. (1985) urged Levine-Critchley syndrome as the best
designation for this disorder. They felt that choreoacanthocytosis is
inappropriate because tics, dystonia, or parkinsonism may dominate the
clinical picture (Spitz et al., 1985). Neuroacanthocytosis is also
inappropriate because it might include the Bassen-Kornzweig syndrome
(200100). Jankovic et al. (1985) suggested that there are 2 other
neuroacanthocytoses: that associated with hypobetalipoproteinemia
(107730) and that which is part of the McLeod syndrome, an X-linked
disorder (314850).

See Kay (1991) for a discussion of band 3 protein (109270) as the site
of the mutation in choreoacanthocytosis.

*FIELD* SA
Betts et al. (1970); Kito et al. (1980)
*FIELD* RF
1. Aminoff, M. J.: Acanthocytosis and neurological disease. Brain 95:
749-760, 1972.

2. Betts, J. J.; Nicholson, J. T.; Critchley, E. M. R.: Acanthocytosis
with normolipoproteinaemia: biophysical aspects. Postgrad. Med.
J. 46: 702-707, 1970.

3. Bird, T. D.; Cederbaum, S.; Valpey, R. W.; Stahl, W. L.: Familial
degeneration of the basal ganglia with acanthocytosis: a clinical,
neuropathological and neurochemical study. Ann. Neurol. 3: 253-258,
1978.

4. Copeland, B. R.; Todd, S. A.; Furlong, C. E.: High resolution
two-dimensional gel electrophoresis of human erythrocyte membrane
proteins. Am. J. Hum. Genet. 34: 15-31, 1982.

5. Critchley, E. M. R.; Betts, J. J.; Nicholson, J. T.; Weatherall,
D. J.: Acanthocytosis, normolipoproteinaemia and multiple tics. Postgrad.
Med. J. 46: 698-701, 1970.

6. Critchley, E. M. R.; Clark, D. B.; Wikler, A.: An adult form of
acanthocytosis. Trans. Am. Neurol. Assoc. 92: 132-137, 1967.

7. Estes, J. W.; Morley, T. J.; Levine, I. M.; Emerson, C. P.: A
new hereditary acanthocytosis syndrome. Am. J. Med. 42: 868-881,
1967.

8. Jankovic, J.; Killian, J. M.; Spitz, M. C.: Neuroacanthocytosis
syndrome and choreoacanthocytosis (Levine-Critchley syndrome). (Letter) Neurology 35:
1679, 1985.

9. Kartsounis, L. D.; Hardie, R. J.: The pattern of cognitive impairments
in neuroacanthocytosis: a frontosubcortical dementia. Arch. Neurol. 53:
77-80, 1996.

10. Kay, M. M. B.: Band 3 in aging and neurological disease. Ann.
N.Y. Acad. Sci. 621: 179-204, 1991.

11. Kito, S.; Itoga, E.; Hiroshige, Y.; Matsumoto, N.; Miwa, S.:
A pedigree of amyotrophic chorea with acanthocytosis. Arch. Neurol. 37:
514-517, 1980.

12. Levine, I. M.; Estes, J. W.; Looney, J. M.: Hereditary neurological
disease with acanthocytosis: a new syndrome. Arch. Neurol. 19:
403-409, 1968.

13. Motulsky, A. G.: Personal Communication. Seattle, Washington
4/21/1982.

14. Rinne, J. O.; Daniel, S. E.; Scaravilli, F.; Harding, A. E.; Marsden,
C. D.: Nigral degeneration in neuroacanthocytosis. Neurology 44:
1629-1632, 1994.

15. Sakai, T.; Iwashita, H.; Kakugawa, M.: Neuroacanthocytosis syndrome
and choreoacanthocytosis (Levine-Critchley syndrome). (Letter) Neurology 35:
1679, 1985.

16. Spitz, M. C.; Jankovic, J.; Killian, J. M.: Familial tic disorder,
parkinsonism, motor neuron disease, and acanthocytosis: a new syndrome.
Neurology 35: 366-370, 1985.

17. Vance, J. M.; Pericak-Vance, M. A.; Bowman, M. H.; Payne, C. S.;
Fredane, L.; Siddique, T.; Roses, A. D.; Massey, E. W.: Chorea-acanthocytosis:
a report of three new families and implications for genetic counselling.
Am. J. Med. Genet. 28: 403-410, 1987.

*FIELD* CS

Neuro:
   Chorea;
   Tics;
   Dystonia;
   Parkinsonism;
   Absent tendon reflexes;
   Abnormal bladder function;
   Self-mutilation of tongue, lips and cheeks

Muscle:
   Myopathy;
   Girdle and proximal limb muscle wasting

Misc:
   Adult form of acanthocytosis

Lab:
   Acanthocytosis;
   Normal serum lipoproteins;
   Neuronal loss and gliosis of the caudate and putamen

Inheritance:
   Autosomal dominant;
   also autosomal recessive form

*FIELD* CN
Orest Hurko - updated: 4/1/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/15/1996
mark: 4/1/1996
terry: 4/1/1996
terry: 2/15/1996
carol: 12/12/1994
warfield: 4/7/1994
mimadm: 3/11/1994
carol: 3/10/1993
supermim: 3/16/1992
carol: 8/23/1990

*RECORD*
*FIELD* NO
100600
*FIELD* TI
*100600 ACANTHOSIS NIGRICANS
*FIELD* TX
Acanthosis nigricans consists of thickening and hyperpigmentation of the
skin of the entire body but especially in flexural areas. In 26 patients
with malignant acanthosis nigricans (secondary to visceral carcinoma),
Curth and Aschner (1959) found no other affected persons in the family.
On the other hand, benign acanthosis nigricans may be inherited as a
mendelian dominant. Curth and Aschner (1959) had families with
acanthosis nigricans in successive generations, 3 in 1 family and 2 in 2
others, including instances of male-to-male transmission. Jung et al.
(1965) observed affected mother and daughter. Lawrence et al. (1971)
described a patient with acanthosis nigricans inherited from the father
and telangiectasia (187300) inherited from the mother. Tasjian and
Jarratt (1984) observed affected mother and daughter. Skin lesions were
first noted in infancy. In addition to the association with insulin
resistance (147670), Seip syndrome (269700), and malignancy, acanthosis
nigricans can be drug-induced; nicotinic acid, diethylstilbestrol, oral
contraceptives, and exogenous glucocorticoids have been incriminated.
Clear mendelian inheritance is seen when acanthosis nigricans is part of
syndromes, e.g., Seip syndrome. Autosomal dominant acanthosis nigricans
should be studied for insulin resistance. Schwenk et al. (1986) studied
a white family in which acanthosis nigricans occurred in a mother and 3
daughters; insulin binding was normal but insulin response was reduced,
consistent with a postbinding defect (see 147670). Perhaps one should
speak of types A1 and A2 of acanthosis nigricans, A1 being the form with
a defect in the insulin receptor and A2 representing a postbinding
defect. Seemanova et al. (1992) investigated a family in which at least
4 men in 3 generations had a syndrome of obesity, mild mental
retardation, delayed puberty, macroorchidism, acanthosis nigricans,
hyperinsulinemia, and, later, overt insulin-resistant diabetes mellitus
(noninsulin-dependent diabetes mellitus; NIDDM). The patients had
markedly curly scalp hair and deficient hair of the face and body. Teeth
were normal. There was normal insulin binding to fibroblasts; however,
insulin-stimulated RNA synthesis was decreased as compared to that of
normal control individuals, suggesting a postbinding defect in insulin
action. The pedigree showed an autosomal dominant pattern of
inheritance.

Acanthosis nigricans in association with insulin resistance behaves as
either a dominant (e.g., 147670.0001) or a recessive (e.g.,
147670.0004). The polycystic ovary syndrome is sometimes reported. The
autosomal dominant mutations in the insulin receptor gene are 'dominant
negatives'; the mutant receptor protein interferes with the function of
the normal receptor.

Chuang et al. (1995) reported familial acanthosis nigricans affecting a
35-year-old woman, her 7-year-old son, and 5-year-old daughter. Absence
of the eyebrows and eyelashes was also present in the affected members
of this family. The mother had no axillary hair and her pubic hair was
sparse. The boy also suffered from congenital heart disease and a
congenital cataract in the left eye. Chuang et al. (1995) suggested that
the combination of acanthosis nigricans and ectodermal defects in this
family may represent a distinct nosologic entity. They referred to the
hair problem as madarosis (loss of the eyebrows or of the eyelashes).

*FIELD* SA
Hermann  (1955)
*FIELD* RF
1. Chuang, S.-D.; Jee, S.-H.; Chiu, H.-C.; Chen, J.-S.; Lin, J.-T.
: Familial acanthosis nigricans with madarosis. Brit. J. Derm. 133:
104-108, 1995.

2. Curth, H. O.; Aschner, B. M.: Genetic studies on acanthosis nigricans. Arch.
Derm. 79: 55-66, 1959.

3. Hermann, H.: Zur Erbpathologie der Acanthosis nigricans. Z. Menschl.
Vererb. Konstitutionsl. 33: 193-202, 1955.

4. Jung, H. D.; Bruns, W.; Wulfert, P.; Mieler, W.: Ein Beitrag zum
Krankheitsbild der Acanthosis nigricans benigna familiaris. Dtsch.
Med. Wschr. 90: 1669-1673, 1965.

5. Lawrence, G.; Thurston, C.; Shultz, K.; Mengel, M. C.: Acanthosis
nigricans, telangiectasia and diabetes mellitus. Birth Defects Orig.
Art. Ser. VII(8): 322-323, 1971.

6. Schwenk, W. F.; Rizza, R. A.; Mandarino, L. J.; Gerich, J. E.;
Hayles, A. B.; Haymond, M. W.: Familial insulin resistance and acanthosis
nigricans: presence of a postbinding defect. Diabetes 35: 33-37,
1986.

7. Seemanova, E.; Rudiger, H. W.; Dreyer, M.: Autosomal dominant
insulin resistance syndrome due to a postbinding defect. Am. J. Med.
Genet. 44: 705-712, 1992.

8. Tasjian, D.; Jarratt, M.: Familial acanthosis nigricans. Arch.
Derm. 120: 1351-1354, 1984.

*FIELD* CS

Skin:
   Benign acanthosis nigricans;
   Thick hyperpigmented flexural area skin

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 04/03/1997
mark: 10/13/1995
mimadm: 6/26/1994
carol: 3/12/1994
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
100640
*FIELD* TI
*100640 ACETALDEHYDE DEHYDROGENASE-1
ALDEHYDE DEHYDROGENASE-1; ALDH1;;
ALDH, LIVER CYTOSOLIC
*FIELD* TX
Acetaldehyde dehydrogenase (EC 1.2.1.3) is the next enzyme after alcohol
dehydrogenase (103700) in the major pathway of alcohol metabolism. On
the basis of population studies of isozyme patterns, Harada et al.
(1978) proposed that there are 3 loci determining acetaldehyde
dehydrogenase. They suggested that the rarer of the alleles at the
postulated ALDH1, ALDH2 and ALDH3 loci have a frequency of 0.022, 0.029
and 0.151, respectively. The sample numbered only 68 specimens, however.

Harada et al. (1980) presented evidence that aldehyde dehydrogenase is
polymorphic in Japanese. As in previous studies in Europeans, they found
2 isozymes of ALDH in liver specimens of Japanese, but unlike the study
of specimens of Europeans, they found that 52% of Japanese specimens
showed absence of the faster migrating isozyme (which has a low Km for
acetaldehyde). The authors suggested that the intoxicating symptoms
after alcohol drinking in many Japanese may be due to delayed oxidation
of acetaldehyde. The lack of ALDH isozyme I with a low Km for aldehyde
is apparently responsible for the higher blood acetaldehyde levels in
mongoloid peoples, leading to facial flushing and other vasomotor
symptoms after alcohol intake. Agarwal et al. (1981) performed a
population genetic study in Orientals of several different extractions.
They investigated ALDH isozymes in hair root lysates with a sensitive
isoelectric focusing method. Between 40 and 80% of the several Oriental
groups were found to be deficient in isozyme I of ALDH, whereas not a
single European individual was deficient. Deficiency was invariably
associated with sensitivity to alcohol. Family studies suggested
autosomal recessive inheritance of the deficiency. Harada et al. (1981)
found the deficiency in 43% of Japanese; all deficient persons had
flushing symptoms and, after alcohol drinking, showed a mean
concentration of acetaldehyde of 37.3 micromoles as compared with 2.1
micromoles in nondeficient persons.

Thomas et al. (1982) found low cytosolic acetaldehyde dehydrogenase in
the liver of alcoholic patients with fatty liver; mitochondrial ALDH was
normal. Abstaining alcoholics showed persistently low cytosolic ALDH.
Isoelectric focusing showed that the cytosolic and mitochondrial ALDHs
are distinct isozymes. Impraim et al. (1982) investigated the basis of
the lack in about 50% of Orientals of 1 of the 2 major liver ALDH
isozymes. Consistent with a convention of nomenclature adopted by the
HGM workshops, ALDH1 is cytosolic and ALDH2 is mitochondrial. It is the
latter that is missing in Orientals. Inoue et al. (1979) purified and
partially characterized aldehyde dehydrogenase from human erythrocytes.
This is the cytosolic form, present in only low concentration in red
cells. Goedde et al. (1979) proposed that the high frequency of acute
alcoholic intoxication in Orientals is related to the high frequency of
persons with absence of ALDH2 liver isozyme. On the other hand,
Stamatoyannopoulos et al. (1975) suggested that the racial difference in
alcohol intoxication is due to rapid acetaldehyde formation as a result
of the highly active atypical alcohol dehydrogenase isozyme found in
high frequency in Orientals. ALDH1 and ALDH2 have molecular weights of
245,000 and 225,000, respectively, and both are tetramers. Structural
and genetic interrelationships are unknown; e.g., does each consist of a
single type subunit or do they share a common subunit? Impraim et al.
(1982) found that the ALDH2 in an 'atypical' Japanese liver was
enzymatically inactive but immunologically cross-reactive. Thus, a
structural mutation at the ALDH2 locus is presumably the genetic basis.

Goedde et al. (1983) pointed to the existence of 4 isozymes of
NAD-dependent aldehyde dehydrogenase, designated ALDH I, II, III, or IV
according to their decreasing electrophoretic mobility and increasing
isoelectric point. The frequency of absent ALDH I isozyme varied from
69% in Indians of the Ecuador Highlands to 44% in Japanese and 35% in
Chinese to 0% in Egyptians, Liberians, Kenyans, and Europeans. They
suggested that deficiency is related to flushing and a slower metabolism
of acetaldehyde, and in turn a lower frequency of alcoholism and
alcohol-related problems.

Yoshida et al. (1989) demonstrated that among Caucasians alcohol
flushing can be related to abnormalities of ALDH1. In 9 unrelated
Caucasian alcohol flushers, they found 1 who exhibited low activity
(10-20% of normal) and another who exhibited moderately low activity
(60%) and altered kinetic properties. The electrophoretic mobilities of
these 2 samples were not altered. Immunologic quantitation indicated
that the amount of protein in the 2 samples was not reduced in parallel
with the enzyme deficiency. In the first case, the daughter of the
proposita also had very low enzyme activity and alcohol flushing.

ALDH1 is cytosolic, is associated with a low Km for NAD and a high Km
for acetaldehyde, and is strongly inactivated by disulfiram. ALDH2
(100650) is mitochondrial, has a high Km for NAD and a low Km for
acetaldehyde, and is insensitive to disulfiram. About 50% of Orientals
lack ALDH2 activity but have defective enzyme immunologically related to
ALDH2 (Yoshida et al., 1984). In some Orientals absence of ALDH1
activity and the presence of an enzymatically inactive protein is
demonstrable (Yoshida et al., 1983). Yoshida (1984) concluded that one
can substitute hair roots for liver biopsy specimens if sample size for
isoelectric focusing is adjusted using MDH or IDH as an internal
reference. The liver of humans and other mammals contains 2 major and
several minor aldehyde dehydrogenase isozymes. The major isozymes are
ALDH1 of cytosolic origin and ALDH2 of mitochondrial origin. (The
confusion in the numerology of the aldehyde dehydrogenases is evident.
ALDH I and ALDH II of Goedde and colleagues is ALDH2 and ALDH1 of other
workers.) In contrast to the wide prevalence of deficiency of ALDH2
(called ALDH I by Goedde), variants of ALDH1 (called ALDH II by Goedde)
are rare; Eckey et al. (1986) described one such variant.

With cDNA probes for Southern blot analysis of somatic cell hybrids, Hsu
et al. (1985, 1986) assigned the ALDH1 locus to 9q and the ALDH2 locus
to chromosome 12. Hsu et al. (1989) found that the ALDH1 gene is about
53 kb long and is divided into 13 exons which encode 501 amino acid
residues. A similar intron-exon organization is found in ALDH2 which
also has 13 exons with 9 of the 12 introns interrupting the coding
sequence at positions homologous to those in ALDH1. Thus, the 2 isozymes
appear to have evolved after duplication of a common ancestral gene.

*FIELD* SA
Harada et al. (1981); Hsu et al. (1985)
*FIELD* RF
1. Agarwal, D. P.; Meier-Tackmann, D.; Harada, S.; Goedde, H. W.;
Du, R.: Mechanism of biological sensitivity to alcohol: inherited
deficiency of aldehyde dehydrogenase isoenzyme I in Mongoloids.  (Abstract) Sixth
Int. Cong. Hum. Genet., Jerusalem 102 only, 1981.

2. Eckey, R.; Agarwal, D. P.; Saha, N.; Goedde, H. W.: Detection
and partial characterization of a variant form of cytosolic aldehyde
dehydrogenase isozyme. Hum. Genet. 72: 95-97, 1986.

3. Goedde, H. W.; Agarwal, D. P.; Harada, S.; Meier-Tackmann, D.;
Ruofu, D.; Bienzle, U.; Kroeger, A.; Hussein, L.: Population genetic
studies on aldehyde dehydrogenase isozyme deficiency and alcohol sensitivity.
Am. J. Hum. Genet. 35: 769-772, 1983.

4. Goedde, H. W.; Harada, S.; Agarwal, D. P.: Racial differences
in alcohol sensitivity: a new hypothesis. Hum. Genet. 51: 331-334,
1979.

5. Harada, S.; Agarwal, D. P.; Goedde, H. W.: Isozyme variations
in acetaldehyde dehydrogenase (E.C. 1.2.1.3) in human tissues. Hum.
Genet. 44: 181-185, 1978.

6. Harada, S.; Agarwal, D. P.; Goedde, H. W.: Aldehyde metabolism
and polymorphism of aldehyde dehydrogenase in Japanese.  (Abstract) Sixth
Int. Cong. Hum. Genet., Jerusalem 103 only, 1981.

7. Harada, S.; Agarwal, D. P.; Goedde, H. W.: Aldehyde dehydrogenase
deficiency as cause of facial flushing reaction to alcohol in Japanese.
(Letter) Lancet II: 982 only, 1981.

8. Harada, S.; Misawa, S.; Agarwal, D. P.; Goedde, H. W.: Liver alcohol
dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme
variation and its possible role in alcohol intoxication. Am. J.
Hum. Genet. 32: 8-15, 1980.

9. Hsu, L. C.; Chang, W.-C.; Yoshida, A.: Genomic structure of the
human cytosolic aldehyde dehydrogenase gene. Genomics 5: 857-865,
1989.

10. Hsu, L. C.; Tani, K.; Fujiyoshi, T.; Kurachi, K.; Yoshida, A.
: Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2. Proc.
Nat. Acad. Sci. 82: 3771-3775, 1985.

11. Hsu, L. C.; Yoshida, A.; Mohandas, T.: Chromosomal assignment
of the genes for human aldehyde dehydrogenase 1 (ALDH1) and aldehyde
dehydrogenase 2 (ALDH2).  (Abstract) Cytogenet. Cell Genet. 40:
656-657, 1985.

12. Hsu, L. C.; Yoshida, A.; Mohandas, T.: Chromosomal assignment
of the genes for human aldehyde dehydrogenase-1 and aldehyde dehydrogenase-2.
Am. J. Hum. Genet. 38: 641-648, 1986.

13. Impraim, C.; Wang, G.; Yoshida, A.: Structural mutation in a
major human aldehyde dehydrogenase gene results in loss of enzyme
activity. Am. J. Hum. Genet. 34: 837-841, 1982.

14. Inoue, K.; Nishimukai, H.; Yamasawa, K.: Purification and partial
characterization of aldehyde dehydrogenase from human erythrocytes.
Biochim. Biophys. Acta 569: 117-123, 1979.

15. Stamatoyannopoulos, G.; Chen, S.-H.; Fukui, M.: Liver alcohol
dehydrogenase in Japanese: high population frequency of atypical form
and its possible role in alcohol sensitivity. Am. J. Hum. Genet. 27:
789-796, 1975.

16. Thomas, M.; Halsall, S.; Peters, T. J.: Role of hepatic acetaldehyde
dehydrogenase in alcoholism: demonstration of persistent reduction
of cytosolic activity in abstaining patients. Lancet II: 1057-1059,
1982.

17. Yoshida, A.: Determination of aldehyde dehydrogenase phenotypes
using hair roots: re-examination. Hum. Genet. 66: 296-299, 1984.

18. Yoshida, A.; Dave, V.; Ward, R. J.; Peters, T. J.: Cytosolic
aldehyde dehydrogenase (ALDH1) variants found in alcohol flushers.
Ann. Hum. Genet. 53: 1-7, 1989.

19. Yoshida, A.; Huang, I.-Y.; Ikawa, M.: Molecular abnormality of
an inactive aldehyde dehydrogenase variant commonly found in Orientals.
Proc. Nat. Acad. Sci. 81: 258-261, 1984.

20. Yoshida, A.; Wang, G.; Dave, V.: Determination of genotypes of
human aldehyde dehydrogenase ALDH2 locus. Am. J. Hum. Genet. 35:
1107-1116, 1983.

*FIELD* CS

Metabolic:
   Increased intoxicating symptoms after alcohol drinking

Skin:
   Facial flushing after alcohol intake

Misc:
   Caucasian type alcohol flushing with abnormal ALDH1

Lab:
   Cytosolic acetaldehyde dehydrogenase;
   Delayed oxidation of acetaldehyde;
   Low Km for NAD;
   High Km for acetaldehyde;
   Disulfiram sensitive

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990
carol: 12/14/1989
carol: 11/2/1989

*RECORD*
*FIELD* NO
100650
*FIELD* TI
*100650 ALDEHYDE DEHYDROGENASE-2; ALDH2
ALDH, LIVER MITOCHONDRIAL;;
ACETALDEHYDE DEHYDROGENASE-2
ALCOHOL SENSITIVITY, INCLUDED
*FIELD* TX
See 100640. Almost all Caucasians have 2 major ALDH isozymes in the
liver: a cytosolic ALDH1 and a mitochondrial ALDH2 (EC 1.2.1.3). On the
other hand, about 50% of Orientals are missing the ALDH2 isozyme.
Impraim et al. (1982) showed that the livers of such persons show an
enzymatically inactive but immunologically cross-reactive material (CRM)
corresponding to the ALDH2 isozyme. The remarkable difference in
Orientals of 2 alcohol-metabolizing enzymes, ADH2 (103720) and ALDH2,
cannot have been coincidence. Ikuta et al. (1986) suggested that the
explanation is coadaptation to an environment, such as particular diet,
to which Orientals were exposed, since ADH and ALDH are complementary in
the metabolic pathway of various alcohols. Fenna et al. (1971) concluded
that ethanol is metabolized significantly faster in whites than in
Eskimos or American Indians, but Bennion and Li (1976) could find no
evidence that this is the case. Wolff (1972) demonstrated that members
of the Mongoloid race, after drinking amounts of alcohol that have no
detectable effect on Caucasoids, respond with marked facial flushing and
mild to moderate symptoms of intoxication. Wolff (1972) believed that
group differences, which are present at birth, were attributable to
differences in autonomic reactivity. Absence of the enzyme coded by
ALDH2, frequent in Mongoloid persons, 'causes' alcohol intolerance
(Goedde et al., 1979). Individuals lacking the enzyme suffer the
alcohol-flush reaction when they drink alcoholic beverages. The reaction
is the result of excessive acetaldehyde accumulation, and the unpleasant
symptoms tend to reduce alcohol consumption. The lower incidence of
alcoholism in certain Mongoloid groups may have its basis in these
observations.

Hsu et al. (1985) assigned the ALDH2 locus to chromosome 12 by means of
a cDNA probe and Southern blot analysis of somatic cell hybrids. With a
cDNA fragment corresponding to the 3-prime-coding part of human ALDH-1
mRNA, Braun et al. (1986) studied human-rodent somatic cell hybrids to
confirm the assignment to chromosome 12. (The cytosolic form is on
chromosome 9; see 100640.) The mitochondrial and cytosolic forms of ALDH
are coded by mouse chromosomes 4 and 19, respectively (Mather and
Holmes, 1984). Comparative mapping in man, mouse, and bovine led Womack
(1990) to suggest that ALDH2 is in the distal part of 12q, distal to
IFNG (147570), a conclusion consistent with other information on the
mapping of these 2 loci.

The ALDH2 alleles encoding the active and inactive subunits are termed
'ALDH2*1' and 'ALDH2*2,' respectively; see 100650.0001. It had been
thought that the 2 alleles were expressed codominantly, and that only
individuals homozygous for ALDH2*2 were ALDH2-deficient. However,
studies of the inheritance of alcohol-induced flushing in families
suggested that the trait is dominant (Schwitters et al., 1982). Crabb et
al. (1989) did genotyping on the liver from 24 Japanese individuals,
using the PCR technique for amplification of genomic DNA. In correlating
genotype with phenotype, they found that both heterozygotes and
homozygotes for ALDH2*2 are deficient in ALDH2 activity; that is, the
ALDH2*2 allele is dominant. Since ALDH2 is a homotetrameric enzyme,
random association of active and inactive subunits, equally expressed,
should generate about 6% normal tetramers; the remainder would contain
at least 1 mutant subunit. Thus, if all tetramers containing at least 1
mutant subunit were inactive, there would be only 6% activity in
heterozygotes. This low amount of activity is likely to be below the
detection limit of activity staining of the gels. Hsu et al. (1987)
developed a method for distinguishing the 2 main alleles by means of
allele-specific 21-base synthetic oligonucleotides. Shibuya et al.
(1988) studied 23 Japanese with alcoholic liver disease. No difference
was found in the genotypes at the ADH2 locus. However, at the ALDH2
locus, 20 of the 23 patients were homozygous for the Caucasian type,
only 3 were heterozygous, and none of the patients was homozygous for
the Oriental type. The results were interpreted as indicating that
Japanese with the atypical allele are at a much lower risk for alcoholic
liver disease, presumably due to their sensitivity to alcohol
intoxication. By means of a pair of synthetic oligonucleotides, 1
complementary to the usual ALDH2 allele and the other complementary to
the atypical ALDH2 allele, Shibuya and Yoshida (1988) determined the
genotypes of 49 unrelated Japanese persons and 12 Caucasians. The
frequency of the atypical allele was found to be 0.35 in the Japanese
samples examined. The atypical gene was not found in the Caucasians.
Using allele-specific oligonucleotides for ALDH2*2, Singh et al. (1989)
studied phenotypically deficient individuals in the Chinese, Japanese,
and South Korean families to determine heterozygous or homozygous
status. All individuals with a heterozygous genotype were found to be
deficient, thus demonstrating that only the normal homotetrameric enzyme
is catalytically active. As suggested by other workers, a random
tetramerization of the 2 allele products will result in a residual
enzyme activity of 6.25% of the normal value in heterozygotes if both
normal and mutant subunits are produced in the same proportions. In
these studies ALDH phenotype was determined in hair roots, and DNA was
prepared from peripheral blood. Exon 12 of the gene was amplified by PCR
for subsequent allele-specific hybridization.

Crabb (1990) pointed out that the single base mutation in ALDH2,
responsible for acute alcohol-flushing reaction in Asians, is the
best-characterized genetic factor influencing alcohol drinking behavior.
He raised the possibility that polymorphism in the several alcohol
dehydrogenase genes might be related to risk of fetal alcohol syndrome
(FAS). It is noteworthy that a genetic influence in fetal alcohol
syndrome is suggested by twin studies: Streissguth and Dehaene (1993)
established that the rate of concordance for the diagnosis of fetal
alcohol syndrome was 5 out of 5 for monozygotic and 7 out of 11 for
dizygotic twins. In 2 DZ pairs, one twin had FAS, while the other had
fetal alcohol effects (FAE). In 2 other DZ pairs, one twin had no
evident abnormality, while the other had FAE. IQ scores were most
similar within pairs of MZ twins and least similar within pairs of DZ
twins discordant for diagnosis. Johnson et al. (1996) documented the
central nervous system anomalies of FAS by magnetic resonance imaging
(MRI). CNS and craniofacial abnormalities were predominantly symmetric
and central or midline. The authors stated that the association
emphasized the concept of the midline as a special developmental field,
vulnerable to adverse factors during embryogenesis and fetal growth and
development.

Thomasson et al. (1991) hypothesized that the polymorphisms of both of
the liver enzymes responsible for the oxidative metabolism of ethanol
may modify the predisposition to development of alcoholism. Using
leukocyte DNA amplified by PCR and allele-specific oligonucleotides in a
study of Chinese men living in Taiwan, they demonstrated that alcoholics
had significantly lower frequencies not only of ALDH2*2 but also of
ADH2*2 and ADH3*1 (103730). Goedde et al. (1992) gave extensive
population frequency data on ALDH2 as well as on ADH2. They again showed
that the atypical ALDH2 gene (ALDH2*2) is extremely rare in Caucasoids,
Negroids, Papua New Guineans, Australian Aborigines, and Aurocanians
(South Chile), but widely prevalent among Mongoloids. They cited
evidence indicating that individuals possessing the ALDH2*2 allele show
alcohol-related sensitivity responses such as facial flushing, are
usually not habitual drinkers, and appear to suffer less from alcoholism
and alcohol-related liver disease.

Muramatsu et al. (1995) used the PCR/RFLP method to determine the
genotypes of the ADH2 and ALDH2 loci of alcoholic and nonalcoholic
Chinese living in Shanghai. They found that the alcoholics had
significantly lower frequencies of the ADH2*2 and ALDH2*2 alleles than
did the nonalcoholics, suggesting the inhibitory effects of these
alleles for the development of alcoholism. In the nonalcoholic subjects,
ADH2*2 had little, if any, effect, despite the significant effect of the
ALDH2*2 allele in decreasing the alcohol consumption of the individual.
Taken together, these results were considered consistent with the
proposed hypothesis for the development of alcoholism, i.e., drinking
behavior is greatly influenced by the individual's genotype of
alcohol-metabolizing enzymes and the risk of becoming alcoholic is
proportionate with the ethanol consumption of the individual.

The ALDH2*2 allele is considered to be a genetic deterrent for
alcoholism; however, Muramatsu et al. (1996) found that 80 of 655
Japanese alcoholics had the mutant allele. The authors postulated that
these alcoholics had some other factor that overcame the adverse effects
of acetaldehydemia and that such a factor might reside in the brain's
'reward system,' in which dopamine plays a crucial role. Muramatsu et
al. (1996) studied variation at the DRD4 locus (126452) and found in the
alcoholics a higher frequency of a 5-repeat allele of the DRD4 receptor
48-bp repeat polymorphism in alcoholics with ALDH2*2 than in 100 other
alcoholics and 144 controls. They found that alcoholics with the
5-repeat allele also abused other drugs more often.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
ALCOHOL INTOLERANCE, ACUTE
ACETALDEHYDE DEHYDROGENASE-2, ALLELE 2 ALDH2*2
ALDH2, GLU487LYS
The ALDH2*2-encoded protein has a change from glutamic acid (glutamate)
to lysine at residue 487 (Yoshida et al., 1984). Hempel et al. (1985)
and Hsu et al. (1985) also showed that the catalytic deficiency in
mitochondrial ALDH in Orientals can be traced to a structural point
mutation at amino acid position 487 of the polypeptide. A substitution
of lysine for glutamic acid results from a transition of G-C to A-T.

To study the mechanism by which the ALDH2*2 allele exerts its dominant
effect in decreasing ALDH2 activity in liver extracts and producing
cutaneous flushing when the subject drinks alcohol, Xiao et al. (1995)
cloned ALDH2*1 cDNA and generated the ALDH2*2 allele by site-directed
mutagenesis. These cDNAs were transduced using retroviral vectors into
HeLa and CV1 cells, which do not express ALDH2. The normal allele
directed synthesis of immunoreactive ALDH2 protein with the expected
isoelectric point and increased aldehyde dehydrogenase activity. The
ALDH2*2 allele directed synthesis of mRNA and immunoreactive protein,
but the protein lacked enzymatic activity. When ALDH2*1-expressing cells
were transduced with ALDH2*2 vectors, both mRNAs were expressed and
immunoreactive proteins with isoelectric points ranging between those of
the 2 gene products were present, indicating that the subunits formed
heteromers. ALDH2 activity in these cells was reduced below that of the
parental ALDH2*1-expressing cells. Thus, the authors concluded that
ALDH2*2 allele is sufficient to cause ALDH2 deficiency in vitro.

Xiao et al. (1996) referred to the ALDH2 enzyme encoded by the ALDH2*1
allele (the wildtype form) as ALDH2E and the enzyme subunit encoded by
ALDH2*2 as ALDH2K. They found that the ALDH2E enzyme was very stable,
with a half-life of at least 22 hours. ALDH2K, on the other hand, had an
enzyme half-life of only 14 hours. In cells expressing both subunits,
most of the subunits assemble as heterotetramers, and these enzymes had
a half-life of 13 hours. Thus, the effect of ALDH2K on enzyme turnover
is dominant. Their studies indicated that ALDH2*2 exerts its dominant
effect both by interfering with the catalytic activity of the enzyme and
by increasing its turnover.

*FIELD* SA
Agarwal et al. (1981); Goedde et al. (1986); Hsu et al. (1985); Reed
(1977); Wolff  (1973); Yoshida et al. (1983)
*FIELD* RF
1. Agarwal, D. P.; Harada, S.; Goedde, H. W.: Racial differences
in biological sensitivity to ethanol: the role of alcohol dehydrogenase
and aldehyde dehydrogenase isozymes. Alcoholism 5: 12-16, 1981.

2. Bennion, L. J.; Li, T.-K.: Alcohol metabolism in American Indians
and Whites: lack of racial differences in metabolic rate and liver
alcohol dehydrogenase. New Eng. J. Med. 294: 9-13, 1976.

3. Braun, T.; Grzeschik, K. H.; Bober, E.; Singh, S.; Agarwal, D.
P.; Goedde, H. W.: The structural gene for the mitochondrial aldehyde
dehydrogenase maps to human chromosome 12. Hum. Genet. 73: 365-367,
1986.

4. Crabb, D. W.: Biological markers for increased risk of alcoholism
and for quantitation of alcohol consumption. J. Clin. Invest. 85:
311-315, 1990.

5. Crabb, D. W.; Edenberg, H. J.; Bosron, W. F.; Li, T.-K.: Genotypes
for aldehyde dehydrogenase deficiency and alcohol sensitivity: the
inactive ALDH2*2 allele is dominant. J. Clin. Invest. 83: 314-316,
1989.

6. Fenna, D.; Mix, L.; Schaefer, O.; Gilbert, J. A. L.: Ethanol metabolism
in various racial groups. Canad. Med. Assoc. J. 105: 472-475, 1971.

7. Goedde, H. W.; Agarwal, D. P.; Fritze, G.; Meier-Tackmann, D.;
Singh, S.; Beckmann, G.; Bhatia, K.; Chen, L. Z.; Fang, B.; Lisker,
R.; Paik, Y. K.; Rothhammer, F.; Saha, N.; Segal, B.; Srivastava,
L. M.; Czeizel, A.: Distribution of ADH-2 and ALDH2 genotypes in
different populations. Hum. Genet. 88: 344-346, 1992.

8. Goedde, H. W.; Agarwal, D. P.; Harada, S.; Rothhammer, F.; Whittaker,
J. O.; Lisker, R.: Aldehyde dehydrogenase polymorphism in North American,
South American, and Mexican Indian populations. Am. J. Hum. Genet. 38:
395-399, 1986.

9. Goedde, H. W.; Harada, S.; Agarwal, D. P.: Racial differences
in alcohol sensitivity: a new hypothesis. Hum. Genet. 51: 331-334,
1979.

10. Hempel, J.; Kaiser, R.; Jornvall, H.: Mitochondrial aldehyde
dehydrogenase from human liver: primary structure, differences in
relation to the cytosolic enzyme and functional correlations. Europ.
J. Biochem. 153: 13-28, 1985.

11. Hsu, L. C.; Bendel, R. E.; Yoshida, A.: Direct detection of usual
and atypical alleles on the human aldehyde dehydrogenase-2 (ALDH2)
locus. Am. J. Hum. Genet. 41: 996-1001, 1987.

12. Hsu, L. C.; Tani, K.; Fujiyoshi, T.; Kurachi, K.; Yoshida, A.
: Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2. Proc.
Nat. Acad. Sci. 82: 3771-3775, 1985.

13. Hsu, L. C.; Yoshida, A.; Mohandas, T.: Chromosomal assignment
of the genes for human aldehyde dehydrogenase 1 (ALDH1) and aldehyde
dehydrogenase 2 (ALDH2).(Abstract) Cytogenet. Cell Genet. 40: 656-657,
1985.

14. Ikuta, T.; Szeto, S.; Yoshida, A.: Three human alcohol dehydrogenase
subunits: cDNA structure and molecular and evolutionary divergence. Proc.
Nat. Acad. Sci. 83: 634-638, 1986.

15. Impraim, C.; Wang, G.; Yoshida, A.: Structural mutation in a
major human aldehyde dehydrogenase gene results in loss of enzyme
activity. Am. J. Hum. Genet. 34: 837-841, 1982.

16. Johnson, V. P.; Swayze, V. W., II; Sato, Y.; Andreasen, N. C.
: Fetal alcohol syndrome: craniofacial and central nervous system
manifestations. Am. J. Med. Genet. 61: 329-339, 1996.

17. Mather, P. B.; Holmes, R. S.: Biochemical genetics of aldehyde
dehydrogenase isoenzymes in the mouse: evidence for stomach and testis-specific
isoenzymes. Biochem. Genet. 22: 981-995, 1984.

18. Muramatsu, T.; Higuchi, S.; Murayama, M.; Matsushita, S.; Hayashida,
M.: Association between alcoholism and the dopamine D4 receptor gene. J.
Med. Genet. 33: 113-115, 1996.

19. Muramatsu, T.; Zu-Cheng, W.; Yi-Ru, F.; Kou-Bao, H.; Heqin, Y.;
Yamada, K.; Higuchi, S.; Harada, S.; Kono, H.: Alcohol and aldehyde
dehydrogenase genotypes and drinking behavior of Chinese living in
Shanghai. Hum. Genet. 96: 151-154, 1995.

20. Reed, T. E.: Three heritable responses to alcohol in a heterogeneous
randomly mated mouse strain: inferences for humans. J. Studies Alcohol 38:
618-632, 1977.

21. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

22. Schwitters, S. Y.; Johnson, R. C.; Johnson, S. B.; Ahern, F. M.
: Familial resemblances in flushing following alcohol use. Behav.
Genet. 12: 349-352, 1982.

23. Shibuya, A.; Ikuta, T.; Hsu, L. C.; Yoshida, A.: Genotypes of
alcohol metabolizing enzymes in Japanese with alcoholic liver diseases:
a strong association of the usual Caucasian type aldehyde dehydrogenase
allele (ALDH2) with the disease.(Abstract) Am. J. Hum. Genet. 43:
A201, 1988.

24. Shibuya, A.; Yoshida, A.: Frequency of the atypical aldehyde
dehydrogenase-2 gene (ALDH2/2) in Japanese and Caucasians. Am. J.
Hum. Genet. 43: 741-743, 1988.

25. Singh, S.; Fritze, G.; Fang, B.; Harada, S.; Paik, Y. K.; Eckey,
R.; Agarwal, D. P.; Goedde, H. W.: Inheritance of mitochondrial aldehyde
dehydrogenase: genotyping in Chinese, Japanese and South Korean families
reveals dominance of the mutant allele. Hum. Genet. 83: 119-121,
1989.

26. Streissguth, A. P.; Dehaene, P.: Fetal alcohol syndrome in twins
of alcoholic mothers: concordance of diagnosis and IQ. Am. J. Med.
Genet. 47: 857-861, 1993.

27. Thomasson, H. R.; Edenberg, H. J.; Crabb, D. W.; Mai, X.-L.; Jerome,
R. E.; Li, T.-K.; Wang, S.-P.; Lin, Y.-T.; Lu, R.-B.; Yin, S.-J.:
Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese
men. Am. J. Hum. Genet. 48: 677-681, 1991.

28. Wolff, P. H.: Ethnic differences in alcohol sensitivity. Science 175:
449-450, 1972.

29. Wolff, P. H.: Vasomotor sensitivity to alcohol in diverse mongoloid
populations. Am. J. Hum. Genet. 25: 193-199, 1973.

30. Womack, J. E.: Personal Communication. College Station, Texas
2/26/1990.

31. Xiao, Q.; Weiner, H.; Crabb, D. W.: The mutation in the mitochondrial
aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced
flushing increases turnover of the enzyme tetramers in a dominant
fashion. J. Clin. Invest. 98: 2027-2032, 1996.

32. Xiao, Q.; Weiner, H.; Johnston, T.; Crabb, D. W.: The aldehyde
dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced
HeLa cells. J. Clin. Invest. 96: 2180-2186, 1995.

33. Yoshida, A.; Huang, I.-Y.; Ikawa, M.: Molecular abnormality of
an inactive aldehyde dehydrogenase variant commonly found in Orientals. Proc.
Nat. Acad. Sci. 81: 258-261, 1984.

34. Yoshida, A.; Wang, G.; Dave, V.: Determination of genotypes of
human aldehyde dehydrogenase ALDH-2 locus. Am. J. Hum. Genet. 35:
1107-1116, 1983.

*FIELD* CS

Metabolic:
   Increased intoxicating symptoms after alcohol drinking

Skin:
   Facial flushing after alcohol intake

Misc:
   Oriental type alcohol flushing with abnormal ALDH2

Lab:
   Mitochondrial acetaldehyde dehydrogenase;
   Delayed oxidation of acetaldehyde;
   High Km for NAD;
   Low Km foracetaldehyde;
   Disulfiram insensitive

*FIELD* CN
Mark H. Paalman - updated: 6/12/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/06/1996
mark: 6/12/1996
mark: 2/26/1996
terry: 2/20/1996
mark: 2/2/1996
terry: 1/26/1996
mark: 10/15/1995
warfield: 3/31/1994
mimadm: 3/11/1994
carol: 1/26/1994
carol: 6/9/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
100660
*FIELD* TI
*100660 ACETALDEHYDE DEHYDROGENASE-3
ALDEHYDE DEHYDROGENASE-3; ALDH3;;
STOMACH ALDH
*FIELD* TX
See 100640. In stomach tissue, Teng (1981) described an isozymic form of
aldehyde dehydrogenase (ALDH). It did not use formaldehyde, acetaldehyde
or pyruvic aldehyde. Furfuraldehyde and, to a lesser extent,
propionaldehyde were readily oxidized. Teng (1981) found 1 genetic
variant among 71 Chinese stomach specimens and a second different
variant among 33 Asiatic Indian specimens. Unlike liver ALDH, which
appears to be a tetramer, the electrophoretic pattern in the
heterozygotes suggested that stomach ALDH is a monomer. ALDH3 is also
present in lung. By study of somatic cell hybrids, Santisteban et al.
(1985) assigned the ALDH3 gene to chromosome 17. By in situ
hybridization, Hiraoka et al. (1995) mapped the ALDH3 gene to 17p11.2.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* RF
1. Hiraoka, L. R.; Hsu, L.; Hsieh, C.-L.: Assignment of ALDH3 to
human chromosome 17p11.2 and ALDH5 to human chromosome 9p13. Genomics 25:
323-325, 1995.

2. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

3. Santisteban, I.; Povey, S.; West, L. F.; Parrington, J. M.; Hopkinson,
D. A.: Chromosome assignment, biochemical and immunological studies
on a human aldehyde dehydrogenase, ALDH3. Ann. Hum. Genet. 49:
87-100, 1985.

4. Teng, Y.-S.: Stomach aldehyde dehydrogenase: report of a new locus.
Hum. Hered. 31: 74-77, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 2/7/1995
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 12/6/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
100670
*FIELD* TI
*100670 ACETALDEHYDE DEHYDROGENASE-5
ALDEHYDE DEHYDROGENASE-5; ALDH5
*FIELD* TX
The 2 aldehyde dehydrogenase isozymes that play a major role in ethanol
detoxification, ALDH1 (100640) and ALDH2 (100650), are cytosolic and
mitochondrial forms, respectively. Their organization is basically
similar; their sizes are 53 kb and 44 kb, respectively, and both contain
13 coding exons interrupted by 12 introns of comparable lengths. Hsu et
al. (1989) cloned a new ALDH gene from a cosmid human DNA library.
Although it contains no introns, Northern blot hybridization of human
liver RNA revealed a unique mRNA component that hybridized with this
gene probe but with neither the ALDH1 probe or the ALDH2 probe. The new
gene encoded 517 amino acid residues, suggesting that it is similar to
ALDH2, and indeed its deduced sequence was 70.6% identical to that of
ALDH2 and only 62.8% identical to that of ALDH1. Hsu et al. (1989)
assigned the ALDH5 gene to chromosome 9 by Southern blot analysis of
rodent-human hybrid cell DNAs. Hsu and Chang (1991) provided a full
report on this gene which they referred to as ALDHx.

By in situ hybridization, Hiraoka et al. (1995) mapped the ALDH5 gene to
9p13.

*FIELD* SA
Harada et al. (1980)
*FIELD* RF
1. Harada, S.; Agarwal, D. P.; Goedde, H. W.: Electrophoretic and
biochemical studies of human aldehyde dehydrogenase isozymes in various
tissues. Life Sci. 26: 1773-1780, 1980.

2. Hiraoka, L. R.; Hsu, L.; Hsieh, C.-L.: Assignment of ALDH3 to
human chromosome 17p11.2 and ALDH5 to human chromosome 9p13. Genomics 25:
323-325, 1995.

3. Hsu, L. C.; Chang, W.-C.; Yoshida, A.: Cloning of a new human
aldehyde dehydrogenase gene and comparison with liver cytosolic ALDH1
and mitochondrial ALDH2 genes.  (Abstract) Am. J. Hum. Genet. 45
(suppl.): A196 only, 1989.

4. Hsu, L. C.; Chang, W. C.: Cloning and characterization of a new
functional human aldehyde dehydrogenase gene. J. Biol. Chem. 266:
12257-12265, 1991.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 2/7/1995
carol: 10/22/1992
carol: 8/28/1992
supermim: 3/16/1992
supermim: 3/20/1990
carol: 11/7/1989

*RECORD*
*FIELD* NO
100675
*FIELD* TI
100675 ACETAMINOPHEN METABOLISM
*FIELD* TX
Acetaminophen (paracetamol) is extensively conjugated with glucuronic
acid and sulfate before renal excretion. A minor metabolic route
involves microsomal oxidation of acetaminophen to a hepatotoxic reactive
intermediate, which subsequently undergoes glutathione (GSH)
conjugation, yielding cysteine and mercapturate conjugates, both of
which are excreted in the urine (Slattery et al., 1987). Evidence was
presented by de Morais et al. (1989) that, in comparison with normal
subjects, glucuronidation of acetaminophen is impaired in subjects with
Gilbert syndrome (143500), a disorder in which glucuronidation of
bilirubin is impaired. In studies of 125 Caucasian and 33 Oriental
subjects, Patel et al. (1992) found no difference in the mean fraction
of acetaminophen excreted as glucuronide: 51.5% in Caucasians vs 51.8%
in Orientals. However, bimodality was apparent in both groups, with 20%
of Caucasians and 33% of Oriental subjects displaying relatively
extensive glucuronidation. In addition, glucuronidation displayed a
strong negative correlation with sulfation (r = -0.97), suggesting a
compensatory or complementary relationship between the 2 metabolic
pathways. The mean fractional excretions of cysteine and mercapturate
conjugates between Caucasians and Orientals did show significant
differences (p = less than 0.005).

*FIELD* RF
1. de Morais, S. M. F.; Uetrecht, J. P.; Wells, P. G.: Decreased
glucuronidation and increased bioactivation of acetaminophen in Gilbert's
disease.  (Abstract) FASEB J. 3: A739 only, 1989.

2. Patel, M.; Tang, B. K.; Kalow, W.: Variability of acetaminophen
metabolism in Caucasians and Orientals. Pharmacogenetics 2: 38-45,
1992.

3. Slattery, J. T.; Wilson, J. M.; Kalhorn, T. F.; Nelson, S. D.:
Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione
depletion in humans. Clin. Pharm. Therap. 41: 413-418, 1987.

*FIELD* CS

Skin:
   Jaundice

Lab:
   Impaired acetaminophen glucuronidation in Gilbert syndrome (143500)

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 7/21/1992

*FIELD* ED
mimadm: 4/14/1994
carol: 10/13/1992
carol: 8/10/1992
carol: 7/21/1992

*RECORD*
*FIELD* NO
100678
*FIELD* TI
*100678 ACETYL-CoA ACETYLTRANSFERASE-2; ACAT2
ACETOCOENZYME A ACETYLTRANSFERASE-2;;
ACETOACETYL-CoA THIOLASE
ACAT2 DEFICIENCY, INCLUDED
*FIELD* TX
The TCP1 gene (186980) is located on 6p in the vicinity of the major
histocompatibility complex, and the murine homolog, Tcp-1, is located in
the t-complex region of mouse chromosome 17. In the mouse, a related
gene, Tcp-1x, is tightly linked to Tcp-1. Ashworth (1993) showed that 2
genes located 3-prime to the murine Tcp-1 and Tcp-1x genes code for
proteins highly homologous to acetyl-CoA acetyltransferases. These Acat
genes are in opposite orientation to the Tcp-1 genes, and transcription
results in mRNA species that contain the last exon of Tcp-1 or Tcp-1x
within the 3-prime untranslated region of the respective Acat mRNA. Both
Acat genes appear to be transcribed in several mouse tissues. Willison
et al. (1987) showed (their fig. 2b) that in humans TCP1 and ACAT genes
also overlap. Retention of this close linkage during mammalian evolution
suggests the possibility of some functional significance. Transcription
of both DNA strands at a given locus is common in prokaryotic and viral
systems. For examples of overlapping transcriptional units in humans,
see Morel et al. (1989) and Laudet et al. (1991).

It is proposed to use ACAT2 to designate the ACAT gene on human
chromosome 6; the ACAT1 gene is the one previously mapped to human
chromosome 11 and found to be mutant in cases of 3-ketothiolase
deficiency (203750).

Song et al. (1994) cloned cDNA for human cytosolic acetoacetyl-CoA
thiolase by use of an antibody against the human enzyme. The deduced
amino acid sequence had a 34 to 57% homology with 4 other human
thiolases and 4 acetoacetyl-CoA thiolases of microorganisms.

As the human TCP1 gene had been assigned to 6q25-q27 by study of somatic
cell hybrids and by in situ hybridization, the ACAT2 gene was suspected
to be localized to the same chromosome region. By fluorescence in situ
hybridization, Masuno et al. (1996) demonstrated that the ACAT2 gene is
located on 6q25.3-q26.

Reported patients with ACTA2 deficiency have shown severe mental
retardation and hypotonus. Laboratory findings, including urinary
organic acids were not specific (Bennett et al., 1984).

*FIELD* RF
1. Ashworth, A.: Two acetyl-CoA acetyltransferase genes located in
the t-complex region of mouse chromosome 17 partially overlap the
Tcp-1 and Tcp-1x genes. Genomics 18: 195-198, 1993.

2. Bennett, M. J.; Hosking, G. P.; Smith, M. F.; Gray, R. G. F.; Middleton,
B.: Biochemical investigations on a patient with a defect in cytosolic
acetoacetyl-CoA thiolase, associated with mental retardation. J.
Inherit. Metab. Dis. 7: 125-128, 1984.

3. Laudet, V.; Begue, A.; Henry-Duthoit, C.; Joubel, A.; Martin, P.;
Stehelin, D.; Saule, S.: Genomic organization of the human thyroid
hormone alpha (c-erbA-1) gene. Nucleic Acids Res. 19: 1105-1112,
1991.

4. Masuno, M.; Fukao, T.; Song, X.-Q.; Yamaguchi, S.; Orii, T.; Kondo,
N.; Imaizumi, K.; Kuroki, Y.: Assignment of the human cytosolic acetoacetyl-coenzyme
A thiolase (ACAT2) gene to chromosome 6q25.3-q26. Genomics 36: 217-218,
1996.

5. Morel, Y.; Bristow, J.; Gitelman, S. E.; Miller, W. L.: Transcript
encoded on the opposite strand of the human steroid 21-hydroxylase/complement
component C4 gene locus. Proc. Nat. Acad. Sci. 86: 6582-6586, 1989.

6. Song, X.-Q.; Fukao, T.; Yamaguchi, S.; Miyazawa, S.; Hashimoto,
T.; Orii, T.: Molecular cloning and nucleotide sequence of complementary
DNA for human hepatic cytosolic acetoacetyl-coenzyme A thiolase. Biochem.
Biophys. Res. Commun. 201: 478-485, 1994.

7. Willison, K.; Kelly, A.; Dudley, K.; Goodfellow, P.; Spurr, N.;
Groves, V.; Gorman, P.; Sheer, D.; Trowsdale, J.: The human homologue
of the mouse t-complex gene, TCP1, is located on chromosome 6 but
is not near the HLA region. EMBO J. 6: 1967-1974, 1987.

*FIELD* CD
Victor A. McKusick: 12/2/1993

*FIELD* ED
mark: 09/12/1996
terry: 9/4/1996
carol: 10/12/1994
carol: 12/20/1993
carol: 12/2/1993

*RECORD*
*FIELD* NO
100680
*FIELD* TI
100680 ACETYLCHOLINESTERASE EXPRESSION; ACEE
REGULATOR OF ACETYLCHOLINESTERASE; RACH
*FIELD* TX
Chen et al. (1978) studied three strains of human fibroblasts that were
trisomic for chromosome 2 and had an average level of ACE over 28 times
higher than the average fibroblasts. The mean pseudocholinesterase level
of the trisomy-2 strains was normal. The 19 control strains comprised 10
trisomic for other autosomes and 9 euploid strains. The ACE activity of
control fibroblasts did not differ significantly from zero. Despite the
unusual elevation of ACE in trisomy-2 fibroblasts, the level, expressed
in terms of micrograms of DNA, was only 1.5% of that in cerebral cortex.
Two other enzymes, xanthine oxidase and choline acetyltransferase,
which, like ACE, have a restricted distribution in human tissues, were
absent from all 22 strains of fibroblasts. The results were interpreted
as evidence for a gene on chromosome 2 involved in regulation of ACE.

*FIELD* RF
1. Chen, Y.-T.; Worthy, T. E.; Krooth, R. S.: Evidence for a striking
increase in acetylcholinesterase activity in cultured human fibroblasts
which are trisomic for chromosome two. Somat. Cell Genet. 4: 265-298,
1978.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 7/13/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
100690
*FIELD* TI
*100690 CHOLINERGIC RECEPTOR, NICOTINIC, ALPHA POLYPEPTIDE 1; CHRNA1
CHRNA;;
ACETYLCHOLINE RECEPTOR, MUSCLE, ALPHA SUBUNIT; ACHRA
*FIELD* TX
The acetylcholine receptor of muscle, like the nicotinic acetylcholine
receptor of the fish electric organ, has 5 subunits of 4 different
types: 2 alpha and 1 each of beta, gamma and delta subunits. In the
electric organ the subunits show conspicuous sequence homology. The
transmembrane topology of the subunits and the location of functionally
important regions, such as the acetylcholine binding site and the
transmembrane segments involved in the ionic channel, have been
proposed. Noda et al. (1983) cloned cDNA for the alpha subunit precursor
of the calf skeletal muscle AChR and a human genomic DNA segment
containing the corresponding gene. Nucleotide sequences showed marked
homology with the counterpart of Torpedo sp. (electric ray). The
protein-coding sequence of the human ACHRA gene is divided into 9 exons
by 8 introns, which correspond to different structural and functional
domains of the precursor molecule. Analyzing acetylcholine receptor
clones isolated from a human leg muscle cDNA library, Beeson et al.
(1990) found that the alpha subunit exists in 2 isoforms. A novel exon,
coding for 25 amino acids, was inserted into the alpha subunit, giving
the new isoform 462 amino acids.

Heidmann et al. (1986) analyzed restriction fragment length
polymorphisms of each of the 4 subunits of muscle nicotinic
acetylcholine receptor in crosses between 2 mouse species and showed
that the alpha subunit gene cosegregates with the alpha cardiac actin
gene on mouse chromosome 17. Taylor and Rowe (1989) concluded that the
Acra gene in the mouse in fact is located on chromosome 2. Schoepfer et
al. (1988) showed that a human medulloblastoma cell line expressed a
muscle type rather than a neuronal type of acetylcholine receptor. They
succeeded in isolating cDNA clones for the alpha subunit and suggested
that these should be useful in obtaining large amounts of human
muscle-type acetylcholine receptor alpha-subunit protein for studies of
the autoimmune response in myasthenia gravis. Garchon et al. (1994)
identified 2 stable polymorphic dinucleotide repeats within the first
intron of the CHRNA gene, designated HB and BB. They found that the
HB*14 allele conferred a relative risk for myasthenia gravis of 2.5 in
81 unrelated patients compared with 100 control subjects. Very
significantly, family analysis based on haplotype segregation data
indicated that parental haplotypes associated with HB*14 always
segregated to the child with myasthenia gravis, whereas their
transmission to unaffected sibs was as expected ('was equilibrated,' in
the words of the authors). Myasthenia gravis patients always showed a
high frequency of microsatellite variants not seen in controls.

By means of somatic cell hybridization, Beeson et al. (1989, 1990)
assigned the CHRNA gene to chromosome 2; by in situ hybridization, they
regionalized the gene to 2q24-q32, with the major peak of grains being
at 2q32. By linkage analysis, Lobos (1993) placed the CHRNA gene about
27 cM proximal to the crystallin G pseudogene marker, CRYGP1, located at
2q33-q35; the CHRND (100720) and CHRNG (100730) loci were placed about
31 cM distal to CRYGP1.

*FIELD* AV
.0001
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL
SCCMS
CHRNA1, ASN217LYS
Engel et al. (1996) described a 30-year-old female patient with ocular
and limb weakness, scoliosis, and a family history consistent with
autosomal dominant myasthenia gravis (601462) in 3 generations. The
mutation leading to pathology in this patient was a heterozygous
asn217-to-lys substitution in the AChR-alpha subunit. Engel et al.
(1996) evaluated the pathogenicity of the mutation by engineering the
mutation into the corresponding cDNA of mouse AChR and coexpressing it
with the wildtype cDNA in HEK fibroblasts. Receptor function was
evaluated using patch clamp studies and ACh binding was measured. These
studies revealed that the mutations resulted in an apparent increased
affinity for ACh and prolonged AChR activation episodes rendering the
receptor channel leaky.

*FIELD* SA
Beeson et al. (1990); Mishina et al. (1986)
*FIELD* RF
1. Beeson, D.; Jeremiah, S.; West, L. F.; Povey, S.; Newsom-Davis,
J.: Assignment of the human nicotinic acetylcholine receptor genes:
the alpha and delta subunit genes to chromosome 2 and the beta subunit
gene to chromosome 17. Ann. Hum. Genet. 54: 199-208, 1990.

2. Beeson, D.; Jeremiah, S. J.; West, L. F.; Povey, S.; Newsom-Davis,
J.: Assignment of the human acetylcholine receptor beta subunit gene
to chromosome 17 and the alpha and delta subunit genes to chromosome
2. (Abstract) Cytogenet. Cell Genet. 51: 960 only, 1989.

3. Beeson, D.; Morris, A.; Vincent, A.; Newsom-Davis, J.: The human
muscle nicotinic acetylcholine receptor alpha-subunit exists as two
isoforms: a novel exon. EMBO J. 9: 2101-2106, 1990.

4. Engel, A. G.; Ohno, K.; Milone, M.; Wang, H.-L.; Nakano, S.; Bouzat,
C.; Pruitt, J. N., II; Hutchinson, D. O.; Brengman, J. M.; Bren, N.;
Sieb, J. P.; Sine, S. M.: New mutations in acetylcholine receptor
subunit genes reveal heterogeneity in the slow-channel congenital
myasthenic syndrome. Hum. Molec. Genet. 5: 1217-1227, 1996.

5. Garchon, H.-J.; Djabiri, F.; Viard, J.-P.; Gajdos, P.; Bach, J.-F.
: Involvement of human muscle acetylcholine receptor alpha-subunit
gene (CHRNA) in susceptibility to myasthenia gravis. Proc. Nat. Acad.
Sci. 91: 4668-4672, 1994.

6. Heidmann, O.; Buonanno, A.; Geoffroy, B.; Robert, B.; Guenet, J.-L.;
Merlie, J. P.; Changeux, J.-P.: Chromosomal localization of muscle
nicotinic acetylcholine receptor genes in the mouse. Science 234:
866-868, 1986.

7. Lobos, E. A.: Five subunit genes of the human muscle nicotinic
acetylcholine receptor are mapped to two linkage groups on chromosomes
2 and 17. Genomics 17: 642-650, 1993.

8. Mishina, M.; Takai, T.; Imoto, K.; Noda, M.; Takahashi, T.; Numa,
S.; Methfessel, C.; Sakmann, B.: Molecular distinction between fetal
and adult forms of muscle acetylcholine receptor. Nature 321: 406-411,
1986.

9. Noda, M.; Furutani, Y.; Takahashi, H.; Toyosato, M.; Tanabe, T.;
Shimizu, S.; Kikyotani, S.; Kayano, T.; Hirose, T.; Inayama, S.; Numa,
S.: Cloning and sequence analysis of calf cDNA and human genomic
DNA encoding alpha-subunit precursor of muscle acetylcholine receptor. Nature 305:
818-823, 1983.

10. Schoepfer, R.; Luther, M.; Lindstrom, J.: The human medulloblastoma
cell line TE671 expresses a muscle-like acetylcholine receptor: cloning
of the alpha-subunit cDNA. FEBS Lett. 226: 235-240, 1988.

11. Taylor, B. A.; Rowe, L.: Localization of the gene encoding the
alpha-subunit of the acetylcholine receptor on chromosome 2 of the
mouse. Cytogenet. Cell Genet. 52: 102-103, 1989.

*FIELD* CN
Moyra Smith - updated: 10/09/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/09/1996
carol: 9/19/1994
mimadm: 4/14/1994
carol: 10/13/1993
carol: 9/22/1993
carol: 2/17/1993
carol: 1/5/1993

*RECORD*
*FIELD* NO
100700
*FIELD* TI
100700 ACHARD SYNDROME
*FIELD* TX
Arachnodactyly, receding lower jaw, and joint laxity limited to the
hands and feet are features. When Thursfield (1917-18) reviewed the
literature on Marfan syndrome, he remarked that the skeletal picture in
the cases described by Achard (1902) differed in that the skull was
broad and brachycephalic with small mandible; although there was
arachnodactyly, the body proportions were not altered and the patient
was not excessively tall. Parish (1960) pictured a case. It is not clear
what this condition represented or even that it is a distinct entity.

*FIELD* SA
Parish  (1967)
*FIELD* RF
1. Achard, C.: Arachnodactylie. Bull. Mem. Soc. Med. Hop. Paris 19:
834-840, 1902.

2. Parish, J. G.: Heritable disorders of connective tissues with
arachnodactyly. Proc. Roy. Soc. Med. 53: 515-518, 1960.

3. Parish, J. G.: Skeletal hand charts in inherited connective tissue
disease. J. Med. Genet. 4: 227-238, 1967.

4. Thursfield, H.: Arachnodactyly. St. Bart's Hosp. Rep. 53: 35-40,
1917.

*FIELD* CS

Limbs:
   Arachnodactyly

Joints:
   Joint laxity limited to hands and feet

Skull:
   Broad skull

Head:
   Brachycephaly;
   Micrognathia

Misc:
   Normal body proportions

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
pfoster: 8/18/1994
mimadm: 5/2/1994
supermim: 3/16/1992
supermim: 3/20/1990
carol: 3/6/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
100710
*FIELD* TI
*100710 CHOLINERGIC RECEPTOR, NICOTINIC, BETA POLYPEPTIDE 1; CHRNB1
CHRNB;;
ACETYLCHOLINE RECEPTOR, MUSCLE, BETA SUBUNIT; ACHRB
*FIELD* TX
See 100690. In the Torpedo (electric ray), the 4 subunits of the AChR
show conspicuous sequence homology. Heidmann et al. (1986) analyzed
restriction fragment length polymorphisms of each of the 4 subunits of
muscle nicotinic acetylcholine receptor in crosses between 2 mouse
species. They found that the beta subunit gene is located on mouse
chromosome 11. The beta subunit gene was found to be tightly linked with
the locus encoding the different isoforms (embryonic, perinatal and
adult) of the myosin heavy chain genes which are located on mouse
chromosome 11. In man these genes are located on chromosome 17p
(160730), arguing from likely homology of synteny. The beta subunit of
the acetylcholine receptor may be coded by a gene on human 17p also.
Using a panel of human-rodent somatic cell hybrids segregating human
chromosomes, Beeson et al. (1989) demonstrated that the CHRNB locus is
on human chromosome 17. Beeson et al. (1990) regionalized the CHRNB gene
to 17p12-p11 by in situ hybridization.

*FIELD* AV
.0001
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL
SCCMS
CHRNB1, VAL266MET
Engel et al. (1996) described a 19-year-old female with myasthenic
symptoms since birth involving ocular, cranial, and limb muscles. The
mutation leading to pathology was a heterozygous val266-to-met
substitution in the transmembrane domain of the AChR-beta subunit.
Receptor function was evaluated using patch clamp studies and ACh
binding was measured. These studies revealed that the mutation resulted
in an apparent increased affinity for ACh and prolonged AChR activation
episodes rendering the receptor channel leaky. See also 601462.

*FIELD* SA
Beeson et al. (1989)
*FIELD* RF
1. Beeson, D.; Brydson, M.; Newsom-Davis, J.: Nucleotide sequence
of human muscle acetylcholine receptor beta-subunit. Nucleic Acids
Res. 17: 4391 only, 1989.

2. Beeson, D.; Jeremiah, S.; West, L. F.; Povey, S.; Newsom-Davis,
J.: Assignment of the human nicotinic acetylcholine receptor genes:
the alpha and delta subunit genes to chromosome 2 and the beta subunit
gene to chromosome 17. Ann. Hum. Genet. 54: 199-208, 1990.

3. Beeson, D.; Jeremiah, S. J.; West, L. F.; Povey, S.; Newsom-Davis,
J.: Assignment of the human acetylcholine receptor beta subunit gene
to chromosome 17 and the alpha and delta subunit genes to chromosome
2. (Abstract) Cytogenet. Cell Genet. 51: 960 only, 1989.

4. Engel, A. G.; Ohno, K.; Milone, M.; Wang, H.-L.; Nakano, S.; Bouzat,
C.; Pruitt, J. N., II; Hutchinson, D. O.; Brengman, J. M.; Bren, N.;
Sieb, J. P.; Sine, S. M.: New mutations in acetylcholine receptor
subunit genes reveal heterogeneity in the slow-channel congenital
myasthenic syndrome. Hum. Molec. Genet. 5: 1217-1227, 1996.

5. Heidmann, O.; Buonanno, A.; Geoffroy, B.; Robert, B.; Guenet, J.-L.;
Merlie, J. P.; Changeux, J.-P.: Chromosomal localization of muscle
nicotinic acetylcholine receptor genes in the mouse. Science 234:
866-868, 1986.

*FIELD* CN
Moyra Smith - updated: 10/09/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/09/1996
mark: 8/29/1996
carol: 6/30/1992
carol: 4/7/1992
supermim: 3/16/1992
carol: 2/29/1992
carol: 2/5/1992
carol: 1/29/1991

*RECORD*
*FIELD* NO
100720
*FIELD* TI
*100720 ACETYLCHOLINE RECEPTOR, MUSCLE, DELTA SUBUNIT; ACHRD
CHOLINERGIC RECEPTOR, NICOTINIC, DELTA POLYPEPTIDE; CHRND
*FIELD* TX
See 100690. Heidmann et al. (1986) analyzed restriction fragment length
polymorphisms of the 4 subunits of muscle nicotinic acetylcholine
receptor in 2 mouse species and crosses between the two. They found that
the gamma and delta subunit genes cosegregated with each other and with
the gene of the fast skeletal muscle isoforms of myosin alkali light
chain (160780). The acetylcholine receptor genes cosegregated less
tightly with the gene for isocitrate dehydrogenase-1 (147700). The
myosin locus and the Idh-1 locus are on mouse chromosome 1. IDH1 in man
is located on chromosome 2, which carries another locus homologous to
one on mouse no. 1, namely, the cluster of genes for a gamma polypeptide
of crystallin (123660-123690). Thus, the gamma and delta subunit genes
of acetylcholine receptor may be tightly linked to each other and may be
situated in man on chromosome 2, possibly on the long arm. Lobos et al.
(1989) found at least 1 RFLP in each of the 4 subunit genes. The delta
gene was assigned by in situ hybridization to 2q31-q34. All pairs of
RFLPs were analyzed for linkage disequilibrium. Of the 16 pairs of RFLPs
from the same gene or from the linked gamma and delta genes, 13 showed
evidence of significant disequilibrium (P less than 0.05). By Southern
analysis of a panel of somatic cell hybrids and by in situ
hybridization, Beeson et al. (1990) assigned the CHRND gene to
2q33-qter. Together with the earlier information, this suggests a
location of 2q33-q34. Work of Pasteris et al. (1993) suggested a more
distal location; a molecular analysis of a chromosome 2 deletion mapping
panel suggested the following order: cen--PAX3--COL4A3--CHRND--tel. PAX3
(193500) is located in band 2q35 and COL4A3 (120070) is located in band
2q36.

*FIELD* RF
1. Beeson, D.; Jeremiah, S.; West, L. F.; Povey, S.; Newsom-Davis,
J.: Assignment of the human nicotinic acetylcholine receptor genes:
the alpha and delta subunit genes to chromosome 2 and the beta subunit
gene to chromosome 17. Ann. Hum. Genet. 54: 199-208, 1990.

2. Heidmann, O.; Buonanno, A.; Geoffroy, B.; Robert, B.; Guenet, J.-L.;
Merlie, J. P.; Changeux, J.-P.: Chromosomal localization of muscle
nicotinic acetylcholine receptor genes in the mouse. Science 234:
866-868, 1986.

3. Lobos, E. A.; Rudnick, C. H.; Watson, M. S.; Isenberg, K. E.:
Linkage disequilibrium study of RFLPs detected at the human muscle
nicotinic acetylcholine receptor subunit genes. Am. J. Hum. Genet. 44:
522-533, 1989.

4. Pasteris, N. G.; Trask, B. J.; Sheldon, S.; Gorski, J. L.: Discordant
phenotype of two overlapping deletions involving the PAX3 gene in
chromosome 2q35. Hum. Molec. Genet. 2: 953-959, 1993.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 8/18/1993
carol: 6/30/1992
supermim: 3/16/1992
carol: 10/30/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
100725
*FIELD* TI
*100725 CHOLINERGIC RECEPTOR, NICOTINIC, EPSILON POLYPEPTIDE; CHRNE
ACETYLCHOLINE RECEPTOR, MUSCLE, EPSILON SUBUNIT; ACHRE
*FIELD* TX
Acetylcholine receptors at mature mammalian neuromuscular junctions are
pentameric protein complexes composed of 4 subunits in the ratio of 2
alpha subunits (100690) to 1 beta (100710), 1 epsilon, and 1 delta
subunit (100720). Most, if not all, embryonic acetylcholine receptors
contain a different subunit, gamma (CHRNG; 100730), in place of the
epsilon subunit. It is likely that this change in subunit composition,
which occurs during the first 2 weeks after birth, accounts for the
switch in properties of acetylcholine-activated channels from
low-conductance, long open time to high-conductance, brief open time
that occurs over approximately the same time course. In neonatal mouse
and rat myotubes, epsilon-subunit mRNA is present at low levels, whereas
gamma-subunit mRNA is present at relatively high levels. During the
first 2 weeks after birth, the amount of epsilon-subunit mRNA rises
10-fold and gamma-subunit mRNA falls to undetectable levels. The
increase in epsilon-subunit mRNA appears to be confined to the
developing motor endplate. The switch to the epsilon subunit is mediated
by ARIA (acetylcholine receptor-inducing activity; 100735).

Lobos (1993) concluded that the CHRNE gene is located about 5 cM from
the CHRNB1 gene (100710) in the vicinity of TP53 (191170) on 17p13.1.
Using linkage analysis, the conclusion was confirmed by hybridization of
CHRNE and CHRNB1 probes to a panel of human/hamster somatic cell
hybrids. CHRNB1 was previously assigned to 17p12-p11. Beeson et al.
(1993) isolated cDNA sequences encompassing the full coding region of
the CHRNE and CHRNG genes. The deduced amino acid sequences indicated
that the mature epsilon subunit contains 473 amino acids and is preceded
by a 20-amino acid signal peptide. In common with the human alpha, beta,
gamma, and delta subunits, the epsilon subunit is highly conserved among
mammalian species. By PCR analysis of somatic cell hybrids, Beeson et
al. (1993) demonstrated that the CHRNE gene is located on chromosome 17.

Witzemann et al. (1996) noted that in mammalian muscle the functional
properties of end plate channels change during postnatal development.
The length of channel-opening bursts decreases and, as a consequence,
the duration of miniature end plate current (mEPC) decreases, whereas
the conductance and the Ca(2+) permeability of end plate channels
increase. The underlying molecular mechanism is a switch in the
expression of acetylcholine receptor subunit genes shortly after birth.
The gamma-subunit (CHRNG) is repressed while the epsilon-subunit gene is
activated selectively in the myonuclei underlying the synapse. To
investigate the significance of the CHRNG/CHRNE switch for motor
behavior, Witzemann et al. (1996) ablated the Chrng gene in mouse
embryonic stem (es) cells by homologous recombination and injected
correctly engineered cells of 2 independently isolated clones into
C57BL/6 blastocyts. Chimeric male mice derived from both clones showed
germline transmission of the targeted allele. Homozygous mutant animals
showed that after apparently normal development in early neonatal life,
neuromuscular transmission was progressively impaired. The lack of
epsilon subunits caused muscle weakness, defects in motor behavior, and
premature death 2 to 3 months after birth. Their results demonstrated
that postnatal incorporation of epsilon subunits in acetylcholine
receptors into the end plate is essential for normal development of
skeletal muscle.

*FIELD* AV
.0001
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL
SCCMS; MYASTHENIA, CONGENITAL
CHRNE, THR245PRO
Ohno et al. (1995) demonstrated a mutation in the CHRNE gene in a
20-year-old woman who had myasthenic symptoms since the neonatal period,
a decremental electromyographic response on stimulation of motor nerves,
negative tests for antiacetylcholine receptor (AChR) antibodies, and no
history of similarly affected relatives. Studies of an intercostal
muscle specimen from this patient at age 17 had revealed signs of severe
end plate myopathy, and patch-clamp studies showed markedly prolonged
acetylcholine receptor channel openings. The patient was heterozygous
for an A-to-C transversion at nucleotide 790 in exon 8 of the epsilon
subunit gene, predicting substitution of proline for threonine at codon
264. Genetically engineered mutant AChR expressed in a human embryonic
kidney fibroblast cell line also exhibited markedly prolonged openings
in the presence of agonist and even opened in its absence.

.0002
MYASTHENIC SYNDROME, SLOW-CHANNEL CONGENITAL
SCCMS
CHRNE, LEU269PHE
Engel et al. (1996) described a 16-year-old male patient with myasthenic
symptoms since early infancy involving ocular, trunkal, and limb
muscles. He experienced intermittent episodes of respiratory
insufficiency. SSCP analysis and DNA sequencing revealed that the
pathological mutation in this patient was a heterozygous leu269-to-phe
substitution within the transmembrane domain of the AChR-epsilon
subunit. Engel et al. (1996) evaluated the pathogenicity of the mutation
by engineering the mutation into the corresponding cDNA of mouse AChR
and coexpressing it with the wildtype cDNA in HEK fibroblasts. Receptor
function was evaluated using patch clamp studies and ACh binding was
measured. These studies revealed that the mutations resulted in an
apparent increased affinity for ACh and prolonged AChR activation
episodes rendering the receptor leaky. See also 601462.

*FIELD* SA
Martinou et al. (1991)
*FIELD* RF
1. Beeson, D.; Brydson, M.; Betty, M.; Jeremiah, S.; Povey, S.; Vincent,
A.; Newsom-Davis, J.: Primary structure of the human muscle acetylcholine
receptor cDNA cloning of the gamma and epsilon subunits. Europ. J.
Biochem. 215: 229-238, 1993.

2. Engel, A. G.; Ohno, K.; Milone, M.; Wang, H.-L.; Nakano, S.; Bouzat,
C.; Pruitt, J. N., II; Hutchinson, D. O.; Brengman, J. M.; Bren, N.;
Sieb, J. P.; Sine, S. M.: New mutations in acetylcholine receptor
subunit genes reveal heterogeneity in the slow-channel congenital
myasthenic syndrome. Hum. Molec. Genet. 5: 1217-1227, 1996.

3. Lobos, E. A.: Five subunit genes of the human muscle nicotinic
acetylcholine receptor are mapped to two linkage groups on chromosomes
2 and 17. Genomics 17: 642-650, 1993.

4. Martinou, J.-C.; Falls, D. L.; Fischbach, G. D.; Merlie, J. P.
: Acetylcholine receptor-inducing activity stimulates expression of
the epsilon-subunit gene of the muscle acetylcholine receptor. Proc.
Nat. Acad. Sci. 88: 7669-7673, 1991.

5. Ohno, K.; Hutchinson, D. O.; Milone, M.; Brengman, J. M.; Bouzat,
C.; Sine, S. M.; Engel, A. G.: Congenital myasthenic syndrome caused
by prolonged acetylcholine receptor channel openings due to a mutation
in the M2 domain of the epsilon subunit. Proc. Nat. Acad. Sci. 92:
758-762, 1995.

6. Witzemann, V.; Schwarz, H.; Koenen, M.; Berberich, C.; Villarroel,
A.; Wernig, A.; Brenner, H. R.; Sakmann, B.: Acetylcholine receptor
epsilon-subunit deletion causes muscle weakness and atrophy in juvenile
and adult mice. Proc. Nat. Acad. Sci. 93: 13286-13291, 1996.

*FIELD* CN
Moyra Smith - updated: 10/9/1996

*FIELD* CD
Victor A. McKusick: 1/10/1992

*FIELD* ED
terry: 12/10/1996
terry: 12/5/1996
mark: 10/9/1996
carol: 2/16/1995
mimadm: 4/14/1994
carol: 11/9/1993
carol: 9/22/1993
supermim: 3/16/1992
carol: 1/10/1992

*RECORD*
*FIELD* NO
100730
*FIELD* TI
*100730 ACETYLCHOLINE RECEPTOR, MUSCLE, GAMMA SUBUNIT; ACHRG
CHOLINERGIC RECEPTOR, NICOTINIC, GAMMA POLYPEPTIDE; CHRNG
*FIELD* TX
See 100690. See also 100720 for a discussion of the probable close
linkage of the genes for the gamma and delta subunits and their possible
location on chromosome 2q. Shibahara et al. (1985) showed that the genes
encoding the gamma and delta subunits of CHRN are contained in an EcoRI
restriction fragment of approximately 20 kb. Cohen-Haguenauer et al.
(1989) used a murine full-length 1,900-bp-long cDNA encoding the gamma
subunit to map the gene to chromosome 2 in human/rodent somatic cell
hybrids. (They used conditions of low stringency to favor cross-species
hybridization, and prehybridization with rodent DNA to prevent rodent
background.) The use of a chromosomal translocation t(X;2)(p22;q32.1)
served to localize the CHRNG gene to 2q32-qter.

In the first days of life, a switch occurs from the gamma to the epsilon
subunit (100725) of the acetylcholine receptor. This switch is mediated
by ARIA (acetylcholine receptor-inducing activity; 100735).

Schurr et al. (1990) mapped this gene to mouse chromosome 1 (symbol
Acrg) at a position between Vil (193040) proximally and Col6a3 (120250)
distally.

Two forms of AChR are found in mammalian skeletal muscle cells. The
mature form is predominant in innervated adult muscle and the embryonic
form is present in fetal and denervated muscle. Embryonic and mature
AChR differ by the replacement of the gamma subunit in the pentameric
glycoprotein complex by its isoform, the epsilon subunit (100725), which
is specific to the mature AChR subtype. Transient neonatal myasthenia
gravis occurs in approximately 20% of infants born to mothers with
myasthenia gravis. Symptoms usually appear within hours after birth and
disappear after 2 or 3 weeks. The severity of neonatal MG is highly
variable, ranging from mild hypotonia to respiratory distress requiring
assisted mechanical ventilation. Antenatal onset leading to multiple
joint contractures, hydramnios, and decreased fetal movements is rare.
The disease severity is not correlated to the clinical status of the
mother. Vernet-der Garabedian et al. (1994) studied 22 mothers with
myasthenia gravis and their newborns. Twelve mothers had transmitted MG
to their neonates with, in 3 cases, antenatal injury. A clear
correlation was found between occurrence of neonatal MG and high overall
levels of anti-AChR antibodies. However, a strong correlation was also
found between occurrence of neonatal MG and the ratio of anti-embryonic
AChR to anti-adult muscle AChR antibodies. Taken together, the data
suggested that autoantibodies directed against the embryonic form of
AChR may play a predominant role in the pathogenesis of neonatal MG.
Paradoxically, the 3 cases with antenatal injury, presumably the most
severe form of the disorder, were not associated with high ratio of
anti-embryonic ACh to anti-adult AChR antibodies.

*FIELD* RF
1. Cohen-Haguenauer, O.; Barton, P. J.; Buonanno, A.; Cong, N. V.;
Masset, M.; de Tand, M. F.; Merlie, J.; Frezal, J.: Localization
of the acetylcholine receptor gamma subunit gene to human chromosome
2q32-qter. Cytogenet. Cell Genet. 52: 124-127, 1989.

2. Schurr, E.; Skamene, E.; Morgan, K.; Chu, M.-L.; Gros, P.: Mapping
of Col3a1 and Col6a3 to proximal murine chromosome 1 identifies conserved
linkage of structural protein genes between murine chromosome 1 and
human chromosome 2q. Genomics 8: 477-486, 1990.

3. Shibahara, S.; Kubo, T.; Perski, H. J.; Takahashi, H.; Noda, M.;
Numa, S.: Cloning and sequence analysis of human genomic DNA encoding
gamma subunit precursor of muscle acetylcholine receptor. Europ.
J. Biochem. 146: 15-22, 1985.

4. Vernet-der Garabedian, B.; Lacokova, M.; Eymard, B.; Morel, E.;
Faltin, M.; Zajac, J.; Sadovsky, O.; Dommergues, M.; Tripon, P.; Bach,
J.-F.: Association of neonatal myasthenia gravis with antibodies
against the fetal acetylcholine receptor. J. Clin. Invest. 94:
555-559, 1994.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 9/29/1994
supermim: 3/16/1992
carol: 12/11/1991
carol: 9/27/1991
carol: 10/10/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
100735
*FIELD* TI
*100735 ACETYLCHOLINE RECEPTOR-INDUCING ACTIVITY; ARIA
*FIELD* TX
Martinou et al. (1991) found that acetylcholine receptor-inducing
activity (ARIA), a 42-kD glycoprotein purified on the basis of its
ability to increase the synthesis of acetylcholine receptors in chick
myotubes, increases epsilon-subunit mRNA levels up to 10-fold. Thus,
ARIA appears to be responsible in a major way for the switch from gamma
subunits (100730) to epsilon subunits (100725) in the pentameric
acetylcholine receptor protein complex.

*FIELD* RF
1. Martinou, J.-C.; Falls, D. L.; Fischbach, G. D.; Merlie, J. P.
: Acetylcholine receptor-inducing activity stimulates expression of
the epsilon-subunit gene of the muscle acetylcholine receptor. Proc.
Nat. Acad. Sci. 88: 7669-7673, 1991.

*FIELD* CD
Victor A. McKusick: 9/27/1991

*FIELD* ED
supermim: 3/16/1992
carol: 10/10/1991
carol: 9/27/1991

*RECORD*
*FIELD* NO
100740
*FIELD* TI
*100740 ACETYLCHOLINESTERASE
ACETYLCHOLINE ACETYLHYDROLASE; ACHE
*FIELD* TX
Coates and Simpson (1972) concluded that 3 phenotypic variants of
acetylcholinesterase (EC 3.1.1.7) result from 2 codominant alleles at a
single locus. Rotundo et al. (1988) showed that all the forms of
acetylcholinesterase observed in avian nerves and muscle are encoded by
a single autosomal gene. Differences in assembly and localization of the
multiple synaptic forms of acetylcholinesterase are thought to arise
through posttranscriptional events. Lapidot-Lifson et al. (1989)
referred to the cloning of the gene for acetylcholinesterase. They used
these clones to study the coamplification of acetylcholinesterase and
pseudocholinesterase (butyrylcholinesterase; EC 3.1.1.8; 177400). Their
coamplification in certain leukemias and in disorders of platelet
formation suggest that the 2 loci may be linked. (The
pseudocholinesterase gene is located at 3q25.2.) Whereas
pseudocholinesterase is a soluble plasma enzyme presumed to be produced
by the liver but also present in muscle and brain, acetylcholinesterase
or 'true' cholinesterase is involved in the signal transmission at
neuromuscular junctions and is also intensely expressed in the human
central nervous system and the erythrocyte membrane.

It has been demonstrated that the Yt erythrocyte blood group antigen
system (112100) resides on the acetylcholinesterase molecule. Since this
blood group system has been mapped to the long arm of chromosome 7 in
the proximity of the COL1A2 (120160) locus, one can conclude that this
is the site of the acetylcholinesterase locus. That such was the case
was demonstrated by Getman et al. (1992). By chromosomal in situ
suppression hybridization analysis, they showed that a single gene is
located at 7q22 and confirmed the results by PCR analysis of genomic DNA
from a human/hamster somatic cell hybrid containing a single human
chromosome 7. Thus the gene maps to the same region that is frequently
the site of nonrandom deletion in leukemias of myeloid cell precursors
known to express acetylcholinesterase during normal differentiation.
Ehrlich et al. (1992) mapped the ACHE gene to 7q22 by fluorescence in
situ hybridization and by selective PCR amplification from a somatic
hybrid cell panel and chromosome-sorted DNA libraries. This conforms
well with the previous assignment of the YT blood group to 7q21-q22.
Mapping of the ACHE gene to chromosome 3 was convincingly excluded.
Ehrlich et al. (1992) suggested that the assignment of the gene to 7q22
may provide an explanation of the in vivo amplification of the ACHE gene
observed in ovarian tumors and leukemias and the phenomenon of
tumor-related breakage in 7q. By analysis of a RFLP in recombinant
inbred (RI) strains, Rachinsky et al. (1992) demonstrated that the Ache
gene is located on distal mouse chromosome 5.

*FIELD* AV
.0001
YT BLOOD GROUP POLYMORPHISM
ACHE, HIS322ASN
Bartels et al. (1993) demonstrated that the wildtype sequence of the
ACHE gene, which corresponds to the YT1 blood group antigen, has
histidine at codon 322 (CAC) and that the rare variant, the YT2 blood
group antigen, has asparagine (AAC) at that position.

*FIELD* SA
Telen and Whitsett (1992)
*FIELD* RF
1. Bartels, C. F.; Zelinski, T.; Lockridge, O.: Mutation at codon
322 in the human acetylcholinesterase (ACHE) gene accounts for YT
blood group polymorphism. Am. J. Hum. Genet. 52: 928-936, 1993.

2. Coates, P. M.; Simpson, N. E.: Genetic variation in human erythrocyte
acetylcholinesterase. Science 175: 1466-1467, 1972.

3. Ehrlich, G.; Viegas-Pequignot, E.; Ginzberg, D.; Sindel, L.; Soreq,
H.; Zakut, H.: Mapping the human acetylcholinesterase gene to chromosome
7q22 by fluorescent in situ hybridization coupled with selective PCR
amplification from a somatic hybrid cell panel and chromosome-sorted
DNA libraries. Genomics 13: 1192-1197, 1992.

4. Getman, D. K.; Eubanks, J. H.; Camp, S.; Evans, G. A.; Taylor,
P.: The human gene encoding acetylcholinesterase is located on the
long arm of chromosome 7. Am. J. Hum. Genet. 51: 170-177, 1992.

5. Lapidot-Lifson, Y.; Prody, C. A.; Ginzberg, D.; Meytes, D.; Zakut,
H.; Soreq, H.: Coamplification of human acetylcholinesterase and
butyrylcholinesterase genes in blood cells: correlation with various
leukemias and abnormal megakaryocytopoiesis. Proc. Nat. Acad. Sci. 86:
4715-4719, 1989.

6. Rachinsky, T. L.; Crenshaw, E. B., III; Taylor, P.: Assignment
of the gene for acetylcholinesterase to distal mouse chromosome 5. Genomics 14:
511-514, 1992.

7. Rotundo, R. L.; Gomez, A. M.; Fernandez-Valle, C.; Randall, W.
R.: Allelic variants of acetylcholinesterase: genetic evidence that
all acetylcholinesterase forms in avian nerves and muscles are encoded
by a single gene. Proc. Nat. Acad. Sci. 85: 7805-7809, 1988.

8. Telen, M. J.; Whitsett, C. F.: Erythrocyte acetylcholinesterase
bears the Cartwright blood group antigens. (Abstract) Clin. Res. 40:
170A only, 1992.

*FIELD* CD
Victor A. McKusick: 12/15/1988

*FIELD* ED
mark: 11/27/1996
carol: 4/6/1994
carol: 5/21/1993
carol: 4/14/1993
carol: 11/2/1992
carol: 10/15/1992
carol: 8/13/1992

*RECORD*
*FIELD* NO
100790
*FIELD* TI
*100790 ACHAETE-SCUTE COMPLEX (DROSOPHILA) HOMOLOG-LIKE 1; ASCL1
ACHAETE-SCUTE HOMOLOG; ASH1
*FIELD* TX
Basic helix-loop-helix transcription factors of the achaete-scute family
are instrumental in Drosophila neurosensory development and are
candidate regulators of development in the mammalian central nervous
system and neural crest. Ball et al. (1993) isolated and characterized a
human achaete-scute homolog that is highly expressed in 2 neuroendocrine
cancers, medullary thyroid cancer (155240) and small cell lung cancer
(182280). The human gene, symbolized ASH1 by them, was cloned from a
human MTC cDNA library. It encoded a predicted protein of 238 amino
acids that was 95% homologous to mammalian achaete-scute homolog MASH-1,
a rodent basic helix-loop-helix factor. The proximal coding region of
the cDNA contains a striking 14-copy repeat of the triplet CAG that
exhibits polymorphism in human genomic DNA; thus, ASH1 is a candidate
locus. By analysis of rodent/human somatic cell hybrids, Ball et al.
(1993) assigned the gene to human chromosome 12. Northern blots revealed
ASH1 transcripts in RNA from a human MTC cell line, 2 fresh MTC tumors,
fetal brain, and 3 lines of human SCLC. In contrast, cultured lines of
non-SCLC lung cancers and a panel of normal adult human tissues showed
no detectable ASH1 transcripts. The gene was later symbolized ASCL1.

Achaete-scute homolog-1 was genetically mapped to 12q24.1 by using a CAG
repeat polymorphism within the gene and a CEPH pedigree DNA panel.
Twells et al. (1995) subsequently ruled out ASCL1 and NOS1 as candidates
for spinocerebellar atrophy type 2.

By homologous recombination in embryonic stem cells, Guillemot et al.
(1993) created a null allele of the mouse Ash-1 gene. Homozygous mice
died at birth with apparent breathing and feeding defects. The brain and
spinal cord appeared normal, but the olfactory epithelium and
sympathetic, parasympathetic, and enteric ganglia were severely
affected. These observations suggested that the Ash-1 gene, like its
Drosophila homologs, controls a basic operation in development of
neuronal progenitors in distinct neural lineages.

Ahmad (1995) found that Mash1 is expressed during development of rat
retina and interacts specifically with an E-box identified in the
promoter for the opsin gene during rod photoreceptor differentiation.

Renault et al. (1995) mapped ASCL1 onto a YAC contig distal to PAH
(261600) and proximal to TRA1 (191175). The authors used fluorescence in
situ hybridization to determine the cytogenetic assignment of 12q22-q23.

*FIELD* RF
1. Ahmad, I.: Mash-1 is expressed during ROD photoreceptor differentiation
and binds an E-box, E(opsin-1) in the rat opsin gene. Develop. Brain
Res. 90: 184-189, 1995.

2. Ball, D. W.; Azzoli, C. G.; Baylin, S. B.; Chi, D.; Dou, S.; Donis-Keller,
H.; Cumaraswamy, A.; Borges, M.; Nelkin, B. D.: Identification of
a human achaete-scute homolog highly expressed in neuroendocrine tumors.
Proc. Nat. Acad. Sci. 90: 5648-5652, 1993.

3. Guillemot, F.; Lo, L.-C.; Johnson, J. E.; Auerbach, A.; Anderson,
D. J.; Joyner, A. L.: Mammalian achaete-scute homolog 1 is required
for the early development of olfactory and autonomic neurons. Cell 75:
463-476, 1993.

4. Renault, B.; Lieman, J.; Ward, D.; Krauter, K.; Kucherlapati, R.
: Localization of the human achaete-scute homolog gene (ASCL1) distal
to phenylalanine hydroxylase (PAH) and proximal to tumor rejection
antigen (TRA1) on chromosome 12q22-q23. Genomics 30: 81-83, 1995.

5. Twells, R.; Weiming, X.; Ball, D.; Allotey, R.; Williamson, R.;
Chamberlain, S.: Exclusion of the neuronal nitric oxide synthase
gene and the human achaete-scute homologue 1 gene as candidate loci
for spinal cerebellar ataxia.     (Letter) Am. J. Hum. Genet. 56:
336-337, 1995.

*FIELD* CN
Orest Hurko - updated: 4/3/1996
Alan F. Scott - updated: 11/13/1995

*FIELD* CD
Victor A. McKusick: 7/6/1993

*FIELD* ED
terry: 04/15/1996
mark: 4/3/1996
terry: 3/22/1996
mark: 1/21/1996
pfoster: 6/2/1995
carol: 2/9/1994
carol: 12/9/1993
carol: 7/6/1993

*RECORD*
*FIELD* NO
100800
*FIELD* TI
#100800 ACHONDROPLASIA; ACH
*FIELD* MN
Achondroplasia is the most frequent form of short-limb dwarfism.
Affected individuals have rhizomelic shortening of the limbs, a
characteristic facies with frontal bossing and mid-face hypoplasia,
exaggerated lumbar lordosis, limitation of elbow extension, genu varum,
and trident hand.

The phenotype is distinctive and easily identified clinically and
radiologically at birth. In children, caudad narrowing of the
interpediculate distance, rather than the normal caudad widening, and a
notchlike sacroiliac groove are typical radiologic features, and
epiphyseal ossification centers show a circumflex or chevron seat on the
metaphysis ( Langer et al., 1967). True megalencephaly occurs (Dennis et
al., 1961). Disproportion between the base of the skull and the brain
results in internal hydrocephalus in some cases. Obesity in
achondroplasia is a major problem, which aggravates the morbidity
associated with lumbar stenosis and contributes to the nonspecific joint
problems and to the possible early cardiovascular mortality in this
condition (Hecht et al., 1988).

The large head of the achondroplastic fetus creates an increased risk of
intracranial bleeding during delivery (Hall et al., 1982). The authors
recommended that ultrasonography be done at birth and at 2, 4, and 6
months of age to establish ventricular size, the presence or absence of
hydrocephalus, and possible intracranial bleed. That some achondroplasts
have only brainstem compression is common and may contribute to antral
apnea (Nelson et al., 1988). Pyeritz et al. (1987) reported the results
of laminectomy for spinal stenosis and made recommendations on the
optimal extent of surgery.

Homozygosity for the achondroplasia gene results in a severe disorder of
the skeleton (Hall et al., 1969). Hypochondroplasia (146000) may be
caused by an allele at the achondroplasia locus (Sommer et al., 1987).
The delineation from severe hypochondroplasia may be arbitrary.

Achondroplasia is inherited as an autosomal dominant with essentially
complete penetrance. About seven-eighths of cases are the result of new
mutation, there being a considerable reduction of effective reproductive
fitness. There is a paternal age effect (Penrose, 1955). Gonadal
mosaicism (or spermatogonial mutation) is a possible explanation for the
occasional report of affected sibs from normal parents (Philip et al.,
1988).

The gene for achondroplasia, assigned to 4p16.3 Velinov et al., 1994,
turns out to be the FGFR3 gene for fibroblast growth factor receptor-3
(134934). Almost all achondroplasts have a substitution at nucleotide
1138, in the transmembrane domain of the FGFR3 gene, the most mutable
nucleotide discovered to date Bellus et al., 1995. The
glycine-to-arginine substitution would have a major effect on the
structure and/or function of the hydrophobic transmembrane domain and
most likely would have a significant effect on the function of the
receptor. In embryonic mouse tissues, the highest level of FGFR3 mRNA
outside of the developing central nervous system was found in the
prebone cartilage rudiments of all bones. During endochondrial
ossification, FGFR3 was detected in resting but not hypertrophic
cartilage Peters et al., 1993. FGFR3 codes for at least 2 isoforms of
the gene product by alternate use of 2 different exons that encode the
last half of the third immunoglobulin domain (IgIII), which is primarily
responsible for the ligand-binding specificity. The isoforms are
preferentially activated by the various fibroblast growth factors.

Prenatal diagnosis by mid-trimester ultrasonography is feasible
(Elejalde et al., 1983). The demonstration of a very limited number of
mutations causing achondroplasia and the ease with which they can be
detected (1 PCR and 1 restriction digest) provides a simple method for
prenatal diagnosis of ACH homozygotes Shiang et al., 1994.

The prevalence of achondroplasia is uncertain; most previous estimates
are undoubtedly incorrect because of misdiagnosis. More recent estimates
of frequency range from 0.13 per 10,000 births in Denmark (Andersen and
Hauge, 1989) to 0.5-1.5 per 10,000 births in Latin America (Orioli et
al., 1986).

*FIELD* ED
jenny: 02/04/1997 jamie: 12/20/1996

*FIELD* TX

DESCRIPTION

A number sign is used with this entry because of evidence that
achondroplasia is caused by mutation in the fibroblast growth factor
receptor-3 gene (FGFR3; 134934), which is located at 4p16.3.

Achondroplasia is the most frequent form of short-limb dwarfism.
Affected individuals exhibit short stature caused by rhizomelic
shortening of the limbs, characteristic facies with frontal bossing and
mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow
extension, genu varum, and trident hand.

Achondroplasia is an autosomal dominant disorder; a majority of cases
are sporadic, the result of a de novo mutation.

CLINICAL FEATURES

Whereas many conditions that cause short stature have inappropriately
been called achondroplasia in the past, the phenotype of this
osteochondrodysplasia is so distinctive and so easily identified
clinically and radiologically at birth that confusion should not occur.
It is characterized by a long, narrow trunk, short extremities,
particularly in the proximal (rhizomelic) segments, a large head with
frontal bossing, hypoplasia of the midface and a trident configuration
of the hands. Hyperextensibility of most joints, especially the knees,
is common, but extension and rotation are limited at the elbow. A
thoracolumbar gibbus is typically present at birth, but usually gives
way to exaggerated lumbar lordosis when the child begins to ambulate.
Mild to moderate hypotonia is common, and motor milestones are usually
delayed. Intelligence is normal unless hydrocephalus or other central
nervous system complications arise. In 13 achondroplastic infants, Hecht
et al. (1991) found that cognitive development was average and did not
correlate with motor development which typically was delayed. It was
noteworthy that reduced mental capacity correlated with evidence of
respiratory dysfunction detected by polysomnography.

In children, caudad narrowing of the interpediculate distance, rather
than the normal caudad widening, and a notchlike sacroiliac groove are
typical radiologic features. Also in children, epiphyseal ossification
centers show a circumflex or chevron seat on the metaphysis. Limb
shortening is especially striking in the proximal segments, e.g., the
humerus; hence the description rhizomelic ('root limb'). The radiologic
features of true achondroplasia and much concerning the natural history
of the condition were presented by Langer et al. (1967) on the basis of
a study of 101 cases and by Hall (1988).

True megalencephaly occurs in achondroplasia and has been speculated to
indicate effects of the gene other than those on the skeleton alone
(Dennis et al., 1961). Disproportion between the base of the skull and
the brain results in internal hydrocephalus in some cases. The
hydrocephalus may be caused by increased intracranial venous pressure
due to stenosis of the sigmoid sinus at the level of the narrowed
jugular foramina (Pierre-Kahn et al., 1980). Hall et al. (1982) pointed
out that the large head of the achondroplastic fetus creates an
increased risk of intracranial bleeding during delivery. They
recommended that in the management of achondroplastic infants
ultrasonography be done at birth and at 2, 4 and 6 months of age to
establish ventricular size, the presence or absence of hydrocephalus,
and possible intracranial bleed. They stated the impression that some
achondroplasts have only megalencephaly, others have true communicating
hydrocephalus, and yet others have dilated ventricles without
hydrocephalus. Nelson et al. (1988) concluded that brainstem compression
is common in achondroplasia and may account in part for the abnormal
respiratory function.

Pauli et al. (1984) focused attention on the risk of sudden unexpected
death in infants with achondroplasia. While uncontrolled and
retrospective, their study demonstrated an excess of deaths in the first
year of life, most or all of which were attributable to abnormalities at
the craniocervical junction. Hecht et al. (1987) showed that the excess
risk of death in infants with achondroplasia may approach 7.5%, largely
because of cervical cord compression. Pauli et al. (1995) performed a
prospective assessment of risk for cervical medullary-junction
compression in 53 infants, 5 of whom were judged to have sufficient
craniocervical junction compression to require surgical decompression.
Intraoperative observation showed marked abnormality of the cervical
spinal cord, and all operated-on children showed marked improvement of
neurologic function. The best predictors of need for suboccipital
decompression included lower-limb hyperreflexia or clonus on
examination, central hypopnea demonstrated by polysomnography, and
foramen magnum measures below the mean for children with achondroplasia.

Hecht et al. (1988) reviewed the subject of obesity in achondroplasia,
concluding that it is a major problem which, whatever its underlying
cause, aggravates the morbidity associated with lumbar stenosis and
contributes to the nonspecific joint problems and to the possible early
cardiovascular mortality in this condition. Using data about 409
Caucasian patients with achondroplasia from different countries (1,147
observations), Hunter et al. (1996) developed weight for height (W/H)
curves for these patients. They showed that to a height of about 75 cm,
the mean W/H curves are virtually identical for normal and
achondroplastic children. After this height, the W/H curves for
achondroplastic patients rise above those for the general population.
Hunter et al. (1996) contended that the best estimation of weight excess
for achondroplastic patients aged 3 to 6 years is given by the Quetelet
index, whereas that for patients aged 6 to 18 years is the Rohrer index.

Homozygosity for the achondroplasia gene results in a severe disorder of
the skeleton with radiologic changes qualitatively somewhat different
from those of the usual heterozygous achondroplasia; early death results
from respiratory embarrassment from the small thoracic cage and
neurologic deficit from hydrocephalus (Hall et al., 1969). Yang et al.
(1977) reported upper cervical myelopathy in a homozygote.

Horton et al. (1988) found that the epiphyseal and growth plate
cartilages have a normal appearance histologically, and the major matrix
constituents exhibit a normal distribution by immunostaining; however,
morphometric investigations have indicated that the growth plate is
shorter than normal and that the shortening is greater in homozygous
than in heterozygous achondroplasia, suggesting a gene dosage effect.
Stanescu et al. (1990) reported histochemical, immunohistochemical,
electron microscopic, and biochemical studies on upper tibial cartilage
from a case of homozygous achondroplasia. No specific abnormality was
defined. Aterman et al. (1983) expressed puzzlement at the striking
histologic changes in homozygous achondroplasia despite the virtual
absence of changes in the heterozygote. They pointed out that histologic
studies in the heterozygote at a few weeks or months of age have not
been done. They suggested that because of similarities between what they
called PHA (presumed homozygous achondroplasia) and thanatophoric
dwarfism (187600), some cases of the latter condition may be due to a
particularly severe mutation at the achondroplasia locus.

Hypochondroplasia (146000) may be caused by an allele at the
achondroplasia locus. The evidence comes from observations of a presumed
genetic compound in the offspring of an achondroplastic father and a
hypochondroplastic mother who exhibited growth deficiency and
radiographic abnormalities of the skeleton that were much more severe
than those typically seen in achondroplasia (McKusick et al., 1973;
Sommer et al., 1987) and somewhat less severe than those of the ACH
homozygote. Young et al. (1992) described lethal short-limb dwarfism in
the offspring of a father with spondyloepiphyseal dysplasia congenita
(SEDC; 183900) and a mother with achondroplasia. Young et al. (1992)
suggested that the infant was a double heterozygote for the 2 dominant
genes rather than a compound heterozygote. It was considered unlikely
that SEDC and achondroplasia are allelic because of the evidence that
most, if not all, cases of SEDC result from mutation in the type II
collagen gene (COL2A1; 120140), whereas this gene has been excluded as
the site of the mutation in achondroplasia.

In a presentation of adult genetic skeletal dysplasias found in the
Museum of Pathological Anatomy in Vienna, Beighton et al. (1993)
pictured the skeleton of a 61-year-old man with achondroplasia who died
of transverse myelitis. Randolph et al. (1988) reported an
achondroplastic patient who developed classic ankylosing spondylitis
(106300). There is no fundamental connection between the 2 disorders.
The importance of the observation is mainly to indicate that back
problems in achondroplasts can be due to causes other than the
underlying disease.

INHERITANCE

Achondroplasia is inherited as an autosomal dominant with essentially
complete penetrance. About seven-eighths of cases are the result of new
mutation, there being a considerable reduction of effective reproductive
fitness.

Paternal age effect on mutation was noted by Penrose (1955). Stoll et
al. (1982) reported advanced paternal age in sporadic cases ascertained
through the French counterpart of LPA (Little People of America), APPT
(Association des Personnes de Petite Taille). Thompson et al. (1986)
found that, on average, the severity of achondroplasia tends to be
reduced with increasing parental age. It is doubtful that a recessive
form of achondroplasia, indistinguishable from the dominant form,
exists. Documentation of the diagnosis is inadequate in most reports of
possible recessive inheritance.

Cohn and Weinberg (1956) reported affected twins with an affected sib.
(This may have been achondrogenesis, e.g., 200600.) Chiari (1913)
reported affected half-sibs whose father had achondroplasia. Two first
cousins, whose mothers were average-statured sisters, had undoubted
achondroplasia (Wadia, 1969). Most dominants show sufficient variability
to account for observations such as these on the basis of reduced
penetrance but such is not the case with achondroplasia.

Gonadal mosaicism (or spermatogonial mutation) is a possible explanation
for affected sibs from normal parents. Bowen (1974) described a possible
instance of gonadal mosaicism; 2 daughters of normal parents had
achondroplasia. One of the daughters had 2 children, one of whom was
also achondroplastic. Fryns et al. (1983) reported 3 achondroplastic
sisters born to normal parents. Philip et al. (1988) described the case
of a man who had 3 daughters with classic achondroplasia, by 2 different
women.

Affected cousins could be due to the coincidence of two independent
mutations. Such was probably the case, in McKusick's opinion, in the
second cousins once removed reported by Fitzsimmons (1985). Reiser et
al. (1984) reviewed 6 families with unexpected familial recurrence and
hypothesized that these recurrences were simply the result of two
independent chance events. Dodinval and Le Marec (1987) reported 2
families, each with 2 cases of achondroplasia. In 1 family, a girl and
her great aunt were affected; in the other, male and female first
cousins. Both germinal mosaicism and paternal age effect appear to have
their basis in the way spermatogonia are replenished, a feature that
distinguishes gametogenesis in the male from that in the female. As
outlined by Clermont (1966), spermatogonia go through a few mitotic
divisions before embarking on the meiotic divisions that lead to mature
sperm. Some of the products of the mitotic divisions are returned to the
'cell bank' to replenish the supply of spermatogonia. Mutations
occurring during DNA replication can, therefore, accumulate, providing a
basis for paternal age effect and for germinal mosaicism. Hoo (1984)
suggested a small insertional translocation as a possible mechanism for
recurrent achondroplasia in sibs with normal parents.

The severe phenotype of the homozygote for the ACH gene and the
possibility that hypochondroplasia represents an allelic disorder were
discussed in connection with the discussion of clinical features of
achondroplasia.

Langer et al. (1993) described a patient who was doubly heterozygous for
achondroplasia and pseudoachondroplasia (177170). Woods et al. (1994)
described a family in which the father had pseudoachondroplasia and the
mother had achondroplasia, and 2 daughters were doubly affected and a
son had achondroplasia only. At birth, the 2 daughters appeared to have
achondroplasia. Later, the development of a fixed lumbar gibbus, unusual
radiographic changes in the spine, increasing joint laxity of the hands,
and characteristic gait and hand posture made the appearance of
pseudoachondroplasia apparent.

MAPPING

Strom (1984) and Eng et al. (1985) purported to find abnormality of the
type II collagen gene in achondroplasia. If such a defect is present,
one might expect ocular abnormality in achondroplasia inasmuch as type
II collagen is present in vitreous. SED congenita was a more plausible
candidate for a structural defect of type II collagen because it is a
dominant disorder that combines skeletal dysplasia with vitreous
degeneration and deafness (experimental studies with antibodies to type
II collagen indicate that this collagen type is represented in the
middle ear); subsequently, defects were in fact found in the COL2A1 gene
in SEDC. The report by Eng et al. (1985) was withdrawn in 1986 because
figures, 'which were generated in the laboratory of C. Strom and C. Eng,
were improperly assembled and therefore cannot be used to support the
conclusions of the article.' Francomano and Pyeritz (1988) excluded
COL2A1 as the site of the mutation in achondroplasia by use of probes
spanning the gene in an analysis of genomic DNA from 49 affected persons
and 2 multiplex families. No gross rearrangements were seen on Southern
blot analysis, and linkage studies in the multiplex families
demonstrated discordant inheritance of achondroplasia and COL2A1
alleles. Evidence against linkage to COL2A1 has been presented before by
Ogilvie et al. (1986). From their studies, Finkelstein et al. (1991)
concluded that mutations at the chondroitin sulfate proteoglycan core
protein (CSPGP) locus do not cause achondroplasia or
pseudoachondroplasia (177170).

Edwards et al. (1988) commented on a report, made at the national
meeting of the Neurofibromatosis Foundation, of 2 individuals with
achondroplasia and neurofibromatosis (162200) who had translocations
involving the long arm of chromosome 17. In both cases the breakpoint
was at the region consistent with localization of the neurofibromatosis
gene by linkage studies; a third case of coincident achondroplasia and
neurofibromatosis was also mentioned. Korenberg et al. (1989) and Pulst
et al. (1990) demonstrated by linkage analysis that the achondroplasia
locus does not map between the 2 groups of markers flanking the gene for
neurofibromatosis-1 on human chromosome 17. Verloes et al. (1991)
observed connatal neuroblastoma in an infant with achondroplasia and
suggested that the achondroplasia gene may be located on the short arm
of chromosome 1 where the neuroblastoma gene (256700) appears to be
situated.

By linkage studies using DNA markers, Velinov et al. (1994) and Le
Merrer et al. (1994) mapped the gene for achondroplasia and
hypochondroplasia to the distal area of the short arm of chromosome 4
(4p16.3). Francomano et al. (1994) likewise mapped the ACH gene to
4p16.3, using 18 multigenerational families with achondroplasia and 8
anonymous dinucleotide repeat polymorphic markers from this region. No
evidence of genetic heterogeneity was found. Analysis of a recombinant
family localized the ACH locus to the 2.5-Mb region between D4S43 and
the telomere.

MOLECULAR GENETICS

Once the gene for achondroplasia was assigned to 4p16.3 by linkage
analysis (Le Merrer et al., 1994; Velinov et al., 1994; Francomano et
al., 1994), causative mutations were identified by the candidate gene
approach and reported within 6 months of the first mapping report.
Mutations in the gene for fibroblast growth factor receptor-3 (134934)
were identified by Shiang et al. (1994) and independently by Rousseau et
al. (1994). The FGFR3 gene had previously been mapped to the same
region, 4p16.3, as the ACH gene and the Huntington disease gene. The
mutation in 15 of the 16 achondroplasia-affected chromosomes studied by
Shiang et al. (1994) was the same, a G-to-A transition at nucleotide
1138 (134934.0001) of the cDNA. The mutation on the only other
ACH-affected chromosome 4 without the G-to-A transition at nucleotide
1138 had a G-to-C transversion at this same position (134934.0002). Both
mutations resulted in the substitution of an arginine residue for a
glycine at position 380 of the mature protein, which is in the
transmembrane domain of FGFR3. The mutation was located in a CpG
dinucleotide. Rousseau et al. (1994) found the G380R mutation in all
cases studied: 17 sporadic cases and 6 unrelated familial cases. Because
of the high mutation rate, it might have been predicted that the
achondroplasia gene is large and that any one of many mutations could
lead to the same or a similar (hypochondroplasia) phenotype. Such is
apparently not the case. The fact that there are no reports of
Wolf-Hirschhorn syndrome (194190) patients with stigmata of
achondroplasia may indicate that the phenotype is due to some mechanism
other than haploinsufficiency, i.e., represents a dominant negative
effect. (The independent work of Shiang et al. (1994) and Rousseau et
al. (1994) was reported in the 29 July issue of Cell and the 15
September issue of Nature, respectively.)

Bellus et al. (1995) found that 150 of 154 unrelated achondroplasts had
the G-to-A transition (134934.0001) and 3 had the G-to-C transversion
(134934.0002) at nucleotide 1138 of the FGFR3 gene. All 153 had the
gly380-to-arg substitution; in one individual, an atypical case, the
gly380-to-arg substitution was missing. Nucleotide 1138 of the FGFR3
gene is the most mutable nucleotide discovered to date. Superti-Furga et
al. (1995) reported the case of a newborn with achondroplasia who did
not carry the mutation at nucleotide 1138 changing glycine-380 to
arginine but had a mutation causing substitution of a nearby glycine
with a cysteine (134934.0003).

The FGFR3 gene was isolated and studied in connection with a search for
the Huntington disease gene. The distribution of FGFR3 mRNA in embryonic
mouse tissues was found to be more restricted than that of FGFR1
(136350) and FGFR2 (176943) mRNA. Outside of the developing central
nervous system, the highest level of FGFR3 mRNA was found to be in the
prebone cartilage rudiments of all bones, and during endochondral
ossification, FGFR3 was detected in resting but not hypertrophic
cartilage (Peters et al., 1993). The glycine-to-arginine substitution
would have a major effect on the structure, function, or both of the
hydrophobic transmembrane domain and most likely would have a
significant effect on the function of the receptor. Five of 6 ACH
homozygotes were homozygous for the G-to-A transition and each of 6
sporadic cases, including the parents of 2 of the homozygotes, were
heterozygous for the 1138A allele and the wildtype allele. The fact that
FGFR3 transcripts are present in fetal and adult brain (which has the
highest levels of any tissue) may have relevance in connection with the
megalencephaly which is thought to occur in achondroplasia (Dennis et
al., 1961).

FGFR3 codes for at least 2 isoforms of the gene product by alternate use
of 2 different exons that encode the last half of the third
immunoglobulin domain (IgIII), which is primarily responsible for the
ligand-binding specificity. The isoforms are preferentially activated by
the various fibroblast growth factors.

DIAGNOSIS

The diagnosis is based on the typical clinical and radiologic features;
the delineation from severe hypochondroplasia may be arbitrary.

The demonstration of a very limited number of mutations causing
achondroplasia and the ease with which they can be detected (1 PCR and 1
restriction digest) provides a simple method for prenatal diagnosis of
ACH homozygotes in families at risk and in which the parents are
heterozygous for either the 1138A or 1138C allele (Shiang et al., 1994).
Shiang et al. (1994) expressed the opinion that other than the screening
of at-risk pregnancies for homozygous ACH fetuses, any 'other
application of the diagnostic test for ACH mutations should be
prohibited.' Bellus et al. (1994) practiced prenatal diagnosis by
chorionic villus sampling at 10 weeks and 4 days of gestation, both
parents having achondroplasia. Both parents and the fetus were shown to
be heterozygous for the more common G-to-A transition. Homozygous
achondroplasia was excluded.

CLINICAL MANAGEMENT

Recommendations for follow-up and management were reviewed at the first
international symposium on achondroplasia (Nicoletti et al., 1988) and
by Horton and Hecht (1993). The recommendations included: measurements
of growth and head circumference using growth curves standardized for
achondroplasia (Horton et al., 1978); careful neurologic examinations
(including CT, MRI, somatosensory evoked potentials and polysomnography)
and surgical enlargement of the foramen magnum in cases of severe
stenosis; management of frequent middle ear infections and dental
crowding; measures to control obesity starting in early childhood;
growth hormone therapy (Horton et al., 1992), which is still
experimental, and lengthening of the limb bones; tibial osteotomy or
epiphysiodesis of the fibular growth plate to correct bowing of the
legs; lumbar laminectomy for spinal stenosis which typically manifests
in early adulthood; delivery of pregnant women with achondroplasia by
cesarean section; and prenatal detection of affected fetuses by
ultrasound.

Shohat et al. (1996) investigated the effect of recombinant human growth
hormone (hGH) treatment on the growth rate and proportion of individuals
with achondroplasia and hypochondroplasia. They studied 15 individuals
over 24 months including 6 months of observation, 12 months of hGH
therapy (0.04 mg/kg.day), and 6 months of posttreatment growth rate
determination. The mean growth rate during hGH treatment (5.3 +/- 1.6
cm) of achondroplasts was significantly increased compared to
pretreatment (4.0 +/- 1.0 cm/year, P less than 0.01) and posttreatment
periods (3.1 +/- 1.3 cm; P less than 0.001). In the 4 children with
hypochondroplasia, the growth rate during hGH treatment was 7.0 +/- 2.4
cm/year and 4.9 +/- 1.5 cm/year during the pre- and posttreatment
periods, respectively. In achondroplasts, there was a significant
increase in growth rate of only the lower segment (from 1.1 +/- 1.6
cm/year to 3.1 +/- 1.2 cm/year, P less than 0.02). Unexpectedly, this
treatment does not seem to have a lesser effect on limbs than on trunk
growth rate and, therefore, during 1 year of treatment, does not
increase body disproportion.

Hunter et al. (1996) recommended that achondroplastic children stay
within 1 SD of the mean weight for height curves for achondroplasts.

Waters et al. (1995) studied the results of treatment of obstructive
sleep apnea in achondroplasia. Treatment included adenotonsillectomy,
weight loss, and nasal-mask continuous positive airway pressure (CPAP).
They observed improvements in measurements of disturbed sleep
architecture and some evidence of improvement in neurologic function.

Weber et al. (1996) studied the effects of recombinant human growth
hormone treatment in 6 prepubertal children with achondroplasia, ranging
in age from 2 to 8 years. They were given a GH dose of 0.1 IU/kg/day
subcutaneously. During the year of treatment the growth velocity
increased from 1.1 to 2.6 cm/year in 3 patients while in the others no
variation was detected. No side effects were observed during the trial
apart from the slight advancement of bone age in 2 patients. Their
findings confirmed the individual variability in the response to GH
treatment.

POPULATION GENETICS

The prevalence of achondroplasia is uncertain; previous estimates are
undoubtedly incorrect because of misdiagnosis. For example, Wallace et
al. (1970) reported 2 female sibs as examples of achondroplasia; both
died in the neonatal period and showed, in addition to chondrodystrophy,
central harelip, hypoplastic lungs, and hydrocephalus. Without
radiographic studies it is impossible to identify the nature of this
condition, but it is certainly not true achondroplasia; Jeune
asphyxiating thoracic dystrophy (208500), thanatophoric dwarfism, and
achondrogenesis are each possibilities.

Using modern diagnostic criteria, Gardner (1977) estimated the mutation
rate at 0.000014. Orioli et al. (1986) reported on the frequency of
skeletal dysplasias among 349,470 births (live and stillbirths). The
prevalence rate for achondroplasia was between 0.5 and 1.5/10,000
births. The mutation rate was estimated to be between 1.72 and 5.57 x
10(-5) per gamete per generation. The stated range is a consequence of
the uncertainty of diagnosis in some cases. (The thanatophoric
dysplasia/achondrogenesis group had a prevalence between 0.2 and
0.5/10,000 births. Osteogenesis imperfecta had a prevalence of
0.4/10,000 births. Only 1 case of diastrophic dysplasia was identified.)
In the county of Fyn in Denmark, Andersen and Hauge (1989) determined
the prevalence of generalized bone dysplasias by study of all children
born in a 14-year period. The figures, which they referred to as
'point-prevalence at birth,' showed that achondroplasia was less common
than generally thought (1.3 per 100,000), while osteogenesis imperfecta
(21.8), multiple epiphyseal dysplasia tarda (9.0), achondrogenesis
(6.4), osteopetrosis (5.1), and thanatophoric dysplasia (3.8) were found
to be more frequent. Stoll et al. (1989) found a mutation rate of 3.3 x
10(-5) per gamete per generation. In Spain, Martinez-Frias et al. (1991)
found a frequency of achondroplasia of 2.53 per 100,000 live births.
Total prevalence of autosomal dominant malformation syndromes was 12.1
per 100,000 live births.

HISTORY

It is of historic interest that Weinberg (1912), of Hardy-Weinberg law
fame, noted in the data collected by Rischbieth and Barrington that
sporadic cases were more often last-born than first-born. The studies by
Morch (1941) in Denmark and by Hobaek (1961) were early examples of full
population studies.

*FIELD* SA
Beighton and Bathfield (1981); Cohen et al. (1967); Durr  (1968);
Elejalde et al. (1983); Fremion et al. (1984); Hall et al. (1979);
Maroteaux and Lamy (1964); Morgan and Young (1980); Murdoch et al.
(1970); Oberklaid et al. (1979); Opitz  (1984); Pauli et al. (1983);
Penrose  (1957); Pyeritz et al. (1987); Rimoin et al. (1970); Siebens
et al. (1978)
*FIELD* RF
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a clinical, radiological, and epidemiological survey. J. Med. Genet. 26:
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2. Aterman, K.; Welch, J. P.; Taylor, P. G.: Presumed homozygous
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3. Beighton, P.; Bathfield, C. A.: Gibbal achondroplasia. J. Bone
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4. Beighton, P.; Sujansky, E.; Patzak, B.; Portele, K. A.: Genetic
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5. Bellus, G. A.; Escallon, C. S.; de Luna, R. O.; Shumway, J. B.;
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6. Bellus, G. A.; Hefferon, T. W.; Ortiz de Luna, R. I.; Hecht, J.
T.; Horton, W. A.; Machado, M.; Kaitila, I.; McIntosh, I.; Francomano,
C. A.: Achondroplasia is defined by recurrent G380R mutations of
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12. Dennis, J. P.; Rosenberg, H. S.; Alvord, E. C., Jr.: Megalencephaly,
internal hydrocephalus and other neurological aspects of achondroplasia. Brain 84:
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13. Dodinval, P.; Le Marec, B.: Genetic counselling in unexpected
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1987.

14. Durr, D. K.: Eine neue Dysostoseform mit Mikromelie bei zwei
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15. Edwards, J. H.; Huson, S.; Ponder, B.: Neurofibromatosis. (Letter) Lancet II:
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16. Elejalde, B. R.; Elejalde, M. M.; Hamilton, P. R.; Lombardi, J.
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17. Eng, C. E. L.; Pauli, R. M.; Strom, C. M.: Nonrandom association
of a type II procollagen genotype with achondroplasia. Proc. Nat.
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18. Finkelstein, J. E.; Doege, K.; Yamada, Y.; Pyeritz, R. E.; Graham,
J. M., Jr.; Moeschler, J. B.; Pauli, R. M.; Hecht, J. T.; Francomano,
C. A.: Analysis of the chondroitin sulfate proteoglycan core protein
(CSPGP) gene in achondroplasia and pseudoachondroplasia. Am. J. Hum.
Genet. 48: 97-102, 1991.

19. Fitzsimmons, J. S.: Familial recurrence of achondroplasia. Am.
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20. Francomano, C. A.; Ortiz de Luna, R. I.; Hefferon, T. W.; Bellus,
G. A.; Turner, C. E.; Taylor, E.; Meyers, D. A.; Blanton, S. H.; Murray,
J. C.; McIntosh, I.; Hecht, J. T.: Localization of the achondroplasia
gene to the distal 2.5 Mb of human chromosome 4p. Hum. Molec. Genet. 3:
787-792, 1994.

21. Francomano, C. A.; Pyeritz, R. E.: Achondroplasia is not caused
by mutation in the gene for type II collagen. Am. J. Med. Genet. 29:
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22. Fremion, A. S.; Garg, B. P.; Kalsbeck, J.: Apnea as the sole
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23. Fryns, J. P.; Kleczkowska, A.; Verresen, H.; van den Berghe, H.
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24. Gardner, R. J. M.: A new estimate of the achondroplasia mutation
rate. Clin. Genet. 11: 31-38, 1977.

25. Hall, J. G.: The natural history of achondroplasia.In: Nicoletti,
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A Multidisciplinary Approach.  New York: Plenum Press (pub.)  1988.
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26. Hall, J. G.; Dorst, J. P.; Taybi, H.; Scott, C. I., Jr.; Langer,
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1969.

27. Hall, J. G.; Golbus, M. S.; Graham, C. B.; Pagon, R. A.; Luthy,
D. A.; Filly, R. A.: Failure of early prenatal diagnosis in classic
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28. Hall, J. G.; Horton, W.; Kelly, T.; Scott, C. I.: Head growth
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29. Hecht, J. T.; Francomano, C. A.; Horton, W. A.; Annegers, J. F.
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30. Hecht, J. T.; Hood, O. J.; Schwartz, R. J.; Hennessey, J. C.;
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J. Med. Genet. 31: 597-602, 1988.

31. Hecht, J. T.; Thompson, N. M.; Weir, T.; Patchell, L.; Horton,
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32. Hobaek, A.: Problems of Hereditary Chondrodysplasia.  Oslo:
Oslo Univ. Press (pub.)  1961.

33. Hoo, J. J.: Alternative explanations for recurrent achondroplasia
in siblings with normal parents. Clin. Genet. 25: 553-554, 1984.

34. Horton, W. A.; Hecht, J. T.: The chondrodysplasias.In: Royce,
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35. Horton, W. A.; Hecht, J. T.; Hood, O. J.; Marshall, R. N.; Moore,
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36. Horton, W. A.; Hood, O. J.; Machado, M. A.; Campbell, D.: Growth
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37. Horton, W. A.; Rotter, J. I.; Rimoin, D. L.; Scott, C. L.; Hall,
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435-438, 1978.

38. Hunter, A. G. W.; Hecht, J. T.; Scott, Jr., C. I.: Standard weight
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39. Korenberg, J. R.; Barker, D.; Fain, P.; Graham, J.; Pribyl, T.;
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40. Langer, L. O., Jr.; Baumann, P. A.; Gorlin, R. J.: Achondroplasia. Am.
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41. Langer, L. O., Jr.; Schaefer, G. B.; Wadsworth, D. T.: Patient
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42. Le Merrer, M.; Rousseau, F.; Legeai-Mallet, L.; Landais, J.-C.;
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43. Maroteaux, P.; Lamy, P.: Achondroplasia in man and animals. Clin.
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44. Martinez-Frias, M. L.; Cereijo, A.; Bermejo, E.; Lopez, M.; Sanchez,
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45. McKusick, V. A.; Kelly, T. E.; Dorst, J. P.: Observations suggesting
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46. Morch, E. T.: Chondrodystrophic dwarfs in Denmark. Op. Ex Domo
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47. Morgan, D. F.; Young, R. F.: Spinal neurological complications
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48. Murdoch, J. L.; Walker, B. A.; Hall, J. G.; Abbey, H.; Smith,
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49. Nelson, F. W.; Hecht, J. T.; Horton, W. A.; Butler, I. J.; Goldie,
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50. Nicoletti, B.; Kopits, S. E.; Ascani, E.; McKusick, V. A.: Human
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51. Oberklaid, F.; Danks, D. M.; Jensen, F.; Stace, L.; Rosshandler,
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52. Ogilvie, D.; Wordsworth, P.; Thompson, E.; Sykes, B.: Evidence
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53. Opitz, J. M.: 'Unstable premutation' in achondroplasia: penetrance
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54. Orioli, I. M.; Castilla, E. E.; Barbosa-Neto, J. G.: The birth
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55. Pauli, R. M.; Conroy, M. M.; Langer, L. O., Jr.; McLone, D. G.;
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56. Pauli, R. M.; Horton, V. K.; Glinski, L. P.; Reiser, C. A.: Prospective
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57. Pauli, R. M.; Scott, C. I.; Wassman, E. R., Jr.; Gilbert, E. F.;
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J. T.; Lebovitz, R.: Apnea and sudden unexpected death in infants
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58. Penrose, L. S.: Parental age in achondroplasia and mongolism. Am.
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59. Penrose, L. S.: Parental age and mutation. Lancet II: 312-313,
1955.

60. Peters, K.; Ornitz, D.; Werner, S.; Williams, L.: Unique expression
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61. Philip, N.; Auger, M.; Mattei, J. F.; Giraud, F.: Achondroplasia
in sibs of normal parents. J. Med. Genet. 25: 857-859, 1988.

62. Pierre-Kahn, A.; Hirsch, J. F.; Renier, D.; Metzger, J.; Maroteaux,
P.: Hydrocephalus and achondroplasia: a study of 25 observations. Child's
Brain 7: 205-219, 1980.

63. Pulst, S.-M.; Graham, J. M., Jr.; Fain, P.; Barker, D.; Pribyl,
T.; Korenberg, J. R.: The achondroplasia gene is not linked to the
locus for neurofibromatosis 1 on chromosome 17. Hum. Genet. 85:
12-14, 1990.

64. Pyeritz, R. E.; Sack, G. H., Jr.; Udvarhelyi, G. B.: Thoracolumbosacral
laminectomy in achondroplasia: long-term results in 22 patients. Am.
J. Med. Genet. 28: 433-444, 1987.

65. Randolph, L. M.; Shohat, M.; Miller, D.; Lachman, R.; Rimoin,
D. L.: Achondroplasia with ankylosing spondylitis. Am. J. Med. Genet. 31:
117-121, 1988.

66. Reiser, C. A.; Pauli, R. M.; Hall, J. G.: Achondroplasia: unexpected
familial recurrence. Am. J. Med. Genet. 19: 245-250, 1984.

67. Rimoin, D. L.; Hughes, G. N.; Kaufman, R. L.; Rosenthal, R. E.;
McAlister, W. H.; Silberberg, R.: Endochondral ossification in achondroplastic
dwarfism. New Eng. J. Med. 283: 728-735, 1970.

68. Rousseau, F.; Bonaventure, J.; Legeai-Mallet, L.; Pelet, A.; Rozet,
J.-M.; Maroteaux, P.; Le Merrer, M.; Munnich, A.: Mutations in the
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252-254, 1994.

69. Shiang, R.; Thompson, L. M.; Zhu, Y.-Z.; Church, D. M.; Fielder,
T. J.; Bocian, M.; Winokur, S. T.; Wasmuth, J. J.: Mutations in the
transmembrane domain of FGFR3 cause the most common genetic form of
dwarfism, achondroplasia. Cell 78: 335-342, 1994.

70. Shohat, M.; Tick, D.; Barakat, S.; Bu, X.; Melmed, S.; Rimoin,
D.L.: Short-term recombinant human growth hormone treatment increases
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1996.

71. Siebens, A. A.; Hungerford, D. S.; Kirby, N. A.: Curves of the
achondroplastic spine: a new hypothesis. Johns Hopkins Med. J. 142:
205-210, 1978.

72. Sommer, A.; Young-Wee, T.; Frye, T.: Achondroplasia-hypochondroplasia
complex. Am. J. Med. Genet. 26: 949-957, 1987.

73. Stanescu, R.; Stanescu, V.; Maroteaux, P.: Homozygous achondroplasia:
morphologic and biochemical study of cartilage. Am. J. Med. Genet. 37:
412-421, 1990.

74. Stoll, C.; Dott, B.; Roth, M.-P.; Alembik, Y.: Birth prevalence
rates of skeletal dysplasias. Clin. Genet. 35: 88-92, 1989.

75. Stoll, C.; Roth, M.-P.; Bigel, P.: A reexamination of parental
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Papadatos, C. J.; Bartsocas, C. S.: Skeletal Dysplasias.  New York:
Alan R. Liss (pub.)  1982. Pp. 419-426.

76. Strom, C. M.: Achondroplasia due to DNA insertion into the type
II collagen gene. (Abstract) Pediat. Res. 18: 226A, 1984.

77. Superti-Furga, A.; Eich, G.; Bucher, H. U.; Wisser, J.; Giedion,
A.; Gitzelmann, R.; Steinmann, B.: A glycine 375-to-cysteine substitution
in the transmembrane domain of the fibroblast growth factor receptor-3
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1995.

78. Thompson, J. N., Jr.; Schaefer, G. B.; Conley, M. C.; Mascie-Taylor,
C. G. N.: Achondroplasia and parental age. (Letter) New Eng. J.
Med. 314: 521-522, 1986.

79. Velinov, M.; Slaugenhaupt, S. A.; Stoilov, I.; Scott, C. I., Jr.;
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the telomeric region of chromosome 4p. Nature Genet. 6: 318-321,
1994.

80. Verloes, A.; Massart, B.; Jossa, V.; Langhendries, J. P.; Hainaut,
H.; Paquot, J. P.; Koulischer, L.: Neuroblastoma in a dwarfed newborn:
possible clue to the chromosomal localization of the gene for achondroplasia?. Ann.
Genet. 34: 25-26, 1991.

81. Wadia, R.: Achondroplasia in two first cousins. Birth Defects
Orig. Art. Ser. V(4): 227-230, 1969.

82. Wallace, D. C.; Exton, L. A.; Pritchard, D. A.; Leung, Y.; Cooke,
R. A.: Severe achondroplasia: demonstration of probable heterogeneity
within this clinical syndrome. J. Med. Genet. 7: 22-26, 1970.

83. Waters, K. A.; Everett, F.; Sillence, D. O.; Fagan, E. R.; Sullivan,
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84. Weber, G.; Prinster, C.; Meneghel, M.; Russo, F.; Mora, S.; Puzzovio,
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396-400, 1996.

85. Weinberg, W.: Zur Vererbung des Zwergwuchses. Arch. Rass. Ges.
Biol. 9: 710-717, 1912.

86. Woods, C. G.; Rogers, J. G.; Mayne, V.: Two sibs who are double
heterozygotes for achondroplasia and pseudoachondroplastic dysplasia. J.
Med. Genet. 31: 565-569, 1994.

87. Yang, S. S.; Corbett, D. P.; Brough, A. J.; Heidelberger, K. P.;
Bernstein, J.: Upper cervical myelopathy in achondroplasia. Am.
J. Clin. Path. 68: 68-72, 1977.

88. Young, I. D.; Ruggins, N. R.; Somers, J. M.; Zuccollo, J. M.;
Rutter, N.: Lethal skeletal dysplasia owing to a double heterozygosity
for achondroplasia and spondyloepiphyseal dysplasia congenita. J.
Med. Genet. 29: 831-833, 1992.

*FIELD* CS
Skel:
   Osteochondrodysplasia

Growth:
   Short-limb dwarfism identifiable at birth;
Mean male adult height: 131 cm;
Mean female height: 124 cm;
   Obesity, tendency to

Head:
   Frontal bossing;
   Megalencephaly

Facies:
   Midfacial hypoplasia;
   Low nasal bridge

Eyes:
   Strabismus

Ears:
   Recurrent otitis media in infancy and childhood;
   Conductive hearing loss

Resp:
   Respiratory insufficiency;
   Upper airway obstruction

Spine:
   Lumbar gibbus in infancy;
   Exaggerated lumbar lordosis during childhood and adulthood

Joints:
   Limited elbow and hip extension

Limbs:
   Trident hand;
   Brachydactyly;
   Limited extension at elbows;
   Genu varum;
   Bowleg;
   Rhizomelia

Neuro:
   Hydrocephalus, occasional;
   Mild hypotonia in infancy and early childhood;
   Lumbar spinal stenosis common;
   Occasional thoracic or cervical spinal stenosis;
   Radiculopathy;
   Brain stem compression

Misc:
   Paternal age mutation effect

Radiology:
   Cuboidal vertebral bodies;
   Progressive lumbar interpediculate narrowing after first year;
   Vertebral canal narrows in cranio-caudal direction;
   Notch-like sacroiliac groove;
   Metaphyseal flaring;
   Circumflex or chevron seated epiphyseal ossification centers on the
   metaphysis;
   Short narrow femoral neck;
   Vertebral scalloping;
   Wide intervertebral discs;
   Foraminal narrowing;
   Flat roofed acetabula;
   Small foramen magnum;
   Short cranial base;
   Early sphenooccipital closure

Inheritance:
   Autosomal dominant with complete penetrance;
   most (7/8) cases new mutations

*FIELD* CN
Victor A. McKusick - edited: 02/04/1997

*FIELD* ED
joanna: 02/04/1997

*FIELD* CN
John A. Phillips, III - updated: 4/1/1997
Victor A. McKusick - updated: 2/4/1997
Iosif W. Lurie - updated: 7/1/1996
Beat Steinmann - updated: 2/4/1994

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
jenny: 04/04/1997
jenny: 4/1/1997
joanna: 2/14/1997
joanna: 2/4/1997
terry: 12/17/1996
carol: 7/1/1996
mark: 4/11/1996
mark: 2/26/1996
terry: 2/20/1996
mark: 1/17/1996
terry: 1/16/1996
mark: 7/19/1995
terry: 2/27/1995
carol: 1/18/1995
mimadm: 6/8/1994
warfield: 3/31/1994

*RECORD*
*FIELD* NO
100820
*FIELD* TI
*100820 ACHOO SYNDROME
AUTOSOMAL DOMINANT COMPELLING HELIOOPHTHALMIC OUTBURST SYNDROME;;
PHOTIC SNEEZE REFLEX;;
SNEEZING FROM LIGHT EXPOSURE;;
PEROUTKA SNEEZE
*FIELD* TX
Collie et al. (1978) described a 'disorder' characterized by nearly
uncontrollable paroxysms of sneezing provoked in a reflex fashion by the
sudden exposure of a dark-adapted subject to intensely bright light,
usually sunlight. The number of successive sneezes was usually 2 or 3,
but could be as many as 43. The 4 authors were the probands of the 4
families they reported. Several instances of male-to-male transmission
were noted. Sneezing in response to bright light was said by Peroutka
and Peroutka (1984) to be a common yet poorly understood phenomenon.
Photic sneeze reflex was suggested as the appropriate designation by
Everett (1964), who found it in 23% of Johns Hopkins medical students.
In a poll of 25 neurologists at Johns Hopkins, Peroutka and Peroutka
(1984) found the phenomenon in 9, but only 2 of the respondents knew
that such a specific reflex exists. The Peroutkas (father and daughter)
reported the reflex in 3 generations of their family: grandfather, the
father (the proband), his brother and his daughter. The index subject
(S.J.P.) invariably sneezes twice when he moves from indoors into bright
sunlight. Lewkonia (1969) described sneezing as a complication of slit
lamp examination. Katz et al. (1990) found light-induced sneezing in 5
of 19 patients with nephropathic cystinosis (219800). This was
presumably related to the crystal deposition in the cornea. Lerner
(1991) took Hunter (1990) to task for referring to the photic sneeze
reflex as a 'comic syndrome.' He cited reports by Beckman and Nordenson
(1983), Forrester (1985), Morris (1987), and Lang and Howland (1987), in
addition to those already cited here. Benbow (1991) reported that he had
suffered from photic sneezing for over 20 years and having just learned
of its existence found that the 'symptoms are more easily tolerated if
you can put a name to them, even if that produces only an illusory
understanding of their significance.' He commented on the potential
hazards of photic sneezing if it occurs while one is driving a car on a
sunny day. He said that he found that 'sudden exposure to sunlight when
emerging from a road tunnel of sufficient length is sure to induce a
sneeze.' Furthermore, 'driving through sunlit gaps in otherwise dense
forest or past blocks of buildings can bring on a sneeze.'

Duncan (1995) pointed out public awareness of the ACHOO syndrome is much
more widespread than one might guess, to the point that it has entered
into the popular wisdom conveyed to preschoolers. In a best-selling
children's book by Berenstain and Berenstain (1981), Papa and Mama bear
are taking sister bear and brother bear to their pediatrician, Dr.
Grizzly, for a check-up. The cubs are expressing their apprehension
about the possibility of injections when Papa bear suddenly cuts loose
with an explosive sneeze. 'Bless you!' said Mama.' 'It's just this
bright sunlight,' sniffed Papa. 'I never get sick.'

*FIELD* RF
1. Beckman, L.; Nordenson, I.: Individual differences with respect
to the sneezing reflex: an inherited physiological trait in man?.
Hum. Hered. 33: 390-391, 1983.

2. Benbow, E. W.: Practical hazards of photic sneezing.  (Letter) Brit.
J. Ophthal. 75: 447 only, 1991.

3. Berenstain, S.; Berenstain, J.: The Berenstain Bears Go to the
Doctor.  New York: Random House (pub.)  1981.

4. Collie, W. R.; Pagon, R. A.; Hall, J. G.; Shokeir, M. H. K.: ACHOO
syndrome (helio-ophthalmic outburst syndrome). Birth Defects Orig.
Art. Ser. XIV(6B): 361-363, 1978.

5. Duncan, R.: Personal Communication. Los Angeles, Calif.  2/1/1995.

6. Everett, H. C.: Sneezing in response to light. Neurology 14:
483-490, 1964.

7. Forrester, J. M.: Sneezing on exposure to bright light as an inherited
response. Hum. Hered. 35: 113-114, 1985.

8. Hunter, K. M.: An N of one: syndrome letters in the New England
Journal of Medicine. Perspect. Biol. Med. 33: 237-251, 1990.

9. Katz, B.; Melles, R. B.; Swenson, M. R.; Schneider, J. A.: Photic
sneeze reflex in nephropathic cystinosis. Brit. J. Ophthal. 74:
706-708, 1990.

10. Lang, D. M.; Howland, W. C., III: Solar sneeze reflex.  (Letter) J.A.M.A. 257:
1330-1331, 1987.

11. Lerner, D. L.: Letter to the editor. Perspect. Biol. Med. 34:
469-470, 1991.

12. Lewkonia, I.: An infrequent response to slit lamp examination.
Brit. J. Ophthal. 53: 493-495, 1969.

13. Morris, H. H., III: ACHOO syndrome: prevalence and inheritance.
Cleveland Clin. J. Med. 54: 431-433, 1987.

14. Peroutka, S. J.; Peroutka, L. A.: Autosomal dominant transmission
of the 'photic sneeze reflex.'.  (Letter) New Eng. J. Med. 310:
599-600, 1984.

*FIELD* CS

Neuro:
   Paroxysmal sneezing;
   Light-induced sneezing

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/20/1995
davew: 7/19/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 9/18/1991
carol: 7/22/1991

*RECORD*
*FIELD* NO
100850
*FIELD* TI
*100850 ACONITASE, MITOCHONDRIAL; ACO2
*FIELD* TX
Slaughter et al. (1975) reported that an electrophoretic survey had
demonstrated 2 alleles at this locus. From the findings in
heterozygotes, they concluded that both aconitases are monomeric.
Sparkes et al. (1978) assigned this locus to chromosome 22 by study of
Chinese hamster-human hybrid cells. See also Meera Khan et al. (1978)
and Slaughter et al. (1978). From study of human-rodent hybrid clones,
Geurts van Kessel et al. (1980) concluded that ACO2 is located between
22q11 and 22q13.

*FIELD* SA
Slaughter et al. (1977); Sparkes et al. (1978)
*FIELD* RF
1. Geurts van Kessel, A. H. M.; Westerveld, A.; de Groot, P. G.; Meera
Khan, P.; Hagemeijer, A.: Regional localization of the genes coding
for human ACO2, ARSA, and NAGA on chromosome 22. Cytogenet. Cell
Genet. 28: 169-172, 1980.

2. Meera Khan, P.; Wijnen, L. M. M.; Pearson, P. L.: Assignment of
the mitochondrial aconitase gene (ACON-M) to human chromosome 22.
Cytogenet. Cell Genet. 22: 212-214, 1978.

3. Slaughter, C. A.; Hopkinson, D. A.; Harris, H.: Aconitase polymorphism
in man. Ann. Hum. Genet. 39: 193-202, 1975.

4. Slaughter, C. A.; Hopkinson, D. A.; Harris, H.: The distribution
and properties of aconitase isozymes in man. Ann. Hum. Genet. 40:
385-401, 1977.

5. Slaughter, C. A.; Povey, S.; Carritt, B.; Solomon, E.; Bobrow,
M.: Assignment of the locus ACON-M to chromosome 22. Cytogenet.
Cell Genet. 22: 223-225, 1978.

6. Sparkes, R. S.; Mohandas, T.; Sparkes, M. C.; Shulkin, J. D.:
Assignment of the aconitase (EC 4.2.1.3) mitochondrial locus (ACON-M)
to human chromosome 22. Biochem. Genet. 16: 751-756, 1978.

7. Sparkes, R. S.; Mohandas, T.; Sparkes, M. C.; Shulkin, J. D.:
Aconitase (E. C. 4.2.1.3) mitochondrial locus (ACON-M) mapped to human
chromosome 22. Cytogenet. Cell Genet. 22: 226-227, 1978.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987

*RECORD*
*FIELD* NO
100880
*FIELD* TI
*100880 ACONITASE, SOLUBLE; ACO1
*FIELD* TX
Slaughter et al. (1975) reported that an electrophoretic survey had
demonstrated 7 alleles at this locus. Among the populations studied,
Nigerians showed polymorphism for ACON-S. Aconitase catalyzes the
conversion of cis-aconitate to isocitrate. In studies of man-Chinese
hamster somatic cell hybrids, Westerveld et al. (1975) showed that human
gal-1-p uridyl transferase (GALT; 230400) and aconitase are syntenic.
Povey et al. (1976) assigned ACO1 to chromosome 9. ACO1 and GALT are on
9p in man and on chromosome 4 in the mouse (Nadeau and Eicher, 1982).
The location in the mouse was predicted from the human linkage. The
smallest region of overlap (SRO) for ACO1 was estimated to be 9p22-p13
(Robson and Meera Khan, 1982).

Aconitase-1 and aconitase-2 (ACO2; 100850) are isozymes present in the
cytosol and mitochondria, respectively. Other pairs of cytosolic and
mitochondrial isozymes are ALDH1 (100640) and ALDH2 (100650), GOT1
(138180) and GOT2 (138150), IDH1 (147700) and IDH2 (147650), MDH1
(154200) and MDH2 (154100), SOD1 (147450) and SOD2 (147460), and TK1
(188300) and TK2 (188250). In all these cases, the 2 isozymes of
different subcellular localization, although similar in structure and
function, are encoded by genes on different chromosomes, i.e., are
nonsyntenic. The presumption is that in each case both originated from a
common ancestral gene in a primordial genome, but that whereas the
cytosolic isozyme is encoded by a gene that is a direct descendant from
a nuclear progenitor gene, the mitochondrial isozyme, although now
encoded by a nuclear gene, is descended from a gene in the
bacterium-like progenitor of the mitochondrion. When this primitive
organism took up intracellular existence, most of its genes were
transferred to the nuclear genome and since they inserted more or less
at random into the nuclear genome, it was to be expected that the
cytosolic and mitochondrial forms of the enzyme would end up being
encoded by genes on different chromosomes. That mitochondrial DNA can be
inserted into the nuclear genome is indicated by work such as that of
Shay and Werbin (1992) who characterized in detail 2 instances of
mitochondrial DNA fragments that had been inserted into the nucleus of
HeLa cells. In one of these cases, the mitochondrial sequence encoding
cytochrome c oxidase subunit III was contiguous with and 5-prime of
exons 2 and 3 of the MYC oncogene (190080) and the chimeric gene was
transcribed. Shay and Werbin (1992) discussed possible mechanisms for
the transfer of mitochondrial DNA into the nucleus.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Azevedo et al. (1979); Mohandas et al. (1979); Robson et al. (1977);
Shows and Brown (1977); Teng et al. (1978)
*FIELD* RF
1. Azevedo, E. S.; Da Silva, M. C. B. O.; Lima, A. M. V.; Fonseca,
E. F.; Conseicao, M. M.: Human aconitase polymorphism in three samples
from northeastern Brazil. Ann. Hum. Genet. 43: 7-10, 1979.

2. Mohandas, T.; Sparkes, R. S.; Sparkes, M. C.; Shulkin, J. D.; Toomey,
K. E.; Funderburk, S. J.: Regional localization of human gene loci
on chromosome 9: studies of somatic cell hybrids containing human
translocations. Am. J. Hum. Genet. 31: 586-600, 1979.

3. Nadeau, J. H.; Eicher, E. M.: Conserved linkage of soluble aconitase
and galactose-1-phosphate uridyl transferase in mouse and man: assignment
of these genes to mouse chromosome 4. Cytogenet. Cell Genet. 34:
271-281, 1982.

4. Povey, S.; Slaughter, C. A.; Wilson, D. E.; Gormley, I. P.; Buckton,
K. E.; Perry, P.; Bobrow, M.: Evidence for the assignment of the
loci AK 1, AK 3 and ACON to chromosome 9 in man. Ann. Hum. Genet. 39:
413-422, 1976.

5. Robson, E. B.; Cook, P. J. L.; Buckton, K. E.: Family studies
with the chromosome 9 markers ABO, AK-1, ACON-S and 9qh. Ann. Hum.
Genet. 41: 53-60, 1977.

6. Robson, E. B.; Meera Khan, P.: Report of the committee on the
genetic constitution of chromosomes 7, 8, and 9. Cytogenet. Cell
Genet. 32: 144-152, 1982.

7. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

8. Shay, J. W.; Werbin, H.: New evidence for the insertion of mitochondrial
DNA into the human genome: significance for cancer and aging. Mutat.
Res. 275: 227-235, 1992.

9. Shows, T. B.; Brown, J. A.: Mapping AK-1, ACON-S, and AK-3 to
chromosome 9 in man employing an X-9 translocation and somatic cell
hybrids. Cytogenet. Cell Genet. 19: 26-37, 1977.

10. Slaughter, C. A.; Hopkinson, D. A.; Harris, H.: Aconitase polymorphism
in man. Ann. Hum. Genet. 39: 193-202, 1975.

11. Teng, Y. S.; Tan, S. G.; Lopez, C. G.: Red cell glyoxalase I
and placental soluble aconitase polymorphisms in the three major ethnic
groups of Malaysia. Jpn. J. Hum. Genet. 23: 211-215, 1978.

12. Westerveld, A.; van Henegouwen, B. H. M. A.; Van Someren, H.:
Evidence for synteny between the human loci for galactose-1-phosphate
uridyl transferase and aconitase in man-Chinese hamster somatic cell
hybrids. Cytogenet. Cell Genet. 14: 453-454, 1975.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 2/11/1994
carol: 2/17/1993
carol: 2/2/1993
carol: 8/25/1992
supermim: 3/16/1992
carol: 12/6/1990

*RECORD*
*FIELD* NO
100900
*FIELD* TI
*100900 ACONITATE HYDRATASE, SOLUBLE
*FIELD* TX
Aconitate hydratase (citrate, or isocitrate, hydrolyase, EC 4.2.1.3)
exists in structurally distinct soluble and mitochondrial forms. Schmitt
and Ritter (1974) found electrophoretic variants of the soluble form in
human placenta. No mitochondrial variants were found.

*FIELD* RF
1. Schmitt, J.; Ritter, H.: Genetic variation of aconitate hydratase
in man. Humangenetik 22: 263-264, 1974.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
101000
*FIELD* TI
*101000 NEUROFIBROMATOSIS, TYPE II
NEUROFIBROMATOSIS, CENTRAL TYPE;;
ACOUSTIC SCHWANNOMAS, BILATERAL;;
BILATERAL ACOUSTIC NEUROFIBROMATOSIS; BANF
NEUROFIBROMIN 2; NF2, INCLUDED;;
ACOUSTIC NEURINOMA, BILATERAL; ACN, INCLUDED;;
MERLIN, INCLUDED;;
SCHWANNOMIN; SCH, INCLUDED
*FIELD* MN

The central form of neurofibromatosis is characterized by tumors of the
eighth cranial nerve (usually bilateral), meningiomas of the brain, and
schwannomas of the dorsal roots of the spinal cord. There is a high
frequency of presenile posterior subcapsular, capsular, or peripheral
cortical cataracts which sometimes require surgery and may predate the
symptoms of bilateral acoustic neurofibromatosis (Bouzas et al., 1993).
Other causes of decreased vision were damage in the optic pathways,
macular hamartomas, and corneal opacities. Most patients with the
central form have no cafe-au-lait spots or peripheral neurofibromata.
Acoustic neuroma is almost always unilateral (Nager, 1969). Bilateral
tumours, in addition to their autosomal dominant inheritance and
association with neurofibromatosis, differ from unilateral ones in that
they can reach a remarkably large size with extensive involvement of the
temporal bone and the nerves therein. According to an NIH Consensus
Development Conference (1988) the criteria for NF2 are (1) bilateral
eighth nerve masses seen with appropriate imaging techniques (e.g., CT
or MRI); or (2) a first-degree relative with NF2 and either unilateral
eighth nerve mass, or two of the following: neurofibroma, meningioma,
glioma, schwannoma, or juvenile posterior subcapsular lenticular
opacity. Small (less than 8 mm) acoustic neuromas can be detected in
asymptomatic individuals by the use of gadolinium-enhanced MRI (Pastores
et al.,1991).

The natural history of the condition was described by Evans et al.
(1992). The mean age at onset was 21.6 years and no patient presented
after 55 years of age. Patients presented with symptoms attributable to
vestibular schwannomas (acoustic neuromas), cranial meningiomas, and
spinal tumors. Forty-four percent presented with deafness, unilateral in
35%. Muscle weakness or wasting was the first symptom in 12%. A
generalized and isolated neuropathy appears to be a relatively common
feature. Cafe-au-lait spots occurred in 43% of the patients but only 1
of 150 had as many as 6 spots. Cataract was detected in 39%. Of three
types of skin tumors, the least common (20% of patients) was similar to
the intradermal papillary skin neurofibroma with violaceous coloring
occurring in NF1. The second type (33%) comprised subcutaneous
well-circumscribed, often spherical, tumors that appeared to be located
on peripheral nerves. The most frequent type (47%) were discrete
well-circumscribed, slightly raised, roughened areas of skin often
pigmented and accompanied by excess hair. Cases of NF2 can be divided
into the Wishart type, with early onset, rapid course, and multiple
other tumors in addition to bilateral vestibular schwannomas, and the
Gardner type with late onset, more benign course, and usually only
bilateral vestibular schwannomas. Birth incidence of NF2 was estimated
to be 1 in 33,000-40,562. Half of the cases were new mutations. There
was a maternal effect on severity (age of onset) and a preponderance of
maternally inherited cases.

Loss of heterozygosity of alleles from chromosome 22 has been found in
acoustic neuromas, neurofibromas, and meningiomas from patients with
bilateral acoustic neurofibromatosis (Wolff et al.,1992). Rouleau et al.
(1993) found a gene, designated Schwannomin (symbol=SCH), bearing
homology to erythrocyte protein 4.1 and the ezrin/moesin/talin family of
genes, and showed that this gene is the site of the mutations causing
NF2 by demonstrating germline and somatic SCH mutations in NF2 patients
and in NF2-related tumors. Most of the variants were nonsense,
frameshift, or splice mutations predicted to lead to the synthesis of a
truncated SCH protein.

Loss of heterozygosity for polymorphic DNA markers flanking NF2 on
chromosome 22 was found in 60% of 170 primary sporadic meningiomas
(Ruttledge et al.,1994), and of 30 vestibular schwannomas (Sainz et
al.,1994). It appears that loss of NF2 protein function is a necessary
step in schwannoma pathogenesis and that the NF2 gene functions as a
recessive tumor suppressor gene.Using polymorphic DNA markers it is
possible to determine, with a high degree of certainty, the carrier
status of about 85% of persons at risk (Ruttledge et al., 1993).

*FIELD* TX
The central form of neurofibromatosis, characterized by tumors of the
eighth cranial nerve (usually bilateral), meningiomas of the brain and
schwannomas of the dorsal roots of the spinal cord, has few of the
hallmarks of the peripheral form of neurofibromatosis (162200). Most
patients with the central form have no cafe-au-lait spots or peripheral
neurofibromata and no patients in one large series had 6 or more
cafe-au-lait spots (Eldridge, 1981). The term von Recklinghausen disease
should be reserved for the peripheral form of neurofibromatosis. Gardner
and Frazier (1933) reported a family of 5 generations in which 38
members were deaf because of acoustic neuromas; of these, 15 later
became blind. The average age of onset of deafness was 20 years. The
average age at death of affected persons in the second generation was
72, in the third generation 63, in the fourth 42, and in the fifth 28.
Follow-up of this family (Gardner and Turner, 1940; Young et al., 1970)
revealed no evidence of the systemic manifestations of von
Recklinghausen disease. Other families with no evidence of the latter
disease were reported by Worster-Drought et al. (1937), Feiling and Ward
(1920), and Moyes (1968). Worster-Drought et al. (1937) pointed out that
Wishart reported the first case of bilateral acoustic neuroma in 1822.
Wishart's patient, Michael Blair, was 21 years old when he consulted Mr.
Wishart, president of the Royal College of Surgeons of Edinburgh,
because of bilateral deafness. He had a peculiarly shaped head from
infancy, and blindness in the right eye was discovered at about 4 months
after birth. He became completely blind and deaf toward the end of his
life. Autopsy revealed tumors of the dura mater and brain and also a
'tumour of the size of a small nut, and very hard, being attached to
each of them (auditory nerves), just where they enter the meatus
auditorius internus.'

Nager (1969) showed that in about 4% of cases acoustic neuroma is
bilateral. In addition to their autosomal dominant inheritance and
association with neurofibromatosis, bilateral tumors differ from
unilateral ones in that they can reach a remarkably large size with
extensive involvement of the temporal bone and the nerves therein. More
than 30 kindreds with 'central neurofibromatosis' have been reported
(Fabricant et al., 1979). Kanter et al. (1980), who reviewed 9
personally studied kindreds and 15 reported ones, with a total of 130
cases, showed an increase only in antigenic activity of nerve growth
factor (NGF) in central neurofibromatosis and only in functional
activity in peripheral neurofibromatosis. Thus, these disorders may
involve different defects in NGF synthesis and/or regulation. In a
review of NF2, Martuza and Eldridge (1988) defined criteria for the
diagnosis of both NF1 and NF2. An NIH Consensus Development Conference
(1988) concluded that the criteria for NF2 are met if a person is found
to have '(1) bilateral eighth nerve masses seen with appropriate imaging
techniques (e.g., CT or MRI); or (2) a first-degree relative with NF2
and either unilateral eighth nerve mass, or two of the following:
neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior
subcapsular lenticular opacity.' Pearson-Webb et al. (1986) pointed out
that Lisch nodules, which are iris hamartomas, are not found in NF2.
They found, however, an apparently high frequency of presenile posterior
subcapsular and nuclear cataracts which sometimes required surgery
and/or predated the symptoms of bilateral acoustic neurofibromatosis.
Kaiser-Kupfer et al. (1989) found posterior capsular lens opacities in
20 NF2 patients in 11 families. Parry et al. (1991) extended these
observations. In 26 persons who were first-degree relatives of an
affected individual, they found posterior capsular cataracts in 21. Of
14 at-risk individuals, i.e., persons with mild changes of NF but not
NF1, persons under age 40 with unilateral acoustic neuroma, a child with
meningioma and/or schwannoma, and a person with multiple meningioma,
they found posterior capsular lens opacities in 13. These patients
probably represented new mutations. The presence of posterior capsular
opacities in a relative of persons with NF2 was suggestive of NF2.
Furthermore, NF2 should be considered in young persons without NF1 but
with mild skin findings of NF or CNS tumors with posterior capsular
opacities. Bouzas et al. (1993) found posterior subcapsular/capsular
cataracts in 36 (80%) of 45 affected individuals in 29 families. In
addition, the association of peripheral cortical lens opacities with NF2
was found to be statistically significant: such cataracts were found in
17 of the patients (37.8%) but in none of the unaffected family members
(p less than 0.0001). In 3 patients, peripheral cortical opacities were
present despite the absence of posterior subcapsular/capsular cataracts.
Bouzas et al. (1993), reporting further on the NIH experience, reviewed
visual impairment in 54 NF2 patients, 51 of whom had bilateral
vestibular schwannomas. Causes of decreased vision were cataracts,
damage in the optic pathways, macular hamartomas, and corneal opacities.
Although lens opacities are an important marker for NF2, they usually do
not interfere with vision; some progress, requiring cataract extraction.
In 6 patients, decreased visual acuity was due to corneal opacifications
secondary to either seventh or fifth cranial nerve damage, or both.
Damage to the seventh cranial nerve caused lagophthalmos and decreased
lacrimal secretion; damage to the fifth cranial nerve caused corneal
hypesthesia. The nerves were damaged by the growth of vestibular tumors
in 1 patient, but in most patients they were damaged during
neurosurgical procedures.

Pastores et al. (1991) demonstrated that small (less than 8 mm) acoustic
neuromas can be detected in asymptomatic individuals by the use of
gadolinium-enhanced MRI. They demonstrated such neuromas in 2
asymptomatic children, aged 7 and 11 years, one of whom had normal
audiometric and brainstem-evoked response testing. Landau et al. (1990)
described combined pigment epithelial and retinal hamartoma (CEPRH) in
NF2. In a series reported by Mrazek et al. (1988), 1 of 41 acoustic
neurinoma cases was bilateral. This was in a 10-year-old girl with von
Recklinghausen neurofibromatosis, whose first tumor had been diagnosed
at age 6. Mayfrank et al. (1990) studied 10 patients with NF2 and found
that all were sporadic cases, each presumably the result of a new
mutational event. From a survey of these patients and those in the
literature, they concluded that sporadic cases are characterized by a
high incidence of multiple meningiomas and spinal tumors in addition to
bilateral acoustic neurinomas. Pulst et al. (1991) described a family
with spinal neurofibromatosis without cafe-au-lait spots or other
manifestations of either NF1 or NF2 such as cutaneous tumors, Lisch
nodules, or acoustic tumors. Mutation at the NF1 locus was excluded with
odds greater than 100,000:1. Markers with the NF2 locus were
uninformative in this family.

Evans et al. (1992) studied 150 patients. The mean age at onset was
21.57 years (n = 110) and no patient presented after 55 years of age.
Patients presented with symptoms attributable to vestibular schwannomas
(acoustic neuroma), cranial meningiomas, and spinal tumors. In 100
patients studied personally by the authors, 44 presented with deafness,
which was unilateral in 35. Deafness was accompanied by tinnitus in 10.
Muscle weakness or wasting was the first symptom in 12%. In 3 of the 100
patients, there was a distal symmetrical sensorimotor neuropathy,
confirmed by nerve conduction studies and electromyography. Although
similar features may result from the multiple spinal and intracranial
tumors that occur in this condition, a generalized and isolated
neuropathy appears to be a relatively common feature of NF2.
Cafe-au-lait spots occurred in 43 of the 100 patients but only 1 had as
many as 6 spots. Cataract was detected in 34 of 90 patients. Cataracts
were probably congenital in 4 patients in this study. Three types of
skin tumors were recognized. The first and least common was similar to
the intradermal papillary skin neurofibroma with violaceous coloring
occurring in NF1. The second type comprised subcutaneous
well-circumscribed, often spherical, tumors that appeared to be located
on peripheral nerves; the thickened nerve could often be palpated at
either end of the tumor, the skin being mobile and separate from the
tumor. The third and most frequent type, first described by Martuza and
Eldridge (1988), was represented by discrete well-circumscribed,
slightly raised, roughened areas of skin often pigmented and accompanied
by excess hair. Skin tumors of some kind were found in 68% of patients,
type 1 being present in 20%, type 2 in 33%, and type 3 in 47%. Evans et
al. (1992) divided their 120 cases of NF2 into 2 types: the Wishart
(1822) type, with early onset, rapid course, and multiple other tumors
in addition to bilateral vestibular schwannomas, and the Gardner type
(1930, 1933, 1940), with late onset, more benign course, and usually
only bilateral vestibular schwannomas. This classification had been
suggested by Eldridge et al. (1991). Evans et al. (1992) found no
evidence for the existence of a third type of generalized
meningiomatosis that might be designated the Lee-Abbott type (Lee and
Abbott, 1969). They could find no evidence that either pregnancy or
contraceptive pill has adverse effects on vestibular schwannomas or
other manifestations. Evans et al. (1992) provided useful advice on the
follow-up of persons identified as having NF2 and the management of
persons at risk of developing NF2. The age at onset of deafness and the
age at diagnosis were almost identical in the 2 sexes. Birth incidence
of NF2 was estimated to be 1 in 33,000-40,562. Evans et al. (1992)
considered 49% of the 150 cases to represent new mutations. The mutation
rate was estimated to be 6.5 x 10(-6). A maternal effect on severity was
noted in that age of onset was 18.17 years in 36 maternally inherited
cases and 24.5 years in 20 paternally inherited cases (p = 0.027). A
preponderance of maternally inherited cases was also significant (p =
0.03). (A maternal effect on severity had been noted also for
neurofibromatosis, type I (NF1; 162200).)

Parry et al. (1994) assessed possible heterogeneity in NF2 by evaluating
63 affected members of 32 families. In addition to skin and neurologic
examinations, workup included audiometry, complete ophthalmologic
examination with slit-lamp biomicroscopy of the lens and fundus, and
gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean
age-at-onset in 58 individuals was 20.3 years; initial symptoms were
related to vestibular schwannomas (44.4%), other CNS tumors (22.2%),
skin tumors (12.7%), and ocular manifestations including cataracts and
retinal hamartomas (12.7%). Screening uncovered 5 affected but
asymptomatic family members; vestibular schwannomas were demonstrated in
62 (98.4%). Other findings included cataracts (81.0%), skin tumors
(67.7%), spinal tumors (67.4%), and meningiomas (49.2%). As a rule,
clinical manifestations and clinical course were similar within families
but differed among families. Parry et al. (1994) concluded that 2
subtypes but not 3 can be defined.

Ragge et al. (1995) concluded that the most common ocular abnormalities
in NF2 are posterior subcapsular or capsular, cortical, or mixed lens
opacities, found in 33 of 49 patients (67%), and retinal hamartomas
found in 11 of 49 patients (22%). The types of cataract that were most
suggestive of NF2 were plaque-like posterior subcapsular or capsular
cataract and cortical cataract with onset under the age of 30 years.

Seizinger et al. (1986) found loss of genes on chromosome 22 in acoustic
neuromas; i.e., whereas normal tissue was heterozygous, tumor tissue was
hemizygous (or homozygous) for the polymorphic markers SIS (190040),
IGLC (147220), and the anonymous DNA locus D22S1. They were prompted to
undertake the study by analogy to retinoblastoma and Wilms tumor and by
the facts that meningioma occurs in association with familial acoustic
neuroma and that cytologic change in chromosome 22 is frequent in
meningioma (see 156100). Seizinger et al. (1987) found specific loss of
alleles from chromosome 22 in 2 acoustic neuromas, 2 neurofibromas, and
1 meningioma from patients with bilateral acoustic neurofibromatosis. In
each case, a partial deletion occurred with a breakpoint distal to the
D22S9 locus in band 22q11. Wertelecki et al. (1988) confirmed
localization of the gene on chromosome 22 (22q11.21-q13.1) by
demonstration of linkage in family studies to markers on chromosome 22.
Wertelecki et al. (1988) also presented the clinical data on 15 affected
male and 8 affected female members of the 1 large kindred they studied
for linkage data. Rouleau et al. (1990) identified markers bracketing
the NF2 gene which are therefore useful for accurate presymptomatic and
prenatal diagnosis, as well as for isolating the defective gene. Narod
et al. (1992) concluded that there is no evidence of genetic
heterogeneity in NF2. They indicated that the presence of bilateral
vestibular schwannomas, as they termed the acoustic neuromas, is
sufficient for the diagnosis. Using 8 polymorphic loci on chromosome 22
to study tumor and constitutional DNAs isolated from 39 unrelated
patients with sporadic or NF2-associated acoustic neuromas, meningiomas,
schwannomas, and ependymomas, Wolff et al. (1992) found 2 tumors with
loss of heterozygosity (LOH) patterns consistent with the presence of
chromosome 22 terminal deletions. By use of additional polymorphic
markers, the terminal deletion breakpoint in one of the tumors, an
acoustic neuroma from an NF2 patient, was mapped within the previously
defined NF2 region. In addition, they identified a sporadic acoustic
neuroma with an LOH pattern consistent with mitotic recombination or
deletion and reduplication. The findings lent further support to the
recessive tumor-suppressor model for the NF2 gene. Arai et al. (1992)
described a patient with bilateral acoustic neurinomas and other tumors
in the central nervous system and a constitutional translocation
t(4;22)(q12;q12.2). Thus, 22q12.2 is a refined localization for the NF2
gene. The same karyotype that was seen in cultured peripheral
lymphocytes was found in a paraspinal neurinoma. The patient's father
was also a carrier of the translocation but he had no clinical symptoms
of NF2, nor did other relatives. As explanation for the failure of
expression in the father, Arai et al. (1992) suggested various
possibilities including nonpenetrance, mosaicism, or genetic imprinting.
They quoted Kanter et al. (1980) as demonstrating earlier onset of
symptoms when NF2 is transmitted by the mother. In a family with the
mild or so-called Gardner type of neurofibromatosis type 2, Watson et
al. (1993) defined a submicroscopic deletion which involved the
neurofilament heavy chain locus (NEFH; 162230) but did not extend as far
as the Ewing sarcoma region (EWS; 133450) proximally or the leukemia
inhibitory factor locus (LIF; 159540) distally. They estimated that the
deletion was about 700 kb long.

Claudio et al. (1994) demonstrated that the mouse homolog of the NF2
gene is located in the proximal region of chromosome 11. The
localization was achieved by analysis of allele distribution in
recombinant inbred strains using a simple sequence repeat polymorphism
in the 3-prime untranslated region of the mouse NF2 cDNA. The region of
chromosome 11 also contains genes for leukemia inhibitory factor (LIF;
159540) and neurofilament heavy chain polypeptide (NFH; 162230), both of
which map to the same region of human chromosome 22 as does NF2.

Trofatter et al. (1993) identified a candidate gene for the NF2 tumor
suppressor that had suffered nonoverlapping deletions in DNA from 2
independent NF2 families as well as alterations in the meningiomas from
2 unrelated NF2 patients. The candidate gene encoded a 587-amino acid
protein with striking similarity to several members of a family of
proteins proposed to link cytoskeletal components with proteins in the
cell membrane; these included moesin (309845), ezrin (123900), and
radixin (179410). Because of the resemblance to these 3 proteins (45-47%
identity), Trofatter et al. (1993) called the NF2 gene product merlin.
The NF2 gene may represent a novel class of tumor suppressor genes.
Schwannomin (symbol = SCH) was the designation used by Rouleau et al.
(1993), who likewise isolated a gene bearing homology to erythrocyte
protein 4.1 and the ezrin/moesin/talin family of genes. They provided
incontrovertible evidence that this gene is the site of the mutations
causing NF2 by demonstrating germline and somatic SCH mutations in NF2
patients and in NF2-related tumors. To isolate the gene, they cloned the
region between 2 flanking polymorphic markers in which they found
several genes, only one of which carried mutations in NF2. Rouleau et
al. (1993) found 16 mutations, 15 of which were predicted to result in
truncated proteins. Consistent with the classic Knudson theory of tumor
suppressor genes, loss of the wildtype allele at the NF2 locus was
demonstrated in 6 of 8 tumors containing NF2 mutations (Trofatter et
al., 1993; Rouleau et al., 1993). For example, in a meningioma in a
patient without features of NF2, they found deletion of 2 nucleotides,
TC, from codon 61 resulting in a frameshift; the normal allele on the
other chromosome had been lost. In 2 instances of schwannoma occurring
in patients without evidence of NF2, Rouleau et al. (1993) found
nonsense mutations that were absent in the patient's blood DNA; in these
instances also the normal allele had been lost.

Using polymorphic DNA markers in a study of 13 NF2 kindreds, Ruttledge
et al. (1993) concluded that it is possible to determine, with a high
degree of certainty, the carrier status of about 85% of persons at risk.
Risk prediction was possible in every case in which DNA was available
from both parents. In 76% of informative individuals, it was possible to
assign a decreased risk of being carriers. Thus, the use of probes for
construction of chromosome 22 haplotypes for risk assessment should
result in a greatly reduced number of individuals who will require
periodic screening.

Bianchi et al. (1994) described a novel isoform of the NF2 transcript
that shows differential tissue expression and encodes a modified C
terminus of the predicted protein. Mutations affecting both isoforms of
the NF2 transcript were detected in multiple tumor types including
melanoma and breast carcinoma. These findings provided evidence that
alterations in the NF2 transcript occurred not only in the hereditary
brain neoplasms typically associated with NF, but also as somatic
mutations in their sporadic counterparts.

By November 1993, 24 mutations, including both germline and somatic
mutations, had been detected in schwannomin (Thomas, 1993). Most of the
mutations cause the synthesis of a truncated schwannomin protein. After
examining 8 of the 16 known NF2 exons in 151 meningiomas, Ruttledge et
al. (1994) characterized 24 inactivating mutations. Significantly, these
aberrations were exclusively detected in tumors that lost the other
chromosome 22 allele. These results provided strong evidence that the
suppressor gene on chromosome 22, frequently inactivated in meningioma,
is the NF2 gene. The same group had found loss of heterozygosity (LOH)
for polymorphic DNA markers flanking NF2 on chromosome 22 in 102 (60%)
of 170 primary sporadic meningiomas. Thus, another gene may be involved
in the development of 40% of meningiomas. It is probably noteworthy that
all 24 of the inactivating mutations found by Ruttledge et al. (1994) in
sporadic meningiomas were nonsense, frameshift (due to small deletions),
or splice site mutations; there were no missense mutations.
Wellenreuther et al. (1995) likewise concluded that NF2 represents the
meningioma locus on chromosome 22. There was a significant association
of loss of heterozygosity on chromosome 22 with mutations in the NF2
gene. They analyzed the entire coding region of the NF2 gene in 70
sporadic meningiomas and identified 43 mutations in 41 patients. These
resulted predominantly in immediate truncation, splicing abnormalities,
or an altered reading frame of the predicted protein product. All
mutations occurred in the first 13 exons, the region of homology with
the filopodial proteins moesin, ezrin, and radixin.

Parry et al. (1996) used SSCP analysis to screen for mutations in DNA
from 32 unrelated NF2 patients. Mutations were identified in 66% of
patients and 20 different mutations were found in 21 patients. They
reported that their results confirm the association between nonsense and
frameshift mutations and clinical manifestations compatible with severe
disease. Parry et al. (1996) stated that their data raise questions
regarding the role of factors, other than the intrinsic properties of
individual mutations, that might influence the phenotype.

Sainz et al. (1994) performed mutational analysis in 30 vestibular
schwannomas and found 18 mutations, 7 of which contained loss or
mutation of both NF2 alleles. Most mutations predicted a truncated
protein. Mutational hot spots were not identified. Only 1 of the
mutations was in a tumor from a patient with NF2. Immunocytochemical
studies using antibodies to the NF2 protein showed complete absence of
staining in tumor Schwann cells, whereas staining was observed in normal
vestibular nerve. These data indicated that loss of NF2 protein function
is a necessary step in schwannoma pathogenesis and that the NF2 gene
functions as a recessive tumor suppressor gene. In studies of 34
vestibular schwannomas and 14 schwannomas at other locations, Bijlsma et
al. (1994) found that the SCH gene is implicated in the development of
these tumors in all locations of the nervous system. Using a screening
method based on denaturing gradient gel electrophoresis, which allows
the detection of mutations in 95% of the coding sequence, Merel et al.
(1995) observed mutations in 17 of 57 meningiomas and in 30 of 89
schwannomas. All of the meningiomas and half of the schwannomas with
identified NF2 mutations demonstrated chromosome 22 allelic losses. No
mutations were observed in 17 ependymomas, 70 gliomas, 23 primary
melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas,
15 colon cancers, and 15 breast cancers. This led Merel et al. (1995) to
conclude that the involvement of the NF2 gene is restricted to
schwannomas and meningiomas, where it is frequently inactivated by a
2-hit process.

Neurilemmomatosis, first reported by Niimura (1973) as neurofibromatosis
type 3, is characterized by multiple cutaneous neurilemmomas and spinal
schwannomas, without acoustic tumors or other signs of NF1 or NF2. In
neurilemmomas, the tumor consists of Schwann cells. Honda et al. (1995)
analyzed the peripheral leukocytes and tissue from cutaneous
neurilemmomas of 7 patients with neurilemmomatosis using DNA markers for
different regions of chromosome 22. They detected allele losses in 3 of
7 tumors from 7 patients with a probe for the NF2 region and the
germline mutations in 2 of 3 tumors from the same 3 patients. They
concluded that neurilemmomatosis is a form of NF2. The mutations they
described included a deletion from codon 334 to 579 (at least) and a G
insertion at codon 42.

Ruttledge et al. (1996) reported that when individuals harboring
protein-truncating mutations are compared with patients having single
codon alterations, a significant correlation (p less than 0.001) with
clinical outcome is observed. They noted that 24 of 28 patients with
mutations that cause premature truncation of the NF2 protein present
with severe phenotypes. In contrast, all 16 cases from 3 families with
mutations that affect only a single amino acid have mild NF2.

Malignant mesotheliomas (MMs) are aggressive tumors that develop most
frequently in the pleura of patients exposed to asbestos. In contrast to
many other cancers, relatively few molecular alterations had been
described in MMs. The most frequent numerical cytogenetic abnormality in
MMs is loss of chromosome 22. This prompted Bianchi et al. (1995) to
investigate the status of the NF2 gene in these tumors. In studies of
cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary
tumors, NF2 mutations predicting either interstitial inframe deletions
or truncation of the NF2-encoded protein (merlin) were detected in 8
cell lines (53%), 6 of which were confirmed in primary tumor DNAs. In 2
samples that showed NF2 gene transcript alterations, no genomic DNA
mutations were detected, suggesting that aberrant splicing may
constitute an additional mechanism for merlin inactivation. Unlike
previously described NF2-related tumors, MM derived from the mesoderm;
malignancies of this origin had not previously been associated with
frequent alterations of the NF2 gene. In a commentary in the same
journal issue, Knudson (1995) wrote: 'We are left wondering why
mesothelioma is not a feature of the hereditary disease NF2.'

*FIELD* AV
.0001
NEUROFIBROMATOSIS, TYPE 2
NF2, LEU360PRO
After isolating a candidate gene for neurofibromatosis type 2 by cloning
the region of chromosome 22 between 2 flanking markers, Rouleau et al.
(1993) succeeded in demonstrating that the gene is indeed the site of
germline mutations in NF2 patients and of somatic mutations in
NF2-related tumors. The search was initiated by first determining the
exons and intron-exon boundaries within the coding sequence of the gene
they referred to as schwannomin (SCH). Specific exons were amplified by
polymerase chain reaction (PCR) and the resulting products were analyzed
using denaturing gradient gel electrophoresis as described by Myers et
al. (1985). A total of 15 genetic variants were identified. With the
exception of a leu360-to-pro mutation due to a T-to-C transition, all
the variants were nonsense, frameshift, or splice mutations predicted to
lead to the synthesis of a truncated SCH protein. Whenever it was
possible to investigate several family members in 2 generations, the SCH
mutations were found to segregate with the disease. In 3 instances, the
DNA variants were present only in the patient's constitutional DNA and
not in either of the unaffected parents, providing strong evidence for a
causal relationship between the occurrence of a new mutation and the
development of the disease.

.0002
NEUROFIBROMATOSIS, TYPE 2
NF2, IVS2DS, G-T, +1
In a patient with hereditary neurofibromatosis type 2, Rouleau et al.
(1993) identified a change from AGgt to AGtt at the junction between
codons 80 and 81 (presumably the splice donor site of intron 2).

.0003
MENINGIOMA, SPORADIC
NF2, 1BP DEL, A993
Among the 24 inactivating mutations in the NF2 gene found by Ruttledge
et al. (1994) in sporadic meningiomas were 7 instances of deletion of 1
bp. One of these was deletion of adenine at position 993 resulting in
frameshift. An LOH pattern consistent with monosomy for chromosome 22,
i.e., loss of the homologous NF2 locus, was found in this as well as in
most of the other 23 tumors.

.0004
MENINGIOMA, SPORADIC
NF2, ARG57TER
Papi et al. (1995) analyzed 61 sporadic meningiomas for loss of
heterozygosity of 22q and for mutations in the NF2 gene. LOH was
detected in 36 of the 60 informative tumors. They used single-strand
conformational polymorphism analysis to identify 9 mutations in 5 of the
8 exons of the NF2 gene studied. The 9 tumors with an altered NF2 gene
also showed LOH for 22q markers, supporting the hypothesis that the NF2
gene acts as a tumor suppressor. Papi et al. (1995) found no germline
mutations in these cases. One of the fibroblastic meningiomas in a
62-year-old female had a C-to-T transition at codon 57 in exon 2,
resulting in a premature stop codon.

.0005
NEUROFIBROMATOSIS, TYPE 2
NF2, LEU535PRO
Evans et al. (1995) reported a family with type 2 neurofibromatosis and
late-onset tumors. Hearing loss developed late in life in 5 members of
the family, 2 of whom were first shown to have NF2 in their 70s. Three
other obligate gene carriers died undiagnosed at ages 64, 72, and 78
years of age. Evans et al. (1995) demonstrated a missense mutation at
the the C-terminal end of the NF2 protein; a T-to-C transition at
nucleotide 1604 caused a leu535-to-pro amino acid substitution.

.0006
NEUROFIBROMATOSIS, TYPE 2
NF2, GLN538PRO
In a family with 4 affected members, Kluwe and Mautner (1996) found a
gln538-to-pro mutation in exon 15 of the NF2 gene by studying lymphocyte
DNA. They suggested that missense mutations such as this were rare.
Although both of the 2 affected members of the family who were studied
developed bilateral vestibular schwannomas, the first showed onset of
the disease at the age of 31 years and presented with various central,
peripheral, and abdominal tumors, while the second patient showed later
onset of clinical symptoms (at age 52 years) and presented with only 2
additional small spinal tumors.

.0007
NEUROFIBROMATOSIS, TYPE 2
NF2, PHE96DEL
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
an inframe deletion of 3 basepairs corresponding to codon 96 (CTT) in
exon 3. The mutation causes a deletion of phenylalanine at position 96.

.0008
NEUROFIBROMATOSIS, TYPE 2
NF2, GLU182TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a G-to-T substitution at nucleotide 544 in exon 6, resulting in a stop
codon at position 182.

.0009
NEUROFIBROMATOSIS, TYPE 2
NF2, ARG262TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a C-to-T substitution at nucleotide 784 in exon 8, resulting in a stop
codon at position 262.

.0010
NEUROFIBROMATOSIS, TYPE 2
NF2, GLN320TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a C-to-T substitution at nucleotide 958 in exon 10, resulting in a stop
codon at position 320.

.0011
NEUROFIBROMATOSIS, TYPE 2
NF2, ARG341TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a C-to-T substitution at nucleotide 1021 in exon 11, resulting in a stop
codon at position 341.

.0012
NEUROFIBROMATOSIS, TYPE 2
NF2, GLN407TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a C-to-T substitution at nucleotide 1219 in exon 12, resulting in a stop
codon at position 407.

.0013
NEUROFIBROMATOSIS, TYPE 2
NF2, GLU463TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a G-to-T substitution at nucleotide 1387 in exon 13, resulting in a stop
codon at position 463.

.0014
NEUROFIBROMATOSIS, TYPE 2
NF2, ARG466TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a C-to-T substitution at nucleotide 1396 in exon 13, resulting in a stop
codon at position 466.

.0015
NEUROFIBROMATOSIS, TYPE 2
NF2, GLU527TER
In a study of 33 unrelated patients, MacCollin et al. (1994) identified
a G-to-T substitution at nucleotide 1579 in exon 15, resulting in a stop
codon at position 527.

.0016
NEUROFIBROMATOSIS, TYPE 2
NF2, PHE62SER
Scoles et al. (1996) found a T-to-C transition at nucleotide 185 in exon
2 resulting in a substitution of serine for phenylalanine-62 in a family
with both mild and severe NF2 phenotypes. This mutation had previously
been reported by Bourn et al. (1994) in a family in which the NF2
phenotype was uniformly mild.

*FIELD* SA
Bouzas et al. (1993); Evans et al. (1992); Evans et al. (1992); Gardner
and Frazier (1930); Martuza and Ojemann (1982); Nager  (1964); Perez
Demoura et al. (1969); Rouleau et al. (1987); Rouleau et al. (1987);
Siggers et al. (1975)
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brain. Edinburgh Med. Surg. J. 18: 393-397, 1822.

67. Wolff, R. K.; Frazer, K. A.; Jackler, R. K.; Lanser, M. J.; Pitts,
L. H.; Cox, D. R.: Analysis of chromosome 22 deletions in neurofibromatosis
type 2-related tumors. Am. J. Hum. Genet. 51: 478-485, 1992.

68. Worster-Drought, C.; Dickson, W. E. C.; McMenemey, W. H.: Multiple
meningeal and perineural tumors with analogous changes in the glia
and ependyma (neurofibroblastomatosis). Brain 60: 85-117, 1937.

69. Young, D. F.; Eldridge, R.; Gardner, W. J.: Bilateral acoustic
neuroma in a large kindred. J.A.M.A. 214: 347-353, 1970.

*FIELD* CS

Neuro:
   Bilateral acoustic neuroma;
   Meningioma;
   Glioma;
   Schwannoma;
   Generalized and isolated neuropathy

Eyes:
   Visual loss;
   Juvenile posterior subcapsular or nuclear cataract;
   No Lisch nodules;
   Macular hamartoma;
   Lagophthalmos;
   Decreased lacrimal secretion;
   Corneal hypesthesia

Ears:
   Hearing loss;
   Tinnitus

Skin:
   Usually less than 6 cafe-au-lait spots;
   Often no peripheral neurofibromata;
   Discrete well-circumscribed, slightly raised, roughened skin areas
   often pigmented and hairy;
   Spherical subcutaneous tumors on peripheral nerves;
   Intradermal violaceous papillary skin neurofibroma

Inheritance:
   Autosomal dominant (22q12.2)

*FIELD* CN
Orest Hurko - updated: 11/6/1996
Moyra Smith - updated: 10/1/1996
Moyra Smith - updated: 9/13/1996
Stylianos E. Antonarakis - updated: 7/4/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/31/1997
mark: 11/6/1996
terry: 10/23/1996
mark: 10/1/1996
mark: 9/13/1996
carol: 7/4/1996
terry: 7/1/1996
mark: 6/7/1996
joanna: 5/6/1996
mark: 3/3/1996
terry: 2/26/1996
mark: 2/16/1996
mark: 2/13/1996
mark: 12/12/1995
terry: 12/11/1995
mark: 9/10/1995
terry: 5/25/1995
carol: 2/17/1995
jason: 7/25/1994
mimadm: 6/26/1994
warfield: 4/7/1994

*RECORD*
*FIELD* NO
101120
*FIELD* TI
101120 ACROCEPHALOPOLYSYNDACTYLY TYPE III
ACPS III;;
ACPS WITH LEG HYPOPLASIA;;
SAKATI-NYHAN SYNDROME
*FIELD* TX
This designation may be appropriate for the malformation syndrome
described by Sakati et al. (1971) in a single male. The calvaria was
large and the face disproportionately small. All cranial sutures were
fused. The ears were dysplastic and low-set. Maxillary hypoplasia,
dental crowding, prognathism and short neck with low hairline were
features. A sixth digit had been removed from the right hand. The feet
were adducted and showed polysyndactyly with 7 toes on the right and 6
toes on the left. The tibias were hypoplastic and the fibulas were
deformed and displaced. The chromosomes were normal. Advanced parental
age supported new dominant mutation as the cause. No other cases have,
it seems, been reported.

*FIELD* RF
1. Sakati, N.; Nyhan, W. L.; Tisdale, W. K.: A new syndrome with
acrocephalopolydactyly, cardiac disease, and distinctive defects of
the ear, skin and lower limbs. J. Pediat. 79: 104-109, 1971.

*FIELD* CS

Skull:
   Craniosynostosis;
   Acrocephaly

Facies:
   Flat facies;
   Small facies;
   Prognathism;
   Maxillary hypoplasia

Eyes:
   Shallow orbits;
   Hypertelorism

Ears:
   Dysplastic ears;
   Low-set ears

Teeth:
   Dental crowding

Limbs:
   Preaxial polydactyly;
   Syndactyly;
   Broad thumbs and broad great toes;
   Hypoplastic legs

Neck:
   Short neck with low hairline

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987

*RECORD*
*FIELD* NO
101200
*FIELD* TI
#101200 ACROCEPHALOSYNDACTYLY TYPE I; ACS1
ACS I;;
APERT SYNDROME
APERT-CROUZON DISEASE; ACS II, INCLUDED;;
VOGT CEPHALODACTYLY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence (Wilkie et
al., 1995) that Apert syndrome results from mutations in the gene
encoding fibroblast growth factor receptor-2 (176943).

Apert (1906) defined a syndrome characterized by skull malformation
(acrocephaly of brachysphenocephalic type) and syndactyly of the hands
and feet of a special type (complete distal fusion with a tendency to
fusion also of the bony structures). The hand, when all the fingers are
webbed, has been compared to a spoon and, when the thumb is free, to an
obstetric hand. Blank (1960) assembled case material on 54 patients born
in Great Britain. Two clinical categories were distinguished: (1)
'typical' acrocephalosyndactyly, to which Apert's name is appropriately
applied; and (2) other forms lumped together as 'atypical'
acrocephalosyndactyly. The feature distinguishing the two types is a
middigital hand mass with a single nail common to digits 2-4, found in
Apert syndrome and lacking in the others. Thirty-nine of the 54 were of
Apert type. Six of 12 autopsies showed visceral anomalies but in none
were these identical. A frequency of Apert syndrome of 1 in 160,000
births was estimated.

Varying degrees of mental deficiency are associated with the syndrome;
however, individuals with normal intelligence have been reported.
Individuals who have craniectomy early in life may have improved
intelligence. Patton et al. (1988) did a longterm follow-up on 29
patients of whom 14 (48%) had a normal or borderline IQ, 9 had mild
mental retardation (IQ, 50-70), 4 were moderately retarded (IQ, 35-49),
and 2 (7%) were severely retarded (IQ less than 35). Early craniectomy
did not appear to improve intellectual outcome. Six of 7 school
drop-outs with normal or borderline intelligence were in full-time
employment or vocational training. Contrary to early conclusions such as
that of Park and Powers (1920), Cohen and Kreiborg (1990) concluded that
many patients are mentally retarded. They had information on 30 patients
with malformations of the corpus callosum, the limbic structures, or
both. A variety of other malformations were observed. The authors
suggested that these malformations may be responsible for mental
retardation. Progressive hydrocephalus seemed to be uncommon and was
frequently confused with nonprogressive ventriculomegaly.

Cinalli et al. (1995) found that only 4 of their series of 65 patients
with Apert syndrome required shunting for progressive hydrocephalus.
Only 1.9% of their Apert's patients had chronic herniation of the
cerebellar tonsils, the finding present in 72.7% in Crouzon (123500)
patients. In reviewing their series of 70 children with Apert syndrome,
Reiner et al. (1996) found an IQ greater than 70 in 50% of the children
who had a skull decompression before 1 year of age versus only 7.1% in
those operated on later in life. Malformations of the corpus callosum
and ventricular size did not correlate with the final IQ whereas
anomalies of the septum pellucidum did. The third significant factor in
intellectual achievement was the setting in which the children were
raised. Only 12.5% of institutionalized children had a normal IQ,
whereas 39.3% were from those living with their families.

Pelz et al. (1994) reported an 18-month-old girl who had distal
esophageal stenosis in addition to typical manifestations of Apert
syndrome.

Schauerte and St-Aubin (1966) pointed out that progressive synostosis
occurs in the feet, hands, carpus, tarsus, cervical vertebrae, and
skull, and proposed 'progressive synosteosis with syndactyly' as a more
appropriate designation.

Most cases of Apert syndrome are sporadic, but there are at least 2
reported instances of parent-to-child transmission. Roberts and Hall
(1971) observed affected mother and daughter. Van den Bosch (quoted by
Blank, 1960) observed the typical deformity in mother and son, and Weech
(1927) reported mother and daughter. Low frequency of consanguinity and
failure to observe multiple sibs make recessive inheritance unlikely.
The evidence strongly suggests dominant inheritance, presumably
autosomal in view of the equal sex ratio. Paternal age effect is
demonstrable. Allanson (1986) described 2 sisters with Apert syndrome,
born to normal, unrelated parents. Paternity appeared to be legitimate.
Germinal mosaicism was proposed. Rollnick (1988) described what is
purportedly the first example of male transmission; a father and
daughter were affected. Dodson et al. (1970) described
deletion-translocation of the short arm of a chromosome 2 to the long
arm of a chromosome 11 or 12 in a patient with Apert syndrome. They
found reports of chromosomal abnormalities (all involving the A group)
in 3 other cases of Apert syndrome. Cohen (1973) provided a review of
all the 'craniosynostosis syndromes.' Cohen et al. (1992) studied the
birth prevalence of Apert syndrome in Denmark, Italy, Spain, and 4 areas
of the United States. A total of 57 cases gave a birth prevalence
calculated to be approximately 15.5 per million births, which is twice
the rate determined in earlier studies. The mutation rate was calculated
to be 7.8 x 10(-6) per gene per generation. Apert syndrome accounted for
about 4.5% of all cases of craniosynostosis. Czeizel et al. (1993)
reported a validated birth prevalence of Apert syndrome in Hungary to be
9.9 per million live births. The mutation rate was calculated to be 4.6
x 10(-5) per gene per generation. Data on 14 other 'sentinel' anomalies
observed between 1980 and 1989 were given.

Kreiborg et al. (1992) found fusion of cervical vertebrae in 68% of
patients with Apert syndrome: single fusions in 37% and multiple fusions
in 31%. C5-C6 fusion was most common. In contrast, cervical fusion
occurs in 25% of patients with Crouzon disease (123500) and most
commonly involves C2-C3 only. Kreiborg et al. (1992) concluded that when
fusions are present, C5-C6 involvement in the Apert syndrome and C2-C3
involvement in Crouzon disease separate the 2 conditions in most cases.
Radiographic study of the cervical spine is imperative before
undertaking anesthesia for surgery in these patients.

Cohen and Kreiborg (1995) commented on the cutaneous manifestations in a
series of 136 cases of Apert syndrome (Cohen and Kreiborg, 1993).
Hyperhidrosis was found in all patients. At adolescence and thereafter
the skin was oily. Acniform lesions were particularly prevalent on the
face, chest, back, and upper arms. They commented on and illustrated the
phenomenon of 'interrupted eyebrows.' The explanation probably involves
the underlying bony defect. The orbital plate of the frontal bone is
very short, resulting in early fusion of the sphenoparietal suture. This
leads to marked retrusion and elevation of the supraorbital wings, most
pronounced laterally. Interruption of the eyebrows corresponds to this
defect. Several patients had excessive skin wrinkling of the forehead.

Vogt (1933) described cases presenting the hand and foot malformations
characteristic of Apert disease, together with the facial
characteristics of Crouzon disease, caused by a very hypoplastic
maxilla. The syndactyly was less severe than in Apert disease and the
thumbs and little fingers were usually free. Nager and de Reynier (1948)
gave this deformity the name of Vogt cephalodactyly, while other authors
called it Apert-Crouzon disease, indicating the similarity to both
abnormalities. Temtamy and McKusick (1969) called it ACS II in an
earlier classification. There were no reported instances of hereditary
transmission of this specific phenotype, but this could be due simply to
low reproductive fitness. In a report on Crouzon disease, Dodge et al.
(1959) described 2 sporadic cases of Crouzon-type craniofacial changes
with syndactyly of both hands and feet. Most conclude that this disorder
is actually Apert syndrome with unusually marked facial features
(Temtamy and McKusick, 1978). Maroteaux and Fonfria (1987) described
seemingly typical Apert syndrome except that postaxial polydactyly was
present in the hands, and polydactyly of the feet was apparently
preaxial. Maroteaux and Fonfria (1987) could not discern whether this
represented a low frequency finding of Apert syndrome or a distinct
syndrome. Sidhu and Deshmukh (1988) reported a somewhat similar case in
the child of a first-cousin couple. Gorlin (1989) doubted the existence
of a separate recessive entity because polysyndactyly in the feet,
especially replication of metatarsals, is not rare in Apert syndrome and
because parental consanguinity is probably frequent in the population
studied by Sidhu and Deshmukh (1988).

In a study of mutations in the FGFR2 gene in Apert syndrome, Wilkie et
al. (1995) scored the severity of the syndactyly according to a modified
version of the classification of Upton (1991). In the Apert hand, the
central 3 digits are always syndactylous; in the least severe instance
(type 1), the thumb and part of the finger are separate from the
syndactylous mass; in type 2, the little finger is not separate; and in
type 3, the thumb and all fingers are included. Similarly, syndactyly in
the foot may involve mainly the 3 lateral digits (type 1) or digits 2-5
with a separate big toe (type 2), or be continuous (type 3).

Cohen and Kreiborg (1995) studied 44 pairs of hands and 37 pairs of feet
in Apert syndrome, using clinical, dermatoglyphic, and radiographic
methods. They also studied histologic sections of the hand from a
31-week stillborn fetus. They suggested that acrocephalosyndactyly vs.
acrocephalopolysyndactyly represents a pseudodistinction and that use of
these terms should be discontinued. As generalizations, they pointed out
that in Apert syndrome, the upper limb is more severely affected than
the lower limb. Coalition of distal phalanges and synonychia found in
the hands is never present in the feet.

Park et al. (1995) performed a phenotype/genotype survey of 36 Apert
syndrome patients. In all but one patient, an FGFR2 mutation, either
S252W (176943.0010) or P253R (176943.0011), was found in exon IIIa (exon
U or 7). The frequency was 71% and 26% for these 2 mutations,
respectively. These mutations occur in the linker region between
immunoglobulin-like domains II and III, which are involved in activation
of the receptor by ligand binding and dimerization. The fact that one
patient did not have a mutation in this region suggests further genetic
heterogeneity in Apert syndrome. Study of 29 different clinical features
demonstrated no statistically significant differences between the 2
subgroups defined by the 2 major mutations. Since these mutations
involve adjacent amino acids, Park et al. (1995) reasoned that they
might be expected to have similar biologic and phenotypic consequences.

Moloney et al. (1996) provided information on the mutational spectrum
and the parental origin of the Apert mutation. Their analysis of 118
unrelated patients with new mutations revealed that the mutational
spectrum in Apert syndrome is remarkably narrow. The ser252to-trp
(934C-G) mutation occurred in 74 patients and the pro253-to-arg (937C-G)
mutation in 44 patients. To determine the parental origin of the new
mutations in these sporadic cases of Apert syndrome, Moloney et al.
(1996) carried out sequence analysis of the upstream and downstream
introns that flanked the mutation-prone exon. Sequence analysis on 48
normal individuals led to the identification of common sequence
polymorphisms. They then used a novel PCR-based assay, ARMS
(amplification refractory mutation system), to determine the phase of
the mutant allele and the natural occurring polymorphisms present in the
introns flanking the Apert mutation. Based on this assay, Moloney et al.
(1996) determined that in all 57 informative Apert families, the mutant
allele was paternal in origin. They noted that a paternal bias for point
mutations is evident in a number of disorders, but that the extreme
skewing in favor of paternal mutations observed in Apert syndrome is
unusual. A paternal age effect was noted. Their data suggested a
stronger paternal age effect for the 934C-G mutation, which involves a
CpG dinucleotide, than for the 937C-G mutation, which does not.

Slaney et al. (1996) found differential effects of the 2 FGFR2 mutations
on syndactyly and cleft palate in Apert syndrome. Among 70 unrelated
patients with Apert syndrome, 45 had the ser252-to-trp mutation and 25
had the pro253-to-arg mutation. The syndactyly was more severe with the
pro253-to-arg mutation, for both the hands and the feet. In contrast,
cleft palate was significantly more common in the S252W patients. No
convincing differences were found in the prevalence of other
malformations associated with Apert syndrome.

*FIELD* SA
Cohen  (1977); Cohen and Kreiborg (1995); Erickson  (1974); Hoover
et al. (1970); Leonard et al. (1982); Solomon et al. (1970)
*FIELD* RF
1. Allanson, J. E.: Germinal mosaicism in Apert syndrome. Clin.
Genet. 29: 429-433, 1986.

2. Apert, M. E.: De l'acrocephalosyndactylie. Bull. Mem. Soc. Med.
Hop. Paris 23: 1310-1330, 1906.

3. Blank, C. E.: Apert's syndrome (a type of acrocephalosyndactyly):
observations on a British series of thirty-nine cases. Ann. Hum.
Genet. 24: 151-164, 1960.

4. Cinalli, G.; Renier, D.; Sebag, G.; Sainte-Rose, C.; Arnaud, E.;
Pierre-Kahn, A.: Chronic tonsillar herniation in Crouzon's and Apert's
syndromes: the role of premature synostosis of the lambdoid suture. J.
Neurosurg. 83: 575-582, 1995.

5. Cohen, M. M., Jr.: Genetic perspectives on craniosynostosis and
syndromes with craniosynostosis. J. Neurosurg. 47: 886-898, 1977.

6. Cohen, M. M., Jr.: An etiologic and nosologic overview of craniosynostosis
syndromes. Birth Defects Orig. Art. Ser. XI(2): 137-189, 1973.

7. Cohen, M. M., Jr.; Kreiborg, S.: Cutaneous manifestations of Apert
syndrome. (Letter) Am. J. Med. Genet. 58: 94-96, 1995.

8. Cohen, M. M., Jr.; Kreiborg, S.: Hands and feet in the Apert syndrome. Am.
J. Med. Genet. 57: 82-96, 1995.

9. Cohen, M. M., Jr.; Kreiborg, S.: The central nervous system in
the Apert syndrome. Am. J. Med. Genet. 35: 36-45, 1990.

10. Cohen, M. M., Jr.; Kreiborg, S.: Visceral anomalies in the Apert
syndrome. Am. J. Med. Genet. 45: 758-760, 1993.

11. Cohen, M. M., Jr.; Kreiborg, S.; Lammer, E. J.; Cordero, J. F.;
Mastroiacovo, P.; Erickson, J. D.; Roeper, P.; Martinez-Frias, M.
L.: Birth prevalence study of the Apert syndrome. Am. J. Med. Genet. 42:
655-659, 1992.

12. Czeizel, A. E.; Elek, C.; Susanszky, E.: Birth prevalence study
of Apert syndrome. (Letter) Am. J. Med. Genet. 45: 392, 1993.

13. Dodge, H. W.; Wood, M. W.; Kennedy, R. L. J.: Craniofacial dysostosis:
Crouzon's disease. Pediatrics 23: 98-106, 1959.

14. Dodson, W. E.; Museles, M.; Kennedy, J. L., Jr.; Al-Aish, M.:
Acrocephalosyndactylia associated with a chromosomal translocation:
46,XX,t(2p-;Cq+). Am. J. Dis. Child. 120: 360-362, 1970.

15. Erickson, J. D.: A study of parental age effects on the occurrence
of fresh mutations for the Apert syndrome. Ann. Hum. Genet. 38:
89-96, 1974.

16. Gorlin, R. J.: Apert syndrome with polysyndactyly of the feet.
(Letter) Am. J. Med. Genet. 32: 557, 1989.

17. Hoover, G. H.; Flatt, A. E.; Weiss, M. W.: The hand and Apert's
syndrome. J. Bone Joint Surg. 52A: 878-895, 1970.

18. Kreiborg, A.; Barr, M., Jr.; Cohen, M. M., Jr.: Cervical spine
in the Apert syndrome. Am. J. Med. Genet. 43: 704-708, 1992.

19. Leonard, C. O.; Daikoku, N. H.; Winn, K.: Prenatal fetoscopic
diagnosis of the Apert syndrome. Am. J. Med. Genet. 11: 5-9, 1982.

20. Maroteaux, P.; Fonfria, M. C.: Apparent Apert syndrome with polydactyly:
rare pleiotropic manifestation or new syndrome?. Am. J. Med. Genet. 28:
153-158, 1987.

21. Moloney, D. M.; Slaney, S. F.; Oldridge, M.; Wall, S. A.; Sahlin,
P.; Stenman, G.; Wilkie, A. O. M.: Exclusive paternal origin of new
mutations in Apert syndrome. Nature Genet. 13: 48-53, 1996.

22. Nager, F. R.; de Reynier, J. P.: Das Gehoerorgan bei den angeborenen
Kopfmissbildungen. Pract. Otorhinolaryng. 10 (suppl. 2): 1-128,
1948.

23. Park, E. A.; Powers, G. F.: Acrocephaly and scaphocephaly with
symmetrically distributed malformations of the extremities. Am. J.
Dis. Child. 20: 235-315, 1920.

24. Park, W.-J.; Theda, C.; Maestri, N. E.; Meyers, G. A.; Fryburg,
J. S.; Dufresne, C.; Cohen, M. M., Jr.; Jabs, E. W.: Analysis of
phenotypic features and FGFR2 mutations in Apert syndrome. Am. J.
Hum. Genet. 57: 321-328, 1995.

25. Patton, M. A.; Goodship, J.; Hayward, R.; Lansdown, R.: Intellectual
development in Apert's syndrome: a long term follow up of 29 patients. J.
Med. Genet. 25: 164-167, 1988.

26. Pelz, L.; Unger, K.; Radke, M.: Esophageal stenosis in acrocephalosyndactyly
type I. (Letter) Am. J. Med. Genet. 53: 91 only, 1994.

27. Reiner, D.; Arnaud, E.; Cinalli, G.; Sebag, G.; Zerah, M.; Marchac,
D.: Prognosis for mental function in Apert's syndrome. J. Neurosurg. 85:
66-72, 1996.

28. Roberts, K. B.; Hall, J. G.: Apert's acrocephalosyndactyly in
mother and daughter: cleft palate in the mother. Birth Defects Orig.
Art. Ser. VII(7): 262-264, 1971.

29. Rollnick, B. R.: Male transmission of Apert syndrome. Clin.
Genet. 33: 87-90, 1988.

30. Schauerte, E. W.; St-Aubin, P. M.: Progressive synosteosis in
Apert's syndrome (acrocephalosyndactyly): with a description of roentgenographic
changes in the feet. Am. J. Roentgen. 97: 67-73, 1966.

31. Sidhu, S. S.; Deshmukh, R.: Recessive inheritance of apparent
Apert syndrome with polysyndactyly? (Letter) Am. J. Med. Genet. 31:
179-180, 1988.

32. Slaney, S. F.; Oldridge, M.; Hurst, J. A.; Morriss-Kay, G. M.;
Hall, C. M.; Poole, M. D.; Wilkie, A. O. M.: Differential effects
of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am.
J. Hum. Genet. 58: 923-932, 1996.

33. Solomon, L. M.; Fretzin, D. F.; Pruzansky, S.: Pilosebaceous
abnormalities in Apert's syndrome. Arch. Derm. 102: 381-385, 1970.

34. Temtamy, S. A.; McKusick, V. A.: Synopsis of hand malformations
with particular emphasis on genetic factors. Birth Defects Orig.
Art. Ser. V(3): 125-184, 1969.

35. Temtamy, S. A.; McKusick, V. A.: The Genetics of Hand Malformations.
New York: National Foundation-March of Dimes (pub.)  1978.

36. Upton, J.: Classification and pathologic anatomy of limb anomalies. Clin.
Plast. Surg. 18: 321-355, 1991.

37. Vogt, A.: Dyskephalie (dysostosis craniofacialis, maladie De
Crouzon 1912) und eine neuartige Kombination dieser Krankheit mit
Syndaktylie der 4 Extremitaeten (Dyskephalodaktylie). Klin. Mbl.
Augenheilk. 90: 441-454, 1933.

38. Weech, A. A.: Combined acrocephaly and syndactylism occurring
in mother and daughter: a case report. Bull. Johns Hopkins Hosp. 40:
73-76, 1927.

39. Wilkie, A. O. M.; Slaney, S. F.; Oldridge, M.; Poole, M. D.; Ashworth,
G. J.; Hockley, A. D.; Hayward, R. D.; David, D. J.; Pulleyn, L. J.;
Rutland, P.; Malcolm, S.; Winter, R. M.; Reardon, W.: Apert syndrome
results from localized mutations of FGFR2 and is allelic with Crouzon
syndrome. Nature Genet. 9: 165-172, 1995.

*FIELD* CS

Facies:
   Flat facies

Eyes:
   Shallow orbits;
   Hypertelorism

Mouth:
   Narrow palate

Skull:
   Craniosynostosis;
   Brachysphenocephalic acrocephaly

Limbs:
   Syndactyly;
   Broad thumb;
   Broad great toe

Nails:
   Single nail digits 2-4

Neuro:
   Variable mental retardation;
   Corpus callosum and/or limbic malformations

Spine:
   Fused cervical vertebrae

Inheritance:
   Autosomal dominant;
   paternal age effect

*FIELD* CN
Orest Hurko - updated: 11/05/1996
Iosif W. Lurie - updated: 8/10/1996
Moyra Smith - updated: 4/29/1996
Orest Hurko - updated: 4/1/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 11/05/1996
terry: 10/23/1996
carol: 8/10/1996
mark: 7/11/1996
carol: 5/22/1996
terry: 5/3/1996
mark: 5/3/1996
carol: 4/29/1996
terry: 4/15/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 3/3/1996
mark: 2/5/1996
mark: 8/30/1995
carol: 2/17/1995
pfoster: 8/18/1994
warfield: 4/6/1994
mimadm: 3/11/1994
carol: 11/3/1993

*RECORD*
*FIELD* NO
101400
*FIELD* TI
#101400 ACROCEPHALOSYNDACTYLY TYPE III
ACS III; ACS3;;
CHOTZEN SYNDROME;;
SAETHRE-CHOTZEN SYNDROME; SCS;;
ACROCEPHALY, SKULL ASYMMETRY, AND MILD SYNDACTYLY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Saethre-Chotzen syndrome is caused by mutations in the TWIST
transcription factor gene (601622).

In the family described by Saethre (1931), a mother, 2 daughters, and
probably other maternal relatives showed mild acrocephaly, asymmetry of
the skull, and partial soft tissue syndactyly of fingers 2 and 3 and
toes 3 and 4. Chotzen (1932) found identical malformations in a father
and 2 sons. Bartsocas et al. (1970) described a Lithuanian kindred
living in the United States in which 10 persons in 3 generations were
affected, with several instances of male-to-male transmission. In 1961
Waardenburg reported asymmetry of the skull and orbits (plagiocephaly),
strabismus, and a thin, long, pointed nose in 6 generations of a
kindred. Some affected persons had bifid terminal phalanges of digits 2
and 3 and absence of the first metatarsal. Cleft palate, hydrophthalmos,
cardiac malformation, and contractures of elbows and knees were present
in some. Aase and Smith (1970) described a syndrome comprising asymmetry
of the face (hypoplasia of the left side), unusually shaped ear with
prominent crus (see their Fig. 2), and Simian crease in 5 members of 3
generations (with 1 instance of male-to-male transmission). They pointed
out similarities to and differences from the asymmetry of the face and
skull with abnormalities of the digits described by Waardenburg et al.
(1961). Gorlin (1971) thought the syndrome described by Aase and Smith
(1970) was Chotzen syndrome. Carter et al. (1982) recognized 9 patients,
including familial cases. Like Aase and Smith (1970), they recognized a
long and prominent ear crus as a valuable sign. Kurczynski and Casperson
(1988) described mother and daughter with craniosynostosis and
symmetrical syndactyly involving the fourth and fifth toes. In addition,
both had a short columella and small pinnae. Kurczynski and Casperson
(1988) concluded that this represented a new form of
acrocephalosyndactyly and suggested the designation
auralcephalosyndactyly (109050). Legius et al. (1989) described mother
and son with bilateral symmetrical syndactyly of the third, fourth and
fifth toes, mild craniosynostosis, and small pinnae. In addition, the
mother had fusion of 2 cervical vertebrae and partial duplication of the
first metatarsal. Furthermore, the distal phalanges of both great toes
were bifid. These skeletal changes in combination with cutaneous
syndactyly of the toes, abnormal auricles, and acrocephaly have been
described in the Saethre-Chotzen syndrome (Kopysc et al., 1980) and also
in the Robinow-Sorauf syndrome (Carter et al., 1982). Legius et al.
(1989) concluded that the Saethre-Chotzen, auralcephalosyndactyly, and
Robinow-Sorauf (180750) syndromes may be somewhat different expressions
of the same dominant gene. Marini et al. (1991) presented a family
illustrating the mild and easily missed expression of the gene in a
parent. Niemann-Seyde et al. (1991) observed ACS III in 9 members of 4
generations of a family; 5 of them were severely affected. Russo et al.
(1991) described a case of renotubular dysgenesis (267430) in an infant
who had widely patent cranial fontanels and whose father and sister
showed acrocephalosyndactyly of the Saethre-Chotzen type. This was
probably a coincidental association between a recessive disorder and a
dominant disorder.

See craniosynostosis (123100) for well-established mapping to
7p21.3-p21.2 on the basis of structural alterations in that region. The
gene for Greig cephalopolysyndactyly syndrome (GCPS; 175700) appears to
be located at 7p13. Brueton et al. (1992) presented molecular genetic
linkage studies suggesting localization of the gene for the
Saethre-Chotzen syndrome on distal 7p. Sixteen families with involvement
in 2 or more generations were available for study. One of their families
(number 16) had characteristics suggesting the Jackson-Weiss syndrome
(123150). Excluding this family and pedigree number 15 which had a
Pfeiffer-like syndrome (101600), Brueton et al. (1992) found tight
linkage to D7S370 (maximum lod = 3.00 at theta = 0.00) and with D7S10
(maximum lod = 2.39 at theta = 0.00). The relationship to other forms of
craniosynostosis with hand anomalies that map to 7p remains to be
determined. In linkage analysis on 6 ACS III families using 5 CA repeat
polymorphisms from 7p, Malcolm et al. (1993) found evidence suggesting
location between D7S493 and D7S516. Two patients, a father and daughter,
were found with ACS III and a balanced translocation t(7;10)(p21;q21.2).
Reid et al. (1993) reported 2 additional patients, a male infant and his
mother, with an apparently balanced translocation t(2;7)(p23;p22).
Lewanda et al. (1994) confirmed linkage of the Saethre-Chotzen syndrome
to 7p. The tightest linkage was to D7S493; linkage and haplotype
analyses refined the location of the gene to the region between D7S513
and D7S516. On the basis of 4 patients with apparently balanced
translocations at 7p21.2, Rose et al. (1994) narrowed the localization
of the ACS3 gene to a 6-cM region. By fluorescence in situ
hybridization, they showed that the breakpoints were situated within the
region flanked by genetic markers D7S488 and D7S493 in distal 7p.
Lewanda et al. (1994) used linkage and haplotype analyses to narrow the
disease locus to an 8-cM region between D7S664 and D7S507. The tightest
linkage was to D7S664; maximum lod = 7.16 at theta = 0.00. Studying the
t(2;7)(p23;p22) in a patient with Saethre-Chotzen syndrome, Lewanda et
al. (1994) found that the D7S664 locus lay distal to the 7p22
breakpoint, whereas the D7S507 locus was deleted from the translocation
chromosome. Wilkie et al. (1995) reported 3 further families, each
segregating a different reciprocal chromosomal translocation involving
7p21. A total of 7 apparently balanced carriers were identified and all
manifest features of the Saethre-Chotzen syndrome, although only 2 had
overt craniosynostosis. In one family, the carriers were immediately
recognized by their unusual ears, and clefts of the hard or soft palate
were present in all 3 families. The abnormally configured ear was
pictured in 1 member from each of 3 generations.

Ma et al. (1996) studied 3 further families to provide additional
support to the localization of a disease gene between D7S493 and D7S664.
There was a suspicion that at least 2 disease-causing genes may map to
7p, 1 distal and 1 proximal to D7S488. The MEOX2 gene (600535) maps to
the same region of 7p (as does SCS), and is a major candidate gene in
SCS, as it is expressed in the mesenchyma of craniofacial and limb
structures during early mouse embryogenesis.

Reardon and Winter (1994) wrote as follows: 'Clinical geneticists are
inured to anecdotes recounting odd presentations of dysmorphic
syndromes. Saethre-Chotzen syndrome is a case in point. A consultation
for schizophrenia led to the first report from the Norwegian
psychiatrist, Haakon Saethre...' (Saethre, 1931). Chotzen (1932)
reported a father and 2 sons with the syndrome that came to carry his
name.

Howard et al. (1997) and El Ghouzzi et al. (1997) demonstrated that the
Saethre-Chotzen syndrome results from mutations in the TWIST gene
(601622). They were prompted to evaluate the TWIST gene, which encodes a
basic helix-loop-helix transcription factor, because its expression
pattern and mutant phenotypes in Drosophila and mouse are consistent
with the SCS phenotype in humans. Howard et al. (1997) mapped the human
TWIST gene by PCR analysis of somatic cell hybrids to 7p22-p21 in a
region homologous to the region of mouse chromosome 12 where the murine
TWIST gene had been mapped. They assigned it to a specific YAC which was
known to contain the breakpoint of a chromosome translocation in 1
Saethre-Chotzen syndrome case. Bourgeois et al. (1996) had previously
cloned human TWIST and mapped it to 7p21. Howard et al. (1997)
identified nonsense, missense, insertion, and deletion mutations in
TWIST in patients with Saethre-Chotzen syndrome. El Ghouzzi et al.
(1997) reported 21-bp insertions and nonsense mutations in the TWIST
gene in 7 probands with SCS.

*FIELD* SA
Bianchi et al. (1985); Escobar et al. (1977); Kreiborg et al. (1972);
Lewanda et al. (1994); McKeon-Kern and Mamunes (1977); Pantke et al.
(1975)
*FIELD* RF
1. Aase, J. M.; Smith, D. W.: Facial asymmetry and abnormalities
of palms and ears: a dominantly inherited developmental syndrome. J.
Pediat. 76: 928-930, 1970.

2. Bartsocas, C. S.; Weber, A. L.; Crawford, J. D.: Acrocephalosyndactyly
type 3: Chotzen's syndrome. J. Pediat. 77: 267-272, 1970.

3. Bianchi, E.; Arico, M.; Podesta, A. F.; Grana, M.; Fiori, P.; Beluffi,
G.: A family with the Saethre-Chotzen syndrome. Am. J. Med. Genet. 22:
649-658, 1985.

4. Bourgeois, P.; Stoetzel, C.; Bolcato-Bellemin, A. L.; Mattei, M.
G.; Perrin-Schmitt, F.: The human H-twist gene is located at 7p21
and encodes a B-HLH protein that is 96% similar to its murine M-twist
counterpart. Mammalian Genome 7: 915-917, 1996.

5. Brueton, L. A.; van Herwerden, L.; Chotai, K. A.; Winter, R. M.
: The mapping of a gene for craniosynostosis: evidence for linkage
of the Saethre-Chotzen syndrome to distal chromosome 7p. J. Med.
Genet. 29: 681-685, 1992.

6. Carter, C. O.; Till, K.; Fraser, V.; Coffey, R.: A family study
of craniosynostosis, with probable recognition of a distinct syndrome. J.
Med. Genet. 19: 280-285, 1982.

7. Chotzen, F.: Eine eigenartige familiaere Entwicklungsstoerung
(Akrocephalosyndaktylie, Dysostosis craniofacialis und Hypertelorismus). Mschr.
Kinderheilk. 55: 97-122, 1932.

8. El Ghouzzi, V.; Le Merrer, M.; Perrin-Schmitt, F.; Lajeunie, E.;
Benit, P.; Renier, D.; Bourgeois, P.; Bolcato-Bellemin, A.-L.; Munnich,
A.; Bonaventure, J.: Mutations of the TWIST gene in the Saethre-Chotzen
syndrome. Nature Genet. 15: 42-46, 1997.

9. Escobar, V.; Brandt, I. K.; Bixler, D.: Unusual association of
Saethre-Chotzen syndrome and congenital adrenal hyperplasia. Clin.
Genet. 11: 365-371, 1977.

10. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.
1971.

11. Howard, T. D.; Paznekas, W. A.; Green, E. D.; Chiang, L. C.; Ma,
N.; Ortiz De Luna, R. I.; Delgado, C. G.; Gonzalez-Ramos, M.; Kline,
A. D.; Jabs, E. W.: Mutations in TWIST, a basic helix-loop-helix
transcription factor, in Saethre-Chotzen syndrome. Nature Genet. 15:
36-41, 1997.

12. Kopysc, Z.; Stanska, M.; Ryzko, J.; Kulczyk, B.: The Saethre-Chotzen
syndrome with partial bifid of the distal phalanges of the great toes:
observations of three cases in one family. Hum. Genet. 56: 195-204,
1980.

13. Kreiborg, S.; Pruzansky, S.; Pashayan, H.: The Saethre-Chotzen
syndrome. Teratology 6: 287-294, 1972.

14. Kurczynski, T. W.; Casperson, S. M.: Auralcephalosyndactyly:
a new hereditary craniosynostosis syndrome. J. Med. Genet. 25: 491-493,
1988.

15. Legius, E.; Fryns, J. P.; Van den Berghe, H.: Auralcephalosyndactyly:
a new craniosynostosis syndrome or a variant of the Saethre-Chotzen
syndrome?. J. Med. Genet. 26: 522-524, 1989.

16. Lewanda, A. F.; Cohen, M. M., Jr.; Jackson, C. E.; Taylor, E.
W.; Li, X.; Beloff, M.; Day, D.; Clarren, S. K.; Ortiz, R.; Garcia,
C.; Hauselman, E.; Figueroa, A.; Wulfsberg, E.; Wilson, M.; Warman,
M. L.; Padwa, B. L.; Whiteman, D. A. H.; Mulliken, J. B.; Jabs, E.
W.: Genetic heterogeneity among craniosynostosis syndromes: mapping
the Saethre-Chotzen syndrome locus between D7S513 and D7S516 and exclusion
of Jackson-Weiss and Crouzon syndrome loci from 7p. Genomics 19:
115-119, 1994.

17. Lewanda, A. F.; Green, E. D.; Weissenbach, J.; Jerald, H.; Taylor,
E.; Summar, M. L.; Phillips, J. A., III; Cohen, M.; Feingold, M.;
Mouradian, W.; Clarren, S. K.; Jabs, E. W.: Evidence that the Saethre-Chotzen
syndrome locus lies between D7S664 and D7S507, by genetic analysis
and detection of a microdeletion in a patient. Am. J. Hum. Genet. 55:
1195-1201, 1994.

18. Ma, H. W.; Lajeunie, E.; de Parseval, N.; Munnich, A.; Renier,
D.; Le Merrer, M.: Possible genetic heterogeneity in the Saethre-Chotzen
syndrome. Hum. Genet. 98: 228-232, 1996.

19. Malcolm, S.; Rose, C. P. S.; van Herwerden, L.; Reardon, W.; Brueton,
L.; Weissenbach, J.; Winter, R. M.: Mapping of Saethre-Chotzen syndrome
(ACS III) to 7p21. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A136
only, 1993.

20. Marini, R.; Temple, K.; Chitty, L.; Genet, S.; Baraitser, M.:
Pitfalls in counselling: the craniosynostoses. J. Med. Genet. 28:
117-121, 1991.

21. McKeon-Kern, C.; Mamunes, P.: A case of Saethre-Chotzen syndrome. Med.
Coll. Va. Quart. 13(4): 186-188, 1977.

22. Niemann-Seyde, S. C.; Eber, S. W.; Zoll, B.: Saethre-Chotzen
syndrome (ACS III) in four generations. Clin. Genet. 40: 271-276,
1991.

23. Pantke, O. A.; Cohen, M. M., Jr.; Witkop, C. J., Jr.; Feingold,
M.; Schaumann, B.; Pantke, H. C.; Gorlin, R. J.: The Saethre-Chotzen
syndrome. Birth Defects Orig. Art. Ser. XI(2): 190-225, 1975.

24. Reardon, W.; Winter, R. M.: Saethre-Chotzen syndrome. J. Med.
Genet. 31: 393-396, 1994.

25. Reid, C. S.; McMorrow, L. E.; McDonald-McGinn, D. M.; Grace, K.
J.; Ramos, F. J.; Zackai, E. H.; Cohen, M. M., Jr.; Jabs, E. W.:
Saethre-Chotzen syndrome with familial translocation at chromosome
7p22. Am. J. Med. Genet. 47: 637-639, 1993.

26. Rose, C. S. P.; King, A. A. J.; Summers, D.; Palmer, R.; Yang,
S.; Wilkie, A. O. M.; Reardon, W.; Malcolm, S.; Winter, R. M.: Localization
of the genetic locus for Saethre-Chotzen syndrome to a 6 cM region
of chromosome 7 using four cases with apparently balanced translocations
at 7p21.2. Hum. Molec. Genet. 3: 1405-1408, 1994.

27. Russo, R.; D'Armiento, M.; Vecchione, R.: Renal tubular dysgenesis
and very large cranial fontanels in a family with acrocephalosyndactyly
S.C. type. Am. J. Med. Genet. 39: 482-485, 1991.

28. Saethre, M.: Ein Beitrag zum Turmschaedelproblem (Pathogenese,
Erblichkeit und Symptomatologie). Dtsch. Z. Nervenheilk. 119: 533-555,
1931.

29. Waardenburg, P. J.; Franceschetti, A.; Klein, D.: Genetics and
Ophthalmology.  Springfield, Ill.: Charles C Thomas (pub.)  1:
1961. Pp. 301-354.

30. Wilkie, A. O. M.; Yang, S. P.; Summers, D.; Poole, M. D.; Reardon,
W.; Winter, R. M.: Saethre-Chotzen syndrome associated with balanced
translocations involving 7p21: three further families. J. Med. Genet. 32:
174-180, 1995.

*FIELD* CS

Facies:
   Flat facies;
   Thin, long, pointed nose

Eyes:
   Shallow orbits;
   Hypertelorism;
   Plagiocephaly (asymmetry of orbits);
   Strabismus;
   Hydrophthalmos

Ears:
   Long and prominent ear crus

Mouth:
   Cleft palate

Skull:
   Craniosynostosis;
   Acrocephaly;
   Cranial asymmetry

Limbs:
   Mild syndactyly;
   Bifid terminal phalanges digits 2 and 3;
   Absent first metatarsal

Cardiac:
   Congenital heart defect

Joints:
   Contractures of elbows and knees

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jenny: 01/14/1997
terry: 1/8/1997
terry: 12/13/1996
terry: 4/19/1995
carol: 1/4/1995
pfoster: 3/31/1994
mimadm: 3/28/1994
carol: 10/29/1993
carol: 10/20/1993

*RECORD*
*FIELD* NO
101600
*FIELD* TI
#101600 ACROCEPHALOSYNDACTYLY TYPE V; ACS5
ACS V;;
PFEIFFER TYPE ACROCEPHALOSYNDACTYLY
NOACK SYNDROME, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of the evidence
presented by Muenke et al. (1994) that mutations in the gene for
fibroblast growth factor receptor-1 (FGFR1; 136350) cause one form of
familial Pfeiffer syndrome. Other cases are caused by mutation in the
gene for fibroblast growth factor receptor-2 (FGFR2; 176943); the
original family reported by Pfeiffer (1964) was of this type (Muenke,
1996). Yet other families cannot be related to either the FGFR1 locus on
chromosome 8 or the FGFR2 locus on chromosome 10 by linkage studies.

Pfeiffer (1964) found 8 affected in 3 generations, with 2 instances of
male-to-male transmission. The striking feature was broad, short thumbs
and big toes. The proximal phalanx of the thumb was either triangular or
trapezoid (and occasionally fused with the distal phalanx) so that the
thumb pointed outward (i.e., away from the other digits). Martsolf et
al. (1971) described the case of an affected boy whose mother and
maternal half-brother were said to be affected also. Another pedigree
consistent with autosomal dominant inheritance was reported by Saldino
et al. (1972).

Acrocephalopolysyndactyly differs from Apert syndrome
(acrocephalosyndactyly; 101200) in the presence of polydactyly as an
additional feature. Earlier (Temtamy and McKusick, 1969), 2 types were
thought to exist: type I, or Noack syndrome, a dominant, and type II, or
Carpenter syndrome, a recessive (201000). Only the latter is, it seems,
a valid entity.

Robin et al. (1994) demonstrated linkage of markers from chromosome 8 in
some Pfeiffer syndrome families. By performing fluorescence in situ
hybridization on artificial chromosomes (YACs) that contained the linked
DNA markers, they localized one gene for Pfeiffer syndrome to the
pericentromeric region of chromosome 8. Genetic heterogeneity in the
syndrome was demonstrated by exclusion of close linkage in other
families. Because FGFR1 had been mapped to 8p12-p11.2, it became a
strong candidate gene for Pfeiffer syndrome. Muenke et al. (1994)
identified a specific mutation in this gene in all affected members of 5
unrelated Pfeiffer syndrome families. Schell et al. (1995) demonstrated
that Pfeiffer syndrome can also result from point mutations in the gene
for fibroblast growth factor receptor-2.

The genetic heterogeneity reflected by the linkage studies was also
indicated by studies of the molecular defect: Lajeunie et al. (1995) and
Rutland et al. (1995) found mutations in the FGFR2 gene in some patients
with Pfeiffer syndrome. Crouzon syndrome (CFD1; 123500) had been the
type of craniosynostosis hitherto related to mutations in the FGFR2
gene. Lajeunie et al. (1995) described FGFR2 mutations in one sporadic
case and one familial form of Pfeiffer syndrome. Rutland et al. (1995)
reported point mutations in FGFR2 in 7 sporadic Pfeiffer syndrome
patients. Six of the 7 Pfeiffer syndrome patients shared 2 missense
mutations that had also been reported in Crouzon syndrome. The Crouzon
and Pfeiffer phenotypes usually 'breed true' within families and the
finding of identical mutations in unrelated individuals giving different
phenotypes was a highly unexpected observation.

Noack (1959) reported a 43-year-old man and his 11-month-old daughter,
both of whom exhibited acrocephaly and polysyndactyly. Enlarged thumbs
and great toes with duplication of the latter (preaxial polydactyly)
were described, as well as syndactyly. Intelligence was apparently
normal. Follow-up of Noack's kindred by Pfeiffer (1964) indicated that
the disorder is the same as acrocephalosyndactyly type V. Robinow and
Sorauf (1975) described an extensively affected kindred which
illustrates the extent to which penetrance can be reduced. The proband
showed marked valgus of unduly broad great toes, which radiologically
showed duplication of the phalanges. In commenting on the paper, Temtamy
(1976) stated that in her view the Noack and Pfeiffer types are one.
(The disorder in the family reported by Robinow and Sorauf (1975) is
treated as a separate entity and discussed under 180750.)

Baraitser et al. (1980) reported a kindred particularly instructive as
to the range of variability. The proband had the full-blown syndrome,
whereas 8 persons in 4 sibships of the previous 3 generations had large
halluces and partial syndactyly of the toes (mainly toes 2 and 3). The
variability of expression was also illustrated by Vanek and Losan
(1982). Kroczek et al. (1986) described Kleblattschaedel in association
with Pfeiffer syndrome. Rasmussen and Frias (1988) described a girl with
severe manifestations of Pfeiffer syndrome. The case was thought to
represent a new mutation until the mother was examined in detail and
found to show abnormalities of the right thumb consistent with mild
expression of the Pfeiffer syndrome. The mother was thought to have mild
mid-facial hypoplasia. The possibility of mosaicism in the mother seems
strong. The mother's father was 40 years old at the time of her birth.

Stone et al. (1990) described an infant with the Pfeiffer syndrome in
whom the trachea showed replacement of the cartilaginous rings by a
solid cartilaginous plate extending the full length of the trachea and
beyond the carina. This resulted in tracheal stenosis. Devine et al.
(1984) described a completely cartilaginous trachea without ring
formation in a child with Crouzon syndrome (123500) who continued to
have respiratory distress despite surgical repair of choanal stenosis.
Death from respiratory problems occurred at the age of 23 months.
Soekarman et al. (1992) described classic Pfeiffer syndrome in mother
and son. The infant son had cloverleaf skull anomaly. The development in
the child after surgery appeared to be normal, indicating that all
children with the cloverleaf skull abnormality do not have a dire
prognosis.

Cohen (1993) stated that 7 Pfeiffer syndrome pedigrees (three
3-generation and four 2-generation) had been reported, in addition to at
least a dozen sporadic cases. Cohen (1993) recognized 3 clinical
subtypes which, he suggested, do not have status as separate entities
but have important diagnostic and prognostic implications nonetheless.
The classic syndrome is designated type 1. Type 2 consists of cloverleaf
skull with Pfeiffer hands and feet, together with ankylosis of the
elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular
proptosis is severe, and the anterior cranial base is markedly short.
Various visceral malformations have been found in association with type
3. Cohen and Barone (1994) further tabulated the findings in the 3 types
of Pfeiffer syndrome. Early demise is characteristic of both type 2 and
type 3, which to date have occurred only as sporadic cases.

Bellus et al. (1996) described a pro250-to-arg mutation in the
extracellular domain of the FGFR3 gene (134934.0014) in 10 unrelated
families with dominant craniosynostosis syndromes. This mutation
(749C-G) occurs precisely at the position in FGFR3 analogous to that of
mutations in FGFR1 (P252R; 136350.0001) and FGFR2 (P253R; 176943.0011)
previously reported in Pfeiffer syndrome and Apert syndrome,
respectively. The FGFR mutations in Pfeiffer syndrome and nonsyndromic
craniosynostosis were reviewed in detail.

*FIELD* SA
Cremers  (1981); Eastman et al. (1978); Escobar and Bixler (1977);
Gnamey and Farriaux (1972); Naveh and Friedman (1976)
*FIELD* RF
1. Baraitser, M.; Bowen-Bravery, M.; Saldana-Garcia, P.: Pitfalls
of genetic counselling in Pfeiffer's syndrome. J. Med. Genet. 17:
250-256, 1980.

2. Bellus, G. A.; Gaudenz, K.; Zackai, E. H.; Clarke, L. A.; Szabo,
J.; Francomano, C. A.; Muenke, M.: Identical mutations in three different
fibroblast growth factor receptor genes in autosomal dominant craniosynostosis
syndromes. Nature Genet. 14: 174-176, 1996.

3. Cohen, M. M., Jr.: Pfeiffer syndrome update, clinical subtypes,
and guidelines for differential diagnosis. Am. J. Med. Genet. 45:
300-307, 1993.

4. Cohen, M. M., Jr.; Barone, C. M.: Reply to Dr. Winter. (Letter) Am.
J. Med. Genet. 49: 358-359, 1994.

5. Cremers, C. W. R. J.: Hearing loss in Pfeiffer's syndrome. Int.
J. Pediat. Otorhinolaryng. 3: 343-353, 1981.

6. Devine, P.; Bhan, M.; Feingold, M.; Leonidas, J.; Wolpert, S.:
Completely cartilaginous trachea in a child with Crouzon syndrome. Am.
J. Dis. Child. 138: 40-43, 1984.

7. Eastman, J. R.; Escobar, V.; Bixler, D.: Linkage analysis in dominant
acrocephalosyndactyly. J. Med. Genet. 15: 292-293, 1978.

8. Escobar, V.; Bixler, D.: The acrocephalosyndactyly syndrome: a
metacarpophalangeal pattern profile analysis. Clin. Genet. 11: 295-305,
1977.

9. Gnamey, D.; Farriaux, J.-P.: Syndrome dominant associant polysyndactylie,
pouces en spatule, anomalies facials et retard mental (une forme particuliere
de l'acrocephalo-polysyndactylie de type Noack). J. Genet. Hum. 19:
299-316, 1972.

10. Kroczek, R. A.; Muhlbauer, W.; Zimmermann, I.: Cloverleaf skull
associated with Pfeiffer syndrome: pathology and management. Europ.
J. Pediat. 145: 442-445, 1986.

11. Lajeunie, E.; Ma, H. W.; Bonaventure, J.; Munnich, A.; Le Merrer,
M.; Renier, D.: FGFR2 mutations in Pfeiffer syndrome. (Letter) Nature
Genet. 9: 108, 1995.

12. Martsolf, J. T.; Cracco, J. B.; Carpenter, G. G.; O'Hara, A. E.
: Pfeiffer syndrome: an unusual type of acrocephalosyndactyly with
broad thumbs and great toes. Am. J. Dis. Child. 121: 257-262, 1971.

13. Muenke, M.: Personal Communication. Philadelphia, Pennsylvania
2/25/1996.

14. Muenke, M.; Schell, U.; Hehr, A.; Robin, N. H.; Losken, H. W.;
Schinzel, A.; Pulleyn, L. J.; Rutland, P.; Reardon, W.; Malcolm, S.;
Winter, R. M.: A common mutation in the fibroblast growth factor
receptor 1 gene in Pfeiffer syndrome. Nature Genet. 8: 269-274,
1994.

15. Naveh, Y.; Friedman, A.: Pfeiffer syndrome: report of a family
and review of the literature. J. Med. Genet. 13: 277-280, 1976.

16. Noack, M.: Ein Beitrag zum Krankheitsbild der Akrozephalosyndaktylie
(Apert). Arch. Kinderheilk. 160: 168-171, 1959.

17. Pfeiffer, R. A.: Dominant erbliche Akrocephalosyndaktylie. Z.
Kinderheilk. 90: 301-320, 1964.

18. Rasmussen, S. A.; Frias, J. L.: Mild expression of the Pfeiffer
syndrome. Clin. Genet. 33: 5-10, 1988.

19. Robin, N. H.; Feldman, G. J.; Mitchell, H. F.; Lorenz, P.; Wilroy,
R. S.; Zackai, E. H.; Allanson, J. E.; Reich, E. W.; Pfeiffer, R.
A.; Clarke, L. A.; Warman, M. L.; Mulliken, J. B.; Brueton, L. A.;
Winter, R. M.; Price, R. A.; Gasser, D. L.; Muenke, M.: Linkage of
Pfeiffer syndrome to chromosome 8 centromere and evidence for genetic
heterogeneity. Hum. Molec. Genet. 3: 2153-2158, 1994.

20. Robinow, M.; Sorauf, T. J.: Acrocephalopolysyndactyly, type Noack,
in a large kindred. Birth Defects Orig. Art. Ser. XI(5): 99-106,
1975.

21. Rutland, P.; Pulleyn, L. J.; Reardon, W.; Baraitser, M.; Hayward,
R.; Jones, B.; Malcolm, S.; Winter, R. M.; Oldridge, M.; Slaney, S.
F.; Poole, M. D.; Wilkie, A. O. M.: Identical mutations in the FGFR2
gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nature
Genet. 9: 173-176, 1995.

22. Saldino, R. M.; Steinbach, H. L.; Epstein, C. J.: Familial acrocephalosyndactyly
(Pfeiffer syndrome). Am. J. Roentgen. 116: 609-622, 1972.

23. Schell, U.; Hehr, A.; Feldman, G. J.; Robin, N. H.; Zackai, E.
H.; de Die-Smulders, C.; Viskochil, D. H.; Stewart, J. M.; Wolff,
G.; Ohashi, H.; Price, R. A.; Cohen, M. M., Jr.; Muenke, M.: Mutations
in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum.
Molec. Genet. 4: 323-328, 1995.

24. Soekarman, D.; Fryns, J. P.; van den Berghe, H.: Pfeiffer acrocephalosyndactyly
syndrome in mother and son with cloverleaf skull anomaly in the child. Genetic
Counseling 3: 217-220, 1992.

25. Stone, P.; Trevenen, C. L.; Mitchell, I.; Rudd, N.: Congenital
tracheal stenosis in Pfeiffer syndrome. Clin. Genet. 38: 145-148,
1990.

26. Temtamy, S.: Personal Communication. Cairo, Egypt  1976.

27. Temtamy, S.; McKusick, V. A.: Synopsis of hand malformations
with particular emphasis on genetic factors. Birth Defects Orig.
Art. Ser. V(3): 125-184, 1969.

28. Vanek, J.; Losan, F.: Pfeiffer's type of acrocephalosyndactyly
in two families. J. Med. Genet. 19: 289-292, 1982.

*FIELD* CS

Facies:
   Flat facies

Eyes:
   Shallow orbits;
   Hypertelorism

Skull:
   Mild craniosynostosis;
   Acrocephaly

Limbs:
   Broad thumb;
   Broad great toe;
   Polysyndactyly

Radiology:
   Thumb proximal phalanx triangular or trapezoid, occasionally fused
   with distal phalanx

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/05/1996
terry: 10/2/1996
carol: 8/20/1996
mark: 3/3/1996
terry: 2/27/1996
mark: 8/11/1995
carol: 2/13/1995
terry: 1/31/1995
warfield: 4/7/1994
mimadm: 3/11/1994
carol: 10/14/1993

*RECORD*
*FIELD* NO
101800
*FIELD* TI
*101800 ACRODYSOSTOSIS
*FIELD* TX
Maroteaux and Malamut (1968) suggested that 'peripheral dysostosis'
(q.v.) is a heterogeneous class. They described acrodysostosis as a
condition in which peculiar facies (short nose, open mouth and
prognathism) is associated with the small hands and feet. Mental
deficiency is frequent. Cone epiphyses occur in this condition. Robinow
et al. (1971) reported 9 cases and reviewed 11 from the literature. None
was familial. Jones et al. (1975) found elevated average paternal age in
this disorder, thus supporting autosomal dominant inheritance. It is
possible that at least some cases that have been labeled acrodysostosis
represent the normocalcemic form of pseudohypoparathyroidism (300800).
Butler et al. (1988) reported an affected 13-year-old boy and reviewed
the literature. They emphasized the features of nasal and maxillary
hypoplasia, peripheral dysostosis, decreased interpedicular distance,
advanced skeletal maturation, and mental retardation. In their review
they also found that parental age was increased. They suggested that the
metacarpophalangeal pattern profile is characteristically abnormal and
that this can be a useful diagnostic tool. The first ray in the foot may
be relatively hyperplastic. Viljoen and Beighton (1991) reviewed the
radiologic features in 12 affected children and found that epiphyseal
stippling is a consistent and prominent characteristic during infancy.
Butler et al. (1988) found a pattern of autosomal dominant inheritance
in 2 families (Niikawa et al., 1978; Frey et al., 1982). Niikawa et al.
(1978) described Japanese brother and sister, aged 7 months and 2 years,
respectively, with severe nasal hypoplasia, peripheral dysostosis, blue
eyes, and mental retardation. The mother showed nasal hypoplasia and
irregular shortening of fingers and toes. Hernandez et al. (1991)
described an affected mother and daughter. Steiner and Pagon (1992) also
described an affected mother and daughter. The mother had been diagnosed
at the age of 4 years and was pictured in the 1982 edition of Smith's
Recognizable Patterns of Human Malformation. At the age of 20, she
suffered from recurrent carpal tunnel syndrome. The daughter showed
cone-shaped epiphyses as in the mother.

Because of the similarity between acrodysostosis and Albright hereditary
osteodystrophy (AHO; 103580), both of which show shortening of the
tubular bones of the hands and feet with cone-shaped epiphyses, Wilson
et al. (1997) looked for abnormalities in the alpha subunit of the
signal transducing protein, Gs, and in the GNAS1 gene (139320). In 2
unrelated patients with acrodysostosis, they found that Gs-alpha
bioactivity in erythrocyte membranes was normal. Mutation analysis of
the GNAS1 gene showed no sequence variation in 12 of the 13 exons
examined. The results were interpreted as indicating that, at least in a
proportion of patients with acrodysostosis, the condition is
etiologically distinct from AHO.

*FIELD* SA
Arkless and Graham (1967); Smith  (1982)
*FIELD* RF
1. Arkless, R.; Graham, C. B.: An unusual case of brachydactyly. Am.
J. Roentgen. 99: 724-735, 1967.

2. Butler, M. G.; Rames, L. J.; Wadlington, W. B.: Acrodysostosis:
report of a 13-year-old boy with review of literature and metacarpophalangeal
pattern profile analysis. Am. J. Med. Genet. 30: 971-980, 1988.

3. Frey, V. G.; Martin, J.; Diefel, K.: Die Akrodysostose--eine autosomal-dominant
verebte periphere Dysplasie. Kinderarztl. Prax. 3: 149-153, 1982.

4. Hernandez, R. M.; Miranda, A.; Kofman-Alfaro, S.: Acrodysostosis
in two generations: an autosomal dominant syndrome. Clin. Genet. 39:
376-382, 1991.

5. Jones, K. L.; Smith, D. W.; Harvey, M. A. S.; Hall, B. D.; Quan,
L.: Older paternal age and fresh gene mutation: data on additional
disorders. J. Pediat. 86: 84-88, 1975.

6. Maroteaux, P.; Malamut, G.: L'acrodysostose. Presse Med. 76:
2189-2192, 1968.

7. Niikawa, N.; Matsuda, I.; Ohsawa, T.; Kajii, T.: Familial occurrence
of a syndrome with mental retardation, nasal hypoplasia, peripheral
dysostosis, and blue eyes in Japanese siblings. Hum. Genet. 42:
227-232, 1978.

8. Robinow, M.; Pfeiffer, R. A.; Gorlin, R. J.; McKusick, V. A.; Renuart,
A. W.; Johnson, G. F.; Summitt, R. L.: Acrodysostosis: a syndrome
of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am.
J. Dis. Child. 121: 195-203, 1971.

9. Smith, D. W.: Recognizable Patterns of Human Malformation: Genetic,
Embryologic and Clinical Aspects.  Philadelphia: W. B. Saunders (pub.)
(3rd ed.): 1982. Pp. 322-323.

10. Steiner, R. D.; Pagon, R. A.: Autosomal dominant transmission
of acrodysostosis. Clin. Dysmorph. 1: 201-206, 1992.

11. Viljoen, D.; Beighton, P.: Epiphyseal stippling in acrodysostosis. Am.
J. Med. Genet. 38: 43-45, 1991.

12. Wilson, L. C.; Oude Luttikhuis, M. E. M.; Baraitser, M.; Kingston,
H. M.; Trembath, R. C.: Normal erythrocyte membrane Gs-alpha bioactivity
in two unrelated patients with acrodysostosis. J. Med. Genet. 34:
133-136, 1997.

*FIELD* CS

Facies:
   Short nose;
   Nasal hypoplasia;
   Open mouth;
   Maxillary hypoplasia;
   Prognathism

Limbs:
   Small hands and feet

Neuro:
   Mental retardation

Misc:
   Increased average paternal age

Radiology:
   Cone epiphyses;
   Peripheral dysostosis;
   Decreased interpedicular distance;
   Advanced skeletal maturation;
   Abnormal metacarpophalangeal pattern profile;
   Hyperplastic foot first ray;
   Epiphyseal stippling

Inheritance:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 03/06/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/06/1997
terry: 3/5/1997
davew: 8/1/1994
mimadm: 3/11/1994
carol: 12/6/1993
carol: 11/11/1993
supermim: 3/16/1992
carol: 5/29/1991

*RECORD*
*FIELD* NO
101805
*FIELD* TI
101805 ACROFACIAL DYSOSTOSIS, CATANIA TYPE
AFD, CATANIA TYPE
*FIELD* TX
Opitz et al. (1993) reported a 'new' form of acrofacial dysostosis in a
Sicilian woman and her 4 sons. Features included apparent mild
intrauterine growth retardation and postnatal shortness of stature,
microcephaly, widow's peak, mandibulofacial dysostosis without cleft
palate, mild pre- and more conspicuous postaxial upper limb involvement
with short hands, simian creases, mild interdigital webbing, low total
ridge count, and facultative preauricular fistulae, cryptorchidism,
hypospadias, inguinal hernia, and spina bifida occulta of C1. Although
X-linked dominant inheritance was possible, the authors considered
autosomal dominant inheritance more likely because the mother was as
severely affected as her sons. Wulfsberg et al. (1996) described a
similar association in a 5-year-old girl and her mother. In addition to
typical manifestations of the syndrome, the mother had an edentulous
upper jaw and carious teeth in both lower and upper jaw.

*FIELD* RF
1. Opitz, J. M.; Mollica, F.; Sorge, G.; Milana, G.; Cimino, G.; Caltabiano,
M.: Acrofacial dysostoses: review and report of a previously undescribed
condition: the autosomal or X-linked dominant Catania form of acrofacial
dysostosis. Am. J. Med. Genet. 47: 660-678, 1993.

2. Wulfsberg, E. A.; Campbell, A. B.; Lurie, I. W.; Eanet, K. R.:
Confirmation of the Catania brachydactylous type of acrofacial dysostosis:
report of a second family. Am. J. Med. Genet. 63: 554-557, 1996.

*FIELD* CN
Iosif W. Lurie - updated: 08/11/1996

*FIELD* CD
Victor A. McKusick: 11/4/1993

*FIELD* ED
carol: 08/11/1996
carol: 11/4/1993

*RECORD*
*FIELD* NO
101840
*FIELD* TI
101840 ACROKERATODERMA, HEREDITARY PAPULOTRANSLUCENT
*FIELD* TX
Onwukwe et al. (1973) described a family in which multiple members of 4
generations and by inference a fifth, in a pattern consistent with
autosomal dominant inheritance (including male-to-male transmission),
had persistent, asymptomatic, yellowish-white, translucent papules and
plaques on the hands and feet, associated with fine-textured scalp hair
and atopic diathesis. Histologic study of the translucent lesions showed
orthohypergranulosis, acanthosis, and a relatively normal dermis.
Onwukwe et al. (1973) suggested that this might be a new variant of
familial punctate keratoderma. De Wit and Hulsmans (1986) observed a
Surinam woman with abnormalities of palmar and plantar skin. Her father
was reported to have similar changes confined to the feet. The index
patient was observed to have both classical keratosis punctata palmaris
et plantaris (175860) and papulotranslucent acrokeratoderma.

*FIELD* RF
1. de Wit, F. S.; Hulsmans, R. F. H. J.: Hereditair papulotranslucent
keratoderma van de acra als variant van en in combinatie met keratosis
punctata palmaris et plantaris. Nederl. T. Geneesk. 130: 2015 only,
1986.

2. Onwukwe, M. F.; Mihm, M. C., Jr.; Toda, K.: Hereditary papulotranslucent
acrokeratoderma: a new variant of familial punctate keratoderma?.
Arch. Derm. 108: 108-110, 1973.

*FIELD* CS

Skin:
   Persistent, asymptomatic, yellowish-white, translucent papules and
   plaques of hands and feet

Hair:
   Fine-textured scalp hair

Immunology:
   Atopic diathesis

Lab:
   Skin lesions show orthohypergranulosis, acanthosis, and a relatively
   normal dermis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 4/1/1991

*FIELD* ED
mimadm: 3/11/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 4/5/1991
carol: 4/1/1991

*RECORD*
*FIELD* NO
101850
*FIELD* TI
*101850 ACROKERATOELASTOIDOSIS; AKE
COLLAGENOUS PLAQUES OF HANDS
*FIELD* TX
This disorder was first described and named by Costa (1953). Jung (1973)
studied an extensively affected family. The palms and soles are
primarily affected, but involvement may extend to the dorsum of the
hands and feet in severe cases. The lesions are nodular and yellow with
hyperkeratotic surfaces. The histology combines hyperkeratosis and
disorganization of elastic fibers. No systemic manifestation has been
detected. The differential diagnosis includes other forms of
palmoplantar keratosis and palmoplantar xanthomata. Matthews and Harman
(1977) observed the disorder in 2 brothers whose mother was also
affected. In a linkage study of the large kindred reported by Jung
(1973), Greiner et al. (1983) found a suggestion of linkage of AKE to
ACP1 (171500), Jk (111000) and IGKC (147200). Although the lod scores
did not reach the level of significance considered to be proof, the fact
that all three of these markers are on 2p suggests that AKE may be there
also. Maximum lod scores were as follows: with IGKC, 0.57 at theta 0.16;
with ACP1, 0.18 at theta 0.22; with Jk, 0.11 at theta 0.31.

Stevens et al. (1996) classified focal acrohyperkeratosis, otherwise
known as acrokeratoelastoidosis, as type III punctate PPK.

*FIELD* SA
Costa  (1954); Matthews and Harman (1974)
*FIELD* RF
1. Costa, O. G.: Acrokeratoelastoidosis: a hitherto undescribed skin
disease. Dermatologica 107: 164-167, 1953.

2. Costa, O. G.: Ackrokeratoelastoidosis. Arch. Derm. Syph. 70:
228-231, 1954.

3. Greiner, J.; Kruger, J.; Palden, L.; Jung, E. G.; Vogel, F.: A
linkage study of acrokeratoelastoidosis: possible mapping to chromosome
2. Hum. Genet. 63: 222-227, 1983.

4. Jung, E. G.: Acrokeratoelastoidosis. Humangenetik 17: 357-358,
1973.

5. Matthews, C. N. A.; Harman, R. R. M.: Acrokerato-elastoidosis
(without elastorrhexis). Proc. Roy. Soc. Med. 67: 1237-1238, 1974.
Derm. 132: 640-651, 1996.

6. Matthews, C. N. A.; Harman, R. R. M.: Acrokerato-elastoidosis
in a Somerset mother and her two sons. Brit. J. Derm. 97 (suppl.
15): 42-43, 1977.

7. Stevens, H. P.; Kelsell, D. P.; Bryant, S. P.; Bishop, D. T.; Spurr,
N. K.; Weissenbach, J.; Marger, D.; Marger, R. S.; Leigh, I. M.:
Linkage of an American pedigree with palmoplantar keratoderma and
malignancy (palmoplantar ectodermal dysplasia type III) to 17q24:
literature survey and proposed updated classification of the keratodermas. Arch.
Derm. 132: 640-651, 1996.

*FIELD* CS

Skin:
   Acrokeratoelastoidosis;
   Hyperkeratosis;
   Acrokeratosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/03/1996
terry: 11/8/1996
mimadm: 3/11/1994
carol: 8/25/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 4/20/1988

*RECORD*
*FIELD* NO
101900
*FIELD* TI
*101900 ACROKERATOSIS VERRUCIFORMIS
HOPF DISEASE
*FIELD* TX
Warty hyperkeratotic lesions are found on the dorsal aspect of the hands
and feet and on the knees and elbows. The pedigree studied by Niedelman
and McKusick (1962) contained instances of male-to-male transmission as
well as unaffected daughters of affected males. Herndon and Wilson
(1966) emphasized the phenotypic overlap between this entity and
Darier-White disease (124200) and even proposed that they may not be
separate entities. In the family they studied, 7 persons had typical
acrokeratosis verruciformis, 1 or possibly 2 had Darier disease, and 3
had minor disturbances of keratinization (white nails from subungual
hyperkeratosis, or punctate keratoses of palms or soles). Also see
benign familial pemphigus (169600).

*FIELD* RF
1. Herndon, J. H., Jr.; Wilson, J. D.: Acrokeratosis verruciformis
(Hopf) and Darier's disease: genetic evidence for a unitary origin.
Arch. Derm. 93: 305-310, 1966.

2. Niedelman, M. L.; McKusick, V. A.: Acrokeratosis verruciformis
(Hopf): a follow-up study. Arch. Derm. 86: 779-782, 1962.

*FIELD* CS

Skin:
   Acrokeratosis;
   Warty hyperkeratosis, dorsal hands, feet, knees and elbows;
   Acrokeratosis verruciformis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 4/19/1995
pfoster: 9/2/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
102000
*FIELD* TI
102000 ACROLEUKOPATHY, SYMMETRIC
*FIELD* TX
Sugai et al. (1965) described mother and daughter with symmetric
depigmentation of the great toes.

*FIELD* RF
1. Sugai, T.; Saito, T.; Hamada, T.: Symmetric acroleukopathy in
mother and daughter. Arch. Derm. 92: 172-173, 1965.

*FIELD* CS

Skin:
   Symmetric great toe depigmentation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
102100
*FIELD* TI
*102100 ACROMEGALOID CHANGES, CUTIS VERTICIS GYRATA, AND CORNEAL LEUKOMA
ROSENTHAL-KLOEPFER SYNDROME
*FIELD* TX
Rosenthal and Kloepfer (1962) described a 'new' syndrome with these
three features in 13 persons of 4 generations of a Louisiana black
family. Through the courtesy of Kloepfer, I saw affected members of this
family in 1971. The corneal leukoma is an epithelial change. The hands,
feet and chin are very large and the affected persons unusually tall.
Although growth hormone assays had not been done, other endocrine
studies and x-ray views of the sella turcica gave no indication of
pituitary dysfunction. One of the affected females examined had 9 living
children. The skin of the hands is unusually soft and has an abnormal
dermal ridge pattern, referred to as 'split ridges,' which permits
identification of the disorder in children of preclinical age. A
possible difference from the usual cutis verticis gyrata is a
longitudinal orientation of the skin folds rather than transverse
orientation. X-ray features were reported by Harbison and Nice (1971).

*FIELD* RF
1. Harbison, J. B.; Nice, C. M., Jr.: Familial pachydermoperiostosis
presenting as an acromegaly-like syndrome. Am. J. Roentgen. 112:
532-536, 1971.

2. Rosenthal, J. W.; Kloepfer, H. W.: An acromegaloid, cutis verticis
gyrata, corneal leukoma syndrome. Arch. Ophthal. 68: 722-726, 1962.

*FIELD* CS

Eyes:
   Corneal leukoma

Limbs:
   Large hands and feet

Facies:
   Large chin

Growth:
   Tall stature

Skin:
   Soft skin;
   Split ridge dermal ridge pattern;
   Cutis verticis gyrata with longitudinal folding

Radiology:
   Periostosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/6/1994
mimadm: 3/11/1994
carol: 3/24/1992
supermim: 3/16/1992
supermim: 5/15/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
102150
*FIELD* TI
*102150 ACROMEGALOID FACIAL APPEARANCE SYNDROME
AFA SYNDROME;;
THICK LIPS AND ORAL MUCOSA
*FIELD* TX
In many members of a kindred through at least 5 generations, Hughes et
al. (1985) described a syndrome of acromegaloid facial features:
thickened lips (without a true 'double lip'), overgrowth of the
intraoral mucosa resulting in exaggerated rugae and frenula, and
thickened upper eyelids leading to narrow palpebral fissures
(blepharophimosis). The nose tended to be bulbous. The hands were large
and doughy without clubbing. Highly arched eyebrows were striking in
published photographs. There was no evident impairment of general
health. Pachydermoperiostosis (167100), Ascher syndrome (109900), and
multiple neuroma syndrome (162300) were considered in the differential
diagnosis. Low positive lod scores were obtained for linkage between AFA
and Rh and PGM1 (on 1p), GLO (on 6p), IGHG and PI (on 14q), and HP (on
16q). Dallapiccola et al. (1992) reported a family with the disorder in
2 generations. Five affected persons, a mother and 4 children, showed a
striking resemblance to the patients reported by Hughes et al. (1985).
They had progressively coarsening acromegaloid facial appearance, narrow
palpebral fissures, bulbous nose, and thickening of the lips and
intraoral mucosa, resulting in exaggerated rugae of the tongue and
frenula. The patients had increased birth weight and dull mentality.
Tapering fingers in the mother and one daughter, somewhat like those in
the Coffin-Lowry syndrome (303600), were pictured.

*FIELD* RF
1. Dallapiccola, B.; Zelante, L.; Accadia, L.; Mingarelli, R.: Acromegaloid
facial appearance (AFA) syndrome: report of a second family. J.
Med. Genet. 29: 419-422, 1992.

2. Hughes, H. E.; McAlpine, P. J.; Cox, D. W.; Philipps, S.: An autosomal
dominant syndrome with 'acromegaloid' features and thickened oral
mucosa. J. Med. Genet. 22: 119-125, 1985.

*FIELD* CS

Mouth:
   Thickened lips;
   Intraoral mucosal overgrowth;
   Exaggerated oral rugae and frenula

Eyes:
   Thickened upper eyelids;
   Blepharophimosis;
   Highly arched eyebrows

Nose:
   Bulbous nose

Limbs:
   Large doughy hands;
   Tapering fingers

Growth:
   Increased birth weight

Neuro:
   Dull mentality

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
carol: 7/1/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
102200
*FIELD* TI
*102200 ACROMEGALY
SOMATOTROPHINOMA, INCLUDED
*FIELD* TX
Koch and Tiwisina (1959) reviewed 8 examples of affected persons in 2
successive generations, including 4 instances of father and 1 or more
sons affected. Some reported instances of familial acromegaly may in
fact be pachydermoperiostosis (167100), acromegaloid-cutis verticis
gyrata-leukoma syndrome (102100), or cerebral gigantism (117550).
Furthermore, familial acromegaly can be a partial expression of the
multiple endocrine adenomatosis syndrome, specifically multiple
endocrine neoplasia type I (MEN1; 131100). Levin et al. (1974) reported
the cases of 2 brothers with acromegaly confirmed by elevated growth
hormone levels. Both had acanthosis nigricans and pituitary tumors.
Pestell et al. (1989) described a family in which 5 members over 3
generations had isolated functional pituitary adenomas. In 4 cases this
was associated with acromegaly, and in the fifth galactorrhea from
prolactin excess was the presenting feature. The tumors were
histologically of either atypical mixed cell or undifferentiated cell
type. No parent-child transmission was observed. The 5 individuals were
related as uncle and nephew or uncle and niece or as second cousins.
There were no consanguineous marriages in the family. Autosomal dominant
inheritance with reduced penetrance was proposed. Pestell et al. (1989)
considered the disorder in this family to be distinct from MEN1. Jones
et al. (1984), Abbassioun et al. (1986), and McCarthy et al. (1990) also
reported cases of familial acromegaly.

Growth hormone secreting pituitary adenomas (somatotrophinomas) occur in
families either as an isolated autosomal dominant endocrinopathy (as
illustrated by the examples cited above) or as part of MEN1. Thakker et
al. (1993) compared DNA in somatotrophinomas and peripheral leukocytes
obtained from 13 patients with acromegaly; one patient also suffered
from MEN1. Five DNA probes identifying RFLPs from 11q demonstrated
allele loss in pituitary tumors from 5 patients, 4 non-MEN1 and 1 MEN1.
Deletion mapping revealed that the region of allele loss common to the
somatotrophinomas involved 11q13. Similar allelic deletions at 12 other
loci distributed through the genome did not reveal generalized allele
loss in the somatotrophinomas. Thakker et al. (1993) interpreted these
results as indicating that a recessive oncogene on 11q13 is specifically
involved in the monoclonal development of somatotrophinomas; 11q13 is
also the site of the gene for MEN1 in which somatotrophinomas are a
feature. (It is a well known phenomenon that tumors that occur as a
component of a familial neoplasia syndrome also occur as sporadic tumors
on the basis of somatic mutation. Is it not possible that the findings
of Thakker et al. (1993) have the same basis as sporadic meningioma due
to mutation in the NF2 gene (e.g., 101000.0003), cerebellar
hemangioblastoma, sporadic cerebellar hemangioblastoma, or sporadic
renal carcinoma due to mutation in the gene for von Hippel-Lindau
syndrome (e.g., 193300.0002 and 193300.0007, respectively)? VAM.)

In addition, Thakker et al. (1993) found mutations in the GNAS1 gene
(139320) in 2 non-MEN1 somatotrophinomas, one of which also demonstrated
allele loss of chromosome 11. (The authors referred to GNAS1 as GSP.)

*FIELD* SA
Koch  (1949)
*FIELD* RF
1. Abbassioun, K.; Fatourehchi, V.; Amirjamshidi, A.; Meibodi, N.
A.: Familial acromegaly with pituitary adenoma: report of three affected
siblings. J. Neurosurg. 64: 510-512, 1986.

2. Jones, M. K.; Evans, P. J.; Jones, I. R.; Thomas, J. P.: Familial
acromegaly. Clin. Endocr. 20: 355-358, 1984.

3. Koch, G.: Erbliche Hirngeschwuelste. Z. Menschl. Vererb. Konstitutionsl. 29:
400-423, 1949.

4. Koch, G.; Tiwisina, T.: Beitrag zur Erblichkeit der Akromegalie
und der Hyperostosis generalisata mit Pachydermie. Aerztl. Forsch. 13:
489-504, 1959.

5. Levin, S. R.; Hafeldt, F. D.; Becker, N.; Wilson, C. B.; Seymour,
R.; Forsham, P. H.: Hypersomatotropism and acanthosis nigricans in
two brothers. Arch. Intern. Med. 134: 365-367, 1974.

6. McCarthy, M. I.; Noonan, K.; Wass, J. A. H.; Monson, J. P.: Familial
acromegaly: studies in three families. Clin. Endocr. 32: 719-728,
1990.

7. Pestell, R. G.; Alford, F. P.; Best, J. D.: Familial acromegaly. Acta
Endocr. 121: 286-289, 1989.

8. Thakker, R. V.; Pook, M. A.; Wooding, C.; Boscaro, M.; Scanarini,
M.; Clayton, R. N.: Association of somatotrophinomas with loss of
alleles on chromosome 11 and with gsp mutations. J. Clin. Invest. 91:
2815-2821, 1993.

*FIELD* CS

Endocrine:
   Acromegaly;
   Functional pituitary adenoma

Lab:
   Elevated growth hormone levels

Skin:
   Acanthosis nigricans;
   Galactorrhea from prolactin excess

Oncology:
   Somatotrophinoma

Inheritance:
   Autosomal dominant;
   recessive gene loss at 11q13 for somatotrophinoma

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/13/1997
terry: 2/5/1997
mark: 12/30/1996
mark: 12/26/1996
terry: 12/16/1996
mark: 9/22/1995
mimadm: 3/11/1994
carol: 7/9/1993
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
102300
*FIELD* TI
*102300 ACROMELALGIA, HEREDITARY
RESTLESS LEGS
*FIELD* TX
Because of paresthesia when first going to bed or sitting still for a
time, the affected person cannot resist fidgeting with his or her feet.
Huizinga (1957) described a family with affected persons in 5
generations. The condition, which began in adolescence, was relieved by
cold. Ekbom (1960) and Bornstein (1961) also described familial
aggregation. Autosomal dominant inheritance was particularly well
documented by Boghen and Peyronnard (1976), who furthermore described
myoclonic jerks in 10 of 18 affected persons. The jerks occurred at
night before sleep and severely interfered with it. The authors referred
to the 'painful-legs--moving-toes syndrome' in a patient whose relatives
had the restless legs syndrome and proposed that the disorders are the
same. Sudden bodily jerking on falling asleep is a frequent finding in
normal persons (Oswald, 1959).

Trenkwalder et al. (1996) found evidence of anticipation in restless
legs syndrome in 1 large German pedigree. The disorder had a 30-year
age-at-onset difference between generations.

*FIELD* RF
1. Boghen, D.; Peyronnard, J.-M.: Myoclonus in familial restless
legs syndrome. Arch. Neurol. 33: 368-370, 1976.

2. Bornstein, B.: Restless legs. Psychiat. Neurol. 141: 165-201,
1961.

3. Ekbom, K. A.: Restless legs syndrome. Neurology 10: 868-873,
1960.

4. Huizinga, J.: Hereditary acromelalgia (or 'restless legs'). Acta
Genet. Statist. Med. 7: 121-123, 1957.

5. Oswald, I.: Sudden bodily jerks on falling asleep. Brain 82:
92-103, 1959.

6. Trenkwalder, C.; Seidel, V. C.; Gasser, T.; Oertel, W. H.: Clinical
symptoms and possible anticipation in a large kindred with familial
restless legs syndrome. Mov. Disord. 11: 389-394, 1996.

*FIELD* CS

Neuro:
   Acromelalgia;
   Myoclonus;
   Paresthesia;
   Restless legs

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/29/1996
terry: 12/20/1996
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987

*RECORD*
*FIELD* NO
102350
*FIELD* TI
*102350 ACROMIAL DIMPLES
SUPRASPINOUS FOSSAE, CONGENITAL
*FIELD* TX
Dimples overlying the acromial process of the scapula, i.e., on the back
of the shoulders, is a regular feature of the 18q- syndrome. Bianchine
(1974) described acromial dimples in a 4-year-old girl, her 30-year-old
mother, and her 65-year-old maternal grandmother. All 3 were generally
healthy. Gorlin (1974) told me of acromial dimples transmitted through 4
and probably 5 generations. Halal (1980) observed segregation in 2
kindreds but found no instance of male-to-male transmission. Mehes and
Meggyessy (1987) described acromial dimples in a 1-year-old boy and his
healthy 29-year-old father. In another family, a 3-year-old girl, her
31-year-old mother, and her 6-year-old brother had bilateral acromial
dimples. Wood (1990) and Samlaska (1991) described inherited symmetric
shoulder dimpling over the acromial process, which they referred to as
congenital supraspinous fossae. The familial pattern was consistent with
autosomal dominant inheritance. Acromial dimples occur as a virtually
constant feature of 18q deletion (Insley, 1967).

*FIELD* RF
1. Bianchine, J. W.: Acromial dimples: a benign familial trait. Am.
J. Hum. Genet. 26: 412-413, 1974.

2. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.  6/10/1974.

3. Halal, F.: Dominant inheritance of acromial skin dimples. Am.
J. Med. Genet. 6: 259-262, 1980.

4. Insley, J.: Syndrome associated with a deficiency of part of the
long arm of chromosome no. 18. Arch. Dis. Child. 42: 140-146, 1967.

5. Mehes, K.; Meggyessy, V.: Autosomal dominant inheritance of benign
bilateral acromial dimples. Hum. Genet. 76: 206 only, 1987.

6. Samlaska, C. P.: Congenital supraspinous fossae. J. Am. Acad.
Derm. 25: 1078-1079, 1991.

7. Wood, V. E.: Congenital skin fossae about the shoulder. Plast.
Reconst. Surg. 85: 798-800, 1990.

*FIELD* CS

Skin:
   Acromial dimples

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
mimadm: 3/11/1994
carol: 11/20/1992
carol: 3/31/1992
supermim: 3/16/1992
carol: 1/21/1992

*RECORD*
*FIELD* NO
102370
*FIELD* TI
102370 ACROMICRIC DYSPLASIA
*FIELD* TX
Maroteaux et al. (1986) described (and named) a 'new' entity on the
basis of 6 patients. Features were mild facial anomalies, markedly
shortened hands and feet, and growth retardation that was severe in
most. The metacarpals and phalanges were short and stubby; the proximal
portion of the second metacarpal showed a notch on its radial side and
the fifth metacarpal had a notch on its ulnar side. Similar histologic
changes were found in biopsy of the proximal tibial growth cartilage in
2 cases: disorganization of the growth zone with islands of cells and
abnormal arrangement of collagen. Both sexes were affected. All 6 cases
were sporadic (with normal parental age and no parental consanguinity).
In an addendum, Maroteaux et al. (1986) stated that they had observed
acromicric dysplasia in mother and son.

*FIELD* RF
1. Maroteaux, P.; Stanescu, R.; Stanescu, V.; Rappaport, R.: Acromicric
dysplasia. Am. J. Med. Genet. 24: 447-459, 1986.

*FIELD* CS

Facies:
   Mild facial anomalies

Limbs:
   Short hands and feet

Growth:
   Severe growth retardation

Radiology:
   Short stubby metacarpals and phalanges;
   Second metacarpal notched proximally on radial side;
   Fifth metacarpal notched on ulnar side

Lab:
   Growth cartilage disorganized, with islands of cells and abnormal
   collagen arrangement

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/16/1986

*RECORD*
*FIELD* NO
102400
*FIELD* TI
102400 ACROOSTEOLYSIS
*FIELD* TX
Schinz et al. (1951) described dominant inheritance of slowly
progressive osteolysis of the phalanges in the hands and feet associated
with recurrent ulcers of the fingers and soles, elimination of bone
sequestra, and healing with loss of toes or fingers, with onset between
8 and 22 years. Lamy and Maroteaux (1961) described a dominant form in
mother and son. Members of 2 earlier generations were also affected. No
abnormality of sensation was present. Maroteaux (1970) found no basilar
impression or other changes in the skull or long bones to suggest that
this was Cheney syndrome (102500). A phenocopy is produced in men
working in the polymerization of vinyl chloride (Harris and Adams, 1967;
Ross, 1970). Reed (1974) told me of other families.

*FIELD* SA
Harms  (1954)
*FIELD* RF
1. Harms, I.: Ueber die familiaere Akro-osteolyse. Fortschr. Roentgenstr. 80:
727-733, 1954.

2. Harris, D. K.; Adams, W. G. F.: Acro-osteolysis occurring in men
engaged in the polymerization of vinyl chloride. Brit. Med. J. 3:
712-714, 1967.

3. Lamy, M.; Maroteaux, P.: Acro-osteolyse dominante. Arch. Franc.
Pediat. 18: 693-702, 1961.

4. Maroteaux, P.: Personal Communication. Paris, France  1970.

5. Reed, W. B.: Personal Communication. Burbank, Calif.  1974.

6. Ross, J. A.: An unusual occupational bone change. In: Jelliffe,
A. M.; Strickland, B.: Symposium Ossium.  London: Livingstone (pub.)
1970.

7. Schinz, H. R.; Baensch, W. E.; Friedl, E.; Uehlinger, E.: Roentgen-diagnostics.
Trans. in English by J. T. Case.  New York: Grune and Stratton (pub.)
1: 1951. Pp. 734 only. Note: Fig. 969.

*FIELD* CS

Limbs:
   Osteolysis of phalanges;
   Recurrent ulcers, fingers and soles;
   Bone sequestra;
   Loss of toes or fingers

Misc:
   Onset 8 to 22 years;
   Phenocopy in vinyl chloride workers

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/28/1994
pfoster: 3/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
102480
*FIELD* TI
*102480 ACROSIN; ACR
PROACROSIN, INCLUDED;;
PREPROACROSIN, INCLUDED
*FIELD* TX
Acrosin (EC 3.4.21.10) is the major proteinase present in the acrosome
of mature spermatozoa. It is a typical serine proteinase with
trypsin-like specificity. It is stored in the acrosome in its precursor
form, proacrosin. The active enzyme functions in the lysis of the zona
pellucida, thus facilitating penetration of the sperm through the
innermost glycoprotein layers of the ovum. In many species, it is shown
that biosynthesis of acrosin is confined to the haploid phase of
spermatogenesis. By indirect immunofluorescent techniques,
Florke-Gerloff et al. (1983) demonstrated that in man (pro)acrosin first
appears in the haploid spermatids. Adham et al. (1989, 1990) isolated a
full-length cDNA clone for human proacrosin. The deduced amino acid
sequence of human proacrosin in the proline-rich domain is different
from the corresponding sequence of boar proacrosin. This domain may be
involved in a species-specific binding of spermatozoa to the zona
pellucida. The mRNA for proacrosin is synthesized only in the
postmeiotic stages of spermatogenesis. The cDNA sequence indicates that
acrosin is synthesized as a preproacrosin. Adham et al. (1989) used
somatic cell hybrid analysis to localize the human proacrosin gene to
chromosome 22q13-qter. By in situ hybridization, Engel (1990) assigned
the acrosin gene to mouse chromosome 15 and rat chromosome 7; see
Kremling et al. (1991). Furthermore, by an immunohistologic method,
Engel (1990) demonstrated deficiency of acrosin in spermatids of
infertile males. Keime et al. (1990) used cDNA clones as probes to
isolate the gene for proacrosin from a human leukocyte genomic library.
They found that the gene contains 4 introns varying in length from 0.2
to 4.5 kb. Klemm et al. (1991) provided a review. Vazquez-Levin et al.
(1992) reported on the sequence and structure of the proacrosin gene and
pointed to differences from previously reported data. Adham et al.
(1992) defended the validity of the previous data.

*FIELD* SA
Adham et al. (1989); Adham et al. (1989)
*FIELD* RF
1. Adham, I. M.; Grzeschik, K.-H.; Geurts van Kessel, A. H. M.; Engel,
W.: Localization of human preproacrosin to chromosome 22q13-qter
by somatic cell hybrid analysis.  (Abstract) Cytogenet. Cell Genet. 51:
948 only, 1989.

2. Adham, I. M.; Grzeschik, K.-H.; Geurts van Kessel, A. H. M.; Engel,
W.: The gene encoding the human preproacrosin (ACR) maps to the q13-qter
region on chromosome 22. Hum. Genet. 84: 59-62, 1989.

3. Adham, I. M.; Klemm, U.; Maier, W.-M.; Engel, W.: Molecular cloning
of human preproacrosin cDNA. Hum. Genet. 84: 125-128, 1990.

4. Adham, I. M.; Klemm, U.; Maier, W.-M.; Tsaousidou, S.; Engel, W.
: Molecular cloning and expression of boar and human proacrosin cDNA.
(Abstract) Meeting of Gesellschaft fuer Humangenetik, Munich 149
only, 4/4/1989.

5. Adham, I. M.; Spitzer, U.; Schlosser, M.; Kremling, H.; Keime,
S.; Engel, W.: A reply: the human proacrosin gene. Europ. J. Biochem. 207:
27-28, 1992.

6. Engel, W.: Personal Communication. Goettingen, Germany  5/17/1990.

7. Florke-Gerloff, S.; Topfer-Petersen, E.; Muller-Esterl, W.; Schill,
W.-B.; Engel, W.: Acrosin and the acrosome in human spermatogenesis.
Hum. Genet. 65: 61-67, 1983.

8. Keime, S.; Adham, I. M.; Engel, W.: Nucleotide sequence and exon-intron
organization of the human proacrosin gene. Europ. J. Biochem. 190:
195-200, 1990.

9. Klemm, U.; Muller-Esterl, W.; Engel, W.: Acrosin, the peculiar
sperm-specific serine protease. Hum. Genet. 87: 635-641, 1991.

10. Kremling, H.; Keime, S.; Wilhelm, K.; Adham, I. M.; Hameister,
H.; Engel, W.: Mouse proacrosin gene: nucleotide sequence, diploid
expression and chromosomal localization. Genomics 11: 828-834,
1991.

11. Vazquez-Levin, M. H.; Reventos, J.; Gordon, J. W.: Molecular
cloning, sequencing and restriction mapping of the genomic sequence
encoding human proacrosin. Europ. J. Biochem. 207: 23-26, 1992.

*FIELD* CD
Victor A. McKusick: 5/5/1989

*FIELD* ED
warfield: 4/7/1994
carol: 9/1/1992
supermim: 3/16/1992
carol: 12/5/1991
carol: 11/25/1991
carol: 9/7/1990

*RECORD*
*FIELD* NO
102490
*FIELD* TI
102490 ACRORENOOCULAR SYNDROME
*FIELD* TX
Halal et al. (1984) reported a French-Canadian family in which 7 persons
in 3 generations had various combinations of acral, renal, and ocular
defects. The acral anomalies varied from mild hypoplasia of the distal
part of the thumb with limitation of motion at the interphalangeal joint
to severe thumb hypoplasia and preaxial polydactyly. Renal anomalies
varied from mild malrotation to crossed renal ectopia without fusion;
other urinary tract anomalies were vesicoureteral reflux and bladder
diverticula. Ocular features included 'complete' coloboma, coloboma of
the optic nerve, ptosis, and Duane anomaly (126800). The disorder
behaved as an autosomal dominant (with 1 instance of male-to-male
transmission) with high penetrance but variable expressivity.
Dermatoglyphic abnormalities were described. Temtamy and McKusick (1978)
described father and son with some combination of Duane anomaly, radial
defects, and kidney anomalies. The father had Duane anomaly, bilateral
thenar and thumb hypoplasia with syndactyly of the index finger and
unilateral clubhand deformity, and malrotation of both kidneys with
partial horseshoe anomaly. The son had apparently normal eyes, bilateral
clubhand with absent thumbs and absent right kidney with malrotation of
the left kidney. Halal et al. (1984) thought that the disorder in the
Temtamy-McKusick family might be different because extensive pectoral
and upper limb involvement present in those cases was absent in all the
Halal cases.

Naito et al. (1989) and Pierquin et al. (1991) described 3 more cases of
acrorenoocular syndrome. Aalfs et al. (1996) reported an affected family
from the Dutch Antilles. Hypoplasia of the right thumb and absence of
the left thumb, hypoplastic left forearm, microphthalmia, microcornea,
coloboma of iris and choroidea, cataract, and left-crossed renal ectopia
with fusion were the main manifestations in the proband. His mother had
hypoplastic left thumb and cataract (possibly due to diabetes mellitus).
The sister of the proband demonstrated absence of both thumbs, radii and
ulnae, and bilateral chorioretinal scars between optic disc and fovea.
Urologic investigations could not be done in the proband's mother and
sister. The clinical picture in this family fit all criteria for
acrorenoocular syndrome.

*FIELD* SA
Temtamy  (1986); Temtamy et al. (1975)
*FIELD* RF
1. Aalfs, C. M.; van Schooneveld, M. J.; van Keulen, E. M.; Hennekem,
R. C. M.: Further delineation of the acro-renal-ocular syndrome.
Am. J. Med. Genet. 62: 276-281, 1996.

2. Halal, F.; Homsy, M.; Perreault, G.: Acro-renal-ocular syndrome:
autosomal dominant thumb hypoplasia, renal ectopia, and eye defect.
Am. J. Med. Genet. 17: 753-762, 1984.

3. Naito, T.; Kida, H.; Yokoyama, H.; Abe, T.; Takeda, S.; Uno, D.;
Hattori, N.: Nature of renal involvement in the acro-renal-ocular
syndrome. Nephron 51: 115-118, 1989.

4. Pierquin, G.; Hall, M.; Vanhelleputte, C.; Van Regemorter, N.:
A new case of acro-renal-ocular (radio-renal-ocular) syndrome with
cleft palate and costo-vertebral defects? A brief clinical report. Ophthal.
Paediat. Genet. 12: 183-186, 1991.

5. Temtamy, S. A.: The DR syndrome or the Okihiro syndrome?.  (Letter) Am.
J. Med. Genet. 25: 173-174, 1986.

6. Temtamy, S. A.; McKusick, V. A.: The Genetics of Hand Malformations.
New York: Alan R. Liss (pub.)  1978. Pp. 133-135.

7. Temtamy, S. A.; Shoukry, A. S.; Ghaly, I.; El-Meligy, R.; Boulos,
S. Y.: The Duane radial dysplasia syndrome: an autosomal dominant
disorder. Birth Defects Orig. Art. Ser. XI(5): 344-345, 1975.

*FIELD* CS

Limbs:
   Thumb hypoplasia/aplasia;
   Stiff thumb;
   Preaxial polydactyly;
   Radial defects;
   Thenar hypoplasia;
   Syndactyly;
   Clubhand deformity

GU:
   Renal malrotation/ectopia;
   Partial horseshoe kidney;
   Vesicoureteral reflux;
   Bladder diverticula

Eyes:
   Complete coloboma;
   Optic nerve coloboma;
   Ptosis;
   Duane anomaly (126800)

Skin:
   Abnormal dermatoglyphics

Inheritance:
   Autosomal dominant

*FIELD* CN
Iosif W. Lurie - updated: 7/1/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 07/02/1996
carol: 7/1/1996
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987

*RECORD*
*FIELD* NO
102500
*FIELD* TI
*102500 ACROOSTEOLYSIS WITH OSTEOPOROSIS AND CHANGES IN SKULL AND MANDIBLE
CHENEY SYNDROME;;
HAJDU-CHENEY SYNDROME;;
ARTHRODENTOOSTEODYSPLASIA
*FIELD* TX
Cheney (1965) described this connective tissue disorder in a family
living in the upper peninsula of Michigan. The mother and 4 children had
acroosteolysis, multiple wormian bones, and hypoplasia of ramus of
mandible. Unlike pycnodysostosis (265800), a recessive with
osteosclerosis, the condition in Cheney's patients included osteoporosis
with basilar impression as a feature. The mother was 57 and the affected
children (4 of 6) were 35, 26, 21 and 13 years of age. Dorst and
McKusick (1969) described a case. Herrmann et al. (1973) exhaustively
reviewed the previously reported cases and described 1 new case. They
pointed out that the changes in the terminal phalanges in this condition
as well as in pycnodysostosis are 'pseudo-osteolysis,' that is, the
disorder is one of defective development of bone rather than destruction
of bone already formed. They observed that acroosteolysis, generalized
osteoporosis and multiple fractures of the skull, spine and digits,
short stature, persistent cranial sutures, multiple wormian bones, early
loss of teeth, and joint laxity were features associated in varying
degrees. The authors suggested the name arthrodentoosteodysplasia and
the eponym Hajdu-Cheney syndrome for this disorder. The patients show
bathrocephaly (projection of the occipital area and a deep groove at the
lambdoidal sutures between the occipital and parietal bones).
Loose-jointedness, dislocations of the patella, and hernia occur. Some
have suggested that short stature is a consistent feature; a patient of
mine (P20775) had height of 173 cm at age 16. In addition to
micrognathia and narrow high palate, prominent (projecting) ears may be
a feature. Unusually deep voice has also been noted. Silverman et al.
(1974) provided useful long-term follow-up on 2 cases. They believed the
patient reported by Gilula et al. (1976) had a nonfamilial disorder.
Although literally true in that instance, the disorder may have been
genetic and may be the same as (or perhaps an allelic form of) the
Cheney syndrome.

Elias et al. (1978) reported Cheney syndrome in a mother and son, one of
whom had an enlarged sella turcica associated with normal endocrine
function. Histologic studies made in an area of active osteolysis in a
phalanx suggested to the authors 'a neurovascular dysfunction with local
release of osteolytic mediators.' Matisonn and Ziady (1973) described
affected father and 2 sons; only the sons were personally examined.
Udell et al. (1986) found this disorder in a 27-year-old man who for 7
years had gradually progressive loss of distal phalangeal mass with pain
in the affected fingers. His mother had similar 'shrinking fingers,'
which first appeared at about age 50, progressed for 2 years, and then
became asymptomatic. Udell et al. (1986) were impressed with the
abundance of mast cells in the affected tissues and suggested that these
cells might be elaborating a local factor causing or promoting
osteolysis. They pointed to the osteopenia that occurs with large doses
of heparin and with systemic mast cell disease (154800). Magnetic
resonance imaging was reported by Kawamura et al. (1991). Ades et al.
(1993) described a child with this disorder complicated by basilar
invagination and hydrocephalus. MRI showed Arnold-Chiari malformation
and obstruction to cerebrospinal fluid flow at the level of the foramen
magnum. A ventriculoperitoneal shunt was inserted at the age of 10
years. Kaler et al. (1990) described a 21-year-old woman with
Hajdu-Cheney syndrome who had severe mitral regurgitation and mild
aortic stenosis necessitating mitral valve replacement and aortic
valvotomy at the age of 14 years. Pathologic examination of the mitral
valve showed myxomatous degeneration with thickened valve leaflets and
foci of calcification. At the age of 18, pacemaker implantation was
necessitated by the development of heart block. At the age of 20,
balloon aortic valvuloplasty was attempted for worsening aortic
stenosis, but was unsuccessful because of thick and calcified valve
leaflets; aortic valve replacement was required. O'Reilly and Shaw
(1994) gave an extensive description of the radiologic features in a
15-year-old girl. From early in life the face was dysmorphic with a
prominent premaxilla, hypertelorism, and downward sloping eyes with
narrow palpebral fissures. Joint laxity and hyperextensibility developed
as the child grew older. Height and weight remained at the third
percentile for age but head circumference was above the 98th percentile,
with an enlarged pituitary fossa on skull radiographs. Kyphoscoliosis
required bracing and eventually spinal fusion. The permanent teeth were
all lost soon after eruption. Basilar impression with multiple wormian
bones and osteolysis of the terminal phalanges with overlying soft
tissue swelling were illustrated.

On the basis of 2 unrelated patients with typical Hajdu-Cheney syndrome
and cystic kidneys with ultrasonographic changes similar to those of
autosomal dominant polycystic kidney disease (173900), Kaplan et al.
(1995) concluded that cystic kidneys are an important component of this
disorder. Neither patient had a family history of polycystic kidney or
Hajdu-Cheney syndrome. One of the patients died of complications of the
latter condition at the age of 16 years.

*FIELD* SA
Brown et al. (1976); Hajdu and Kauntze (1948); Weleber and Beals (1976)
*FIELD* RF
1. Ades, L. C.; Morris, L. L.; Haan, E. A.: Hydrocephalus in Hajdu-Cheney
syndrome.  (Letter) J. Med. Genet. 30: 175 only, 1993.

2. Brown, D. M.; Bradford, D. S.; Gorlin, R. J.; Desnick, R. J.; Langer,
L. O., Jr.; Jowsey, J.; Sauk, J. J., Jr.: The acro-osteolysis syndrome:
morphologic and biochemical studies. J. Pediat. 88: 573-580, 1976.

3. Cheney, W. D.: Acro-osteolysis. Am. J. Roentgen. 94: 595-607,
1965.

4. Dorst, J. P.; McKusick, V. A.: Acro-osteolysis (Cheney syndrome).
Birth Defects Orig. Art. Ser. V(3): 215-217, 1969.

5. Elias, A. N.; Pinals, R. S.; Anderson, H. C.; Gould, L. V.; Streeten,
D. H. P.: Hereditary osteodysplasia with acro-osteolysis (the Hajdu-Cheney
syndrome). Am. J. Med. 65: 627-636, 1978.

6. Gilula, L. A.; Bliznak, J.; Staple, T. W.: Idiopathic nonfamilial
acro-osteolysis with cortical defects and mandibular ramus osteolysis.
Radiology 121: 63-68, 1976.

7. Hajdu, N.; Kauntze, R.: Cranioskeletal dysplasia. Brit. J. Radiol. 21:
42-48, 1948.

8. Herrmann, J.; Zugibe, F. T.; Gilbert, E. F.; Opitz, J. M.: Arthro-dento-osteodysplasia
(Hajdu-Cheney syndrome): review of a genetic 'acro-osteolysis' syndrome.
Z. Kinderheilk. 114: 93-110, 1973.

9. Kaler, S. G.; Geggel, R. L.; Sadeghi-Nejad, A.: Hajdu-Cheney syndrome
associated with severe cardiac valvular and conduction disease. Dysmorph.
Clin. Genet. 4: 43-47, 1990.

10. Kaplan, P.; Ramos, F.; Zackai, E. H.; Bellah, R. D.; Kaplan, B.
S.: Cystic kidney disease in Hajdu-Cheney syndrome. Am. J. Med.
Genet. 56: 25-30, 1995.

11. Kawamura, J.; Miki, Y.; Yamazaki, S.; Ogawa, M.: Hajdu-Cheney
syndrome: MR imaging. Neuroradiology 33: 441-442, 1991.

12. Matisonn, A.; Ziady, F.: Familial acro-osteolysis. S. Afr.
Med. J. 47: 2060-2063, 1973.

13. O'Reilly, M. A. R.; Shaw, D. G.: Hajdu-Cheney syndrome. Ann.
Rheum. Dis. 53: 276-279, 1994.

14. Silverman, F. N.; Dorst, J. P.; Hajdu, N.: Acro-osteolysis (Hajdu-Cheney
syndrome). In: Bergsma, D.: Skeletal Dysplasias.  Amsterdam: Excerpta
Medica (pub.)  1974. Pp. 106-123.

15. Udell, J.; Schumacher, H. R., Jr.; Kaplan, F.; Fallon, M. D.:
Idiopathic familial acroosteolysis: histomorphometric study of bone
and literature review of the Hajdu-Cheney syndrome. Arthritis Rheum. 29:
1032-1038, 1986.

16. Weleber, R. G.; Beals, R. K.: Hajdu-Cheney syndrome--report of
2 cases and review of literature. J. Pediat. 88: 243-249, 1976.

*FIELD* CS

Limbs:
   Acroosteolysis;
   Terminal phalangeal pseudo-osteolysis;
   Patellar dislocation

Skull:
   Multiple wormian bones;
   Mandibular ramus hypoplasia;
   Osteoporosis with basilar impression;
   Persistent cranial sutures

Skel:
   Generalized osteoporosis;
   Multiple fractures

Growth:
   Short stature

Teeth:
   Early teeth loss

Joints:
   Joint laxity

Abdomen:
   Hernia

Mouth:
   Micrognathia;
   Narrow high palate

Ears:
   Prominent (projecting) ears

Voice:
   Unusually deep voice

Neuro:
   Hydrocephalus

Radiology:
   Bathrocephaly;
   Arnold-Chiari malformation on MRI

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 4/25/1995
jason: 6/13/1994
carol: 4/6/1994
mimadm: 3/11/1994
carol: 3/20/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
102510
*FIELD* TI
*102510 ACROPECTOROVERTEBRAL DYSPLASIA, F-FORM OF
*FIELD* TX
Grosse et al. (1969) described 8 persons in 4 generations of a kindred
(of surname beginning with F) who showed a skeletal dysplasia.
Male-to-male transmission was observed. The hand malformation was mainly
abnormal segmentation of the first ray. The broad, short thumbs showed
incipient duplication of the distal phalanx and were, to a variable
degree, webbing with the index finger, which deviated radially,
especially when the webbing was extensive. In some, the web contained an
extra bone, which seemed to be derived from the thumb phalanges and was
associated with the formation of a bony bridge between the tip of the
thumb and a radial projection from the distal end of the first index
phalanx. In some, the web between the first two digits was complete and
the two distal phalanges of the index finger were then hypoplastic and
formed part of a bone 'chain' connecting the tips of the thumb and index
finger. Capitate and hamate were invariably fused; other carpals were
sometimes incorporated into the fusion. The toes were also webbed,
especially the first and second, and malformed. Pectoral and vertebral
anomalies were sternal deformity and spina bifida occulta at L5 or S1.
According to Opitz (1982), this family remained a unique observation.

Camera et al. (1995) reported on a father and daughter in a second
family. Synostoses between capitate and hamate, and between talus and
navicular, invariable features in the 8 affected members of the family
reported by Grosse et al. (1969), were found. The hand malformation
involved principally the first 2 rays. In the father and daughter, the
short and malformed thumb was webbed with the index finger, which was
radially deviated with duplication of the middle and distal phalanges.
In the feet, polydactyly and severe metatarsal and toe anomalies were
present. The father had a prominent sternum with pectus excavatum,
whereas the daughter had no sternal deformity. Both of them had a mild
failure of fusion of posterior arch L5 and/or S1.

*FIELD* RF
1. Camera, G.; Camera, A.; Pozzolo, S.; Costa, M.; Mantero, R.: F-syndrome
(F-form of acro-pectoro-vertebral dysplasia): report on a second family.
Am. J. Med. Genet. 57: 472-475, 1995.

2. Grosse, F. R.; Herrmann, J.; Opitz, J. M.: The F-form of acropectorovertebral
dysplasia: the F-syndrome. Birth Defects Orig. Art. Ser. V(3):
48-63, 1969.

3. Opitz, J. M.: Personal Communication. Helena, Mont.  1982.

*FIELD* CS

Skel:
   Skeletal dysplasia

Limbs:
   Abnormal segmentation of the first ray;
   Broad, short thumbs;
   Incipient distal thumb phalanx duplication;
   Thumb and index finger syndactyly;
   Index finger deviated radially;
   Fused capitate and hamate;
   Syndactyly of toes;
   Malformed toes

Thorax:
   Pectoral anomaly;
   Sternal deformity

Spine:
   Vertebral anomalies;
   Spina bifida occulta at L5 or S1

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 7/16/1995
warfield: 4/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
102520
*FIELD* TI
102520 ACRORENAL SYNDROME
*FIELD* TX
Dieker and Opitz (1969) described 3 patients with the association of
major malformations of the kidneys and limbs, mainly absence deformities
of digits. Curran and Curran (1972) described a case and pointed out
that paternal age was sometimes increased (44 years in their case and 57
years in one of Dieker and Opitz). All cases have been male and
sporadic, without parental consanguinity. Opitz (1982) pointed out that
this is not, to use his terminology, a causal entity, but rather a
nonspecific developmental field defect.

*FIELD* RF
1. Curran, A. S.; Curran, J. P.: Associated acral and renal malformations:
a new syndrome?. Pediatrics 49: 716-725, 1972.

2. Dieker, H.; Opitz, J. M.: Associated acral and renal malformations.
Birth Defects Orig. Art. Ser. V(3): 68-77, 1969.

3. Opitz, J. M.: Personal Communication. Helena, Mont.  4/1982.

*FIELD* CS

GU:
   Renal malformation

Limbs:
   Absent digits

Misc:
   Male, sporadic developmental field defect

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
mimadm: 4/2/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
102525
*FIELD* TI
*102525 ACROSOMAL VESICLE PROTEIN-1; ACRV1
SP-10 PROTEIN
*FIELD* TX
The SP-10 protein is a testis-specific, differentiation antigen that
arises within the acrosomal vesicle during spermatogenesis. Herr et al.
(1991) used a 634-bp fragment of the SP-10 sequence as a probe on
Southern blots of EcoRI digested DNA from human-mouse somatic cell
hybrids. Cosegregation of the ACRV1 gene with human chromosome 11 was
observed. Use of hybrid cell lines containing translocations of human
chromosome 11 allowed further refinement of localization to 11p12-q13.
However, by fluorescence in situ hybridization using cDNA, ribo, and
genomic versions of probes for SP-10 coupled to analysis of an expanded
series of somatic cell hybrids, Golden et al. (1993) showed that the
location of ACRV1 is at the junction between 11q23 and 11q24. Golden et
al. (1993) emphasized the utility of riboprobes for chromosome
localization of single-copy genes. Riboprobes are complementary RNA
(cRNA) probes produced using a phage-encoded RNA polymerase. Golden
(1994) found them better than cDNA probes when the probe was short.

*FIELD* RF
1. Golden, W. L.: Personal Communication. Charlottesville, Va.
1/12/1994.

2. Golden, W. L.; von Kap-herr, C.; Kurth, B.; Wright, R. M.; Flickinger,
C. J.; Eddy, R.; Shows, T.; Herr, J. C.: Refinement of the localization
of the gene for human intraacrosomal protein SP-10 (ACRV1) to the
junction of bands q23-q24 of chromosome 11 by nonisotopic in situ
hybridization. Genomics 18: 446-449, 1993.

3. Herr, J. C.; Wright, R. M.; Flickinger, C. J.; Eddy, R. L.; Shows,
T. B.: Assignment of the gene for human intra-acrosomal protein SP-10
(ACRV1) to the p12-q13 region of chromosome 11.  (Abstract) Cytogenet.
Cell Genet. 58: 1963 only, 1991.

*FIELD* CD
Victor A. McKusick: 9/30/1991

*FIELD* ED
carol: 1/14/1994
carol: 11/30/1993
supermim: 3/16/1992
carol: 2/23/1992
carol: 9/30/1991

*RECORD*
*FIELD* NO
102530
*FIELD* TI
102530 ACROSOME MALFORMATION OF SPERMATOZOA
ROUND-HEADED SPERMATOZOA;;
SPERMATOZOA, ROUND-HEADED
GLOBOZOOSPERMIA, INCLUDED
*FIELD* TX
Vegni-Talluri et al. (1977) observed acrosome malformations of
spermatids and spermatozoa in the testes of 2 infertile males who were
investigated by light and electron microscopy. The first visible
abnormality appeared at early spermatid stages. Defective
differentiation of the acrosome granule in spermatids appeared to be
responsible for the malformation of mature spermatozoa. The fact that
about half the early spermatids lacked the acrosome granule suggested
that the original cause is genetic and that the gene is expressed in the
haploid phase. The gene might be X-linked or autosomal. The authors
referred to comparable abnormalities of the acrosome observed in bulls
and boars and thought to have a mendelian basis. Complete lack of the
acrosome during spermiogenesis, resulting in round-headed spermatozoa
incapable of fertilization, has been observed in man and has been
thought to have a primary genetic basis. Furthermore, the authors drew
analogies to abnormalities of spermatozoa related to the T-locus of the
mouse. Abnormalities of spermiogenesis in mammals were reviewed by
Bishop (1972). Kullander and Rausing (1975) observed only round-headed
spermatozoa in 2 infertile brothers and suggested that homozygosity for
an autosomal gene defect underlies this phenotype. In Friesian bulls, a
characteristic defect of the acrosome ('knobbed' spermatozoa) associated
with sterility appears to be autosomal recessive.

Florke-Gerloff et al. (1983) showed that the acrosomal membrane proteins
are first detectable in early spermatids. (The acrosome is a caplike
compartment in the apical part of the sperm head. It is a lysosome-like
organelle derived from the Golgi apparatus. In the fertilization
process, fusion of the sperm plasma membrane and outer acrosomal
membrane (OAM) occurs with discharge of the acrosomal endosol.)
Florke-Gerloff et al. (1983) found that the round-headed spermatozoa of
an infertile patient with globozoospermia lacked the constituting
components of the outer acrosomal membrane as well as the intraacrosomal
acrosin system (see 102480). Nistal et al. (1978) observed 2 infertile
brothers with round-headed spermatozoa. Florke-Gerloff et al. (1984)
also found 2 affected brothers and studied their father as well. Whereas
the brothers, like other reported cases, had all round-headed
spermatozoa, the father had more than 94% normally shaped sperm. Theirs
was the first study to quantitate the abnormality; in 9 infertile men
the proportion of round-headed sperm varied from 14 to 71%. They showed
that the round-headed spermatozoa lacked both acrosin and OAM, as
indicated by immunofluorescent and immunoperoxidase staining techniques
and confirmed by the gelatinolysis test. The normally shaped sperm of 6
of the 9 men were positive for acrosin and OAM. In the father of the
affected brothers, only 10% of the normally shaped spermatozoa were
acrosin positive and only 30% were positive for OAM. Florke-Gerloff et
al. (1984) suggested that the round-headed spermatozoa syndrome is
polygenic in its inheritance.

*FIELD* SA
Donald and Hancock (1953)
*FIELD* RF
1. Bishop, M. W. H.: Genetically determined abnormalities of the
reproductive system. J. Reprod. Fertil. 15 (suppl.): 51-78, 1972.

2. Donald, H. P.; Hancock, J. L.: Evidence of gene-controlled sterility
in bulls. J. Agricult. Sci. 43: 178-181, 1953.

3. Florke-Gerloff, S.; Topfer-Petersen, E.; Muller-Esterl, W.; Mansouri,
A.; Schatz, R.; Schirren, C.; Schill, W.; Engel, W.: Biochemical
and genetic investigation of round-headed spermatozoa in infertile
men including two brothers and their father. Andrologia 16: 187-202,
1984.

4. Florke-Gerloff, S.; Topfer-Petersen, E.; Muller-Esterl, W.; Schill,
W.-B.; Engel, W.: Acrosin and the acrosome in human spermatogenesis.
Hum. Genet. 65: 61-67, 1983.

5. Kullander, S.; Rausing, A.: On round-headed human spermatozoa.
Int. J. Fertil. 20: 33-40, 1975.

6. Nistal, M.; Herruzo, A.; Sanchez-Corral, F.: Teratozoospermia
absoluta de presentacion familiar. Espermatozoides microcefalos irregulares
sin acrosoma. Andrologia 10: 234-240, 1978.

7. Vegni-Talluri, M.; Menchini-Fabris, F.; Renieri, T.: A possible
haploid effect in acrosome malformations of human spermatozoa. Andrologia 9:
315-322, 1977.

*FIELD* CS

GU:
   Infertility

Lab:
   Malformed acrosomes of spermatids and spermatozoa

Inheritance:
   Autosomal dominant vs. X-linked or polygenic

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
carol: 4/6/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 5/5/1989

*RECORD*
*FIELD* NO
102540
*FIELD* TI
*102540 ACTIN, ALPHA, CARDIAC MUSCLE; ACTC
SMOOTH MUSCLE ACTIN;;
ALPHA-ACTIN;;
ACTIN, ALPHA
*FIELD* TX
Actin has been identified in many kinds of cells including muscle, where
it is a major constituent of the thin filament, and platelets. Muscle
actins from sources as diverse as rabbits and fish are very similar in
amino acid sequence. Elzinga et al. (1976) examined whether actin in
different tissues of the same organism are products of the same gene.
They found that human platelet and human cardiac actins differ by one
amino acid, viz., threonine and valine, respectively, at position 129.
Thus they must be determined by different genes. Actins can be separated
by isoelectric focusing into 3 main groups which show more than 90%
homology of amino acid sequence. Firtel (1981) referred to the actin of
smooth muscle, the most acidic form, as alpha type and the two
cytoplasmic forms as beta and gamma. Beta and gamma actins are involved
in the cytoskeleton and in internal cell mobility phenomena. The actins
constitute multiple gene families. There is only a 4% amino acid
difference in the actins of Physarum and mammals. In mammals, 4
different muscle actins have been sequenced: from fast muscle, heart,
aorta, and stomach. These vary only by 4 to 6 amino acids from each
other, and by about 25 amino acids from the beta and gamma actins. Thus,
from the protein data, at least 6 actin genes would be expected in
mammals. Recombinant DNA probes for both actin and myosin of the mouse
have been made (Weydert et al., 1981). Because actin is a highly
conserved protein, Engel et al. (1981) could use cloned actin genes from
Drosophila and from chicken to isolate 12 actin gene fragments from a
human DNA library. Restriction endonuclease studies of each indicated
that they are not allelic and are from nonoverlapping regions of the
genome. In all, 25 to 30 EcoRI fragments homologous to actin genes were
found in the human genome and no restriction site polymorphism was found
indicating evolutionary conservatism. Humphries et al. (1981) used
probes from the mouse to detect actin genes in human DNA and concluded
that there are about 20 actin genes in the human genome. Three lines of
evidence supported this number: the rate of hybridization of the mouse
probe with human DNA; the fact that the probe hybridizes to 17-20 bands
in Southern blots of restriction enzyme digests of total human DNA;
restriction enzyme mapping of individual human actin genes indicating at
least 9 different genes, judged on probability grounds to have been
picked from a pool of at least 20. Litt and Luty (1989) used PCR to
amplify a microsatellite hypervariable repeat in the human cardiac actin
gene. They detected 12 different allelic fragments in 37 unrelated
individuals, of whom 32 were heterozygous. (Weber and May (1989) also
found that (GT)n repeats within human loci are highly polymorphic.) In
vertebrates, 6 actin isoforms are known: 4 muscle types (skeletal,
cardiac, and 2 smooth muscle types) and 2 nonmuscle types (cytoplasmic
actins).

Hamada et al. (1982) isolated and characterized the human cardiac actin
gene. The cardiac and skeletal actin genes showed close similarity,
suggesting a relatively recent derivation from a common ancestral gene.
Nucleotide sequences of all exon/intron boundaries agreed with the GT/AG
rule (GT at the 5-prime and AG at the 3-prime termini of each intron).
The cardiac actin gene and the skeletal actin gene (102610; on
chromosome 1) are coexpressed in both skeletal and heart muscle.
Buckingham et al. (1986) provided a summary of the actin and myosin
multigene families in mouse and man. Certain inbred mouse lines, e.g.,
BALB/c, have a mutant cardiac actin locus (Garner et al., 1986). The
first 3 coding exons and promoter region of the gene are present as a
duplication immediately upstream from the cardiac actin gene. The
upstream promoter is active, and partial gene transcripts are generated
which are correctly spliced for the first 3 coding exons but which
terminate at cryptic sites in the region between the duplication and the
gene. Transcriptional activity at the upstream promoter interferes with
the downstream promoter of the bona fide cardiac actin gene, leading to
a 5- to 6-fold reduction in cardiac actin mRNA in the hearts of BALB/c
mice. In this situation there is an accumulation of skeletal actin gene
transcripts in the adult hearts of these mice, which partially
compensates for the reduction in cardiac actin transcripts. BALB/c mice
have a normal life span and their hearts do not undergo hypertrophy.
Apparently, cardiac and skeletal actins, which differ only by 4 out of
375 amino acids, are to some extent interchangeable. Schwartz et al.
(1986) found that under conditions of aortic stenosis leading to cardiac
overload and cardiac hypertrophy, skeletal actin gene transcripts are
found in adult rodent hearts in addition to the cardiac actin gene
products normally present.

Using a cDNA fragment from an intron of the human cardiac actin gene in
somatic hybrid cell studies, Shows et al. (1984) showed that the gene is
coded by the segment 15q11-qter. Crosby et al. (1989) showed that in the
mouse the cardiac actin gene (Actc-1) is not on chromosome 17 as
previously reported (Czosnek et al., 1983) but is located on chromosome
2. It is closely linked to beta-2-microglobulin as indicated by mapping
studies using restriction fragment variants in recombinant inbred
strains. Using a highly polymorphic CA repeat microsatellite within
intron 4 of the ACTC gene, Kramer et al. (1992) did family linkage
studies with multiple markers on 15q, thus permitting the gene to be
placed on the chromosome linkage map. They demonstrated that it lies
about 0.06 cM proximal to D15S49 which is about 0.05 cM proximal to
D15S25 which in turn is about 0.07 cM proximal to D15S1; D15S1 is
tightly linked to the Marfan syndrome and to fibrillin. Thus ACTC may be
about 0.18 cM proximal to the fibrillin locus and no more distal than
15q21.1.

By fluorescence in situ hybridization, Ueyama et al. (1995) assigned the
ACTC gene to 15q14.

*FIELD* SA
Gunning et al. (1984)
*FIELD* RF
1. Buckingham, M.; Alonso, S.; Barton, P.; Cohen, A.; Daubas, P.;
Garner, I.; Robert, B.; Weydert, A.: Actin and myosin multigene families:
their expression during the formation and maturation of striated muscle. Am.
J. Med. Genet. 25: 623-634, 1986.

2. Crosby, J. L.; Phillips, S. J.; Nadeau, J. H.: The cardiac actin
locus (Actc-1) is not on mouse chromosome 17 but is linked to beta-2-microglobulin
on chromosome 2. Genomics 5: 19-23, 1989.

3. Czosnek, H.; Nudel, U.; Mayer, Y.; Barker, P. E.; Pravtcheva, D.
D.; Ruddle, F. H.; Yaffe, D.: The genes coding for the cardiac muscle
actin, the skeletal muscle actin and the cytoplasmic beta-actin are
located on three different mouse chromosomes. EMBO J. 2: 1977-1979,
1983.

4. Elzinga, M.; Maron, B. J.; Adelstein, R. S.: Human heart and platelet
actins are products of different genes. Science 191: 94-95, 1976.

5. Engel, J. N.; Gunning, P. W.; Kedes, L.: Isolation and characterization
of human actin genes. Proc. Nat. Acad. Sci. 78: 4674-4678, 1981.

6. Firtel, R. A.: Multigene families encoding actin and tubulin. Cell 24:
6-7, 1981.

7. Garner, I.; Minty, A. J.; Alonso, S.; Barton, P. J.; Buckingham,
M. E.: A 5-prime duplication of the alpha-cardiac actin gene in BALB/c
mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal
actin mRNAs in adult cardiac tissue. EMBO J. 5: 2559-2567, 1986.

8. Gunning, P.; Ponte, P.; Kedes, L.; Eddy, R.; Shows, T.: Chromosomal
location of the co-expressed human skeletal and cardiac actin genes. Proc.
Nat. Acad. Sci. 81: 1813-1817, 1984.

9. Hamada, H.; Petrino, M. G.; Kakunaga, T.: Molecular structure
and evolutionary origin of human cardiac muscle actin gene. Proc.
Nat. Acad. Sci. 79: 5901-5905, 1982.

10. Humphries, S. E.; Whittall, R.; Minty, A.; Buckingham, M.; Williamson,
R.: There are approximately 20 actin genes in the human genome. Nucleic
Acids Res. 9: 4895-4908, 1981.

11. Kramer, P. L.; Luty, J. A.; Litt, M.: Regional localization of
the gene for cardiac muscle actin (ACTC) on chromosome 15q. Genomics 13:
904-905, 1992.

12. Litt, M.; Luty, J. A.: A hypervariable microsatellite revealed
by in vitro amplification of a dinucleotide repeat within the cardiac
muscle actin gene. Am. J. Hum. Genet. 44: 397-401, 1989.

13. Schwartz, K.; de la Bastie, D.; Bouveret, P.; Oliviero, P.; Alonso,
S.; Buckingham, M.: Alpha-skeletal muscle actin mRNAs accumulate
in hypertrophied adult rat hearts. Circulation Res. 59: 551-555,
1986.

14. Shows, T.; Eddy, R. L.; Haley, L.; Byers, M.; Henry, M.; Gunning,
P.; Ponte, P.; Kedes, L.: The coexpressed genes for human alpha (ACTA)
and cardiac actin (ACTC) are on chromosomes 1 and 15, respectively.
(Abstract) Cytogenet. Cell Genet. 37: 583 only, 1984.

15. Ueyama, H.; Inazawa, J.; Ariyama, T.; Nishino, H.; Ochiai, Y.;
Ohkubo, I.; Miwa, T.: Reexamination of chromosomal loci of human
muscle actin genes by fluorescence in situ hybridization. Jpn. J.
Hum. Genet. 40: 145-148, 1995.

16. Weber, J. L.; May, P. E.: Abundant class of human DNA polymorphisms
which can be typed using the polymerase chain reaction. Am. J. Hum.
Genet. 44: 388-396, 1989.

17. Weydert, A.; Robert, B.; Alonso, S.; Caravatti, M.; Cohen, A.;
Daubas, P.; Minty, A.; Buckingham, M.: Multigene families of contractile
proteins: the actins and myosins. (Abstract) Sixth Int. Cong. Hum.
Genet., Jerusalem 39 only, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/27/1996
terry: 6/16/1995
carol: 11/18/1994
carol: 10/13/1993
carol: 8/25/1992
carol: 6/29/1992
carol: 3/20/1992

*RECORD*
*FIELD* NO
102545
*FIELD* TI
*102545 ACTIN, GAMMA-2, SMOOTH MUSCLE, ENTERIC; ACTG2
ACTSG;;
ACTE;;
ACTIN, ALPHA-3, PREVIOUSLY;;
ACTA3, PREVIOUSLY
*FIELD* TX
Miwa et al. (1991) isolated recombinant phages that carried the human
smooth muscle (enteric) gamma-actin gene (which they symbolized ACTSG)
from human genomic DNA libraries. The gene, designated ACTG2, contained
one 5-prime untranslated exon and 8 coding exons extending for 27 kb;
the mapping of the gene to chromosome 2 was demonstrated by study of
rodent-human somatic cell hybrids. Ueyama et al. (1995) isolated genomic
clones containing the gene (which has also been symbolized ACTA3) and
mapped the gene to 2p13.1 by fluorescence in situ hybridization. From
the characterized molecular structures of the 6 human actin isoform
genes, Miwa et al. (1991) proposed a hypothesis of the evolutionary
pathway of the actin gene family. Each of the 5 other actin genes maps
to a separate chromosome. Ueyama et al. (1995) demonstrated that the
HindIII RFLP in the first intron of the gene is due to the
presence/absence of a 24-bp sequence harboring a HindIII restriction
site. A biallelic system was found to have allelic frequencies of 45
(HindIII-minus):55 (HindIII-Plus).

Szucsik and Lessard (1995) characterized the mouse smooth muscle
(enteric) gamma-actin gene. It represented the largest isoactin gene
characterized to that time, measuring over 23,000 bp from the
transcription start site to the polyadenylation signal. The gene had 9
exons and encoded a mature actin protein of 374 amino acids.

*FIELD* RF
1. Miwa, T.; Manabe, Y.; Kurokawa, K.; Kamada, S.; Kanda, N.; Bruns,
G.; Ueyama, H.; Kakunaga, T.: Structure, chromosome location, and
expression of the human smooth muscle (enteric type) gamma-actin gene:
evolution of six human actin genes. Molec. Cell. Biol. 11: 3296-3306,
1991.

2. Szucsik, J. C.; Lessard, J. L.: Cloning and sequence analysis
of the mouse smooth muscle gamma-enteric actin gene. Genomics 28:
154-162, 1995.

3. Ueyama, H.; Inazawa, J.; Nishino, H.; Han-Xiang, D.; Ochiai, Y.;
Ohkubo, I.: Chromosomal mapping of the human smooth muscle actin
gene (enteric type, ACTA3) to 2p13.1 and molecular nature of the HindIII
polymorphism. Genomics 25: 720-723, 1995.

*FIELD* CD
Victor A. McKusick: 7/10/1991

*FIELD* ED
mark: 8/25/1995
supermim: 3/16/1992
carol: 8/22/1991
carol: 7/10/1991

*RECORD*
*FIELD* NO
^102550
*FIELD* TI
^102550 MOVED TO 102630
*FIELD* TX
This entry was incorporated into entry 102630 on 10 April 1997.

*FIELD* CN
Mark H. Paalman - edited: 4/10/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
jenny: 04/15/1997
jenny: 4/10/1997
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986
*RECORD*
*FIELD* NO
102560
*FIELD* TI
*102560 ACTIN, GAMMA-1; ACTG1
ACTIN, GAMMA; ACTG;;
CYTOSKELETAL GAMMA-ACTIN;;
ACTIN, CYTOPLASMIC, 2
*FIELD* TX
Microfilaments, which are involved in cell motility, organelle
transport, cytokinesis, and muscle contraction, are linear polymers of
actin. In mammalian nonmuscle cells, 2 classes of actin are recognized
on isoelectric focusing gels: beta and gamma. These 2 isoforms differ by
4 amino acid substitutions at the conserved NH2-end of the molecule.
They are coexpressed in nonmuscle cells. Erba et al. (1986) presented
the complete sequence of gamma cytoskeletal actin mRNA. Erba et al.
(1988) cloned and sequenced the human gamma-actin gene and demonstrated
that it is located on chromosome 17 by Southern analysis of DNA from
human-mouse somatic cell hybrids. Hybridization of the probe to the
genome of a human-mouse cell hybrid containing a 17;9 translocation
indicated that the gene is located in the region 17p11-qter.

Ueyama et al. (1996) mapped the ACTG1 gene to 17q25 and 3 ACTG
pseudogenes to other chromosomes.

*FIELD* RF
1. Erba, H. P.; Eddy, R.; Shows, T.; Kedes, L.; Gunning, P.: Structure,
chromosome location, and expression of the human gamma-actin gene:
differential evolution, location, and expression of the cytoskeletal
beta- and gamma-actin genes. Molec. Cell. Biol. 8: 1775-1789, 1988.

2. Erba, H. P.; Gunning, P.; Kedes, L.: Nucleotide sequence of the
human gamma cytoskeletal actin mRNA: anomalous evolution of vertebrate
non-muscle actin genes. Nucleic Acids Res. 14: 5275-5294, 1986.

3. Ueyama, H.; Inazawa, J.; Nishino, H.; Ohkubo, I.; Miwa, T.: FISH
localization of human cytoplasmic actin genes ACTB to 7p22 and ACTG1
to 17q25 and characterization of related pseudogenes. Cytogenet.
Cell Genet. 74: 221-224, 1996.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/20/1997
terry: 1/13/1997
supermim: 3/16/1992
carol: 7/3/1991
carol: 3/19/1991
supermim: 3/20/1990
ddp: 10/26/1989
root: 6/3/1988

*RECORD*
*FIELD* NO
102565
*FIELD* TI
*102565 FILAMIN 2; FLN2
ACTIN BINDING PROTEIN-280, AUTOSOMAL FORM; ABP-280A;;
ABPA
*FIELD* TX
See 300017. Gariboldi et al. (1994) mapped the FLN2 gene to human
7q32-q35 by analysis of somatic cell hybrids containing portions of
chromosome 7. By using a mapping panel from an interspecific murine
cross, they mapped the corresponding murine locus to chromosome 6 in a
region homologous to human chromosome 7.

*FIELD* RF
1. Gariboldi, M.; Maestrini, E.; Canzian, F.; Manenti, G.; De Gregorio,
L.; Rivella, S.; Chatterjee, A.; Herman, G. E.; Archidiacono, N.;
Antonacci, R.; Pierotti, M. A.; Dragani, T. A.; Toniolo, D.: Comparative
mapping of the actin-binding protein 280 genes in human and mouse. Genomics 21:
428-430, 1994.

*FIELD* CD
Victor A. McKusick: 7/8/1993

*FIELD* ED
mark: 04/10/1997
jason: 6/8/1994
carol: 4/13/1994
carol: 8/16/1993
carol: 7/8/1993

*RECORD*
*FIELD* NO
102570
*FIELD* TI
*102570 ACTIN, PLATELET
*FIELD* TX
See 102540.

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986
*RECORD*
*FIELD* NO
102573
*FIELD* TI
*102573 ACTININ, ALPHA-2; ACTN2
*FIELD* TX
Alpha-actinin is an actin-binding protein with multiple roles in
different cell types. In nonmuscle cells, the cytoskeletal isoform is
found along microfilament bundles and adherens-type junctions, where it
is involved in binding actin to the membrane (see ACTN1; 102575). In
contrast, skeletal, cardiac, and smooth muscle isoforms are localized to
the Z-disc and analogous dense bodies, where they help anchor the
myofibrillar actin filaments. Beggs et al. (1992) characterized 2 human
muscle-specific alpha-actinin genes, ACTN2 and ACTN3, and mapped them to
chromosomes 1 and 11, respectively, using somatic cell hybrids. In situ
hybridization placed the ACTN2 locus at 1q42-q43. Beggs et al. (1992)
identified a polymorphic (CA)n repeat within the ACTN2 gene and used it
to position the ACTN2 gene on the CEPH linkage map of chromosome 1.

*FIELD* SA
Beggs et al. (1992)
*FIELD* RF
1. Beggs, A. H.; Byers, T. J.; Knoll, J. H. M.; Boyce, F. M.; Bruns,
G. A. P.; Kunkel, L. M.: Cloning and characterization of two human
skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.
J. Biol. Chem. 267: 9281-9288, 1992.

2. Beggs, A. H.; Phillips, H. A.; Kozman, H.; Mulley, J. C.; Wilton,
S. D.; Kunkel, L. M.; Laing, N. G.: A (CA)n repeat polymorphism for
the human skeletal muscle alpha-actinin gene ACTN2 and its localization
on the linkage map of chromosome 1. Genomics 13: 1314-1315, 1992.

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
carol: 10/13/1992
carol: 9/9/1992
carol: 8/14/1992

*RECORD*
*FIELD* NO
102574
*FIELD* TI
*102574 ACTININ, ALPHA-3; ACTN3
*FIELD* TX
See ACTN2 (102573). Beggs et al. (1992) assigned ACTN3 to human
chromosome 11 by use of somatic cell hybrids and narrowed the
localization to 11q13-q14 by fluorescence in situ hybridization.

*FIELD* RF
1. Beggs, A. H.; Byers, T. J.; Knoll, J. H. M.; Boyce, F. M.; Bruns,
G. A. P.; Kunkel, L. M.: Cloning and characterization of two human
skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.
J. Biol. Chem. 267: 9281-9288, 1992.

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
carol: 4/7/1993
carol: 9/9/1992
carol: 8/14/1992

*RECORD*
*FIELD* NO
102575
*FIELD* TI
*102575 ACTININ, ALPHA-1; ACTN1
*FIELD* TX
Alpha-actinin was initially isolated from rabbit skeletal muscle as a
factor that induces the gelation of F-actin and promotes the
superprecipitation of actomyosin. Subsequently, a number of different
isoforms were isolated from both muscle and nonmuscle cells and from a
wide variety of organisms. The native molecule is thought to be a
homodimer of 97-kD subunits arranged in antiparallel fashion. In
myofibrillar cells, alpha-actinin constitutes a major component of
Z-disks in striated muscle and of the functionally analogous dense
bodies and dense plaques in smooth muscle. In nonmuscle cells, it is
distributed along microfilament bundles and is thought to mediate their
attachment to the membrane at adherens-type junctions. Youssoufian et
al. (1990) cloned and characterized a full-length cDNA encoding the
human cytoskeletal isoform. The gene encodes 891 amino acids with 96 to
98% sequence identity at the amino acid level to chicken nonskeletal
muscle alpha-actinin. Transient expression in COS cells produced a
protein of about 104 kD. By analysis of somatic cell hybrids and by in
situ hybridization, Youssoufian et al. (1990) mapped the gene to
14q22-q24. Pulsed-field gel analysis of genomic DNA showed that the
ACTN1 gene and that for erythroid beta-spectrin (182870) are located in
the same restriction fragment. This finding is of great interest because
of the structural homology between spectrin and actinin.

*FIELD* RF
1. Youssoufian, H.; McAfee, M.; Kwiatkowski, D. J.: Cloning and chromosomal
localization of the human cytoskeletal alpha-actinin gene reveals
linkage to the beta-spectrin gene. Am. J. Hum. Genet. 47: 62-72,
1990.

*FIELD* CD
Victor A. McKusick: 7/12/1990

*FIELD* ED
mark: 04/10/1997
carol: 8/14/1992
supermim: 3/16/1992
carol: 8/20/1990
carol: 7/12/1990

*RECORD*
*FIELD* NO
102576
*FIELD* TI
*102576 ACTIVIN A RECEPTOR, TYPE I; ACVR1
*FIELD* TX
Although activins were discovered by virtue of their capacity to
stimulate the production of follicle-stimulating hormone (FSH; 136530)
by the pituitary gland and inhibins were initially characterized as FSH
inhibitors, activins and inhibins are dimeric proteins that share a
common subunit. There are 3 activins (A, B, and A-B), comprising
different combinations of 2 closely related beta subunits
(beta-A/beta-A; beta-B/beta-B; and beta-A/beta-B, respectively) and 2
inhibins (A and B), consisting of 1 beta-subunit and an inhibin-specific
alpha subunit (alpha/beta-A and alpha/beta-B). Activins impinge on a
much broader spectrum of cells than do inhibins; however, in those
systems in which both proteins are functional, they have opposing
biologic effects. Activins are members of a family of polypeptide growth
factors that includes also the transforming growth factors-beta (190180,
190220, 190230), mullerian duct-inhibiting substance, and several bone
morphogenetic proteins. Mathews and Vale (1991) cloned the activin
receptor by use of a method that has been used to clone other receptors,
such as that for erythropoietin. The cloning is based on the ability of
the receptor to bind a labeled ligand following expression of a cDNA
library in mammalian cells. The cDNA coded for a protein of 494 amino
acids comprising a ligand-binding extracellular domain, a single
membrane-spanning domain, and an intracellular kinase domain with
predicted serine/threonine specificity.

Two types of activin receptors were identified on the basis of
affinity-crosslinking studies. The type I receptor has a molecular size
of 65 kD, while the molecular size of the type II receptor is 85 kD
(Mathews and Vale, 1991).

*FIELD* RF
1. Mathews, L. S.; Vale, W. W.: Expression cloning of an activin
receptor, a predicted transmembrane serine kinase. Cell 65: 973-982,
1991.

*FIELD* CD
Victor A. McKusick: 8/9/1991

*FIELD* ED
carol: 3/30/1994
supermim: 3/16/1992
carol: 8/30/1991
carol: 8/9/1991

*RECORD*
*FIELD* NO
102577
*FIELD* TI
*102577 ACTIVATOR 1, 37-KILODALTON SUBUNIT
A1, 37-KD SUBUNIT;;
REPLICATION FACTOR C, 37-KD SUBUNIT;;
RFC, 37-KD SUBUNIT;;
REPLICATION FACTOR C4; RFC4
*FIELD* TX
The elongation of primed DNA templates by DNA polymerase delta and DNA
polymerase epsilon requires the action of 2 accessory proteins,
proliferating cell nuclear antigen (PCNA; 176740) and activator 1 (A1;
also called replication factor C). A1 is an enzyme that contains 5
different subunits of 140, 40, 38, 37, and 36 kD. Chen et al. (1992)
isolated the gene encoding the 37-kD subunit from HeLa cells. The
deduced amino acid sequence showed a high degree of homology to the
40-kD subunit of A1 but, unlike the 40-kD protein, the 37-kD expressed
protein did not bind ATP. Other findings suggested that both the 37- and
40-kD subunits of A1 are required for the biologic role of A1 and that
they may function differently in this process.

Okumura et al. (1995) mapped RFC4 to 3q27 by a combination of PCR
amplification of DNAs from a panel of somatic hybrids and by
fluorescence in situ hybridization.See replication factor C, subunit 2
(RFC2; 600404).

*FIELD* RF
1. Chen, M.; Pan, Z.-Q.; Hurwitz, J.: Studies of the cloned 37-kDa
subunit of activator 1 (replication factor C) of HeLa cells. Proc.
Nat. Acad. Sci. 89: 5211-5215, 1992.

2. Okumura, K.; Nogami, M.; Taguchi, H.; Dean, F. B.; Chen, M.; Pan,
Z.-Q.; Hurwitz, J.; Shiratori, A.; Murakami, Y.; Ozawa, K.; Eki, T.
: Assignment of the 36.5-kDa (RFC5), 37-kDa (RFC4), 38-kDa (RFC3),
and 40-kDa (RFC2) subunit genes of human replication factor C to chromosome
bands 12q24.2-q24.3, 3q27, 13q12.3-q13, and 7q11.23. Genomics 25:
274-278, 1995.

*FIELD* CD
Victor A. McKusick: 7/7/1992

*FIELD* ED
carol: 3/19/1995
carol: 12/14/1993
carol: 7/7/1992

*RECORD*
*FIELD* NO
102578
*FIELD* TI
*102578 ACUTE PROMYELOCYTIC LEUKEMIA, INDUCER OF; PML
*FIELD* TX
In the process of analyzing the retinoic acid receptor alpha (RARA;
180240) gene in the t(15;17)(q22;q11.2-q12) translocation specifically
associated with acute promyelocytic leukemia (APL), de The et al. (1990)
identified a new gene on chromosome 15 which is involved with the RARA
gene in the formation of a fusion product. This gene, which they called
MYL for 'myelocytic leukemia,' was transcribed in the same direction as
RARA on the translocated allele. They identified a 144-bp region,
flanked by canonical splice acceptor and donor sequences, that had a
high probability of being an exon and showed no significant similarity
to any sequence in a protein data bank, thus suggesting that MYL is a
previously undescribed gene. In the chimeric gene, the promoter and
first exon of the RARA gene were replaced by part of the MYL gene. De
The et al. (1990) established that the translocation chromosome
generates an MYL/RARA chimeric transcript. The findings strongly
implicated retinoic acid receptor alpha in leukemogenesis. The
possibility was raised that the altered retinoic acid receptor behaves
as a dominant negative mutant that blocks the expression of retinoic
acid target genes involved in granulocytic differentiation. In a later
report, de The et al. (1991) changed the name of the gene from MYL to
PML. They reported, furthermore, that the gene product contains a novel
zinc finger motif common to several DNA-binding proteins. The PML-RARA
mRNA encoded a predicted 106-kd chimeric protein containing most of the
PML sequences fused to a large part of the RARA gene, including its DNA-
and hormone-binding domains. Goddard et al. (1991) demonstrated that PML
is a putative zinc finger protein and potential transcription factor
that is commonly expressed, with at least 3 major transcription
products. The PML breakpoints are clustered in 2 regions on either side
of an alternatively spliced exon. Although leukemic cells with
translocations characteristically expressed only one fusion product,
both PML/RARA (on the 15q+ derivative chromosome) and RARA/PML (on the
17q- derivative) were transcribed. The contribution of PML to the
oncogenicity of the fusion products was demonstrated by the following:
no mutations affecting RARA alone were observed in 20 APLs analyzed; 2
APLs cytogenetically lacking t(15;17) chromosomes were found to have
rearrangements of both PML and RARA; and PML, but not RARA, was
molecularly rearranged in a variant APL translocation in which
chromosome 15 had been translocated to another chromosome with no
visible involvement of chromosome 17. Tong et al. (1992) found that in
20 of 22 patients with a detectable MYL rearrangement the breakpoints
were clustered within a 4.4-kb segment, which they designated MYL(bcr).
The 2 remaining patients exhibited a more 5-prime rearrangement at about
10-kb upstream of the MYL(bcr) region, indicating the lack of at least
one MYL gene exon in the resulting MYL-RARA fusion gene. Cleary (1991)
pointed out that detection of the PML-RARA fusion links a specific
molecular defect in neoplasia with a characteristic biologic and
clinical response to pharmacologic therapy. It is a useful marker for
the diagnosis of APL and for the identification of patients who may
benefit from retinoid treatment.

PML, the gene involved in the breakpoint on chromosome 15, is a putative
transcription factor: it contains a cysteine-rich motif that resembles a
zinc finger DNA-binding domain common to several classes of
transcriptional factors. Its physiologic role is unknown. Two fusion
genes, PML-RARA and RARA-PML, are formed as a result of the
characteristic translocation in acute promyelocytic leukemia.
Heterogeneity of the chromosome 15 breakpoints accounts for the diverse
architecture of the PML-RARA mRNAs isolated from different APL patients,
and alternative splicing of PML exons gives rise to multiple isoforms of
the PML-RARA mRNAs even within a single patient. Alcalay et al. (1992)
investigated the organization and expression pattern of the RARA-PML
gene in a series of APL patients. An RARA-PML transcript was present in
most, but not all, APL patients. Among 70 patients with APL, Diverio et
al. (1992) found an abnormality in intron 2 of the RARA gene in all
cases, with clustering of rearrangements within the 20-kb intronic
region separating exons 2 and 3. A curious difference was found in the
location of breakpoints in males and females: breakpoints at the 5-prime
end of intron 2 of the RARA gene occurred in females and 3-prime
breakpoints predominated in males.

From their analysis of the phosphoamino acids of the PML protein, Chang
et al. (1995) concluded that both tyrosine and serine residues are
phosphorylated. To investigate whether expression of the PML protein is
cell-cycle related, HeLa cells synchronized at various phases of the
cell cycle were analyzed by immunofluorescence staining and confocal
microscopy. They found that PML was expressed at a lower level in S, G2,
and M phases and at a significantly higher level in G1 phase. Other
studies showed that PML is a phosphoprotein and is associated with the
nuclear matrix. Chang et al. (1995) noted that PML shares many
properties with tumor suppressors, such as RB (180200).

Goddard et al. (1995) cloned the murine Pml gene and determined its
intron/exon organization. The predicted amino acid sequence of the mouse
Pml, a ring-finger protein, shows 80% similarity to that of the human
homolog with greater than 90% similarity in the proposed functional
domains. Chromosomal localization of the Pml locus by somatic cell
hybrids and by linkage analysis indicated that the gene maps to a region
of mouse chromosome 9 with known homology of synteny to the region of
15q where PML is located.

Brown et al. (1997) established a transgenic mouse model that documented
the ability of the chimeric PMLRAR-alpha gene to initiate
leukemogenesis. The mice developed 2 currently unrelated abnormalities.
The first was a severe papillomatosis of the skin; the second was a
disturbance of hematopoiesis that presented as a partial block of
differentiation in the neutrophil lineage of the transgenic mice and
then progressed at low frequency to overt APL. The leukemia appeared to
be a faithful reproduction of the human disease, including a therapeutic
response to retinoic acid that reflected differentiation of the leukemic
cells. Both the preleukemic state and the overt leukemia could be
transplanted into nontransgenic hosts. Brown et al. (1997) commented
that the model should be useful for exploring the pathogenesis and
treatment of APL.

*FIELD* RF
1. Alcalay, M.; Zangrilli, D.; Fagioli, M.; Pandolfi, P. P.; Mencarelli,
A.; Lo Coco, F.; Biondi, A.; Grignani, F.; Pelicci, P. G.: Expression
pattern of the RAR-alpha-PML fusion gene in acute promyelocytic leukemia. Proc.
Nat. Acad. Sci. 89: 4840-4844, 1992.

2. Brown, D.; Kogan, S.; Lagasse, E.; Weissman, I.; Alcalay, M.; Pelicci,
P. G.; Atwater, S.; Bishop, J. M.: A PMLRAR-alpha transgene initiates
murine acute promyelocytic leukemia. Proc. Nat. Acad. Sci. 94: 2551-2556,
1997.

3. Chang, K.-S.; Fan, Y.-H.; Andreeff, M.; Liu, J.; Mu, Z.-M.: The
PML gene encodes a phosphoprotein associated with the nuclear matrix. Blood 85:
3646-3653, 1995.

4. Cleary, M. L.: Oncogenic conversion of transcription factors by
chromosomal translocations. Cell 66: 619-622, 1991.

5. de The, H.; Chomienne, C.; Lanotte, M.; Degos, L.; Dejean, A.:
The t(15;17) translocation of acute promyelocytic leukaemia fuses
the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347:
558-561, 1990.

6. de The, H.; Lavau, C.; Marchio, A.; Chomienne, C.; Degos, L.; Dejean,
A.: The PML-RAR-alpha fusion mRNA generated by the t(15;17) translocation
in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66:
675-684, 1991.

7. Diverio, D.; Lo Coco, F.; D'Adamo, F.; Biondi, A.; Fagioli, M.;
Grignani, F.; Rambaldi, A.; Rossi, V.; Avvisati, G.; Petti, M. C.;
Testi, A. M.; Liso, V.; Specchia, G.; Fioritoni, G.; Recchia, A.;
Frassoni, F.; Ciolli, S.; Pelicci, P. G.: Identification of DNA rearrangements
at the retinoic acid receptor-alpha (RAR-alpha) locus in all patients
with acute promyelocytic leukemia and mapping of APL breakpoints within
the RAR-alpha second intron. Blood 79: 3331-3336, 1992.

8. Goddard, A. D.; Borrow, J.; Freemont, P. S.; Solomon, E.: Characterization
of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic
leukemia. Science 254: 1371-1374, 1991.

9. Goddard, A. D.; Yuan, J. Q.; Fairbairn, L.; Dexter, M.; Borrow,
J.; Kozak, C.; Solomon, E.: Cloning of the murine homolog of the
leukemia-associated PML gene. Mammalian Genome 6: 732-737, 1995.

10. Tong, J.-H.; Dong, S.; Geng, J.-P.; Huang, W.; Wang, Z.-Y.; Sun,
G.-L.; Chen, S.-J.; Chen, Z.; Larsen, C.-J.; Berger, R.: Molecular
rearrangements of the MYL gene in acute promyelocytic leukemia (APL,
M3) define a breakpoint cluster region as well as some molecular variants. Oncogene 7:
311-316, 1992.

*FIELD* CN
Victor A. McKusick - updated: 04/21/1997

*FIELD* CD
Victor A. McKusick: 11/30/1990

*FIELD* ED
jenny: 04/21/1997
terry: 4/12/1997
mark: 11/30/1995
mark: 10/5/1995
carol: 8/13/1992
carol: 6/16/1992
carol: 5/28/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
102579
*FIELD* TI
*102579 ACTIVATOR 1, 140-KILODALTON SUBUNIT
A1, 140-KD SUBUNIT;;
REPLICATION FACTOR C, 140-KD SUBUNIT;;
RFC, 140-KD SUBUNIT;;
RFC140;;
RFC1;;
RECC1
*FIELD* TX
Replication factor C is a multisubunit, DNA polymerase accessory protein
required for the coordinated synthesis of both DNA strands during simian
virus 40 DNA replication in vitro. It is a DNA-dependent ATPase that
binds in a structure-specific manner to the 3-prime end of a primer
hybridized to a template DNA, an activity thought intrinsic to the
140-kD component of this multisubunit complex. Bunz et al. (1993)
isolated and analyzed cDNAs encoding the 140-kD subunit. An open reading
frame of 3.4 kb was predicted to encode a 1,148-amino acid protein with
a predicted molecular mass of 130 kD. A putative ATP-binding motif was
observed that is similar to a motif in several of the smaller subunits
of RFC and in functionally homologous replication factors of bacterial
and viral origin. The predicted protein showed similarities to other
DNA-binding proteins.

Luckow et al. (1994) isolated a full-length mouse cDNA which encodes a
protein that binds in a sequence-unspecific manner to DNA, is localized
exclusively in the nucleus, and represented, they concluded, the 140-kD
subunit of mouse replication factor C. They found that it showed 83%
identity to the human protein. Luckow et al. (1994) assigned the gene
for the largest subunit of replication factor C (RFC1) to 4p14-p13 by
fluorescence in situ hybridization. They mapped the homolog in the mouse
to chromosome 5. Lossie et al. (1995) likewise mapped this gene, which
they symbolized Recc1, to human chromosome 4 by human/rodent somatic
cell hybrid analysis and to mouse chromosome 5 by haplotype analysis of
an interspecific backcross.

*FIELD* RF
1. Bunz, F.; Kobayashi, R.; Stillman, B.: cDNAs encoding the large
subunit of human replication factor C. Proc. Nat. Acad. Sci. 90:
11014-11018, 1993.

2. Lossie, A. C.; Haugen, B. R.; Wood, W. M.; Camper, S. A.; Gordon,
D. F.: Chromosomal localization of the large subunit of mouse replication
factor C in the mouse and human. Mammalian Genome 6: 58-59, 1995.

3. Luckow, B.; Bunz, F.; Stillman, B.; Lichter, P.; Schutz, G.: Cloning,
expression, and chromosomal localization of the 140-kilodalton subunit
of replication factor C from mice and humans. Molec. Cell. Biol. 14:
1626-1634, 1994.

*FIELD* CD
Victor A. McKusick: 12/14/1993

*FIELD* ED
terry: 4/18/1995
carol: 2/20/1995
carol: 12/14/1993

*RECORD*
*FIELD* NO
102581
*FIELD* TI
*102581 ACTIVIN A RECEPTOR, TYPE II; ACVR2
*FIELD* TX
Two types of activin receptors were identified by affinity-crosslinking
studies. The type I receptor (ACVR1; 102576) has a molecular weight of
65 kD, while the molecular size of the type II receptor is 85 kD
(Mathews and Vale, 1991). Donaldson et al. (1992) cloned cDNAs encoding
type II activin receptor of the human. Activin has been suggested to be
an autocrine/paracrine regulator in the human placenta. This is
supported by the work of Peng et al. (1993), who demonstrated ACVR2 mRNA
in human trophoblast cells. They also provided the first evidence of
expression of the gene in human brain and ovary.

Two different forms of activin receptor type 2 have been found in mouse
and chick (Feijen et al., 1994). Both forms show tissue-specific and
temporal-specific differences in the timing of their expression during
mouse embryogenesis.

*FIELD* RF
1. Donaldson, C. J.; Mathews, L. S.; Vale, W. W.: Molecular cloning
and binding properties of the human type II activin receptor. Biochem.
Biophys. Res. Commun. 184: 310-316, 1992.

2. Feijen, A.; Goumans, M. J.; van den Eijnden-van Raaij, A. J.:
Expression of activin subunits, activin receptors and follistatin
in postimplantation mouse embryos suggests specific developmental
functions for different activins. Development 120: 3621-3637, 1994.

3. Mathews, L. S.; Vale, W. W.: Expression cloning of an activin
receptor, a predicted transmembrane serine kinase. Cell 65: 973-982,
1991.

4. Peng, C.; Huang, T.-H. J.; Jeung, E.-B.; Donaldson, C. J.; Vale,
W. W.; Leung, P. C. K.: Expression of the type II activin receptor
gene in the human placenta. Endocrinology 133: 3046-3049, 1993.

*FIELD* CN
Moyra Smith - Updated: 05/16/1996

*FIELD* CD
Victor A. McKusick: 3/30/1994

*FIELD* ED
carol: 05/16/1996
carol: 3/30/1994

*RECORD*
*FIELD* NO
102582
*FIELD* TI
*102582 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3
ACUTE-PHASE RESPONSE FACTOR; APRF
*FIELD* TX
Acute-phase response factor is a latent cytoplasmic transcription factor
that is rapidly activated in response to interleukin-5 (147850),
interleukin-6 (147620), epidermal growth factor (131530), leukemia
inhibitory factor (159540), oncostatin M (165095), interleukin-11
(147681), and ciliary neurotrophic factor (118945). After activation,
the 89-kD protein binds to IL6 response elements identified in the
promoter regions of various IL6-induced plasma-protein and
intermediate-early genes. Lutticken et al. (1994) demonstrated that the
above listed cytokines cause tyrosine phosphorylation of the APRF.
Protein kinases of the JAK family (e.g., 147795) were also rapidly
tyrosine phosphorylated, and both APRF and JAK1 associated with the
signal transducer gp130 (162820). Akira et al. (1994) suggested that
APRF may play a major role in the gp130-mediated signaling pathway. They
purified APRF and cloned the cDNA. At the amino acid level, APRF
exhibited 52.5% overall homology with p91, a component of the interferon
(IFN)-stimulated gene factor-3 complexes. See STAT1 (600555).

Binding of interleukin-5 to its specific receptor activates JAK2
(147796) which leads to the tyrosine phosphorylation of STAT3 proteins.
Caldenhoven et al. (1996) reported the cloning of a cDNA encoding a
variant of the transcription factor STAT3 (named STAT3-beta) that was
isolated by screening an eosinophil cDNA library. Compared to wildtype
STAT3, STAT3-beta lacks an internal domain of 50 bp located near the C
terminus. This splice product is a naturally occurring isoform of STAT3
and encodes an 80-kD protein. Like STAT3, STAT3-beta is phosphorylated
on tyrosine and binds to the pIRE from the ICAM1 (147840) promoter after
IL-5 stimulation. Coexpression of STAT3-beta inhibits the
transactivation potential of STAT3. These results suggested that
STAT3-beta functions as a negative regulator of transcription.

The leptin receptor (601007) is found in many tissues in several
alternatively spliced forms, raising the possibility that leptin exerts
effects on many tissues including the hypothalamus. The leptin receptor
is a member of the gp130 family of cytokine receptors that are known to
stimulate gene transcription via activation of cytosolic STAT proteins.
In order to identify the sites of leptin action in vivo, Vaisse et al.
(1996) assayed for activation of STAT proteins in mice treated with
leptin. The STAT proteins bind to phosphotyrosine residues in the
cytoplasmic domain of the ligand-activated receptor, where they are
subsequently phosphorylated. The activated STAT proteins dimerize and
translocate to the nucleus where they bind DNA and activate
transcription. The investigators assayed the activation of STAT proteins
in response to leptin in a variety of mouse tissues known to express
Obr. Leptin injection activated Stat3 but no other STAT protein in the
hypothalamus of ob/ob and wildtype mice but not db/db mice, mutants that
lack an isoform of the leptin receptor. Leptin did not induce STAT
activation in any of the other tissues tested. The dose-dependent
activation of STAT3 by leptin was first observed after 15 minutes and
maximal in 30 minutes. The data indicated to Vaisse et al. (1996) that
the hypothalamus is a direct target of leptin action and this activation
is critically dependent on the gp130-like leptin receptor isoform
missing in db/db mice.

*FIELD* RF
1. Akira, S.; Nishio, Y.; Inoue, M.; Wang, X.-J.; Wei, S.; Matsusaka,
T.; Yoshida, K.; Sudo, T.; Naruto, M.; Kishimoto, T.: Molecular cloning
of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription
factor involved in the gp130-mediated signaling pathway. Cell 77:
63-71, 1994.

2. Caldenhoven, E.; van Dijk, T. B.; Solari, R.; Armstrong, J.; Raaijmakers,
J. A. M.; Lammers, J.-W. J.; Koenderman, L.; de Groot, R. P.: STAT3-beta,
a splice variant of transcription factor STAT3, is a dominant negative
regulator of transcription. J. Biol. Chem. 271: 13221-13227, 1996.

3. Lutticken, C.; Wegenka, U. M.; Yuan, J.; Buschmann, J.; Schindler,
C.; Ziemiecki, A.; Harpur, A. G.; Wilks, A. F.; Yasukawa, K.; Taga,
T.; Kishimoto, T.; Barbieri, G.; Pellegrini, S.; Sendtner, M.; Heinrich,
P. C.; Horn, F.: Association of transcription factor APRF and protein
kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263:
89-92, 1994.

4. Vaisse, C.; Halaas, J. L.; Horvath, C. M.; Darnell, J. E., Jr.;
Stoffel, M.; Friedman, J. M.: Leptin activation of Stat3 in the hypothalamus
of wildtype and ob/ob mice but not in db/db mice. Nature Genet. 14:
95-100, 1996.

*FIELD* CN
Mark H. Paalman - edited: 9/10/1996

*FIELD* CD
Victor A. McKusick: 7/13/1994

*FIELD* ED
terry: 12/30/1996
terry: 12/11/1996
mark: 9/12/1996
mark: 9/11/1996
mark: 9/10/1996
jason: 7/13/1994

*RECORD*
*FIELD* NO
102590
*FIELD* TI
102590 ACYLASE, COBALT-ACTIVATED
*FIELD* TX
By polyacrylamide gel electrophoresis, Ziomek and Szewczuk (1978)
demonstrated polymorphism of Co(2+)-activated acylase of human liver,
kidney and small intestine as well as serum from patients with viral
hepatitis. Family studies were not reported. This enzyme is an
N-acylamino acid amidohydrolase that cleaves the low-molecular-weight
carboxylic acids from acylated amino acids. It is distinct from
aminoacylases 1 and 2 (104620).

*FIELD* RF
1. Ziomek, E.; Szewczuk, A.: Polymorphism of the cobalt-activated
acylase in human tissues. Acta Biochim. Polon. 25: 3-14, 1978.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
102593
*FIELD* TI
*102593 ACYLOXYACYL HYDROLASE; AOAH
*FIELD* TX
Acyloxyacyl hydrolase (AOAH) is a 2-subunit lipase present in phagocytic
cells. This enzyme specifically hydrolyzes the secondary acyl chains of
the lipopolysaccharide found in the walls of gram-negative bacteria.
Although the physiologic function of AOAH has not been clearly defined,
its action on lipopolysaccharide (or endotoxin) suggests that it
modulates the host's inflammatory response to gram-negative bacteria.
This hypothesis is supported by studies showing that the deacylation of
lipopolysaccharide by AOAH in vitro greatly reduces its toxicity and
activity. Hagen et al. (1991) cloned and characterized cDNA for human
AOAH and showed that its 2 subunits are translated from a single mRNA
molecule about 2.2 kb long. By fluorescence in situ hybridization,
Whitmore et al. (1994) mapped the AOAH gene to 7p14-p12.

*FIELD* RF
1. Hagen, F. S.; Grant, F. J.; Kuijper, J. L.; Slaughter, C. A.; Moomaw,
C. R.; Orth, K.; O'Hara, P. J.; Munford, R. S.: Expression and characterization
of recombinant human acyloxyacyl hydrolase, a leukocyte enzyme that
deacylates bacterial lipopolysaccharides. Biochemistry 30: 8415-8423,
1991.

2. Whitmore, T. E.; Mathewes, S. L.; O'Hara, P. J.; Durnam, D. M.
: Chromosomal localization of the acyloxyacyl hydrolase (AOAH) gene
to 7p14-p12 using fluorescence in situ hybridization. Genomics 21:
457-458, 1994.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
jason: 6/17/1994

*RECORD*
*FIELD* NO
102595
*FIELD* TI
*102595 ACYLPHOSPHATASE, MUSCLE; ACYP
*FIELD* TX
Acylphosphatase (EC 3.6.1.7) is a hydrolase that specifically catalyzes
the hydrolysis of the carboxyl-phosphate bond of acylphosphates. It is a
small (relative molecular mass about 11,000) and stable enzyme that is
distributed among a wide variety of species and tissues. The enzyme has
been purified from skeletal muscle of various mammals and birds and the
primary structures determined. The primary structure is well conserved
among different species. Liguri et al. (1986) reported the isolation and
characterization of a human erythrocyte acylphosphatase isoenzyme; see
600875. Modesti et al. (1993) constructed a DNA sequence coding for
human muscle acylphosphatase and studied its expression in E. coli and
S. cerevisiae.

*FIELD* RF
1. Liguri, G.; Camici, G.; Manao, G.; Cappugi, G.; Nassi, P.; Modesti,
A.; Ramponi, G.: A new acylphosphatase isoenzyme from human erythrocytes:
purification, characterization, and primary structure. Biochemistry 25:
8089-8094, 1986.

2. Modesti, A.; Raugei, G.; Taddei, N.; Marzocchini, R.; Vecchi, M.;
Camici, G.; Manao, G.; Ramponi, G.: Chemical synthesis and expression
of a gene coding for human muscle acylphosphatase. Biochim. Biophys.
Acta 1216: 369-374, 1993.

*FIELD* CD
Victor A. McKusick: 3/26/1994

*FIELD* ED
mark: 10/16/1995
carol: 3/26/1994

*RECORD*
*FIELD* NO
102600
*FIELD* TI
*102600 ADENINE PHOSPHORIBOSYLTRANSFERASE; APRT
2,8-@DIHYDROXYADENINE UROLITHIASIS, INCLUDED;;
DHA-UROLITHIASIS, INCLUDED;;
APRT, AUTOSOMAL RECESSIVE, INCLUDED
*FIELD* MN
Patients with complete deficiency of APRT excrete gravel consisting of
stones of 2,8-dihydroxyadenine (DHA) in urine, but do not have
hyperuricemia or gout. Treatment with allopurinol and a low purine diet
stops stone formation. Homozygotes can be detected by raised urinary
adenine levels and no detectable red cell APRT (Simmonds et al., 1992).
In Japanese, partial deficiency of APRT may lead to 2,8-dihydroxyadenine
urolithiasis (Kamatani et al., 1992), whereas all Caucasian patients
with 2,8-DHA urolithiasis have been completely deficient. The common
Japanese mutant allele is known as APRT*J.

Renal biopsy shows changes similar to those of uric acid nephropathy.
Families carrying the mutant APRT gene need to be aware of it since
acute renal failure may be the presenting symptom and this may be
reversible, although some patients progress to chronic renal failure
requiring dialysis and transplantation. There is a simple test for
distinguishing uric acid calculi from 2,8-DHA calculi (Maddocks, 1992)
and even visual examination can distinguish the two: 2,8-DHA stones are
soft, friable, reddish-brown when wet and grayish when dry (Ward and
Addison, 1992). The presence of round, brownish urine crystals, even
without radiolucent kidney stones, should alert the physician to the
diagnosis.

The APRT gene is located at 16q24 (Fratini et al., 1986). It is about
2.6 kb long and contains 5 exons. Its promoter region, like that of
several other 'housekeeping' genes, lacks the 'TATA' and 'CCAAT' boxes
but contains 5 GC boxes that are potential binding sites for the Sp1
transcription factor (Broderick et al., 1987). Mutations include
basepair deletions, insertions, and substitutions. The estimated gene
frequency among Japanese is about 1.2% (Kamatani et al., 1992).

*FIELD* ED
carol: 07/06/1996 joanna: 6/25/1996

*FIELD* CD
F. Clarke Fraser: 5/9/1996
*FIELD* TX
Mutant forms of APRT (EC 2.4.2.7) have been described by Kelley et al.
(1968) and by Henderson et al. (1969) who found the inheritance to be
autosomal. (The other purine phosphoribosyltransferase (HGPRT) is
determined by an X-linked locus and is mutant in the Lesch-Nyhan
syndrome (308000).) The heat-stable enzyme allele has a frequency of
about 15% and the heat-labile enzyme allele a frequency of about 85%.
Kelley et al. (1968) found apparent heterozygosity in 4 persons in 3
generations of a family. The level of enzyme activity ranged from 21 to
37%, requiring some special explanation. That the enzyme is a dimer is
one possibility. Fox et al. (1973) described a second family with
partial deficiency of red cell APRT. Delbarre et al. (1974) found
deficiency of APRT in persons with gout but recognized that purine
overproduction was not necessarily caused by the APRT deficiency.
Emmerson et al. (1975) described a family with dominant inheritance of
APRT deficiency. Although the proband was a female with gout, a
relationship to the APRT deficiency was considered unproved. The
partially purified enzyme showed no difference in Michaelis constants,
heat stability, or electrophoresis.

Debray et al. (1976) observed a child with urolithiasis and complete
deficiency of APRT. Both parents had partial deficiency. Van Acker et
al. (1977) described brothers with complete deficiency of APRT. They
were detected by the fact that one had from birth excreted gravel
consisting of stones of 2,8-dihydroxyadenine in urine. Neither showed
hyperuricemia or gout. Treatment with allopurinol and a low purine diet
stopped stone formation. Homozygotes can be detected by raised urinary
adenine levels and absence of detectable red cell APRT. Rappaport and
DeMars (1973) identified clones of cells resistant to 2,6-diaminopurine
(DAP) in skin fibroblast cultures derived from 13 of 21 normal humans.
In some of the mutant cultures adenine phosphoribosyltransferase was
normal. Two mutants from unrelated boys had little or no detectable APRT
activity. Resistance resulted from reduced ability to convert DAP to its
toxic ribonucleotide. The authors reasoned that mutant-yielding cultures
were heterozygous to begin with. If so, DAP resistance has a
heterozygote frequency as high as 0.2. This contrasts with the very low
frequency of electrophoretic variants of APRT. There may be other
mechanisms (mutation at other loci) for DAP-resistance. Azaguanine
resistance is determined by mutation at the X-linked HGPRT locus.
Barratt et al. (1979) reported a child of consanguineous Arab parents,
the third case in which 2,8-dihydroxyadenine stones have been identified
as the result of complete lack of APRT. Kishi et al. (1984) found only
10 reported cases of complete deficiency of APRT, beginning with the
case of Cartier et al. (1974). Kishi et al. (1984) reported 3 cases in 2
families. Although APRT deficiency occurred in mononuclear cells and
polymorphonuclear leukocytes as well as in red cells, no abnormality of
immunologic or phagocytic function was detected. The sole clinical
manifestation was urinary calculi composed of 2,8-DHA. In Japanese,
partial deficiency of APRT leads to 2,8-dihydroxyadenine urolithiasis,
whereas all Caucasian patients with 2,8-DHA urolithiasis have been
completely deficient. Fujimori et al. (1985) found that partially
purified enzyme from Japanese families has a reduced affinity for
phosphoribosylpyrophosphate (PRPP), as well as increased resistance to
heat and reduced sensitivity to the stabilizing effect of PRPP. They
referred to this common Japanese mutant allele as APRT*J. Kamatani et
al. (1987) examined samples from 19 Japanese families with
DHA-urolithiasis. In 15 of the 19 families, the patients had only
partial APRT deficiency. All patients with DHA-urolithiasis were
homozygotes regardless of whether the deficiency was complete or
partial. They estimated that about 1% of the Japanese population are
carriers. Kamatani et al. (1987) described a method for identifying
heterozygotes for the Japanese allele of APRT. Manyak et al. (1987)
found DHA-urolithiasis in a 50-year-old white woman. The patient was
homozygous for APRT deficiency. Glicklich et al. (1988) reported the
second case of homozygous APRT deficiency from the United States. The
disorder was recognized 23 years after the patient, a black woman from
Bermuda, had her initial episode of renal colic, and after
2,8-dihydroxyadenine stones had recurred after renal transplant.
Ishidate et al. (1991) reported father and daughter with
DHA-urolithiasis. The father and his wife were first cousins; thus, this
was an example of pseudodominance.

Gault et al. (1981) described 2,8-dihydroxyadenine urolithiasis in a
white woman who lived in Newfoundland and first developed symptoms of
urolithiasis at the age of 42. The use of infrared or x-ray diffraction
analysis of calculi that are positive for uric acid with standard wet
chemical tests can make the diagnosis. Adults may first present with
renal failure. Renal biopsy shows changes like those of uric acid
nephropathy. Maddocks and Al-Safi (1988) used identification of adenine
in the urine by thin layer chromatography to diagnose APRT deficiency.
Simmonds et al. (1992) pointed out that patients who are mistakenly
diagnosed as having uric acid lithiasis will be treated successfully
with allopurinol despite the incorrect diagnosis. This may be
responsible for underdiagnosis of the disorder. Families carrying the
mutant APRT gene need to be aware of it since acute renal failure may be
the presenting symptom and this may be reversible, though some patients
progress to chronic renal failure requiring dialysis and
transplantation. Maddocks (1992) described a simple test for
distinguishing uric acid calculi from 2,8-DHA calculi. Ward and Addison
(1992) indicated that even visual examination can distinguish the two:
2,8-DHA stones are reddish-brown when wet and grayish when dry; they are
also very soft and friable. Stones composed mainly of uric acid are very
rare in children. Laxdal and Jonasson (1988) found 2 children and 2
adults in 4 unrelated families with 2,8-dihydroxyadenine crystalluria.
They suggested that the presence of round, brownish urine crystals, even
without radiolucent kidney stones, should alert the physician to the
diagnosis. Thirteen heterozygotes were identified by study of the
families. Laxdal (1992) pointed out that Iceland contributed 8 of the 62
APRT-deficient type I homozygotes. The 8 cases were from 8 different
families. Although remote ancestral connections were identified, all 8
cases were detected by the finding of typical round reddish-brown
crystals in the urine on light microscopy. The importance of alert
laboratory technicians in making the diagnosis was emphasized.

By cell hybridization studies, Tischfield and Ruddle (1974) concluded
that the APRT locus is on chromosome 16. Marimo and Giannelli (1975)
confirmed this assignment by demonstrating a 1.69-fold increase in
enzyme level in trisomy 16 cells. The same cells showed no difference in
the levels of HGPRT, G6PD (305900) or adenosine kinase (102750) from
controls. Barg et al. (1982) assigned APRT to 16q12-pter. Lavinha et al.
(1984) assigned APRT and DIA4 (125860) to 16q12-q22 by study of
rearranged chromosomes 16 in somatic cell hybrids. For APRT,
Ferguson-Smith and Cox (1984) found a smallest region of overlap (SRO)
of 16q22.2-q22.3. Castiglione et al. (1985) found no evidence of linkage
between HP (140100) and HPRT within 12 map units, despite both loci
having been mapped to band 16q22. Fratini et al. (1986) mapped the APRT
locus with respect to the HP locus and the fragile site at 16q23.2
(FRA16D). A subclone of the APRT gene and a cDNA clone of HP were used
for molecular hybridization to DNA from mouse-human hybrid cell lines
containing specific chromosome 16 translocations. The APRT subclone was
used for in situ hybridization to chromosomes expressing FRA16D. APRT
was found to be distal to HP and FRA16D and was localized at 16q24,
making the gene order cen--FRA16B--HP--FRA16D--APRT--qter. Broderick et
al. (1987) found that in species as widely separated in evolution as
man, mouse, hamster, and E. coli, CpG dinucleotides are conserved at a
frequency higher than expected on the basis of randomness considering
the G+C content of the gene. This suggested some importance of this
sequence to the function of the gene. Although the intron I sequences of
mouse and man had no apparent homology, both had retained a very high
CpG content. The APRT gene is about 2.6 kb long and contains 5 exons.
The promoter region of the human APRT gene, like that of several other
'housekeeping' genes, lacks the 'TATA' and 'CCAAT' boxes but contains 5
GC boxes that are potential binding sites for the Sp1 transcription
factor. Hidaka et al. (1987) also prepared a complete sequence of the
APRT gene and found a number of discrepancies from the sequence reported
by Broderick et al. (1987), all occurring within noncoding regions.
Hakoda et al. (1990) made the interesting observation that 2-step
mutations leading to homozygous deficiencies at the somatic cell level,
as proposed by the Knudson hypothesis of carcinogenesis in
retinoblastoma (180200) and some other human tumors, occur at other
autosomal loci. They cloned and enumerated somatic T cells with
mutations at the APRT locus by taking advantage of the presence of
heterozygous APRT deficiency and an effective selection procedure for
homozygosity. They cultured peripheral blood mononuclear cells with
2,6-diaminopurine, an APRT-dependent cytotoxin, to search for in vivo
mutational cells. In all 4 heterozygotes studied, homozygously deficient
T cells were found, at an average frequency of 1.3 x 10(-4). Among 310
normal persons, Hakoda et al. (1990) identified only 1 homozygous
APRT-deficient clone, with a calculated frequency of 5.0 x 10(-9).
Homozygous cells were found at rather high frequencies in 15 putative
heterozygotes, as reported by Hakoda et al. (1991). Analysis of genomic
DNA in 82 resistant clones from 2 of the heterozygotes showed that 64
(78%) had lost the germinally intact alleles. This approach may prove
useful for identifying heterozygotes for other enzyme deficiencies.

Kamatani et al. (1992) stated that about 70 Japanese families with
homozygous APRT deficiency have been reported, whereas the number of
reported non-Japanese families is about 36. The estimated gene frequency
among Japanese is about 1.2%.

Terai et al. (1995) detected homozygous APRT deficiency by the finding
of 2,8-dihydroxyadenine-like spherical crystals in the urinary sediment.
The molecular diagnosis was established using PCR-SSCP with the
demonstration of the APRT*J allele (102600.0003).

According to the numerology used by Hidaka et al. (1988), the adenine in
the initiation codon ATG is counted as nucleotide no. 1 and the
initiator methionine is counted as amino acid no. 1.

Engle et al. (1996) used targeted homologous recombination in embryonic
stem cells to produce mice that lack APRT. Mice homozygous for a null
Aprt allele excreted adenine and DHA crystals in their urine. Renal
histopathology showed extensive tubular dilation, inflammation,
necrosis, and fibrosis that varied in severity between different mouse
backgrounds.

*FIELD* AV
.0001
APRT DEFICIENCY
APRT, PHE173DEL
In cell line '904,' a lymphoblastoid cell line from a Caucasian patient
in Belgium, Hidaka et al. (1987) studied the molecular basis of APRT
deficiency by sequencing both alleles of a patient with complete
deficiency. In 1 allele, a trinucleotide deletion, TTC at positions 2179
to 2181 in exon 4, which corresponded to phenylalanine-173 in the
deduced amino acid sequence, was demonstrated. In the other allele, a
single nucleotide insertion, a T, was found immediately adjacent to the
splice site at the 5-prime end of intron 4. This insertion led to
aberrant splicing, as was demonstrated by the absence of exon 4 in the
cDNA and by altered RNase mapping analysis of the abnormal mRNA.
Frameshift led to premature termination at amino acid 110. The enzyme
activity was less than 1% of normal and the enzyme protein was
immunologically undetectable.

.0002
APRT DEFICIENCY
APRT, IVS4DS INS T
In the second allele of cell line '904,' Hidaka et al. (1987) found
insertion of a thymine at the 5-prime end of intron 4 between
nucleotides 1834 and 1835 resulting in deletion of exon 4 and frameshift
with premature termination at amino acid 110. The insertion changed the
IVS4 splice donor site from gtaa to gttaa. In identical twin brothers
born to nonconsanguineous German parents, Gathof et al. (1991)
demonstrated that the cause of APRT deficiency was a single base
insertion, a T, between bases 1831 and 1832 or 1832 and 1833. (In the
numbering system they used, nucleotide 1831 is the first in intron 4.
The insertion changed the donor site from gtaa to gttaa.) The insertion
altered the consensus sequence at the splice donor site between exon 4
and intron 4, leading to aberrant splicing. They quoted finding of the
same mutation in 2 other Caucasian patients living in the U.S. and as
one of 2 alleles in a Belgian patient with compound heterozygosity. This
is the same mutation as that found by Hidaka et al. (1987).

.0003
APRT DEFICIENCY, JAPANESE TYPE
APRT*J
APRT, MET136THR
Hidaka et al. (1988) identified a T-to-C substitution in exon 5 at
position 2069, giving rise to substitution of threonine for methionine
at position 136 in the Japanese-type APRT deficiency. The enzyme showed
abnormal kinetics and activity that was less than 10.3% of normal. Six
other Japanese homozygotes carried the same mutation on at least 1
allele. In the Japanese type of APRT deficiency, Kamatani et al. (1989)
took advantage of the fact that the only methionine residue in normal
APRT (at position 136) has been changed to threonine. By means of
specific cleavage of the peptide at the methionine residue with cyanogen
bromide (BrCN), they could distinguish normal from mutant proteins.
Kamatani et al. (1989) found that 79% of all Japanese patients with this
disease and more than half of the world's patients have this particular
mutation. Kamatani et al. (1990) found that 24 of 39 Japanese
2,8-dihydroxyadenine urolithiasis patients had only APRT*J alleles. They
found that normal alleles occur in 4 major haplotypes, whereas all
APRT*J alleles occurred in only 2. They interpreted this as meaning that
all APRT*J alleles had a single origin and that this mutant sequence has
been maintained for a long time, as reflected in the frequency of the
recombinant alleles. Sahota et al. (1991) described DHA-lithiasis in a
patient heterozygous for the Japanese mutation. Lithiasis had previously
been observed only in homozygotes. The polyamine pathway is thought to
be the major source of endogenous adenine in the human. Whether
increased polyamine synthesis can lead to increased adenine production,
enhancer to DHA-lithiasis in an APRT heterozygote, remains to be
determined. Among 141 defective APRT alleles from 72 different Japanese
families, Kamatani et al. (1992) found the met136-to-thr mutation in 96
(68%); 30 (21%) and 10 (7%) had the TGG-to-TGA nonsense mutation at
codon 98 (102600.0005) and duplication of a 4-bp sequence in exon 3
(102600.0006), respectively.

.0004
APRT DEFICIENCY, COMPLETE, ICELANDIC TYPE
APRT, ASP65VAL
Chen et al. (1990) analyzed the molecular nature of the mutation in all
5 patients with complete APRT deficiency reported from Iceland. The same
mutation, an A-to-T transversion at position 1350, was identified in all
of the patients (the A of the ATG start codon was designated number 1).
The substitution led to the replacement of aspartic acid (GAC) by valine
(GTC) at amino acid 65 in exon 3. In all 5 patients the mutation was
homozygous. Common ancestors could be identified for only 2 of the
cases.

.0005
APRT DEFICIENCY DUE TO TYPE I ALLELE
APRT, TRP98TER
Mimori et al. (1991) analyzed 7 APRT*Q0 (null) alleles from 4 unrelated
Japanese subjects (3 homozygotes and a heterozygote). In all 7, they
found a G-to-A transition at nucleotide position 1453, which changed
tryptophan-98 to a stop codon. There was also a C-to-T transition at
1456, which did not alter alanine-99. The G-to-A change at 1453 resulted
in the elimination of a PflMI site in the APRT gene.

.0006
APRT DEFICIENCY
APRT, 4-BP DUP, EX3
Among 141 defective APRT alleles from 72 different Japanese families,
Kamatani et al. (1992) found that 10 (7%) had duplication of a CCGA
sequence in exon 3. Duplication resulted in an APRT*Q0 (null) allele.
Two other alleles, APRT*J (102600.0003) and trp98-to-ter (102600.0005),
accounted for 68% and 21%, respectively. The different alleles with the
same mutation had the same haplotype, except for APRT*J. Evidence for a
crossover or a gene conversion event within the APRT gene was observed
in an APRT*J mutant allele.

.0007
APRT DEFICIENCY
APRT, LEU110PRO
Sahota et al. (1994) described 2 sisters from Newfoundland who carried a
leucine-to-proline missense transition at codon position 110 (nucleotide
position 1759). One of the sisters exhibited 2,8-dihyroxyadenine
urolithiasis, whereas the other was disease-free. Restriction mapping
and DNA sequence data were compatible with both sisters being homozygous
for the mutation, although hemizygosity could not be ruled out.

*FIELD* SA
Doppler et al. (1981); Fox et al. (1977); Hidaka et al. (1987); Hirsch-Kauffmann
and Doppler (1981); Johnson et al. (1977); Kamatani et al. (1990);
Kamatani et al. (1987); Lester et al. (1980); Nesterova et al. (1987);
Simmonds  (1979); Simon and Taylor (1983); Takeuchi et al. (1985);
Wilson et al. (1986)
*FIELD* RF
1. Barg, R.; Barton, P.; Caine, A.; Clements, R. L.; Ferguson-Smith,
M. A.; Malcolm, S.; Morrison, N.; Murphy, C. S.: Regional localization
of the human alpha-globin gene to the short arm of chromosome 16 (16p12-pter)
using both somatic cell hybrids and in situ hybridization. Cytogenet.
Cell Genet. 32: 252-253, 1982.

2. Barratt, T. M.; Simmonds, H. A.; Cameron, J. S.; Potter, C. F.;
Rose, G. A.; Arkell, D. G.; Williams, D. I.: Complete deficiency
of adenine phosphoribosyltransferase: a third case presenting as renal
stones in a young child. Arch. Dis. Child. 54: 25-31, 1979.

3. Broderick, T. P.; Schaff, D. A.; Bertino, A. M.; Dush, M. K.; Tischfield,
J. A.; Stambrook, P. J.: Comparative anatomy of the human APRT gene
and enzyme: nucleotide sequence divergence and conservation of a nonrandom
CpG dinucleotide arrangement. Proc. Nat. Acad. Sci. 84: 3349-3353,
1987.

4. Cartier, P.; Hamet, M.; Hamburger, J.: Une nouvelle maladie metabolique:
le deficit complet en adenine phosphoribosyltransferase avec lithiase
de 2,8-dihydroxyadenine. C. R. Seances Acad. Sci. 279: 883-886,
1974.

5. Castiglione, C. M.; Kidd, J. R.; Tischfield, J. A.; Stambrook,
P. J.; Murphy, P. D.; Sparkes, R. A.; Kidd, K. K.: Polymorphism and
linkage of APRT.(Abstract) Cytogenet. Cell Genet. 40: 601 only,
1985.

6. Chen, J.; Sahota, A.; Laxdal, T.; Stambrook, P. J.; Tischfield,
J. A.: Demonstration of a common mutation at the adenine phosphoribosyltransferase
(APRT) locus in the Icelandic population.(Abstract) Am. J. Hum. Genet. 47
(suppl.): A152 only, 1990.

7. Debray, H.; Cartier, P.; Temstet, A.; Cendron, J.: Child's urinary
lithiasis revealing a complete deficit in adenine phosphoribosyl transferase.
Pediat. Res. 10: 762-766, 1976.

8. Delbarre, F.; Aucher, C.; Amor, B.; de Gery, A.; Cartier, P.; Hamet,
M.: Gout with adenine phosphoribosyltransferase deficiency. Biomedicine 21:
82-85, 1974.

9. Doppler, W.; Hirsch-Kauffmann, M.; Schabel, F.; Schweiger, M.:
Characterization of the biochemical basis of a complete deficiency
of the adenine phosphoribosyl transferase (APRT). Hum. Genet. 57:
404-410, 1981.

10. Emmerson, B. T.; Gordon, R. B.; Thompson, L.: Adenine phosphoribosyltransferase
deficiency: its inheritance and occurrence in a female with gout and
renal disease. Aust. New Zeal. J. Med. 5: 440-446, 1975.

11. Engle, S. J.; Stockelman, M. G.; Chen, J.; Boivin, G.; Yum, M.-N.;
Davies, P. M.; Ying, M. Y.; Sahota, A.; Simmonds, H. A.; Stambrook,
P. J.; Tischfield, J. A.: Adenine phosphoribosyltransferase-deficient
mice develop 2,8-dihydroxyadenine nephrolithiasis. Proc. Nat. Acad.
Sci. 93: 5307-5312, 1996.

12. Ferguson-Smith, M. A.; Cox, D. R.: Report of the committee on
the genetic constitution of chromosomes 13, 14, 15, 16 and 17. Cytogenet.
Cell Genet. 37: 127-154, 1984.

13. Fox, I. H.; Lacroix, S.; Planet, G.; Moore, M.: Partial deficiency
of adenine phosphoribosyltransferase in man. Medicine 56: 515-526,
1977.

14. Fox, I. H.; Meade, J. C.; Kelley, W. N.: Adenine phosphoribosyltransferase
deficiency in man: report of a second family. Am. J. Med. 55: 614-619,
1973.

15. Fratini, A.; Simmers, R. N.; Callen, D. F.; Hyland, V. J.; Tischfield,
J. A.; Stambrook, P. J.; Sutherland, G. R.: A new location for the
human adenine phosphoribosyltransferase gene (APRT) distal to the
haptoglobin (HP) and fra(16)(q23) (FRA16D) loci. Cytogenet. Cell
Genet. 43: 10-13, 1986.

16. Fujimori, S.; Akaoka, I.; Sakamoto, K.; Yamanaka, H.; Nishioka,
K.; Kamatani, N.: Common characteristics of mutant adenine phosphoribosyltransferases
from four separate Japanese families with 2,8-dihydroxyadenine urolithiasis
associated with partial enzyme deficiencies. Hum. Genet. 71: 171-176,
1985.

17. Gathof, B. S.; Sahota, A.; Gresser, U.; Chen, J.; Stambrook, P.
J.; Tischfield, J. A.; Zollner, N.: Identification of a splice mutation
at the adenine phosphoribosyltransferase locus in a German family.
Klin. Wschr. 69: 1152-1155, 1991.

18. Gault, M. H.; Simmonds, H. A.; Snedden, W.; Dow, D.; Churchill,
D. N.; Penney, H.: Urolithiasis due to 2,8-dihydroxyadenine in an
adult. New Eng. J. Med. 305: 1570-1572, 1981.

19. Glicklich, D.; Gruber, H. E.; Matas, A. J.; Tellis, V. A.; Karwa,
G.; Finley, K.; Salem, C.; Soberman, R.; Seegmiller, J. E.: 2,8-Dihydroxyadenine
urolithiasis: report of a case first diagnosed after renal transplant.
Quart. J. Med. (N.S.) 69: 785-793, 1988.

20. Hakoda, M.; Nishioka, K.; Kamatani, N.: Homozygous deficiency
at autosomal locus APRT in human somatic cells in vivo induced by
two different mechanisms. Cancer Res. 50: 1738-1741, 1990.

21. Hakoda, M.; Yamanaka, H.; Kamatani, N.; Kamatani, N.: Diagnosis
of heterozygous states for adenine phosphoribosyltransferase deficiency
based on detection of in vivo somatic mutants in blood T cells: application
to screening of heterozygotes. Am. J. Hum. Genet. 48: 552-562,
1991.

22. Henderson, J. F.; Kelley, W. N.; Rosenbloom, F. M.; Seegmiller,
J. E.: Inheritance of purine phosphoribosyltransferases in man. Am.
J. Hum. Genet. 21: 61-70, 1969.

23. Hidaka, Y.; Palella, T. D.; O'Toole, T. E.; Tarle, S. A.; Kelley,
W. N.: Human adenine phosphoribosyltransferase: identification of
allelic mutations at the nucleotide level as a cause of complete deficiency
of the enzyme. J. Clin. Invest. 80: 1409-1415, 1987.

24. Hidaka, Y.; Tarle, S. A.; Fujimori, S.; Kamatani, N.; Kelley,
W. N.; Palella, T. D.: Human adenine phosphoribosyltransferase deficiency:
demonstration of a single mutant allele common to the Japanese. J.
Clin. Invest. 81: 945-950, 1988.

25. Hidaka, Y.; Tarle, S. A.; O'Toole, T. E.; Kelley, W. N.; Palella,
T. D.: Nucleotide sequence of the human APRT gene. Nucleic Acids
Res. 15: 9086, 1987.

26. Hirsch-Kauffmann, M.; Doppler, W.: Biochemical studies on a patient
with complete APRT-deficiency.(Abstract) Sixth Int. Cong. Hum. Genet.,
Jerusalem 96 only, 1981.

27. Ishidate, T.; Igarashi, S.; Kamatani, N.: Pseudodominant transmission
of an autosomal recessive disease, adenine phosphoribosyltransferase
deficiency. J. Pediat. 118: 90-91, 1991.

28. Johnson, L. A.; Gordon, R. B.; Emmerson, B. T.: Adenine phosphoribosyltransferase:
a simple spectrophotometric assay and the incidence of mutation in
the normal population. Biochem. Genet. 15: 265-272, 1977.

29. Kamatani, N.; Hakoda, M.; Otsuka, S.; Yoshikawa, H.; Kashiwazaki,
S.: Only three mutations account for almost all defective alleles
causing adenine phosphoribosyltransferase deficiency in Japanese patients.
J. Clin. Invest. 90: 130-135, 1992.

30. Kamatani, N.; Kuroshima, S.; Hakoda, M.; Palella, T. D.; Hidaka,
Y.: Crossovers within a short DNA sequence indicate a long evolutionary
history of the APRT*J mutation. Hum. Genet. 85: 600-604, 1990.

31. Kamatani, N.; Kuroshima, S.; Terai, C.; Hidaka, Y.; Palella, T.
D.; Nishioka, K.: Detection of an amino acid substitution in the
mutant enzyme for a special type of adenine phosphoribosyltransferase
(APRT) deficiency by sequence-specific protein cleavage. Am. J.
Hum. Genet. 45: 325-331, 1989.

32. Kamatani, N.; Kuroshima, S.; Terai, C.; Kawai, K.; Mikanagi, K.;
Nishioka, K.: Selection of human cells having two different types
of mutations in individual cells (genetic/artificial mutants): application
to the diagnosis of the heterozygous state for a type of adenine phosphoribosyltransferase
deficiency. Hum. Genet. 76: 148-152, 1987.

33. Kamatani, N.; Kuroshima, S.; Yamanaka, H.; Nakashe, S.; Take,
H.; Hakoda, M.: Identification of a compound heterozygote for adenine
phosphoribosyltransferase deficiency (APRT*J/APRT*Q0) leading to 2,8-dihydroxyadenine
urolithiasis. Hum. Genet. 85: 500-504, 1990.

34. Kamatani, N.; Terai, C.; Kuroshima, S.; Nishioka, K.; Mikanagi,
K.: Genetic and clinical studies on 19 families with adenine phosphoribosyltransferase
deficiencies. Hum. Genet. 75: 163-168, 1987.

35. Kelley, W. N.; Levy, R. I.; Rosenbloom, F. M.; Henderson, J. F.;
Seegmiller, J. E.: Adenine phosphoribosyltransferase deficiency:
a previously undescribed genetic defect in man. J. Clin. Invest. 47:
2281-2289, 1968.

36. Kishi, T.; Kidani, K.; Komazawa, Y.; Sakura, N.; Matsuura, R.;
Kobayashi, M.; Tanabe, A.; Hyodo, S.; Kittaka, E.; Sakano, T.; Tanaka,
Y.; Kobayashi, Y.; Nakamoto, T.; Nakatsu, H.; Moriyama, H.; Hayashi,
M.; Nihira, H.; Usui, T.: Complete deficiency of adenine phosphoribosyltransferase:
a report of three cases and immunologic and phagocytic investigations.
Pediat. Res. 18: 30-34, 1984.

37. Lavinha, J.; Morrison, N.; Glasgow, L.; Ferguson-Smith, M. A.
: Further evidence for the regional localization of human APRT and
DIA4 on chromosome 16.(Abstract) Cytogenet. Cell Genet. 37: 517
only, 1984.

38. Laxdal, T.: 2,8-Dihydroxyadenine crystalluria vs urolithiasis.(Letter) Lancet 340:
184 only, 1992.

39. Laxdal, T.; Jonasson, T. A.: Adenine phosphoribosyltransferase
deficiency in Iceland. Acta Med. Scand. 224: 621-626, 1988.

40. Lester, S. C.; LeVan, S. K.; Steglich, C.; DeMars, R.: Expression
of human genes of adenine phosphoribosyltransferase and hypoxanthine-guanine
phosphoribosyltransferase after genetic transformation of mouse cells
with purified human DNA. Somat. Cell Genet. 6: 241-259, 1980.

41. Maddocks, J. L.: 2,8-Dihydroxyadenine urolithiasis.(Letter) Lancet 339:
1296 only, 1992.

42. Maddocks, J. L.; Al-Safi, S. A.: Adenine phosphoribosyltransferase
deficiency: a simple diagnostic test. Clin. Sci. 75: 217-220, 1988.

43. Manyak, M. J.; Frensilli, F. J.; Miller, H. C.: 2,8-Dihydroxyadenine
urolithiasis: report of an adult case in the United States. J. Urol. 137:
312-314, 1987.

44. Marimo, B.; Giannelli, F.: Gene dosage effect in human trisomy
16. Nature 256: 204-206, 1975.

45. Mimori, A.; Hidaka, Y.; Wu, V. C.; Tarle, S. A.; Kamatani, N.;
Kelley, W. N.; Pallela, T. D.: A mutant allele common to the type
I adenine phosphoribosyltransferase deficiency in Japanese subjects.
Am. J. Hum. Genet. 48: 103-107, 1991.

46. Nesterova, T. B.; Borodin, P. M.; Zakian, S. M.; Serov, O. L.
: Assignment of the gene for adenine phosphoribosyltransferase on
the genetic map of mouse chromosome 8. Biochem. Genet. 25: 563-568,
1987.

47. Rappaport, H.; DeMars, R.: Diaminopurine-resistant mutants of
cultured, diploid human fibroblasts. Genetics 75: 335-345, 1973.

48. Sahota, A.; Chen, J.; Behzadian, M. A.; Ravindra, R.; Takeuchi,
H.; Stambrook, P. J.; Tischfield, J. A.: 2,8-Dihydroxyadenine lithiasis
in a Japanese patient heterozygous at the adenine phosphoribosyltransferase
locus. Am. J. Hum. Genet. 48: 983-989, 1991.

49. Sahota, A.; Chen, J.; Boyadijev, S. A.; Gault, M. H.; Tischfield,
J. A.: Missense mutation in the adenine phosphoribosyltransferase
gene causing 2,8-dihydroxyadenine urolithiasis. Hum. Molec. Genet. 3:
817-818, 1994.

50. Simmonds, H. A.: 2,8-Dihydroxyadeninuria--or when is a uric acid
stone not a uric acid stone?. Clin. Nephrol. 12: 195-197, 1979.

51. Simmonds, H. A.; Van Acker, K. J.; Sahota, A. S.: 2,8-Dihydroxyadenine
urolithiasis.(Letter) Lancet 339: 1295-1296, 1992.

52. Simon, A. E.; Taylor, M. W.: High-frequency mutation at the adenine
phosphoribosyltransferase locus in Chinese hamster ovary cells due
to deletion of the gene. Proc. Nat. Acad. Sci. 80: 810-814, 1983.

53. Takeuchi, F.; Matsuta, K.; Miyamoto, T.; Enomoto, S.; Fujimori,
S.; Akaoka, I.; Kamatani, N.; Nishioka, K.: Rapid method for the
diagnosis of partial adenine phosphoribosyltransferase deficiencies
causing 2,8-dihydroxyadenine urolithiasis. Hum. Genet. 71: 167-170,
1985.

54. Terai, C.; Hakoda, M.; Yamanaka, H.; Kamatani, N.; Okai, M.; Takahashi,
F.; Kashiwazaki, S.: Adenine phosphoribosyltransferase deficiency
identified by urinary sediment analysis: cellular and molecular confirmation. Clin.
Genet. 48: 246-250, 1995.

55. Tischfield, J. A.; Ruddle, F. H.: Assignment of the gene for
adenine phosphoribosyltransferase to human chromosome 16 by mouse-human
somatic cell hybridization. Proc. Nat. Acad. Sci. 71: 45-49, 1974.

56. Van Acker, K. J.; Simmonds, H. A.; Potter, C.; Cameron, J. S.
: Complete deficiency of adenine phosphoribosyltransferase: report
of a family. New Eng. J. Med. 297: 127-132, 1977.

57. Ward, I. D.; Addison, G. M.: 2,8-Dihydroxyadenine urolithiasis.
(Letter) Lancet 339: 1296, 1992.

58. Wilson, J. M.; O'Toole, T. E.; Argos, P.; Shewach, D. S.; Daddona,
P. E.; Kelley, W. N.: Human adenine phosphoribosyltransferase: complete
amino acid sequence of the erythrocyte enzyme. J. Biol. Chem. 261:
13677-13683, 1986.

*FIELD* CS

GU:
   Urolithiasis;
   Renal failure

Lab:
   APRT deficiency;
   2,8-dihydroxyadenine urinary stones;
   Round, brownish urine crystals

Inheritance:
   Autosomal dominant (16q22.2-q22.3), with homozygosity or compound
   heterozygosity in complete deficiency

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 07/06/1996
mark: 6/24/1996
terry: 6/12/1996
carol: 5/18/1996
mark: 1/17/1996
pfoster: 11/29/1994
mimadm: 4/14/1994
warfield: 4/6/1994
carol: 7/9/1993
carol: 2/17/1993
carol: 10/28/1992

*RECORD*
*FIELD* NO
102610
*FIELD* TI
*102610 ACTIN, ALPHA, SKELETAL MUSCLE 1; ACTA1
ASMA
*FIELD* TX
By use of a cDNA probe in somatic cell hybrids, Hanauer et al. (1984)
assigned the gene for the alpha chain of skeletal muscle actin to
chromosome 1. Actin sequences were found at high stringency also at
2p23-qter and 3pter-q21. Under conditions of low or medium stringency,
actin sequences were demonstrated on the X (p11-p12) and Y chromosomes.
Using a cDNA copy of the 3-prime untranslated region of the human
skeletal alpha actin gene, Shows et al. (1984) mapped the gene to
1p12-1qter. This gene and that for cardiac alpha-actin (102540) are
coexpressed in both human skeletal muscle and heart. Coexpression is not
a function of linkage; the loci are on separate chromosomes: 1p21-qter
and 15q11-qter, respectively (Gunning et al., 1984). Akkari et al.
(1994) narrowed the assignment of the ACTA1 gene to 1q42 by fluorescence
in situ hybridization. Also by fluorescence in situ hybridization,
Ueyama et al. (1995) mapped the gene to 1q42.1. Using a panel of somatic
cell hybrids, Alonso et al. (1993) confirmed the localization of the
ACTA1 gene on human chromosome 1. On the basis of analysis of
mouse/hamster somatic cell hybrids segregating mouse chromosomes,
Czosnek et al. (1982) concluded that the skeletal actin gene is located
on mouse chromosome 3. However, Alonso et al. (1993) found by PCR
analysis of a microsatellite in an interspecific backcross that the
gene, symbolized Actsk-1, is closely linked to tyrosine aminotransferase
and adenine phosphoribosyltransferase on mouse chromosome 8. The Actsk-1
gene is situated between Tat and Aprt; the human homologs TAT (276600)
and APRT (102600) are on human chromosome 16. Abonia et al. (1993)
likewise mapped the Actsk-1 gene to mouse chromosome 8 by segregation of
RFLVs in 2 interspecific backcross sets and in 4 recombinant inbred (RI)
mouse sets.

Actin makes up 10 to 20% of cellular protein and has vital roles in cell
integrity, structure, and motility. It is highly conserved throughout
evolution. Its function depends on the balance between monomeric
(globular) G-actin (42 kD) and filamentous F-actin, a linear polymer of
G-actin subunits. Among the cytosolic actin-binding proteins, 3 appear
to be of primary importance in limiting polymerization: profilin
(176590, 176610), thymosin beta-4 (188395), and gelsolin (GSN; 137350).
The existence of intracellular actin-binding proteins allows the
concentration of G-actin to be maintained substantially above the
threshold at which polymerization and the formation of filaments would
normally occur. When released into the extracellular space, actin, which
otherwise is known to have a pathologic effect, is bound by gelsolin and
by the Gc protein (GC; 139200). This is the so-called extracellular
actin-scavenger system (Lee and Galbraith, 1992).

*FIELD* RF
1. Abonia, J. P.; Abel, K. J.; Eddy, R. L.; Elliott, R. W.; Chapman,
V. M.; Shows, T. B.; Gross, K. W.: Linkage of Agt and Actsk-1 to
distal mouse chromosome 8 loci: a new conserved linkage. Mammalian
Genome 4: 25-32, 1993.

2. Akkari, P. A.; Eyre, H. J.; Wilton, S. D.; Callen, D. F.; Lane,
S. A.; Meredith, C.; Kedes, L.; Laing, N. G.: Assignment of the human
skeletal muscle alpha actin gene (ACTA1) to 1q42 by fluorescence in
situ hybridisation. Cytogenet. Cell Genet. 65: 265-267, 1994.

3. Alonso, S.; Montagutelli, X.; Simon-Chazottes, D.; Guenet, J.-L.;
Buckingham, M.: Re-localization of Actsk-1 to mouse chromosome 8,
a new region of homology with human chromosome 1. Mammalian Genome 4:
15-20, 1993.

4. Czosnek, H.; Nudel, U.; Shani, M.; Barker, P. E.; Pravtcheva, D.
D.; Ruddle, F. H.; Yaffe, D.: The genes coding for the muscle contractile
proteins, myosin heavy chain, myosin light chain 2, and skeletal muscle
actin are located on three different mouse chromosomes. EMBO J. 1:
1299-1305, 1982.

5. Gunning, P.; Ponte, P.; Kedes, L.; Eddy, R.; Shows, T.: Chromosomal
location of the co-expressed human skeletal and cardiac actin genes. Proc.
Nat. Acad. Sci. 81: 1813-1817, 1984.

6. Hanauer, A.; Heilig, R.; Levin, M.; Moisan, J. P.; Grzeschik, K.
H.; Mandel, J. L.: The actin gene family in man: assignment of the
gene for skeletal muscle alpha-actin to chromosome 1, and presence
of actin sequences on autosomes 2 and 3, and on the X and Y chromosomes.
(Abstract) Cytogenet. Cell Genet. 37: 487-488, 1984.

7. Lee, W. M.; Galbraith, R. M.: The extracellular actin-scavenger
system and actin toxicity. New Eng. J. Med. 326: 1335-1341, 1992.

8. Shows, T.; Eddy, R. L.; Haley, L.; Byers, M.; Henry, M.; Gunning,
P.; Ponte, P.; Kedes, L.: The coexpressed genes for human alpha (ACTA)
and cardiac actin (ACTC) are on chromosomes 1 and 15, respectively.
(Abstract) Cytogenet. Cell Genet. 37: 583 only, 1984.

9. Ueyama, H.; Inazawa, J.; Ariyama, T.; Nishino, H.; Ochiai, Y.;
Ohkubo, I.; Miwa, T.: Reexamination of chromosomal loci of human
muscle actin genes by fluorescence in situ hybridization. Jpn. J.
Hum. Genet. 40: 145-148, 1995.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/20/1997
terry: 6/16/1995
carol: 5/27/1994
carol: 2/3/1993
carol: 5/28/1992
supermim: 3/16/1992
carol: 7/3/1991

*RECORD*
*FIELD* NO
102620
*FIELD* TI
*102620 ACTIN, ALPHA, SMOOTH MUSCLE, AORTIC; ACTSA
ACTIN, ALPHA-2, SMOOTH MUSCLE, AORTA; ACTA2;;
ACTIN, VASCULAR SMOOTH MUSCLE
*FIELD* TX
Six different actin isoforms have been identified in vertebrates by
amino acid sequencing: skeletal muscle, cardiac muscle, 2 smooth muscle
(enteric and aortic), and 2 cytoplasmic (beta and gamma) (Vandekerckhove
and Weber, 1979). Their amino acid sequences are very similar and well
conserved in evolution; e.g., skeletal and cardiac actins differ by only
4 amino acids, and skeletal muscle and cytoplasmic beta-actins differ by
only 25 amino acids out of a total of 374. Ueyama et al. (1984) isolated
and characterized the human aortic smooth muscle actin gene. It was
found to contain 2 more introns than do skeletal and cardiac muscle
actin genes: between codons 84 and 85 and 121 and 122. The gene also has
a transition point mutation in position 309, substituting thymine for
cytosine. Ueyama et al. (1990) assigned the ACTSA gene to chromosome 10
by Southern blot analysis of DNAs from 18 rodent-human somatic cell
hybrids. Regional mapping by in situ hybridization localized the gene to
10q22-q24. By fluorescence in situ hybridization, Ueyama et al. (1995)
localized the ACTSA gene to 10q23.3.

*FIELD* RF
1. Ueyama, H.; Bruns, G.; Kanda, N.: Assignment of the vascular smooth
muscle actin gene ACTSA to human chromosome 10. Jpn. J. Hum. Genet. 35:
145-150, 1990.

2. Ueyama, H.; Hamada, H.; Battula, N.; Kakunaga, T.: Structure of
a human smooth muscle actin gene (aortic type) with a unique intron
site. Molec. Cell. Biol. 4: 1073-1078, 1984.

3. Ueyama, H.; Inazawa, J.; Ariyama, T.; Nishino, H.; Ochiai, Y.;
Ohkubo, I.; Miwa, T.: Reexamination of chromosomal loci of human
muscle actin genes by fluorescence in situ hybridization. Jpn. J.
Hum. Genet. 40: 145-148, 1995.

4. Vandekerckhove, J.; Weber, K.: The complete amino acid sequence
of actins from bovine aorta, bovine heart, bovine fast skeletal muscle,
and rabbit slow skeletal muscle. Differentiation 14: 123-133, 1979.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 6/16/1995
supermim: 3/16/1992
carol: 2/27/1992
carol: 7/3/1991
carol: 3/19/1991
carol: 9/27/1990

*RECORD*
*FIELD* NO
102630
*FIELD* TI
*102630 ACTIN, BETA; ACTB
BETA-ACTIN
*FIELD* TX
From studies of the amino acid sequence of cytoplasmic and muscle
actins, Vandekerckhove and Weber (1978) concluded that mammalian
cytoplasmic actins are the products of 2 different genes and differ by
many amino acids from muscle actin. In a neoplastic cell line resulting
from treatment of cultured human diploid fibroblasts with a chemical
mutagen, Leavitt et al. (1982) observed a mutant form of beta actin.
Toyama and Toyama (1984) isolated and characterized lines of KB cells
resistant to cytochalasin B. They found that one resistant line had an
alteration in beta-actin. Such cells bound less cytochalasin B than did
parental KB cells. The authors suggested that the primary site of action
of cytochalasin B on cell motility processes is beta-actin.

There are 6 known actin proteins in mammalian cells: 2 sarcomeric muscle
actins (alpha-skeletal and alpha-cardiac), 2 smooth muscle actins (alpha
and gamma), and 2 nonmuscle, cytoskeletal actins (beta and gamma) (Kedes
et al., 1985). The genes of 3 of these have been mapped: beta-actin on
chromosome 7, alpha-skeletal actin (102610) on chromosome 1, and
alpha-cardiac actin (102540) on chromosome 15. Ng et al. (1985) assigned
the ACTB gene to 7pter-q22 by Southern blot analysis of DNA from somatic
cell hybrids. Habets et al. (1992) generated hybrids that harbor only
specific regions of human chromosome 7 and assigned the ACTB locus to
7p15-p12.

Ueyama et al. (1996) used fluorescence in situ hybridization to map ACTB
to 7p22. By PCR of somatic cell hybrid DNAs, they mapped 4 ACTB
pseudogenes to other chromosomes.

- PSEUDOGENES

Ng et al. (1985, 1985) showed that there are about 20 pseudogenes widely
distributed in the genome. ACTBP1 is on Xq13-q22; ACTBP2, on chromosome
5; ACTBP3, on chromosome 18; ACTBP4, on chromosome 5 and ACTBP5, on
7q22-7qter. All have been mapped in somatic cell hybrids by use of DNA
clones.

*FIELD* SA
Erba et al. (1988); Nakajima-Iijima et al. (1985)
*FIELD* RF
1. Erba, H. P.; Eddy, R.; Shows, T.; Kedes, L.; Gunning, P.: Structure,
chromosome location, and expression of the human gamma-actin gene:
differential evolution, location, and expression of the cytoskeletal
beta- and gamma-actin genes. Molec. Cell. Biol. 8: 1775-1789, 1988.

2. Habets, G. G. M.; van der Kammen, R. A.; Willemsen, V.; Balemans,
M.; Wiegant, J.; Collard, J. G.: Sublocalization of an invasion-inducing
locus and other genes on human chromosome 7. Cytogenet. Cell Genet. 60:
200-205, 1992.

3. Kedes, L.; Ng, S.-Y.; Lin, C.-S.; Gunning, P.; Eddy, R.; Shows,
T.; Leavitt, J.: The human beta-actin multigene family. Trans. Assoc.
Am. Phys. 98: 42-46, 1985.

4. Leavitt, J.; Bushar, G.; Kakunaga, T.; Hamada, H.; Hirakawa, T.;
Goldman, D.; Merril, C.: Variations in expression of mutant beta-actin
accompanying incremental increases in human fibroblast tumorigenicity. Cell 28:
259-268, 1982.

5. Nakajima-Iijima, S.; Hamada, H.; Reddy, P.; Kakunaga, T.: Molecular
structure of the human cytoplasmic beta-actin gene; interspecies homology
of sequences in the introns. Proc. Nat. Acad. Sci. 82: 6133-6137,
1985.

6. Ng, S.-Y.; Gunning, P.; Eddy, R.; Ponte, P.; Leavitt, J.; Kedes,
L.; Shows, T.: Chromosome 7 assignment of the human beta-actin functional
gene (ACTB) and the chromosomal dispersion of pseudogenes. (Abstract) Cytogenet.
Cell Genet. 40: 712 only, 1985.

7. Ng, S.-Y.; Gunning, P.; Eddy, R.; Ponte, P.; Leavitt, J.; Shows,
T.; Kedes, L.: Evolution of the functional human beta-actin gene
and its multi-pseudogene family: conservation of the noncoding regions
and chromosomal dispersion of pseudogenes. Molec. Cell. Biol. 5:
2720-2732, 1985.

8. Toyama, S.; Toyama, S.: A variant form of beta-actin in a mutant
of KB cells resistant to cytochalasin B. Cell 37: 609-614, 1984.

9. Ueyama, H.; Inazawa, J.; Nishino, H.; Ohkubo, I.; Miwa, T.: FISH
localization of human cytoplasmic actin genes ACTB to 7p22 and ACTG1
to 17q25 and characterization of related pseudogenes. Cytogenet.
Cell Genet. 74: 221-224, 1996.

10. Vandekerckhove, J.; Weber, K.: Mammalian cytoplasmic actins are
the products of at least two genes and differ in primary structure
in at least 25 identified positions from skeletal muscle actins. Proc.
Nat. Acad. Sci. 75: 1106-1110, 1978.

*FIELD* CN
Mark H. Paalman - edited: 4/18/1997
Mark H. Paalman - edited: 4/10/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 04/18/1997
mark: 4/18/1997
jenny: 4/10/1997
terry: 1/13/1997
carol: 7/1/1993
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 5/18/1988

*RECORD*
*FIELD* NO
^102640
*FIELD* TI
^102640 MOVED TO 102630
*FIELD* TX
This entry was incorporated into entry 102630 on 18 April 1997.

*FIELD* CN
Mark H. Paalman - edited: 04/18/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
mark: 04/18/1997
supermim: 3/16/1992
carol: 3/3/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987
*RECORD*
*FIELD* NO
102642
*FIELD* TI
*102642 STEROL O-ACYLTRANSFERASE; SOAT
ACYL-CoA:CHOLESTEROL ACYLTRANSFERASE; ACACT;;
STEROL ACYLTRANSFERASE
*FIELD* TX
Accumulation of cholesterol esters as cytoplasmic lipid droplets within
macrophages and smooth muscle cells is a characteristic feature of the
early stages of atherosclerotic plaques. Intracellularly, an essential
element in forming cholesterol ester from cholesterol is the enzyme
acyl-coenzyme A:cholesterol acyltransferase (ACACT; EC 2.3.1.26). ACACT
is a membrane protein located in the endoplasmic reticulum. Cadigan et
al. (1988) isolated a cell line lacking ACACT activity from mutagenized
Chinese hamster ovary cells. By DNA-mediated gene transfer into
ACACT-deficient cells, Cadigan et al. (1989) obtained transfectant cells
stably expressing human ACACT activity. Using genomic DNAs of these
transfectant cells as starting materials, Chang et al. (1993) cloned a
human macrophage cDNA encoding ACACT. The cDNA contained a single open
reading frame of approximately 1.7 kb. Protein homology analysis of this
ORF indicated that it represents a structural gene for ACACT.

By fluorescence in situ hybridization and by Southern blot analysis of
human/hamster somatic cell hybrid panels, Chang et al. (1994) mapped the
ACACT gene to 1q25.

Unesterified sterol modulates the function of eukaryotic membranes. In
human cells, sterol is esterified to a storage form by acyl-coenzyme A
(CoA):cholesterol acyltransferase. Yang et al. (1996) identified 2 genes
designated ARE1 and ARE2 by them that encode related enzymes in yeast.
The yeast enzymes are 49% identical to each other and exhibit 23%
identity and 49% similarity to human sterol O-acyltransferase. A
deletion of ARE2 reduced the sterol ester levels to approximately 25% of
normal levels, whereas disruption of ARE1 did not affect sterol ester
biosynthesis. Deletion of both genes resulted in a viable cell with
undetectable esterified sterol. With the use of a consensus sequence to
the yeast and human genes, an additional member of the SOAT gene family
was identified in humans; see 601311.

Meiner et al. (1996) noted that ACAT activity is found in many tissues,
including macrophages, adrenal glands, and liver. In macrophages, ACAT
is thought to participate in foam cell formation and thereby to
contribute to the development of atherosclerotic lesions. Meiner et al.
(1996) disrupted the homologous gene (Acact) in mice, which resulted in
decreased cholesterol esterification in Acact-deficient fibroblasts and
adrenal membranes and markedly reduced cholesterol ester levels in
adrenal glands and peritoneal macrophages. In contrast, the livers of
Acact-deficient mice contained substantial amounts of cholesterol esters
and exhibited no reduction in cholesterol esterification activity. These
tissue-specific reductions in cholesterol esterification provided
evidence that in mammals this process involves more than 1 form of
esterification enzyme.

Nomenclature: The preferred symbol for this gene is SOAT, for steryl
O-acyltransferase. Chang et al. (1993) and Yang et al. (1996) used the
abbreviation ACAT for the enzyme; this, however, has been used for
another enzyme with ketothiolase activity (203750). Literature symbols
used for this gene include ACACT and STAT (not to be confused with a
family of signal transducer/transcription activator genes; see 600555).

*FIELD* RF
1. Cadigan, K. M.; Chang, C. C. Y.; Chang, T.-Y.: Isolation of Chinese
hamster ovary cell lines expressing human acyl-coenzyme A/cholesterol
acyltransferase activity. J. Cell Biol. 108: 2201-2210, 1989.

2. Cadigan, K. M.; Heider, J. G.; Chang, T.-Y.: Isolation and characterization
of Chinese hamster ovary cell mutants deficient in acyl-coenzyme A:cholesterol
acyltransferase activity. J. Biol. Chem. 263: 274-282, 1988.

3. Chang, C. C. Y.; Huh, H. Y.; Cadigan, K. M.; Chang, T. Y.: Molecular
cloning and functional expression of human acyl-coenzyme A:cholesterol
acyltransferase cDNA in mutant Chinese hamster ovary cells. J. Biol.
Chem. 268: 20747-20755, 1993.

4. Chang, C. C. Y.; Noll, W. W.; Nutile-McMenemy, N.; Lindsay, E.
A.; Baldini, A.; Chang, W.; Chang, T. Y.: Localization of acyl coenzyme
A:cholesterol acyltransferase gene to human chromosome 1q25. Somat.
Cell Molec. Genet. 20: 71-74, 1994.

5. Meiner, V. L.; Cases, S.; Myers, H. M.; Sande, E. R.; Bellosta,
S.; Schambelan, M.; Pitas, R. E.; McGuire, J.; Herz, J.; Farese, R.
V., Jr.: Disruption of the acyl-CoA:cholesterol acyltransferase gene
in mice: evidence suggesting multiple cholesterol esterification enzymes
in mammals. Proc. Nat. Acad. Sci. 93: 14041-14046, 1996.

6. Yang, H.; Bard, M.; Bruner, D. A.; Gleeson, A.; Deckelbaum, R.
J.; Aljinovic, G.; Pohl, T. M.; Rothstein, R.; Sturley, S. L.: Sterol
esterification in yeast: a two-gene process. Science 272: 1353-1356,
1996.

*FIELD* CD
Victor A. McKusick: 11/10/1993

*FIELD* ED
terry: 01/23/1997
mark: 1/18/1997
terry: 1/10/1997
mark: 6/17/1996
terry: 6/17/1996
terry: 6/13/1996
mark: 3/8/1996
carol: 10/10/1994
terry: 8/25/1994
carol: 11/12/1993
carol: 11/10/1993

*RECORD*
*FIELD* NO
102645
*FIELD* TI
*102645 ACYLPEPTIDE HYDROLASE; APH
N-ACYLAMINOACYLPEPTIDE HYDROLASE; APEH
*FIELD* TX
Harper and Saunders (1981) mapped a probe called lambda-H3 to chromosome
1 by in situ hybridization. This was subsequently called D1S1. Further
studies by Carritt et al. (1986) and Goode et al. (1986) indicated that
this single copy sequence actually originated from chromosome 3 and that
several homologous sequences were located on chromosome 1. The locus on
chromosome 3 was designated DNF15S2 and the locus on chromosome 1 was
designated DNF15S1. The DNF15S2 locus was shown to have a high rate of
allele loss in both small cell lung cancer and renal cell carcinoma.
Naylor et al. (1989) showed that the DNF15S2 locus is located at 3p21
and that it is transcribed in normal lung and in small cell lung cancer.
They presented the sequence of the gene. They pointed out that the
activity of aminoacylase-1, which is encoded by the ACY1 gene located at
3p21 (104620), was lacking in the same small cell lung cancer cell line
that lacked DNF15S1. Jones et al. (1991) pointed out an 87% identity
between the cDNA sequence that encodes acylpeptide hydrolase from
porcine liver (Mitta et al., 1989) and the cDNA transcribed from DNF15S2
(Naylor et al., 1989). Acylpeptide hydrolase (EC 3.4.19.1) catalyzes the
hydrolysis of the terminal acetylated amino acid preferentially from
small acetylated peptides. The acetylamino acid formed by acylpeptide
hydrolase is further processed to acetate and a free amino acid by an
aminoacylase. The substrates for the acylpeptide hydrolase and the
acylase behave in a reciprocal manner since acylpeptide hydrolase binds
but does not process acetylamino acids and the acylase binds
acetylpeptides but does not hydrolyze them; however, the 2 enzymes share
the same specificity for the acyl group. All of these findings indicate
common functional features in the protein structures of the 2 enzymes,
which are encoded by the same region of human chromosome 3, namely,
3p21. Jones et al. (1991) suggested that there may be a relationship
between the expression of these 2 enzymes and acetylated peptide growth
factors in some carcinomas. The locus on 3p21, formerly called DNF15S2
and now symbolized APH, is known to have 2 polymorphic sites, both
detectable with HindIII (Carritt et al., 1986; Goode et al., 1986).
(This locus was labeled DNF15S2 by HGM9 in Paris in 1987, D3F15S2E by
HGM10 in New Haven in 1989, and D3F15S2 by HGM10.5 in Oxford in 1990.)

A polymorphic locus, D3S94, previously localized to 3pter-p14.2 (Kiousis
et al., 1989), contains 2 CpG islands and sequences conserved in the
hamster and mouse. Ginzinger et al. (1992) isolated cDNAs homologous to
the conserved fragments and found 96% sequence similarity to a cDNA
derived from the DNF15S2 locus. Furthermore, the sequence of cDNAs
derived from both the rat and pig acylpeptide hydrolase showed a high
degree of sequence similarity to cDNAs derived from D3S94 and DNF15S2,
suggesting that they are all the same locus. The locus in question was
mapped to 3p21.3 by fluorescence in situ hybridization (FISH). ACY1 and
APH map to slightly different regions of 3p, 3p21.1 and 3p21.3,
respectively. Using pulsed field gel electrophoresis, Boldog et al.
(1989) showed that the DNF15S2 locus is not linked to D3S2; since D3S2
is within the same 2.5-Mb region as ACY1, it is likely that ACY1 and APH
are not closely linked physically. The homologous gene is located on
mouse chromosome 9 and rat chromosome 8 in a region highly homologous to
human chromosome 3 (Pausova et al., 1994).

*FIELD* RF
1. Boldog, F.; Erlandsson, R.; Klein, G.; Sumegi, J.: Long-range
restriction enzyme maps of DNF15S2, D3S2 and c-raf1 loci on the short
arm of human chromosome 3. Cancer Genet. Cytogenet. 42: 295-306,
1989.

2. Carritt, B.; Welch, H. M.; Parry-Jones, N. J.: Sequences homologous
to the human D1S1 locus present on human chromosome 3. Am. J. Hum.
Genet. 38: 428-436, 1986.

3. Ginzinger, D. G.; Shridhar, V.; Baldini, A.; Taggart, R. T.; Miller,
O. J.; Smith, D. I.: The human loci DNF15S2 and D3S94 have a high
degree of sequence similarity to acyl-peptide hydrolase and are located
at 3p21.3. Am. J. Hum. Genet. 50: 826-833, 1992.

4. Goode, M. E.; vanTuinen, P.; Ledbetter, D. H.; Daiger, S. P.:
The anonymous polymorphic DNA clone D1S1, previously mapped to human
chromosome 1p36 by in situ hybridization, is from chromosome 3 and
is duplicated on chromosome 1. Am. J. Hum. Genet. 38: 437-446,
1986.

5. Harper, M. E.; Saunders, G. E.: Localization of single copy DNA
sequences on G-banded human chromosomes by in situ hybridization.
Chromosoma 83: 431-439, 1981.

6. Jones, W. M.; Scaloni, A.; Bossa, F.; Popowicz, A. M.; Schneewind,
O.; Manning, J. M.: Genetic relationship between acylpeptide hydrolase
and acylase, two hydrolytic enzymes with similar binding but different
catalytic specificities. Proc. Nat. Acad. Sci. 88: 2194-2198, 1991.

7. Kiousis, S.; Drabkin, H.; Smith, D. I.: Isolation and mapping
of a polymorphic DNA sequence (cA476) on chromosome 3 (D3S94). Nucleic
Acids Res. 17: 5876 only, 1989.

8. Mitta, M.; Asada, K.; Uchimura, Y.; Kimizuka, F.; Kato, I.; Sakiyama,
F.; Tsunasawa, S.: The primary structure of porcine liver acylamino
acid-releasing enzyme deduced from cDNA sequences. J. Biochem. 106:
548-551, 1989.

9. Naylor, S. L.; Marshall, A.; Hensel, C.; Martinez, P. F.; Holley,
B.; Sakaguchi, A. Y.: The DNF15S2 locus at 3p21 is transcribed in
normal lung and small cell lung cancer. Genomics 4: 355-361, 1989.

10. Pausova, Z.; Bourdon, J.; Clayton, D.; Mattei, M.-G.; Seldin,
M. F.; Janicic, N.; Riviere, M.; Szpirer, J.; Levan, G.; Szpirer,
C.; Goltzman, D.; Hendy, G. N.: Cloning of a parathyroid hormone/parathyroid
hormone-related peptide receptor (PTHR) cDNA from a rat osteosarcoma
(UMR 106) cell line: chromosomal assignment of the gene in the human,
mouse, and rat genomes. Genomics 20: 20-26, 1994.

*FIELD* CD
Victor A. McKusick: 3/25/1991

*FIELD* ED
carol: 4/5/1994
carol: 4/6/1993
carol: 10/13/1992
supermim: 7/28/1992

*RECORD*
*FIELD* NO
102650
*FIELD* TI
102650 ADACTYLIA, UNILATERAL
TERMINAL TRANSVERSE DEFECTS OF HAND, UNILATERAL
*FIELD* TX
Graham et al. (1986) described adult female twins with unilateral
terminal transverse defects affecting the left hand in one and the right
hand in the other. The latter woman had a daughter with a unilateral
transverse defect affecting the left hand. The hand anomaly was
characterized by absence of the terminal portions of digits 2 to 5 with
a mildly hypoplastic thumb. Tiny nail remnants were evident on the
digital stumps. No soft tissue syndactyly was present. The other hand
and both feet were clinically and radiologically normal in each of the 3
persons. No other similar families were found in the literature.

*FIELD* RF
1. Graham, J. M., Jr.; Brown, F. E.; Struckmeyer, C. L.; Hallowell,
C.: Dominantly inherited unilateral terminal transverse defects of
the hand (adactylia) in twin sisters and one daughter. Pediatrics 78:
103-106, 1986.

*FIELD* CS

Limbs:
   Unilateral terminal transverse hand defect;
   Absent terminal portions of digits 2 to 5;
   Mildly hypoplastic thumb

Nails:
   Tiny nail remnants on digital stumps

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 9/8/1988

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 9/13/1988
root: 9/8/1988

*RECORD*
*FIELD* NO
102660
*FIELD* TI
102660 ADAMANTINOMA OF LONG BONES
*FIELD* TX
Adamantinoma of the long bones is a rare, low-grade malignant neoplasm
of unknown histogenesis, which affects mainly the tibia of young adults
(Keeney et al., 1989). Sozzi et al. (1990) demonstrated a translocation
t(7;13)(q32;q14) in a lung metastasis from an adamantinoma of the tibia
in a boy who showed the same translocation constitutionally (in normal
fibroblasts and lymphoid cells). The identical translocation was found
in his normal father. The breakpoint in chromosome 13 was in the same
region as that in retinoblastoma (180200). The level of esterase D was
normal in the patient and his parents.

*FIELD* RF
1. Keeney, G. L.; Unni, K. K.; Beabout, J. W.; Pritchard, D. J.:
Adamantinoma of long bones: a clinicopathologic study of 85 cases.
Cancer 64: 730-737, 1989.

2. Sozzi, G.; Miozzo, M.; Di Palma, S.; Minelli, A.; Calderone, C.;
Danesino, C.; Pastorino, U.; Pierotti, M. A.; Della Porta, G.: Involvement
of the region 13q14 in a patient with adamantinoma of the long bones.
Hum. Genet. 85: 513-515, 1990.

*FIELD* CS

Oncology:
   Adamantinoma of long bones

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 11/21/1990

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 11/21/1990

*RECORD*
*FIELD* NO
102670
*FIELD* TI
*102670 ADDRESSIN, MUCOSAL
MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1;;
MAdCAM-1; MACAM1
*FIELD* TX
Tissue-specific homing of lymphocytes is regulated by interactions with
the endothelium of specialized venules, such as the high endothelial
venules (HEV) in lymph nodes and mucosal lymphoid tissues. The mucosal
vascular addressin, a 58-66K glycoprotein adhesion receptor for
lymphocytes, is selectively expressed on HEV of the mucosal lymphoid
organ and on lamina propria venules and helps direct lymphocyte traffic
to these mucosal tissues. Briskin et al. (1993) isolated a cDNA that, on
transfection into COS cells, encoded immunoreactive addressin that
specifically bound a mucosal HEV-binding T-cell lymphoma. The predicted
amino acid sequence defined the mucosal addressin as a novel
immunoglobulin family member with 2 amino-terminal domains that
displayed strong homology to previously described vascular adhesion
receptors for leukocytes: ICAM1 (147840) and VCAM1 (192225). The
membrane proximal domain was found to be homologous to the third domain
of another mucosa-associated member of the immunoglobulin family,
namely, IgA1.

*FIELD* RF
1. Briskin, M. J.; McEvoy, L. M.; Butcher, E. C.: MAdCAM-1 has homology
to immunoglobulin and mucin-like adhesion receptors and to IgA1. Nature 363:
461-464, 1993.

*FIELD* CD
Victor A. McKusick: 6/22/1993

*FIELD* ED
carol: 6/22/1993

*RECORD*
*FIELD* NO
102680
*FIELD* TI
*102680 ADDUCIN, ALPHA SUBUNIT; ADDA
ADDUCIN-1; ADD1
*FIELD* TX
Adducin is a cell-membrane skeletal protein that was first purified from
human erythrocytes by Gardner and Bennett (1986) and subsequently
isolated from bovine brain membranes. Isoforms of this protein have been
detected in lung, kidney, testes, and liver. Erythrocyte adducin is a
200-kD heterodimer protein present at about 30,000 copies per cell. It
binds with high affinity to Ca(2+)/calmodulin and is a substrate for
protein kinases A and C. Joshi and Bennett (1990) investigated the
structure and function of the separate domains of the protein. Adducin
is a heterodimeric protein. The related subunits, alpha and beta
(102681), are produced from distinct genes but share a similar
structure, with a protease-resistant N-terminal region and a
protease-sensitive, hydrophilic C-terminal region. Joshi et al. (1991)
isolated reticulocyte cDNAs for alpha- and beta-adducin and, by somatic
cell hybrid analysis, provisionally assigned the ADDA gene to chromosome
4 and the ADDB gene to chromosome 2. Both alpha-adducin and beta-adducin
show alternative splicing; thus, there may be several different
heterodimeric or homodimeric forms of adducin, each with a different
functional specificity. Adducin is thought to promote assembly of
spectrin-actin complexes in the formation of the membrane cytoskeleton
(the name comes from the Latin adducere, meaning 'to bring together').
At least in brain, alpha-adducin is encoded by alternatively spliced
mRNAs. See Gilligan and Bennett (1993) for a review of adducin and the
other components of the junctional complex of the cell membrane
skeleton.

Using the technique of exon amplification to isolate genes from the
4p16.3 region where Huntington disease (HD; 143100) appears to be
located, Taylor et al. (1992) identified exons corresponding to the
alpha subunit of adducin. The alpha-adducin gene (ADDA) maps immediately
telomeric to D4S95, in a region likely to contain the HD defect, and
therefore is a candidate gene for Huntington disease. (Buckler et al.
(1991) described a vector system that allows selection and amplification
of exons from genomic DNA, a method referred to as 'exon trapping.')
Goldberg et al. (1992) reported the isolation and cloning of cDNA for
the human brain alpha-adducin gene which they found to be located within
20 kb of D4S95, a marker showing strong linkage disequilibrium with HD.
Ankyrin and adducin appear to have different functions in the membrane
skeleton but both play a role in the interaction with spectrin and the
maintenance of normal membrane integrity. Studies of red cells,
fibroblasts, lymphocytes and neurons in HD patients pointed to a
possible generalized disturbance in membrane structure and function in
this disorder (review by Hayden, 1981). The functional consequences of
defects in the adducin gene are unknown. However, mice deficient in
ankyrin have, in addition to hemolytic anemia, significant neurologic
dysfunction associated with Purkinje cell degeneration in the cerebellum
and the development of a late-onset neurologic syndrome characterized by
persistent tremor and gait disturbance (Peters et al., 1991). Goldberg
et al. (1992) identified a 4-kb alpha-adducin transcript that was
abundantly expressed in the caudate nucleus, the site of major neuronal
loss in HD. No sequence alterations specific to HD were discovered in
sequencing the brain alpha-adducin cDNA from 2 HD patients and an
age-matched control. Brain cDNA from both patients and control showed 2
alternately spliced brain exons not previously described in erythrocyte
cDNA. Further assessment of the role of this gene in the pathogenesis of
HD was considered warranted.

Bianchi et al. (1994) showed that 1 point mutation in each of the 2
genes coding for adducin is associated with blood pressure level in the
Milan strain of hypertensive rats. The hypertensive and normal rats
differed, respectively, by the amino acids tyrosine and phenylalanine at
position 316 of the alpha subunit; at the beta-adducin locus, the
hypertensive strain was always homozygous for arginine at position 529,
while the normal strain showed either arginine or glutamine in that
position. The arg/gln heterozygotes showed lower blood pressure than any
of the homozygotes. In vitro phosphorylation studies suggested that both
of these amino acid substitutions occurred within protein kinase
recognition sites. Analysis of an F2 generation demonstrated that Y
(tyrosine) alleles segregated with a significant increment in blood
pressure. This effect was modulated by the presence of the R (arginine)
allele of the beta subunit. Taken together, these findings strongly
supported a role for adducin polymorphisms in causing variation of blood
pressure in the Milan strain of rats. In the rat, the beta- and
alpha-adducin genes were said to be located on chromosomes 4 and 14,
respectively, according to unpublished data.

Nasir et al. (1994) used an interspecific backcross to map the mouse
homolog of human alpha-adducin (Add1) to mouse chromosome 5, within the
region of conserved synteny with the short arm of human chromosome 4.
Grosson et al. (1994) also mapped the murine homolog to mouse chromosome
5 in a continuous linkage group that included the Huntington disease
homolog.

*FIELD* RF
1. Bianchi, G.; Tripodi, G.; Casari, G.; Salardi, S.; Barber, B. R.;
Garcia, R.; Leoni, P.; Torielli, L.; Cusi, D.; Ferrandi, M.; Pinna,
L. A.; Baralle, F. E.; Ferrari, P.: Two point mutations within the
adducin genes are involved in blood pressure variation. Proc. Nat.
Acad. Sci. 91: 3999-4003, 1994.

2. Buckler, A. J.; Chang, D. D.; Graw, S. L.; Brook, J. D.; Haber,
D. A.; Sharp, P. A.; Housman, D. E.: Exon amplification: a strategy
to isolate mammalian genes based on RNA splicing. Proc. Nat. Acad.
Sci. 88: 4005-4009, 1991.

3. Gardner, K.; Bennett, V.: A new erythrocyte membrane-associated
protein with calmodulin binding activity: identification and purification.
J. Biol. Chem. 261: 1339-1348, 1986.

4. Gilligan, D. M.; Bennett, V.: The junctional complex of the membrane
skeleton. Seminars Hemat. 30: 74-83, 1993.

5. Goldberg, Y. P.; Lin, B.-Y.; Andrew, S. E.; Nasir, J.; Graham,
R.; Glaves, M. L.; Hutchinson, G.; Theilmann, J.; Ginzinger, D. G.;
Schappert, K.; Clarke, L.; Rommens, J. M.; Hayden, M. R.: Cloning
and mapping of the alpha-adducin gene close to D4S95 and assessment
of its relationship to Huntington disease. Hum. Molec. Genet. 1:
669-675, 1992.

6. Grosson, C. L. S.; MacDonald, M. E.; Duyao, M. P.; Ambrose, C.
M.; Roffler-Tarlov, S.; Gusella, J. F.: Synteny conservation of the
Huntington's disease gene and surrounding loci on mouse chromosome
5. Mammalian Genome 5: 424-428, 1994.

7. Hayden, M. R.: Huntington's Chorea.  New York: Springer-Verlag
(pub.)  1981.

8. Joshi, R.; Bennett, V.: Mapping the domain structure of human
erythrocyte adducin. J. Biol. Chem. 265: 13130-13136, 1990.

9. Joshi, R.; Gilligan, D. M.; Otto, E.; McLaughlin, T.; Bennett,
V.: Primary structure and domain organization of human alpha and
beta adducin. J. Cell Biol. 115: 665-675, 1991.

10. Nasir, J.; Lin, B.; Bucan, M.; Koizumi, T.; Nadeau, J. H.; Hayden,
M. R.: The murine homologues of the Huntington disease gene (Hdh)
and the alpha-adducin gene (Add1) map to mouse chromosome 5 within
a region of conserved synteny with human chromosome 4p16.3. Genomics 22:
198-201, 1994.

11. Peters, L. L.; Birkenmeier, C. S.; Bronson, R. T.; White, R. A.;
Lux, S. E.; Otto, E.; Bennett, V.; Higgins, A.; Barker, J. E.: Purkinje
cell degeneration associated with erythroid ankyrin deficiency in
nb/nb mice. J. Cell Biol. 114: 1233-1241, 1991.

12. Taylor, S. A. M.; Snell, R. G.; Buckler, A.; Ambrose, C.; Duyao,
M.; Church, D.; Lin, C. S.; Altherr, M.; Bates, G. P.; Groot, N.;
Barnes, G.; Shaw, D. J.; Lehrach, H.; Wasmuth, J. J.; Harper, P. S.;
Housman, D. E.; MacDonald, M. E.; Gusella, J. F.: Cloning of the
alpha-adducin gene from the Huntington's disease candidate region
of chromosome 4 by exon amplification. Nature Genet. 2: 223-227,
1992.

*FIELD* CD
Victor A. McKusick: 12/9/1991

*FIELD* ED
terry: 8/26/1994
jason: 7/19/1994
carol: 6/1/1994
carol: 3/20/1993
carol: 2/18/1993
carol: 2/2/1993

*RECORD*
*FIELD* NO
102681
*FIELD* TI
*102681 ADDUCIN 2; ADD2
ADDUCIN, BETA SUBUNIT; ADDB
*FIELD* TX
See adducin, alpha subunit (102680). Adducin is a heterodimeric
calmodulin (114180)-binding protein of the cell-membrane skeleton, which
is thought to play a role in assembly of the spectrin-actin lattice that
underlies the plasma membrane (see also 182860 and 102560). Missense
mutations in both the alpha and beta ADD genes that alter amino acids
that are normally phosphorylated have been associated with the
regulation of blood pressure in the Milan Hypertensive Strain (MHS) of
rats (Bianchi et al., 1994).

Joshi et al. (1991) determined the sequence of cDNAs encoding both the
alpha and beta human adducins. The 726-amino acid predicted beta subunit
is 49% identical to the alpha adducin sequence. Tisminetzky et al.
(1995) determined the genomic organization of the human beta adducin
gene and showed that it consists of 13 exons spanning approximately 50
kb. The authors showed that alternative splicing results in the
production of several different transcripts.

By somatic cell hybrid analysis, Joshi et al. (1991) found that the
alpha and beta subunits are encoded by separate genes, the alpha gene
being located on 4p16.3 and the ADDB gene (symbol = ADD2) being located
on chromosome 2. Gilligan et al. (1995) mapped ADD2 to 2p14-p13 by
fluorescence in situ hybridization. White et al. (1995) mapped the mouse
Add2 gene to chromosome 6 by haplotype analysis in interspecific
backcross mice. Mapping of the human gene to chromosome 2 was confirmed
by study of somatic cell hybrid panels by Southern blotting. The gene
was further localized to 2pter-p11.2 by study of somatic cell hybrids
containing portions of chromosome 2. Tisminetzky et al. (1995)
regionally mapped ADD2 to 2p15-cen by in situ hybridization.

*FIELD* RF
1. Bianchi, G.; Tripodi, G.; Casari, G.; Salardi, S.; Barber, B. R.;
Garcia, R.; Leoni, P.; Torielli, L.; Cusi, D.; Ferrandi, M.; Pinna,
L. A.; Baralle, F. E.; Ferrari, P.: Two point mutations within the
adducin genes are involved in blood pressure variation. Proc. Nat.
Acad. Sci. 91: 3999-4003, 1994.

2. Gilligan, D. M.; Lieman, J.; Bennett, V.: Assignment of the human
beta-adducin gene (ADD2) to 2p13-p14 by in situ hybridization. Genomics 28:
610-612, 1995.

3. Joshi, R.; Gilligan, D. M.; Otto, E.; McLaughlin, T.; Bennett,
V.: Primary structure and domain organization of human alpha and
beta adducin. J. Cell Biol. 115: 665-675, 1991.

4. Tisminetzky, S.; Devescovi, G.; Tripodi, G.; Muro, A.; Bianchi,
G.; Colombi, M.; Moro, L.; Barlati, S.; Tuteja, R.; Baralle, F. E.
: Genomic organisation and chromosomal localisation of the gene encoding
human beta adducin. Gene 167: 313-316, 1995.

5. White, R. A.; Angeloni, S. V.; Pasztor, L. M.: Chromosomal localization
of the beta-adducin gene to mouse chromosome 6 and human chromosome
2. Mammalian Genome 6: 741-743, 1995.

*FIELD* CN
Alan F. Scott - updated: 5/13/1996
Alan F. Scott - updated: 9/27/1995

*FIELD* CD
Victor A. McKusick: 11/23/1992

*FIELD* ED
terry: 05/13/1996
mark: 5/13/1996
terry: 4/17/1996
mark: 4/1/1996
mark: 1/21/1996
mark: 11/30/1995
carol: 4/8/1994
carol: 1/4/1993
carol: 11/23/1992

*RECORD*
*FIELD* NO
102699
*FIELD* TI
*102699 ADENO-ASSOCIATED VIRUS INTEGRATION SITE 1; AAVS1
*FIELD* TX
Kotin et al. (1990) isolated cellular sequences flanking integrated
copies of the adeno-associated virus (AAV) genome from a latently
infected clonal human cell line and used them to probe genomic blots
derived from an additional 21 independently derived clones of human
cells latently infected with AAV. In genomic blots of uninfected human
cell lines and of primary human tissue, each flanking-sequence probe
hybridized to unique bands. Kotin et al. (1990) concluded that the AAV
genome preferentially integrates into a specific region of the cellular
genome. By somatic cell hybrid mapping, they determined that the
integration site is unique to chromosome 19. The human parvovirus AAV is
unique among eukaryotic DNA viruses in its ability to integrate site
specifically. By means of in situ hybridization, Kotin et al. (1991)
mapped the integration site to 19q13-qter.

Samulski et al. (1991) mapped the AAVS1 gene to 19q13.4-qter by in situ
hybridization of AAV DNA to chromosomes from latently infected cells.
The findings suggested that this nonpathogenic parvovirus establishes
viral latency by integrating its DNA specifically into 1 chromosomal
region. Such specific integration was considered unique among the
eukaryotic DNA viruses. The incorporation of site-specific integration
into AAV vector schemes should make this vector system attractive for
human gene therapy strategies.

By analysis of the proviral junctions, Kotin et al. (1992) determined
that integration of the AAV DNA occurred via a nonhomologous
recombination pathway. Direct repeats at a much greater than random
occurrence were found distributed nonuniformly throughout the AAVS1
sequence.

*FIELD* RF
1. Kotin, R. M.; Linden, R. M.; Berns, K. I.: Characterization of
a preferred site on human chromosome 19q for integration of adeno-associated
virus DNA by non-homologous recombination. EMBO J. 11: 5071-5078,
1992.

2. Kotin, R. M.; Menninger, J. C.; Ward, D. C.; Berns, K. I.: Mapping
and direct visualization of a region-specific viral DNA integration
site on chromosome 19q13-qter. Genomics 10: 831-834, 1991.

3. Kotin, R. M.; Siniscalco, M.; Samulski, R. J.; Zhu, X. D.; Hunter,
L.; Laughlin, C. A.; McLaughlin, S.; Muzyczka, N.; Rocchi, M.; Berns,
K. I.: Site-specific integration by adeno-associated virus. Proc.
Nat. Acad. Sci. 87: 2211-2215, 1990.

4. Samulski, R. J.; Zhu, X.; Xiao, X.; Brook, J. D.; Housman, D. E.;
Epstein, N.; Hunter, L. A.: Targeted integration of adeno-associated
virus (AAV) into human chromosome 19. EMBO J. 10: 3941-3950, 1991.

*FIELD* CD
Victor A. McKusick: 9/9/1990

*FIELD* ED
carol: 2/4/1993
carol: 1/15/1993
supermim: 3/16/1992
carol: 6/4/1991
carol: 2/19/1991
carol: 2/15/1991

*RECORD*
*FIELD* NO
102700
*FIELD* TI
*102700 ADENOSINE DEAMINASE; ADA
ADENOSINE AMINOHYDROLASE
SEVERE COMBINED IMMUNODEFICIENCY DUE TO ADA DEFICIENCY, INCLUDED;;
SCID DUE TO ADA DEFICIENCY, INCLUDED;;
ADA-SCID, INCLUDED
*FIELD* MN
ADA deficiency is the cause of one form of severe combined
immunodeficiency disease (SCID), in which there is dysfunction of both B
and T lymphocytes with impaired cellular immunity and decreased
production of immunoglobulins. ADA deficiency accounts for about
one-half of cases of autosomal recessive SCID. In 85 to 90% of cases the
disorder is severe with skeletal lesions. In the remainder the disorder
is milder with progressive manifestations, mainly involving cellular
immunity, beginning after age 2 years or even in adulthood (Shovlin et
al., 1993).

The ADA gene is located on 20q12-q13.11 (Rothschild et al., 1993). The
complete sequence and structure of the gene is known (Wiginton et al.,
1986). A variety of mutant alleles have been identified, including
basepair substitutions (Hirschhorn et al., 1990) and deletions (Berkvens
et al., 1990). These mutations and compound heterozygosity account for
much of the variation in expression. Somatic mosaicism may be the basis
for delayed presentation and unusual course of ADA deficiency in some
cases (Hirschhorn et al., 1994). Striking disparity in clinical
phenotype of sibs may also result from differences in efficiency of
splicing (Arredondo-Vega et al., 1994). See 102710 and 102720 for
descriptions of adenosine deaminase complexing proteins, coded by loci
on chromosomes 6 and 2, respectively, which may be involved in some
cases.

There are 3 genetically determined isozymes of erythrocyte adenosine
deaminase: ADA 1, ADA 2-1 and ADA 2. The ADA 2 allozyme is a more basic
electrophoretic variant that is codominantly inherited with the usual
ADA 1 allozyme (Hirschhorn et al., 1994). The variant has been found in
all populations studied and results in only minimally reduced enzyme
activity in erythrocytes. The frequency of the ADA2 allele was estimated
at 0.06 in Europeans, 0.04 in Blacks, and 0.11 in Asiatic Indians
(Spencer et al., 1968). An overrepresention of West Indian ancestry and
the finding of multiple new mutations suggest that partial ADA
deficiency may have had a selective advantage.

Most lymphocyte ADA is of the same electrophoretic type as red cell ADA.
Bone marrow or fetal liver has been used for transplantation purposes.
Blood transfusion can result in graft-versus-host disease due to donor
lymphocytes. However, use of packed erythrocytes, subjected to freezing
and irradiation to eliminate lymphocytes, has been effective therapy
(Markert et al., 1987). Successful use of polyethylene glycol
(PEG)-modified bovine intestinal ADA administered intramuscularly has
been reported (Hershfield et al., 1987). Gene therapy trials are in
progress.

*FIELD* ED
carol: 07/23/1996 marlene: 7/23/1996 joanna: 7/11/1996

*FIELD* CD
F. Clarke Fraser: 5/9/1996
*FIELD* TX
By means of a new and specific method, Spencer et al. (1968)
demonstrated isozymes of erythrocyte adenosine deaminase (adenosine
aminohydrolase; EC 3.5.4.4) and showed that there are 3 genetically
determined phenotypes: ADA 1, ADA 2-1 and ADA 2. The frequency of the
ADA 2 allele was estimated at 0.06 in Europeans, 0.04 in Blacks, and
0.11 in Asiatic Indians. Data on gene frequencies of allelic variants
were tabulated by Roychoudhury and Nei (1988).

Wiginton et al. (1986) reported the complete sequence and structure of
the gene for human ADA. By study of mouse-man somatic cell hybrids,
Creagan et al. (1973) and Tischfield et al. (1974) showed that the locus
for ADA is on chromosome 20. Gene dosage studies of adenosine deaminase
and inosine triphosphatase provided corroboration of partial trisomy 20
diagnosed cytogenetically (Rudd et al., 1979). Valerio et al. (1984)
used an ADA cDNA probe in Southern hybridizations with DNA from a hybrid
cell panel to assign the gene to chromosome 20. Mohandas et al. (1984)
reported that the genes for ADA and SAHH are on separate parts of 20q,
separated by 20q13.1. Nielsen et al. (1986) studied ADA in a case of
partial trisomy 20q resulting from a familial t(3;20) translocation.
Gene dosage studies seemed to exclude the ADA gene from the distal part
of 20q (20q13.1-qter). By dosage effect in a patient with deletion of
20q, Petersen et al. (1987) assigned the ADA locus to 20q13.11. By means
of in situ hybridization to high resolution spreads of somatic and
pachytene chromosomes, Jhanwar et al. (1989) localized the ADA gene to
20q12-q13.11. Rothschild et al. (1993) identified and mapped new
dinucleotide repeat polymorphisms associated with the ADA locus. These
increased the PIC of the ADA locus to 0.89.

Adenosine deaminase shows not only polymorphism but also deficiency. ADA
deficiency is the cause of one form of severe combined immunodeficiency
disease (SCID), in which there is dysfunction of both B and T
lymphocytes with impaired cellular immunity and decreased production of
immunoglobulins. Multiple forms of SCID exist; see Swiss type of
agammaglobulinemia (202500, 300400), nucleoside phosphorylase (164050),
and transcobalamin II deficiency (275350). ADA deficiency accounts for
about one-half of cases of autosomal recessive SCID. In 85 to 90% of
cases the disorder is severe with skeletal lesions. In the remainder the
disorder is milder with progressive manifestations, mainly involving
cellular immunity, beginning after age 2 years. Bony changes in patients
with ADA-deficient SCID suggest that ADA may be the defect in at least
some cases of reported 'achondroplasia and Swiss-type
agammaglobulinemia' (200900). Note also that cartilage-hair hypoplasia
(250250) involves a defect in cellular immunity in association with
skeletal changes. Giblett et al. (1972) described 2 girls in separate
families with impaired cellular immunity and absent red cell adenosine
deaminase. One child, aged 22 months, showed recurrent respiratory
infections, candidiasis, and marked lymphopenia from birth. The other,
aged 3.5 years, was allegedly normal in the first 2 years of life. Mild
upper respiratory infections began at age 24 months and progressed to
severe pulmonary insufficiency and hepatosplenomegaly by age 30 months.
The parents of the first child were related and the second child had a
sister who died in consequence of a major immunologic defect (Hong et
al., 1970). The finding that both pairs of parents had an intermediate
level of red cell ADA supports recessive inheritance. Possibly a
different allele is present in the 2 families because in the first
family the parents showed about a 50% level of ADA whereas it was about
two-thirds normal in the second pair. Hirschhorn et al. (1980) pointed
to the neurologic abnormalities that had been reported in 2 of 23
ADA-deficient patients and reported a third who showed improvement of
these features with enzyme replacement by red cell infusion. Bortin and
Rimm (1977) reported on the characteristics and results of treatment in
69 patients with SCID; in 25 patients tested, deficiency of ADA was
found in 4 (16%). In surveying 18 cases of SCID that survived bone
marrow transplantation, Kenny and Hitzig (1979) found that 3 had ADA
deficiency. Mitchell et al. (1978) found that deoxyadenosine and
deoxyguanosine are particularly toxic to T cells but not to B cells.
Addition of deoxycytidine or dipyridamole prevented deoxyribonucleoside
toxicity. See 102710 and 102720 for descriptions of adenosine deaminase
complexing proteins, coded by loci on chromosomes 6 and 2, respectively.
Are some cases of SCID due to deficiency of ADCP rather than of the
enzyme itself? Koch and Shows (1980) showed that ADA deficiency in SCID
segregates with chromosome 20 alone in interspecific somatic cell
hybrids, suggesting that a structural gene mutation at the ADA locus is
the primary cause of ADA-deficient SCID. Boss et al. (1981) concluded
that ecto-5-prime-nucleotidase deficiency is secondary to the primary
defect of ADA. Herbschleb-Voogt et al. (1983) demonstrated
CRM-negativity in a patient with ADA-deficiency SCID. Wiginton et al.
(1983) cloned cDNA sequences of human ADA. Two B-lymphoblast lines from
cases of hereditary ADA deficiency contained unstable ADA protein but
had 3 to 4 times the normal level of ADA mRNA. ADA and
S-adenosylhomocysteine hydrolase (SAHH; 180960) have related metabolic
functions. In SCID due to ADA deficiency, red cells also show very low
levels (less than 2% of controls) of SAHH. The latter finding has been
attributed to a suicide-like inactivation of SAHH by
2-prime-deoxyadenine. SAHH is also coded by a gene on chromosome 20.

Shovlin et al. (1993) described an adult form of ADA deficiency in 2
sisters who presented with chronic chest disease and recurrent
bacterial, viral, and fungal infections together with laboratory
phenotypes similar to those of advanced HIV disease, including severe
CD4 lymphopenia. Both were HIV negative. These were the oldest patients
ever described with a new diagnosis of primary ADA deficiency. One
woman, aged 34 years, had had asthma and recurrent chest infections from
childhood. Records revealed lymphopenia from age 20 years. She had
widespread viral warts, recurrent oral and vaginal candidosis, and had
had 2 episodes of dermatomal zoster. The sister, aged 35 years, was well
until age 17 when she developed idiopathic thrombocytopenic purpura
necessitating splenectomy, azathioprine for 7 years, and prednisolone
until the time of report. By age 20 she had asthma, recurrent chest
infections, vaginal and oral candidosis, widespread viral warts, and
recurrent dermatomal zoster. Records showed lymphopenia from age 17.
Both sisters had clinical and radiologic evidence of extensive lung
damage. Shovlin et al. (1994) demonstrated that the sisters were
compound heterozygotes: in the paternal allele, there was a deletion
resulting from homologous recombination between 2 Alu elements; this
allele predicted a null phenotype. In the mutant allele inherited from
the mother, a C-to-T transition in a CpG dinucleotide changed the codon
for arginine-211, which lies in a conserved sequence close to the active
site, to that for cysteine. This mutation had previously been observed
in a child thought to have partial ADA deficiency by Hirschhorn et al.
(1990); see 102700.0014. Shovlin et al. (1994) suggested that immune
function in children with partial ADA deficiency may deteriorate with
time.

The enzyme defect in ADA deficiency is expressed in all cells, and
therefore the substrates for the enzyme, adenosine and
2-prime-deoxyadenosine, accumulate in cells of all types.
Immunodeficiency is the consequence of the particular sensitivity of
immature lymphoid cells to the toxic effects of these 2 substrates. In
addition, some patients have neurologic abnormalities that may be due to
ADA deficiency (Hershfield and Mitchell, 1995). Unlike humans, mice that
express no adenosine deaminase die perinatally of severe hepatocellular
degeneration (Migchielsen et al., 1995; Wakamiya et al., 1995).
Bollinger et al. (1996) described a human neonate with ADA deficiency
and prolonged hyperbilirubinemia with hepatitis that resolved after the
institution of adenonsine deaminase replacement therapy. Percutaneous
liver biopsy showed early giant-cell transformation, with enlarged foamy
hepatocytes and portal and lobular eosinophilic infiltrates. The patient
was a compound heterozygote for the gly74-to-val mutation (102700.0025)
and the ala329-to-val mutation (102700.0006).

In studies of 4 unrelated patients with 'partial' ADA deficiency,
Hirschhorn et al. (1983) found in 3 of them evidence of a different
mutation at the structural locus: 1) an acidic, low activity,
heat-labile mutation; 2) a basic, somewhat higher activity, heat-labile
mutation; and 3) a relatively normal activity, heat-labile mutation. In
the fourth patient, there was no compelling evidence for a mutation at
the structural locus for ADA and a mutation at a regulatory locus could
not be excluded. These children lacked ADA in red cells but retained
variable amounts of activity in lymphoid cells; none had significant
immunologic deficiency. Since at least 2 of the partially deficient
families were black and a third came from the Mediterranean basin,
Hirschhorn et al. (1983) were tempted to speculate that a partial ADA
gene might confer some advantage against intraerythrocytic parasites
such as malaria. Hirschhorn and Ellenbogen (1986) found 5 different
mutations in 5 unrelated new patients. Of the 5, 3 were shown to be
genetic compounds by the presence of 2 electrophoretically
distinguishable allozymes or by family studies that demonstrated a
'null' allele in addition to an electrophoretically abnormal enzyme. A
seemingly increased West Indian ethnic representation strengthened the
speculation that partial ADA deficiency may have a selective advantage,
perhaps because many intraerythrocytic parasites such as those of
malaria and babesiosis require exogenous purines derived from the host.
Hart et al. (1986) reported an example of partial adenosine deaminase
deficiency of the general type previously reported by Hirschhorn et al.
(1979), Daddona et al. (1983), and Hirschhorn and Ellenbogen (1986),
among others. Their proband, a Bantu-speaking Xhosa man, proved to be a
genetic compound. The previous case observed in South Africa had been a
Kalahari San ('Bushman') reported by Jenkins et al. (1976). Akeson et
al. (1987) reported an ADA-deficient patient who was a genetic compound;
one allele caused an amino acid change of alanine to valine
(102700.0006) and the other a change from arginine to histidine
(102700.0004). In a second cell line from an ADA-deficient patient, one
allele was found to cause an alanine to valine substitution whereas the
other allele was found to produce an mRNA in which exon 4 had been
spliced out (102700.0007). Several of the ADA cDNA clones extended
5-prime of the major initiation start site, indicating multiple start
sites for ADA transcription. Furthermore, analysis of ADA cDNAs from
different cell lines detected aberrant RNA species that either included
intron 7 or excluded exon 7. This was interpreted as indicating aberrant
splicing of pre-mRNAs, unrelated to the mutations that cause ADA
deficiency. Tzall et al. (1989) identified and/or characterized at least
9 RFLPs at the ADA locus and studied these in 17 patients with complete
deficiency and in 10 patients with partial deficiency. Genetic compounds
were identified among both types of patients, but there was, as
expected, a decreased incidence of heterozygosity. Two additional
haplotypes not found in the normal population were identified in
homozygous form in patients. Akeson et al. (1989) reviewed substitutions
found in ADA in cases of ADA deficiency. Out of the 7 different
mutations found in the 14 chromosomes of 7 consecutively ascertained
patients in the New York State newborn screening program, 6 were found
by Hirschhorn et al. (1990) to have mutations involving CpG
dinucleotides. Six of the 7 children either came from a limited area in
the Caribbean or shared a black ethnic background, suggesting that a
single mutation might have been derived from a common progenitor through
a founder effect. The fact that multiple new mutations were found
suggests that partial ADA deficiency may have had a selective advantage.

Most lymphocyte ADA is of the same electrophoretic type as red cell ADA.
Bone marrow or fetal liver has been used for transplantation purposes.
Blood transfusion can result in graft-versus-host disease due to donor
lymphocytes. However, use of packed erythrocytes, subjected to freezing
and irradiation to eliminate lymphocytes, has been effective therapy.
The infused normal red cells are in equilibrium with freely diffusing
adenosine. The ADA they contain lowers the level of adenosine in the
plasma. The lymphocyte count rises and responsiveness to mixed
lymphocyte culture and phytohemagglutinin returns. Retransfusion is
necessary every few weeks (Hirschhorn, 1976). Markert et al. (1987)
evaluated response to therapy in ADA deficiency and in purine nucleoside
phosphorylase deficiency. Hershfield et al. (1987) reported successful
use of polyethylene glycol-modified ADA (PEG-ADA) administered
intramuscularly. Covalent attachment of polyethylene glycol appears to
block access to sites on the surface of the protein, inhibiting
clearance from the circulation, attack by degraded enzymes and binding
of antibodies, and processing by antigen-presenting cells required for
generation of an immune response. Hershfield et al. (1987) used
PEG-modified bovine intestinal ADA in 2 children with SCID due to ADA
deficiency. They found that the modified enzyme was rapidly absorbed
after intramuscular injection and had a half-life in plasma of 48 to 72
hours. Weekly doses could maintain plasma ADA activity at 2 to 3 times
the level of red cell ADA in normal subjects. The principal biochemical
consequences of the deficiency were almost completely reversed. In red
cells, adenosine nucleotides increased and the toxic deoxyadenosine
nucleotides decreased to less than 0.5% of total adenine nucleotides.
The activity of S-adenosylhomocysteine hydrolase, which is inactivated
by deoxyadenosine, increased to normal in red cells and nucleated marrow
cells. Neither toxic effects nor hypersensitivity reactions were
observed. In vitro tests of cellular immune function of each patient
showed marked improvement, together with an increase in T lymphocytes.
This approach might be useful in other inherited metabolic diseases in
which accumulated metabolites equilibrate with plasma. Gaucher disease,
Fabry disease, nucleoside phosphorylase deficiency, and some disorders
of amino acid and urea cycle metabolism in which accumulated metabolites
equilibrate with plasma are candidates for this therapeutic approach.
Levy et al. (1988) reported a child who did not develop trouble from her
ADA deficiency until age 3 years. Treatment with PEG-modified ADA was
effective. Hershfield (1995) summarized the results of treatment with
PEG-ADA. This treatment is indicated for patients who lack an
HLA-identical bone marrow donor but are at too high a risk for
HLA-haploidentical marrow transplantation. Treatment almost completely
corrects metabolic abnormalities, allowing the recovery of a variable
degree of immune function that in most cases has been sufficient to
protect against opportunistic infections. Mortality with PEG-ADA is
lower than that with haploidentical bone marrow transplantation.
Hershfield (1995) noted, however, that the cost per patient of PEG-ADA
is 'very high,' approximately $100,000 yearly for an infant and 2 to 3
times this in older patients.

Santisteban et al. (1993) examined the genetic basis for ADA deficiency
in 7 patients with late/delayed onset of immunodeficiency, which they
characterized as an underdiagnosed and relatively unstudied condition.
Deoxyadenosine-mediated metabolic abnormalities were less severe than in
the usual, early-onset disorder. Six patients were compound
heterozygotes; 7 of 10 mutations found were novel. Tissue-specific
variation in splicing efficiency may ameliorate disease severity in
patients with splicing mutations, of which 3 were found.

Hirschhorn et al. (1994) found that somatic mosaicism was the basis for
delayed presentation and unusual course of ADA deficiency in a currently
healthy young adult who had received no therapy. He was diagnosed at age
2.5 years because of life-threatening pneumonia, recurrent infections,
failure of normal growth, and lymphopenia, but retained significant
cellular immune function. A fibroblast cell line and a B-cell line,
established at the time of diagnosis, lacked ADA activity and were
heteroallelic for a splice-donor-site mutation in IVS1 and a missense
mutation, arg101-to-gln (102700.0003). All clones isolated from the
B-cell mRNA carried the missense mutation, indicating that the allele
with the splice site mutation produced unstable mRNA. In striking
contrast, a B-cell line established at age 16 expressed 50% of normal
ADA; 50% of ADA mRNA had normal sequence, and 50% had the missense
mutation. Genomic DNA contained the missense mutation but not the splice
site mutation. In vivo somatic mosaicism was demonstrated in genomic DNA
from peripheral blood cells obtained at 16 years of age, in that less
than half the DNA carried the splice-site mutation (P less than 0.002,
vs original B-cell line). Consistent with the mosaicism, erythrocyte
content of the toxic metabolite deoxyATP was only minimally elevated.
Somatic mosaicism could have arisen by somatic mutation or by reversion
at the site of mutation. Selection in vivo for ADA normal hematopoietic
cells may have played a role in the return to normal health, in the
absence of therapy.

Abbott et al. (1986) presented evidence that 'wasted' (wst) in mice is
caused by a mutation in the structural gene for ADA. As occurs in humans
with ADA deficiency, wasted mice are immunodeficient, develop neurologic
abnormalities, and die soon after weaning. This animal model may be
useful in studies of gene therapy. Using a retroviral vector for human
ADA, Ferrari et al. (1991) transduced peripheral blood lymphocytes from
patients affected by ADA-negative SCID and injected them into
immunodeficient mice. Longterm survival of vector-transduced human cells
was demonstrated in recipient animals. Expression of vector-derived ADA
restored immune functions, as indicated by the presence of human
immunoglobulin and antigen-specific T cells in reconstituted animals.
The experiments demonstrated that gene transfer is necessary and
sufficient for development of specific immune functions in vivo and has
therapeutic potential.

Bordignon et al. (1995) used 2 different retroviral vectors to transfer
the human ADA minigene ex vivo into bone marrow cells and peripheral
blood lymphocytes from 2 patients undergoing exogenous enzyme
replacement therapy. After 2 years of treatment, longterm survival of T
and B lymphocytes, marrow cells, and granulocytes expressing the
transferred ADA gene was demonstrated and resulted in normalization of
the immune repertoire and restoration of cellular and humeral immunity.
After discontinuation of treatment, T lymphocytes, derived from
transduced peripheral blood lymphocytes, were progressively replaced by
marrow-derived T cells in both patients. These results indicated
successful gene transfer into long lasting progenitor cells, producing a
functional multilineage progeny. Blaese et al. (1995) reported results
of a clinical trial which started in 1990 using retroviral-mediated
transfer of the ADA gene into the T cells of 2 children with
ADA-deficient SCID. Patient 1 was begun on gene therapy on 14 September
1990 and received a total of 11 infusions. Patient 2 began gene therapy
on 31 January 1991 and received a total of 12 infusions. The number of
blood T lymphocytes normalized as did many cellular and humeral immune
responses. Gene treatment ended after 2 years, but integrated vector and
ADA gene expression in T cells persisted. Blaese et al. (1995) concluded
that although many components remained to be perfected, gene therapy was
a safe and effective addition the treatment for some patients with this
form of SCID.

Hirschhorn et al. (1996) described an unusual instance of somatic
mosaicism due to in vivo reversion to normal of an inherited mutation in
the ADA gene. In the proband ADA activity was not detectable in
erythroctyes at age 5, but concentrations of deoxy-ATP in RBCs and
deoxyadenosine in urine were only minimally elevated, as compared to
concentrations found in patients with early onset ADA(-) SCID. Both
parents exhibited approximately 50% of the normal erythrocyte ADA as did
2 young adult healthy sibs. Enzyme activity in lymphocytes was
diminished to approximately 15% of normal in the proband and 20-25% of
normal (within the heterozygote range) in both parents. Lymphoid cell
lines established from the proband and both parents also exhibited
markedly diminished ADA. The considerable residual enzyme activity in
nonerythroid cells and low concentrations of metabolites were similar to
findings in 'partially' ADA-deficient children ascertained by population
screening who had remained healthy during the first year of life
(Hirschhorn et al., 1990). By contrast, the death in infancy due to
immunodeficiency of a prior sib and the abnormal immunologic findings in
the proband during the first years of life were more consistent with
complete ADA deficiency. Hirschhorn et al. (1996) provided an
explanation by molecular analysis of the family. The father was
heterozygous for a splice site mutation at the invariant G of the
5-prime donor site in IVS5 of the ADA gene leading to deletion of the
116-bp sequence contained in exon 5 (102700.0026). The mother was a
mosaic of normal lymphocytes and lymphocytes containing a G-to-A
transition at nt 467, predicting an arg156-to-his substitution (a
deleterious mutation previously reported by Santisteban et al. (1993) in
ADA-deficient immunodeficient patients); in 13/15 authenticated B cell
lines and in 17% of single alleles cloned from blood DNA, the maternally
transmitted deleterious mutation was absent in the proband, despite
retention of a maternal 'private' ADA polymorphism linked to the
mutation. Hirschhorn et al. (1996) speculated that these cells had a
strong selective advantage, thus accounting for the mild phenotype
compared to the brother.

*FIELD* AV
.0001
ADA DEFICIENCY
ADA, LYS80ARG
In cell line GM2471, Valerio et al. (1986) found 2 point mutations in
the ADA gene of a patient with severe combined immunodeficiency: a
change from lys to arg at position 80 and a change from leu to arg at
position 304 (102700.0005). Studies with expression clones mutagenized
in vitro showed that the mutation at position 304 was responsible for
ADA inactivation. This resulted from a T-to-G mutation at nucleotide
1006. This was the change on only 1 of the chromosomes in the cell line
studied; the patient was a genetic compound. (The GM numbers relate to
individuals from whom cell lines were derived for deposit in the human
genetic mutant cell repository at the Coriell Institute in Camden, New
Jersey.)

.0002
ADA DEFICIENCY
ADA, ARG101TRP
Akeson et al. (1988) summarized the point mutations identified in ADA
deficiency cases. They came from 5 different patients, each of whom
proved to be a compound heterozygote. GM2606 was found to have change of
arg101 to trp resulting from a change of CGG to TGG as well as
substitution of his for arg211 (102700.0004) as a result of change of
CGT to CAT (Akeson et al., 1988). Arredondo-Vega et al. (1990) studied T
cells from the patient from whom the ADA-deficient B-cell line GM2606
had been established. They found that the arg101-to-trp mutation can be
expressed selectively in IL2-dependent T cells as a stable, active
enzyme. Cultured T cells from other patients with the arg211his mutation
did not express significant ADA activity, while some B-cell lines from a
patient with an arg101-to-gln mutation had been found to express normal
ADA activity. Arredondo-Vega et al. (1990) speculated that arg101 may be
at a site that determines degradation of ADA by a protease that is under
negative control by IL2 in T cells, and is variably expressed in B
cells.

.0003
ADA DEFICIENCY
ADA, ARG101GLN
In cell line GM1715 from an immunodeficient patient, Bonthron et al.
(1985) found a point mutation in codon 101 (CGG to CAG) of ADA; this
change predicts an amino acid change from arginine to glutamine. The
mutation was apparently responsible for loss of function in the gene
because the predicted primary structure of the enzyme was otherwise
entirely normal. The demonstration of 2 different mutations in codon 101
leading to ADA deficiency indicates that this amino acid position is
critical for stability and/or activity of the enzyme protein. In GM2756,
Akeson et al. (1987) demonstrated 2 different mutant alleles: one was
arg101 to gln (as in GM1715); the other was ala329 to val (102700.0006).

.0004
ADA DEFICIENCY
ADA, ARG211HIS
Akeson et al. (1988) found this change in cell line GM2606 and Akeson et
al. (1987) found it in cell line GM2756.

.0005
ADA DEFICIENCY
ADA, LEU304ARG
In cell line GM2471 from a genetic compound, Valerio et al. (1986)
demonstrated 2 point mutations: lys80 to arg and leu304 to arg. The
latter resulted from a T-to-G mutation in nucleotide 1006 and was shown
to cause ADA inactivation in studies with expression clones mutagenized
in vitro.

.0006
ADA DEFICIENCY
ADA, ALA329VAL
In cell line GM2756, Akeson et al. (1987) demonstrated 2 different
mutant alleles: one was arg101 to gln (102700.0003); the other was
ala329 to val. Cell line GM2825A was found to have a substitution of
valine for alanine-329 resulting from a C-to-T transition at base 1081.
Markert et al. (1989) also identified a point mutation at position 1081
of the adenosine deaminase cDNA, causing an alanine-to-valine
substitution at position 329 of the protein sequence. Because the
mutation created a new BalI restriction site, Southern analysis was used
to screen for the frequency of this mutation. It was found in 7 of 22
alleles with known or suspected point mutations and was associated with
3 distinct ADA haplotypes. Hirschhorn et al. (1992) found that 5
missense mutations accounted for one-third of 45 'ADA-negative'
chromosomes studied. The ala329-to-val mutation was the most frequent,
being found in 4 persons heterozygous for the mutation and 1 person
homozygous for it.

.0007
ADA DEFICIENCY
ADA, ALA39VAL
Akeson et al. (1987, 1988) found that cell line GM2825A was a genetic
compound. One allele had an ala39-to-val change (102700.0006); the other
allele had a point mutation from A to G in the 3-prime splice site of
intron 3, resulting in elimination of exon 4 from the mature mRNA.

.0008
ADA DEFICIENCY
ADA, 3.25KB DEL, ALU-RELATED
Berkvens et al. (1987) found a 3.2-kb deletion spanning the ADA promoter
and the first exon in an infant with ADA deficiency. The parents were
consanguineous, and the infant was homozygous for the deletion. Markert
et al. (1987) reported an apparent deletion mutation in a patient with
ADA deficiency and SCID who had a major structural alteration in the
5-prime end of the ADA gene. The patient had no ADA enzyme activity in
his lymphocytes, no detectable ADA mRNA by Northern RNA analysis, and a
deletion in the region of the first exon of the ADA gene by Southern DNA
analysis. Markert et al. (1988) defined the precise boundaries of the
deletion and the mechanism of the defect, namely, homologous
recombination between 2 repetitive DNA sequences of the Alu family,
resulting in a deletion of the ADA promoter and first exon. By direct
sequencing of in vitro amplified DNA, Berkvens et al. (1990) showed that
the 3,250-bp deletion in their patient was due to recombination within
the left arms of 2 direct AluI repeats. They pointed out that the
mutation was identical to that in the unrelated patient reported by
Markert et al. (1988). Neither the pedigree of the Belgian family nor a
comparison of haplotype data suggested a relationship between the
American and Belgian patients.

.0009
ADA DEFICIENCY
ADA, PRO297GLN
In a partially ADA-deficient child from Santo Domingo, Hirschhorn et al.
(1989) demonstrated a C-to-A transversion that resulted in the
replacement of a proline by a glutamine residue at codon 297. Since this
mutation generated a new recognition site in exon 10 of genomic DNA for
the enzyme AluI, Hirschhorn et al. (1989) could use Southern blot
analysis to establish that this child was homozygous for the mutation
and that the same mutation was present in another patient. The point
mutation resulted in heat-lability of the enzyme.

.0010
ADA DEFICIENCY
ADA, ARG76TRP
In cell lines GM5816, GM6200 and GM7103, Hirschhorn et al. (1990) found
a C-to-T transition at nucleotide 226 resulting in a change of
arginine-76 to tryptophan.

.0011
ADA DEFICIENCY
ADA, ARG149GLN
In cell line GM6143A, Hirschhorn et al. (1990) found a substitution of
glutamine for arginine at amino acid 149 resulting from a G-to-A
transition at nucleotide 446.

.0012
ADA DEFICIENCY
ADA, PRO274LEU
In cell line GM5816, Hirschhorn et al. (1990) found a substitution of
leucine for proline-274 resulting from a C-to-T transition at nucleotide
821.

.0013
ADA DEFICIENCY
ADA, LEU107PRO
In GM7103 and GM4396, both cell lines from compound heterozygous
patients, Hirschhorn et al. (1990) found a substitution of proline for
leucine at amino acid 107 resulting from a T-to-C transition in
nucleotide 320 in exon 4.

.0014
ADA DEFICIENCY
ADA, ARG211CYS
In cell line GM4396, from a compound heterozygous patient, Hirschhorn et
al. (1990) found substitution of cysteine for arginine at amino acid 211
resulting from a C-to-T transition of nucleotide 631.

.0015
ADA DEFICIENCY
ADA, ALA215THR
In cell line GM2294, Hirschhorn et al. (1990) found homozygosity for a
G-to-A transition of nucleotide 643 in exon 7 resulting in a change of
alanine215-to-threonine.

.0016
ADA DEFICIENCY
ADA, GLY216ARG
In a patient with very severe combined immunodeficiency, Hirschhorn et
al. (1991) identified a transition of G-646 to A at a CG dinucleotide,
predicting a glycine-to-arginine substitution at codon 216 of the ADA
protein. The patient was homozygous, the offspring of consanguineous
Amish parents from eastern Pennsylvania. Onset of symptoms was at 3 days
of age with respiratory distress from pneumonia unresponsive to
antibiotics. Of 9 patients, this one had the highest concentration of
the toxic metabolite deoxyATP and a relatively poor immunologic response
during the initial 2 years of therapy with polyethylene glycol-adenosine
deaminase. Heterozygosity for the same mutation was found in 2 of 21
additional patients with ADA-SCID.

.0017
ADA DEFICIENCY
ADA, A-G, 3-PRIME IVS3, EX4DEL
See 102700.0007.

.0018
ADA DEFICIENCY
ADA, ARG156CYS
In 2 patients with SCID who were unusual for reportedly responding to
the limited form of enzyme therapy provided by repeated partial exchange
transfusions (Polmar et al., 1976; Dyminski et al., 1979), Hirschhorn
(1992) found two new missense mutations, arg156-to-cys and ser291-to-leu
(102700.0019). The first of these was found in cell line GM2471 and
represented a CGC-to-TGC transition at codon 156.

.0019
ADA DEFICIENCY
ADA, SER291LEU
See 102700.0018. Hirschhorn (1992) found the S291L mutation in cell line
GM4258.

.0020
COMBINED IMMUNODEFICIENCY DISEASE, LATE/DELAYED ONSET
ADA, IVS10AS, G-A, -34
In a patient with late-onset combined immunodeficiency in whom the
diagnosis of ADA deficiency was first made at the age of 15 years,
Santisteban et al. (1993) found homozygosity for a single base change in
intron 10 which activated a cryptic splice acceptor, resulting in a
protein with 100 extra amino acids. The G(-34) was changed to A, thereby
converting a GG dinucleotide to AG, and creating a new splice acceptor
site with all the cis-acting elements of a functional 3-prime splice
junction. Besides introducing 9 new codons after leu325, use of the
cryptic splice site shifted the reading frame to include 268 bp of the
normal 3-prime noncoding region before a new TGA stop codon was
generated 16 bp from the polyA addition signal. The mutant protein was
predicted to consist of 463 residues.

.0021
ADENOSINE DEAMINASE 2 ALLOZYME
ADA*2
ADA, ASP8ASN
Hirschhorn et al. (1994) determined the molecular basis for the common
electrophoretic variant of ADA, the ADA2 allozyme, which is a more basic
electrophoretic variant that is codominantly inherited with the usual
ADA1 allozyme. The variant has been found in all populations studied and
results in only minimally reduced enzyme activity in erythrocytes. The
gene frequency of the ADA2 allozyme is estimated as 0.06 in Western
populations, lower among individuals of African descent, and higher in
Southeast Asian populations. Hirschhorn et al. (1994) found that the
ADA*2 allele contains a G-to-A transition at nucleotide 22 (counting
from the ATG initiator methionine) that results in substitution of
asparagine for aspartic acid at codon 8. Introduction of the nucleotide
substitution into an ADA1 cDNA and transfection into monkey kidney (COS)
cells confirmed that the mutation resulted in expression of an enzyme
that comigrated with a naturally occurring ADA2 allozyme. The nucleotide
substitution was found on at least 2 different genetic backgrounds, 1 of
Ashkenazi Jewish ancestry and 1 in a large Mormon pedigree from Utah,
suggesting independent recurrence of the mutation. Consistent with
independent recurrence, the G-to-A transition was located in a CpG
dinucleotide of the type subject to a high frequency of mutation.
Hirschhorn et al. (1994) also found a probable intragenic crossover in
the very large first intron that is rich in repetitive DNA sequences.

.0022
ADA DEFICIENCY
ADA, IVS2DS, G-A, +1
Arredondo-Vega et al. (1994) characterized the mutations responsible for
ADA deficiency in sibs with striking disparity in clinical phenotype.
Residual ADA activity was detectable in the cultured T cells,
fibroblasts, and B lymphoblasts of 1 sib but not in the cells of the
other. ADA mRNA was undetectable by Northern analysis in the cells of
both patients. Both sibs were found to be compound heterozygotes for the
following novel splicing defects: (1) a G-to-A substitution at the +1
position of the 5-prime splice site of IVS2, and (2) a complex 17-bp
rearrangement of the 3-prime splice site of IVS8, which inserted a run
of 7 purines into the polypyrimidine tract and altered the reading frame
of exon 9 (102700.0023). PCR-amplified ADA cDNA clones with premature
translation stop codons arising from aberrant pre-mRNA splicing were
identified, which were consistent with these mutations. However, some
cDNA clones from T cells of both patients and from fibroblasts and
EBV-transformed B cells of the first patient were normally spliced at
both the exon 2/3 and 8/9 junctions. A normal coding sequence was
documented for clones from both sibs. Findings were interpreted as
indicating that a low level of normal pre-mRNA splicing may occur
despite mutation of the invariant first nucleotide of the 5-prime splice
donor sequence and that differences in efficiency of such splicing may
account for the difference in residual ADA activity, immune dysfunction,
and clinical severity in the 2 sibs. These 2 sisters were reported by
Umetsu et al. (1994). The second-born child presented first with serious
infections and failure to thrive at age 4 months; the diagnosis of SCID
and ADA deficiency was made at age 9 months when the child was
hospitalized for Pseudomonas sepsis and Pneumocystis pneumonia. Her
healthy 39-month-old sister was then tested and found to be ADA
deficient. She had an unremarkable history, including normal development
(weight in 97th percentile) and uncomplicated varicella zoster at age 6
months. Although she was lymphopenic, antibody production, delayed
hypersensitivity, and in vitro T-cell function were intact. She became
more lymphopenic over a period of 6 to 7 months and developed persistent
upper respiratory infections. Along with her sister, she was then
treated by enzyme replacement with polyethylene glycol (PEG)-ADA.

.0023
ADA DEFICIENCY
ADA, IVS8AS, 7BP INS
See 102700.0022 and Arredondo-Vega et al. (1994).

.0024
ADA DEFICIENCY
ADA, IVS1DS, G-C, +1
Hirschhorn et al. (1994) found that fibroblast and B-cell lines
established at the time of diagnosis of ADA deficiency (GM2445 and
GM1715) were heteroallelic for a newly identified splice-site mutation
(+1 GT-to-CT transversion) at the donor splice site in IVS1 and for a
previously described arg101-to-gln missense mutation in exon 4
(102700.0003). As described earlier, by the time the patient was 16
years of age, the mutation had disappeared from the B cells but not from
the fibroblasts and the patient had undergone spontaneous recovery from
ADA deficiency.

.0025
ADA DEFICIENCY
ADA, GLY74VAL
In a newborn with hepatic dysfunction as a complication of ADA
deficiency, Bollinger et al. (1996) found compound heterozygosity for
the ala329-to-val (102700.0006) mutation and a change of codon 74 from
GGC (gly) to GTC (val).

.0026
ADA DEFICIENCY
ADA, IVS5DS, G-A, +1, 116BP DEL, EX5 DEL
Hirschhorn et al. (1996) identified compound heterozygosity for this
splice site mutation, which resulted in deletion of the 116-bp sequence
contained in exon 5 of the ADA gene. The other allele of the patient
carried a G-to-A transition at nucleotide 467, predicting an
arg156-to-his substitution, a previously reported deleterious mutation
found in ADA SCID patients (Santisteban et al., 1993). Hirschhorn et al.
(1996) found that this mutation had undergone reversion in a certain
proportion of cells, leading to a relatively mild phenotype.

*FIELD* SA
Adrian et al. (1984); Adrian et al. (1984); Aitken and Ferguson-Smith
(1978); Aitken et al. (1980); Chen et al. (1978); Chen et al. (1979);
Chen et al. (1974); Cohen et al. (1978); Cook et al. (1970); Daddona
and Kelley (1979); Detter et al. (1970); Dissing and Knudsen (1972);
Dissing and Knudsen (1969); Hershfield and Kredich (1978); Hirschhorn
et al. (1974); Hirschhorn et al. (1979); Hirschhorn et al. (1994);
Honig et al. (1984); Hopkinson et al. (1969); Hutton et al. (1981);
Kaitila et al. (1976); Kellems et al. (1985); Kredich and Martin (1977);
Markert et al. (1987); Meuwissen et al. (1975); Orkin et al. (1983);
Palmer et al. (1987); Parkman et al. (1975); Ratech et al. (1985);
Ritter et al. (1971); Rubinstein et al. (1979); Schmalstieg et al.
(1983); Schrader et al. (1978); Scott et al. (1974); Tariverdian and
Ritter (1969); Valerio et al. (1985); Valerio et al. (1984); Valerio
et al. (1984); Van der Weyden and Kelley (1974); Weitkamp  (1971);
Weitkamp  (1972); Wiginton et al. (1984); Wiginton and Hutton (1982);
Yokoyama et al. (1979); Yount et al. (1974); Ziegler et al. (1980);
Ziegler et al. (1981)
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45. Hirschhorn, R.; Martiniuk, F.; Roegner-Maniscalco, V.; Ellenbogen,
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46. Hirschhorn, R.; Papageorgiou, P. S.; Kesarwala, H. H.; Taft, L.
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in adenosine deaminase deficiency. New Eng. J. Med. 303: 377-380,
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47. Hirschhorn, R.; Roegner, V.; Jenkins, T.; Seaman, C.; Piomelli,
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48. Hirschhorn, R.; Tzall, S.; Ellenbogen, A.: Hot spot mutations
in adenosine deaminase deficiency. Proc. Nat. Acad. Sci. 87: 6171-6175,
1990.

49. Hirschhorn, R.; Tzall, S.; Ellenbogen, A.; Orkin, S. H.: Identification
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50. Hirschhorn, R.; Vawter, G. F.; Kirkpatrick, J. A., Jr.; Rosen,
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51. Hirschhorn, R.; Yang, D. R.; Israni, A.: An asp8-to-asn substitution
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52. Hirschhorn, R.; Yang, D. R.; Israni, A.; Huie, M. L.; Ownby, D.
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53. Hirschhorn, R.; Yang, D. R.; Puck, J. M.; Huie, M. L.; Jiang,
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54. Hong, R.; Galti, R.; Rathbun, J. C.; Good, R. A.: Thymic hypoplasia
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55. Honig, J.; Martiniuk, F.; D'Eustachio, P.; Zamfirescu, C.; Desnick,
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56. Hopkinson, D. A.; Cook, P. J. L.; Harris, H.: Further data on
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57. Hutton, J. J.; Wiginton, D. A.; Coleman, M. S.; Fuller, S. A.;
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58. Jenkins, T.; Rabson, A. R.; Nurse, G. T.; Lane, A. B.; Hopkinson,
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59. Jhanwar, S. C.; Berkvens, T. M.; Breukel, C.; van Ormondt, H.;
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60. Kaitila, I.; Rimoin, D. L.; Cederbaum, S. D.; Stiehm, E. R.; Lechman,
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61. Kellems, R. E.; Yeung, C.-Y.; Ingolia, D. E.: Adenosine deaminase
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62. Kenny, A. B.; Hitzig, W. H.: Bone marrow transplantation for
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63. Koch, G.; Shows, T. B.: Somatic cell genetics of adenosine deaminase
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64. Kredich, N. M.; Martin, D. W., Jr.: Role of 5-adenosylhomocysteine
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65. Levy, Y.; Hershfield, M. S.; Fernandez-Mejia, C.; Polmar, S. H.;
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66. Markert, M. L.; Hershfield, M. S.; Schiff, R. I.; Buckley, R.
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67. Markert, M. L.; Hershfield, M. S.; Wiginton, D. A.; States, J.
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68. Markert, M. L.; Hutton, J. J.; Wiginton, D. A.; States, J. C.;
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69. Markert, M. L.; Norby-Slycord, C.; Ward, F. E.: A high proportion
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70. Meuwissen, H. J.; Pollara, B.; Pickering, R. J.: Combined immunodeficiency
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71. Migchielsen, A. A. J.; Breuer, M. L.; van Roon, M. A.; te Riele,
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72. Mitchell, B. S.; Mejias, E.; Daddona, P. E.; Kelley, W. N.: Purinogenic
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73. Mohandas, T.; Sparkes, R. S.; Suh, E. J.; Hershfield, M. S.:
Regional localization of the human genes for S-adenosylhomocysteine
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74. Nielsen, K. B.; Tommerup, N.; Jespersen, B.; Nygaard, P.; Kleif,
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75. Orkin, S. H.; Daddona, P. E.; Shewach, D. S.; Markham, A. F.;
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76. Palmer, T. D.; Hock, R. A.; Osborne, W. R. A.; Miller, A. D.:
Efficient retrovirus-mediated transfer and expression of a human adenosine
deaminase gene in diploid skin fibroblasts from an adenosine deaminase-deficient
human. Proc. Nat. Acad. Sci. 84: 1055-1059, 1987.

77. Parkman, R.; Gelfand, E. W.; Rosen, F. S.; Sanderson, A.; Hirschhorn,
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78. Petersen, M. B.; Tranebjaerg, L.; Tommerup, N.; Nygaard, P.; Edwards,
H.: New assignment of the adenosine deaminase gene locus to chromosome
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Med. Genet. 24: 93-96, 1987.

79. Polmar, S. H.; Stern, R. C.; Schwartz, A. L.; Wetzler, E. M.;
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80. Ratech, H.; Greco, M. A.; Gallo, G.; Rimoin, D. L.; Kamino, H.;
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81. Ritter, H.; Wendt, G. G.; Tariverdian, G.; Zelch, J.; Rube, M.;
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69-71, 1971.

82. Rothschild, C. B.; Akots, G.; Hayworth, R.; Pettenati, M. J.;
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83. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
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84. Rubinstein, A.; Hirschhorn, R.; Sicklick, M.; Murphy, R. A.:
In vivo and in vitro effects of thymosin and adenosine deaminase on
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85. Rudd, N. L.; Bain, H. W.; Giblett, E.; Chen, S.-H.; Worton, R.
G.: Partial trisomy 20 confirmed by gene dosage studies. Am. J.
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86. Santisteban, I.; Arredondo-Vega, F. X.; Kelly, S.; Mary, A.; Fischer,
A.; Hummell, D. S.; Lawton, A.; Sorensen, R. U.; Stiehm, E. R.; Uribe,
L.; Weinberg, K.; Hershfield, M. S.: Novel splicing, missense, and
deletion mutations in seven adenosine deaminase-deficient patients
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of genotype to phenotype. J. Clin. Invest. 92: 2291-2302, 1993.

87. Schmalstieg, F. C.; Mills, G. C.; Tsuda, H.; Goldman, A. S.:
Severe combined immunodeficiency in a child with a healthy adenosine
deaminase deficient mother. Pediat. Res. 17: 935-940, 1983.

88. Schrader, W. P.; Pollara, B.; Meuwissen, H. J.: Characterization
of the residual adenosine deaminating activity in the spleen of a
patient with combined immunodeficiency disease and adenosine deaminase
deficiency. Proc. Nat. Acad. Sci. 75: 446-450, 1978.

89. Scott, C. R.; Chen, S.-H.; Giblett, E. R.: Deletion of the carrier
state in combined immunodeficiency disease associated with deaminase
deficiency. J. Clin. Invest. 53: 1194-1196, 1974.

90. Shovlin, C. L.; Hughes, J. M. B.; Simmonds, H. A.; Fairbanks,
L.; Deacock, S.; Lechler, R.; Roberts, I.; Webster, A. D. B.: Adult
presentation of adenosine deaminase deficiency. (Letter) Lancet 341:
1471, 1993.

91. Shovlin, C. L.; Simmonds, H. A.; Fairbanks, L. D.; Deacock, S.
J.; Hughes, J. M. B.; Lechler, R. I.; Webster, A. D. B.; Sun, X.-M.;
Webb, J. C.; Soutar, A. K.: Adult onset immunodeficiency caused by
inherited adenosine deaminase deficiency. J. Immun. 153: 2331-2339,
1994.

92. Spencer, N.; Hopkinson, D. A.; Harris, H.: Adenosine deaminase
polymorphism in man. Ann. Hum. Genet. 32: 9-14, 1968.

93. Tariverdian, G.; Ritter, H.: Adenosine deaminase polymorphism
(EC 3.5.4.4): formal genetics and linkage relations. Humangenetik 7:
176-178, 1969.

94. Tischfield, J. A.; Creagan, R. P.; Nichols, E. A.; Ruddle, F.
H.: Assignment of a gene for adenosine deaminase to human chromosome
20. Hum. Hered. 24: 1-11, 1974.

95. Tzall, S.; Ellenbogen, A.; Eng, F.; Hirschhorn, R.: Identification
and characterization of nine RFLPs at the adenosine deaminase (ADA)
locus. Am. J. Hum. Genet. 44: 864-875, 1989.

96. Umetsu, D. T.; Schlossman, C. M.; Ochs, H. D.; Hershfield, M.
S.: Heterogeneity of phenotype in two siblings with adenosine deaminase
deficiency. J. Allergy Clin. Immunol. 93: 543-550, 1994.

97. Valerio, D.; Dekker, B. M. M.; Duyvesteyn, M. G. C.; van der Voorn,
L.; Berkvens, T. M.; van Ormondt, H.; van der Eb, A. J.: One adenosine
deaminase allele in a patient with severe combined immunodeficiency
contains a point mutation abolishing enzyme activity. EMBO J. 5:
113-119, 1986.

98. Valerio, D.; Duyvesteyn, M. G. C.; Dekker, B. M. M.; Weeda, G.;
Berkvens, T. M.; van der Voorn, L.; van Ormondt, H.; van der Eb, A.
J.: Adenosine deaminase: characterization and expression of a gene
with a remarkable promoter. EMBO J. 4: 437-443, 1985.

99. Valerio, D.; Duyvesteyn, M. G. C.; Meera Khan, P.; Pearson, P.
L.; Geurts van Kessel, A.; van Ormondt, H.: Direct assignment of
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599, 1984.

100. Valerio, D.; Duyvesteyn, M. G. C.; van Ormondt, H.; Meera Khan,
P.; van der Eb, A. J.: Adenosine deaminase (ADA) deficiency in cells
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1984.

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C.; van Ormondt, H.; van der Eb, A. J.; Martin, D. W., Jr.: Cloning
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102. Van der Weyden, M. B.; Kelley, W. N.: Adenosine deaminase deficiency
in severe combined immunodeficiency: evidence for a posttranslational
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103. Wakamiya, M.; Blackburn, M. R.; Jurecic, R.; McArthur, M. J.;
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104. Weitkamp, L. R.: Further data on the genetic linkage relations
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105. Weitkamp, L. R.: Genetic linkage relationships of the ADA and
6-PGD loci in 'Humangenetik.' (Letter) Humangenetik 15: 359-360,
1972.

106. Wiginton, D. A.; Adrian, G. S.; Friedman, R. L.; Suttle, D. P.;
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adenosine deaminase cDNA including the coding region and a small intron. Nucleic
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108. Wiginton, D. A.; Hutton, J. J.: Immunoreactive protein in adenosine
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3211-3217, 1982.

109. Wiginton, D. A.; Kaplan, D. J.; States, J. C.; Akeson, A. L.;
Perme, C. M.; Bilyk, I. J.; Vaughn, A. J.; Lattier, D. L.; Hutton,
J. J.: Complete sequence and structure of the gene for human adenosine
deaminase. Biochemistry 25: 8234-8244, 1986.

110. Yokoyama, S.; Hayashi, T.; Yoshimura, Y.; Irimada, K.; Saito,
T.; Akiba, T.; Tsuchiya, S.: Severe combined immunodeficiency disease
with adenosine deaminase deficiency. Tohoku J. Exp. Med. 129: 197-202,
1979.

111. Yount, J.; Nichols, P.; Ochs, H. D.; Hammar, S. P.; Scott, C.
R.; Chen, S.-H.; Giblett, E. R.; Wedgwood, R. J.: Absence of erythrocyte
adenosine deaminase associated with severe combined immunodeficiency. J.
Pediat. 84: 173-177, 1974.

112. Ziegler, J. B.; Lee, C. H.; Van Der Weyden, M. B.; Bagnara, A.
S.; Beveridge, J.: Severe combined immunodeficiency and adenosine
deaminase deficiency: failure of enzyme replacement therapy. Arch.
Dis. Child. 55: 452-457, 1980.

113. Ziegler, J. B.; Van Der Weyden, M. B.; Lee, C. H.; Daniel, A.
: Prenatal diagnosis for adenosine deaminase deficiency. J. Med.
Genet. 18: 154-156, 1981.

*FIELD* CS

Immunology:
   Severe combined immunodeficiency disease

Skel:
   Skeletal dysplasia

Head:
   Normocephaly

Facies:
   Normal

Heme:
   B-cell deficiency;
   T-cell deficiency;
   CD4 lymphopenia;
   Idiopathic thrombocytopenic purpura

Pulm:
   Recurrent respiratory infections;
   Asthma

GI:
   Hepatosplenomegaly

Misc:
   Late onset CID with allelic variant .0020;
   Recurrent bacterial, viral, and fungal infections

Lab:
   Adenosine deaminase deficiency

Inheritance:
   Autosomal dominant (20q13.11);
   the deficiency syndrome is an autosomal recessive disorder

*FIELD* CN
Iosif W. Lurie - updated: 09/26/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 09/26/1996
carol: 7/23/1996
carol: 6/29/1996
mark: 6/27/1996
terry: 6/25/1996
terry: 6/6/1996
terry: 6/4/1996
carol: 5/18/1996
mark: 12/12/1995
terry: 12/5/1995
carol: 11/10/1994
terry: 8/30/1994
jason: 7/26/1994
warfield: 4/7/1994
pfoster: 3/25/1994
mimadm: 3/13/1994

*RECORD*
*FIELD* NO
102710
*FIELD* TI
102710 ADENOSINE DEAMINASE COMPLEXING PROTEIN-1; ADCP1
*FIELD* TX
ADA occurs in a small molecular form (MW 33,000) called red cell ADA
(102700) and in a large molecular form (MW 200,000) called
tissue-specific ADA. The five ADA tissue enzymes consist of one or more
molecules of red cell ADA and one molecule of adenosine deaminase
complexing protein (also known as a conversion factor). Koch and Shows
(1978) concluded that one tissue enzyme, ADA-d, is dependent upon at
least two genes--the chromosome 20 gene for ADA and a gene on chromosome
6 which determines an ADA-complexing protein (ADCP1). Herbschleb-Voogt
et al. (1979) and Koch and Shows (1979) concluded that expression of
ADA-d is dependent on another gene, ADCP2 (102720), located on
chromosome 2. The assignment of an ADCP gene to chromosome 6 might be
considered 'in limbo' (Shows, 1982).

*FIELD* SA
Daddona and Kelley (1979); Koch and Shows (1980)
*FIELD* RF
1. Daddona, P. E.; Kelley, W. N.: Human adenosine deaminase: stoichiometry
of the adenosine deaminase-binding protein complex. Biochim. Biophys.
Acta 580: 302-311, 1979.

2. Herbschleb-Voogt, E.; Grzeschik, K.-H.; de Wit, J.; Pearson, P.
L.; Meera Khan, P.: Assignment of a structural gene for adenosine
deaminase complexing protein (ADCP) to human chromosome 2 in interspecific
somatic cell hybrids.  (Abstract) Cytogenet. Cell Genet. 25: 163
only, 1979.

3. Koch, G.; Shows, T. B.: A gene on human chromosome 6 functions
in assembly of tissue-specific adenosine deaminase isozymes. Proc.
Nat. Acad. Sci. 75: 3876-3880, 1978.

4. Koch, G.; Shows, T. B.: Somatic cell genetics of adenosine deaminase
expression and severe combined immune deficiency disease in man. Proc.
Nat. Acad. Sci. 77: 4211-4215, 1980.

5. Koch, G. A.; Shows, T. B.: Genes on human chromosomes 2 and 6
are required for expression of the adenosine deaminase complexing
protein (ADCP) in human-mouse somatic cell hybrids.  (Abstract) Cytogenet.
Cell Genet. 25: 174 only, 1979.

6. Shows, T. B.: Personal Communication. Buffalo, N. Y.  5/5/1982.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/30/1988

*RECORD*
*FIELD* NO
102720
*FIELD* TI
*102720 ADENOSINE DEAMINASE COMPLEXING PROTEIN-2; ADCP2
T-CELL ACTIVATION ANTIGEN CD26; CD26;;
DIPEPTIDYLPEPTIDASE IV; DPP4;;
DIPEPTIDYLPEPTIDASE, INTESTINAL
*FIELD* TX
Koch and Shows (1979, 1980) concluded that at least 3 genes are involved
in the expression of adenosine deaminase complexing protein: ADA
(102700) on chromosome 20, ADCP1 (102710) on chromosome 6, and ADCP2 on
chromosome 2. On the other hand, from studies in mouse-man and
hamster-man hybrid cells, Herbschleb-Voogt et al. (1981) concluded that
a gene or genes on human chromosome 2 determine the expression of ADCP
and that neither chromosome 6 nor any other chromosome of man carries
genes involved in the formation of ADCP. Van Cong et al. (1981)
concluded that the gene for ADCP on chromosome 2 is located between MDH1
(154200) and IDH1 (147700), i.e., in the segment 2p23-q32. Could one
form of adenosine deaminase deficiency (leading to severe combined
immunodeficiency) represent, in fact, deficiency of the complexing
protein?

Data presented by Kameoka et al. (1993) and partial amino acid sequence
data presented by Morrison et al. (1993) indicated that the ADA binding
protein is identical to CD26, a T-cell activation molecule and a 110-kD
glycoprotein that is present also on epithelial cells of various tissues
including the liver, kidney, and intestine. Kameoka et al. (1993) listed
the reasons for thinking that ADA on the T-cell surface is regulated
during the process of T-cell activation, that CD26 may be involved in
regulating the extracellular concentration of ADA, and that some cases
of SCID may be related to mutation in this gene.

The CD4 antigen (186940) is essential for binding human immunodeficiency
virus (HIV) particles, but is not sufficient for efficient viral entry
and infection. Callebaut et al. (1993) demonstrated that a cofactor
necessary for efficient function is CD26. Coexpression of human CD4 and
CD26 in murine NIH 3T3 cells rendered them permissive to infection by
HIV. They suggested the possibility of developing specific inhibitors
that would block the function of CD26 and thus be useful as effective
therapeutic agents in AIDS patients.

Dipeptidylpeptidase IV (DPP4; EC 3.4.14.5) is identical to ADA
complexing protein-2 and to the T-cell activation antigen CD26. DPP4 is
a serine exopeptidase that cleaves X-proline dipeptides from the
N-terminus of polypeptides. It is an intrinsic membrane glycoprotein
anchored into the cell membrane by its N-terminal end. High levels of
the enzyme are found in the brush-border membranes of the kidney
proximal tubule and of the small intestine, but several other tissues
also express the enzyme. The enzyme is present in the fetal colon but
disappears at birth. It is ectopically expressed in some human colon
adenocarcinomas and human colon cancer cell lines. From such a colon
cancer cell line, Darmoul et al. (1990) isolated a cDNA probe for
intestinal dipeptidylpeptidase IV and, by Southern analysis of somatic
cell hybrids, assigned the gene to chromosome 2. This assignment was
confirmed by Mathew et al. (1994), who sublocalized the DPP4 gene to
2q23 by fluorescence in situ hybridization. Misumi et al. (1992)
isolated and sequenced the cDNA coding for DPP4. The nucleotide sequence
(3,465 bp) of the cDNA contained an open reading frame encoding a
polypeptide comprising 766 amino acids, 1 residue less than those of the
rat protein. The predicted amino acid sequence exhibited 84.9% identity
to that of the rat enzyme.

Abbott et al. (1994) demonstrated that CD26 spans approximately 70 kb
and contains 26 exons, ranging in size from 45 bp to 1.4 kb. The
nucleotides that encode the serine recognition site (G-W-S-Y-G) are
split between 2 exons. This clearly distinguishes the genomic
organization of the prolyl oligopeptidase family from that of the
classic serine protease family. CD26 encodes 2 messages sized at about
4.2 and 2.8 kb. These are both expressed at high levels in the placenta
and kidney and at moderate levels in the lung and liver. Only the 4.2 kb
mRNA was expressed at low levels in skeletal muscle, heart, brain, and
pancreas. By fluorescence in situ hybridization, Abbott et al. (1994)
mapped the gene to 2q24.3.

*FIELD* RF
1. Abbott, C. A.; Baker, E.; Sutherland, G. R.; McCaughan, G. W.:
Genomic organization, exact localization, and tissue expression of
the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics 40:
331-338, 1994.

2. Callebaut, C.; Krust, B.; Jacotot, E.; Hovanessian, A. G.: T cell
activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells.
Science 262: 2045-2050, 1993.

3. Darmoul, D.; Lacasa, M.; Chantret, I.; Swallow, D. M.; Trugnan,
G.: Isolation of a cDNA probe for the human intestinal dipeptidylpeptidase
IV and assignment of the gene locus DPP4 to chromosome 2. Ann. Hum.
Genet. 54: 191-197, 1990.

4. Herbschleb-Voogt, E.; Grzeschik, K.-H.; Pearson, P. L.; Meera Khan,
P.: Assignment of adenosine deaminase complexing protein (ADCP) gene(s)
to human chromosome 2 in rodent-human somatic cell hybrids. Hum.
Genet. 59: 317-323, 1981.

5. Kameoka, J.; Tanaka, T.; Nojima, Y.; Schlossman, S. F.; Morimoto,
C.: Direct association of adenosine deaminase with a T cell activation
antigen, CD26. Science 261: 466-469, 1993.

6. Koch, G.; Shows, T. B.: Somatic cell genetics of adenosine deaminase
expression and severe combined immune deficiency disease in man. Proc.
Nat. Acad. Sci. 77: 4211-4215, 1980.

7. Koch, G. A.; Shows, T. B.: Genes on human chromosomes 2 and 6
are required for expression of the adenosine deaminase complexing
protein (ADCP) in human-mouse somatic cell hybrids.  (Abstract) Cytogenet.
Cell Genet. 25: 174, 1979.

8. Mathew, S.; Morrison, M. E.; Murty, V. V. V. S.; Houghton, A. N.;
Chaganti, R. S. K.: Assignment of the DPP4 gene encoding adenosine
deaminase binding protein (CD26/dipeptidylpeptidase IV) to 2q23. Genomics 22:
211-212, 1994.

9. Misumi, Y.; Hayashi, Y.; Arakawa, F.; Ikehara, Y.: Molecular cloning
and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase
on the cell surface. Biochim. Biophys. Acta 1131: 333-336, 1992.

10. Morrison, M. E.; Vijayasaradhi, S.; Engelstein, D.; Albino, A.
P.; Houghton, A. N.: A marker for neoplastic progression of human
melanocytes is a cell surface ectopeptidase. J. Exp. Med. 117:
1135-1143, 1993.

11. Van Cong, N.; Weil, D.; Gross, M.-S.; Foubert, C.; Jami, J.; Frezal,
J.: Controle genetique et epigenetique de l'expression de l'adenosine
deaminase. Analyse des cellules humaines et hybrides homme-rongeur.
Ann. Genet. 24: 141-147, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 05/18/1996
carol: 1/19/1995
carol: 12/22/1993
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
102730
*FIELD* TI
102730 ADENOSINE DEAMINASE, ELEVATED, HEMOLYTIC ANEMIA DUE TO
*FIELD* TX
In addition to the polymorphism of red cell ADA (EC 3.5.4.4.) and the
deficiency state of the enzyme leading to immunodeficiency (102700),
elevated red cell ADA (with decreased ATP) has been reported, first by
Valentine et al. (1977) in Los Angeles and later by Miwa et al. (1978)
and Fujii et al. (1980) in Japan and by Perignon et al. (1982) in
France. The proband in the case reported by Miwa et al. (1978) was a
38-year-old Japanese male with compensated hemolytic anemia. His red
cells showed moderate stomatocytosis and his red cell ADA activity was
40 times normal. The mother showed a 4-fold increase in red cell ADA;
the father's enzyme levels were normal. In lymphocytes ADA levels were
nearly normal. Valentine's patient also showed stomatocytosis. In his
family 12 affected persons in 3 generations showed ADA levels of 45 to
70 times the normal and no one showed intermediate levels as in the
mother of Miwa's family. Serum uric acid levels were mildly elevated.
This mutation probably involves a regulatory gene at a locus separate
from the structural locus for ADA carried on chromosome 20. In the
10-year-old affected male with severe hemolytic disease reported by
Perignon et al. (1982), the level of ADA was about 85 times the normal.
Evidence was presented that the excessive ADA activity in red cells was
due to an abnormal amount of a catalytically and immunologically normal
enzyme. Novelli et al. (1986) found a 4-fold increase in red cell ADA in
a 16-month-old Libyan infant without hemolytic anemia but with mild
anisopoikilocytosis. The parents, who were related as first cousins, and
a healthy brother had normal red cell ADA levels. Glader et al. (1983)
suggested that elevated ADA activity is a feature of Blackfan-Diamond
anemia (205900).

Chottiner et al. (1987) studied the family originally described by
Valentine et al. (1977). They verified that red cell ADA-specific
activity was 70 to 100 times the normal levels. Western blots
demonstrated a corresponding increase in red cell ADA-specific
immunoreactive protein. Analysis of genomic DNA showed no evidence for
amplification or major structural changes in the ADA gene. ADA-specific
mRNA from proband reticulocytes was comparable in size and amount to
mRNA from control reticulocytes. This finding excluded increased
transcription of the gene or increased stability of red cell ADA mRNA.
On the other hand, Chottiner et al. (1987) found evidence of
posttranslational abnormality. In vitro translation and
immunoprecipitation experiments consistently showed a band of about
42,000 molecular weight synthesized from proband reticulocyte mRNA but
not control mRNA. These data strongly suggested that red cell ADA
overabundance in this disorder was due to an abnormality intrinsic to
reticulocyte ADA mRNA that results in its increased translation. There
have been several examples of mutations that affect the translational
efficiency of specific mRNAs, usually mutations in the 5-prime noncoding
region. The reason for the tissue specificity of the abnormality was not
clear. The in vitro translation experiments made the possibility of a
transacting factor coded by a separate locus less likely.

In the form of severe combined immunodeficiency with deficiency of ADA,
structural changes such as point mutations have been identified in the
ADA gene on chromosome 20 and the deficiency is found in all tissues. In
the disorder of ADA excess, only the erythroid elements show the
abnormality and the ADA molecule is structurally normal by all the usual
criteria, including electrophoretic migration, kinetics for various
substrates and inhibitors, heat stability, specific activity, pH
optimum, immunologic reactivity, amino acid composition, and peptide
patterns. The defect is transmitted as an autosomal dominant. The
mutation is presumably in a gene separate from the structural gene for
ADA. The study of these families with DNA markers located in the region
of the ADA gene on 20q might prove conclusively that the determinant is
at a site remote from the ADA gene. Such experiments were performed by
Chen et al. (1993), who, to determine whether increased ADA mRNA is due
to a cis-acting or a trans-acting mutation, took advantage of a highly
polymorphic TAAA repeat located at the tail end of an Alu repeat
approximately 1.1 kb upstream of the ADA gene. Using PCR to amplify this
region, they identified 5 different alleles in 19 members of an affected
family. All 11 affected individuals had an ADA allele with 12 TAAA
repeats, whereas none of the 8 normal individuals did. They concluded
that this disorder results from a cis-acting mutation in the vicinity of
the ADA gene. Chen and Mitchell (1994) examined reporter gene activity
using constructs containing 10.6 kb of 5-prime flanking sequence and
12.3 kb of the first intron of the ADA gene from normal and mutant
alleles. No differences in chloramphenicol acetyltransferase (CAT)
activity were found in transient transfection experiments using
erythroleukemia cell lines. Furthermore, transgenic mice containing the
ADA constructs showed CAT activities in erythrocytes and bone marrow
that did not differ between the normal and mutant alleles. Results were
interpreted as indicating that the mutation responsible for ADA
overexpression is unlikely to reside in the 5-prime and promoter regions
or in the regulatory regions of the first intron.

*FIELD* RF
1. Chen, E. H.; Mitchell, B. S.: Hereditary overexpression of adenosine
deaminase in erythrocytes: studies in erythroid cell lines and transgenic
mice. Blood 84: 2346-2353, 1994.

2. Chen, E. H.; Tartaglia, A. P.; Mitchell, B. S.: Hereditary overexpression
of adenosine deaminase in erythrocytes: evidence for a cis-acting
mutation. Am. J. Hum. Genet. 53: 889-893, 1993.

3. Chottiner, E. C.; Cloft, H. J.; Tartaglia, A. P.; Mitchell, B.
S.: Elevated adenosine deaminase activity and hereditary hemolytic
anemia: evidence for abnormal translational control of protein synthesis.
J. Clin. Invest. 79: 1001-1005, 1987.

4. Fujii, H.; Miwa, S.; Suzuki, K.: Purification and properties of
adenosine deaminase in normal and hereditary hemolytic anemia with
increased red cell activity. Hemoglobin 4: 693-705, 1980.

5. Glader, B. E.; Backer, K.; Diamond, L. K.: Elevated erythrocyte
adenosine deaminase activity in congenital hypoplastic anemia. New
Eng. J. Med. 309: 1486-1490, 1983.

6. Miwa, S.; Fujii, H.; Matsumoto, N.; Nakatsuji, T.; Oda, S.; Asano,
H.; Asano, S.; Miura, Y.: A case of red-cell adenosine deaminase
over-production associated with hereditary hemolytic anemia found
in Japan. Am. J. Hemat. 5: 107-115, 1978.

7. Novelli, G.; Stocchi, V.; Giannotti, A.; Magnani, M.; Dallapiccola,
B.: Increased erythrocyte adenosine deaminase activity without haemolytic
anaemia. Hum. Hered. 36: 37-40, 1986.

8. Perignon, J.-L.; Hamet, M.; Buc, H. A.; Cartier, P. H.; Derycke,
M.: Biochemical study of a case of hemolytic anemia with increased
(85-fold) red cell adenosine deaminase. Clin. Chim. Acta 124: 205-212,
1982.

9. Valentine, W. N.; Paglia, D. E.; Tartaglia, A. P.; Gilsanz, F.
: Hereditary hemolytic anemia with increased red cell adenosine deaminase
(45- to 70-fold) and decreased adenosine triphosphate. Science 195:
783-785, 1977.

*FIELD* CS

Heme:
   Hemolytic anemia;
   Red cell stomatocytosis;
   Anisopoikilocytosis

Lab:
   Elevated red cell ADA;
   Decreased ATP;
   Serum uric acid mildly elevated

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
terry: 12/20/1994
carol: 4/6/1994
mimadm: 3/11/1994
carol: 10/12/1993
carol: 10/7/1993
carol: 3/31/1992

*RECORD*
*FIELD* NO
102750
*FIELD* TI
*102750 ADENOSINE KINASE; ADK
*FIELD* TX
Adenosine kinase (ATP:adenosine 5-prime-phosphotransferase; EC 2.7.1.20)
is an abundant enzyme in mammalian tissues that catalyzes the transfer
of the gamma-phosphate from ATP to adenosine, thereby serving as a
potentially important regulator of concentrations of both extracellular
adenosine and intracellular adenine nucleotides. Adenosine has
widespread effects on the cardiovascular, nervous, respiratory, and
immune systems and inhibitors of ADK could play an important
pharmacological role in increasing intravascular adenosine
concentrations and acting as antiinflammatory agents. Spychala et al.
(1996) obtained full-length cDNA clones encoding catalytically active
ADK from lymphocyte, placental, and liver cDNA libraries. On Northern
blots of all tissues examined, they identified mRNA species of 1.3 and
1.8 kb, attributable to alternative polyadenylation sites at the 3-prime
end of the gene. The encoded protein consisted of 345 amino acids with a
calculated molecular size of 38.7 kD and without any sequence
similarities to other well-characterized mammalian nucleoside kinases.
In contrast, 2 regions were identified with significant sequence
identity to microbial ribokinase and fructokinases and a bacterial
inosine/guanosine kinase. Thus, ADK is a structurally distinct mammalian
nucleoside kinase that appears to be akin to sugar kinases of microbial
origin.

The structural gene for this enzyme was tentatively assigned to
chromosome 10 by somatic cell hybrid studies (Klobutcher et al., 1976).
By the principle of gene dosage, Francke and Thompson (1979) concluded
by exclusion that ADK must be in the region 10q11-10q24. In a case of
trisomy 10p, Snyder et al. (1984) found normal levels of ADK.

*FIELD* SA
Chan et al. (1978)
*FIELD* RF
1. Chan, T.-S.; Cregan, R. P.; Reardon, M. P.: Adenosine kinase as
a new selective marker in somatic cell genetics: isolation of adenosine
kinase-deficient mouse cell lines and human-mouse hybrid cell lines
containing adenosine kinase. Somat. Cell Genet. 4: 1-12, 1978.

2. Francke, U.; Thompson, L.: Regional mapping, by exclusion, of
adenosine kinase (ADK) on human chromosome 10 using the gene dosage
approach.    (Abstract) Cytogenet. Cell Genet. 25: 156, 1979.

3. Klobutcher, L. A.; Nichols, E. A.; Kucherlapati, R. S.; Ruddle,
F. H.: Assignment of the gene for human adenosine kinase to chromosome
10 using a somatic cell hybrid clone panel. Cytogenet. Cell Genet. 16:
171-174, 1976.

4. Snyder, F. F.; Lin, C. C.; Rudd, N. L.; Shearer, J. E.; Heikkila,
E. M.; Hoo, J. J.: A de novo case of trisomy 10p: gene dosage studies
of hexokinase, inorganic pyrophosphatase and adenosine kinase. Hum.
Genet. 67: 187-189, 1984.

5. Spychala, J.; Datta, N. S.; Takabayashi, K.; Datta, M.; Fox, I.;
Gribbin, T.; Mitchell, B.: Cloning of human adenosine kinase cDNA:
sequenced similarity to microbial ribokinases and fructokinases, Proc.
Nat. Acad. Sci. 93: 1232-1237, 1996.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/26/1996
mark: 2/20/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
102770
*FIELD* TI
*102770 ADENOSINE MONOPHOSPHATE DEAMINASE-1; AMPD1
AMP DEAMINASE
MYOADENYLATE DEAMINASE DEFICIENCY, MYOPATHY DUE TO, INCLUDED;;
MAD DEFICIENCY, INCLUDED;;
MADA DEFICIENCY, INCLUDED
*FIELD* TX
Morton et al. (1989) used in situ hybridization and somatic cell hybrid
analysis to demonstrate that the AMPD1 gene maps to human chromosome 1.
Moseley et al. (1990) demonstrated that the murine equivalent is located
close to Ampd-2 on distal mouse chromosome 3. Sabina et al. (1990)
stated that tissue-specific isoforms of AMP deaminase are produced by
differential expression of 2 genes as well as by alternative splicing of
the primary transcript of 1 of these genes. The gene is approximately 20
kb long with 16 exons ranging in size from 101 to 220 nucleotides, with
the exception of exon 2, which comprises only 12 nucleotides. Intron
size ranges from 159 bp for intron 14 to several kilobases. By in situ
hybridization and analysis of human-mouse somatic cell hybrids, Sabina
et al. (1990) localized the AMPD1 gene to 1p21-p13.

Morisaki et al. (1990) found that AMPD1 is expressed at high levels in
skeletal muscle of the adult rat, whereas AMPD2 is the predominant gene
expressed in nonmuscle tissues and smooth muscle of the adult rat and is
also the predominant gene expressed in embryonic muscle and
undifferentiated myoblasts. Both genes are expressed in cardiac muscle
of the adult rat. The peptides encoded by these 2 genes have distinct
immunologic properties. The conservation of nucleotide sequence and
exon/intron boundaries in these 2 genes, as well as their close linkage,
suggests that they arose by duplication of a common primordial gene.

Myoadenylate deaminase (MADA; EC 3.5.4.6) catalyzes the deamination of
AMP to IMP in skeletal muscle and plays an important role in the purine
nucleotide cycle. Deficiency of the muscle-specific myoadenylate
deaminase is apparently a common cause of exercise-induced myopathy and
probably the most common cause of metabolic myopathy in the human. It is
the experience of most large centers that 1 to 2% of all muscle biopsies
submitted for pathologic examination are deficient in AMP deaminase
enzyme activity. Fishbein et al. (1978) found deficiency of MADA in 5
unrelated white males with muscle weakness and/or postexertional
cramping. Adenosine deaminase and creatine phosphokinase were normal in
muscle. MADA is 10 times higher in skeletal muscle than in any other
tissue. Increase in plasma ammonia (relative to lactate) after the
exercise of sponge-squeezing may be low in this disorder, and this may
be a useful clinical test. The authors suggested that this may be a
common form of myopathy of the nonprogressive, 'limp infant' and benign
congenital hypotonia type. Red cell adenylate deaminase was normal,
suggesting that it is under different genetic control from that of
muscle. This accords with evidence that myoadenylate deaminase is
antigenically unique to muscle and that the isozyme from red cells has
distinctive kinetic properties. No instances of multiple affected sibs
have been encountered but since muscle biopsy was relied on by Fishbein
et al. (1979) for diagnosis this may mean little. Family study using the
ammonia-lactate ratio in the ischemic forearm exercise test would be of
interest. Fishbein et al. (1979) had one instance of a mother with an
intermediate value in the test. Sabina et al. (1980) reported studies of
a 35-year-old woman which indicated that depletion of the ATP pool of
muscle and slow repletion are responsible for the symptoms. The chief
complaint, often dating from childhood, is muscle weakness or cramping
after exercise. Fatigue after exertion is prolonged. Valen et al. (1987)
found decreased purine release after exercise in MADA-deficient patients
compared with that in normal subjects and pointed out that this finding
increases the specificity of the forearm ischemic exercise test. Using
the standardized ischemic forearm test, Sinkeler et al. (1988) studied
36 relatives of 9 unrelated MAD-deficient patients. Eight new cases of
myoadenylate deaminase deficiency were detected, 5 of which were
confirmed histochemically and biochemically. Obligate heterozygotes
showed a normal ammonia production and MAD staining, but the mean
activity of the enzyme was significantly less than in controls. Only 2
of the 8 newly found MAD-deficient persons complained of exertional
myalgia.

Normally, AMP deaminase is about 95% inhibited by guanosine triphosphate
(GTP) and may be the limiting step in adenine nucleotide catabolism. Van
den Berghe and Hers (1980) studied the liver from a man with familial
primary gout and found defective inhibition of AMP deaminase by GTP. The
authors had suggested that a genetically determined reduction in
sensitivity of AMP deaminase to inhibition might be a basis for primary
gout. Morisaki et al. (1993) presented a study that provided the
possible molecular explanation for the fact that this AMPD1 mutation so
rarely causes significant symptoms. Alternative splicing eliminates exon
2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle.
Expression studies documented that AMPD1 mRNA, which has exon 2 deleted,
encodes a functional AMPD peptide. Variations in splicing patterns may
contribute to the variability in clinical symptoms.

*FIELD* AV
.0001
AMPD DEFICIENCY
AMPD1, GLN12TER, PRO48LEU
The index case in the family studied by Morisaki et al. (1992) was an
18-year-old German female, who first noted calf pain at 4 years of age,
usually related to exercise. Because of persistence of these symptoms
and weakness of the upper arms, muscle biopsy was performed,
demonstrating absence of AMPD activity with normal phosphorylase and
phosphofructokinase activities. In this patient and 10 other unrelated
individuals with AMPD deficiency, Morisaki et al. (1992) demonstrated
homozygosity for a C-to-T transition at nucleotide 34 (codon 12 in exon
2) and at nucleotide 143 (codon 48 in exon 3). The C-to-T transition
resulted in a nonsense mutation predicting a severely truncated AMPD
peptide (gln12-to-ter). Consistent with this prediction, no
immunoreactive AMPD1 peptide was detectable in skeletal muscle of these
patients. The mutation at nucleotide 143 resulted in a change of
proline-48 to leucine. The mutant allele was found in 12% of Caucasians
and 19% of African-Americans, whereas none of 106 Japanese subjects
surveyed had this mutant allele. The frequency of the mutant allele
would account for the 2% reported incidence of AMPD deficiency in muscle
biopsies. The restricted distribution and high frequency of this doubly
mutated allele suggested that it arose in a remote ancestor of
individuals of western European descent.

*FIELD* SA
Fishbein  (1985); Fishbein et al. (1984); Kar and Pearson (1981);
Kelemen et al. (1983); Kelemen et al. (1982); Lecky  (1983); Sabina
et al. (1984); Shumate  (1983); Shumate et al. (1980)
*FIELD* RF
1. Fishbein, W. N.: Myoadenylate deaminase deficiency: inherited
and acquired forms. Biochem. Med. 33: 158-169, 1985.

2. Fishbein, W. N.; Armbrustmacher, V. W.; Griffin, J. L.: Myo-adenylate
deaminase deficiency: a new disease of muscle. Science 200: 545-548,
1978.

3. Fishbein, W. N.; Armbrustmacher, V. W.; Griffin, J. L.; Davis,
J. I.; Foster, W. D.: Levels of adenylate deaminase, adenylate kinase,
and creatine kinase in frozen human muscle biopsy specimens relative
to type1/type2 fiber distribution: evidence for a carrier state of
myoadenylate deaminase deficiency. Ann. Neurol. 15: 271-277, 1984.

4. Fishbein, W. N.; Griffin, J. L.; Nagarajan, K.; Winkert, J. W.;
Armbrustmacher, V. W.: Immunologic uniqueness of muscle adenylate
deaminase (mAD) and genetic transmission of the deficiency state.
(Abstract) Clin. Res. 27: 274A only, 1979.

5. Kar, N. C.; Pearson, C. M.: Muscle adenylate deaminase deficiency:
report of six new cases. Arch. Neurol. 38: 279-281, 1981.

6. Kelemen, J.; Bradley, W. G.; DiMauro, S.: Reply to J. B. Shumate.
(Letter) Neurology 33: 1534 only, 1983.

7. Kelemen, J.; Rice, D. R.; Bradley, W. G.; Munsat, T. L.; DiMauro,
S.; Hogan, E. L.: Familial myoadenylate deaminase deficiency and
exertional myalgia. Neurology 32: 857-863, 1982.

8. Lecky, B. R. F.: Failure of D-ribose in myoadenylate deaminase
deficiency.  (Letter) Lancet I: 193 only, 1983.

9. Morisaki, H.; Morisaki, T.; Newby, L. K.; Holmes, E. W.: Alternative
splicing: a mechanism for phenotypic rescue of a common inherited
defect. J. Clin. Invest. 91: 2275-2280, 1993.

10. Morisaki, T.; Gross, M.; Morisaki, H.; Pongratz, D.; Zollner,
N.; Holmes, E. W.: Molecular basis of AMP deaminase deficiency in
skeletal muscle. Proc. Nat. Acad. Sci. 89: 6457-6461, 1992.

11. Morisaki, T.; Sabina, R. L.; Holmes, E. W.: Adenylate deaminase:
a multigene family in humans and rats. J. Biol. Chem. 265: 11482-11486,
1990.

12. Morton, C. C.; Eddy, R. L.; Shows, T. B.; Clark, P. R. H.; Sabina,
R. L.; Holmes, E. W.: Human AMP deaminase-1 gene (AMPD1) is mapped
to chromosome 1.  (Abstract) Cytogenet. Cell Genet. 51: 1048-1049,
1989.

13. Moseley, W. S.; Morisaki, T.; Sabina, R. L.; Holmes, E. W.; Seldin,
M. F.: Ampd-2 maps to distal mouse chromosome 3 in linkage with Ampd-1.
Genomics 6: 572-574, 1990.

14. Sabina, R. L.; Morisaki, T.; Clarke, P.; Eddy, R.; Shows, T. B.;
Morton, C. C.; Holmes, E. W.: Characterization of the human and rat
myoadenylate deaminase genes. J. Biol. Chem. 265: 9423-9433, 1990.

15. Sabina, R. L.; Swain, J. L.; Olanow, C. W.; Bradley, W. G.; Fishbein,
W. N.; DiMauro, S.; Holmes, E. W.: Myoadenylate deaminase deficiency:
functional and metabolic abnormalities associated with disruption
of the purine nucleotide cycle. J. Clin. Invest. 73: 720-730, 1984.

16. Sabina, R. L.; Swain, J. L.; Patten, B. M.; Ashizawa, T.; O'Brien,
W. E.; Holmes, E. W.: Disruption of the purine nucleotide cycle:
a potential explanation for muscle dysfunction in myoadenylate deaminase
deficiency. J. Clin. Invest. 66: 1419-1423, 1980.

17. Shumate, J. B.: Myoadenylate deaminase deficiency--a nonfamilial,
nondisease?.  (Letter) Neurology 33: 1533-1534, 1983.

18. Shumate, J. B.; Kaiser, K. K.; Carroll, J. E.; Brooke, M. H.:
Adenylate deaminase deficiency in a hypotonic infant. J. Pediat. 96:
885-887, 1980.

19. Sinkeler, S. P. T.; Joosten, E. M. G.; Wevers, R. A.; Oei, T.
L.; Jacobs, A. E. M.; Veerkamp, J. H.; Hamel, B. C. J.: Myoadenylate
deaminase deficiency: a clinical, genetic, and biochemical study in
nine families. Muscle Nerve 11: 312-317, 1988.

20. Valen, P. A.; Nakayama, D. A.; Veum, J.; Sulaiman, A. R.; Wortmann,
R. L.: Myoadenylate deaminase deficiency and forearm ischemic exercise
testing. Arthritis Rheum. 30: 661-668, 1987.

21. van den Berghe, G.; Hers, H. G.: Abnormal AMP deaminase in primary
gout.  (Letter) Lancet II: 1090 only, 1980.

*FIELD* CS

Muscle:
   Exercise-induced myopathy;
   Postexertional muscle weakness or cramping;
   Prolonged fatigue after exertion

Neuro:
   Limp infant;
   Benign congenital hypotonia

Lab:
   Muscle-specific myoadenylate deaminase deficiency;
   Normal muscle adenosine deaminase and creatine phosphokinase;
   Low increase in plasma ammonia (relative to lactate) after sponge-squeezing
   exercise;
   Decreased purine release after exercise

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
carol: 6/4/1993
carol: 8/28/1992
carol: 8/19/1992
supermim: 3/16/1992
carol: 11/12/1990

*RECORD*
*FIELD* NO
102771
*FIELD* TI
*102771 ADENOSINE MONOPHOSPHATE DEAMINASE-2; AMPD2
*FIELD* TX
Southern blotting demonstrated that distinct restriction fragments in
the rat and human genome hybridized to AMPD1 (102770) and AMPD2 cDNAs.
Indirect evidence suggests that the 2 genes are linked: L6 myoblasts
resistant to coformycin coamplified both genes while expressing only
AMPD2. Moseley et al. (1990) demonstrated further that Ampd-1 and Ampd-2
are closely linked on distal mouse chromosome 3. Mapping of the human
AMPD2 gene had not been achieved, but it is presumably located in the
same region (1p21-p13) as AMPD1. Eddy et al. (1993) indeed demonstrated
that the AMPD2 gene is localized to 1p by studies of human/mouse somatic
cell hybrids. They indicated that AMPD1 encodes isoform M (muscle) and
AMPD2 isoform L (liver). AMPD3 encodes the erythrocytic form (102772).

Bausch-Jurken et al. (1992) isolated cDNA clones for human AMPD2 from
T-lymphoblast and placental lambda-gt11 libraries using a previously
cloned rat partial AMPD2 cDNA as the probe. By screening of a human
spleen cDNA library and by use of PCR techniques, Yamada et al. (1992)
determined the nucleotide sequence of AMPD2 cDNA. The 3.7-kb cDNA
contained an open reading frame of 2,301 bp that encodes 767 amino acids
to form an 89-kD protein.

*FIELD* RF
1. Bausch-Jurken, M. T.; Mahnke-Zizelman, D. K.; Morisaki, T.; Sabina,
R. L.: Molecular cloning of AMP deaminase isoform L. J. Biol. Chem. 267:
22407-22413, 1992.

2. Eddy, R. L.; Mahne-Zizelman, D. K.; Bausch-Jurken, M. T.; Sabina,
R. L.; Shows, T. B.: Distribution of the AMP deaminase multigene
family within the human genome: assignment of the AMPD2 to chromosome
1p21-p34 and AMPD3 to chromosome 11p13-pter.   (Abstract) Human Genome
Mapping Workshop 93 24, 1993.

3. Moseley, W. S.; Morisaki, T.; Sabina, R. L.; Holmes, E. W.; Seldin,
M. F.: Ampd-2 maps to distal mouse chromosome 3 in linkage with Ampd-1.
Genomics 6: 572-574, 1990.

4. Yamada, Y.; Goto, H.; Ogasawara, N.: Cloning and nucleotide sequence
of the cDNA encoding human erythrocyte-specific AMP deaminase. Biochim.
Biophys. Acta 1171: 125-128, 1992.

*FIELD* CD
Victor A. McKusick: 3/1/1990

*FIELD* ED
joanna: 02/05/1996
mimadm: 3/11/1994
carol: 12/6/1993
carol: 1/28/1993
carol: 1/4/1993
supermim: 3/16/1992
carol: 7/6/1990

*RECORD*
*FIELD* NO
102772
*FIELD* TI
*102772 ADENOSINE MONOPHOSPHATE DEAMINASE-3; AMPD3
ERYTHROCYTE AMP DEAMINASE DEFICIENCY, INCLUDED
*FIELD* TX
AMP deaminase (EC 3.5.4.6) is a highly regulated purine nucleotide
catabolic and interconverting enzyme. Multiple isoforms have been
identified. An inherited defect in AMPD1 results in deficiency of
isoform M (muscle) and associated exercise-induced myopathy (102770).
The AMPD2 gene (102771) encodes the L (liver) isoform. The AMPD3 gene
encodes 2 erythrocytic isoforms, E1 and E2. An inherited defect in AMPD3
results in combined deficiency of these isoforms. Whereas the AMPD1 and
AMPD2 genes both are situated in the 1p21-p13 region of chromosome 1,
Eddy et al. (1993) demonstrated that the AMPD3 gene is located on
chromosome 11 in the region pter-p13.

Ogasawara et al. (1987) observed 6 related individuals with complete
deficiency of erythrocyte AMP deaminase. All were healthy and had no
hematologic disorders. The deficiency was limited to isozyme E, which is
the red cell type. The deficiency was inherited as an autosomal
recessive trait as demonstrated by the fact that both parents had
partial deficiency in each case in which this could be studied and all
children of completely deficient individuals were partially deficient.
The frequency of the mutant gene was surprisingly high; heterozygotes
had a frequency of about 1 in 30 in Japan, Seoul, and Taipei. The ATP
level was approximately 50% higher in AMP-deficient red cells compared
to the level in the control cells. Degradation of adenine nucleotide was
slower in the deficient erythrocytes than in the control erythrocytes.
Yamada et al. (1994) stated that AMPD3 deficiency had been found in
Europe and that the frequency in northern Poland was almost the same as
that in east Asia.

*FIELD* AV
.0001
AMP DEAMINASE DEFICIENCY OF ERYTHROCYTE
AMPD3, ARG573CYS
Yamada et al. (1994) identified a C-to-T transition in the AMPD3 gene,
resulting in an amino acid change of arg to cys at codon 573. Two
individuals with complete deficiency were homozygous and 2 with partial
deficiency were heterozygous. The missense mutation resulted in a
catalytically inactive enzyme.

*FIELD* RF
1. Eddy, R. L.; Mahne-Zizelman, D. K.; Bausch-Jurken, M. T.; Sabina,
R. L.; Shows, T. B.: Distribution of the AMP deaminase multigene
family within the human genome: assignment of the AMPD2 to chromosome
1p21-p34 and AMPD3 to chromosome 11p13-pter.  (Abstract) Human Genome
Mapping Workshop 93 24 only, 1993.

2. Ogasawara, N.; Goto, H.; Yamada, Y.; Nishigaki, I.; Itoh, T.; Hasegawa,
I.; Park, K. S.: Deficiency of AMP deaminase in erythrocytes. Hum.
Genet. 75: 15-18, 1987.

3. Yamada, Y.; Goto, H.; Ogasawara, N.: A point mutation responsible
for human erythrocyte AMP deaminase deficiency. Hum. Molec. Genet. 3:
331-334, 1994.

*FIELD* CD
Victor A. McKusick: 12/6/1993

*FIELD* ED
carol: 4/13/1994
carol: 12/6/1993

*RECORD*
*FIELD* NO
102775
*FIELD* TI
*102775 ADENOSINE A1 RECEPTOR; ADORA1; RDC7
*FIELD* TX
Diverse physiologic effects of adenosine were recognized as early as the
1920s (Drury and Szent-Gyorgyi, 1929; Berne, 1963). Once released,
adenosine activates adenosine receptors, which in turn regulate a
diverse set of physiologic functions including cardiac rate and
contractility, smooth muscle tone, sedation, release of
neurotransmitters, platelet function, lipolysis, renal function, and
white blood cell function. Stiles (1992) reviewed the structure and
function of adenosine receptors important in the mediation of these
multiple effects. Also see adenosine A2 receptor (ADORA2; 102776).
Libert et al. (1991) obtained cDNA clones for 4 new receptors of the
G-protein-coupled receptor family by selective amplification of cloning
from thyroid cDNA and termed them RDC1, RDC4, RDC7, and RDC8. RDC7 and
RDC8 were identified as A1 and A2 adenosine receptors, respectively. By
in situ hybridization, Libert et al. (1991) assigned the RDC7 gene to
22q11.2-q13.1.

Using fluorescence in situ hybridization, Townsend-Nicholson et al.
(1995) demonstrated that, in fact, the ADORA1 gene is located on 1q32.1.

*FIELD* RF
1. Berne, R. M.: Cardiac nucleotides in hypoxia: possible role in
regulation of coronary blood flow. Am. J. Physiol. 204: 317-322,
1963.

2. Drury, A. N.; Szent-Gyorgyi, A.: The physiological activity of
adenine compounds with especial reference to their action upon the
mammalian heart. J. Physiol. 68: 213-237, 1929.

3. Libert, F.; Passage, E.; Parmentier, M.; Simons, M.-J.; Vassart,
G.; Mattei, M.-G.: Chromosomal mapping of A1 and A2 adenosine receptors,
VIP receptor, and a new subtype of serotonin receptor. Genomics 11:
225-227, 1991.

4. Stiles, G. L.: Adenosine receptors. J. Biol. Chem. 267: 6451-6454,
1992.

5. Townsend-Nicholson, A.; Baker, E.; Schofield, P. R.; Sutherland,
G. R.: Localization of the adenosine A1 receptor subtype gene (ADORA1)
to chromosome 1q32.1. Genomics 26: 423-425, 1995.

*FIELD* CD
Victor A. McKusick: 9/9/1991

*FIELD* ED
terry: 4/18/1995
carol: 6/22/1992
carol: 6/19/1992
supermim: 3/16/1992
carol: 9/9/1991

*RECORD*
*FIELD* NO
102776
*FIELD* TI
*102776 ADENOSINE A2 RECEPTOR; ADORA2A
ADORA2;;
RDC8
*FIELD* TX
See 102775. By in situ hybridization, Libert et al. (1991) assigned the
RDC8 gene to 11q11-q13. Szepetowski et al. (1993) used
amplification-based mapping of the 11q13 region to demonstrate that the
ADORA2 gene is located in that band proximal to BCL1 (151400). It was
found to be in the coamplification group closest to BCL1 in 11q13 along
with PPP1A (176875) and GST3 (138370). Physical mapping by hybridization
of the same probes to DNA fragments generated by rare-cutting
restriction endonucleases and separated by pulsed field gel
electrophoresis confirmed the findings. MacCollin et al. (1994)
suggested that the assignment to chromosome 11 was in error; they
localized the gene to chromosome 22 both by analysis of cosmid clones
from a human chromosome 22 library and by Southern hybridization with a
comprehensive somatic cell hybrid panel. It may be that they were
dealing with a different gene. Libert et al. (1991) and Szepetowski et
al. (1993) were clearly mapping the same locus since they used precisely
the same RDC8 probe. Although the probe used by MacCollin et al. (1994)
was reportedly very similar in sequence, it must in fact have come from
a different locus (Gusella, 1994; Gaudray, 1994).

By fluorescence in situ hybridization and PCR analysis of human/hamster
hybrid cell panels, Le et al. (1996) demonstrated that the ADORA2A gene
is located on 22q11.2. This was in contrast to previous reports
(subsequently retracted) which mapped the gene to 11q11-q13; see erratum
for Libert et al. (1991).

*FIELD* RF
1. Gaudray, P.: Personal Communication. Nice, France  6/1/1994.

2. Gusella, J. F.: Personal Communication. Boston, Mass.  4/17/1994.

3. Le, F.; Townsend-Nicholson, A.; Baker, E.; Sutherland, G. R.; Schofield,
P. R.: Characterization and chromosomal localization of the human
A2a adenosine receptor gene: ADORA2A. Biochem. Biophys. Res. Commun. 223:
461-467, 1996.

4. Libert, F.; Passage, E.; Parmentier, M.; Simons, M.-J.; Vassart,
G.; Mattei, M.-G.: Chromosomal mapping of A1 and A2 adenosine receptors,
VIP receptor, and a new subtype of serotonin receptor. Genomics 11:
225-227, 1991. Note: Erratum: Genomics 23:305 only, 1994.

5. MacCollin, M.; Peterfreund, R.; MacDonald, M.; Fink, J. S.; Gusella,
J.: Mapping of a human A2a adenosine receptor (ADORA2) to chromosome
22. Genomics 20: 332-333, 1994.

6. Szepetowski, P.; Perucca-Lostanlen, D.; Gaudray, P.: Mapping genes
according to their amplification status in tumor cells: contribution
to the map of 11q13. Genomics 16: 745-750, 1993.

*FIELD* CD
Victor A. McKusick: 9/9/1991

*FIELD* ED
jamie: 12/04/1996
terry: 11/8/1996
carol: 9/28/1994
carol: 6/24/1993
carol: 3/2/1993
supermim: 3/16/1992
carol: 2/27/1992
carol: 9/9/1991

*RECORD*
*FIELD* NO
102777
*FIELD* TI
*102777 ADENOSINE A2B RECEPTOR-LIKE
ADORA2B-LIKE;;
ADORA2L
*FIELD* TX
The nucleoside adenosine acts through cell surface receptors to
influence a wide variety of physiologic processes. Based on
pharmacologic and functional properties, adenosine receptors have been
divided into 2 main types: A1 adenosine receptors, which inhibit
adenylyl cyclase, and A2 adenosine receptors which stimulate adenylyl
cyclase. A2 adenosine receptors are further divided into A2a and A2b
subtypes based on pharmacologic criteria. Rivkees and Reppert (1992)
characterized the pharmacologic properties of a cDNA clone for A2b
adenosine receptor in stably transfected CHO cells by examining cAMP
responses to drug treatments. Libert et al. (1991), who used the gene
symbol ADORA2L, mapped the gene to 10q25.3-q26.3 by in situ
hybridization.

*FIELD* RF
1. Libert, F.; Passage, E.; Parmentier, M.; Simons, M.-J.; Vassart,
G.; Mattei, M.-G.: Chromosomal mapping of A1 and A2 adenosine receptors,
VIP receptor, and a new subtype of serotonin receptor. Genomics 11:
225-227, 1991.

2. Rivkees, S. A.; Reppert, S. M.: RFL9 encodes an A2b adenosine
receptor. Molec. Endocr. 6: 1598-1604, 1992.

*FIELD* CD
Victor A. McKusick: 1/12/1993

*FIELD* ED
carol: 3/9/1995
carol: 3/2/1993
carol: 1/12/1993

*RECORD*
*FIELD* NO
102800
*FIELD* TI
*102800 ADENOSINE TRIPHOSPHATASE DEFICIENCY, ANEMIA DUE TO
*FIELD* TX
In 2 kindreds Harvald et al. (1964) observed nonspherocytic hemolytic
anemia due to deficiency of ATP-ase. At least 2 generations were
affected in each family and father-son transmission was noted. Hanel et
al. (1971) restudied the families and concluded that the trait is an
irregular dominant. Probably a minority of the heterozygotes have
hemolytic anemia.

*FIELD* SA
Paglia et al. (1970)
*FIELD* RF
1. Hanel, H. K.; Cohn, J.; Harvald, B.: Adenosine-triphosphatase
deficiency in a family with non-spherocytic haemolytic anaemia. Hum.
Hered. 21: 313-319, 1971.

2. Harvald, B.; Hanel, K. H.; Squires, R.; Trap-Jensen, J.: Adenosine-triphosphatase
deficiency in patients with non-spherocytic haemolytic anaemia. Lancet II:
18-19, 1964.

3. Paglia, D. E.; Valentine, W. N.; Tartaglia, A. P.; Konrad, P. N.
: Adenine nucleotide reductions associated with a dominantly transmitted
form of nonspherocytic hemolytic anemia.  (Abstract) Blood 36: 837
only, 1970.

*FIELD* CS

Heme:
   Infrequent nonspherocytic hemolytic anemia

Lab:
   ATP-ase deficiency

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/28/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
102900
*FIELD* TI
102900 ADENOSINE TRIPHOSPHATE, ELEVATED, OF ERYTHROCYTES
PYRUVATE KINASE HYPERACTIVITY
*FIELD* TX
Brewer (1965) in the United States and Zurcher et al. (1965) in Holland
described high erythrocyte adenosine triphosphate as a dominantly
inherited trait. 'High red cell ATP syndrome' may be a heterogeneous
category. For example, pyrimidine-5-prime-nucleotidase deficiency
(266120) hemolytic anemia shows this feature. Max-Audit et al. (1980)
described a family in which 4 persons had polycythemia and pyruvate
kinase hyperactivity. They showed low 2,3-diphosphoglycerate (2,3-DPG)
and high adenosine triphosphate (ATP) levels. The PK electrophoretic
patterns in these persons were abnormal by the presence of several
additional bands.

*FIELD* SA
Loos et al. (1967)
*FIELD* RF
1. Brewer, G. J.: A new inherited abnormality of human erythrocyte--elevated
erythrocyte adenosine triphosphate. Biochem. Biophys. Res. Commun. 18:
430-434, 1965.

2. Loos, J. A.; Prins, H. K.; Zurcher, C.: Elevated ATP levels in
human erythrocytes. In: Beutler, E.: Hereditary Disorders of Erythrocyte
Metabolism.  New York: Grune and Stratton (pub.)  1967.

3. Max-Audit, I.; Rosa, R.; Marie, J.: Pyruvate kinase hyperactivity
genetically determined: metabolic consequences and molecular characterization.
Blood 56: 902-909, 1980.

4. Zurcher, C.; Loos, J. A.; Prins, H. K.: Hereditary high ATP content
of human erythrocytes. Folia Haemat. 83: 366-376, 1965.

*FIELD* CS

Heme:
   Polycythemia

Lab:
   High erythrocyte adenosine triphosphate;
   Pyruvate kinase hyperactivity;
   Low 2,3-diphosphoglycerate (2,3-DPG);
   Additional PK electrophoretic bands

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
102910
*FIELD* TI
*102910 ADENOSINE TRIPHOSPHATE SYNTHASE, MITOCHONDRIAL, BETA SUBUNIT; ATP5B;
ATPSB; ATPMB
*FIELD* TX
The beta subunit of mitochondrial ATP synthase is encoded by a nuclear
gene and assembled with the other subunits encoded by both mitochondrial
and nuclear genes. The enzyme catalyzes ATP formation, using the energy
of proton flux through the inner membrane during oxidative
phosphorylation. Two subunits are encoded by a mitochondrial gene and
the others by a nuclear gene. The numbers of mitochondria per cell vary
greatly depending on the developmental stage, cell activity, and type of
tissue. The molecular mechanism for coordinating the 2 genetic systems
is unknown. Ohta et al. (1988) cloned cDNA of the human beta subunit.
The gene contains 10 exons, with the first exon corresponding to the
noncoding region and most of the presequence which targets this protein
to the mitochondria. Neckelmann et al. (1989) sequenced the human ATP
synthase beta subunit gene and demonstrated that it is preferentially
expressed in heart and skeletal muscle. The gene was found to have 10
exons encoding a leader peptide of 49 amino acids and a mature protein
of 480 amino acids. Kudoh et al. (1989) assigned the ATPMB locus to the
p13-qter region of human chromosome 12 by analysis of human-mouse
somatic cell hybrid DNA and by use of flow-sorted chromosomes. They
assigned 2 related sequences, ATPMBL1 and ATPMBL2, to chromosome 2 and
17, respectively.

*FIELD* SA
Neckelmann et al. (1989)
*FIELD* RF
1. Kudoh, J.; Minoshima, S.; Fukuyama, R.; Maekawa, M.; Neckelmann,
N.; Wallace, D. C.; Shimizu, Y.; Shimizu, N.: Assignment of ATP synthase
beta subunit (ATPMB) gene to the p13-qter region of human chromosome
12.  (Abstract) Cytogenet. Cell Genet. 51: 1026 only, 1989.

2. Neckelmann, N.; Warner, C. K.; Chung, A.; Kudoh, J.; Minoshima,
S.; Fukuyama, R.; Maekawa, M.; Shimizu, Y.; Shimizu, N.; Liu, J. D.;
Wallace, D. C.: The human ATP synthase beta subunit gene: sequence
analysis, chromosome assignment, and differential expression. Genomics 5:
829-843, 1989.

3. Neckelmann, N. S.; Chung, A. B.; Warner, C. K.; Hodge, J. A.; Wallace,
D. C.: The human ATP synthase beta subunit gene has been sequenced
and shown to be preferentially expressed in heart and skeletal muscle.
(Abstract) Cytogenet. Cell Genet. 51: 1051 only, 1989.

4. Ohta, S.; Tomura, H.; Matsuda, K.; Kagawa, Y.: Gene structure
of the human mitochondrial adenosine triphosphate synthase beta subunit.
J. Biol. Chem. 263: 11257-11262, 1988.

*FIELD* CD
Victor A. McKusick: 10/10/1988

*FIELD* ED
jason: 7/29/1994
supermim: 3/16/1992
carol: 2/7/1991
supermim: 3/20/1990
carol: 12/14/1989
ddp: 10/27/1989

*RECORD*
*FIELD* NO
102920
*FIELD* TI
*102920 ADENOVIRUS-12 CHROMOSOME MODIFICATION SITE-1p; A12M2
*FIELD* TX
Steffensen et al. (1976) found a second adenovirus 12 gap in chromosome
1, at 1p36. It has been considered that this site may correspond to that
of adenylate kinase-2 (103020); however, AK2 appears to be at 1p34.
McDougall (1979) identified 2 sites on 1p: 1p32 and 1p36.

*FIELD* RF
1. McDougall, J. K.: The interactions of adenovirus with host cell
gene loci.  (Abstract) Cytogenet. Cell Genet. 25: 183 only, 1979.

2. Steffensen, D. M.; Szabo, P.; McDougall, J. K.: Adenovirus 12
uncoiler regions of human chromosome 1 in relation to the 5S rRNA
genes. Exp. Cell Res. 100: 436-439, 1976.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987

*RECORD*
*FIELD* NO
102930
*FIELD* TI
*102930 ADENOVIRUS-12 CHROMOSOME MODIFICATION SITE-1q1; A12M1
*FIELD* TX
A site on the long arm of chromosome 1 is altered by exposure of cells
in vitro to adenovirus 12 (HGM2, Rotterdam, July, 1974). See McDougall
(1971). Steffensen et al. (1976) concluded that this uncoiler region is
at 1q42 and that 5S rRNA genes are located immediately distal to it at
1q42-1q43. This order is the reverse of that presented tentatively at
the Rotterdam Gene Mapping Conference. This site may be identical to
that of guanylate kinase (139270). McDougall (1979) identified 2 sites
on 1q: 1q21 and 1q42.

*FIELD* RF
1. McDougall, J. K.: Adenovirus induced chromosome aberrations in
human cells. J. Gen. Virol. 12: 43-51, 1971.

2. McDougall, J. K.: The interactions of adenovirus with host cell
gene loci.  (Abstract) Cytogenet. Cell Genet. 25: 183 only, 1979.

3. Steffensen, D. M.; Szabo, P.; McDougall, J. K.: Adenovirus 12
uncoiler regions of human chromosome 1 in relation to the 5S rRNA
genes. Exp. Cell Res. 100: 436-439, 1976.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 7/20/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
root: 4/28/1988

*RECORD*
*FIELD* NO
102940
*FIELD* TI
*102940 ADENOVIRUS-12 CHROMOSOME MODIFICATION SITE-1q2; A12M3
*FIELD* TX
This is the site at 1q21. See 102930.

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987
marie: 1/7/1987
*RECORD*
*FIELD* NO
102970
*FIELD* TI
*102970 ADENOVIRUS-12 CHROMOSOME MODIFICATION SITE-17; A12M4
*FIELD* TX
Adenovirus 12 produces an uncoiled segment in the long arm of chromosome
17. This is associated with elevated thymidine kinase (TK) activity. The
TK locus (188300) is in the same region of 17q as that which shows the
morphologic change. Lindgren et al. (1985) pointed out that the 3 major
adenovirus-12 modification sites are the location of small nuclear RNA
genes: U1 genes (180680) are at 1p36, class 1 U1 pseudogenes are at
1q21, and U2 snRNA genes (180690) are at 17q21-17q22. On this basis,
they suggested that snRNA genes are the major targets of viral
chromosome modification.

*FIELD* SA
McDougall  (1971); McDougall et al. (1973)
*FIELD* RF
1. Lindgren, V.; Ares, M., Jr.; Weiner, A. M.; Francke, U.: Human
genes for U2 small nuclear RNA map to a major adenovirus 12 modification
site on chromosome 17. Nature 314: 115-116, 1985.

2. McDougall, J. K.: Adenovirus induced chromosome aberrations in
human cells. J. Gen. Virol. 12: 43-51, 1971.

3. McDougall, J. K.; Kucherlapati, R. S.; Ruddle, F. H.: Localization
and induction of the human thymidine kinase gene by adenovirus 12.
Nature N.B. 245: 172-175, 1973.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 6/1/1988
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
102980
*FIELD* TI
*102980 ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE 1
ADCYAP1;;
PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE; PACAP
*FIELD* TX
Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel
bioactive peptide that was originally isolated from ovine hypothalamus
on the basis of its ability to stimulate adenylate cyclase in rat
anterior pituitary cell cultures. The amino-terminal amino acid sequence
of PACAP showed 68% identity with vasoactive intestinal peptide (VIP;
192320) and more limited similarity with growth hormone releasing
hormone (GHRH; 139190). Hosoya et al. (1992) isolated the human PACAP
gene and by comparison with a human PACAP cDNA determined its
exon/intron organization. On the basis of DNA isolated from a mouse A9
microcell hybrid clone containing a single human chromosome, the PACAP
gene was assigned to chromosome 18; it was regionalized to 18p11 by in
situ hybridization. Perez-Jurado and Francke (1993) described a
dinucleotide repeat polymorphism in the 3-prime untranslated region of
the PACAP gene.

*FIELD* RF
1. Hosoya, M.; Kimura, C.; Ogi, K.; Ohkubo, S.; Miyamoto, Y.; Kugoh,
H.; Shimizu, M.; Onda, H.; Oshimura, M.; Arimura, A.; Fujino, M.:
Structure of the human pituitary adenylate cyclase activating polypeptide
(PACAP) gene. Biochim. Biophys. Acta 1129: 199-206, 1992.

2. Perez-Jurado, L. A.; Francke, U.: Dinucleotide repeat polymorphism
at the human pituitary adenylate cyclase activating polypeptide (PACAP)
gene. Hum. Molec. Genet. 2: 827 only, 1993.

*FIELD* CD
Victor A. McKusick: 7/8/1993

*FIELD* ED
carol: 8/31/1993
carol: 7/8/1993

*RECORD*
*FIELD* NO
102981
*FIELD* TI
*102981 ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE 1, RECEPTOR FOR; ADCYAP1R1
PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE RECEPTOR, TYPE;;
I;;
PACAP RECEPTOR, TYPE I
*FIELD* TX
Pituitary adenylate cyclase activating polypeptide (PACAP; 102980) is a
hormone that was originally isolated from sheep hypothalamus on the
basis of its ability to stimulate adenylate cyclase in rat anterior
pituitary cell cultures (Arimura, 1992). PACAP is present not only in
the central nervous system but also in peripheral tissues, including
gastrointestinal tract, adrenal gland, and testis. Its actions include
the stimulation of secretion of growth hormone, ACTH, catecholamines,
and insulin, as well as other hormones. In addition, it appears to
function as a neuromodulator/neurotransmitter in the central and
peripheral nervous systems. The diverse biologic actions of PACAP are
mediated by receptors that are positively coupled to adenylate cyclase
by G(s-alpha). Three different receptors for PACAP have been identified,
each of which contains 7 transmembrane segments and shares significant
homology with members of the glucagon/secretin receptor family. The type
1 receptor, which is found in the hypothalamus, brain stem, pituitary,
adrenal gland, pancreas, and testes, has a high affinity only for PACAP
(Ogi et al., 1993). The type 2 receptor is found in the brain. The
adrenal gland has a high affinity for both PACAP and for vasoactive
intestinal peptide (VIP; 192320).

By PCR analysis of genomic DNA from a human/rodent somatic cell hybrid
mapping panel, Stoffel et al. (1994) mapped the human type 1 PACAP
receptor gene, symbolized ADCYAP1R1, to chromosome 7. The assignment was
confirmed and the gene localized to 7p14 by fluorescence in situ
hybridization. Brabet et al. (1996) likewise mapped this gene to
7p15-p14 by fluorescence in situ hybridization.

*FIELD* RF
1. Arimura, A.: Pituitary adenylate cyclase activating polypeptide
(PACAP): discovery and current status of research. Regul. Pept. 37:
287-303, 1992.

2. Brabet, P.; Diriong, S.; Journot, L.; Bockaert, J.; Taviaux, S.
: Localization of the human pituitary adenylate cyclase-activating
polypeptide receptor (PACAP-1-R) gene to 7p15-p14 by fluorescence
in situ hybridization. Genomics 38: 100-102, 1996.

3. Ogi, K.; Miyamoto, Y.; Masuda, Y.; Habata, Y.; Hosoya, M.; Ohtaki,
T.; Masuo, Y.; Onda, H.; Fujino, M.: Molecular cloning and functional
expression of a cDNA encoding a human pituitary adenylate cyclase
activating polypeptide receptor. Biochem. Biophys. Res. Commun. 196:
1511-1521, 1993.

4. Stoffel, M.; Espinosa, R., III; Trabb, J. B.; Le Beau, M. M.; Bell,
G. I.: Human type I pituitary adenylate cyclase activating polypeptide
receptor (ADCYAP1R): localization to chromosome band 7p14 and integration
into the cytogenetic, physical, and genetic map of chromosome 7. Genomics 23:
697-699, 1994.

*FIELD* CD
Victor A. McKusick: 4/20/1995

*FIELD* ED
terry: 12/11/1996
carol: 4/20/1995

*RECORD*
*FIELD* NO
102990
*FIELD* TI
102990 ADENYLATE KINASE, MUSCLE, DEFICIENCY OF
*FIELD* TX
Schmitt et al. (1974) studied biopsied skeletal muscle from the father,
mother, brother and sister of 2 children (sex not given) who had died of
malignant hyperpyrexia (muscle rigidity, hyperthermia, tachycardia,
hyperventilation, myoglobinuria and renal failure) after halothane
anesthesia (see 145600). Deficiency of muscle adenylate kinase (AK) was
found in the mother and sister. Adenylate kinase, also known as
myokinase, is a phosphotransferase that catalyzes the reversible
conversion of 2 molecules of ADP to 1 of ATP plus 1 of AMP. Because red
cell adenylate was normal, the authors concluded that muscle and red
cell (103000) AK are under separate genetic control.

*FIELD* RF
1. Schmitt, J.; Schmidt, K.; Ritter, H.: Hereditary malignant hyperpyrexia
associated with muscle adenylate kinase deficiency. Humangenetik 24:
253-357, 1974.

*FIELD* CS

Misc:
   Malignant hyperpyrexia after halothane anesthesia

Muscle:
   Muscle rigidity

Metabolic:
   Hyperthermia

Cardiac:
   Tachycardia

Resp:
   Hyperventilation

GU:
   Renal failure

Lab:
   Myoglobinuria;
   Muscle adenylate kinase (AK or myokinase) deficiency;
   Normal red cell adenylate kinase

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
103000
*FIELD* TI
*103000 ADENYLATE KINASE-1; AK1
ADENYLATE KINASE, SOLUBLE
ADENYLATE KINASE DEFICIENCY, INCLUDED
*FIELD* TX
Adenylate kinase is present in red cells as well as in muscle (see
102990). Fildes and Harris (1966) found electrophoretic variation in red
cells and defined 3 phenotypes, designated AK1, AK2-1 and AK2. All of
the 141 children of two AK1 parents (62 such matings) were also AK1.
Among the 136 children of AK1 by AK2-1 matings, 72 were AK1 and 64
AK2-1. AK1 and AK2 persons were thought to be homozygotes for a
two-allele system and AK2-1 persons heterozygotes. The frequency of the
rarer AK2 allele was about 0.05 in the English and about 1 in 400
persons would be expected to be homozygous for this allele. Survey and
family data were consistent. Singer and Brock (1971) identified a
probably silent allele at the AK locus. Matsuura et al. (1989) cloned
the AK1 gene and determined its structure. The gene is 12 kb long and
has 7 exons.

Rapley et al. (1967) concluded that the AK locus is linked to the ABO
(110300) locus with a recombination value of about 0.20. Schleutermann
et al. (1969) found that the nail-patella syndrome locus (161200) and
the AK locus are closely linked. No recombination was found in 53
opportunities. Fenger and Sorensen (1975) found a 1.33 to 1 ratio for
the female to male recombination fractions between ABO and AK, but the
difference between the recombination fractions was not significantly
different from zero. All published data combined showed the most likely
recombination fraction to be about 14%. Westerveld et al. (1976) found
evidence that the AK locus assigned to chromosome 9 is the AK1 locus, or
so-called red cell AK. Cook et al. (1978) collated evidence that ABO-AK1
lie in band 9q34. They could exclude MNSs, GPT and Gc from chromosome 9.
Cavalli-Sforza et al. (1979) presented evidence for linkage of
transcobalamin II and adenylate kinase (lod score 1.78 at theta 0.139).
This was not subsequently confirmed. AK1 is proximal to the break in the
Philadelphia chromosome rearrangement (Geurts van Kessel et al., 1982).
On the basis of a chromosome 9 aberration, an inverted paracentric
insertion, inv ins(9)(q22.1q34.3q34.1), Allderdice et al. (1986)
concluded that AK1 is located in 9q34.1-q34.3. Since AK1 is in 9q34 and
is proximal to the breakpoint that creates the Philadelphia chromosome
in chronic myeloid leukemia, located in band 9q34.1, AK1 and probably
the linked ABO locus may be in the proximal part of 9q34.1. In a patient
with deletion 9q32-qter secondary to a balanced maternal translocation,
Zuffardi et al. (1989) found normal levels of adenylate kinase.
Comparing this to previously published data, the authors concluded that
the AK1 locus may be situated in 9q32.

In 2 offspring of second-cousin Arab parents, Szeinberg et al. (1969)
found marked AK deficiency with intermediate levels in the presumed
heterozygotes. Severe anemia was present in both. Presumably this
mutation is at the same locus as that which controls the polymorphism of
AK. In the study of a black family, Beutler et al. (1982) found that
despite barely detectable levels of adenylate kinase activity, probably
representing guanylate kinase, red cells are able to maintain their
adenine nucleotide levels and to circulate normally. They concluded that
previously reported cases of AK deficiency represent a chance
association of hemolysis with the enzyme deficiency, and not a
cause-and-effect relationship. In the family reported by Boivin et al.
(1971), the proband had psychomotor retardation and moderate congenital
hemolytic anemia with markedly diminished red cell AK activity. The
parents had half-normal AK activity. Autosomal recessive inheritance was
proposed. Another family, Japanese, was reported by Miwa et al. (1983).
The proband, a 10-year-old girl, had normal physical and mental
development, mild to moderate hemolytic anemia from the neonatal period,
and hepatosplenomegaly. Red cell AK activity was 44% of normal.
Puzzlingly, the proband's mother, younger sister and maternal
grandfather showed a half-normal enzyme activity. Lachant et al. (1991)
reported a fifth family with AK deficiency associated with hemolytic
anemia. In none of the families had a cause-and-effect relationship to
AK deficiency been established. Lachant et al. (1991) suggested that
defects occur in multiple phosphotransferases in AK-deficient red blood
cells and that these other defects produce deleterious lesions that
promote the shortened red cell survival. Toren et al. (1994) described a
family in which 6 children showed AK deficiency; in 3 of them, G6PD
deficiency was found in combination with AK deficiency. Although
heterozygotes were asymptomatic, homozygotes had congenital chronic
nonspherocytic hemolytic anemia with hemoglobin levels of 8-9 g/dl.
Patients also deficient in G6PD suffered from a more severe hemolytic
anemia with hemoglobin levels around 6 g/dl. The AK-deficient children
were also mentally retarded. Splenectomy performed in 5 of the 6
children resulted in complete remission of the hemolytic process.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
ADENYLATE KINASE DEFICIENCY, HEMOLYTIC ANEMIA DUE TO
AK1, ARG128TRP
In a patient with hemolytic anemia, Matsuura et al. (1989) demonstrated
a transition (C-to-T) in exon 6 which resulted in an arg-to-trp
(CGG-to-TGG) substitution at the 128th residue of AK1. Mutant chicken
AK1, produced by introducing an arg-to-trp substitution at the same
position by oligodeoxynucleotide-directed mutagenesis, showed reduced
catalytic activity as well as decreased solubility when expressed in E.
coli.

*FIELD* SA
Boivin et al. (1970); Bowman et al. (1967); Brock  (1970); Ferguson-Smith
et al. (1976); Mohandas et al. (1979); Povey et al. (1976); Seger
et al. (1978); Szeinberg et al. (1969); Weitkamp et al. (1969)
*FIELD* RF
1. Allderdice, P. W.; Kaita, H.; Lewis, M.; McAlpine, P. J.; Wong,
P.; Anderson, J.; Giblett, E. R.: Segregation of marker loci in families
with an inherited paracentric insertion of chromosome 9. Am. J.
Hum. Genet. 39: 612-617, 1986.

2. Beutler, E.; Carson, D. A.; Dannawi, H.; Forman, L.; Kuhl, W.;
West, C.; Westwood, B.: Red cell adenylate kinase deficiency: another
non-disease?.  (Abstract) Blood 60: 33A only, 1982.

3. Boivin, P.; Galand, C.; Hakim, J.; Simony, D.; Seligman, M.: Deficit
congenital en adenylate-kinase erythrocytaire.  (Letter) Presse Med. 78:
1443 only, 1970.

4. Boivin, P.; Galand, C.; Hakim, J.; Simony, D.; Seligman, M.: Une
nouvelle erythroenzymopathie: anemie hemolytique congenitale non spherocytaire
et deficit hereditaire en adenylate-kinase erythrocytaire. Presse
Med. 79: 215-218, 1971.

5. Bowman, J. E.; Frischer, H.; Ajmar, F.; Carson, P. E.; Gower, M.
K.: Population, family and biochemical investigation of human adenylate
kinase polymorphism. Nature 214: 1156-1158, 1967.

6. Brock, D. J. H.: Evidence against a common subunit in adenylate
kinase and pyruvate kinase. Humangenetik 10: 30-34, 1970.

7. Cavalli-Sforza, L. L.; King, M. C.; Go, R. C. P.; Namboodiri, K.
K.; Lynch, H. T.; Wong, L.; Kaplan, E. B.; Elston, R. C.: Possible
linkage between transcobalamin II (TC II) and adenylate kinase (AK).
(Abstract) Cytogenet. Cell Genet. 25: 140-141, 1979.

8. Cook, P. J. L.; Robson, E. B.; Buckton, K. E.; Slaughter, C. A.;
Gray, J. E.; Blank, C. E.; James, F. E.; Ridler, M. A. C.; Insley,
J.; Hulten, M.: Segregation of ABO, AK(1) and ACONs in families with
abnormalities of chromosome 9. Ann. Hum. Genet. 41: 365-377, 1978.

9. Fenger, K.; Sorensen, S. A.: Evaluation of a possible sex difference
in recombination for the ABO-AK linkage. Am. J. Hum. Genet. 27:
784-788, 1975.

10. Ferguson-Smith, M. A.; Aitken, D. A.; Turleau, C.; de Grouchy,
J.: Localisation of the human ABO: Np-1: AK-1 linkage group by regional
assignment of AK-1 to 9q34. Hum. Genet. 34: 35-43, 1976.

11. Fildes, R. A.; Harris, H.: Genetically determined variation of
adenylate kinase in man. Nature 209: 261-262, 1966.

12. Geurts van Kessel, A. H. M.; Hagemeijer, A.; Westerveld, A.; Meera
Khan, P.; de Groot, P. G.; Pearson, P. L.: Characterization of chromosomal
abnormalities in chronic myeloid leukemia using somatic cell hybrids.
(Abstract) Cytogenet. Cell Genet. 32: 280 only, 1982.

13. Lachant, N. A.; Zerez, C. R.; Barredo, J.; Lee, D. W.; Savely,
S. M.; Tanaka, K. R.: Hereditary erythrocyte adenylate kinase deficiency:
a defect of multiple phosphotransferases?. Blood 77: 2774-2784,
1991.

14. Matsuura, S.; Igarashi, M.; Tanizawa, Y.; Yamada, M.; Kishi, F.;
Kajii, T.; Fujii, H.; Miwa, S.; Sakurai, M.; Nakazawa, A.: Human
adenylate kinase deficiency associated with hemolytic anemia: a single
base substitution affecting solubility and catalytic activity of the
cytosolic adenylate kinase. J. Biol. Chem. 264: 10148-10155, 1989.

15. Miwa, S.; Fujii, H.; Tani, K.; Takahashi, K.; Takizawa, T.; Igarashi,
T.: Red cell adenylate kinase deficiency associated with hereditary
nonspherocytic hemolytic anemia: clinical and biochemical studies.
Am. J. Hemat. 14: 325-333, 1983.

16. Mohandas, T.; Sparkes, R. S.; Sparkes, M. C.; Shulkin, J. D.;
Toomey, K. E.; Funderburk, S. J.: Regional localization of human
gene loci on chromosome 9: studies of somatic cell hybrids containing
human translocations. Am. J. Hum. Genet. 31: 586-600, 1979.

17. Povey, S.; Slaughter, C. A.; Wilson, D. E.; Gormley, I. P.; Buckton,
K. E.; Perry, P.; Bobrow, M.: Evidence for the assignment of loci
AK 1, AK 3 and ACON to chromosome 9 in man. Ann. Hum. Genet. 39:
413-422, 1976.

18. Rapley, S.; Robson, E. B.; Harris, H.; Smith, S. M.: Data on
the incidence, segregation and linkage relations of the adenylate
kinase (AK) polymorphism. Ann. Hum. Genet. 31: 237-242, 1967.

19. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

20. Schleutermann, D. A.; Bias, W. B.; Murdoch, J. L.; McKusick, V.
A.: Linkage of the loci for the nail-patella syndrome and adenylate
kinase. Am. J. Hum. Genet. 21: 606-630, 1969.

21. Seger, J.; Tchen, P.; Feingold, N.; Grenand, F.; Bois, E.: Homozygosity
of adenylate kinase allele 3: two cases. Hum. Genet. 43: 337-339,
1978.

22. Singer, J. D.; Brock, D. J.: Half-normal adenylate kinase activity
in three generations. Ann. Hum. Genet. 35: 109-114, 1971.

23. Szeinberg, A.; Gavendo, S.; Cahane, D.: Erythrocyte adenylate-kinase
deficiency.  (Letter) Lancet I: 315-316, 1969.

24. Szeinberg, A.; Kahana, D.; Gavendo, S.; Zaidman, J.; Ben-Ezzer,
J.: Hereditary deficiency of adenylate kinase in red blood cells.
Acta Haemat. 42: 111-126, 1969.

25. Toren, A.; Brok-Simoni, F.; Ben-Bassat, I.; Holtzman, F.; Mandel,
M.; Neumann, Y.; Ramot, B.; Rechavi, G.; Kende, G.: Congenital haemolytic
anaemia associated with adenylate kinase deficiency. Brit. J. Haemat. 87:
376-380, 1994.

26. Weitkamp, L. R.; Sing, C. F.; Shreffler, D. C.; Guttormsen, S.
A.: The genetic linkage relations of adenylate kinase: further data
on the ABO-AK linkage group. Am. J. Hum. Genet. 21: 600-605, 1969.

27. Westerveld, A.; Jongsma, A. P. M.; Meera Khan, P.; Van Someren,
H.; Bootsma, D.: Assignment of the AK(1): Np: AKO linkage group to
human chromosome 9. Proc. Nat. Acad. Sci. 73: 895-899, 1976.

28. Zuffardi, O.; Caiulo, A.; Maraschio, P.; Tupler, R.; Bianchi,
E.; Amisano, P.; Beluffi, G.; Moratti, R.; Liguri, G.: Regional assignment
of the loci for adenylate kinase to 9q32 and for alpha(1)-acid glycoprotein
to 9q31-q32: a locus for Goltz syndrome in region 9q32-qter?. Hum.
Genet. 82: 17-19, 1989.

*FIELD* CS

Heme:
   Hemolytic anemia

Lab:
   Red cell adenylate kinase deficiency

Inheritance:
   Autosomal dominant;
   anemia recessive

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 8/30/1994
mimadm: 3/11/1994
carol: 5/12/1993
supermim: 3/16/1992
carol: 1/27/1992
carol: 10/3/1991

*RECORD*
*FIELD* NO
103020
*FIELD* TI
*103020 ADENYLATE KINASE-2; AK2
ADENYLATE KINASE, MITOCHONDRIAL
*FIELD* TX
The existence of a second adenylate kinase (EC 2.7.4.3) locus linked to
PGM1 and peptidase C, i.e., on chromosome 1, was suggested by cell
hybridization studies by Van Cong et al. (1972). The Goss-Harris method
of mapping combines features of recombinational study in families and
synteny tests in hybrid cells. As applied to chromosome 1, the method
shows that AK2 and UMPK are distal to PGM1 and that the order of the
loci is PGM1: UMPK: (AK2, alpha-FUC): ENO1 (Goss and Harris, 1977).
Carritt et al. (1982) presented evidence that AK2 is in 1p34.

*FIELD* SA
Bruns and Regina (1977)
*FIELD* RF
1. Bruns, G. A. P.; Regina, V. M.: Adenylate kinase-2, a mitochondrial
enzyme. Biochem. Genet. 15: 477-486, 1977.

2. Carritt, B.; King, J.; Welch, H. M.: Gene order and localization
of enzyme loci on the short arm of chromosome 1. Ann. Hum. Genet. 46:
329-335, 1982.

3. Goss, S. J.; Harris, H.: Gene transfer by means of cell fusion.
II. The mapping of 8 loci on human chromosome 1 by statistical analysis
of gene assortment in somatic cell hybrids. J. Cell Sci. 25: 39-57,
1977.

4. Van Cong, N.; Billardon, C.; Rebourcet, R.; Kaouel, C. L.-B.; Picard,
J. Y.; Weil, D.; Frezal, J.: The existence of a second adenylate
kinase locus linked to PGM-1 and peptidase-C. Ann. Genet. 15: 213-218,
1972.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987
marie: 1/7/1987

*RECORD*
*FIELD* NO
103030
*FIELD* TI
*103030 ADENYLATE KINASE-3; AK3
ADENYLATE KINASE, MITOCHONDRIAL
*FIELD* TX
The adenylate kinases are a family of structurally and functionally
related enzymes that catalyze a similar reaction, MgNTP + AMP = MgNDP +
ADP (N = A or G). The AK enzymes are important for maintenance of
homeostasis of the adenine and guanine nucleotide pools. AK1 (103000) is
a cytosolic enzyme for which ATP is the substrate. AK2 (103020)
catalyzes the same reaction as AK1, but it is localized in the
mitochondrial intermembrane space. AK3 is present in the mitochondrial
matrix and prefers GTP over ATP as the substrate. Wilson et al. (1976)
pointed out that AK3 is nucleosidetriphosphate-adenylate kinase. In the
course of their efforts to identify the gene causing neurofibromatosis
(NF1; 162200), Viskochil et al. (1990) found a gene first designated
HB15, which Xu et al. (1992) subsequently concluded is probably a
processed pseudogene of AK3. It is intronless and contains a
polyadenylate tract, but retains coding potential because the open
reading frame was not impaired by any observed base substitutions. One
presumed processed pseudogene of AK3 is located within an intron of the
NF1 gene. Xu et al. (1992) also characterized cDNA clones for the
authentic AK3.

By study of somatic cell hybrids, Povey et al. (1976) assigned AK3 to
chromosome 9. The SRO (smallest region of overlap) for AK3 was estimated
to be 9p24-p13 (Robson and Meera Khan, 1982).

By interspecific backcross linkage analysis, Pilz et al. (1995) mapped
the Ak3 gene to mouse chromosome 4.

*FIELD* SA
Cook et al. (1976); Mohandas et al. (1979); Steinbach and Benz (1983)
*FIELD* RF
1. Cook, P. J. L.; Buckton, K. E.; Spowart, G.: Family studies on
chromosome 9. Cytogenet. Cell Genet. 16: 284-288, 1976.

2. Mohandas, T.; Sparkes, R. S.; Sparkes, M. C.; Shulkin, J. D.; Toomey,
K. E.; Funderburk, S. J.: Regional localization of human gene loci
on chromosome 9: studies of somatic cell hybrids containing human
translocation. Am. J. Hum. Genet. 31: 586-600, 1979.

3. Pilz, A.; Woodward, K.; Povey, S.; Abbott, C.: Comparative mapping
of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25:
139-149, 1995.

4. Povey, S.; Slaughter, C. A.; Wilson, D. E.; Gormley, I. P.; Buckton,
K. E.; Perry, P.; Bobrow, M.: Evidence for the assignment of the
loci AK 1, AK 3 and ACON to chromosome 9 in man. Ann. Hum. Genet. 39:
413-422, 1976.

5. Robson, E. B.; Meera Khan, P.: Report of the committee on the
genetic constitution of chromosomes 7, 8, and 9. Cytogenet. Cell
Genet. 32: 144-152, 1982.

6. Steinbach, P.; Benz, R.: Demonstration of gene dosage effects
for AK3 and GALT in fibroblasts from a fetus with 9p trisomy. Hum.
Genet. 63: 290-291, 1983.

7. Viskochil, D.; Buchberg, A. M.; Xu, G.; Cawthon, R. M.; Stevens,
J.; Wolff, R. K.; Culver, M.; Carey, J. C.; Copeland, N. G.; Jenkins,
N. A.; White, R.; O'Connell, P.: Deletions and a translocation interrupt
a cloned gene at the neurofibromatosis type 1 locus. Cell 62: 187-192,
1990.

8. Wilson, D. E., Jr.; Povey, S.; Harris, H.: Adenylate kinases in
man: evidence for a third locus. Ann. Hum. Genet. 39: 305-313,
1976.

9. Xu, G.; O'Connell, P.; Stevens, J.; White, R.: Characterization
of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene
to an intron of the NF1 gene. Genomics 13: 537-542, 1992.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/7/1995
jason: 6/28/1994
carol: 8/11/1992
carol: 6/29/1992
supermim: 3/16/1992
carol: 2/29/1992

*RECORD*
*FIELD* NO
103050
*FIELD* TI
*103050 ADENYLOSUCCINATE LYASE; ADSL
ADENYLOSUCCINASE
ADENYLOSUCCINASE DEFICIENCY, INCLUDED;;
SUCCINYLPURINEMIC AUTISM, INCLUDED
*FIELD* TX
Van Keuren et al. (1986, 1987) used the strategy of somatic cell
hybridization of human cells with Chinese hamster ovary (CHO-K1) mutants
deficient in specific steps of the purine biosynthesis pathway to map
the human gene correcting deficiency of the enzyme adenylosuccinase (EC
4.3.2.2). This CHO-K1 mutant has been designated ade(-)I.
Adenylosuccinase carries out two independent but similar steps of purine
biosynthesis: the removal of a fumarate from succinylaminoimidazole
carboxamide (SAICA) ribotide to give aminoimidazole carboxamide ribotide
and removal of fumarate from adenylosuccinate to give AMP. These are the
ninth and the thirteenth steps of adenylate biosynthesis. Ade(-)I cells
require exogenous adenine for growth. Cell hybrids made by fusing
ade(-)I in human cell lines were selected for purine prototrophy in
adenine-free medium. Human chromosome 22 was found to be required for
growth without adenine. Assignment of the gene for adenylosuccinase to
chromosome 22 was confirmed by Southern blot analysis with a DNA probe
that had been isolated from a human fetal brain library and previously
mapped to chromosome 22. By Southern blotting techniques using somatic
cell hybrids, Budarf et al. (1991) demonstrated that ADSL maps to
22q13.1, distal to the Ewing sarcoma breakpoint (133450). Using both a
somatic cell hybrid mapping panel and fluorescence in situ
hybridization, Fon et al. (1993) localized the ADSL gene to
22q13.1-q13.2.

Homozygosity for mutations in the adenylosuccinase gene results in a
clinical disorder called succinylpurinemic autism. In 3 children with
severe psychomotor delay and autism, Jaeken and Van den Berghe (1984)
found succinyladenosine and succinylaminoimidazole carboxamide ribotide
in the body fluids. Concentrations of both compounds were about 100
micromol/l in CSF, between 5 and 10 micromol/l in plasma, and in the
millimol/l range in urine. Normally these compounds are not found in
blood and CSF but may be detected in trace amounts in urine. The
compounds are dephosphorylated derivatives of the intracellular
metabolites adenylosuccinate and succinylaminoimidazole carboxamide
ribotide, the 2 substrates of adenylosuccinase (adenylosuccinate lyase).
This enzyme is involved in both de novo synthesis of purines and
formation of adenosine monophosphate from inosine monophosphate. Assays
of the enzyme in 1 patient showed marked reduction of activity in liver
and absence of activity in the kidney. Two of the 3 affected children
were brother and sister, offspring of related Moroccan parents. (At one
point the authors stated that the parents were related; at another they
stated that the boy's 'grandparents were first cousins.' Does this mean
that the parents were second cousins?) The authors suggested that
adenylosuccinase deficiency is a specific autosomal recessive cause of
autism. (Stone et al. (1992) demonstrated a point mutation in the ADSL
gene in the 2 Moroccan sibs; see 103050.0001.) Jaeken et al. (1988)
presented clinical and biochemical data on 8 children with
adenylosuccinase deficiency. Seven of the 8 children showed severe
psychomotor retardation. Epilepsy was documented in 5, autistic features
in 3, and growth retardation associated with muscular wasting in a
brother and sister. One female patient was strikingly less retarded
mentally and had only mild psychomotor retardation. In this patient the
ratio of the 2 metabolites in body fluids was quite different from that
in the severely retarded patients, showing an approximately 5-fold
excess of succinyladenosine. In addition, adenylosuccinase activity in
fibroblasts was only about 6% of normal, whereas it was about 40% of
normal in 6 severely retarded patients. At least 2 of the patients from
separate families were the offspring of consanguineous parents. Maddocks
and Reed (1989) described a seemingly sensitive and specific test for
succinyladenosine in the urine. Jaeken et al. (1992) described a patient
with an intermediate severity. Chemical findings in the patient
supported the impression that there is an inverse relationship between
the degree of clinical involvement and the excess of succinyladenosine
over SAICA riboside. Jaeken et al. (1992) concluded that SAICA riboside
may be the offending compound that interferes with neurofunction and
that succinyladenosine may protect against its effects. For purposes of
screening, they suggested that a modified Bratton-Marshall test,
originally designed as an assay for sulfonamides, is the most practical
method, provided the patients are not receiving sulfonamides.

Wong and O'Brien (1995) found that the cDNA of human and mouse ADSL has
94 and 87% identity at the amino acid and nucleotide levels,
respectively. (Adenylosuccinate lyase catalyzes 2 similar reactions in
the de novo purine biosynthetic pathway, both of which are cleavages
that produce fumarate as one of the products.) The gene in the mouse is
about 27 kb and contains 13 exons. Comparison of the exon/intron
structure of this gene with the argininosuccinate lyase gene (ASL;
207900) did not suggest gene duplication or exon shuffling as a
mechanism of evolution in the fumarate gene family.

*FIELD* AV
.0001
SUCCINYLPURINEMIC AUTISM
ADSL, SER413PRO
In the 2 Moroccan sibs originally reported by Jaeken and Van den Berghe
(1984), Stone et al. (1992) demonstrated a ser413-to-pro substitution
that led to structural instability of the mutant enzyme.

*FIELD* RF
1. Budarf, M. L.; Emanuel, B. S.; Collins, J.; Fibison, W.; Barshop,
B. A.: Isolation and regional localization of the human adenylosuccinate
lyase gene. (Abstract) Cytogenet. Cell Genet. 58: 2046 only, 1991.

2. Fon, E. A.; Demczuk, S.; Delattre, O.; Thomas, G.; Rouleau, G.
A.: Mapping of the human adenylosuccinate lyase (ADSL) gene to chromosome
22q13.1-q13.2. Cytogenet. Cell Genet. 64: 201-203, 1993.

3. Jaeken, J.; Van den Bergh, F.; Vincent, M. F.; Casaer, P.; Van
den Berghe, G.: Adenylosuccinase deficiency: a newly recognized variant. J.
Inherit. Metab. Dis. 15: 416-418, 1992.

4. Jaeken, J.; Van den Berghe, G.: An infantile autistic syndrome
characterised by the presence of succinylpurines in body fluids. Lancet II:
1058-1061, 1984.

5. Jaeken, J.; Wadman, S. K.; Duran, M.; van Sprang, F. J.; Beemer,
F. A.; Holl, R. A.; Theunissen, P. M.; de Cock, P.; van den Bergh,
F.; Vincent, M. F.; van den Berghe, G.: Adenylosuccinase deficiency:
an inborn error of purine nucleotide synthesis. Europ. J. Pediat. 148:
126-131, 1988.

6. Maddocks, J.; Reed, T.: Urine test for adenylosuccinase deficiency
in autistic children. (Letter) Lancet I: 158-159, 1989.

7. Stone, R. L.; Aimi, J.; Barshop, B. A.; Jaeken, J.; Van den Berghe,
G.; Zalkin, H.; Dixon, J. E.: A mutation in adenylosuccinate lyase
associated with mental retardation and autistic features. Nature
Genet. 1: 59-63, 1992.

8. Van Keuren, M. L.; Hart, I.; Kao, F.-T.; Neve, R. L.; Bruns, G.
A. P.; Kurnit, D. M.; Patterson, D.: Human chromosome 22 corrects
the defect in the CHO mutant (Ade-I) lacking adenylosuccinase activity.
(Abstract) Am. J. Hum. Genet. 39: A172 only, 1986.

9. Van Keuren, M. L.; Hart, I. M.; Kao, F.-T.; Neve, R. L.; Bruns,
G. A. P.; Kurnit, D. M.; Patterson, D.: A somatic cell hybrid with
a single human chromosome 22 corrects the defect in the CHO mutant
(Ade-I) lacking adenylosuccinase activity. Cytogenet. Cell Genet. 44:
142-147, 1987.

10. Wong, L.-J. C.; O'Brien, W. E.: Characterization of the cDNA
and the gene encoding murine adenylosuccinate lyase. Genomics 28:
341-343, 1995.

*FIELD* CS

Neuro:
   Autism;
   Severe psychomotor delay;
   Seizures

Growth:
   Growth retardation

Muscle:
   Muscular wasting

Lab:
   High succinyladenosine and succinylaminoimidazole carboxamide ribotide
   in body fluids;
   Adenylosuccinase deficiency

Inheritance:
   Autosomal recessive (22q13.1)

*FIELD* CD
Victor A. McKusick: 12/15/1986

*FIELD* ED
terry: 02/11/1997
mark: 8/25/1995
mimadm: 3/11/1994
carol: 11/3/1993
carol: 3/25/1993
carol: 11/5/1992
carol: 9/29/1992

*RECORD*
*FIELD* NO
103060
*FIELD* TI
*103060 ADENYLOSUCCINATE SYNTHETASE; ADSS
Ade(-)H, COMPLEMENT OF; ADEH
*FIELD* TX
Somatic cell hybrids between human cells and Chinese hamster ovary cells
deficient in specific steps in the purine biosynthetic pathway permitted
mapping of human genes correcting the defects. The ade(-)H mutant is
missing the enzyme adenylosuccinate synthetase (IMP:L-aspartate ligase;
EC 6.3.4.4.), which carries out the first of a 2-step sequence in the
biosynthesis of AMP from IMP. Thus, ade(-)H cells require exogenous
adenine for growth. Lai et al. (1989) found that in somatic cell hybrids
human chromosome 1 corrected the defect so that the hybrid cell
containing chromosome 1 grew without adenine. Lai et al. (1991) reported
that analysis of a human/CHO translocation chromosome that arose in 1 of
the hybrids suggested that the gene correcting the defect lies in the
region 1cen-q12. (See their Figure 1 for a useful diagram of the purine
biosynthesis pathway and the purine nucleotide cycle pathway, together
with the location of the genes for the enzymes when known.) AMP
deaminase, which converts AMP back to IMP, is coded by a gene, perhaps 2
genes, in region 1p21-p13; see 102770.

From a human liver library, Powell et al. (1992) isolated a cDNA that
encoded a protein of 455 amino acids. Alignment with the sequence of the
ADSS gene in mouse, Dictyostelium discoideum, and E. coli pointed to
invariant residues that are likely to be important for structure and/or
catalysis. The human ADSS sequence also showed some similarity to
argininosuccinate synthetase, which catalyzes a chemically similar
reaction.

*FIELD* RF
1. Lai, L.; Hart, I.; Patterson, D.: Human chromosome 1 corrects
the defect in the CHO mutant (Ade-H) deficient in a branch point enzyme
in purine de novo biosynthesis.  (Abstract) Cytogenet. Cell Genet. 51:
1028 only, 1989.

2. Lai, L.-W.; Hart, I. M.; Patterson, D.: A gene correcting the
defect in the CHO mutant Ade(-)H, deficient in a branch point enzyme
(adenylosuccinate synthetase) of de novo purine biosynthesis, is located
on the long arm of chromosome 1. Genomics 9: 322-328, 1991.

3. Powell, S. M.; Zalkin, H.; Dixon, J. E.: Cloning and characterization
of the cDNA encoding human adenylosuccinate synthetase. FEBS Lett. 303:
4-10, 1992.

*FIELD* CD
Victor A. McKusick: 6/1/1989

*FIELD* ED
carol: 8/17/1992
supermim: 3/16/1992
carol: 2/5/1992
carol: 1/15/1991
supermim: 3/20/1990
ddp: 10/27/1989

*RECORD*
*FIELD* NO
103070
*FIELD* TI
*103070 ADENYLYL CYCLASE, BRAIN, TYPE I
ADENYLATE CYCLASE 8; ADCY8;;
ADENYLATE CYCLASE 3, FORMERLY; ADCY3, FORMERLY
*FIELD* TX
Adenylyl cyclase (EC 4.6.1.1) catalyzes the transformation of ATP into
cyclic AMP. The enzymatic activity is under the control of several
hormones, and different polypeptides participate in the transduction of
the signal from the receptor to the catalytic moiety. Stimulatory or
inhibitory receptors (Rs and Ri) interact with G proteins (Gs and Gi)
that exhibit GTPase activity and they modulate the activity of the
catalytic subunit of the adenylyl cyclase. Parma et al. (1991) cloned a
cDNA corresponding to human brain adenylyl cyclase, symbolized by them
as HBAC1. By in situ hybridization to metaphase chromosomal spreads
using the human brain cDNA probe, Stengel et al. (1992) showed that the
gene is located on 8q24.2. A highly homologous gene, ADCY2 (103071), was
assigned to 5p15.3 by the same method.

*FIELD* RF
1. Parma, J.; Stengel, D.; Gannage, M.-H.; Poyard, M.; Barouki, R.;
Hanoune, J.: Sequence of a human brain adenylyl cyclase partial cDNA:
evidence for a consensus cyclase domain. Biochem. Biophys. Res.
Commun. 179: 455-462, 1991.

2. Stengel, D.; Parma, J.; Gannage, M.-H.; Roeckel, N.; Mattei, M.-G.;
Barouki, R.; Hanoune, J.: Different chromosomal localization of two
adenylyl cyclase genes expressed in human brain. Hum. Genet. 90:
126-130, 1992.

*FIELD* CD
Victor A. McKusick: 12/4/1992

*FIELD* ED
carol: 9/19/1994
carol: 5/27/1993
carol: 5/26/1993
carol: 1/12/1993
carol: 12/30/1992
carol: 12/4/1992

*RECORD*
*FIELD* NO
103071
*FIELD* TI
*103071 ADENYLYL CYCLASE, BRAIN, TYPE II
ADENYLATE CYCLASE 2; ADCY2
*FIELD* TX
Stengel et al. (1992) identified a brain cDNA corresponding to a gene
that encodes a human brain adenylyl cyclase, which they symbolized
HBAC2. The amino acid sequence of ADCY2 displayed significant homology
with ADCY8 (103070) in the highly conserved adenylyl cyclase domain (250
amino acids) found in the 3-prime cytoplasmic portion of all mammalian
adenylyl cyclases. However, outside this domain, the homology was
extremely low. By in situ hybridization to metaphase chromosomal spreads
using a human brain cDNA probe, they demonstrated that the ADCY2 gene
maps to 5p15.3. There was no cross-reactivity with the site on 8q24.2
where ADCY8 was found to map. Using Southern blot analysis of somatic
cell hybrid DNAs, Gaudin et al. (1994) likewise mapped type II adenylyl
cyclase to chromosome 5. Furthermore, they determined the chromosomal
location of 4 other isoforms: type III on chromosome 2, type IV on
chromosome 14, type V on chromosome 3, and type VI on chromosome 12. By
fluorescence in situ hybridization, Edelhoff et al. (1995) mapped the
mouse homolog to chromosome 13 in the C1 region.

*FIELD* RF
1. Edelhoff, S.; Villacres, E. C.; Storm, D. R.; Disteche, C. M.:
Mapping of adenylyl cyclase genes type I, II, III, IV, V, and VI in
mouse. Mammalian Genome 6: 111-113, 1995.

2. Gaudin, C.; Homcy, C. J.; Ishikawa, Y.: Mammalian adenylyl cyclase
family members are randomly located on different chromosomes. Hum.
Genet. 94: 527-529, 1994.

3. Stengel, D.; Parma, J.; Gannage, M.-H.; Roeckel, N.; Mattei, M.-G.;
Barouki, R.; Hanoune, J.: Different chromosomal localization of two
adenylyl cyclase genes expressed in human brain. Hum. Genet. 90:
126-130, 1992.

*FIELD* CD
Victor A. McKusick: 12/4/1992

*FIELD* ED
mark: 4/10/1995
terry: 1/9/1995
carol: 9/19/1994
carol: 5/27/1993
carol: 1/12/1993
carol: 12/4/1992

*RECORD*
*FIELD* NO
103072
*FIELD* TI
*103072 ADENYLYL CYCLASE, FETAL BRAIN, TYPE I
ADENYLATE CYCLASE 1; ADCY1
*FIELD* TX
The neural-specific, calmodulin-sensitive adenylyl cyclase (type I),
which was first cloned from bovine brain, has been implicated in
learning and memory. Villacres et al. (1993) cloned the gene for human
fetal brain type I adenylyl cyclase and showed by in situ hybridization
that the gene lies in the region 7p13-p12. See 103070 and 103071 for
genes encoding other forms of brain adenylyl cyclase. Gaudin et al.
(1994) likewise mapped the ADCY1 gene to chromosome 7 by Southern blot
analysis of somatic cell hybrid DNAs. By fluorescence in situ
hybridization, Edelhoff et al. (1995) mapped the mouse homolog to
chromosome 11 in the A2 region.

*FIELD* RF
1. Edelhoff, S.; Villacres, E. C.; Storm, D. R.; Disteche, C. M.:
Mapping of adenylyl cyclase genes type I, II, III, IV, V, and VI in
mouse. Mammalian Genome 6: 111-113, 1995.

2. Gaudin, C.; Homcy, C. J.; Ishikawa, Y.: Mammalian adenylyl cyclase
family members are randomly located on different chromosomes. Hum.
Genet. 94: 527-529, 1994.

3. Villacres, E. C.; Xia, Z.; Bookbinder, L. H.; Edelhoff, S.; Disteche,
C. M.; Storm, D. R.: Cloning, chromosomal mapping, and expression
of human fetal brain type I adenylyl cyclase. Genomics 16: 473-478,
1993.

*FIELD* CD
Victor A. McKusick: 5/26/1993

*FIELD* ED
mark: 4/10/1995
carol: 1/9/1995
carol: 5/27/1993
carol: 5/26/1993

*RECORD*
*FIELD* NO
103100
*FIELD* TI
103100 ADIE SYNDROME
*FIELD* TX
This is a stationary, harmless disorder characterized by tonic,
sluggishly reacting pupil and hypoactive or absent tendon reflexes. De
Rudolf (1936) described it in mother and daughter, McKinney and Frocht
(1940) in father and son, and Mylius (1938) in sibs. The pupil (Laties
and Scheie, 1965) is excessively sensitive to mecholyl (methacholine).
In familial dysautonomia, a recessive (q.v.), the pupil is also
mecholyl-sensitive and tendon reflexes are absent. It would be of
interest to determine whether the reflexes return with parenteral
administration of mecholyl as occurs in dysautonomia. An autopsied case
was reported by Harriman and Garland (1968), who found neuronal
degeneration in the ciliary ganglion. Selective degeneration of neurons
in dorsal root ganglia may have been the basis for areflexia. Miyasaki
et al. (1988) concluded from electrophysiologic studies carried out in
11 patients with Adie syndrome that the hyporeflexia in this condition
is due to the loss of large spindle afferents or the reduced
effectiveness of their monosynaptic connections to motoneurons.

*FIELD* SA
Adie  (1932)
*FIELD* RF
1. Adie, W. J.: Tonic pupils and absent tendon reflexes: a benign
disorder sui generis: its complete and incomplete forms. Brain 55:
98-113, 1932.

2. De Rudolf, G.: Tonic pupils with absent tendon reflexes in mother
and daughter. J. Neurol. Neurosurg. Psychiat. 16: 367-368, 1936.

3. Harriman, D. G. F.; Garland, H.: The pathology of Adie's syndrome.
Brain 91: 401-418, 1968.

4. Laties, A. M.; Scheie, H. G.: Adie's syndrome: duration of methacholine
sensitivity. Arch. Ophthal. 74: 458-459, 1965.

5. McKinney, J. M.; Frocht, M.: Adie's syndrome: a non-luetic disease
simulating tabes dorsalis. Am. J. Med. Sci. 199: 546-555, 1940.

6. Miyasaki, J. M.; Ashby, P.; Sharpe, J. A.; Fletcher, W. A.: On
the cause of hyporeflexia in the Holmes-Adie syndrome. Neurology 38:
262-265, 1988.

7. Mylius, (NI): Ueber familiaeres Vorkommen der Pupillotonie. Klin.
Mbl. Augenheilk. 101: 598-599, 1938.

*FIELD* CS

Eyes:
   Sluggish pupillary response;
   Mecholyl-sensitive pupil

Neuro:
   Hyporeflexia

Misc:
   Stationary, harmless disorder

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/1/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 6/7/1988

*RECORD*
*FIELD* NO
103180
*FIELD* TI
*103180 ADP-RIBOSYLATION FACTOR-1; ARF1
*FIELD* TX
ADP-ribosylation factors (ARFs), small guanine nucleotide-binding
proteins that enhance the enzymatic activities of cholera toxin,
constitute 1 family of the RAS superfamily. Monomeric guanine
nucleotide-binding proteins of the RAS superfamily function in a variety
of cellular processes including signaling, growth, immunity, and protein
transport. ARFs are essential and ubiquitous in eukaryotes, being
involved in vesicular transport and functioning as an activator of
phospholipase D. The functions of ARF proteins in membrane traffic and
organelle integrity are intimately tied to its reversible association
with membranes and specific interactions with membrane phospholipids. A
common feature of these functions is their regulation by the binding and
hydrolysis of GTP. Amor et al. (1994) described the 3-dimensional
structure of full-length human ARF1 in its GDP-bound nonmyristoylated
form.

Bobak et al. (1989) cloned 2 ARF cDNAs, ARF1 and ARF3 (103190), from a
human cerebellum library. Based on deduced amino acid sequences and
patterns of hybridization of cDNA and oligonucleotide probes with
mammalian brain poly(a)+ RNA, human ARF1 is the homolog of bovine ARF1.
Human ARF3, however, appeared to represent a newly identified, third
type of ARF, which differs from bovine ARF1 and bovine ARF2. Peng et al.
(1989) also reported cloning of ADP-ribosylation factor.

Lee et al. (1992) found that the human ARF-1 is identical to its bovine
counterpart, has a distinctive pattern of tissue and developmental
expression, and is encoded by an mRNA of approximately 1.9 kb. With 4
introns, the human ARF1 gene spans approximately 16.5 kb. Exon 1 (46 bp)
contains only untranslated sequence. The 5-prime-flanking region has a
high GC content but no TATA or CAAT box, as found in housekeeping genes.
The authors stated that the 2 human class I ARF genes, ARF1 and ARF3,
have similar exon/intron organizations and use GC-rich promoters.

Hirai et al. (1996) obtained an expressed sequence tag (EST) containing
the ARF1 gene and used fluorescence in situ hybridization to assign ARF1
to 1q42.

*FIELD* RF
1. Amor, J. C.; Harrison, D. H.; Kahn, R. A.; Ringe, D.: Structure
of the human ADP-ribosylation factor 1 complexed with GDP. Nature 372:
704-708, 1994.

2. Bobak, D. A.; Nightingale, M. S.; Murtagh, J. J.; Price, S. R.;
Moss, J.; Vaughan, M.: Molecular cloning, characterization, and expression
of human ADP-ribosylation factors: two guanine nucleotide-dependent
activators of cholera toxin. Proc. Nat. Acad. Sci. 86: 6101-6105,
1989.

3. Hirai, M.; Kusuda, J.; Hashimoto, K.: Assignment of human ADP
ribosylation factor (ARF) genes ARF1 and ARF3 to chromosomes 1q42
and 12q13, respectively. Genomics 34: 263-265, 1996.

4. Lee, C.-M.; Haun, R. S.; Tsai, S.-C.; Moss, J.; Vaughan, M.: Characterization
of the human gene encoding ADP-ribosylation factor 1, a guanine nucleotide-binding
activator of cholera toxin. J. Biol. Chem. 267: 9028-9034, 1992.

5. Peng, Z. G.; Calvert, I.; Clark, J.; Helman, L.; Kahn, R.; Kung,
H. F.: Molecular cloning, sequence analysis and mRNA expression of
human ADP-ribosylation factor. Biofactors 2: 45-49, 1989.

*FIELD* CN
Lori M. Kelman - updated: 8/22/1996

*FIELD* CD
Victor A. McKusick: 9/26/1989

*FIELD* ED
joanna: 04/10/1997
mark: 8/22/1996
terry: 8/22/1996
mark: 8/21/1996
mark: 1/5/1996
terry: 1/3/1996
terry: 1/6/1995
carol: 9/23/1994
supermim: 3/16/1992
carol: 7/5/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
103188
*FIELD* TI
*103188 ADP-RIBOSYLATION FACTOR-5; ARF5
*FIELD* TX
ADP-ribosylation factors (ARFs) are guanine nucleotide-binding proteins,
approximately 20 kD in size, that serve as GTP-dependent allosteric
activators of cholera toxin ADP-ribosyltransferase activity. To the 4
species of mammalian ARF, termed ARF1-4, previously identified by
cloning, Tsuchiya et al. (1991) added new ARF-like genes, ARF5 and 6
(600464), encoding proteins of 180 and 175 amino acids, respectively.
Both proteins contain consensus sequences believed to be involved in
guanine nucleotide binding and GTP hydrolysis. ARF5 was more similar in
deduced amino acid sequence to ARF4, which also has 180 amino acids.

*FIELD* RF
1. Tsuchiya, M.; Price, S. R.; Tsai, S.-C.; Moss, J.; Vaughan, M.
: Molecular identification of ADP-ribosylation factor mRNAs and their
expression in mammalian cells. J. Biol. Chem. 266: 2772-2777, 1991.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
mark: 3/23/1995
jason: 6/17/1994

*RECORD*
*FIELD* NO
103190
*FIELD* TI
*103190 ADP-RIBOSYLATION FACTOR-3; ARF3
*FIELD* TX
See 103180.

*FIELD* CD
Victor A. McKusick: 9/26/1989
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/9/1989
root: 9/26/1989
*RECORD*
*FIELD* NO
103195
*FIELD* TI
*103195 ADIPOSE DIFFERENTIATION-RELATED PROTEIN; ADRP
*FIELD* TX
Adipose differentiation-related protein is a novel 50-kD
membrane-associated protein whose mRNA levels are induced rapidly and
maximally after triggering adipocyte differentiation. Eisinger and
Serrero (1993) isolated and characterized the mouse gene, which spans 14
kb and contains 8 exons and 7 introns. It maps to mouse chromosome 4.

*FIELD* RF
1. Eisinger, D. P.; Serrero, G.: Structure of the gene encoding mouse
adipose differentiation-related protein (ADRP). Genomics 16: 638-644,
1993.

*FIELD* CD
Victor A. McKusick: 6/24/1993

*FIELD* ED
carol: 1/14/1994
carol: 6/24/1993

*RECORD*
*FIELD* NO
103200
*FIELD* TI
103200 ADIPOSIS DOLOROSA
DERCUM DISEASE
*FIELD* TX
This disorder, which was first described by Dercum (1892), is
characterized by painful subcutaneous lipomas in a background of
obesity. It is about 5 times more frequent in females than in males.
Onset of symptoms is generally in middle age. The fatty tumors are most
often located on the trunk and limbs with sparing of the face and hands.
Severe asthenia has been emphasized as a feature by some (Wohl and
Pastor, 1938). Lynch and Harlan (1963) observed the disease in 4 members
of 3 generations of 1 family and in 2, possibly 4, persons in 2
generations of a second family.

*FIELD* SA
Cantu et al. (1973)
*FIELD* RF
1. Cantu, J. M.; Ruiz-Barquin, E.; Jimenez, M.; Castillo, L.; Macotela-Ruiz,
E.: Autosomal dominant inheritance in adiposis dolorosa (Dercum's
disease). Humangenetik 18: 89-91, 1973.

2. Dercum, F. X.: Three cases of a hitherto unclassified affection
resembling in its grosser aspects obesity, but associated with special
nervous symptoms: adiposis dolorosa. Am. J. Med. Sci. 104: 521-535,
1892.

3. Lynch, H. T.; Harlan, W. L.: Hereditary factors in adiposis dolorosa
(Dercum's disease). Am. J. Hum. Genet. 15: 184-190, 1963.

4. Wohl, M. G.; Pastor, N.: Adipositas dolorosa (Dercum's disease).
J.A.M.A. 110: 1261-1264, 1938.

*FIELD* CS

Skin:
   Painful trunk and limb subcutaneous lipomas

Growth:
   Obesity

Misc:
Female to male ratio 5:1;
   Middle age onset

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 10/8/1991
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
103220
*FIELD* TI
*103220 ADENINE NUCLEOTIDE TRANSLOCATOR 1; ANT1
ADP/ATP TRANSLOCATOR OF SKELETAL MUSCLE;;
ANT;;
ADP/ATP TRANSLOCASE 1
*FIELD* TX
The ADP/ATP translocator, or adenine nucleotide translocator (ANT), is
the most abundant mitochondrial protein. In its functional state, it is
a homodimer of 30-kD subunits embedded asymmetrically in the inner
mitochondrial membrane. The dimer forms a gated pore through which ADP
is moved from the matrix into the cytoplasm. Neckelmann et al. (1987)
characterized a 1,400-nucleotide cDNA for human skeletal muscle ANT.
They compared the sequence with that of the human fibroblast ANT cognate
as reported by Battini et al. (1987). This showed that the 2 distinct
ANTs diverged about 275 million years ago. The skeletal muscle ANT is
expressed in heart, kidney, liver, skeletal muscle, and HeLa cells. The
rate of evolution of the skeletal muscle ANT is 10 to 12 times slower
than that of the mitochondrial Ox/Phos genes. Mitochondrial energy
production varies greatly among human tissues. Because the ANT
determines the rate of ADP/ATP flux between the mitochondrion and the
cytosol, it is a logical candidate for regulator of cellular dependence
on oxidative energy metabolism. Li et al. (1989) reported on the cloning
and differential expression of the human ANT1 locus. The gene is 5.8 kb
long and contains 4 exons and 3 introns. The mRNA is 1.4 kb and most
abundant in heart and skeletal muscle, but barely detectable in liver,
kidney, or brain. A second full-length ANT cDNA, ANT2 (300150), derived
from fibroblasts is present in all of the above-mentioned tissues at
relatively constant levels. A third cDNA, ANT3 (300151), has been cloned
from human liver (Houldsworth and Attardi, 1988). ANT1, ANT2 and ANT3
are approximately 90% homologous at the amino acid level.

Minoshima et al. (1989) used hybridization to flow-sorted human
chromosomes and Southern blot hybridization to mouse/human somatic cell
hybrids to demonstrate that the ANT1 gene localizes to human chromosome
4. See Li et al. (1989). Fan et al. (1992) regionalized the ANT1 gene to
4q35 by fluorescence in situ hybridization. Haraguchi et al. (1993)
mapped the ANT1 gene to 4q35-qter using somatic cell hybrids containing
various deletions of chromosome 4. The regional location was further
refined through family studies using ANT1 intron and promoter nucleotide
polymorphisms recognized by 3 different restriction endonucleases.
Family studies suggested that ANT1 is located centromeric to D4S139
which in turn is centromeric to the locus for facioscapulohumeral
muscular dystrophy (FSHD; 158900). Wijmenga et al. (1993) likewise
mapped the ANT1 gene to 4q35 to a site proximal to the FSHD gene.
Studies using a polymorphic CA-repeat 5 kb upstream of the ANT1 gene as
a marker in FSHD and CEPH families suggested that the ANT1 gene is
centromeric to FSHD and is separated from it by several markers,
including the factor XI gene (264900).

Mills et al. (1996) demonstrated that the murine homolog Ant1 is located
on chromosome 8 by studies of an interspecific cross. The gene had been
previously localized to chromosome 8 by PCR of a somatic cell hybrid
mapping panel with primers from the cDNA sequence. Only a single
recombination event in 227 chromosomes was observed between Ant1 and the
plasma kalikrein gene Klk3 (229000) which in the human maps to 4q35 as
does also ANT1.

Bakker et al. (1993) described an 8-year-old boy who was first
investigated at the age of 3.5 years because of shortness of breath and
rapid fatigue. Lactate levels in serum and cerebrospinal fluid were
greatly elevated, and histochemical and electron-microscopic examination
of skeletal muscle suggested a mitochondrial myopathy. Great clinical
improvement was observed with the administration of vitamin E.

*FIELD* SA
Bakker et al. (1993); Li et al. (1989)
*FIELD* RF
1. Bakker, H. D.; Scholte, H. R.; Van den Bogert, C.; Jeneson, J.
A. L.; Ruitenbeek, W.; Wanders, R. J. A.; Abeling, N. G. G. M.; van
Gennip, A. H.: Adenine nucleotide translocator deficiency in muscle:
potential therapeutic value of vitamin E. J. Inherit. Metab. Dis. 16:
548-552, 1993.

2. Bakker, H. D.; Scholte, H. R.; Van den Bogert, C.; Ruitenbeek,
W.; Jeneson, J. A. L.; Wanders, R. J. A.; Abeling, N. G. G. M.; Dorland,
B.; Sengers, R. C. A.; van Gennip, A. H.: Deficiency of the adenine
nucleotide translocator in muscle of a patient with myopathy and lactic
acidosis: a new mitochondrial defect. Pediat. Res. 33: 412-417,
1993.

3. Battini, R.; Ferrari, S.; Kaczmarek, L.; Calabretta, B.; Chen,
S.; Baserga, R.: Molecular cloning of a cDNA for a human ADP/ATP
carrier which is growth-regulated. J. Biol. Chem. 262: 4355-4359,
1987.

4. Fan, Y.-S.; Yang, H.-M.; Lin, C. C.: Assignment of the human muscle
adenine nucleotide translocator gene (ANT1) to 4q35 by fluorescence
in situ hybridization. Cytogenet. Cell Genet. 60: 29-30, 1992.

5. Haraguchi, Y.; Chung, A. B.; Torroni, A.; Stepien, G.; Shoffner,
J. M.; Wasmuth, J. J.; Costigan, D. A.; Polak, M.; Altherr, M. R.;
Winokur, S. T.; Wallace, D. C.: Genetic mapping of human heart-skeletal
muscle adenine nucleotide translocator and its relationship to the
facioscapulohumeral muscular dystrophy locus. Genomics 16: 479-485,
1993.

6. Houldsworth, J.; Attardi, G.: Two distinct genes for ADP/ATP translocase
are expressed at the mRNA level in adult human liver. Proc. Nat.
Acad. Sci. 85: 377-381, 1988.

7. Li, K.; Warner, C. K.; Hodge, J. A.; Minoshima, S.; Kudoh, J.;
Fukuyama, R.; Maekawa, M.; Shimizu, Y.; Shimizu, N.; Wallace, D. C.
: A human muscle adenine nucleotide translocator gene has four exons,
is located on chromosome 4, and is differentially expressed. J. Biol.
Chem. 264: 13998-14004, 1989.

8. Li, K.; Warner, C. K.; Hodge, J. A.; Wallace, D. C.: Cloning and
tissue-differential expression of human heart-skeletal muscle adenine
nucleotide translocator gene. (Abstract) Cytogenet. Cell Genet. 51:
1032-1033, 1989.

9. Mills, K. A.; Ellison, J. W.; Mathews, K. D.: The Ant1 gene maps
near Klk3 on proximal mouse chromosome 8. Mammalian Genome 7: 707
only, 1996.

10. Minoshima, S.; Kudoh, J.; Fukuyama, R.; Maekawa, M.; Shimizu,
Y.; Li, K.; Wallace, D. C.; Shimizu, N.: Mapping of the human muscle
adenine nucleotide translocator gene (ANT1) to chromosome 4. (Abstract) Cytogenet.
Cell Genet. 51: 1044-1045, 1989.

11. Neckelmann, N.; Li, K.; Wade, R. P.; Shuster, R.; Wallace, D.
C.: cDNA sequence of a human skeletal muscle ADP/ATP translocator:
lack of a leader peptide, divergence from a fibroblast translocator
cDNA, and coevolution with mitochondrial DNA genes. Proc. Nat. Acad.
Sci. 84: 7580-7584, 1987.

12. Wijmenga, C.; Winokur, S. T.; Padberg, G. W.; Skraastad, M. I.;
Altherr, M. R.; Wasmuth, J. J.; Murray, J. C.; Hofker, M. H.; Frants,
R. R.: The human skeletal muscle adenine nucleotide translocator
gene maps to chromosome 4q35 in the region of the facioscapulohumeral
muscular dystrophy locus. Hum. Genet. 92: 198-203, 1993.

*FIELD* CD
Victor A. McKusick: 12/3/1987

*FIELD* ED
mark: 10/26/1996
terry: 10/17/1996
carol: 5/10/1994
carol: 10/26/1993
carol: 9/13/1993
carol: 5/26/1993
carol: 4/7/1993
carol: 1/26/1993

*RECORD*
*FIELD* NO
103230
*FIELD* TI
103230 ADRENOCORTICAL HYPOFUNCTION, CHRONIC PRIMARY CONGENITAL
ADDISON DISEASE, CONGENITAL
*FIELD* TX
Chuandi et al. (1985) reported a Chinese kindred in which persons in 3
generations, and by implication at least 1 person in a fourth earlier
generation, had chronic adrenal insufficiency. This was manifest by
hyperpigmentation, hypernatriuria, hypokaliuria, and decreased plasma
total cortisol and urine free cortisol; PTC, UFC and 17-OHCS did not
respond to ACTH stimulation. Eleven affected persons in 5 sibships were
identified, including several instances of male-to-male transmission.

*FIELD* RF
1. Chuandi, L.; Junqing, C.; Ruohua, S.; Ruqian, Z.; Guilin, Y.; Wei,
L.; Wenying, Y.; Qing, Z.; Guirong, L.; Heling, L.; Shiqin, D.: Addison's
disease of autosomal dominant inheritance: a report of 11 cases in
one family. Kexue Tongbao 30: 981-984, 1985.

*FIELD* CS

Endocrine:
   Chronic adrenal insufficiency

Skin:
   Hyperpigmentation

Lab:
   Hypernatriuria;
   Hypokaliuria;
   Decreased plasma total cortisol;
   Decreased urine free cortisol;
   No response of PTC, UFC and 17-OHCS to ACTH stimulation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/11/1988

*RECORD*
*FIELD* NO
103260
*FIELD* TI
*103260 ADRENODOXIN; ADX
FERREDOXIN 1, INCLUDED;;
FDX1, INCLUDED
*FIELD* TX
Ferredoxin is a small, acidic, iron-sulfur protein that functions as an
electron transport intermediate for mitochondrial cytochromes P450
involved in steroid, vitamin D, and bile acid metabolism. Electrons are
transferred from NADPH through a flavin-containing protein (ferredoxin
oxidoreductase) and ferredoxin to the terminal cytochrome P450 for
oxidation/reduction reactions. Mitochondrial P450s and their ferredoxin
are found mainly in the steroidogenic tissues, including adrenal, ovary,
testis, and placenta (Jefcoate et al., 1986). Small amounts of them are
also found in the liver and kidney for bile acid and vitamin D
synthesis. Because of its relative abundance, the adrenal ferredoxin,
designated adrenodoxin, has been characterized in the most detail. It is
synthesized as a precursor in which 60 amino acids of the signal peptide
are later cleaved upon transport into the mitochondrial inner matrix to
form a mature protein of 124 amino acids (Okamura et al., 1985). In
almost all human tissues, Morel et al. (1987, 1988) found ADX mRNA in 3
sizes: 1.1, 1.4, and 1.65 kb. Cloning and sequencing of 3 ADX cDNAs
showed that the mRNAs of various sizes resulted from alternate
polyadenylation sites yielding 3-prime untranslated regions of 229, 530,
and 790 bp, respectively. The 540-bp coding region and the 5-prime
untranslated region were identical in all cases. By means of Southern
blot analysis of DNA from somatic cell hybrids using stringent
conditions of hybridization, 2 chromosomal sites were identified for the
ADX gene: chromosomes 11 and 20. One sequence was suspected to represent
a processed, intronless pseudogene. Because of the restriction pattern,
Morel et al. (1987) suggested that the sequence on chromosome 20 is a
pseudogene. Chang et al. (1988) found that the ADX gene spans more than
20 kb and contains 4 exons and 3 introns. The first exon encodes the
60-amino acid signal peptide, which directs transport of the protein
into the inner mitochondrial matrix. The mature peptide of 124 amino
acids is encoded by the other 3 exons. The third exon encodes the
portion of the protein containing the ion-sulfur center and a domain
that binds other components of the electron transport chain.

By analysis of somatic cell hybrids, Morel et al. (1988) and Chang et
al. (1990) assigned the ADX gene to 11q13-qter. Chang et al. (1990)
identified pseudogenes on both chromosome 20 and chromosome 21. The
pseudogenes lacked introns and contained numerous mutations, including
an insertion, deletion, and substitution, which rendered them inactive.
They concluded that there are 2 expressed genes, but only 1 gene product
and that both expressed genes are located on chromosome 11. Human
adrenodoxin and placental ferredoxin cDNAs share an identical sequence,
suggesting that they are the same (Mittal et al., 1988). Chashchin et
al. (1986) found that adrenodoxin is identical in sequence to liver
ferredoxin (hepatoredoxin). Renal ferredoxin (renodoxin) has similar
optic, renal, and immunochemical properties to adrenodoxin, although
Maruya et al. (1983) suggested that the 2 have minor differences.
Because they identified only 1 protein sequence, Chang et al. (1990)
suggested that there is no need to designate ferredoxin according to the
tissue origin. By in situ hybridization, Sparkes et al. (1991) refined
the assignment of ADX to 11q22 and demonstrated pseudogenes on
20q11-q12.

*FIELD* SA
Picado-Leonard et al. (1988)
*FIELD* RF
1. Chang, C.-Y.; Wu, D.-A.; Lai, C.-C.; Miller, W. L.; Chung, B.-C.
: Cloning and structure of the human adrenodoxin gene. DNA 7: 609-615,
1988.

2. Chang, C.-Y.; Wu, D.-A.; Mohandas, T. K.; Chung, B.-C.: Structure,
sequence, chromosomal location, and evolution of the human ferredoxin
gene family. DNA Cell Biol. 9: 205-212, 1990.

3. Chashchin, V. L.; Lapko, V. N.; Adamovich, T. B.; Kirillova, N.
M.; Lapko, A. G.; Akhrem, A. A.: The primary structure of hepatoredoxin
from bovine liver mitochondria. Bioorg. Khim. 12: 1286-1289, 1986.

4. Jefcoate, C. R.; McNamara, B. C.; DiBartolomeis, M. J.: Control
of steroid synthesis in adrenal fasciculata cells. Endocr. Res. 12:
314-350, 1986.

5. Maruya, N.; Hiwatashi, A.; Ichikawa, Y.; Yamano, T.: Purification
and characterization of renal ferredoxin from bovine renal mitochondria.
J. Biochem. 93: 1239-1247, 1983.

6. Mittal, S.; Zhu, Y. Z.; Vickery, L. E.: Molecular cloning and
sequence analysis of human placental ferredoxin. Arch. Biochem.
Biophys. 264: 383-391, 1988.

7. Morel, Y.; Picado-Leonard, J.; Mohandas, T. K.; Miller, W. L.:
Two highly homologous genes for adrenodoxin lie on human chromosomes
11 and 20.  (Abstract) Am. J. Hum. Genet. 41: A178 only, 1987.

8. Morel, Y.; Picado-Leonard, J.; Wu, D.-A.; Chang, C.-Y.; Mohandas,
T. K.; Chung, B.-C.; Miller, W. L.: Assignment of the functional
gene for human adrenodoxin to chromosome 11q13-qter and of adrenodoxin
pseudogenes to chromosome 20cen-q13.1. Am. J. Hum. Genet. 43: 52-59,
1988.

9. Okamura, T.; John, M. E.; Zuber, M. X.; Simpson, E. R.; Waterman,
M. R.: Molecular cloning and amino acid sequence of the precursor
form of bovine adrenodoxin: evidence for a previously unidentified
COOH-terminal peptide. Proc. Nat. Acad. Sci. 82: 5705-5709, 1985.

10. Picado-Leonard, J.; Voutilainen, R.; Kao, L.-C.; Chung, B.-C.;
Strauss, J. F., III; Miller, W. L.: Human adrenodoxin: cloning of
three cDNAs and cycloheximide enhancement in JEG-3 cells. J. Biol.
Chem. 263: 3240-3244, 1988.

11. Sparkes, R. S.; Klisak, I.; Miller, W. L.: Regional mapping of
genes encoding human steroidogenic enzymes: P450scc to 15q23-q24;
adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17
to 10q24-q25. DNA Cell Biol. 10: 359-365, 1991.

*FIELD* CD
Victor A. McKusick: 10/22/1987

*FIELD* ED
mimadm: 4/14/1994
carol: 10/15/1993
carol: 10/27/1992
carol: 10/26/1992
supermim: 3/16/1992
carol: 2/29/1992

*RECORD*
*FIELD* NO
103270
*FIELD* TI
*103270 ADRENODOXIN REDUCTASE; ADXR
FERREDOXIN:NADP(+) REDUCTASE; FDXR
*FIELD* TX
Adrenodoxin reductase (ferredoxin:NADP(+) oxidoreductase; EC 1.18.1.2)
is a mitochondrial flavoprotein that receives electrons from NADPH, thus
initiating the electron-transport chain serving mitochondrial
cytochromes P450. Solish et al. (1988) cloned and sequenced 2 human ADXR
cDNAs that differed by the presence of 6 additional codons in the middle
of 1 clone. The sequence in this region of the clones indicated that
these 6 extra codons rose by alternative splicing of the pre-mRNA.
Southern blot analysis indicated that the human genome contains only 1
ADXR gene. Lin et al. (1990) found that the ADXR gene is 12 kb long and
consists of 12 exons. The first exon encodes the first 26 of the 32
amino acids of the signal peptide, and the second exon encodes the
remainder of the signal peptide and the apparent FAD binding site. The
remaining 10 exons are clustered in a region of only 4.3 kb, separated
from the first 2 exons by a large intron of about 5.6 kb. Lin et al.
(1990) also found 2 forms of mRNA, which differed by the absence or
presence of 18 bases in the middle of the sequence; these arise through
alternative splicing at the 5-prime end of exon 7. By analysis of DNA
from a panel of mouse-human somatic cell hybrids, Solish et al. (1988)
localized the gene to 17cen-q25. By in situ hybridization, Sparkes et
al. (1991) refined the assignment to 17q24-q25.

*FIELD* RF
1. Lin, D.; Shi, Y.; Miller, W. L.: Cloning and sequence of the human
adrenodoxin reductase gene. Proc. Nat. Acad. Sci. 87: 8516-8520,
1990.

2. Solish, S. B.; Picado-Leonard, J.; Morel, Y.; Kuhn, R. W.; Mohandas,
T. K.; Hanukoglu, I.; Miller, W. L.: Human adrenodoxin reductase:
two mRNAs encoded by a single gene on chromosome 17cen-q25 are expressed
in steroidogenic tissues. Proc. Nat. Acad. Sci. 85: 7104-7108,
1988.

3. Sparkes, R. S.; Klisak, I.; Miller, W. L.: Regional mapping of
genes encoding human steroidogenic enzymes: P450scc to 15q23-q24;
adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17
to 10q24-q25. DNA Cell Biol. 10: 359-365, 1991.

*FIELD* CD
Victor A. McKusick: 10/12/1988

*FIELD* ED
carol: 10/26/1992
supermim: 3/16/1992
carol: 8/19/1991
carol: 12/3/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
103275
*FIELD* TI
*103275 ADRENOMEDULLIN; AM
ADM
*FIELD* TX
Adrenomedullin, a hypotensive peptide found in human pheochromocytoma,
consists of 52 amino acids, has 1 intramolecular disulfide bond, and
shows a slight homology with the calcitonin gene-related peptide (CGRP;
114130). It may function as a hormone in circulation control because it
is found in blood in a considerable concentration. Kitamura et al.
(1993) constructed a cDNA library of pheochromocytoma and isolated
therefrom a cDNA clone encoding an adrenomedullin precursor. The
precursor, called preproadrenomedullin, is 185 amino acids long. By
RNA-blot analysis, human adrenomedullin mRNA was found to be highly
expressed in several tissues, including adrenal medulla, cardiac
ventricle, lung, and kidney, as well as pheochromocytoma. Ishimitsu et
al. (1994) found that the genomic AM DNA consists of 4 exons and 3
introns, with the 5-prime flanking region containing TATA, CAAT, and GC
boxes. There are also multiple binding sites for activator protein-2
(AP2TF; 107580) and a cAMP-regulated enhancer element. Southern blot
analyses of human/hamster somatic hybrid cell lines demonstrated that
the AM gene is represented by a single locus on chromosome 11.

Richards et al. (1996) reviewed information accumulated on
adrenomedullin since its original description by Kitamura et al. (1993).

*FIELD* RF
1. Ishimitsu, T.; Kojima, M.; Kangawa, K.; Hino, J.; Matsuoka, H.;
Kitamura, K.; Eto, T.; Matsuo, H.: Genomic structure of human adrenomedullin
gene. Biochem. Biophys. Res. Commun. 203: 631-639, 1994.

2. Kitamura, K.; Sakata, J.; Kangawa, K.; Kojima, M.; Matsuo, H.;
Eto, T.: Cloning and characterization of cDNA encoding a precursor
for human adrenomedullin. Biochem. Biophys. Res. Commun. 194: 720-725,
1993.

3. Richards, A. M.; Nicholls, M. G.; Lewis, L.; Lainchbury, J. G.
: Adrenomedullin. Clin. Sci. 91: 3-16, 1996.

*FIELD* CD
Victor A. McKusick: 9/23/1993

*FIELD* ED
terry: 11/11/1996
terry: 10/31/1994
carol: 10/26/1993
carol: 9/23/1993

*RECORD*
*FIELD* NO
103280
*FIELD* TI
*103280 ADULT SKELETAL MUSCLE GENE
ASM;;
ASM1;;
H19 GENE;;
D11S813E
*FIELD* TX
Leibovitch et al. (1991) used a rat skeletal muscle probe originating
from a rhabdomyosarcoma to isolate a cDNA probe from a human placental
cDNA library. In the rat, while the corresponding mRNA and protein were
not expressed in fetal muscle, an increasing accumulation of the
corresponding mRNA and protein were observed during postnatal
development of skeletal muscle, and this accumulation was maximal in
adulthood. As no expression was found in any other tissue, the gene was
referred to as the adult skeletal muscle (ASM) gene. Leibovitch et al.
(1991) mapped the human gene to 11p15 by a combination of somatic hybrid
cell analysis and in situ hybridization. (D11S813E was the designation
assigned by HGM11 (Nguyen et al., 1991).)

A gene coding for an abundant fetal transcript in mice had been
identified by Bartolomei et al. (1991), who designated it H19. The H19
gene is expressed in a number of organs during a restricted period of
fetal development, and in embryonal carcinoma cells after induction of
differentiation. The gene shows a restricted pattern of expression in
adult tissues; expression is confined to skeletal and cardiac muscle.
Leibovitch et al. (1991) presented evidence that the human H19 gene has
a transcript that gives rise to a 29-kD protein.

The human H19 gene is 2.7 kb long and includes 4 small introns. Zhang
and Tycko (1992) found restriction site polymorphisms in the human H19
gene and, by examination of the representation of these polymorphisms in
cDNAs from fetal organs, demonstrated that H19 expression was largely or
exclusively from a single allele. Expression of the WT1 gene (194070),
which, like H19, maps to 11p and shows fetal expression, was found to
have biallelic expression. In the context of previous studies of allelic
losses in 11p15 in human embryonal tumors, the findings of Zhang and
Tycko (1992) supported the possibility of single-step inactivation of
monoallelically expressed growth-regulating genes in human oncogenesis.
It was not determined in this study whether the expression was
uniparental to indicate parental imprinting. The H19 gene and 2 other
genes, insulinlike growth factor II (147470) and insulinlike growth
factor II receptor (147280), show monoallelic expression in mice. IGF2
is, like H19, located in 11p15. Zhang and Tycko (1992) commented that,
if IGF2 also shows monoallelic expression, it may indicate that that
region is a 'hot spot' for this phenomenon.

In the mouse, the H19 gene is located on chromosome 7 in a region of
conservation of synteny with human 11p (Jones et al., 1992). Like the
H19 gene, the Igf2 gene is imprinted in the mouse, although in the
opposite parents, one paternally imprinted, the other maternally. Zemel
et al. (1992) showed that the Igf2 gene lies about 90 kb 5-prime to H19,
in the same transcriptional orientation. Based on similar pulsed field
gel analysis, they showed that this physical proximity is conserved in
humans. Both genes hybridized to a fragment of about 200 kb. Zemel et
al. (1992) proposed a model to account for the imprinting of 2 linked
genes in opposite directions, i.e., one (H19) being paternally imprinted
and the other (IGF2) maternally imprinted. They pointed out that the
IGF2/H19 domain is a candidate for the Beckwith-Wiedemann syndrome (BWS;
130650) since the genes show imprinting and chimeric mouse embryos that
are paternally disomic for distal mouse chromosome 7 show an overgrowth
phenotype similar to that of BWS (Ferguson-Smith et al., 1991).

From the study of the androgenetic complete hydatidiform mole,
Rachmilewitz et al. (1992) presented strong evidence of parental
imprinting of the human H19 gene, with the maternally derived allele as
the active one. Furthermore, they showed that the paternally derived
allele of the IGF2 is expressed. Thus, the situation in the human is the
same as that in the mouse. Rainier et al. (1993) found that both H19 and
IGF2 show monoallelic expression in human tissues and that, as in mouse,
H19 is expressed from the maternal allele and IGF2 from the paternal
allele. In contrast, 69% of Wilms tumors not undergoing loss of
heterozygosity at 11p showed biallelic expression of one or both genes,
suggesting that relaxation or loss of imprinting may represent a new
epigenetic mutational mechanism in carcinogenesis.

Mutter et al. (1993) found that normal gestations express H19 only from
the maternal allele and express IGF2 from the paternal allele, whereas
neither is expressed from the maternal genome of gynogenetic gestations,
and both are expressed from the paternal genome of androgenetic
gestations. Coexpression of H19 and IGF2 in the androgenetic tissues was
in a single population of cells, mononuclear trophoblast--the same cell
type expressing these genes in biparental placentas. These results
demonstrated that a biparental genome may be required for expression of
the reciprocal IGF2/H19 imprint.

In the mouse, the imprinted H19 gene, which encodes an untranslated RNA,
lies at the end of a cluster of imprinted genes. Leighton et al. (1995)
found that imprinting of the insulin-2 gene and the insulin-like growth
factor 2 gene, which lie about 100 kb upstream of H19, can be disrupted
by maternal inheritance of a targeted deletion of the H19 gene and its
flanking sequence. Animals inheriting the H19 mutation from their
mothers were 27% heavier than those inheriting from their fathers.
Paternal inheritance of the disruption had no effect, which presumably
reflects the normally silent state of the paternal gene. The somatic
overgrowth of heterozygotes for the maternal deletion was attributed to
a gain-of-function of the Igf2 gene rather than a loss of function of
H19.

H19 is abundantly expressed in both extraembryonic and fetal tissues.
Jinno et al. (1995) found that H19 is monoallelically (maternally)
expressed in the human placenta after 10 weeks of gestation, whereas it
is biallelically expressed at earlier stages. Regardless of H19
biallelic or monoallelic expression, IGF2 (147470) is monoallelically
(paternally) expressed in the placenta. Furthermore, with in situ mRNA
hybridization using placenta showing H19 biallelic and IGF2 monoallelic
expression, they demonstrated that defined cell types simultaneously
contained both H19 and IGF2 transcripts. Therefore, the reciprocal
linkage of H19 and IGF2 expression demonstrated in Wilms tumors is not
observed in placentas. Furthermore, Jinno et al. (1995) found that,
unlike methylation analyses of the human H19 gene, the promoter region
of the human H19 gene is hypomethylated at all stages of placental
development. In contrast, allele-dependent methylation of the 3-prime
portion of the gene increases with gestational age.

H19 is a developmentally regulated gene with putative tumor suppressor
activity; loss of H19 expression may be involved in Wilms tumorigenesis.
Han et al. (1996) performed in situ hybridization analysis of H19
expression during normal rabbit development and in human atherosclerotic
plaques. They found that H19 expression in developing skeletal and
smooth muscles correlated with specific differentiation events in these
tissues. Expression of H19 in skeletal muscle correlated with
nonproliferative, actin-positive muscle cells. In the prenatal blood
vessel, H19 expression was both temporally and spatially regulated with
initial loss of expression in the inner smooth muscle layers adjacent to
the lumen. Han et al. (1996) also identified H19-positive cells in adult
atherosclerotic lesions, suggesting that these cells may recapitulate
early developmental events. These results, along with the identification
of the insulin family of growth factors as potent regulatory molecules
for H19 expression, provided additional clues toward understanding the
physiologic regulation and function of H19.

Pfeifer et al. (1996) stated that the product of the H19 gene is an
untranslated RNA that is expressed exclusively from the maternal
chromosome during mammalian development. The H19 gene and its
5-prime-flanking sequence are required for the genomic imprinting of 2
paternally expressed genes in mice, Ins2 and Igf2, that lie 90 and 115
kb 5-prime to the H19 gene, respectively. Pfeifer et al. (1996)
investigated the role of the H19 gene in its own imprinting by
introducing a Mus spretus H19 gene into heterologous locations in the
mouse genome. They found that multiple copies of the transgene were
sufficient for its paternal silencing and DNA methylation. Replacing the
H19 structural gene with a luciferase reporter gene resulted in loss of
imprinting of the transgene; that is, high expression and low levels of
DNA methylation were observed with both paternal and maternal
inheritance. Removal of 701 bp at the 5-prime end of the structural H19
gene resulted in a similar loss of paternal-specific DNA methylation,
arguing that those sequences are required for both the establishment and
maintenance of the sperm-specific gametic mark. The M. spretus H19
transgene could not rescue the loss of IGF-2 imprinting in trans in H19
deletion mice, implying a cis requirement for the H19 gene. In contrast
to a previous report (Brunkow and Tilghman, 1991) in which
overexpression of a marked H19 gene was a prenatal lethal, Pfeifer et
al. (1996) found that expression of the M. spretus transgene had no
deleterious effect, leading them to conclude that the 20-bp insertion in
the marked gene created a neomorphic mutation.

*FIELD* RF
1. Bartolomei, M. S.; Zemel, S.; Tilghman, S. M.: Parental imprinting
of the mouse H19 gene. Nature 351: 153-155, 1991.

2. Brunkow, M. E.; Tilghman, S. M.: Ectopic expression of the H19
gene in mice causes prenatal lethality. Genes Dev. 5: 1092-1101,
1991.

3. Ferguson-Smith, A. C.; Cattanach, B. M.; Barton, S. C.; Beechey,
C. V.; Surani, M. A.: Embryological and molecular investigations
of parental imprinting on mouse chromosome 7. Nature 351: 667-670,
1991.

4. Han, D. K. M.; Khaing, Z. Z.; Pollock, R. A.; Haudenschild, C.
C.; Liau, G.: H19, a marker of developmental transition, is reexpressed
in human atherosclerotic plaques and is regulated by the insulin family
of growth factors in cultured rabbit smooth muscle cells. J. Clin.
Invest. 97: 1276-1285, 1996.

5. Jinno, Y.; Ikeda, Y.; Yun, K.; Maw, M.; Masuzaki, H.; Fukuda, H.;
Inuzuka, K.; Fujishita, A.; Ohtani, Y.; Okimoto, T.; Ishimaru, T.;
Niikawa, N.: Establishment of functional imprinting of the H19 gene
in human developing placentae. Nature Genet. 10: 318-324, 1995.

6. Jones, J. M.; Meisler, M. H.; Seldin, M. F.; Lee, B. K.; Eicher,
E. M.: Localization of insulin-2 (Ins-2) and the obesity mutant tubby
(tub) to distinct regions of mouse chromosome 7. Genomics 14: 197-199,
1992.

7. Leibovitch, M. P.; Nguyen, V. C.; Gross, M. S.; Solhonne, B.; Leibovitch,
S. A.; Bernheim, A.: The human ASM (adult skeletal muscle) gene:
expression and chromosomal assignment to 11p15. Biochem. Biophys.
Res. Commun. 180: 1241-1250, 1991.

8. Leighton, P. A.; Ingram, R. S.; Eggenschwiler, J.; Efstratiadis,
A.; Tilghman, S. M.: Disruption of imprinting caused by deletion
of the H19 gene region in mice. Nature 375: 34-39, 1995.

9. Mutter, G. L.; Stewart, C. L.; Chaponot, M. L.; Pomponio, R. J.
: Oppositely imprinted genes H19 and insulin-like growth factor 2
are coexpressed in human androgenetic trophoblast. Am. J. Hum. Genet. 53:
1096-1102, 1993.

10. Nguyen, V. C.; Leibovitch, M.; Gross, M.; Solhonne, B.; Leibovitch,
S. A.; Bernheim, A.: Assignment of ASM (adult skeletal muscle) to
chromosome 11 (somatic hybrid cell analysis), region 11p15 (in situ
hybridization). (Abstract) Cytogenet. Cell Genet. 58: 1968, 1991.

11. Pfeifer, K.; Leighton, P. A.; Tilghman, S. M.: The structural
H19 gene is required for transgene imprinting. Proc. Nat. Acad. Sci. 93:
13876-13883, 1996.

12. Rachmilewitz, J.; Goshen, R.; Ariel, I.; Schneider, T.; de Groot,
N.; Hochberg, A.: Parental imprinting of the human H19 gene. FEBS
Lett. 309: 25-28, 1992.

13. Rainier, S.; Johnson, L. A.; Dobry, C. J.; Ping, A. J.; Grundy,
P. E.; Feinberg, A. P.: Relaxation of imprinted genes in human cancer. Nature 362:
747-749, 1993.

14. Zemel, S.; Bartolomei, M. S.; Tilghman, S. M.: Physical linkage
of two mammalian imprinted genes, H19 and insulin-like growth factor
2. Nature Genet. 2: 61-65, 1992.

15. Zhang, Y.; Tycko, B.: Monoallelic expression of the human H19
gene. Nature Genet. 1: 40-44, 1992.

*FIELD* CD
Victor A. McKusick: 1/9/1992

*FIELD* ED
terry: 01/23/1997
terry: 1/10/1997
mark: 5/2/1996
terry: 4/24/1996
mark: 7/20/1995
carol: 11/8/1993
carol: 9/24/1993
carol: 10/22/1992
carol: 10/13/1992
carol: 10/7/1992

*RECORD*
*FIELD* NO
103285
*FIELD* TI
103285 ADULT SYNDROME
ACRO-DERMATO-UNGUAL-LACRIMAL-TOOTH SYNDROME
*FIELD* TX
Propping and Zerres (1993) described a family with at least 7 living
members who were affected by a hitherto undescribed syndrome with
variable expression, which bore a close resemblance to the EEC syndrome
(129900). The main manifestations were hypodontia and/or early onset of
permanent teeth, ectrodactyly, obstruction of lacrimal ducts,
onychodysplasia, and excessive freckling. Another finding was
hypoplastic breasts.

*FIELD* RF
1. Propping, P.; Zerres, K.: ADULT-syndrome: an autosomal-dominant
disorder with pigment anomalies, ectrodactyly, nail dysplasia, and
hypodontia. Am. J. Med. Genet. 45: 642-648, 1993.

*FIELD* CS

Teeth:
   Hypodontia;
   Early onset of permanent teeth

Limbs:
   Ectrodactyly

Eyes:
   Lacrimal duct obstruction

Nails:
   Onychodysplasia

Skin:
   Excessive freckling

Thorax:
   Hypoplastic breasts

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/24/1993

*FIELD* ED
mimadm: 3/11/1994
carol: 3/24/1993

*RECORD*
*FIELD* NO
103300
*FIELD* TI
103300 AGLOSSIA-ADACTYLIA
PEROMELIA WITH MICROGNATHISM;;
OROMANDIBULAR LIMB HYPOPLASIA
HANHART SYNDROME, INCLUDED
*FIELD* TX
The features are indicated by the name, although it is to be noted that
both the aglossia and the adactylia may be only partial. In Turkey,
Tuncbilek et al. (1977) observed 3 sporadic cases, each with
consanguineous parents, and espoused autosomal recessive inheritance;
the general consanguinity rate may be high in the population in
question, however. Epicanthus was a feature of the case I saw with
Shokeir (1978). Robinow et al. (1978) observed discordant monozygotic
twins; it is noteworthy, although perhaps coincidental, that the parents
were second cousins. They also described a case with associated 'apple
peel' bowel (243600) which is thought to arise through obliteration of
the superior mesenteric artery. This suggested to them that the
aglossia-adactylia syndrome might likewise be the result of vascular
occlusion, as in the embryopathy experimentally induced by Jost and
Poswillo. Hanhart (1950) described 3 cases of the same disorder; 2 were
related and, in the third, the parents were consanguineous. The disorder
is a nonmendelian developmental disturbance (Opitz, 1982). Buttiens and
Fryns (1986) described Hanhart syndrome in brother and sister. These
persons had retrognathia, microstomia and symmetric severe limb
reduction defects but normal tongue. Thus, it is arguable whether it
should be called Hanhart syndrome. Chandra Sekhar et al. (1987) reported
with photographs 2 remarkable cases in which micrognathia was extreme.
One patient was a male who died in the neonatal period. Structural
abnormalities of the middle ear were described. The second case was a
14-year-old boy with bilateral conductive hearing loss and bilateral
absent thumbs.

*FIELD* SA
Bokesoy et al. (1983); Falk and Murphree (1978); Nevin et al. (1975);
Nevin et al. (1970)
*FIELD* RF
1. Bokesoy, I.; Aksuyek, C.; Deniz, E.: Oromandibular limb hypogenesis/Hanhart's
syndrome: possible drug influence on the malformation. Clin. Genet. 24:
47-49, 1983.

2. Buttiens, M.; Fryns, J.-P.: Hanhart syndrome in siblings.  (Abstract) 7th
Int. Cong. Hum. Genet., Berlin 274 only, 1986.

3. Chandra Sekhar, H. K.; Sachs, M.; Siverls, V. C.: Hanhart's syndrome
with special reference to temporal bone findings. Ann. Otol. Rhinol.
Laryng. 96: 309-314, 1987.

4. Falk, R. E.; Murphree, L.: Colobomatous microphthalmia in the
hypoglossia-hypodactylia syndrome.  (Abstract) Am. J. Hum. Genet. 30:
101A only, 1978.

5. Hanhart, E.: Ueber die Kombination von Peromelie mit Mikrognathie,
ein neues Syndrom beim Menschen, entsprechend der Akroteriasis congenita
von Wriedt und Mohr beim Rind. Arch. Klaus Stift. Vererbungsforsch. 25:
531-543, 1950.

6. Nevin, N. C.; Burrows, D.; Allen, G.; Kernohan, D. C.: Aglossia-adactylia
syndrome. J. Med. Genet. 12: 89-93, 1975.

7. Nevin, N. C.; Dodge, J. A.; Kernohan, D. C.: Aglossia-adactylia
syndrome. Oral Surg. 29: 443-446, 1970.

8. Opitz, J. M.: Personal Communication. Helena, Mont.  1982.

9. Robinow, M.; Marsh, J. L.; Edgerton, M. T.; Sabio, H.; Johnson,
G. F.: Discordance in monozygotic twins for aglossia-adactylia, and
possible clues to the pathogenesis of the syndrome. Birth Defects
Orig. Art. Ser. XIV(6A): 223-230, 1978.

10. Shokeir, M. H. K.: Personal Communication. Saskatoon, Saskatchewan,
Canada  10/3/1978.

11. Tuncbilek, E.; Yalcin, C.; Atasu, M.: Aglossia-adactylia syndrome
(special emphasis on the inheritance pattern). Clin. Genet. 11:
421-423, 1977.

*FIELD* CS

Mouth:
   Aglossia/hypoglossia;
   Abnormal ventral frenulum;
   Retrognathia;
   Microstomia

Limbs:
   Adactylia;
   Hypodactyly;
   Ectrodactyly

Eyes:
   Epicanthus

inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 3/9/1990
carol: 3/6/1990

*RECORD*
*FIELD* NO
103320
*FIELD* TI
*103320 AGRIN; AGRN
*FIELD* TX
One of the important events in synapse formation is the accumulation of
neurotransmitter receptors beneath the presynaptic nerve terminal. Agrin
is a component of the synaptic basal lamina that induces the clustering
(aggregation) of acetylcholine receptors (e.g., 100690) on cultured
muscle fibers. Campanelli et al. (1991) showed that when a cDNA encoding
a putative agrin protein is transfected into cells, the molecule is
secreted and concentrated on the extracellular surface. Coculture of
transfected cells with muscle fibers induced formation of receptor
patches at contact sites. These results demonstrated that expression of
a single gene encoding agrin confers receptor clustering that is
restricted to specific sites of contact between the synthesizing cell
and muscle.

Rupp et al. (1991) isolated cDNAs from a rat embryonic spinal cord
library using an agrin cDNA clone isolated from electromotor neurons of
a marine ray. Analysis of a set of clones predicted a protein with 1,940
amino acids, including 141 cysteine residues. The predicted protein had
9 domains homologous to protease inhibitors, a region similar to domain
III of laminin, and 4 epidermal growth factor repeats. The gene was
expressed in rat embryonic nervous system and muscle. The protein was
concentrated at synapses, where it may play a role in development and
regeneration. Rupp et al. (1992) described alternative RNA splicing in
mammalian agrin resulting in many extracellular matrix protein isoforms.

Rupp et al. (1992) mapped the human AGRN gene to 1pter-p32 by analysis
of Chinese hamster/human somatic cell hybrids, including one that
carried chromosome 1 region p32-qter (which was negative for the human
signal). The mouse gene was mapped to chromosome 4 by study of Chinese
hamster/mouse somatic cell hybrids. Thus, this is another example of
extensive homology of synteny between 1pter-p32 and the distal half of
mouse chromosome 4. Three neurologic mutants in that region of mouse
chromosome 4 were pointed to as possible candidate diseases for
mutations in the Agrn gene.

Data on the structure, expression, and bioactivity of agrin all support
the notion that it plays a central role in regulating postsynaptic
differentiation. However, agrin is only one of several agents that can
cause clustering of acetylcholine receptors in vitro. To test critically
the 'agrin hypothesis' (McMahan, 1990), Gautam et al. (1996) generated
knockout mice deficient for agrin and showed that neuromuscular
differentiation is grossly defective in these mice. Some postsynaptic
differentiation occurred in the mutant, suggesting the existence of a
second nerve-derived synaptic organizing signal.

Formation of the neuromuscular junction depends upon reciprocal
inductive interactions between the developing nerve and muscle,
resulting in the precise juxtaposition of a differentiated nerve
terminal with a highly specialized patch on the muscle membrane, termed
the motor endplate. Agrin is a nerve-derived factor involved in
induction of the molecular reorganization at the motor endplate. Glass
et al. (1996) found that mice lacking either agrin or the receptor
tyrosine kinase they called MuSK (601296) exhibit similar profound
defects at the neuromuscular junction. DeChiara et al. (1996) showed in
knockout mice that MuSK is required for formation of the neuromuscular
junction in vivo.

*FIELD* RF
1. Campanelli, J. T.; Hoch, W.; Rupp, F.; Kreiner, T.; Scheller, R.
H.: Agrin mediates cell contact-induced acetylcholine receptor clustering.
Cell 67: 909-916, 1991.

2. DeChiara, T. M.; Bowen, D. C.; Valenzuela, D. M.; Simmons, M. V.;
Poueymirou, W. T.; Thomas, S.; Kinetz, E.; Compton, D. L.; Rojas,
E.; Park, J. S.; Smith, C.; DiStefano, P. S.; Glass, D. J.; Burden,
S. J.; Yancopoulos, G. D.: The receptor tyrosine kinase MuSK is required
for neuromuscular junction formation in vivo. Cell 85: 501-512,
1996.

3. Gautam, M.; Noakes, P. G.; Moscoso, L.; Rupp, F.; Scheller, R.
H.; Merlie, J. P.; Sanes, J. R.: Defective neuromuscular synaptogenesis
in agrin-deficient mutant mice. Cell 85: 525-535, 1996.

4. Glass, D. J.; Bowen, D. C.; Stitt, T. N.; Radziejewski, C.; Bruno,
J.; Ryan, T. E.; Gies, D. R.; Shah, S.; Mattsson, K.; Burden, S. J.;
DiStefano, P. S.; Valenzuela, D. M.; DeChiara, T. M.; Yancopoulos,
G. D.: Agrin acts via a MuSK receptor complex. Cell 85: 513-523,
1996.

5. McMahan, U. J.: The agrin hypothesis Cold Spring Harb. Symp.
Quant. Biol. 50: 407-418, 1990.

6. Rupp, F.; Ozcelik, T.; Linial, M.; Peterson, K.; Francke, U.; Scheller,
R.: Structure and chromosomal localization of the mammalian agrin
gene. J. Neurosci. 12: 3535-3544, 1992.

7. Rupp, F.; Payan, D. G.; Magill-Solc, C.; Cowan, D. M.; Scheller,
R. H.: Structure and expression of a rat agrin. Neuron 6: 811-823,
1991.

*FIELD* CD
Victor A. McKusick: 12/17/1991

*FIELD* ED
terry: 06/06/1996
terry: 6/4/1996
carol: 3/31/1994
carol: 12/9/1993
supermim: 3/16/1992
carol: 2/17/1992
carol: 12/17/1991

*RECORD*
*FIELD* NO
^103321
*FIELD* TI
^103321 MOVED TO 128239
*FIELD* TX
This entry was incorporated into 128239 on 14 October 1996.

*FIELD* CN
Mark H. Paalman - edited: 10/14/1996

*FIELD* CD
Victor A. McKusick: 3/18/1994
*FIELD* ED
mark: 10/15/1996
mark: 10/14/1996
jason: 6/22/1994
carol: 3/18/1994
*RECORD*
*FIELD* NO
103390
*FIELD* TI
*103390 AHNAK NUCLEOPROTEIN
DESMOYOKIN
*FIELD* TX
Neuroblastoma represents the most primitive neoplasm originating from
migratory neural crest cells and apparently arises as a result of
arrested differentiation. To identify genes whose transcription might be
repressed during the genesis of neuroblastomas, Shtivelman and Bishop
(1991) used subtractive cDNA cloning to detect genes expressed in human
melanomas and pheochromocytomas but not in neuroblastomas. The first of
these genes identified encoded the cell surface protein CD44 (107269),
an integral membrane glycoprotein that is the principal receptor for
hyaluronate on the cell surface. A second gene, originally designated
PM227, attracted their attention because its expression appeared to be
coordinated with that of CD44. Shtivelman et al. (1992) reported that
PM227 encodes a protein whose exceptionally large size of 700 kD caused
them to rename the gene AHNAK (meaning 'giant' in Hebrew). The amino
acid sequence of AHNAK suggested secondary structure with a periodicity
of 2.33 residues per turn. Individual chains could associate to form a
7- or 8-stranded barrel. The resulting structure would be a polyionic
rod with length as great as 1.2 microns. Preliminary evidence indicated
that the protein resides predominantly within the nucleus, but no
function had been discerned. The highly conserved repeated elements
were, for the most part, 128 amino acids long.

AHNAK is thought to be identical to desmoyokin (Hashimoto et al., 1993)
which was first identified as a 680-kD desmosomal plaque protein in
bovine muzzle epidermis. Using a panel of somatic cell hybrids and
Southern blot analysis, Kudoh et al. (1995) mapped the human
AHNAK/desmoyokin gene to chromosome 11. Fluorescence in situ
hybridization experiments independently confirmed the chromosomal
localization and refined it to band 11q12.

*FIELD* RF
1. Hashimoto, T.; Amagai, M.; Parry, D. A. D.; Dixon, T. W.; Tsukita,
S.; Tsukita, S.; Miki, K.; Sakai, K.; Inokuchi, Y.; Kudoh, J.; Shimizu,
N.; Nishikawa, T.: Desmoyokin, a 680 kDa keratinocyte plasma membrane-associated
protein, is homologous to the protein encoded by human gene AHNAK.
J. Cell. Sci. 105: 275-286, 1993.

2. Kudoh, J.; Wang, Y.; Minoshima, S.; Hashimoto, T.; Amagai, M.;
Nishikawa, T.; Shtivelman, E.; Bishop, J. M.; Shimizu, N.: Localization
of the human AHNAK/desmoyokin gene (AHNAK) to chromosome band 11q12
by somatic cell hybrid analysis and fluorescence in situ hybridization.
Cytogenet. Cell Genet. 70: 218-220, 1995.

3. Shtivelman, E.; Bishop, J. M.: Expression of CD44 is repressed
in neuroblastoma cells. Molec. Cell. Biol. 11: 5446-5453, 1991.

4. Shtivelman, E.; Cohen, F. E.; Bishop, J. M.: A human gene (AHNAK)
encoding an unusually large protein with a 1.2-micron polyionic rod
structure. Proc. Nat. Acad. Sci. 89: 5472-5476, 1992.

*FIELD* CD
Victor A. McKusick: 7/7/1992

*FIELD* ED
mark: 10/17/1995
carol: 7/7/1992

*RECORD*
*FIELD* NO
103400
*FIELD* TI
103400 AINHUM
*FIELD* TX
A narrow strip of hardened skin, a constricting ring, forms on the
little toe at the level of the digitoplantar fold and progresses to
spontaneous amputation of the digit. Familial occurrence has been noted
by Maass (1926) and by DaSilva Lima (1880). Simon (1921) reported ainhum
in father and 2 sons. Ainhum-like constriction bands occur with
neurogenic acroosteolysis (201300) and with mutilating keratoderma
(124500, 244850).

*FIELD* SA
Horwitz and Tunick (1937)
*FIELD* RF
1. DaSilva Lima, J. F.: On ainhum. Arch. Derm. Syph. 6: 367-376,
1880.

2. Horwitz, M. T.; Tunick, I.: Ainhum: report of six cases in New
York. Arch. Derm. Syph. 36: 1058-1063, 1937.

3. Maass, E.: Beobachtungen ueber Ainhum. Arch. Schiffs-u. Tropenhygiene 30:
32-34, 1926.

4. Simon, K. M. B.: Ainhum, a family disease. J.A.M.A. 76: 560
only, 1921.

*FIELD* CS

Limbs:
   Little toe spontaneous amputation

inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 5/13/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
103420
*FIELD* TI
*103420 ALACRIMA, CONGENITAL
ALACRIMIA CONGENITA
*FIELD* TX
Mondino and Brown (1976) described a family with 5 persons in 4
generations showing markedly deficient lacrimation from infancy and
punctate corneal epithelial erosions. Male-to-male transmission was
observed. Hypoplasia of the lacrimal glands was suggested by
pharmacologic tests and histopathology of the lacrimal gland. Alacrima
occurs in anhidrotic ectodermal dysplasia (305100) and dysautonomia
(223900) and in association with ocular and adnexal abnormalities.
Krueger (1954) described brother and sister with ptosis, distichiasis,
conjunctivitis, keratitis, and alacrimia congenita. The father and
another brother were said to have defective lacrimation. A nuclear
defect was postulated for this disorder, which may be distinct from that
reported by Mondino and Brown (1976). Milunsky et al. (1990) described
hypoplasia of both lacrimal glands and left nasolacrimal duct atresia in
association with almost total absence of the parotid glands and marked
hypofunction of both submandibular glands; see 180920.

*FIELD* RF
1. Krueger, K. E.: Angeborenes Fehlen der Traenensekretion in einer
Familie. Klin. Mbl. Augenheilk. 124: 711-713, 1954.

2. Milunsky, J. M.; Lee, V. W.; Siegel, B. S.; Milunsky, A.: Agenesis
or hypoplasia of major salivary and lacrimal glands. Am. J. Med.
Genet. 37: 371-374, 1990.

3. Mondino, B. J.; Brown, S. I.: Hereditary congenital alacrima.
Arch. Ophthal. 94: 1478-1480, 1976.

*FIELD* CS

Eyes:
   Congenital alacrima;
   Punctate corneal erosions;
   Lacrimal gland hypoplasia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 12/12/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
103470
*FIELD* TI
103470 ALBINISM, OCULAR, WITH SENSORINEURAL DEAFNESS
*FIELD* TX
Lewis (1978) found 7 affected males and 5 affected females in 3
consecutive generations of a Caucasian kindred. As in the X-linked
Nettleship-Falls form of ocular albinism (300500) and in the autosomal
recessive O'Donnell variety (203310), the patients showed reduced visual
acuity, photophobia, nystagmus, translucent irides, strabismus,
hypermetropic refractive errors, and albinotic fundus with foveal
hypoplasia. The skin lesions showed macromelanosomes as in X-linked
ocular albinism. Deafness, which was accompanied by vestibular
hypofunction, lentigines even in unexposed areas, optic nerve dysplasia,
and dominant inheritance distinguished this form of ocular albinism. (In
the LEOPARD syndrome (151100) vestibular function is normal.) Lewis
(1989) expressed the opinion that the family reported by Bard (1978) as
an instance of Waardenburg syndrome in fact had this disorder. Lewis
(1989) had also been told of 2 other small families with the syndrome.

*FIELD* RF
1. Bard, L. A.: Heterogeneity in Waardenburg's syndrome: report of
a family with ocular albinism. Arch. Ophthal. 96: 1193-1198, 1978.

2. Lewis, R. A.: Ocular albinism and deafness.  (Abstract) Am. J.
Hum. Genet. 30: 57A only, 1978.

3. Lewis, R. A.: Personal Communication. Houston, Texas  9/1989.

*FIELD* CS

Eyes:
   Reduced visual acuity;
   Photophobia;
   Nystagmus;
   Translucent irides;
   Strabismus;
   Hypermetropia;
   Albinotic fundus;
   Foveal hypoplasia;
   Optic nerve dysplasia

Skin:
   Hypomelanosis;
   Lentigines

Ears:
   Deafness;
   Vestibular hypofunction

Lab:
   Macromelanosomes

Inheritance:
   Autosomal dominant form;
   also X-linked

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/14/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
103500
*FIELD* TI
103500 ALBINISM-DEAFNESS OF TIETZ
*FIELD* TX
Tietz (1963) described 14 persons in 6 generations with albinism and
complete nerve deafness. The albinism was generalized but did not affect
the eyes. The irides were blue. Nystagmus and other ocular abnormalities
were absent. The medial canthi and nasal bridge were normal. The
eyebrows were almost totally lacking. The albinism in this trait is
hypopigmentation and not true albinism; the affected individuals tan,
for example. Reed et al. (1967) thought this might have been merely a
dominant type of deafness in unusually blond persons. See 156845.0003
for a description of a mutation in the MITF gene in mother and son with
a syndrome resembling that reported by Tietz (1963).

*FIELD* RF
1. Reed, W. B.; Stone, V. M.; Boder, E.; Ziprkowski, L.: Pigmentary
disorders in association with congenital deafness. Arch. Derm. 95:
176-186, 1967.

2. Tietz, W.: A syndrome of deaf-mutism associated with albinism
showing dominant autosomal inheritance. Am. J. Hum. Genet. 15:
259-264, 1963.

*FIELD* CS

Skin:
   Generalized hypopigmentaion

Ears:
   Complete nerve deafness

Eyes:
   Normal

Hair:
   Absent eyebrows

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/12/1996
terry: 3/5/1996
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
103580
*FIELD* TI
#103580 ALBRIGHT HEREDITARY OSTEODYSTROPHY; AHO
PSEUDOHYPOPARATHYROIDISM, TYPE IA, INCLUDED; PHP;;
PHP-IA, INCLUDED
*FIELD* MN
Albright hereditary osteodystrophy is characterized by ectopic
calcification and ossification, rounded facies, 'absent 4th knuckles,'
and short feet and hands with short metacarpals (particularly the 4th)
and terminal phalanges (Weinberg and Stone, 1971).
Pseudohypoparathyroidism type IA (PHP-IA) is caused by a defect in the
alpha subunit of Gs (Levine et al., 1988). (Gs = stimulatory guanine
nucleotide-binding protein of adenylate cyclase. PHP-IA = disorder in
patients with decreased cell membrane Gs activity; PHP-IB = disorder in
those with normal activity.) The stimulatory and inhibitory G molecules
are composed of beta and gamma subunits common to the two, and alpha
units genetically unique to each. The gene for the alpha subunit of Gs
(GNAS1; 139320) has been mapped to the long arm of chromosome 20. PHP-IB
is presumably a receptor defect. G unit activity is 50% in PHP-IA and
100% in PHP-IB. All cases of PHP-IA and only 15% of cases of PHP-IB have
Albright hereditary osteodystrophy. All cases of both types have renal
resistance to PTH, but thyroid resistance to TSH, hepatic resistance to
glucagon, and gonadal dysfunction, which occur in most cases of PHP-IA,
are rarely if ever seen in PHP-IB. The alpha subunit of Gs is probably
encoded by the same gene in most, if not all, endocrine target cells,
since patients with PHP-IA have reduced responsiveness to many hormones
that act by stimulating adenylate cyclase (Stryer and Bourne, 1986).

Levine et al. (1986) found reductions in red cell membrane Gs activity
in cases of pseudopseudohypoparathyroidism comparable to those in
pseudohypoparathyroidism type IA, but the patients with
pseudopseudohypoparathyroidism did not have obvious endocrine
dysfunction. Other factors must determine whether hormone resistance
occurs with this genetic defect.

In patients whose Gs-protein activity had been determined, 9 of 14
patients with type IA and none of 11 patients with type IB
pseudohypoparathyroidism had mental deficiency (Farfel and Friedman,
1986). Levine et al. (1988) determined that mRNA levels were
approximately 50% reduced for the alpha subunit of the G protein in
affected members of 6 pedigrees studied, whereas they were normal in
affected members of 2 other pedigrees. Some cases of AHO are due to
point mutations in the GNAS1 gene.

Published reports of AHO involving 2 or more generations show a marked
excess of maternal transmission. Furthermore, full expression of the
gene (AHO plus hormone resistance in the form of
pseudohypoparathyroidism) occurs in maternally transmitted cases, and
only partial expression (AHO alone) occurs in paternally transmitted
cases (Davies and Hughes, 1993). The suggestion that genomic imprinting
is involved has not been substantiated (Wilson et al., 1994).

*FIELD* ED
carol: 07/26/1996 marlene: 7/25/1996 joanna: 7/11/1996

*FIELD* CD
F. Clarke Fraser: 5/9/1996
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is known
to be due to mutation in the GNAS1 gene (139320), located on chromosome
20.

See 300800 and 139320. Weinberg and Stone (1971) described a family in
which a brother and sister and a son and daughter of the brother had
typical Albright osteodystrophy. The patients were of normal
intelligence but showed ectopic calcification and ossification, rounded
facies, 'absent 4th knuckles,' and short feet and hands with
particularly short 4th metacarpals. (In subsequent studies of this
family by Levine and Van Dop (1986), Ns (or Gs) was found to be normal.)
Other families suggesting autosomal dominant inheritance were reviewed.
In a large number of patients, Farfel et al. (1981) studied erythrocyte
N-protein, the membrane-bound coupling protein required for stimulation
of adenylate cyclase by hormones and by guanine nucleotides. (This
protein was called 'N' by Bourne et al. (1981) and 'G' by Levine et al.
(1981).) A group of 15 patients with N-protein activity of about 50% of
normal included a mother and daughter and 2 sisters. The authors
suggested that both dominant and recessive inheritance exist. They also
observed families with normal erythrocyte N-protein in which
pseudohypoparathyroidism and hypothyroidism were inherited as an
autosomal dominant. Fitch (1982) favored autosomal dominant inheritance.
She pointed out confusion with myositis ossificans. Short metacarpals
and short terminal phalanges are typical. Izraeli et al. (1992)
described a family in which 5 members of 3 successive generations had
the clinical features of AHO associated with congenital osteoma cutis
(166350). Zung et al. (1996) pictured subcutaneous nodules of the left
heel in a 7-year-old girl with AHO. The mother, aged 38 years, had
multiple subcutaneous masses of the limbs and bilateral shortening of
the fourth metacarpals. A mammogram showed calcified breast nodules
which were also palpable.

The possibility of an anomalous parathormone in one form of PHP is
suggested by observations of Loveridge et al. (1982) using a
cytochemical bioassay in which plasma or a standard reference
preparation of parathormone is added to segments of guinea pig kidney
maintained in organ culture. When exogenous parathormone was added to
plasma of normal subjects or those with hyperparathyroidism or
hypoparathyroidism, response was commensurate with the amount added; 50
to 90% of the exogenous hormone was 'recovered.' When this was done with
the plasma of 10 PHP patients, recovery ranged from less than 1% up to
35%. This seemed to indicate an inhibitor in PHP plasma. Interestingly,
it was not found in the plasma of a PHP patient who had previously
undergone parathyroidectomy. Thus, the PHP patient appears to have an
immunoreactive parathormone which lacks activity on the kidney, acting
much as do certain synthetic parathyroid-hormone peptides, such as 3-34
PTH; these bind to renal receptors without stimulating adenylate cyclase
activity. Levine et al. (1986) found reductions in red cell membrane Gs
activity in cases of pseudopseudohypoparathyroidism that were comparable
to those in pseudohypoparathyroidism type IA. (Gs = stimulatory guanine
nucleotide-binding protein of adenylate cyclase. Synonyms = G/F, G unit,
and Ns. PHP IA = disorder in patients with decreased cell membrane Gs
activity; PHP IB = disorder in those with normal activity.) Yet the
patients with pseudopseudohypoparathyroidism did not have obvious
endocrine dysfunction. Other factors, as yet undefined, must determine
whether hormone resistance occurs with this genetic defect. Autosomal
dominant inheritance is supported by the demonstration of father-to-son
transmission of decreased Gs activity (Van Dop et al., 1984).

Pseudohypoparathyroidism type IA (PHP-IA) is caused by a defect in the
alpha subunit of Gs. (The stimulatory and inhibitory G molecules are
composed of beta and gamma subunits common to the two, and alpha units
genetically unique to each.) The gene for the alpha subunit of Gs has
been mapped to chromosome 20 (see 139320). Thus, the quandary of
autosomal vs X-linked inheritance (see discussion in 300800) was settled
for this form of pseudohypoparathyroidism. PHP-IB is presumably a
receptor defect. G unit activity is 50% in PHP-IA and 100% in PHP-IB.
All cases of PHP-IA and only 15% of cases of PHP-IB have Albright
hereditary osteodystrophy. All of both types have renal resistance to
PTH, but thyroid resistance to TSH, hepatic resistance to glucagon, and
gonadal dysfunction, which occur in most cases of PHP-IA, are rarely if
ever seen in PHP-IB. Studies in frog neuroepithelium showed that the
sense of smell is mediated by a G(s)-adenylate cyclase system. Weinstock
et al. (1986) found that all G(s)-deficient patients (with type IA PHP)
had impaired olfaction whereas all G(s)-normal PHP patients (type IB)
had normal olfaction. This suggested that G(s)-deficient patients may be
resistant or impaired in other cAMP-mediated actions in other
nonendocrine systems. In type IA pseudohypoparathyroidism (PHP-IA), Gs
activity, measured by in vitro complementation of the cyc(-) defect, is
reduced by about 50% in red cells, skin fibroblasts, lymphoblasts, and
renal cells. These findings are consistent with autosomal dominant
inheritance (Spiegel et al., 1985). The cyc(-) complementation assay
measures activity of the alpha subunit of Gs. This subunit is probably
encoded by the same gene in most, if not all, endocrine target cells,
since patients with PHP-IA have reduced responsiveness to many hormones
that act by stimulating adenylate cyclase. Visual excitation is mediated
by a related G protein, transducin (Stryer and Bourne, 1986); see
189970. Mental deficiency occurs in 47 to 75% of patients with
pseudohypoparathyroidism type I.

Because mutations in the adenylate cyclase-cAMP system may affect the
learning ability of Drosophila, Farfel and Friedman (1986) assessed
mental deficiency in 25 patients whose Ns-protein activity had been
determined. Nine of 14 patients with type IA and none of 11 patients
with type IB pseudohypoparathyroidism had mental deficiency. Farfel and
Friedman (1986) concluded that Ns-protein deficiency, reduced cAMP
levels, or both are involved in the mental deficiency of these patients.
Levine et al. (1988) presented evidence that patients with type I
pseudohypoparathyroidism associated with Albright hereditary
osteodystrophy have deficiency of the alpha subunit of the G protein
that stimulates adenylyl cyclase, and examined the nature of the
molecular defect in 8 kindreds. Using a cDNA hybridization probe for
GNAS (139320), they could show no abnormalities of restriction fragments
or gene dosage on restriction analysis with several endonucleases. RNA
blot and dot blot analysis of total RNA from cultured fibroblasts
obtained from the patients revealed about 50% reduced mRNA levels for
the alpha subunit of the G protein in affected members of 6 of the
pedigrees but normal levels in affected members of the other 2
pedigrees. By contrast, mRNA levels encoding the alpha subunit of the G
protein that inhibits adenylyl cyclase (139310) were not altered in any.
Allen et al. (1988) concluded that hypomagnesemia can prevent the
elevation of parathyroid hormone concentrations in familial
pseudohypoparathyroidism; the observation indicates that the parathyroid
gland retains its physiologic response to hypomagnesemia in this
disorder. Gejman et al. (1990) used a combination of PCR, denaturing
gradient gel electrophoresis, and direct sequencing to detect a total of
5 allelic variants in the GNAS1 gene. Only 2 of these, both in exon 10,
were present in AHO affected individuals exclusively. One neutral
polymorphism in exon 5 creates a new FOK1 restriction site which was
used for linkage mapping of the GNAS1 gene in the CEPH reference
pedigrees. A maximal lod score of 9.31 was obtained at a theta of 0.042
with the locus D20S15, previously reported to be on the long arm of
chromosome 20 (Donis-Keller et al., 1987).

Abnormalities of secretion of thyroid hormone (de Wijn and Steendijk,
1982) and gonadotropins (Shapiro et al., 1980) have been described in
patients with pseudohypoparathyroidism. Stirling et al. (1991) described
mother and son with deficiency in production of growth hormone-releasing
factor (GHRH; 139190) in combination with other features characteristic
of this syndrome.

Davies and Hughes (1993) pointed out that published reports of AHO
involving 2 or more generations show a marked excess of maternal
transmission. Furthermore, full expression of the gene (AHO plus hormone
resistance in the form of pseudohypoparathyroidism) occurs in maternally
transmitted cases, and only partial expression (AHO alone) occurs in
paternally transmitted cases. Davies and Hughes (1993) suggested that
genomic imprinting is involved in the expression of this disorder. The
region of chromosome 20 occupied by the Gs protein that is mutant in
this disorder is homologous to an area of mouse chromosome 2 involved in
both maternal and paternal imprinting. Hall (1990) had suggested that
AHO may show imprinting by virtue of location in this area. Schuster et
al. (1994), however, reported findings inconsistent with the imprinting
hypothesis in a family with AHO and reduced GNAS1 activity reported by
Schuster et al. (1993). PHP-Ia was inherited paternally as well as
maternally, suggesting that mechanisms other than genomic imprinting are
responsible for the full expression of hormone resistance, at least
within this family. It may be that additional components of signal
transduction (for example, calmodulin, cAMP phosphodiesterase, or
protein kinase A) are responsible for the difference between PHP-Ia and
PPHP. Along the same line, to establish if GNAS1 is indeed imprinted,
Campbell et al. (1994) examined the parental origin of GNAS1
transcription in human fetal tissues. Of 75 fetuses genotyped, at
gestational ages ranging from 6 to 13 weeks, 13 heterozygous for an FokI
polymorphism in exon 5 of GNAS1 were identified whose mothers were
homozygous for one or another allele. RNA from up to 10 different
tissues from each fetus was analyzed by reverse transcriptase-PCR. In
all cases, expression from both parental alleles was shown by FokI
digestion of RT-PCR products and quantification of the resulting
fragments. No tissue-specific pattern of expression was discerned.
Campbell et al. (1994) concluded that if genomic imprinting regulates
the expression of the GNAS1 gene, the effect must either be subtle and
quantitative or be confined to a small subset of specialized
hormone-responsive cells within the target tissues. Wilson et al. (1994)
likewise used an intragenic GNAS1 FokI polymorphism to determine the
parental origin of the gene mutations in sporadic and familial AHO. A
sporadic case of pseudo-pseudohypoparathyroidism was found to be
associated with a de novo G-to-A substitution at the exon 5 donor splice
junction; the mutation was paternally derived.

*FIELD* SA
Goeminne  (1965); Patten et al. (1989); Winter and Hughes (1980)
*FIELD* RF
1. Allen, D. B.; Friedman, A. L.; Greer, F. R.; Chesney, R. W.: Hypomagnesemia
masking the appearance of elevated parathyroid hormone concentrations
in familial pseudohypoparathyroidism. Am. J. Med. Genet. 31: 153-158,
1988.

2. Bourne, H. R.; Kaslow, H. R.; Brickman, A. S.; Farfel, Z.: Fibroblast
defect in pseudohypoparathyroidism, type I: reduced activity of receptor-cyclase
coupling protein. J. Clin. Endocr. Metab. 53: 636-640, 1981.

3. Campbell, R.; Gosden, C. M.; Bonthron, D. T.: Parental origin
of transcription from the human GNAS1 gene. J. Med. Genet. 31: 607-614,
1994.

4. Davies, S. J.; Hughes, H. E.: Imprinting in Albright's hereditary
osteodystrophy. J. Med. Genet. 30: 101-103, 1993.

5. de Wijn, E. M.; Steendijk, R.: Growth and development in a girl
with pseudohypoparathyroidism and hypothyroidism. Acta Paediat. Scand. 71:
657-660, 1982.

6. Donis-Keller, H.; Green, P.; Helms, C.; Cartinhour, S.; Weiffenbach,
B.; Stephens, K.; Keith, T. P.; Bowden, D. W.; Smith, D. R.; Lander,
E. S.; et al.: A genetic linkage map of the human genome. Cell 51:
319-337, 1987.

7. Farfel, Z.; Brothers, V. M.; Brickman, A. S.; Conte, F.; Neer,
R.; Bourne, H. R.: Pseudohypoparathyroidism: inheritance of deficient
receptor-cyclase coupling activity. Proc. Nat. Acad. Sci. 78: 3098-3102,
1981.

8. Farfel, Z.; Friedman, E.: Mental deficiency in pseudohypoparathyroidism
type I is associated with Ns-protein deficiency. Ann. Intern. Med. 105:
197-199, 1986.

9. Fitch, N.: Albright's hereditary osteodystrophy: a review. Am.
J. Med. Genet. 11: 11-29, 1982.

10. Gejman, P. V.; Weinstein, L. S.; Martinez, M.; Spiegel, A. M.;
Gershon, E. S.: Genetic mapping of the G(s)-alpha gene and detection
of mutations in Albright hereditary osteodystrophy (AHO) by using
polymerase chain reaction (PCR), denaturing gradient gel electrophoresis
(DGGE) and direct sequencing. (Abstract) Am. J. Hum. Genet. 47 (suppl.):
A217 only, 1990.

11. Goeminne, L.: Albright's hereditary poly-osteochondrodystrophy
(pseudo-pseudo-hypoparathyroidism with diabetes, hypertension, arteritis
and polyarthrosis). Acta Genet. Med. Gemellol. 14: 226-281, 1965.

12. Hall, J. G.: Genomic imprinting: review and relevance to human
diseases. Am. J. Hum. Genet. 46: 857-873, 1990.

13. Izraeli, S.; Metzker, A.; Horev, G.; Karmi, D.; Merlob, P.; Farfel,
Z.: Albright hereditary osteodystrophy with hypothyroidism, normocalcemia,
and normal Gs protein activity: a family presenting with congenital
osteoma cutis. Am. J. Med. Genet. 43: 764-767, 1992.

14. Levine, M. A.; Ahn, T. G.; Klupt, S. F.; Kaufman, K. D.; Smallwood,
P. M.; Bourne, H. R.; Sullivan, K. A.; Van Dop, C.: Genetic deficiency
of the alpha subunit of the guanine nucleotide-binding protein G(s)
as the molecular basis for Albright hereditary osteodystrophy. Proc.
Nat. Acad. Sci. 85: 617-621, 1988.

15. Levine, M. A.; Downs, R. W., Jr.; Lasker, R. D.; Marx, S. J.;
Moses, A. M.; Aurbach, G. D.; Spiegel, A. M.: Resistance to multiple
hormones in patients with pseudohyperparathyroidism and deficient
guanine nucleotide regulatory protein. (Abstract) Clin. Res. 29:
412A only, 1981.

16. Levine, M. A.; Jap, T.-S.; Mauseth, R. S.; Downs, R. W.; Spiegel,
A. M.: Activity of the stimulatory guanine nucleotide-binding protein
is reduced in erythrocytes from patients with pseudohypoparathyroidism
and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic
analysis of Albright's hereditary osteodystrophy in six kindreds. J.
Clin. Endocr. Metab. 62: 497-502, 1986.

17. Levine, M. A.; Van Dop, C.: Personal Communication. Baltimore,
Md.  2/27/1986.

18. Loveridge, N.; Fischer, J. A.; Nagant de Deuxchaisnes, C.; Dambacher,
M. A.; Tschopp, F.; Werder, E.; Devogelaer, J.-P.; De Meyer, R.; Bitensky,
L.; Chayen, J.: Inhibition of cytochemical bioactivity of parathyroid
hormone by plasma in pseudohypoparathyroidism type I. J. Clin. Endocr.
Metab. 54: 1274-1275, 1982.

19. Patten, J. L.; Smallwood, P. M.; Eil, C.; Johns, D. R.; Valle,
D.; Steel, G.; Levine, M. A.: An initiator codon mutation in the
gene encoding the alpha subunit of Gs in pseudohypoparathyroidism
type IA (PHP IA). (Abstract) Am. J. Hum. Genet. 45 (suppl.): A212
only, 1989.

20. Schuster, V.; Eschenhagen, T.; Kruse, K.; Gierschik, P.; Kreth,
H. W.: Endocrine and molecular biological studies in a German family
with Albright hereditary osteodystrophy. Europ. J. Pediat. 152:
185-189, 1993.

21. Schuster, V.; Kress, W.; Kruse, K.: Paternal and maternal transmission
of pseudohypoparathyroidism type Ia in a family with Albright hereditary
osteodystrophy: no evidence of genomic imprinting. (Letter) J. Med.
Genet. 31: 84-86, 1994.

22. Shapiro, M. S.; Bernheim, J.; Gutman, A.; Arber, I.; Spitz, I.
M.: Multiple abnormalities of anterior pituitary hormone secretion
in association with pseudohypoparathyroidism. J. Clin. Endocr. Metab. 51:
483-487, 1980.

23. Spiegel, A. M.; Gierschik, P.; Levine, M. A.; Downs, R. W., Jr.
: Clinical implications of guanine nucleotide-binding proteins as
receptor-effector couplers. New Eng. J. Med. 312: 26-33, 1985.

24. Stirling, H. F.; Barr, D. G. D.; Kelnar, C. J. H.: Familial growth
hormone releasing factor deficiency in pseudopseudohypoparathyroidism. Arch.
Dis. Child. 66: 533-535, 1991.

25. Stryer, L.; Bourne, H. R.: G proteins: a family of signal transducers. Annu.
Rev. Cell Biol. 2: 391-419, 1986.

26. Van Dop, C.; Bourne, H. R.; Neer, R. M.: Father to son transmission
of decreased N(s) activity in pseudohypoparathyroidism type Ia. J.
Clin. Endocr. Metab. 59: 825-834, 1984.

27. Weinberg, A. G.; Stone, R. T.: Autosomal dominant inheritance
in Albright's hereditary osteodystrophy. J. Pediat. 79: 996-999,
1971.

28. Weinstock, R. S.; Wright, H. N.; Spiegel, A. M.; Levine, M. A.;
Moses, A. M.: Olfactory dysfunction in humans with deficient guanine
nucleotide-binding protein. Nature 322: 635-636, 1986.

29. Wilson, L. C.; Oude Luttikhuis, M. E. M.; Clayton, P. T.; Fraser,
W. D.; Trembath, R. C.: Parental origin of Gs-alpha gene mutations
in Albright's hereditary osteodystrophy. J. Med. Genet. 31: 835-839,
1994.

30. Winter, J. S. D.; Hughes, I. A.: Familial pseudohypoparathyroidism
without somatic anomalies. J. Canad. Med. Assoc. 123: 26-31, 1980.

31. Zung, A.; Herzenberg, J. E.; Chalew, S. A.: Radiological case
of the month. Arch. Pediat. Adolesc. Med. 15: 643-644, 1996.

*FIELD* CS

Endocrine:
   Pseudohypoparathyroidism;
   Thyrotropin resistance;
   Gonadotropin resistance;
   Hypothyroidism;
   Deficient prolactin release;
   Partial resistance to antidiuretic hormone;
   Hypertension

Growth:
   Short stature;
   Obesity

Limbs:
   Brachydactyly;
   Short metacarpals

GU:
   Oligomenorrhea

Skin:
   Subcutaneous ossifications

Neuro:
   Mental retardation;
   Hypocalcemic tetany;
   Seizures

HEENT:
   Round face;
   Cataract;
   Calcified choroid plexus

Teeth:
   Delayed tooth eruption;
   Enamel hypoplasia

Lab:
   Hypocalcemia;
   Elevated serum parathyroid hormone (PTH) level;
   Parathyroid hyperplasia;
   Low urinary cyclic AMP response to PTH administration;
   Reduced Gs activity in PHP-IA;
   Normal Gs activity in PHP-IB;
   Decreased N protein activity in some patients with PHP-IA;
   Low serum estrogen;
   High LH and FSH;
   Abnormal parathormone-receptor-adenylate cyclase complex of the renal
   cortical cell plasma membrane;
   Abnormal nucleotide-binding regulatory protein activity

Inheritance:
   Autosomal dominant type (20q);
   also X-linked and autosomal recessive varieties

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/27/1996
terry: 11/12/1996
terry: 11/4/1996
carol: 7/26/1996
carol: 3/2/1995
davew: 8/18/1994
terry: 7/18/1994
mimadm: 4/12/1994
warfield: 4/7/1994
pfoster: 3/25/1994

*RECORD*
*FIELD* NO
103581
*FIELD* TI
103581 ALBRIGHT HEREDITARY OSTEODYSTROPHY-2; AHO2
*FIELD* TX
Hedeland et al. (1992) described a mother and daughter with classic
features of pseudohypoparathyroidism type I and Albright hereditary
osteodystrophy in association with proximal deletion of 15q
del(15)(q11q13) similar to that seen in Prader-Willi syndrome (176270)
and Angelman syndrome (105830). Using a series of DNA probes that often
show deletion or uniparental disomy in the latter 2 conditions, Hedeland
et al. (1992) found no evidence for either in the mother or the
daughter. One form of AHO has been demonstrated to be due to point
mutations in the GNAS1 gene (139320) on chromosome 20. It is possible,
of course, that there are other forms of AHO that map elsewhere.

*FIELD* RF
1. Hedeland, H.; Berntorp, K.; Arheden, K.; Kristoffersson, U.: Pseudohypoparathyroidism
type I and Albright's hereditary osteodystrophy with a proximal 15q
chromosomal deletion in mother and daughter. Clin. Genet. 42: 129-134,
1992.

*FIELD* CS

Endocrine:
   Pseudohypoparathyroidism;
   Thyrotropin resistance;
   Gonadotropin resistance;
   Hypothyroidism;
   Deficient prolactin release;
   Partial resistance to antidiuretic hormone;
   Hypertension

Growth:
   Short stature;
   Obesity

Limbs:
   Brachydactyly;
   Short metacarpals

GU:
   Oligomenorrhea

Skin:
   Subcutaneous ossifications

Neuro:
   Mental retardation;
   Hypocalcemic tetany;
   Seizures

HEENT:
   Round face;
   Cataract;
   Calcified choroid plexus

Teeth:
   Delayed tooth eruption;
   Enamel hypoplasia

Lab:
   Hypocalcemia;
   Elevated serum parathyroid hormone (PTH) level;
   Parathyroid hyperplasia;
   Low urinary cyclic AMP response to PTH administration;
   Reduced Gs activity in PHP-IA;
   Normal Gs activity in PHP-IB;
   Decreased N protein activity in some patients with PHP-IA;
   Low serum estrogen;
   High LH and FSH;
   Abnormal parathormone-receptor-adenylate cyclase complex of the renal
   cortical cell plasma membrane;
   Abnormal nucleotide-binding regulatory protein activity

Inheritance:
   ? Autosomal dominant type (?15q);
   also X-linked and autosomal recessive varieties

*FIELD* CD
Victor A. McKusick: 1/21/1993

*FIELD* ED
mimadm: 3/11/1994
carol: 1/21/1993

*RECORD*
*FIELD* NO
103600
*FIELD* TI
*103600 ALBUMIN; ALB
DYSALBUMINEMIC HYPERTHYROXINEMIA, INCLUDED;;
HYPERTHYROXINEMIA, DYSALBUMINEMIC, INCLUDED;;
ANALBUMINEMIA, INCLUDED;;
BISALBUMINEMIA, INCLUDED
*FIELD* MN
Albumin is a soluble, globular, unglycosylated, monomeric protein of
molecular weight 65,000, which comprises about one-half of the blood
serum protein. Albumin functions primarily as a carrier protein for
steroids, fatty acids, and thyroid hormones and plays a role in
stabilizing extracellular fluid volume. The human albumin gene is 16,961
nucleotides long. It is split into 15 exons which are symmetrically
placed within 3 domains (Minghetti et al., 1986). Mutations in the ALB
gene, located on chromosome 4q11-q13 (Harper and Dugaiczyk, 1983),
result in various anomalous proteins (Madison et al., 1994).
'Alloalbuminemia' is the term suggested for the variant albumins
(Blumberg et al., 1968).

Analbuminemia is a rare autosomal recessive disorder in which serum
albumin is absent (Ruffner and Dugaiczyk, 1988). The homozygotes have
remarkably little inconvenience attributable to the lack of serum
albumin. Some fetal hydrops may be caused by analbuminemia. The normal
levels of albumin in heterozygotes may indicate that the mutation is at
a regulatory locus independent of the albumin locus.

The serum albumin locus on 4q is presumably the site of the mutation
responsible for the condition called 'familial dysalbuminemic
hyperthyroxinemia' (FDH) (Ruiz et al., 1982). Patients, who are
euthyroid, show elevated serum thyroxine and free-thyroxine index caused
by an abnormal serum albumin that preferentially binds thyroxine. FDH
can be subdivided into 3 types, depending on the coexistence of T3 and
rT3 excess with hyperthyroxinemia (Lalloz et al., 1985). Seemingly, the
binding of drugs by albumin and the release of thyroid hormone to the
tissues are not altered in ways that have clinical significance though
some patients could mistakenly be treated for hyperthyroidism (Yeo et
al., 1987). Point mutations have been found (Petersen et al., 1994).

*FIELD* ED
carol: 07/25/1996 marlene: 7/23/1996 joanna: 7/11/1996

*FIELD* CD
F. Clarke Fraser: 5/9/1996
*FIELD* TX

DESCRIPTION

Albumin is a soluble, monomeric protein which comprises about one-half
of the blood serum protein. Albumin functions primarily as a carrier
protein for steroids, fatty acids, and thyroid hormones and plays a role
in stabilizing extracellular fluid volume. Mutations in the ALB gene on
chromosome 4 result in various anomalous proteins.

MAPPING

Weitkamp et al. (1966) concluded that the albumin locus is closely
linked with the locus for GC type. Using the Naskapi variant, Kaarsalo
et al. (1967) found close linkage of the albumin and GC loci. Work with
somatic cell hybrids between human leukocytes and rat hepatoma cells
suggested that nucleotide phosphorylase and a human serum albumin locus
may be on the same chromosome (Darlington, 1974); however, these were
subsequently assigned to chromosomes 14 and 4, respectively.

Harper and Dugaiczyk (1983) mapped the albumin gene to chromosome 4 by
in situ hybridization. Dextran sulfate was used to enhance labeling, and
their technique permitted G-banding of the chromosomes with Wright's
stain on the same preparations used for autoradiography without
pretreatment. The regional localization (to 4q11-q13) agreed remarkably
with that arrived at by indirect methods. Kao et al. (1982) assigned the
albumin locus to chromosome 4 by using a human albumin cDNA probe in
human/Chinese hamster somatic cell hybrids. The ALB and
alpha-fetoprotein (AFP; 104150) genes are within 50 kb of each other
(Urano et al., 1984) and show strong linkage disequilibrium (Murray et
al., 1984). Magenis et al. (1989) used in situ hybridization to localize
the ALB and AFP genes to orangutan chromosome 3q11-q15 and gorilla
chromosome 3q11-q12 which are considered homologous to 4q11-q13.

EVOLUTION

The characteristic 3-domain structure of albumin and alpha-fetoprotein
has been conserved throughout mammalian evolution. Thus, 35.2% amino
acid homology is found between bovine serum albumin and murine AFP. Ohno
(1981) addressed the vexing question of why this conservation occurs
despite the nonessential nature of serum albumin as indicated by cases
of analbuminemia. Minghetti et al. (1985) found a high rate of both
silent substitutions and effective substitutions with amino acid changes
in serum albumin. Although the rates of effective substitution in amino
acid changes were not as high in albumin as in alpha-fetoprotein, they
were still faster than those of either hemoglobin or cytochrome c. This
high evolutionary change rate for albumin may be consistent with the
fact that inherited analbuminemia produces surprisingly few symptoms
despite the virtually complete absence of albumin.

Vitamin D binding protein (GC; 139200) and serum protease inhibitor are
linked not only in humans, but also in horse, cattle, and sheep in
mammals, and chicken in avian species. Shibata and Abe (1996) added the
Japanese quail to the group.

GENE STRUCTURE

Albumin is a globular unglycosylated serum protein of molecular weight
65,000. Minghetti et al. (1986) found that the human albumin gene is
16,961 nucleotides long from the putative 'cap' site to the first
poly(A) addition site. It is split into 15 exons which are symmetrically
placed within the 3 domains that are thought to have arisen by
triplication of a single primordial domain.

The albumin variant first described by Fraser et al. (1959) in a Welsh
family was characterized as a dimer by Jamieson and Ganguly (1969). The
amino acid sequence has been determined in fragments of serum albumin of
man (Dayhoff, 1972). By 1980, at least 2 dozen electrophoretic variants
of serum albumin had been reported but only 2 of them had been
characterized with respect to their primary structure: albumin A (the
common form) and albumin B (the variant found mainly in Europeans).

GENE FUNCTION

Albumin is synthesized in the liver as preproalbumin, which has an
N-terminal peptide that is removed before the nascent protein is
released from the rough endoplasmic reticulum. The product, proalbumin,
is in turn cleaved in the Golgi vesicles to give the secreted albumin.

Pinkert et al. (1987) used transgenic mice to locate a cis-acting DNA
element, an enhancer, important for efficient, tissue-specific
expression of the mouse albumin gene in the adult. Chimeric genes with
up to 12 kb of mouse albumin 5-prime flanking region fused to a human
growth hormone 'reporter' gene were tested. Whereas a region located 8.5
to 10.4 kb upstream of the albumin promoter was essential for high-level
expression in adult liver, the region between -8.5 and 0.3 kb was
dispensable.

GENETIC VARIABILITY

- Protein Variations

Fraser et al. (1959) found, on 2-dimensional electrophoresis (paper
first, followed by starch), an anomalous plasma protein in 6 persons in
2 generations of a family. The electrophoretic properties on paper were
the same in the anomalous albumin and in normal albumin. This
distinguishes the protein from that in bisalbuminemia, as does the fact
that the amount of the anomalous protein is much less than that of the
normal albumin in presumably heterozygous persons. That the same locus
as that which determines bisalbuminemia is involved here is suggested by
the finding of Weitkamp et al. (1967) that the Fraser anomalous albumin
is also linked to the GC locus.

'Alloalbuminemia' is the term suggested by Blumberg et al. (1968) for
the variant albumins. Various alloalbuminemias occur relatively
frequently in various American Indians (Arends et al., 1969). Melartin
and Blumberg (1966) found an electrophoretic variant of albumin in high
frequency in Naskapi Indians of Quebec and in lower frequency in other
North American Indians. Homozygotes were found.

Weitkamp et al. (1967), using 2 electrophoretic systems, compared the
serum albumin variants of 19 unrelated families. Five distinct classes
were found. One class of variants was found only in North American
Indians. The others were found only in persons of European descent.

In Punjab, North India, Kaur et al. (1982) found, by electrophoresis, 4
cases of alloalbuminemia among 550 persons. Two appeared to be new
variants. Another was albumin Naskapi. Since this variant has been found
also in North American Indians and Eti Turks, the authors suggested that
albumin Naskapi existed in a common ancestral population before the
migrations eastward and westward.

In describing a new human albumin variant, albumin Carlisle, Hutchinson
et al. (1986) stated that more than 80 genetically inherited variants of
human albumin were known. Fine et al. (1987) found a frequency of
alloalbuminemia in the French population of 0.0004. There was a high
occurrence of albumin B and of 2 proalbumin variants, Christchurch and
Lille.

- Bisalbuminemia

Bisalbuminemia is an asymptomatic variation in serum albumin.
Heterozygotes have 2 species of albumin, a normal type and one which
migrates abnormally rapidly or slowly on electrophoresis. Acrocyanosis
was present in 2 and probably 3 successive generations of the family
reported by Williams and Martin (1960) but 4 other bisalbuminemic
persons did not show acrocyanosis.

Tarnoky and Lestas (1964) described a 'new' type of bisalbuminemia in 2
sibs and the son of one of them. The usual type was demonstrable by
filter paper electrophoresis. The new type was demonstrable by
electrophoresis on cellulose acetate at pH 8.6, but not on filter paper
or starch gel. The term 'paralbuminemia' was suggested by Earle et al.
(1959) as preferable to 'bisalbuminemia' which is perhaps appropriate
for the heterozygous state only.

A phenocopy of hereditary bisalbuminemia, acquired bisalbuminemia,
occurs with overdose of beta-lactam antibiotics (Arvan et al., 1968) and
with pancreatic pseudocyst associated with pleural or ascitic effusion
(Shashaty and Atamer, 1972). The anomalous albumin is anodal to the
normal albumin in its electrophoretic mobility. Vaysse et al. (1981)
described acquired trisalbuminemia in a patient with familial
bisalbuminemia and pancreatic pseudocyst.

- Proalbumin

Rochu and Fine (1986) described a new method for identifying genetic
variants of human proalbumin. Two genetic variants of proalbumin,
proalbumin Christchurch (Brennan and Carrell, 1978) and proalbumin Lille
(Abdo et al., 1981), have been shown to result from a substitution at 1
of the 2 arginyl residues at the dibasic site at which the normal
propeptide is cleaved. Both of these mutations prevent excision of this
basic propeptide, and thus each of these proalbumin variants has a
slower electrophoretic mobility than that of normal albumin. Two genetic
variants, previously described as albumin Gainesville and albumin
Pollibauer, were shown to be identical with proalbumin Christchurch
(Fine et al., 1983) and proalbumin Lille (Galliano et al., 1984),
respectively.

Arai et al. (1989) found that the 2 types of proalbumins most common in
Europe (Lille type, arginine-to-histidine at position -2; Christchurch
type, arginine-to-glutamic acid at position -1) also occur in Japan. The
clustering of these and of several other amino acid exchanges in certain
regions of the albumin molecule, arising as independent mutations,
suggests that certain sites are hypermutable and/or that mutants
involving certain sites are more subject to selection than mutants
involving others. In a study of 15,581 unrelated children in Hiroshima
and Nagasaki, Arai et al. (1989) found 5 rare albumin variants and
determined the single amino acid substitution in each. All of these were
inherited and therefore unrelated to parental exposure at the time of
the bombing. The 5 substitutions were: Nag-1, asp269-to-gly; Nag-2,
asp375-to-asn; Nag-3, his3-to-gln; Hir-1, glu354-to-lys; and Hir-2,
glu382-to-lys. Two of the substitutions (Nag-1 and Nag-2) had previously
been reported (Takahashi et al., 1987). No instances of proalbumin
variants or of albumin B (glu570-to-lys), which are the most common
Caucasian alloalbumins, were found in the Hiroshima-Nagasaki study. Arai
et al. (1989) found 2 instances of albumin B and 1 example of a variant
proalbumin in Japanese from the vicinity of Tokyo. In a review of all
reported mutations, Arai et al. (1989) noted that 7 independent
substitution sites have been identified in the alloalbumins of diverse
populations in a sequence of only 29 amino acids as compared to a total
of 5 sites (excluding proalbumin variants) reported thus far for the
first 353 amino acids. Such a cluster of substitutions may reflect
vulnerability of the albumin gene to mutation in this region or the ease
of accommodation to structural changes in the affected area of the
protein. Arai et al. (1990) studied the albumin genetic variants that
have been reported in Asian populations and listed a total of 26 point
substitutions in diverse ethnic groups.

In the family reported by Laurell and Nilehn (1966), a 'new' type of
paralbuminemia was associated with connective tissue disorders,
including systemic lupus erythematosus, ruptured knee meniscus,
recurrent dislocation of shoulder, and back pain. The albumin variant
was characterized by a broad band in agarose gel electrophoresis that
indicated the presence of a slow component. A family study showed that
the anomalous albumin was present in 9 of 23 members representing 3
generations. Noticing a similarity of the electrophoretic pattern to
that of an albumin with an arg(-2)-to-cys mutation which they described,
Brennan et al. (1990) obtained plasma from 1 of the original subjects of
Laurell and Nilehn (1966) and demonstrated that it indeed showed the
same mutation that they had found in proalbumin Malmo (103600.0030).
This anomalous albumin occurs in about 1 per 1,000 persons in Sweden.

- Analbuminemia

Analbuminemia, a rare autosomal recessive disorder in which serum
albumin is absent, was first reported by Bennhold et al. (1954) of
Tubingen. See review by Ott (1962). In some reported families
analbuminemia is a completely recessive condition; serum albumin has a
normal level in heterozygotes. The homozygotes have remarkably little
inconvenience attributable to the lack of serum albumin. In the kindreds
of Bennhold et al. (1954) and Boman et al. (1976), heterozygotes showed
intermediate levels of serum albumin.

Kallee (1996) reported 2 sibs with analbuminemia who were followed for
38 years. The female patient received replacement therapy with human
serum albumin. Extreme lipodystrophy developed in this patient by the
fourth decade of life. She had juvenile osteoporosis, which normalized
under albumin replacement. She died from a granulosa cell cancer at age
69. Her brother never received albumin. He suffered from severe
osteoporosis with gibbus formation, and died from a colon carcinoma at
age 59. Both sibs had chronic insufficiency of the crural veins, with
chronic ulcerations of both lower legs but no varicosities of the upper
thighs. Despite high cholesterol values and high levels of several blood
clotting factors, neither of the patients had severe atherosclerosis or
thrombotic events. Kallee (1996) concluded that although patients often
fail to exhibit serious clinical signs apart from pathologic laboratory
findings, analbuminemia can no longer be regarded as a harmless anomaly.

Boman et al. (1976) presented data consistent with linkage of the
analbuminemia locus and the Gc locus. Cormode et al. (1975) found very
low plasma tryptophan in a neonate with analbuminemia who was small for
gestational age. Murray et al. (1983) restudied the family reported by
Boman et al. (1976). The proposita showed trace amounts of
immunologically normal serum albumin. With cDNA probes for the albumin
gene, no deletion could be detected. They demonstrated DNA polymorphism
of the albumin gene. In a review, Ruffner and Dugaiczyk (1988) stated
that of 22 reported analbuminemic individuals, 8 were known to be from
consanguineous matings. Dugaiczyk (1989) suggested that some fetal
hydrops may be caused by analbuminemia. The main causes of hydrops
fetalis are thalassemia and fetomaternal incompatibility; instances in
which neither of these can be demonstrated should be investigated for an
albumin defect.

Analbuminemic rats, like analbuminemic humans, are healthy (Nagase et
al., 1979). The use of cDNA probes failed to detect serum albumin gene
transcripts in liver of these analbuminemic rats (Esumi et al., 1980).
Thus, the disorder in the rat and perhaps the human may be the result of
gene deletion. On the other hand, the normal levels of albumin in
heterozygotes may indicate that the mutation is at a regulatory locus
independent of the albumin locus. In the analbuminemic rat, Esumi et al.
(1982) found albumin mRNA precursors in nuclei although such were
missing from the cytoplasm. From this they concluded that analbuminemia
in rats is caused by a unique type of mutation that affects albumin mRNA
maturation. In analbuminemia of the rat, Esumi et al. (1983)
demonstrated that a 7-bp deletion in an intron interferes with mRNA
formation. Shalaby and Shafritz (1990) showed that exon H is skipped in
the Nagase analbuminemic rat as a result of the 7-bp deletion at the
splice donor site of intron H-I. Mendel et al. (1989) could find no
abnormality of thyroxine transport and distribution in Nagase
analbuminemic rats. Murray et al. (1983) found a frequency of DNA
polymorphism in the ALB gene comparable to that in the globin system. No
gross structural rearrangement was found in a case of human
analbuminemia.

- Familial Dysalbuminemic Hyperthyroxinemia

The serum albumin locus on 4q is presumably the site of the mutation
responsible for the condition called by Ruiz et al. (1982) 'familial
dysalbuminemic hyperthyroxinemia.' Ruiz et al. (1982) studied 15
euthyroid patients from 8 families who showed elevated serum thyroxine
and free-thyroxine index, both due to an abnormal serum albumin that
preferentially binds thyroxine. Since there are several different
changes in the albumin molecule that can lead to increased binding of
thyroxine, several types might be expected. Lalloz et al. (1985)
subdivided FDH into 3 types, depending on the coexistence of T3 and rT3
excess with hyperthyroxinemia. Seemingly, the binding of drugs by
albumin and the release of thyroid hormone to the tissues are not
altered in ways that have clinical significance. DeCosimo et al. (1987)
presented evidence indicating that familial dysalbuminemic
hyperthyroxinemia is unusually frequent in Hispanics of Puerto Rican
origin. Yeo et al. (1987) reported the largest kindred with familial
dysalbuminemic hyperthyroxinemia thus far reported. Two of the patients
had mistakenly been treated for hyperthyroidism. Two women with the
disorder were receiving oral contraceptives, which produced an increase
in serum thyroxine-binding globulin (314200). Yeo et al. (1987) pointed
out that the coexistence of acquired high TBG or significant thyroid
malfunction may confound the diagnosis of dysalbuminemic
hyperthyroxinemia. Yabu et al. (1987) described a form of variant
albumin with a markedly enhanced binding activity for
L-3,5,3-prime-triiodothyronine (T3), a somewhat increased activity for
thyroxine (T4), and a normal activity for
3,3-prime,5-prime-triiodothyronine (rT3). The presence of the variant
albumin was recognized in a patient with Graves disease after successful
subtotal thyroidectomy. The findings could be misdiagnosed as T3
toxicosis or peripheral resistance to thyroid hormones. Premachandra et
al. (1988) commented that in patients with familial dysalbuminemic
hyperthyroxinemia, treatment of hypothyroidism with thyroxine has
special considerations because of binding of the drug to the atypical
albumin, and raised the possibility that other forms of drug therapy may
require custom tailoring. It appears that the molecular change in the
ALD gene responsible for familial dysalbuminemic hyperthyroxinemia has
not been determined in any instance (Putnam, 1993).

The ALB gene shows much DNA polymorphism. Except for chain terminations
in 2 Italian variants, all of the albumin mutations determined to that
time had been single base changes, with a preponderance of transitions
and purine mutations.

- Mutation Information

Takahashi et al. (1987) identified the amino acid substitutions in 3
different types of proalbumins designated Gainesville, Taipei, and
Takefu. The first 2 proalbumins were found to be identical to previously
described proalbumins, Christchurch and Lille types, respectively. All
of the variant proalbumins contain a basic propeptide that is not
removed during posttranscriptional processing because of a mutation in
the site of excision, an arg-arg sequence. Takefu resists tryptic
cleavage because of the substitution of proline for arginine at the -1
position. The substitution of glutamine for histidine at position 3 in
the variant albumin Nagasaki-3 decreases metal-binding affinity;
mutations farther down the polypeptide chain do not affect metal-binding
affinity, nor is there any reduction of copper-binding affinity in
albumin from patients with Wilson disease (277900). The variant
proalbumins show a characteristically lowered metal-binding affinity.

Takahashi et al. (1987) reported the amino acid substitution in 4
albumin variants detected by 1-dimensional electrophoresis in population
surveys involving tribal Amerindians and Japanese children. Albumin
Maku, discovered in a Maku Indian woman living among the Yanomama,
showed a substitution of glutamine for lysine at position 541. Albumin
Yanomama-2 appears to represent a true private polymorphism, i.e., it is
the product of an apparently unique allele within a single tribe that
has a frequency well above the 1% allele minimum for a polymorphism. It
has been found only in Yanomama Indians, was present in 491 of 3,504
persons studied, and had the highest frequency of any polypeptide
variant identified in 21 South American Indian tribes. It was found to
have a substitution of glycine for arginine at position 114. This
appears to represent a change from codon CGA to GGA. Albumin Nagasaki-2
showed a substitution of asparagine for aspartic acid at position 375,
corresponding to a single base change in codon GAT to AAT. Albumin
Nagasaki-3 was found to have substitution of glutamine for histidine at
position 3, corresponding with a 1-base change in the codon CAC to
either CAA or CAG.

Takahashi et al. (1987) pointed out that about one-half of the known
mutations in the coding sections in the large albumin gene border an
exonic junction, raising the possibility that hypermutable 'hot spots'
may be clustered there. In Japan, surveys showed that hemoglobin and
albumin variants were of roughly equal frequency and neither protein
appeared exceptionally variable. Since albumin is a much larger protein,
one might expect more genetic variability than in hemoglobin. This might
suggest that selection is relatively active against variants of this
molecule; yet total absence of this protein (analbuminemia) is
consistent with apparently satisfactory health.

Takahashi et al. (1987) tabulated the 13 amino acid substitutions
identified at that time and pointed out that they are unequally
distributed throughout the polypeptide chain. The slower delineation of
the nature of point mutations in albumin variants as compared to
hemoglobin variants can be attributed to 2 primary factors: first,
alloalbumins are not associated with disease or a significant effect on
physiologic function, and most are rare; second, the albumin molecule
consists of a single polypeptide chain with 585 amino acids and 17
disulfide bridges, a circumstance that magnifies the difficulty of
determining the presence of a single substitution.

Madison et al. (1994) provided a tabulation of the molecular changes in
albumin variants.

*FIELD* AV
.0001
ALBUMIN FUKUOKA-2
ALBUMIN TAIPEI
ALBUMIN LILLE
ALBUMIN VARESE
ALB, ARG-2HIS
Substitution of histidine for arginine at position -2 was found in
albumin Fukuoka-2 by Arai et al. (1989), in albumin Taipei by Takahashi
et al. (1987), in albumin Lille by Abdo et al. (1981) and Galliano et
al. (1988), and in albumin Varese by Galliano et al. (1990). A
CGT-to-CAT change is responsible for the substitution.

.0002
ALBUMIN HONOLULU-2
PROALBUMIN CHRISTCHURCH
PROALBUMIN GAINESVILLE
PROALBUMIN FUKUOKA-3
ALB, ARG-1GLN
This albumin has an arg(-1)-to-gln change in the preproprotein (Arai et
al., 1990; Brennan and Carrell, 1978). Brennan and Carrell (1978) found
a family with a circulating variant of proalbumin in members of 4
generations. No clinical abnormality was discernible in any of them. The
variant represents 50% of total albumin and shows an additional
N-terminal sequence, arg-gly-val-phe-arg-gln. Called 'proalbumin
Christchurch,' the variant appears to have a mutation of arginine to
glutamine at the last amino acid of this sequence. Thus, 2 basic amino
acids must be necessary for cleavage of proalbumin in the Golgi
vesicles. Copper binding is expected to be absent in the variant albumin
because of blocking of the high affinity binding site. This is a
situation comparable to Ehlers-Danlos syndrome type VII-A (130060) in
which an amino acid substitution at the site of cleavage of procollagen
results in persistence of procollagen and, in that case, clinically
important abnormalities in collagen fiber formation.

.0003
ALBUMIN HONOLULU-1
PROALBUMIN TAKEFU
ALB, ARG-1PRO
Substitution of proline for arginine at position -1 (Takahashi et al.,
1987).

.0004
ALBUMIN BREMEN
ALBUMIN BLENHEIM
ALBUMIN IOWA CITY-2
ALB, ASP1VAL
See Arai et al. (1990) and Brennan et al. (1990). Brennan et al. (1990)
suggested that hypermutability of 2 CpG dinucleotides in the codons for
the diarginyl sequence may account for the frequency of mutations in the
propeptide. Madison et al. (1991) showed that this mutation is caused by
a GAT-to-GTT change.

.0005
ALBUMIN NAGASAKI-3
ALB, HIS3GLN
See Takahashi et al. (1987).

.0006
ALBUMIN YANOMAMA-2
ALB, ARG114GLY
See Takahashi et al. (1987).

.0007
ALBUMIN NAGOYA
ALB, GLU119LYS
See Arai et al. (1990).

.0008
ALBUMIN NAGASAKI-1
ALBUMIN NIIGATA
ALB, ASP269GLY
See Arai et al. (1989).

.0009
ALBUMIN NEW GUINEA
ALBUMIN TAGLIACOZZO
ALBUMIN COOPERSTOWN
ALB, LYS313ASN
Huss et al. (1988) described an electrophoretically fast alloalbumin in
a family in New York State and called it albumin Cooperstown. It was
found to have a substitution of asparagine for lysine at residue 313 and
was shown to be the same as albumins found in Italy and in New Zealand.
A change from AAG to AAY is responsible for the substitution; Y = either
T or C. Galliano et al. (1990) found this albumin variant in 49
individuals in the Abruzzo region of Italy.

.0010
ALBUMIN REDHILL
ALB, ALA320THR AND ARG-2CYS
Brennan et al. (1990) characterized albumin Redhill, an albumin variant
that does not bind nickel and has a molecular mass 2.5 kD higher than
normal albumin. Its inability to bind nickel was explained by the
finding of an additional residue of arginine at position -1 of the
mature protein, but this did not explain the molecular basis of the
increase in apparent molecular mass. Further studies showed an
ala320-to-thr change, which introduced an asn-tyr-thr oligosaccharide
attachment sequence centered at asn318 and explained the increase in
molecular mass. DNA sequencing of PCR-amplified genomic DNA encoding the
prepro sequence of albumin indicated an additional mutation at position
-2 from arg to cys. Brennan et al. (1990) proposed that the new
phe-cys-arg sequence (replacing -phe-arg-arg-) in the propeptide serves
as an aberrant signal peptidase cleavage site and that the signal
peptidase cleaves the propeptide of albumin Redhill in the lumen of the
endoplasmic reticulum before it reaches the Golgi vesicles, which is the
site of the diarginyl-specific proalbumin convertase. Thus, albumin
Redhill is longer than normal by 1 amino acid at its NH2-terminus. The
ARG-2CYS mutation is the basis of proalbumin Malmo (103600.0030), a
relatively frequent variant.

.0011
ALBUMIN ROMA
ALB, GLU321LYS
Galliano et al. (1988) demonstrated that albumin Roma has a substitution
of lysine for glutamic acid at position 321. A GAG-to-AAG change is
responsible for the substitution. Galliano et al. (1990) found this
albumin variant in 25 individuals from various parts of Italy.

.0012
ALBUMIN HIROSHIMA-1
ALB, GLU354LYS
See Arai et al. (1989).

.0013
ALBUMIN PORTO ALEGRE-1
ALBUMIN COARI 1
ALB, GLU358LYS
Arai et al. (1989) reported on amino acid substitutions in albumin
variants found in Brazil. A previously unreported amino acid
substitution was found in albumins Coari I and Porto Alegre I
(glu358-to-lys).

.0014
ALBUMIN PARKLANDS
ALB, ASP365HIS
See Brennan (1985).

.0015
ALBUMIN MERSIN
ALBUMIN NASKAPI
ALBUMIN MEXICO-1
ALB, LYS372GLU
Franklin et al. (1980) demonstrated apparent identity between the
polymorphic albumin variants Naskapi, found chiefly in the Naskapi
Indians of Quebec, and Mersin, found in the Eti Turks of southeastern
Turkey. They suggested that these were derived from the same mutation
occurring in Asia and spreading with the progenitors of the American
Indians to the North American continent and with Asiatic invaders to
Asia Minor. Takahashi et al. (1987) found that lysine-372 of normal
(common) albumin A was changed to glutamic acid both in albumin Naskapi
and in albumin Mersin. Identity of these albumins may have originated
through descent from a common mid-Asiatic founder of the 2 migrating
ethnic groups, or it may represent identical but independent mutations
of the albumin gene.

.0016
ALBUMIN NAGASAKI-2
ALB, ASP375ASN
See Takahashi et al. (1987) and Arai et al. (1989).

.0017
ALBUMIN TOCHIGI
ALB, GLU376LYS
See Arai et al. (1989).

.0018
ALBUMIN HIROSHIMA-2
ALB, GLU382LYS
See Arai et al. (1989).

.0019
ALBUMIN LAMBADI
ALBUMIN MANAUS-1
ALBUMIN VANCOUVER
ALBUMIN BIRMINGHAM
ALBUMIN ADANA
ALBUMIN PORTO ALEGRE-2
ALB, GLU501LYS
Franklin et al. (1980) found a new variant in Eti Turks, which they
termed albumin Adana. By improved methods, Huss et al. (1988) identified
a substitution of lysine for glutamic acid at position 501 in albumins
Vancouver and Birmingham, both from families that migrated from northern
India, and also in albumin Adana from Turkey. This is the first
substitution reported in an alloalbumin originating from the Indian
subcontinent. Albumin Porto Alegre II also contains a glutamic
acid-to-lysine substitution at position 501.

.0020
ALBUMIN MAKU
ALBUMIN ORIXIMINA-1
ALB, LYS541GLU
See Takahashi et al. (1987). The substitution in albumin Oriximina I is
the same as that found in albumin Maku (lysine to glutamic acid at
position 541) (Arai et al., 1989).

.0021
ALBUMIN MEXICO-2
ALB, ASP550GLY
Franklin et al. (1980) showed that albumin Mexico is in fact 2 separate,
electrophoretically similar variants and that albumin Mexico-2 contains
a substitution of glycine for aspartic acid at position 550.
Substitution of aspartic acid-550 by glycine was found in albumin
Mexico-2 from 4 persons of the Pima tribe (Takahashi et al., 1987).

.0022
ALBUMIN FUKUOKA-1
ALB, ASP563ASN
See Arai et al. (1990).

.0023
ALBUMIN OSAKA-1
ALB, GLU565LYS
See Arai et al. (1990).

.0024
ALBUMIN OSAKA-2
ALBUMIN PHNOM PENH
ALBUMIN B
ALBUMIN OLIPHANT
ALBUMIN NAGANO
ALBUMIN VERONA B
ALB, GLU570LYS
Arai et al. (1989) identified the amino acid substitution characteristic
of albumin B (glutamic acid-to-lysine at position 570) in alloalbumins
from 6 unrelated persons of 5 different European descents and also in 2
Japanese and 1 Cambodian. A GAG-to-AAG change is responsible for this
substitution. Galliano et al. (1990) found this variant in 103
individuals in the Veneto area of Italy.

.0025
ALBUMIN GHENT
ALBUMIN MILANO FAST
ALB, LYS573GLU
An AAA-to-GAA change is responsible for this substitution. Galliano et
al. (1990) found this variant in 80 individuals from the Lombardy area
of Italy. Homozygotes have been identified.

.0026
ALBUMIN VANVES
ALB, LYS574ASN
See Galliano et al. (1988).

.0027
ANALBUMINEMIA, AMERICAN INDIAN TYPE
ALB, IVS6, A-G, -2
Ruffner and Dugaiczyk (1988) identified a structural defect in the serum
albumin gene of an analbuminemic American Indian girl. Sequence
determination of 1.1 kb of the 5-prime regulatory region and of 6 kb
across exonic regions revealed a single AG-to-GG mutation within the
3-prime splice site of intron 6 in the defective gene of the
analbuminemic person. In an in vitro assay on the RNA transcript, this
mutation caused a defect in out-splicing of the intron 6 sequence and in
the subsequent ligation of the exon 6/exon 7 sequences. Using
polymerase-amplified genomic DNA and allele-specific
oligodeoxynucleotide probes, Ruffner and Dugaiczyk (1988) also showed
that the sequence of this intron 6/exon 7 splice junction was normal in
a different, unrelated analbuminemic person.

.0028
ALBUMIN VENEZIA
ALB, EX14DEL
Minchiotti et al. (1989) described the molecular defect of an
electrophoretically fast alloalbumin named Venezia, found in about 90
seemingly unrelated families in Italy, mainly in the Veneto region. In
heterozygous subjects the total albumin content was in the normal range,
with the variant accounting for about 30% of the total protein. Reduced
stability of the mutant was thought to account for the
lower-than-expected percentage. Minchiotti et al. (1989) found that
albumin Venezia possesses a shortened polypeptide chain, 578 residues
instead of 585, completely variant from residue 572 to the
COOH-terminus: 572 pro-thr-met-arg-ile-arg-578 glu. This extensive
modification can be accounted for by deletion of exon 14 and translation
to the first terminator codon of exon 15, which normally does not code
for protein. The absence of a basic COOH-terminal dipeptide in the
mature molecule can be explained by the probable action of serum
carboxypeptidase N. The low serum level of the variant in heterozygous
subjects suggests that the carboxy-terminus of the molecule is critical
for albumin stability. Galliano et al. (1990) found this variant in 105
individuals, particularly in the region of Veneto in Italy.

.0029
ALBUMIN CASTEL DI SANGRO
ALB, LYS536GLU
An AAG-to-GAG change is responsible for this substitution. Galliano et
al. (1990) found this variant in 1 individual in Italy.

.0030
PROALBUMIN MALMO
PROALBUMIN TRADATE
ALB, ARG-2CYS
In a collaborative effort involving laboratories at Malmo, Sweden;
Bloomington, Indiana; Christchurch, New Zealand; Saitama, Japan; and
Pavia, Italy, Brennan et al. (1990) studied the most common Swedish
albumin variant, which is expressed in plasma as a broadened
electrophoretic band indicative of a slow component at pH 8.6. Present
in about 1 per 1,000 persons in Sweden, it was also found in a family of
Scottish descent from Kaikoura, New Zealand, and in 5 families in
Tradate, Italy. The major variant component was found to be
arginyl-albumin, in which arginine at the -1 position of the propeptide
is still attached to the processed albumin. A minor component with the
amino-terminal sequence of proalbumin was also present as 3 to 6% of the
total albumin. The mutation was found to involve a change of arginine to
cysteine at the -2 position. (In albumin Redhill (103600.0010), the
Malmo mutation is combined with another.) A CGT-to-TGT change is
responsible for the substitution.

.0031
PROALBUMIN JAFFNA
ALB, ARG-1LEU
In 2 members of a Tamil family from Jaffna (northern Sri Lanka),
Galliano et al. (1989) found an electrophoretically slow-moving variant
of serum albumin. Sequence analysis demonstrated that the variant is an
abnormal proalbumin arising from a substitution of leucine for arginine
at position -1, which prevents the proteolytic removal of the N-terminal
hexapeptide and allows the mutated proalbumin to enter the circulation.

.0032
ALBUMIN Ge/Ct
ALBUMIN CATANIA
ALB, GLN580LYS
This was the fourth albumin variant to be characterized structurally.
Galliano et al. (1986) found a shortened chain with deletion of a
cytosine in codon 580, causing frameshift and termination after amino
acid 582. The COOH-terminal sequence is leu-val-ala-ala-ser-lys-leu-pro.
Galliano et al. (1990) found this mutation in 62 individuals in Sicily.

.0033
ALBUMIN TORINO
ALB, GLU60LYS
Galliano et al. (1990) found a substitution of lysine for glutamic acid
at position 60 resulting from a GAA-to-AAA change in a single Italian
patient.

.0034
ALBUMIN VIBO VALENTIA
ALB, GLU82LYS
In 2 Italian individuals Galliano et al. (1990) found a GAA-to-AAA
change in codon 82 leading to substitution of lysine for glutamic acid.

.0035
ALBUMIN CASEBROOK
ALB, ASP494ASN
In albumin Casebrook, an electrophoretically slow albumin variant with a
relative molecular mass of 2.5 kD higher than normal albumin, Peach and
Brennan (1991) identified substitution of asparagine for aspartic
acid-494. The mutation introduced an asn-glu-thr N-linked
oligosaccharide attachment sequence centered on asn494, which explained
the increase in molecular mass. The mutant albumin was associated with
no apparent pathology and was detected in 2 unrelated individuals of
Anglo-Saxon descent.

.0036
ALBUMIN IOWA CITY-1
ALB, ASP365VAL
In a survey of alloalbumins in patients at 2 major medical centers in
the United States and nearly 20,000 blood donors in Japan, Madison et
al. (1991) identified 2 previously unreported alloalbumin types. In one
type, found in a Caucasian family and designated Iowa City-1, aspartic
acid at position 365 was replaced by valine. This was the second
reported mutation at position 365; see albumin Parklands (103600.0014).
The codon change was GAT-to-GTT. In the second type, found in a Japanese
blood donor, histidine-128 was replaced by arginine (103600.0037). The
codon change was CAT-to-CGT.

.0037
ALBUMIN KOMAGOME-2
ALB, HIS128ARG
See 103600.0036.

.0038
ALBUMIN RUGBY PARK
ALB, IVS13DS, G-C, +1
Peach et al. (1992) found that 3 members of a family were heterozygous
for an electrophoretically fast albumin variant, designated albumin
Rugby Park, which constituted only 8% of total serum albumin.
Isoelectric focusing indicated an increased negative charge on the
C-terminal CNBr peptide. Sequencing of PCR-amplified DNA indicated a
G-to-C transversion at position 1 of the intron 13. The replacement of
the obligate GT sequence by CT at the exon/intron boundary prevented
splicing of intron 13, and translation continued for 21 nucleotides
until a stop codon was reached. The new protein lacked the 14 amino
acids encoded in exon 14, but these were replaced by 7 new residues,
giving a truncated albumin of 578 residues.

.0039
ALBUMIN HERBORN
ALB, LYS240GLU
Minchiotti et al. (1993) found that albumin Herborn, a variant
discovered in Germany, had a point mutation in codon 240 changing AAA
(lys) to GAA (glu). The mutation was in the region implicated in
bilirubin binding, but Minchiotti et al. (1993) found that the binding
of bilirubin and biliverdin to albumin Herborn was not significantly
reduced.

.0040
ANALBUMINEMIA ROMA
ALB, 1-BP INS, AAT267AAAT, FS274TER
Watkins et al. (1994) investigated analbuminemia in an Italian family by
analysis of DNA from a mother and her daughter. The mother, whose
parents were first cousins, was homozygous for the trait and had a serum
albumin value of less than 0.01 g/dl (about 1/500 normal); the daughter
was heterozygous for the trait and had a nearly normal albumin value.
Molecular cloning and sequence analysis showed that the mutation, called
analbuminemia Roma, was a nucleotide insertion in exon 8, producing a
frameshift that led to a premature stop 7 codons downstream. Watkins et
al. (1994) used heteroduplex hybridization and single-strand
conformation polymorphism to compare the DNA of these 2 individuals with
the DNA of 2 unrelated analbuminemic persons, 1 Italian (called Codogno)
and 1 American (patient G.M.) and showed that each patient had a
different mutation. These mutations also differed from the mutation in
the only human case (in an American Indian) previously studied at the
DNA level (103600.0027). Whereas the normal serum albumin gene has 4 A
residues as nucleotides 9156-9159, the Roma allele had 5 A residues
encompassing 9156-9160. The predicted translation product from the Roma
allele would consist of only 273 amino acids instead of the normal 585
amino acid residues found in mature serum albumin. The insertion of the
additional adenine changed codon 267 from AAT (asn) to AAA (lys) and
changed the reading frame in such a way that codon 274 was changed from
AAA (lys) to TAA (stop).

.0041
DYSALBUMINEMIC HYPERTHYROXINEMIA
ALB, ARG218HIS
In 2 unrelated patients with dysalbuminemic hyperthyroxinemia, Petersen
et al. (1994) identified an arg218-to-his substitution which was caused
by a G (CGC)-to-A (CAG) transition at nucleotide 653. Abnormal affinity
of the albumin from these patients for a thyroxine analog was verified
by an adaptation of the procedure used in routine free T4 measurement.
Both subjects were heterozygous. During the preparation of the
manuscript, a third patient with the same mutation was found, suggesting
that R218H may be the most frequent cause of this disorder. The mutation
created a new HphI restriction site in exon 7 which was used
diagnostically.

.0042
ALBUMIN LARINO
ALB, HIS3TYR
Madison et al. (1994) stated that of the more than 50 different genetic
variants of human serum albumin that had been characterized by amino
acid or DNA sequence analysis, almost half had been identified in Italy
through a longterm electrophoretic survey of serum. They reported 4
other Italian alloalbumins not previously recorded: Lorino, his3-to-tyr;
Tradate-2, lys225-to-gln (103600.0043); Caserta, lys276-to-asn
(103600.0044); and Bazzano, a carboxyl-terminal variant (103600.0045).
The first 3 had point mutations that produced a single amino acid
substitution; a nucleotide deletion caused a frameshift and an altered
and truncated carboxy-terminal sequence in albumin Bazzano. In these 4
instances, the expression of the alloalbumin was variable, ranging from
10 to 70% of the total albumin, in contrast to the usual 50% each for
the normal and mutant albumin. Madison et al. (1994) commented that the
distribution of point mutations in the albumin gene is nonrandom; most
of the 47 reported point substitutions involved charged amino acid
residues on the surface of the molecule that are not concerned with
ligand-binding sites.

.0043
ALBUMIN TRADATE-2
ALB, LYS225GLN
See 103600.0042. In a patient from Tradate (Lombardy region), Madison et
al. (1994) demonstrated a substitution of glutamine for lysine-225. An
AAA-to-CAA change is responsible for the substitution. Albumin Tradate-2
was present in equimolar ratio with albumin A and had a fast mobility.

.0044
ALBUMIN CASERTA
ALB, LYS276ASN
See 103600.0042. In 3 members of a family from Caserta near Naples,
Madison et al. (1994) demonstrated a substitution of asparagine for
lysine-276. An AAG-to-AAC change is responsible for the substitution.
The alloalbumin was identified by its fast mobility. The 3 subjects were
heterozygous, but the variant/normal ratio was 1.5/1 in the serum of the
mother, whereas it was about 2/1 in both sibs. In all 3 cases, an
increased total albumin content was observed.

.0045
ALBUMIN BAZZANO
ALB, TGC567GC, FS583TER
See 103600.0042. Madison et al. (1994) found albumin Bazzano in several
families from Bazzano, a small town close to Bologna. At pH 8.6 the
variant was much slower than normal and comprised only about 18% of the
total albumin. In SDS/PAGE, the molecular weight of the variant appeared
slightly lower than normal. Sequence analysis revealed deletion of the
thymine nucleotide at position 15332 in the genomic sequence. This led
to a frameshift and a divergent amino acid sequence of 16 residues
beginning at position 567, with early termination after 582. The
extensive modification caused an increase in positive charge, which
explained the unusually slow mobility of the alloalbumin. The normal
termination codon in albumin is 586. Other carboxy-terminal variants are
albumin Venezia (103600.0028), albumin Rugby Park (103600.0038), and
albumin Catania (103600.0032).

.0046
ALBUMIN ASOLA
ALB, TYR140CYS
In 2 members of a family living in Asola in Lombardia, Italy, Minchiotti
et al. (1995) detected a slow migrating variant of human serum albumin
present in lower amounts than the normal protein by routine clinical
electrophoresis at pH 8.6. Isoelectric focusing analysis of CNBr
fragments localized the mutation to fragment CNBr3 (amino acid residues
124-298). Amino acid sequence analysis showed a tyr140-to-cys
substitution, confirmed by DNA sequence analysis, which resulted from a
single transition of TAT to TGT at nucleotide 5074. Despite the presence
of an additional cysteine residue, several lines of evidence indicated
that albumin Asola had no free sulfhydryl group; therefore, Minchiotti
et al. (1995) proposed that the mutant amino acid, cysteine, was
involved in the formation of a new disulfide bond with cys34, the only
free sulfydryl group present in the normal protein.

.0047
ALBUMIN MALMO-95
ALB, ASP63ASN
Carlson et al. (1992) demonstrated that albumin Malmo-95 has a
substitution of asparagine for aspartic acid-63. A GAC-to-AAC change is
responsible for the substitution.

.0048
ALBUMIN HAWKES BAY
ALB, CYS177PHE
Brennan and Fellowes (1993) demonstrated that albumin Hawkes Bay has a
substitution of phenylalanine for cysteine-177. A TGC-to-TTC change is
responsible for the substitution.

.0049
ALBUMIN MALMO-10
ALB, GLN268ARG
Carlson et al. (1992) demonstrated that albumin Malmo-10 has a
substitution of arginine for glutamine-268. A CAA-to-CGA change is
responsible for the substitution.

.0050
ALBUMIN MALMO-47
ALB, ASN318LYS
Carlson et al. (1992) demonstrated that albumin Malmo-47 has a
substitution of lysine for asparagine-318. A change from AAC to AAA or
AAG is responsible for the substitution.

.0051
ALBUMIN SONDRIA
ALB, GLU333LYS
Minchiotti et al. (1992) demonstrated that albumin Sondria has a
substitution of lysine for glutamic acid-333. A GAA-to-AAA change is
responsible for the substitution.

.0052
ALBUMIN MALMO-5
ALB, GLU376ASN
Carlson et al. (1992) demonstrated that albumin Malmo-5 has a
substitution of glutamine for glutamic acid-376. A GAA-to-CAA change is
responsible for the substitution.

.0053
ALBUMIN DUBLIN
ALB, GLU479LYS
Sakamoto et al. (1991) demonstrated that albumin Dublin has a
substitution of lysine for glutamic acid-479. A GAA-to-AAA change is
responsible for the substitution.

.0054
ALBUMIN ORTONOVO
ALB, GLU505LYS
Galliano et al. (1993) demonstrated that albumin Ortonovo has a
substitution of lysine for glutamic acid-505. A GAA-to-AAA change is
responsible for the substitution.

*FIELD* SA
Adams  (1966); Arai et al. (1989); Arai et al. (1989); Au et al. (1984);
Barlow et al. (1986); Barlow et al. (1982); Bennhold and Kallee (1959);
Brennan and Herbert (1987); Brennan et al. (1990); Dammacco et al.
(1980); Darlington et al. (1974); Dugaiczyk et al. (1982); Efremov
and Braend (1964); Franklin et al. (1980); Galliano et al. (1988);
Hawkins and Dugaiczyk (1982); Huss et al. (1988); Jensen and Faber
(1987); Kueppers et al. (1969); Kurnit et al. (1982); Lalloz et al.
(1983); Lau et al. (1972); Lavareda de Souza et al. (1984); Melartin
(1967); Melartin et al. (1967); Murray et al. (1983); Prager et al.
(1980); Rajatanavin et al. (1982); Rajatanavin et al. (1984); Sanders
and Tarnoky (1979); Sarcione and Aungst (1962); Sargent et al. (1979);
Sarich  (1972); Schell et al. (1978); Schell and Blumberg (1977);
Silverberg and Premachandra (1982); Swain et al. (1980); Takahashi
et al. (1987); Takahashi et al. (1987); Vanzetti et al. (1979); Weitkamp
(1978); Weitkamp and Buck (1972); Weitkamp and Chagnon (1968); Weitkamp
et al. (1969); Weitkamp et al. (1970); Weitkamp et al. (1968); Weitkamp
et al. (1973); Wieme  (1960); Yabu et al. (1985); Ying et al. (1981)
*FIELD* RF
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75. Minchiotti, L.; Galliano, M.; Stoppini, M.; Ferri, G.; Crespeau,
H.; Rochu, D.; Porta, F.: Two alloalbumins with identical electrophoretic
mobility are produced by differently charged amino acid substitutions. Biochim.
Biophys. Acta 1119: 232-238, 1992.

76. Minchiotti, L.; Galliano, M.; Zapponi, M. C.; Tenni, R.: The
structural characterization and bilirubin-binding properties of albumin
Herborn, a lys240-to-glu albumin mutant. Europ. J. Biochem. 214:
437-444, 1993.

77. Minghetti, P. P.; Law, S. W.; Dugaiczyk, A.: The rate of molecular
evolution of alpha-fetoprotein approaches that of pseudogenes. Molec.
Biol. Evol. 2: 347-358, 1985.

78. Minghetti, P. P.; Ruffner, D. E.; Kuang, W.-J.; Dennison, O. E.;
Hawkins, J. W.; Beattie, W. G.; Dugaiczyk, A.: Molecular structure
of the human albumin gene is revealed by nucleotide sequence within
q11-22 of chromosome 4. J. Biol. Chem. 261: 6747-6757, 1986.

79. Murray, J. C.; Demopulos, C. M.; Lawn, R. M.; Motulsky, A. G.
: Restriction endonuclease study of analbuminemia and polymorphisms
at the albumin locus. (Abstract) Clin. Res. 31: 456A only, 1983.

80. Murray, J. C.; Demopulos, C. M.; Lawn, R. M.; Motulsky, A. G.
: Molecular genetics of human serum albumin: restriction enzyme fragment
length polymorphisms and analbuminemia. Proc. Nat. Acad. Sci. 80:
5951-5955, 1983.

81. Murray, J. C.; Mills, K. A.; Demopulos, C. M.; Hornung, S.; Motulsky,
A. G.: Linkage disequilibrium and evolutionary relationships of DNA
variants (restriction enzyme fragment length polymorphisms) at the
serum albumin locus. Proc. Nat. Acad. Sci. 81: 3486-3490, 1984.

82. Nagase, S.; Shimamune, K.; Shumiya, S.: Albumin-deficient rat
mutant. Science 205: 590-591, 1979.

83. Ohno, S.: Original domain for the serum albumin family arose
from repeated sequences. Proc. Nat. Acad. Sci. 78: 7657-7661, 1981.

84. Ott, H.: Analbuminemia.In: Linneweh, F.: Erbliche Stoffwechselkrankheiten.
Munich: Urban und Schwarzenberg (pub.)  1962. Pp. 44.

85. Peach, R. J.; Brennan, S. O.: Structural characterization of
a glycoprotein variant of human serum albumin: albumin Casebrook (494
asp-to-asn). Biochim. Biophys. Acta 1097: 49-54, 1991.

86. Peach, R. J.; Fellowes, A. P.; Brennan, S. O.; George, P. M.:
Albumin Rugby Park: a truncated albumin variant caused by a G-to-C
splice-site mutation in intron 13. Biochim. Biophys. Acta 1180:
107-110, 1992.

87. Petersen, C. E.; Scottolini, A. G.; Cody, L. R.; Mandel, M.; Reimer,
N.; Bhagavan, N. V.: A point mutation in the human serum albumin
gene results in familial dysalbuminaemic hyperthyroxinaemia. J. Med.
Genet. 31: 355-359, 1994.

88. Pinkert, C. A.; Ornitz, D. M.; Brinster, R. L.; Palmiter, R. D.
: An albumin enhancer located 10 kb upstream functions along with
its promoter to direct efficient, liver-specific expression in transgenic
mice. Genes Dev. 1: 268-276, 1987.

89. Prager, E. M.; Wilson, A. C.; Lowenstein, J. M.; Sarich, V. M.
: Mammoth albumin. Science 209: 287-289, 1980.

90. Premachandra, B. N.; Wolfe, B.; Williams, I. K.: Coexistence
of familial dysalbuminemic hyperthyroxinemia with familial hypercholesterolemia
and multiple lipoprotein type hyperlipidemia. Am. J. Med. 84: 345-351,
1988.

91. Putnam, F. W.: Personal Communication. Bloomington, Ind.  8/4/1993.

92. Rajatanavin, R.; Fournier, L.; DeCosimo, D.; Abreau, C.; Braverman,
L. E.: Elevated serum free thyroxine by thyroxine analog radioimmunoassays
in euthyroid patients with familial dysalbuminemic hyperthyroxinemia. Ann.
Intern. Med. 97: 865-866, 1982.

93. Rajatanavin, R.; Young, R. A.; Braverman, L. E.: Effect of chloride
on serum thyroxine binding in familial dysalbuminemic hyperthyroxinemia. J.
Clin. Endocr. Metab. 58: 388-391, 1984.

94. Rochu, D.; Fine, J. M.: New method for identifying genetic variants
of human proalbumin. Clin. Chem. 32: 2063-2065, 1986.

95. Ruffner, D. E.; Dugaiczyk, A.: Splicing mutation in human hereditary
analbuminemia. Proc. Nat. Acad. Sci. 85: 2125-2129, 1988.

96. Ruiz, M.; Rajatanavin, R.; Young, R. A.; Taylor, C.; Brown, R.;
Braverman, L. E.; Ingbar, S. H.: Familial dysalbuminemic hyperthyroxinemia:
a syndrome that can be confused with thyrotoxicosis. New Eng. J.
Med. 306: 635-639, 1982.

97. Sakamoto, Y.; Davis, E.; Madison, J.; Watkins, S.; McLaughlin,
H.; Leahy, D. T.; Putnam, F. W.: Purification and structural study
of two albumin variants in an Irish population. Clin. Chim. Acta 204:
179-188, 1991.

98. Sanders, G. T. B.; Tarnoky, A. L.: Albumin Amsterdam: a new European
albumin variant. IRCS Med. Sci. 7: 581 only, 1979.

99. Sarcione, E. J.; Aungst, C. W.: Studies in bisalbuminemia: binding
properties of the two albumins. Blood 20: 156-164, 1962.

100. Sargent, T. D.; Wu, J.-R.; Sala-Trepat, J. M.; Wallace, R. B.;
Reyes, A. A.; Bonner, J.: The rat serum albumin gene: analysis of
cloned sequences. Proc. Nat. Acad. Sci. 76: 3256-3260, 1979.

101. Sarich, V. M.: Generation time and albumin evolution. Biochem.
Genet. 7: 205-212, 1972.

102. Schell, L. M.; Agarwal, S. S.; Blumberg, B. S.; Levy, H.; Bennett,
H.; Laughlin, W. S.; Martin, J. P.: Distribution of albumin variants
Naskapi and Mexico among Aleuts, Frobisher Bay Eskimos, and Micmac,
Naskapi, Mohawk, Omaha and Apache Indians. Am. J. Phys. Anthrop. 49:
111-118, 1978.

103. Schell, L. M.; Blumberg, B. S.: The genetics of human serum
albumin.In: Rosenoer, V. M.; Oratz, M.; Rothschild, M. A.: Albumin
Structure, Function and Uses.  Oxford: Pergamon Press (pub.)  1977.
Pp. 113-141.

104. Shalaby, F.; Shafritz, D. A.: Exon skipping during splicing
of albumin mRNA precursors in Nagase analbuminemic rats. Proc. Nat.
Acad. Sci. 87: 2652-2656, 1990.

105. Shashaty, G.; Atamer, M.: Acquired bisalbuminemia with hyperamylasemia. Digest.
Dis. 17: 59-67, 1972.

106. Shibata, T.; Abe, T.: Linkage between the loci for serum albumin
and vitamin D binding protein (GC) in the Japanese quail. Animal
Genet. 27: 195-197, 1996.

107. Silverberg, J. D. H.; Premachandra, B. N.: Familial hyperthyroxinemia
due to abnormal thyroid hormone binding. Ann. Intern. Med. 96: 183-186,
1982.

108. Swain, B. K.; Talukder, G.; Sharma, A.: Bisalbuminaemia: reports
from Calcutta. Biomedicine 33: 172-173, 1980.

109. Takahashi, N.; Takahashi, Y.; Blumberg, B. S.; Putnam, F. W.
: Amino acid substitutions in genetic variants of human serum albumin
and in sequences inferred from molecular cloning. Proc. Nat. Acad.
Sci. 84: 4413-4417, 1987.

110. Takahashi, N.; Takahashi, Y.; Isobe, T.; Putnam, F. W.; Fujita,
M.; Satoh, C.; Neel, J. V.: Amino acid substitutions in inherited
albumin variants from Amerindian and Japanese populations. Proc.
Nat. Acad. Sci. 84: 8001-8005, 1987.

111. Takahashi, N.; Takahashi, Y.; Putnam, F. W.: Structural changes
and metal binding by proalbumins and other amino-terminal genetic
variants of human serum albumin. Proc. Nat. Acad. Sci. 84: 7403-7407,
1987.

112. Tarnoky, A. L.; Lestas, A. N.: A new type of bisalbuminaemia. Clin.
Chim. Acta 9: 551-558, 1964.

113. Urano, Y.; Sakai, M.; Watanabe, K.; Tamaoki, T.: Tandem arrangement
of the albumin and alpha-fetoprotein genes in the human genome. Gene 32:
255-261, 1984.

114. Vanzetti, G.; Porta, F.; Prencipe, L.; Scherini, A.; Fraccaro,
M.: A homozygote for a serum albumin variant of the fast type. Hum.
Genet. 46: 5-9, 1979.

115. Vaysse, J.; Pilardeau, P.; Garnier, M.: Trisalbuminemia. (Letter) New
Eng. J. Med. 305: 833-834, 1981.

116. Watkins, S.; Madison, J.; Galliano, M.; Minchiotti, L.; Putnam,
F. W.: A nucleotide insertion and frameshift cause analbuminemia
in an Italian family. Proc. Nat. Acad. Sci. 91: 2275-2279, 1994.

117. Weitkamp, L. R.: Comparative gene mapping: linkage between the
albumin and Gc loci in the horse. (Abstract) Am. J. Hum. Genet. 30:
128A only, 1978.

118. Weitkamp, L. R.; Buck, A. A.: Phenotype frequencies for four
serum proteins in Afghanistan: two 'new' albumin variants. Humangenetik 15:
335-340, 1972.

119. Weitkamp, L. R.; Chagnon, N. A.: Albumin Maku: a new variant
of human serum albumin. Nature 217: 759-760, 1968.

120. Weitkamp, L. R.; Franglen, G.; Rokala, D. A.; Polesky, H. F.;
Simpson, N. E.; Sunderman, F. W., Jr.; Bell, H. E.; Saave, J.; Lisker,
R.; Bohls, S. W.: An electrophoretic comparison of human serum albumin
variants: eight distinguishable types. Hum. Hered. 19: 159-169,
1969.

121. Weitkamp, L. R.; Renwick, J. H.; Berger, J. P.; Shreffler, D.
C.; Drachmann, O.; Wuhrmann, F.; Braend, M.; Franglen, G.: Additional
data and summary for albumin-GC linkage in man. Hum. Hered. 20:
1-7, 1970.

122. Weitkamp, L. R.; Robson, E. B.; Shreffler, D. C.; Corney, G.
: An unusual human serum albumin variant: further data on genetic
linkage between loci for human serum albumin and group-specific component
(GC). Am. J. Hum. Genet. 20: 392-397, 1968.

123. Weitkamp, L. R.; Rucknagel, D. L.; Gershowitz, H.: Genetic linkage
between structural loci for albumin and group specific component (GC). Am.
J. Hum. Genet. 18: 559-571, 1966.

124. Weitkamp, L. R.; Salzano, F. M.; Neel, J. V.; Porta, F.; Geerdink,
R. A.; Tarnoky, A. L.: Human serum albumin: twenty-three genetic
variants and their population distribution. Ann. Hum. Genet. 36:
381-392, 1973.

125. Weitkamp, L. R.; Shreffler, D. C.; Robbins, J. L.; Drachmann,
O.; Adner, P. L.; Weime, R. J.; Simon, N. M.; Cooke, K. B.; Sandor,
G.; Wuhrmann, F.; Braend, M.; Tarnoky, A. L.: An electrophoretic
comparison of serum albumin variants from nineteen unrelated families. Acta
Genet. Statist. Med. 17: 399-405, 1967.

126. Wieme, R. J.: On the presence of two albumins in certain normal
human sera and its genetic determination. Clin. Chim. Acta 5: 443-445,
1960.

127. Williams, D. I.; Martin, N. H.: Bisalbuminemia with curious
acrocyanotic skin changes (two cases). Proc. Roy. Soc. Med. 53:
566-568, 1960.

128. Yabu, Y.; Amir, S. M.; Ruiz, M.; Braverman, L. E.; Ingbar, S.
H.: Heterogeneity of thyroxine binding by serum albumins in normal
subjects and patients with familial dysalbuminemic hyperthyroxinemia. J.
Clin. Endocr. Metab. 60: 451-459, 1985.

129. Yabu, Y.; Miyai, K.; Kobayashi, A.; Miki, K.; Doi, K.; Takamatsu,
J.; Mozai, T.; Matsuzuka, F.; Kuma, K.: A new type of albumin with
predominantly increased binding affinity for 3,3-prime,5-triiodothyronine
in a patient with Graves' disease. J. Endocr. Invest. 10: 163-169,
1987.

130. Yeo, P. P. B.; Yabu, Y.; Etzkorn, J. R.; Rajatanavin, R.; Braverman,
L. E.; Ingbar, S. H.: A four generation study of dysalbuminemic hyperthyroxinemia:
diagnosis in the presence of an acquired excess of thyroxine-binding
globulin. J. Endocr. Invest. 10: 33-38, 1987.

131. Ying, Q.; Liang, Z.; Wu, H.; Wang, L.: The gene frequency of
serum albumin variants in Chinese and the electrophoretic characterization
of several serum albumin variants. Scientia Sinica 24: 1597-1602,
1981.

*FIELD* CN
Jon B. Obray - updated: 8/27/1996
Stylianos E. Antonarakis - updated: 7/25/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 10/28/1996
terry: 10/22/1996
carol: 8/27/1996
joanna: 8/26/1996
carol: 8/13/1996
carol: 7/27/1996
carol: 7/25/1996
mark: 6/27/1995
jason: 7/13/1994
davew: 8/10/1994
terry: 6/3/1995
carol: 8/30/1994
warfield: 4/7/1994

*RECORD*
*FIELD* NO
103700
*FIELD* TI
*103700 ALCOHOL DEHYDROGENASE-1; ADH1
ADH, ALPHA SUBUNIT
*FIELD* TX
Polymorphism of alcohol dehydrogenase was investigated by Smith et al.
(1971), who concluded that 3 ADH loci are responsible for 3 distinct
polypeptide subunits--alpha, beta and gamma. No electrophoretic or other
allelic variants of ADH1 are known. At each of the ADH2 (103720) and
ADH3 (103730) loci, the evidence indicated that 2 different common
alleles occur. The ADH isozymes are dimers. Any particular isozyme may
be made up of 2 identical subunits coded by a specific allele at one of
the loci, or of 2 nonidentical subunits coded by alleles at 2 separate
loci, or of 2 nonidentical subunits coded by different alleles at the
same locus. At least 3 autosomal gene loci may, they concluded, be
concerned with determining the structure of alcohol dehydrogenase in
man. ADH1, ADH2 and ADH3 show differential tissue and developmental
expression. (Class I ADH isozymes are pyrazole-sensitive and basic.
Class II isozymes are less pyrazole-sensitive and less basic. Class III
isozymes show anodal electrophoretic mobility and low ethanol
dehydrogenase activity.) ADH1 is primarily active in the liver in early
fetal life, becoming less active later in gestation and only weakly
active during adult life when beta subunits and, to a lesser extent,
gamma subunits predominate in liver. With the coenzyme NAD, this enzyme
catalyzes the reversible conversion of organic alcohols to ketones or
aldehydes. The physiologic function for alcohol dehydrogenase in the
liver is the removal of ethanol formed by microorganisms in the
intestinal tract. The enzyme from horse liver is a dimer with 2 very
similar chains, one called E for ethanol-active and the other S for
steroid active. Sequence data are not available in man but the data on
the horse liver enzyme are given in the atlas by Dayhoff (1972). An
atypical liver ADH was described by Von Wartburg and Schuerch (1968) in
2 of 50 English livers and in 12 of 59 Swiss livers. The difference
studied concerned the ratio of activity at pH 10.8 and pH 8.8. About 1%
of protein in horse liver is alcohol dehydrogenase. The list of
substrates on which ADH operates is large. Important drug-ethanol
interactions, e.g., digitalis-ethanol, probably have their basis in this
fact (Vallee, 1979).

Using a cDNA clone from an adult cDNA library in somatic hybrid cell
studies, Smith et al. (1984) concluded that the class I ADH genes are
located distal to 4q21. DNA polymorphism was found in both the ADH2 and
ADH3 genes and Oriental/Caucasian differences were found. By Southern
blot analysis of somatic hybrid cell DNAs, Smith et al. (1985) assigned
the genes for alpha, beta and gamma ADH gene products (ADH1, ADH2, and
ADH3) to chromosome 4 (4q21-4q25). This represents an exception to the
rule that the subunits of heteromeric proteins are coded by separate
chromosomes. The progression from fetal alpha to adult beta (and gamma)
subunits as the predominant ones in adult life may represent an example
of switching between linked genes similar to the changes in the
beta-like globin genes during development. Von Bahr-Lindstrom et al.
(1986) provided information on the cDNA and protein sequence of the
alpha subunit. Smith (1986) stated the location of the class I ADH genes
as 4q21-q24. In situ hybridization permitted a narrowing of the
localization of the cluster to 4q22 (Tsukahara and Yoshida, 1989).
Yasunami et al. (1989) described the organization of the human class I
alcohol dehydrogenase gene cluster on chromosome 4q22. The cluster
includes ADH1, ADH2, and ADH3, which are arranged in the same
head-to-tail transcriptional orientation at intervals of approximately
15 kb. By genomic cloning using a cosmid vector, Yasunami et al. (1990)
showed that the genes for the 3 subunits of class I ADH lie in an 80-kb
segment in the following order: 5-prime--ADH3--ADH2--ADH1--3-prime.
Perhaps significantly, the order of transcriptional activation in
hepatic development, alpha-to-beta-to-gamma, is opposite to the order of
gene arrangement.

*FIELD* SA
Adinolfi and Hopkinson (1978); Adinolfi and Hopkinson (1979); Harada
et al. (1980); Ikuta et al. (1985); Lange et al. (1976); Murray and
Price (1972); Smith et al. (1972); Smith et al. (1973); Smith et al.
(1974)
*FIELD* RF
1. Adinolfi, A.; Hopkinson, D. A.: Blue sepharose chromatography
of human alcohol dehydrogenase: evidence for interlocus and interallelic
differences in affinity characteristics. Ann. Hum. Genet. 41: 399-407,
1978.

2. Adinolfi, A.; Hopkinson, D. A.: Affinity electrophoresis of human
alcohol dehydrogenase (ADH) isozymes. Ann. Hum. Genet. 43: 109-119,
1979.

3. Dayhoff, M. O.: Atlas of Protein Sequence and Structure. Dehydrogenases.
Washington: National Biomedical Research Foundation (pub.)  5:
1972. Pp. D141-D144.

4. Harada, S.; Misawa, S.; Agarwal, D. P.; Goedde, H. W.: Liver alcohol
dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme
variation and its possible role in alcohol intoxication. Am. J.
Hum. Genet. 32: 8-15, 1980.

5. Ikuta, T.; Fujiyoshi, T.; Kurachi, K.; Yoshida, A.: Molecular
cloning of a full-length cDNA for human alcohol dehydrogenase. Proc.
Nat. Acad. Sci. 82: 2703-2707, 1985.

6. Lange, L. G.; Sytkowski, A. J.; Vallee, B. L.: Human liver alcohol
dehydrogenase: purification, composition, and catalytic features.
Biochemistry 15: 4687-4693, 1976.

7. Murray, R. F., Jr.; Price, P. H.: Ontogenetic, polymorphic, and
interethnic variation in the isoenzymes of human alcohol dehydrogenase.
Ann. N.Y. Acad. Sci. 197: 68-72, 1972.

8. Smith, M.: Genetics of human alcohol and aldehyde dehydrogenases.
Adv. Hum. Genet. 15: 249-290, 1986.

9. Smith, M.; Duester, G.; Bilanchone, V.; Carlock, L.; Hatfield,
W.: Derivation of probes for molecular genetic analysis of human
class I alcohol dehydrogenase (ADH), a polymorphic gene family on
chromosome 4.  (Abstract) Am. J. Hum. Genet. 36: 153S only, 1984.

10. Smith, M.; Duester, G.; Carlock, L.; Wasmuth, J.: Assignment
of ADH1, ADH2 and ADH3 genes (class I ADH) to human chromosome 4q21-4q25,
through use of DNA probes.  (Abstract) Cytogenet. Cell Genet. 40:
748 only, 1985.

11. Smith, M.; Hopkinson, D. A.; Harris, H.: Developmental changes
and polymorphism in human alcohol dehydrogenase. Ann. Hum. Genet. 34:
251-272, 1971.

12. Smith, M.; Hopkinson, D. A.; Harris, H.: Alcohol dehydrogenase
isozymes in adult human stomach and liver: evidence for activity of
the ADH(3) locus. Ann. Hum. Genet. 35: 243-253, 1972.

13. Smith, M.; Hopkinson, D. A.; Harris, H.: Studies on the subunit
structure and molecular size of the human dehydrogenase isozymes determined
by the different loci, ADH(1), ADH(2), and ADH(3). Ann. Hum. Genet. 36:
401-414, 1973.

14. Smith, M.; Hopkinson, D. A.; Harris, H.: Studies on the properties
of the human alcohol dehydrogenase isozymes determined by the different
loci ADH(1), ADH(2) and ADH(3). Ann. Hum. Genet. 37: 49-67, 1974.

15. Tsukahara, M.; Yoshida, A.: Chromosomal assignment of the alcohol
dehydrogenase cluster locus to human chromosome 4q21-23 by in situ
hybridization. Genomics 4: 218-220, 1989.

16. Vallee, B.: Personal Communication. Boston, Mass.  1979.

17. von Bahr-Lindstrom, H.; Hoog, J.-O.; Heden, L.-O.; Kaiser, R.;
Fleetwood, L.; Larsson, K.; Lake, M.; Holmquist, B.; Holmgren, A.;
Hempel, J.; Vallee, B. L.; Jornvall, H.: cDNA and protein structure
for the alpha subunit of human liver alcohol dehydrogenase. Biochemistry 25:
2465-2470, 1986.

18. Von Wartburg, J. P.; Schuerch, P. M.: Atypical human liver alcohol
dehydrogenase. Ann. N.Y. Acad. Sci. 151: 936-947, 1968.

19. Yasunami, M.; Kikuchi, I.; Sarapata, D.; Yoshida, A.: The human
class I alcohol dehydrogenase gene cluster: three genes are tandemly
organized in an 80-kb-long segment of the genome. Genomics 7: 152-158,
1990.

20. Yasunami, M.; Kikuchi, I.; Sarapata, D. E.; Yoshida, A.: The
organization of human class I alcohol dehydrogenase gene cluster.
(Abstract) Cytogenet. Cell Genet. 51: 1113 only, 1989.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 6/8/1994
warfield: 4/7/1994
carol: 4/6/1994
pfoster: 4/4/1994
mimadm: 2/11/1994
supermim: 3/16/1992

*RECORD*
*FIELD* NO
103710
*FIELD* TI
*103710 ALCOHOL DEHYDROGENASE 5, CHI POLYPEPTIDE; ADH5
ALCOHOL DEHYDROGENASE, CHI ISOZYME;;
ADH, CLASS III; ADHX
*FIELD* TX
See 103720. Adinolfi et al. (1984) purified the chi isozyme of ADH (EC
1.1.1.1) from human liver and used it to raise immune sera. Its
immunologic properties suggested that it has no structural similarity to
either class I (ADH1, ADH2, ADH3) or class II (ADH4) isozymes. The chi
isozyme was found in most human tissues including fetal specimens of 16
weeks gestational age and showed a preference for long chain primary
alcohols with a double bond in the beta position. Adinolfi et al. (1984)
concluded that the locus, designated ADH5, has a separate evolutionary
origin from other ADH genes. (The class I ADH isozymes are virtually
indistinguishable immunologically; the genes that determine them
presumably originated by gene duplication.) Class III or chi ADH has
specificity for complex alcohols of high molecular weight such as
cinnamyl alcohol. Beisswenger et al. (1985) showed that ADH-chi is the
only ADH isozyme in brain. It oxidizes ethanol very poorly; its function
in brain is unknown. Since its gene is expressed constitutively in
somatic cell hybrids, Carlock et al. (1985) could assign the locus to
chromosome 4, specifically 4q21-q25, by analysis of gene products in
starch gel electrophoresis. Smith (1986) gave the regional assignment as
4q21-q24. Goldman et al. (1989) isolated and sequenced a full-length
cDNA for the class III alcohol dehydrogenase ADH5. By analysis of
human/hamster hybrid cell lines, ADH5 was mapped to chromosome 4 where
other ADH genes have been located, including class I genes and a class
II gene, all of which metabolize ethanol, and the unusual class III ADH,
which does not. Analysis of mouse/hamster hybrid cell lines showed that
the corresponding gene maps to mouse chromosome 3, which carries the
other murine ADH genes. The sequence of ADH5 indicated that it is about
equidistant between class I and class II ADHs. In contrast to other ADHs
whose expression is more restricted, class III ADH was found to be
expressed ubiquitously in human and rodent tissues. Giri et al. (1989)
also mapped the gene to mouse chromosome 3. Matsuo and Yokoyama (1990)
demonstrated a processed pseudogene derived from the ADH5 gene. Engeland
et al. (1993) reported the kinetic characterization of human class III
ADH altered at position 115 to asp and to ala by in vitro mutagenesis.
The results indicated that the arg115 residue is a component of the
binding site for activating fatty acids and is critical for the binding
of S-hydroxymethylglutathione in glutathione-dependent formaldehyde
dehydrogenase activity.

*FIELD* RF
1. Adinolfi, A.; Adinolfi, M.; Hopkinson, D. A.: Immunological and
biochemical characterization of the human alcohol dehydrogenase chi-ADH
isozyme. Ann. Hum. Genet. 48: 1-10, 1984.

2. Beisswenger, T. B.; Holmquist, B.; Vallee, B. L.: Chi-ADH is the
sole alcohol dehydrogenase isozyme of mammalian brains: implications
and inferences. Proc. Nat. Acad. Sci. 82: 8369-8373, 1985.

3. Carlock, L.; Hiroshige, S.; Wasmuth, J.; Smith, M.: Assignment
of the gene coding for class III ADH to human chromosome 4: 4q21-4q25.
(Abstract) Cytogenet. Cell Genet. 40: 598 only, 1985.

4. Engeland, K.; Hoog, J.-O.; Holmquist, B.; Estonius, M.; Jornvall,
H.; Vallee, B. L.: Mutation of arg-115 of human class III alcohol
dehydrogenase: a binding site required for formaldehyde dehydrogenase
activity and fatty acid activation. Proc. Nat. Acad. Sci. 90: 2491-2494,
1993.

5. Giri, P.; Krug, J. F.; Kozak, C.; Moretti, T.; O'Brien, S. J.;
Seuanez, H. N.; Goldman, D.: Cloning and comparative mapping of a
human class III (chi) alcohol dehydrogenase cDNA. Biochem. Biophys.
Res. Commun. 164: 453-460, 1989.

6. Goldman, D.; RathnaGiri, P.; Moretti, T. R.; Krug, J. F.; Kozak,
C.; Dean, M.; Seuanez, H. N.; O'Brien, S. J.: Class III alcohol dehydrogenase
(ADH5): widespread expression and synteny with other ADHs in both
mouse and man.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A141
only, 1989.

7. Matsuo, Y.; Yokoyama, S.: Cloning and sequencing of a processed
pseudogene derived from a human class III alcohol dehydrogenase gene.
Am. J. Hum. Genet. 46: 85-91, 1990.

8. Smith, M.: Genetics of human alcohol and aldehyde dehydrogenases.
Adv. Hum. Genet. 15: 249-290, 1986.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 06/25/1996
carol: 10/21/1993
carol: 10/15/1993
carol: 4/28/1993
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/2/1990

*RECORD*
*FIELD* NO
103720
*FIELD* TI
*103720 ALCOHOL DEHYDROGENASE-2; ADH2
ADH, BETA SUBUNIT
*FIELD* TX
See 103700 for evidence on the mapping of the ADH2 gene in the cluster
of related genes on 4q22. According to the conclusion of Smith et al.
(1973), locus ADH2 is expressed in the lung in early fetal life and
remains active in this tissue throughout life. It is active also in
liver after about the first trimester and gradually increases in
activity so that in adults this locus is responsible for most of the
liver ADH activity. It is active in the adult kidney. The 'atypical pH
ratio' phenotype is probably determined by a variant allele at the ADH2
locus. Stamatoyannopoulos et al. (1975) found that 85% of Japanese carry
an atypical liver ADH (ADH2 type). About the same proportion have
alcohol sensitivity, which they suggest may be due to increased
formation of acetaldehyde by persons with the atypical ADH. Bosron et
al. (1980) found new molecular forms of human ADH, collectively
designated ADH(Indianapolis), in 29% of liver specimens from black
Americans. Three different Indianapolis ADH phenotypes were identified
by starch gel electrophoresis and 4 isolated by affinity and
ion-exchange chromatography. One is a homodimer of a newly discovered
subunit. The other 3 are heterodimers of this new subunit and the known
subunits, alpha, beta-1, and gamma-1. Agarwal et al. (1981) could find
no instance of the Indianapolis variant in Germany or Japan; it may be
confined to American blacks. Bosron et al. (1983) concluded that the
Indianapolis phenotypes reflect polymorphism at the ADH2 locus with the
variant ADH(Indianapolis) allele coding for the beta-Indianapolis
subunit. The frequency of this allele was 0.16 in black Americans and
was not found in any of 63 livers from white Americans. The frequency of
alleles at the ADH3 locus also differs in these 2 populations.

The ADH1, ADH2, and ADH3 loci code for 3 closely related polypeptides:
alpha, beta, and gamma, respectively. Two additional ADH isozymes, pi
and chi, encoded by the ADH4 and ADH5 loci, respectively, differ from
the first three in a number of properties and are not related to them.
The primary structure of the beta subunit (Hempel et al., 1985) and the
nucleotide sequence of the cDNA corresponding to beta mRNA (Heden et
al., 1986) have been determined. Yokoyama et al. (1987) cloned the gene
coding for the beta-1 subunit of human ADH, the 'typical' subunit
encoded by the ADH2*1 allele. A phylogenetic tree for the class I human
ADHs, alpha, beta, and gamma, showed that the alpha and beta subunits
diverged most recently and that their common ancestor diverged from the
ancestor of the gamma subunit earlier. The evolutionary rates of
nucleotide substitution for the 3 subunits showed that the gamma subunit
is evolving at the slowest rate, followed by beta and alpha, in that
order, implying that the gamma subunit may be providing the original
function of ethanol metabolism. Trezise et al. (1989) cloned and
sequenced cDNA encoding baboon liver alcohol dehydrogenase. From the
sequence they concluded that baboon liver class I ADH is of the same
ancestral lineage as human ADH-beta; 363 of 374 residues were identical
in the 2 amino acid sequences. They estimated that the primate class I
ADH gene duplication predated the primate radiation and that the
alpha/beta-gamma separation of human ADH genes occurred about 60 million
years ago. Goedde et al. (1992) presented extensive data on population
frequencies of the ADH2 and ALDH2 (100650) genes.

Muramatsu et al. (1995) used the PCR/RFLP method to determine the
genotypes of the ADH2 and ALDH2 loci of alcoholic and nonalcoholic
Chinese living in Shanghai. They found that the alcoholics had
significantly lower frequencies of the ADH2*2 and ALDH2*2 alleles than
did the nonalcoholics, suggesting the inhibitory effects of these
alleles for the development of alcoholism. In the nonalcoholic subjects,
ADH2*2 had little, if any, effect, despite the significant effect of the
ALDH2*2 allele in decreasing the alcohol consumption of the individual.
Taken together, these results were considered consistent with the
proposed hypothesis for the development of alcoholism, i.e., drinking
behavior is greatly influenced by the individual's genotype of
alcohol-metabolizing enzymes and the risk of becoming alcoholic is
proportionate with the ethanol consumption of the individual.

Takeshita et al. (1996) evaluated the effects of the ADH2 polymorphism
in 524 Japanese individuals who had previously been typed for the ALDH2
polymorphism. In the ALDH2*1/ALDH2*2 heterozygotes, the frequency of
facial flushing following consumption of one glass of beer was
significantly higher in the presence of the ADH2*2 alleles in homozygous
or heterozygous form. The proportion of individuals with ethanol-induced
cutaneous erythema was also higher depending on the presence of the ADH2
allele in ALDH2*1 homozygotes or ALDH2*1/ALDH2*2 heterozygotes.
Takeshita et al. (1996) presented evidence that drinking habits were not
significantly associated with the ADH2 genotype.

Higuchi et al. (1996) reported that higher ADH2*1 and ADH3*2 allele
frequencies were observed in alcoholics than in controls. Their results
suggested that genetic variations in ethanol oxidizing activities are
involved in the development of alcoholism but that these variations do
not have a specific effect in alcoholics with inactive ALDH2, a group at
low genetic risk for alcoholism.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
ALCOHOL DEHYDROGENASE, BETA SUBUNIT, 'TYPICAL'/'ATYPICAL'
ADH2*1/ADH2*2
ADH2, ARG47HIS
Matsuo et al. (1989) showed that the typical and atypical forms of ADH-2
differ by only a single amino acid. In the ADH2*2 ('atypical') allele,
CAC codes for histidine at residue 47; in the corresponding codon of the
ADH2*1 (typical) allele, CGC codes for arginine. Surprisingly, no silent
substitutions were found between the coding regions of the 2 alleles
over the 1,122 nucleotide sites. The kinetic properties of human alcohol
dehydrogenases with various substitutions at residue 47 in the coenzyme
binding site differ considerably. The V(max) of ethanol oxidation
differs by 100-fold between beta-1/beta-1 and beta-2/beta-2 (i.e., the
homozygotes for the ADH2*1 and ADH2*2 alleles, respectively). Using
site-directed mutagenesis, Hurley et al. (1990) studied the effects of
substitution of lysine, histidine, glutamine, and glycine for
arginine-47 in beta-1/beta-1. They expressed the enzymes in E. coli and
compared their kinetics.

.0002
ALCOHOL DEHYDROGENASE, BETA SUBUNIT, INDIANAPOLIS
ADH2*3
ADH2, ARG369CYS
Burnell et al. (1987) demonstrated that in the homozygote for the beta*3
allele, formerly called beta(Indianapolis), the only difference from the
homozygote for the beta*1 allele was a single nucleotide change that
resulted in substitution of cysteine for arginine at position 369.
Burnell et al. (1987) predicted that arg369 interacts with the
nicotinamide phosphate moiety of NAD(H) and that this accounts for the
effect of the arg369-to-cys substitution in decreasing the isoenzyme's
affinity for coenzyme.

*FIELD* SA
Duester et al. (1984); Xu et al. (1988); Yin et al. (1984)
*FIELD* RF
1. Agarwal, D. P.; Meier-Tackmann, D.; Harada, S.; Goedde, H. W.:
A search for the Indianapolis-variant of human alcohol dehydrogenase
in liver autopsy samples from North Germany and Japan. Hum. Genet. 59:
170-171, 1981.

2. Bosron, W. F.; Li, T.-K.; Vallee, B. L.: New molecular forms of
human liver alcohol dehydrogenase: isolation and characterization
of ADH (Indianapolis). Proc. Nat. Acad. Sci. 77: 5784-5788, 1980.

3. Bosron, W. F.; Magnes, L. J.; Li, T.-K.: Human liver alcohol dehydrogenase:
ADH(Indianapolis) results from genetic polymorphism at the ADH-2 gene
locus. Biochem. Genet. 21: 735-744, 1983.

4. Burnell, J. C.; Carr, L. G.; Dwulet, F. E.; Edenberg, H. J.; Li,
T.-K.; Bosron, W. F.: The human beta(3) alcohol dehydrogenase subunit
differs from beta-1 by a cys for arg-369 substitution which decreases
NAD(H) binding. Biochem. Biophys. Res. Commun. 146: 1227-1233,
1987.

5. Duester, G.; Hatfield, G. W.; Buhler, R.; Hempel, J.; Jornvall,
H.; Smith, M.: Molecular cloning and characterization of cDNA for
the beta subunit of human alcohol dehydrogenase. Proc. Nat. Acad.
Sci. 81: 4055-4059, 1984.

6. Goedde, H. W.; Agarwal, D. P.; Fritze, G.; Meier-Tackmann, D.;
Singh, S.; Beckmann, G.; Bhatia, K.; Chen, L. Z.; Fang, B.; Lisker,
R.; Paik, Y. K.; Rothhammer, F.; Saha, N.; Segal, B.; Srivastava,
L. M.; Czeizel, A.: Distribution of ADH-2 and ALDH2 genotypes in
different populations. Hum. Genet. 88: 344-346, 1992.

7. Heden, L.-O.; Hoog, J.-O.; Larsson, K.; Lake, M.; Lagerholm, E.;
Holmgren, A.; Vallee, B. L.; Jornvall, H.; von Bahr-Lindstrom, H.
: cDNA clones coding for the beta-subunit of human liver alcohol dehydrogenase
have differently sized 3-prime-non-coding regions. FEBS Lett. 194:
327-332, 1986.

8. Hempel, J.; Holmquist, B.; Fleetwood, L.; Kaiser, R.; Barros-Soderling,
J.; Buhler, R.; Vallee, B. L.; Jornvall, H.: Structural relationships
among class I isozymes of human liver alcohol dehydrogenase. Biochemistry 24:
5303-5307, 1985.

9. Higuchi, S.; Muramatsu, T.; Matsushita, S.; Murayama, M.; Hayashida,
M.: Polymorphisms of ethanol-oxidizing enzymes in alcoholics with
inactive ALDH2. Hum. Genet. 97: 413-434, 1996.

10. Hurley, T. D.; Edenberg, H. J.; Bosron, W. F.: Expression and
kinetic characterization of variants of human beta-1/beta-1 alcohol
dehydrogenase containing substitutions at amino acid 47. J. Biol.
Chem. 265: 16366-16372, 1990.

11. Matsuo, Y.; Yokoyama, R.; Yokoyama, S.: The genes for human alcohol
dehydrogenases beta-1 and beta-2 differ by only one nucleotide. Europ.
J. Biochem. 183: 317-320, 1989.

12. Muramatsu, T.; Zu-Cheng, W.; Yi-Ru, F.; Kou-Bao, H.; Heqin, Y.;
Yamada, K.; Higuchi, S.; Harada, S.; Kono, H.: Alcohol and aldehyde
dehydrogenase genotypes and drinking behavior of Chinese living in
Shanghai. Hum. Genet. 96: 151-154, 1995.

13. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

14. Smith, M.; Hopkinson, D. A.; Harris, H.: Studies on the subunit
structure and molecular size of the human dehydrogenase isozymes determined
by the different loci, ADH(1), ADH(2), and ADH(3). Ann. Hum. Genet. 36:
401-414, 1973.

15. Stamatoyannopoulos, G.; Chen, S.-H.; Fukui, M.: Liver alcohol
dehydrogenase in Japanese: high population frequency of atypical form
and its possible role in alcohol sensitivity. Am. J. Hum. Genet. 27:
789-796, 1975.

16. Takeshita, T.; Mao, X.-Q.; Morimoto, K.: The contribution of
polymorphism in the alcohol dehydrogenase beta subunit to alcohol
sensitivity in a Japanese population. Hum. Genet. 97: 409-413, 1996.

17. Trezise, A. E. O.; Godfrey, E. A.; Holmes, R. S.; Beacham, I.
F.: Cloning and sequencing of cDNA encoding baboon liver alcohol
dehydrogenase: evidence for a common ancestral lineage with the human
alcohol dehydrogenase beta subunit and for class I ADH gene duplications
predating primate radiation. Proc. Nat. Acad. Sci. 86: 5454-5458,
1989.

18. Xu, Y.; Carr, L. G.; Bosron, W. F.; Li, T.-K.; Edenberg, H. J.
: Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3
loci following DNA sequence amplification. Genomics 2: 209-214,
1988.

19. Yin, S.-J.; Bosron, W. F.; Li, T.-K.; Ohnishi, K.; Okuda, K.;
Ishii, H.; Tsuchiya, M.: Polymorphism of human liver alcohol dehydrogenase:
identification of ADH(2)2-1 and ADH(2)2-2 phenotypes in the Japanese
by isoelectric focusing. Biochem. Genet. 22: 169-180, 1984.

20. Yokoyama, S.; Yokoyama, R.; Rotwein, P.: Molecular characterization
of cDNA clones encoding the human alcohol dehydrogenase beta-1 and
the evolutionary relationship to the other class I subunits alpha
and gamma. Jpn. J. Genet. 62: 241-256, 1987.

*FIELD* CN
Moyra Smith - updated: 03/13/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/13/1996
terry: 3/13/1996
mark: 3/13/1996
mark: 8/22/1995
pfoster: 4/5/1994
warfield: 3/31/1994
mimadm: 2/11/1994
carol: 6/9/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
103730
*FIELD* TI
*103730 ALCOHOL DEHYDROGENASE-3; ADH3
ADH, GAMMA SUBUNIT
*FIELD* TX
See 103700 for evidence on the mapping of the ADH3 gene to the cluster
of related genes on 4q22. According to the conclusion of Smith et al.
(1973), the ADH3 locus is active in intestine and kidney in fetal and
early postnatal life. Two alleles at the ADH3 locus, called 1 and 2,
have a frequency of about 0.63 and 0.37, respectively. Hoog et al.
(1986) determined the cDNA and amino acid structures of the gamma-1 and
gamma-2 subunits of human liver alcohol dehydrogenase. These subunits
are determined by allelic genes at the ADH3 locus, just as the beta-1
and beta-2 and beta-Indianapolis subunits are determined by alleles at
the ADH2 locus (103720). Morris et al. (1989) described a polymorphic
anonymous DNA marker, D4S138, which is closely linked to the ADH3 locus.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
ALCOHOL DEHYDROGENASE, GAMMA-1 TYPE
ADH3*1
ADH3, ARG271,ILE349
Hoog et al. (1986) found 2 amino acid differences between gamma-1 and
gamma-2: at position 349, isoleucine was found in gamma-1 and valine in
gamma-2; at position 271, arginine was found in gamma-1 and glutamine in
gamma-2. Xu et al. (1988) used the ile349-to-val substitution to
distinguish ADH3*1 from ADH3*2 by means of allele-specific
oligonucleotide probes.

.0002
ALCOHOL DEHYDROGENASE, GAMMA-2 TYPE
ADH3*2
ADH3, GLN271,VAL349
See 103730.0001.

*FIELD* SA
Azevedo et al. (1976)
*FIELD* RF
1. Azevedo, E. S.; Da Silva, M. C. B. O.; Tavares-Neto, J.: Human
alcohol dehydrogenase ADH 1, ADH 2 and ADH 3 loci in a mixed population
of Bahia, Brazil. Ann. Hum. Genet. 39: 321-327, 1976.

2. Hoog, J.-O.; Heden, L.-O.; Larsson, K.; Jornvall, H.; von Bahr-Lindstrom,
H.: The gamma-1 and gamma-2 subunits of human liver alcohol dehydrogenase:
cDNA structures, two amino acid replacements, and compatibility with
changes in the enzymatic properties. Europ. J. Biochem. 159: 215-218,
1986.

3. Morris, D. J.; Willem, P.; dos Santos, M.; Povey, S.; Jenkins,
T.: A new chromosome 4q marker, D4S138, closely linked to the ADH3
locus.  (Abstract) Cytogenet. Cell Genet. 51: 1047-1048, 1989.

4. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

5. Smith, M.; Hopkinson, D. A.; Harris, H.: Studies on the subunit
structure and molecular size of the human dehydrogenase isozymes determined
by the different loci, ADH(1), ADH(2), and ADH(3). Ann. Hum. Genet. 36:
401-414, 1973.

6. Xu, Y.; Carr, L. G.; Bosron, W. F.; Li, T.-K.; Edenberg, H. J.
: Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3
loci following DNA sequence amplification. Genomics 2: 209-214,
1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 2/11/1994
carol: 3/20/1992
supermim: 3/16/1992
carol: 2/29/1992
carol: 1/27/1992
carol: 12/3/1990

*RECORD*
*FIELD* NO
103735
*FIELD* TI
*103735 ALCOHOL DEHYDROGENASE-6; ADH6
*FIELD* TX
Yasunami et al. (1991) used cross-hybridization with the ADH2 cDNA probe
to isolate a 'new' ADH gene. cDNA clones corresponding to the gene were
derived from PCR-amplified libraries as well. The coding sequence of a
368-amino acid long open reading frame was interrupted by introns into 8
exons and spanned approximately 17 kb of genome. The gene contains a
glucocorticoid response element at the 5-prime region. The transcript
was detected in stomach and liver. The deduced amino acid sequence of
the open reading frame showed about 60% positional identity with known
human ADHs. This extent of homology is comparable to interclass
similarity within the human ADH family. Thus, the newly identified gene,
designated ADH6, governs synthesis of an enzyme that belongs to another
class of ADHs, presumably with a distinct physiologic function.

*FIELD* RF
1. Yasunami, M.; Chen, C.-S.; Yoshida, A.: A human alcohol dehydrogenase
gene (ADH6) encoding an additional class of isozyme. Proc. Nat.
Acad. Sci. 88: 7610-7614, 1991.

*FIELD* CD
Victor A. McKusick: 9/27/1991

*FIELD* ED
supermim: 3/16/1992
carol: 9/27/1991

*RECORD*
*FIELD* NO
103740
*FIELD* TI
*103740 ALCOHOL DEHYDROGENASE, PI ISOZYME
ALCOHOL DEHYDROGENASE-4; ADH4;;
ADH, CLASS II
*FIELD* TX
Li et al. (1977) described a functionally distinct form of human liver
alcohol dehydrogenase and termed it Pi-alcohol dehydrogenase.
Variability from person to person was found, suggesting genetic
variability. At intoxicating levels of alcohol, this enzyme may account
for as much as 40% of the total ethanol oxidation rate. Unlike the other
alcohol dehydrogenases, this type is not inhibited by pyrazole; hence,
its name. It is called into operation at high levels of ethanol. It
differs immunologically from other alcohol dehydrogenases and also has
different substrate specificities; e.g., ethylene glycol is digested by
other alcohol dehydrogenases but not by the Pi form. ADH4 (pi) isozyme,
characteristic of adult liver, was termed class II by Vallee and Bazzone
(1983), who referred to ADH5 (chi; 103710) as class III. In addition to
the distinct loci determining alcohol dehydrogenase listed here, there
are probably several others as yet not characterized. Mardh et al.
(1986) presented evidence that Pi-ADH has a physiological role in the
degradation of circulating epinephrine and norepinephrine. McPherson et
al. (1989) used a combination of somatic cell hybrid DNA analysis and in
situ hybridization to localize the ADH4 gene locus to human chromosome
4q22 in the cluster of alcohol dehydrogenase genes. Edman and Maret
(1992) described RFLPs for the ADH4 and ADH5 genes. Linkage
disequilibrium was detected between RFLPs in several of the 5 genes in
the ADH cluster on chromosome 4. The disequilibrium between ADH4 and
ADH5 indicated a hitherto unknown physical proximity of these 2 genes of
different ADH classes, class II and class III, respectively.

*FIELD* RF
1. Edman, K.; Maret, W.: Alcohol dehydrogenase genes: restriction
fragment length polymorphisms for ADH4 (pi-ADH) and ADH5 (chi-ADH)
for construction of haplotypes among different ADH classes. Hum.
Genet. 90: 395-401, 1992.

2. Li, T.-K.; Bosron, W. F.; Dafeldecker, W. P.; Lange, L. G.; Vallee,
B. L.: Isolation of PI-alcohol dehydrogenase of human liver: is it
a determinant of alcoholism?. Proc. Nat. Acad. Sci. 74: 4378-4381,
1977.

3. Mardh, G.; Dingley, A. L.; Auld, D. S.; Vallee, B. L.: Human class
II (pi) alcohol dehydrogenase has a redox-specific function in norepinephrine
metabolism. Proc. Nat. Acad. Sci. 83: 8908-8912, 1986.

4. McPherson, J. D.; Smith, M.; Wagner, C.; Wasmuth, J. J.; Hoog,
J.-O.: Mapping of the class II alcohol dehydrogenase gene locus to
4q22.  (Abstract) Cytogenet. Cell Genet. 51: 1043 only, 1989.

5. Vallee, B. L.; Bazzone, T. J.: Isozymes of human liver alcohol
dehydrogenase. In: Rattazzi, M. C.; Scandalios, J. G.; Whitt, G. S.
: Isozymes. Current Topics in Biological and Medical Research.
New York: Alan R. Liss (pub.)  8: 1983. Pp. 219-244.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/9/1994
jason: 6/16/1994
carol: 5/27/1994
pfoster: 3/31/1994
mimadm: 2/11/1994
carol: 4/2/1993

*RECORD*
*FIELD* NO
103780
*FIELD* TI
103780 ALCOHOLISM
*FIELD* TX
The tendency for drinking patterns of children to resemble those of
their parents has been recognized since antiquity, e.g., in the
observations of Plato and Aristotle (Warner and Rosett, 1975).
Alcoholism is probably a multifactorial, genetically influenced disorder
(Goodwin, 1976). The genetic influence is indicated by studies showing
that (1) there is a 25 to 50% lifetime risk for alcoholism in sons and
brothers of severely alcoholic men; (2) alcohol preference can be
selectively bred for in experimental animals; (3) there is a 55% or
higher concordance rate in monozygotic twins with only a 28% rate for
like-sex dizygotic twins; and (4) half-brothers with different fathers
and adopted sons of alcoholic men show a rate of alcoholism more like
that of the biologic father than that of the foster father. A possible
biochemical basis is a metabolic difference such that those prone to
alcoholism have higher levels of a metabolite giving pleasurable effects
or those not prone to alcoholism have higher levels of a metabolite
giving unpleasant effects. Schuckit and Rayses (1979) found that, after
a moderate dose of alcohol, blood acetaldehyde levels were elevated more
in young men with alcoholic parents or sibs than in controls. A certain
degree of organ specificity in the pathologic effects of alcohol is
observed. For example, patients have cardiomyopathy, cirrhosis or
pancreatitis but rarely more than one of these. A genetic basis of organ
specificity is evident in Wernicke-Korsakoff syndrome (277730) and
pancreatitis from type V hyperlipidemia (238400). Cloninger (1987)
identified 2 separate heritable types of alcoholism. Type 1 alcohol
abuse had its usual onset after the age of 25 years and was
characterized by severe psychological dependence and guilt. It occurred
in both men and women and required both genetic and environmental
factors to become manifest. By contrast, type 2 alcohol abuse had its
onset before the age of 25; persons with this type of alcoholism were
characterized by their inability to abstain from alcohol and by frequent
aggressive and antisocial behavior. Type 2 alcoholism was rarely found
in women and was much more heritable. Abnormalities in platelet
monoamine oxidase activity were found only in type 2 alcoholics (Von
Knorring et al., 1985). See comments by Omenn (1988). Crabb (1990)
reviewed biologic markers for increased risk of alcoholism. Aston and
Hill (1990) performed complex segregation analysis of 35
multigenerational families ascertained through a pair of male
alcoholics. They concluded that liability to alcoholism is, in part,
controlled by a major effect with or without additional multifactorial
effects. However, mendelian transmission of this major effect was
rejected, as was the hypothesis that the major effect is due to a single
major locus. The candidate gene approach was used by Blum et al. (1990)
and by Bolos et al. (1990) to investigate a possible relationship of the
dopamine D2 receptor (DRD2; 126450) to alcoholism. Although Blum et al.
(1990) suggested an association between a particular allele at the DRD2
locus, Bolos et al. (1990) could not confirm this. In family studies,
Bolos et al. (1990) excluded linkage between alcoholism and the DRD2
locus.

*FIELD* SA
Propping et al. (1981)
*FIELD* RF
1. Aston, C. E.; Hill, S. Y.: Segregation analysis of alcoholism
in families ascertained through a pair of male alcoholics. Am. J.
Hum. Genet. 46: 879-887, 1990.

2. Blum, K.; Noble, E. P.; Sheridan, P. J.; Montgomery, A.; Ritchie,
T.; Jagadeeswaran, P.; Nogami, H.; Briggs, A. H.; Cohn, J. B.: Allelic
association of human dopamine D(2) receptor gene in alcoholism. J.A.M.A. 263:
2055-2060, 1990.

3. Bolos, A. M.; Dean, M.; Lucas-Derse, S.; Ramsburg, M.; Brown, G.
L.; Goldman, D.: Population and pedigree studies reveal a lack of
association between the dopamine D(2) receptor gene and alcoholism.
J.A.M.A. 264: 3156-3160, 1990.

4. Cloninger, C. R.: Neurogenetic adaptive mechanisms in alcoholism.
Science 236: 410-416, 1987.

5. Crabb, D. W.: Biological markers for increased risk of alcoholism
and for quantitation of alcohol consumption. J. Clin. Invest. 85:
311-315, 1990.

6. Goodwin, D.: Is Alcoholism Hereditary?.  New York: Oxford Univ.
Press (pub.)  1976.

7. Omenn, G. S.: Genetic investigations of alcohol metabolism and
of alcoholism. Am. J. Hum. Genet. 43: 579-581, 1988.

8. Propping, P.; Kruger, J.; Mark, N.: Genetic disposition to alcoholism:
an EEG study in alcoholics and their relatives. Hum. Genet. 59:
51-59, 1981.

9. Schuckit, M. A.; Rayses, V.: Ethanol ingestion: differences in
blood acetaldehyde concentrations in relatives of alcoholics and controls.
Science 203: 54-55, 1979.

10. Von Knorring, A.-L.; Bohman, M.; Von Knorring, L.; Oreland, L.
: Platelet MAO activity as a biological marker in subgroups of alcoholism.
Acta Psychiat. Scand. 72: 51-58, 1985.

11. Warner, R. H.; Rosett, H. L.: The effects of drinking on offspring:
an historical survey of the American and British literature. J.
Studies Alcohol 36: 1395-1420, 1975.

*FIELD* CS

Neuro:
   Alcoholism

Misc:
   25 to 50% lifetime risk for sons and brothers of severely alcoholic
   men

Inheritance:
   Probably multifactorial, genetically influenced

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/14/1994
carol: 4/6/1994
supermim: 3/16/1992
carol: 1/10/1991
carol: 6/4/1990
carol: 6/1/1990

*RECORD*
*FIELD* NO
103800
*FIELD* TI
*103800 ALDER ANOMALY
*FIELD* TX
Azurophilic cytoplasmic inclusions of the polymorphonuclear leukocytes
were thought to be inherited as an autosomal dominant. Alder (1939)
originally described the anomaly in a brother and sister who later at
puberty developed changes in their hip joints. The brother was said to
be in good health at age 28 (Davidson, 1961). This was, in fact, not
true (Steinmann, 1994). Alder (1939) described the granules in a
9-year-old girl with scarlet fever. They persisted after recovery and
were also detectable in the healthy 7-year-old brother, R.W., but not in
3 other sibs and not in the consanguineous parents. Gitzelmann et al.
(1987) had the opportunity to examine R. W. and to study his fibroblasts
which had only 2 to 3% residual arylsulfatase B activity but normal
alpha-iduronidase activity. Thus, he clearly suffered from MPS VI
(253200). Initially, Alder (1939) considered the granules as
constitutional and harmless until the brother (R.W.) developed a
waddling gait. Alder (1939) found in both sibs bony destruction in the
shoulders, hips, and skull, and later in the knees and spine. R.W. had
herniotomy at the age of 36 years, a decompressive laminectomy C1 to C7
at age 50, hip replacement at age 51, and operation for aortic stenosis
at age 60. He was very intelligent and a dedicated violin maker. His
sister died early from an unknown cause. Thus, the granules that Alder
(1939) first described are inherited as an autosomal recessive. They are
part of MPS VI which is the mucopolysaccharidosis that shows the most
striking leukocyte inclusions.

Jordans (1947) reported a Dutch family showing a dominant inheritance
pattern--9 affected persons in 3 generations with male-to-male
transmission. The inclusions are probably morphologically
indistinguishable from the Reilly granulations observed in
mucopolysaccharidoses (Reilly, 1941).

Francois et al. (1960) observed Alder anomaly and Fuchs atrophia gyrata
chorioideae et retinae in the offspring of first-cousin parents, both of
whom had the Alder anomaly. They suggested that the eye disorder is the
homozygous expression of the Alder anomaly gene. It is possible, of
course, that the eye disorder was merely an unrelated recessive disorder
and indeed later observations (see Fuchs atrophia gyrata, 229900)
supported this view.

*FIELD* RF
1. Alder, A.: Ueber konstitutionell bedingte Granulationsveraenderungen
der Leukocyten. Dtsch. Arch. Klin. Med. 183: 372-378, 1939.

2. Davidson, W. M.: Inherited variations in leucocytes. Brit. Med.
Bull. 17: 190-195, 1961.

3. Francois, J.; Barbier, F.; De Rouck, A.: Les conducteurs du gene
de l'atrophia gyrata chorioideae et retinae de Fuchs (anomalie d'Alder).
Acta Genet. Med. Gemellol. 9: 74-91, 1960.

4. Gitzelmann, R.; Steinmann, B.; Wiesmann, U.; Spycher, M.; Herschkowitz,
N.; Marti, H.-R.: Aldersche Granulationsanomalie: Albert Alders Patienten
litten nicht an M. Pfaundler-Hurler.  (Abstract) Helv. Paediat. Acta 42:
90 only, 1987.

5. Jordans, G. H. W.: Hereditary granulation anomaly of the leucocytes
(Alder). Acta Med. Scand. 129: 348-351, 1947.

6. Reilly, W. A.: The granules in the leukocytes in gargoylism. Am.
J. Dis. Child. 62: 489-491, 1941.

7. Steinmann, B.: Personal Communication. Zurich, Switzerland
12/9/1994.

*FIELD* CS

Heme:
   Azurophilic cytoplasmic neutrophil inclusions

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 1/19/1995
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/17/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
103830
*FIELD* TI
*103830 ALDEHYDE REDUCTASE; ALR
*FIELD* TX
Petrash et al. (1981) studied aldose reductase (AR), aldose reductase M
(ARM), and aldehyde reductase (ALR) in a variety of human tissues. Lens
aldose reductase is composed of a single subunit with molecular weight
35K, and liver aldehyde reductase is composed of a single subunit of
molecular weight 32K. Liver aldose reductase M is composed of 2
nonidentical subunits of molecular weights 35K and 42K. Lens has only
AR, liver has ARM and ALR, red cells have only ALR, while brain and
placenta have all three enzymes. Petrash et al. (1981) suggested that
three loci--alpha, beta, and delta--code for these enzymes, and that AR
is a monomer of alpha polypeptide, ARM a dimer of alpha and beta
subunits, and ALR a monomer of delta polypeptide.

*FIELD* RF
1. Petrash, J. M.; Ansari, N. H.; Sadana, I.; Srivastava, S. K.:
Biochemical and genetic interrelationship between aldose reductase,
aldose reductase M and aldehyde reductase in human tissues.  (Abstract) Am.
J. Hum. Genet. 33: 52A only, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 10/24/1990
supermim: 3/20/1990
carol: 12/13/1989
ddp: 10/27/1989
root: 10/26/1989

*RECORD*
*FIELD* NO
103850
*FIELD* TI
*103850 ALDOLASE A, FRUCTOSE-BISPHOSPHATE; ALDOA
FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE A;;
ALDOLASE A; ALDA;;
ALDOLASE-1;;
FRUCTOALDOLASE A
ALDOLASE A DEFICIENCY, INCLUDED
*FIELD* TX
Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a glycolytic enzyme
that catalyzes the reversible conversion of fructose-1,6-bisphosphate to
glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. The enzyme is
a tetramer of identical 40,000-dalton subunits. Vertebrates have 3
aldolase isozymes which are distinguished by their electrophoretic and
catalytic properties. Electrophoretic variants were found by
Charlesworth (1972). The amino acid sequence of the aldolases around the
active site lysine is greatly conserved in evolution. Differences
indicate that aldolases A, B (229600), and C (103870) are distinct
proteins, the products of a family of related genes. Study of the genes
is of interest because expression of the isozymes is regulated during
development and because they represent the poorly characterized class of
'housekeeping genes' which are expressed in all cells. The developing
embryo produces aldolase A, which is produced in even greater amounts in
adult muscle where it can be as much as 5% of total cellular protein. In
adult liver, kidney and intestine, aldolase A expression is repressed
and aldolase B is produced. In brain and other nervous tissue, aldolase
A and C are expressed about equally. In transformed liver cells,
aldolase A replaces aldolase B.

Freemont et al. (1988) presented the complete amino acid sequence of
human skeletal muscle fructose-bisphosphate aldolase, comprising 363
residues. Izzo et al. (1988) found that the cloned gene sequence of
ALDOA spans 7,530 base pairs, includes 12 exons, and occurs as a single
copy per haploid human genome. Eight exons containing the coding
sequence were found to be common to all mRNAs extracted from several
mammalian sources; 4 additional exons were found in the 5-prime
untranslated region, 1 of which was contained in the ubiquitous type of
mRNA, the second in the muscle-specific type of mRNA, and the third and
fourth in a minor species of mRNA found in human liver tissue.
S(1)-nuclease-protection analysis of the 5-prime end of mRNA from
cultured fibroblasts, muscle, and hepatoma cell lines showed the
existence of 4 different transcription-initiation sites. Also, the
presence of conventional sequences for 4 eukaryotic promoters was
demonstrated. The nucleotide similarities in the coding region and the
intron-exon organization of aldolases A, B, and C confirm that they
arose from a common ancestral gene and that aldolase B diverged first.

Harris (1974) concluded that 3 loci determine aldolase. One group
(Cohen-Haguenauer et al., 1985) assigned aldolase A to chromosome 16 and
a second group (Kukita et al., 1985) assigned it to chromosome 22. The
better evidence supported chromosome 16. Kukita et al. (1985) used
Northern blot analysis of RNA isolated from human-mouse somatic cell
hybrids and a cDNA clone for human aldolase mRNA. Later, however, Kukita
et al. (1987) mapped ALDOA to chromosome 16 by 3 different methods:
molecular hybridization to hybrid cell DNA, molecular hybridization to
DNA of sorted metaphase chromosomes, and in situ hybridization. In situ
hybridization indicated that the gene is located on the 16q22-q24 band.
Serero et al. (1988) also assigned the aldolase A gene to chromosome 16
by Southern blot analysis of human genomic DNA with a cDNA probe.
Aldolase A pseudogenes were found on chromosomes 3 and 10. The map
location of the 3 aldolase genes (ALDOA, ALDOB, ALDOC) and the aldolase
pseudogene (see 229600) is of considerable interest from the point of
view of chromosome evolution. The 4 genes are found on 2 pairs of
morphologically similar chromosomes, 9 and 10, and 16 and 17. These
homeologous (i.e., of similar origin) chromosome pairs may have arisen
from 1 or 2 tetraploidization events (Comings, 1972; Ohno, 1973). As
predicted by the chromosomal locations, the coding sequences of the
expressed aldolase-A and -C genes (on chromosomes 16 and 17) are more
homologous to each other than either of them is to the expressed
aldolase-B gene (on chromosome 9).

Beutler et al. (1973) described a son of first-cousin parents who had
nonspherocytic hemolytic anemia, mental retardation and increased
hepatic glycogen due, apparently, to deficiency of red cell aldolase.
Puzzlingly, both parents had normal levels of red cell aldolase. The
patient was presented again at the Birth Defects Conference in Vancouver
in 1976 (Lowry and Hanson, 1977). He showed many dysmorphic features,
some of which (ptosis, epicanthi, short neck, low posterior hairline)
were reminiscent of the Noonan syndrome. The patient reported by Beutler
et al. (1973) had an unstable enzyme which became depleted in enucleated
erythrocytes. Consequently, energy production was impaired and membrane
stability decreased with declining ion-transport activity. Hurst et al.
(1987) described brother and sister with mental retardation, short
stature, delayed puberty, hemolytic anemia, and an abnormal facial
appearance. The similarities to the boy reported by Beutler et al.
(1973) were striking.

Kreuder et al. (1996) described a boy with aldolase deficiency who
presented with predominantly myopathic symptoms, including muscle
weakness and premature muscle fatigue. He had episodes of anemia and
jaundice and was also prone to episodes of rhabdomyolysis during febrile
illness. Biochemical assays revealed a profound reduction in muscle and
red cell aldolase levels and a decrease in thermostability of residual
enzyme. The aldolase A coding sequence was examined following RT-PCR of
mRNA from peripheral blood mononuclear cells and muscle. The patient was
found to be homozygous for a germline mutation in which a negatively
charged glutamic acid is changed to a positively charged lysine at
residue 206, a residue that is highly conserved within the subunit
interface region.

*FIELD* AV
.0001
ALDOLASE DEFICIENCY OF RED CELLS
ALDOA, ASP128GLY
Kishi et al. (1987) studied a case of red cell aldolase deficiency and
found an A-G transversion at nucleotide 386 in the codon for the 128th
amino acid, leading to a change from aspartic acid (GAU) to glycine
(GGU) in the aldolase protein. The patient's enzyme from red cells and
from cultured lymphoblastoid cells was found to be highly thermolabile,
and the enzyme expressed in E. coli was likewise thermolabile. Since
asp128 is conserved in aldolase A, -B, and -C of eukaryotes, including
Drosophila, this residue is likely to have a crucial role in maintaining
the correct spatial structure or in performing the catalytic function of
the enzyme. The parents had intermediate levels of red cell aldolase A.
The change in the second letter of the aspartic acid codon extinguished
an Fok1 restriction site (GGATG to GGGTG). Southern blot analysis of the
genomic DNA showed the patient to be homozygous for a mutation that was
heterozygous in both parents.

*FIELD* SA
Miwa et al. (1981); Penhoet et al. (1966); Rottmann et al. (1984);
Sakakibara et al. (1985); Tolan et al. (1987)
*FIELD* RF
1. Beutler, E.; Scott, S.; Bishop, A.; Margolis, N.; Matsumoto, F.;
Kuhl, W.: Red cell aldolase deficiency and hemolytic anemia: a new
syndrome. Trans. Assoc. Am. Phys. 86: 154-166, 1973.

2. Charlesworth, D.: Starch-gel electrophoresis of four enzymes from
human red blood cells: glyceraldehyde-3-phosphate dehydrogenase, fructoaldolase,
glyoxalase II and sorbitol dehydrogenase. Ann. Hum. Genet. 35:
477-484, 1972.

3. Cohen-Haguenauer, O.; Van Cong, N.; Mennecier, F.; Kahn, A.; Frezal,
J.: The human aldolase A gene is on chromosome 16.(Abstract) Cytogenet.
Cell Genet. 40: 605, 1985.

4. Comings, D. E.: Evidence of ancient tetraploidy and conservation
of linkage groups in mammalian chromosomes. Nature 238: 455-457,
1972.

5. Freemont, P. S.; Dunbar, B.; Fothergill-Gilmore, L. A.: The complete
amino acid sequence of human skeletal-muscle fructose-bisphosphate
aldolase. Biochem. J. 249: 779-788, 1988.

6. Harris, H.: Personal Communication. London, England  1974.

7. Hurst, J. A.; Baraitser, M.; Winter, R. M.: A syndrome of mental
retardation, short stature, hemolytic anemia, delayed puberty, and
abnormal facial appearance: similarities to a report of aldolase A
deficiency. Am. J. Med. Genet. 28: 965-970, 1987.

8. Izzo, P.; Costanzo, P.; Lupo, A.; Rippa, E.; Paolella, G.; Salvatore,
F.: Human aldolase A gene: structural organization and tissue-specific
expression by multiple promoters and alternate mRNA processing. Europ.
J. Biochem. 174: 569-578, 1988.

9. Kishi, H.; Mukai, T.; Hirono, A.; Fujii, H.; Miwa, S.; Hori, K.
: Human aldolase A deficiency associated with a hemolytic anemia:
thermolabile aldolase due to a single base mutation. Proc. Nat.
Acad. Sci. 84: 8623-8627, 1987.

10. Kreuder, J.; Borkhardt, A.; Repp, R.; Pekrun, A.; Gottsche, B.;
Gottschalk, U.; Reichmann, H.; Schachenmayr, W.; Schlegel, K.; Lampert,
F.: Inherited metabolic myopathy and hemolysis due to a mutation
in aldolase A. New Eng. J. Med. 334: 1100-1104, 1996.

11. Kukita, A.; Yoshida, M. C.; Fukushige, S.; Sakakibara, M.; Joh,
K.; Mukai, T.; Hori, K.: Molecular gene mapping of human aldolase
A (ALDOA) gene to chromosome 16. Hum. Genet. 76: 20-26, 1987.

12. Kukita, A.; Yoshida, M. C.; Sakakibara, M.; Mukai, T.; Hori, K.
: Molecular gene mapping of the structural gene for human aldolase
A (ALDOA) to chromosome 22.(Abstract) Cytogenet. Cell Genet. 40:
674, 1985.

13. Lowry, R. B.; Hanson, J. W.: Aldolase A deficiency with syndrome
of growth and developmental retardation, midfacial hypoplasia, hepatomegaly,
and consanguineous parents. Birth Defects Orig. Art. Ser. XIII(3B):
222-228, 1977.

14. Miwa, S.; Fujii, H.; Tani, K.; Takahashi, K.; Takegawa, S.; Fujinami,
N.; Sakurai, M.; Kubo, M.; Tanimoto, Y.; Kato, T.; Matsumoto, N.:
Two cases of red cell aldolase deficiency associated with hereditary
hemolytic anemia in a Japanese family. Am. J. Hemat. 11: 425-437,
1981.

15. Ohno, S.: Ancient linkage groups and frozen accidents. Nature 244:
259-262, 1973.

16. Penhoet, E.; Rajkumar, T.; Rutter, W. I.: Multiple forms of fructose
diphosphate aldolase in mammalian tissues. Proc. Nat. Acad. Sci. 56:
1275-1282, 1966.

17. Rottmann, W. H.; Tolan, D. R.; Penhoet, E. E.: Complete amino
acid sequence for human aldolase B derived from cDNA and genomic clones.
Proc. Nat. Acad. Sci. 81: 2738-2742, 1984.

18. Sakakibara, M.; Mukai, T.; Hori, K.: Nucleotide sequence of a
cDNA clone for human aldolase: a messenger RNA in the liver. Biochem.
Biophys. Res. Commun. 131: 413-420, 1985.

19. Serero, S.; Maire, P.; Van Cong, N.; Cohen-Haguenauer, O.; Gross,
M. S.; Jegou-Foubert, C.; de Tand, M. F.; Kahn, A.; Frezal, J.: Localization
of the active gene of aldolase on chromosome 16, and two aldolase
A pseudogenes on chromosomes 3 and 10. Hum. Genet. 78: 167-174,
1988.

20. Tolan, D. R.; Niclas, J.; Bruce, B. D.; Lebo, R. V.: Evolutionary
implications of the human aldolase-A, -B, -C, and -pseudogene chromosome
locations. Am. J. Hum. Genet. 41: 907-924, 1987.

*FIELD* CS

Heme:
   Congenital nonspherocytic hemolytic anemia;
   Normocytic anemia;
   Normochromic anemia;
   Normal red cell osmotic fragility

Skin:
   Jaundice

GI:
   Splenomegaly;
   Cholelithiasis;
   Cholecystitis

Neuro:
   Mental retardation reported

Eyes:
   Ptosis;
   Epicanthus

Neck:
   Short neck;
   Low posterior hairline

Growth:
   Short stature

Endocrine:
   Delayed puberty

Lab:
   Aldolase A deficiency

Inheritance:
   Autosomal recessive (16q22-q24)

*FIELD* CN
Moyra Smith - updated: 6/3/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 06/04/1996
carol: 6/3/1996
davew: 6/8/1994
warfield: 4/7/1994
carol: 4/6/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 1/27/1992

*RECORD*
*FIELD* NO
103870
*FIELD* TI
*103870 ALDOLASE-3
ALDOLASE C;;
FRUCTOALDOLASE C; ALDC; ALDOC
*FIELD* TX
See aldolase-1 (103850). Rottmann et al. (1987) determined the complete
amino acid sequence of aldolase C from recombinant genomic clones.
Aldolase C was found to share 81% amino acid identity with aldolase A
and 70% identity with aldolase B. The gene structure was found to be the
same as that in other aldolase genes in birds and mammals, having 9
exons separated by 8 introns, all in precisely the same positions, with
only the intron sizes being different. Eight of the exons contained the
protein coding region comprised of 363 amino acids. The entire gene is
approximately 4 kb long. Tolan et al. (1987) reported the mapping of
ALDOC to chromosome 17 by spot-blot analysis of sorted chromosomes.
Rocchi et al. (1989) also mapped the gene and narrowed the assignment to
17cen-q21 by in situ hybridization. In addition, they corroborated the
assignment of ALDOA (103850) to chromosome 16, and of ALDOB (229600) to
chromosome 9. Buono et al. (1988) presented the complete nucleotide
sequence of ALDOC.

*FIELD* RF
1. Buono, P.; Paolella, G.; Mancini, F. P.; Izzo, P.; Salvatore, F.
: The complete nucleotide sequence of the gene coding for the human
aldolase C. Nucleic Acids Res. 16: 4733 only, 1988.

2. Rocchi, M.; Vitale, E.; Covone, A.; Romeo, G.; Santamaria, R.;
Buono, P.; Paolella, G.; Salvatore, F.: Assignment of human aldolase
C gene to chromosome 17, region cen--q21.1. Hum. Genet. 82: 279-282,
1989.

3. Rottmann, W. H.; Deselms, K. R.; Niclas, J.; Camerato, T.; Holman,
P. S.; Green, C. J.; Tolan, D. R.: The complete amino acid sequence
of the human aldolase C isozyme derived from genomic clones. Biochimie 69:
137-145, 1987.

4. Tolan, D. R.; Niclas, J.; Bruce, B. D.; Lebo, R. V.: Evolutionary
implications of the human aldolase-A, -B, -C, and -pseudogene chromosome
locations. Am. J. Hum. Genet. 41: 907-924, 1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 10/13/1993
carol: 3/31/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/7/1989

*RECORD*
*FIELD* NO
103880
*FIELD* TI
*103880 ALDEHYDE REDUCTASE, ALDR1
ALDOSE REDUCTASE, LOW Km
*FIELD* TX
See aldehyde reductase (103830). Aldose reductase (EC 1.1.1.21) is a
member of the monomeric, NADPH-dependent aldoketoreductase family. It
catalyzes the reduction of a number of aldehydes, including the aldehyde
form of glucose, which is reduced to the corresponding sugar alcohol,
sorbitol. Sorbitol is subsequently metabolized to fructose by sorbitol
dehydrogenase. Under normal conditions, this pathway plays a minor role
in glucose metabolism in most tissues. In diabetic hyperglycemia,
however, cells undergoing insulin-independent uptake of glucose produce
significant quantities of sorbitol. The sorbitol accumulates in cells
because of its poor penetration across cellular membranes and its slow
metabolism by sorbitol dehydrogenase. The resulting hyperosmotic stress
to cells may be a cause of diabetic complications such as neuropathy,
retinopathy, and cataracts. Chung and LaMendola (1989) cloned and
sequenced the aldose reductase gene from a human placental cDNA library
using antibodies against the bovine lens aldose reductase. The deduced
amino acid sequence indicated that maturation of aldose reductase
involves removal of the N-terminal methionine. Nishimura et al. (1990)
also cloned the aldose reductase gene using synthetic oligonucleotide
probes based on partial amino acid sequences of purified human psoas
muscle aldose reductase.

Graham et al. (1991) determined the structure and sequence of the ALDR1
gene by analysis of cDNA and genomic clones. The gene extends over
approximately 18 kb and consists of 10 exons, giving rise to a 1,384
nucleotide mRNA, excluding the poly(A) tail. The gene codes for a
316-amino acid protein with a molecular mass of 35,858 Da. The exons
range in size from 82 to 168 bp, whereas the introns range from 325 to
about 7,160 bp. A major site of transcription initiation in liver was
mapped to an adenine residue 31 nucleotides upstream from the the A of
the ATG initiation codon. The promoter region of the gene contains a
TATA (TATTTA) box and a CCAAT box, located 37 and 104 nucleotides
upstream, respectively, from the transcription initiation site. Graham
et al. (1991) found 4 Alu elements in the ALDR1 gene: two in intron 1
and one each in introns 4 and 9. Using the PCR to amplify specifically
the human AR sequence in hamster/human hybrid DNA and also in
mouse/human monochromosome hybrids, Graham et al. (1991) assigned the
gene to chromosome 7. The assignment was confirmed and regionalized to
7q35 by in situ hybridization to human metaphase chromosomes using a
novel, rapid method.

Brown et al. (1992) identified a putative pseudogene (ALDRP1) that
contained no intronic sequences; the functional aldose reductase has 9
introns. In addition, the homology was absent in the region 5-prime to
the transcription start site for the cDNA, implying that regulatory
elements such as the promoter were missing from the pseudogene. They
mapped the pseudogene to chromosome 3 by PCR, using amplimers specific
for it to amplify DNA from somatic cell hybrids.

Using a cDNA clone encoding human aldose reductase, Bateman et al.
(1993) mapped gene sequences to human chromosomes 1, 3, 7, 9, 11, 13,
14, and 18 by analysis of somatic cell hybrids. By in situ
hybridization, sequences were localized to 1q32-q42, 3p12, 7q31-q35,
9q22, 11p14-p15, and 13q14-q21. As a putative functional ALDR1 gene had
been mapped to chromosome 7 and a putative pseudogene (ALDRP1) to
chromosome 3, the sequences on the other 7 chromosomes were thought to
represent other active genes, non-aldose reductase homologous sequences,
or pseudogenes.

*FIELD* SA
Graham et al. (1991)
*FIELD* RF
1. Bateman, J. B.; Kojis, T.; Heinzmann, C.; Klisak, I.; Diep, A.;
Carper, D.; Nishimura, C.; Mohandas, T.; Sparkes, R. S.: Mapping
of aldose reductase gene sequences to human chromosomes 1, 3, 7, 9,
11, and 13. Genomics 17: 560-565, 1993.

2. Brown, L.; Hedge, P. J.; Markham, A. F.; Graham, A.: A human aldehyde
dehydrogenase (aldose reductase) pseudogene: nucleotide sequence analysis
and assignment to chromosome 3. Genomics 13: 465-468, 1992.

3. Chung, S.; LaMendola, J.: Cloning and sequence determination of
human placental aldose reductase gene. J. Biol. Chem. 264: 14775-14777,
1989.

4. Graham, A.; Brown, L.; Hedge, P. J.; Gammack, A. J.; Markham, A.
F.: Structure of the human aldose reductase gene. J. Biol. Chem. 266:
6872-6877, 1991.

5. Graham, A.; Heath, P.; Morten, J. E. N.; Markham, A. F.: The human
aldose reductase gene maps to chromosome region 7q35. Hum. Genet. 86:
509-514, 1991.

6. Nishimura, C.; Matsuura, Y.; Kokai, Y.; Akera, T.; Carper, D.;
Morjana, N.; Lyons, C.; Flynn, T. G.: Cloning and expression of human
aldose reductase. J. Biol. Chem. 265: 9788-9792, 1990.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/27/1996
mark: 2/26/1996
carol: 4/6/1994
carol: 9/21/1993
carol: 12/21/1992
carol: 6/3/1992
supermim: 3/16/1992
carol: 8/19/1991

*RECORD*
*FIELD* NO
103890
*FIELD* TI
*103890 ALDOSE REDUCTASE M; ARM
*FIELD* TX
See aldehyde reductase (103830).

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
supermim: 3/16/1992
carol: 10/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/11/1988
*RECORD*
*FIELD* NO
103900
*FIELD* TI
#103900 ALDOSTERONISM, SENSITIVE TO DEXAMETHASONE
GLUCOCORTICOID-SUPPRESSIBLE HYPERALDOSTERONISM; GSH;;
GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM; GRA;;
ACTH-DEPENDENT HYPERALDOSTERONISM, SYNDROME OF;;
HYPERALDOSTERONISM, FAMILIAL, TYPE 1
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
glucocorticoid-remediable aldosteronism is the result of an
anti-Lepore-type fusion of the CYP11B2 (124080) and CYP11B1 (202010)
genes. (The various hemoglobins Lepore (e.g., 142000.0019) have a fusion
beta-type subunit that is delta globin at the NH2 end and beta globin at
the COOH end. This chimeric structure results from nonhomologous pairing
and unequal crossing-over between the contiguous delta and beta globin
genes. The hemoglobins Lepore result from delta-beta fusion because the
delta globin gene (142000) is located upstream from the beta globin gene
(141900). The hemoglobins anti-Lepore, e.g., Hb Miyada (141900.0179) and
Hb P(Nilotic) (141900.0215), are the reciprocal product of nonhomologous
pairing and unequal crossing-over between the HBD and HBB genes; they
are beta-delta fusion globins. In GRA, the 5-prime portion of the
downstream gene is the 5-prime portion of the fusion gene; hence, it is
an anti-Lepore fusion.)

Sutherland et al. (1966) and Salti et al. (1969) described a father and
son with hypertension, low plasma renin activity, and increased
aldosterone secretion responsive to dexamethasone. Growth and sexual
development were normal. At laparotomy the father was found to have
multiple adrenocortical adenomas. This appears to be distinct from Conn
syndrome (primary aldosteronism) which is not sensitive to
dexamethasone. New and Peterson (1967) described 2 cases in a family.
Giebink et al. (1973) studied 2 brothers and their mother who had
glucocorticoid-remediable aldosteronism. Ganguly et al. (1981) showed
that the paradoxic decline in plasma aldosterone when the patient is in
the upright posture, usually observed in aldosterone-producing adenoma,
is also seen in GSH. Thus, in patients with primary aldosteronism in
whom GSH is suspected on the basis of young age and family history and a
postural decline in plasma aldosterone is demonstrated, treatment with
glucocorticoid should be given for 4 to 6 weeks before localization
procedures are begun. Ganguly et al. (1981) studied 2 families, each
with 3 affected persons. The diagnosis of hyperaldosteronism was
established by failure of saline infusion to suppress plasma aldosterone
normally and by the failure of furosemide or a low sodium diet to
stimulate plasma renin activity. One family had basal serum potassium
levels below 3.5 mmol per liter, whereas values were normal in the
second family. Although primary aldosteronism is rare (about 2% of
hypertensives have it), it has been subdivided into 3 types:
aldosterone-producing adenoma (50-90% of cases), idiopathic form thought
to be due to bilateral adrenal hyperplasia, and GSH (the rarest form).
Mulrow (1981) speculated that the primary defect in GSH resides in the
anterior pituitary gland. Experiments in animals have hinted at the
existence of another aldosterone-regulating hormone, possibly
originating in the pituitary. Mulrow (1981) asked: 'Is it possible that
in the familial disorder of glucocorticoid-suppressible
hyperaldosteronism, the pituitary gland is synthesizing or processing a
more potent form of (a fragment of proopiomelanocortin) that enhances
the response of the adrenal glomerulosa cell to normal concentrations of
ACTH?' If the answer is 'yes,' GSH might appropriately be discussed in
entry 176830. This hypothesis proved untrue, however.

Aldosterone synthase (124080), like steroid 11-beta-hydroxylase
(202010), is expressed in both adrenal fasciculata and glomerulosa; they
are 95% identical (Mornet et al., 1989) and lie on chromosome 8q (Mornet
et al., 1989; Chua et al., 1987). That they are immediately adjacent is
indicated by the fact that a chimeric, anti-Lepore-like gene has been
identified as the cause of glucocorticoid-remediable aldosteronism. In
glucocorticoid-remediable aldosteronism (GRA, an alternative acronym for
GSH) there are high levels of the abnormal adrenal steroids
18-oxocortisol and 18-hydroxycortisol. The hypertension, variable
hyperaldosteronism, and abnormal steroid production are all under the
control of ACTH and suppressible by glucocorticoids. The fusion gene has
the promoter and some other 5-prime parts of the CYP11B2 gene. As is the
practice with other hybrid genes, the details are given as an allelic
variant of the gene that contributes the 5-prime portion; therefore, see
202010.0002.

Glucocorticoid suppressible hyperaldosteronism is the result of CYP11B2
activity under the control of ACTH (which normally regulates CYP11B1)
and results from a unequal crossing-over involving the CYP11B1 and
CYP11B2 genes. Normally, these genes are in the following orientation:
5-prime--CYP11B2--CYP11B1--3-prime; the hybrid anti-Lepore gene lies
between CYP11B2 and CYP11B1 and has B1 sequence at its 5-prime end and
B2 sequence at its 3-prime end. The breakpoints of the various hybrid
genes that have been studied have been found to be 5-prime of intron 4.
Pascoe et al. (1992) demonstrated that hybrid cDNAs containing 5-prime
sequences from CYP11B1 and 3-prime sequences from CYP11B2, when
transfected into COS-1 cells, resulted in aldosterone synthesis at near
normal levels when the constructs contained up to the first 3 exons of
CYP11B1, while those with 5 or more exons from CYP11B1 produced no
detectable aldosterone.

Gordon (1995) stated that 'in a study on approximately 1,000 descendants
of an English convict transported to Australia in 1837 for highway
robbery in Northamptonshire,' his colleagues and he had confirmed, in 21
affected members thus far identified, the extraordinary phenotypic
heterogeneity in glucocorticoid-remediable aldosteronism. The affected
members were often normokalemic, and some remained normotensive until
late in life. This disorder, which he referred to as familial
hyperaldosteronism type 1, is associated with hybrid genes showing
somewhat different crossover points linking the CYP11B1 and CYP11B2
portions. To that extent, the disorder shows genetic heterogeneity;
however, no other gene has been implicated in the syndrome of
ACTH-dependent hyperaldosteronism.

Pascoe et al. (1995) studied a French kindred in which 7 members had
GSH; of the 7, 2 also had adrenal tumors and 2 other members of the
family had micronodular adrenal hyperplasia. One of the adrenal tumors
and the surrounding adrenal tissue had been removed, giving a rare
opportunity to study the regulation and action of the hybrid
CYP11B1/CYP11B2 gene causing the disease. The hybrid gene was
demonstrated to be expressed at higher levels than either CYP11B1 or
CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot
analysis. In situ hybridization showed that both CYP11B1 and the hybrid
chain were expressed in all 3 zones of the cortex. In cell culture
experiments, hybrid gene expression was stimulated by ACTH, leading to
increased production of aldosterone and the hybrid steroids
characteristic of GSH. The genetic basis of the tumors and hyperplasia
in this family was not known but may have been related to the
duplication causing the hyperaldosteronism.

Gates et al. (1996) described 2 large pedigrees with many subjects who
had the abnormal chimeric gene associated with glucocorticoid remediable
aldosteronism. Most of the affected members, who had only mild
hypertension and normal biochemistry, were clinically indistinguishable
from patients with essential hypertension. This suggested to the authors
that GRA is an underdiagnosed condition.

*FIELD* SA
Ganguly et al. (1981); Grim and Weinberger (1980)
*FIELD* RF
1. Chua, S. C.; Szabo, P.; Vitek, A.; Grzeschik, K.-H.; John, M.;
White, P. C.: Cloning of cDNA encoding steroid 11-beta-hydroxylase
(P450C11). Proc. Nat. Acad. Sci. 84: 7193-7197, 1987.

2. Ganguly, A.; Grim, C. E.; Bergstein, J.; Brown, R. D.; Weinberger,
M. H.: Genetic and pathophysiologic studies of a new kindred with
glucocorticoid-suppressible hyperaldosteronism manifest in three generations.
J. Clin. Endocr. Metab. 53: 1040-1046, 1981.

3. Ganguly, A.; Grim, C. E.; Weinberger, M. H.: Anomalous postural
aldosterone response in glucocorticoid-suppressible hyperaldosteronism.
New Eng. J. Med. 305: 991-993, 1981.

4. Gates, L. J.; MacConnachie, A. A.; Lifton, R. P.; Haites, N. E.;
Benjamin, N.: Variation of phenotype in patients with glucocorticoid
remediable aldosteronism. J. Med. Genet. 33: 25-28, 1996.

5. Giebink, G. S.; Gotlin, R. W.; Biglieri, E. G.; Katz, F. H.: A
kindred with familial glucocorticoid-suppressible aldosteronism. J.
Clin. Endocr. 36: 715-723, 1973.

6. Gordon, R. D.: Heterogeneous hypertension. Nature Genet. 11:
6-9, 1995.

7. Grim, C. E.; Weinberger, M. H.: Familial, dexamethasone-suppressible,
normokalemic hyperaldosteronism. Pediatrics 65: 597-604, 1980.

8. Mornet, E.; Dupont, J.; Vitek, A.; White, P. C.: Characterization
of two genes encoding human steroid 11-beta-hydroxylase (P-45011-beta).
J. Biol. Chem. 264: 20961-20967, 1989.

9. Mulrow, P. J.: Glucocorticoid-suppressible hyperaldosteronism:
a clue to the missing hormone?.      (Editorial) New Eng. J. Med. 305:
1013-1014, 1981.

10. New, M. I.; Peterson, R. E.: A new form of congenital adrenal
hyperplasia. J. Clin. Endocr. 27: 300-305, 1967.

11. Pascoe, L.; Curnow, K. M.; White, P. C.: Mutations in the CYP11B1
(11-beta-hydroxylase) and CYP11B2 (aldosterone synthase) genes causing
CMOII deficiency, 11-hydroxylase deficiency and glucocorticoid suppressible
hyperaldosteronism.      (Abstract) Am. J. Hum. Genet. 51 (suppl.):
A28, 1992.

12. Pascoe, L.; Jeunemaitre, X.; Lebrethon, M.-C.; Curnow, K. M.;
Gomez-Sanchez, C. E.; Gasc, J.-M.; Saez, J. M.; Corvol, P.: Glucocorticoid-suppressible
hyperaldosteronism and adrenal tumors occurring in a single French
pedigree. J. Clin. Invest. 96: 2236-2246, 1995.

13. Salti, I. S.; Stiefel, M.; Ruse, J. L.; Laidlaw, J. C.: Non-tumorous
'primary' aldosteronism. I. Type relieved by glucocorticoid (glucocorticoid-remediable
aldosteronism). Canad. Med. Assoc. J. 101: 1-10, 1969.

14. Sutherland, D. J.; Ruse, J. L.; Laidlaw, J. C.: Hypertension,
increased aldosterone secretion and low plasma renin activity relieved
by dexamethasone. Canad. Med. Assoc. J. 95: 1109-1119, 1966.

*FIELD* CS

Endocrine:
   Hypertension;
   Low plasma renin activity;
   Increased aldosterone secretion responsive to dexamethasone

Growth:
   Normal growth

GU:
   Normal sexual development

Oncology:
   Multiple adrenocortical adenomas;
   Hyperaldosteronism;
   Failure of saline infusion to suppress plasma aldosterone;
   Failure of furosemide or low sodium diet to stimulate plasma renin
   activity;
   Low/normal basal serum potassium;
   High levels of 18-oxocortisol and 18-hydroxycortisol

Inheritance:
   Autosomal dominant resulting from unequal crossing-over between CYP11B1
   and CYP11B2 genes

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/17/1996
terry: 2/12/1996
mark: 2/2/1996
terry: 1/26/1996
mark: 8/31/1995
carol: 4/8/1994
mimadm: 3/11/1994
carol: 11/19/1992
carol: 11/18/1992

*RECORD*
*FIELD* NO
103920
*FIELD* TI
103920 ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
*FIELD* TX
Graves et al. (1979) described 2 brothers with identical HLA haplotypes
and allergic bronchopulmonary aspergillosis. A barn near the residence
of the brothers was identified as the probable source. Vithayasai et al.
(1973) also reported familial allergic aspergillosis. However, in 35
unrelated cases no HLA association was found (Flaherty et al., 1978).

*FIELD* RF
1. Flaherty, D. K.; Surfus, J. E.; Geller, M.; Rosenberg, M.; Patterson,
R.; Reed, C. E.: HLA frequencies in allergic bronchopulmonary aspergillosis.
Clin. Allergy 8: 73-76, 1978.

2. Graves, T. S.; Fink, J. N.; Patterson, R.; Kurup, V. P.; Scanlon,
G. T.: A familial occurrence of allergic bronchopulmonary aspergillosis.
Ann. Intern. Med. 91: 378-382, 1979.

3. Vithayasai, V.; Hydes, J. S.; Florio, L.: Allergic aspergillosis
in a family. Indian Med. J. 144: 564-566 and 600 only, 1973.

*FIELD* CS

Immunology:
   Allergic bronchopulmonary aspergillosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
pfoster: 3/30/1994
mimadm: 3/11/1994
carol: 3/31/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
103950
*FIELD* TI
*103950 AL-M
ALPHA-2-MACROGLOBULIN; A2M;;
MACROGLOBULIN, ALPHA-2
ALPHA-2-MACROGLOBULIN DEFICIENCY, INCLUDED
*FIELD* TX
This polymorphism, which has been demonstrated in Japanese persons, is
distinct from Gm, Am, and haptoglobins. It is likewise distinct from Xm
(314900), also a macroglobulin, as indicated by the autosomal
inheritance and specific tests. Gene frequency of the allele whose
product is demonstrated by the antiserum is about 0.16 in Japanese.
Using a rabbit antihuman serum, Gallango and Castillo (1974) also
described a polymorphism of alpha-2-macroglobulin. This may be separate
from that described by Leikola et al. (1972). From comparison of the
sequence of the subunit of human alpha-2-macroglobulin with those of C3
(120700) and C4 (120810, 120820), Sottrup-Jensen et al. (1985) concluded
that these 3 proteins, which all contain a unique activatable
beta-cysteinyl-gamma-glutamyl thiol ester, have a common evolutionary
origin. C5 (120900) also shows sequence homology to A2M. A2M maps,
however, to chromosome 12 (Kan et al., 1985). Kan et al. (1985) isolated
A2M cDNA clones from a human liver cDNA library by using synthetic
oligonucleotides as hybridization probes. They then assigned the A2M
locus to chromosome 12 by Southern blot analysis of DNA from a panel of
mouse/human somatic cell hybrids, using A2M cDNA as a hybridization
probe. Fukushima et al. (1988) assigned the A2M locus to 12p13.3-p12.3
by in situ hybridization. Assignment of the A2M gene to human chromosome
12p13-p12.2 was confirmed by Marynen et al. (1989) by use of in situ
hybridization and somatic cell hybrid DNA analysis. Devriendt et al.
(1989) also assigned A2M to 12p13-p12 by analysis of somatic cell
hybrids and in situ hybridization. They showed, furthermore, that a
closely related gene for pregnancy-zone protein (PZP; 176420) and an A2M
pseudogene map to the same region.

Umans et al. (1994) found that the homologous gene in the mouse contains
36 exons, coding for a 4.8-kb cDNA. Including putative control elements
in the 5-prime flanking region, the gene covers about 45 kb. The
promoter region of the mouse A2m gene differed considerably from the
known promoter sequences of the human and rat genes. Hilliker et al.
(1992) showed that the gene is located on mouse chromosome 6 band F1-G3
in a syntenic group that has its human counterpart on 12p13-p12.

Matthijs et al. (1992) demonstrated that the A2M gene spans
approximately 48 kb and consists of 36 exons, from 21 to 229 bp in size
and with consensus splice sites. Intron sizes range from 125 bp to 7.5
kb. The A2M gene is present in single copy in the haploid genome.

By the electroimmunoassay of Laurell, Bergqvist and Nilsson (1979) found
deficient alpha-2-macroglobulin in a 37-year-old man, his mother, and
one daughter. Alpha-2-macroglobulin is, like alpha-1-antitrypsin,
alpha-2-antiplasmin, and antithrombin III, a protease inhibitor. It
inhibits many proteases, including trypsin, thrombin and collagenase.
The deficient persons were apparently heterozygotes. No clinical
disadvantage resulted from the deficiency. Poller et al. (1989) detected
an alteration in the A2M gene in a patient with serum A2M deficiency and
chronic lung disease since childhood. The alteration involved
restriction sites detected with 10 different enzymes and was thought to
have been caused by major deletion or rearrangement in the gene. Nine of
the restriction enzymes used detected no polymorphism in 40 healthy
control subjects and 39 patients with chronic obstructive pulmonary
disease. The patient was heterozygous for the A2M alteration; Poller et
al. (1989) suggested that this was responsible for the pulmonary
disease.

*FIELD* AV
.0001
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, VAL1000ILE
By direct genomic sequencing of the 2 exons encoding the bait region and
the exon encoding the thiolester site in 30 healthy individuals and in
30 patients with chronic lung disease, Poller et al. (1992) found a
sequence polymorphism near the thiolester site of the gene, changing
val1000 (GTC) to ile (ATC); the 2 alleles had frequencies of 0.30 and
0.70, respectively. No difference of A2M serum levels was observed for
these 2 alleles.

.0002
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, CYS972TYR
In 1 of the 30 patients and in none of the 30 healthy persons studied by
Poller et al. (1992), a mutation within the thiolester site, changing
cys972 (TGT) to tyr (TAT), was found. Since activation of the internal
thiolester formed between cys972 and gln975 in each of the subunits of
the tetrameric A2M molecule is involved in the covalent crosslinking of
the activating proteinase, this mutation was predicted to interfere with
A2M function. The A2M serum level was within the normal range in this
patient.

.0003
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, IVS1 DEL
In 1 healthy individual, Poller et al. (1992) found a deletion of the
intron that ordinarily separates exons 1 and 2. As a result, the 2 exons
that code the bait domain of the alpha-2-macroglobulin gene were fused.

.0004
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, ARG681HIS
Matthijs et al. (1992) demonstrated an amino acid polymorphism in the
bait domain of the alpha-2-macroglobulin molecule which defines the
specific interaction of the molecule with proteinases. A G-to-A
transition in exon 17 was detected in 1 person out of a group of 132
tested. The change predicted an arginine-to-his substitution at position
681. In the mutant allele an MaeII restriction site was lost and a new
NspHI site was created.

*FIELD* SA
Bell et al. (1985); David et al. (1987); Marynen et al. (1985)
*FIELD* RF
1. Bell, G. I.; Rall, L. B.; Sanchez-Pescador, R.; Merryweather, J.
P.; Scott, J.; Eddy, R. L.; Shows, T. B.: Human alpha-2-macroglobulin
gene is located on chromosome 12. Somat. Cell Molec. Genet. 11:
285-289, 1985.

2. Bergqvist, D.; Nilsson, I. M.: Hereditary alpha-2-macroglobulin
deficiency. Scand. J. Haemat. 23: 433-436, 1979.

3. David, F.; Kan, C. C.; Lucotte, G.: Two Taq I RFLPs for human
alpha-2 macroglobulin (alpha-2M) using a full length cDNA probe. Nucleic
Acids Res. 15: 374 only, 1987.

4. Devriendt, K.; Zhang, J.; van Leuven, F.; van den Berghe, H.; Cassiman,
J. J.; Marynen, P.: A cluster of alpha 2-macroglobulin-related genes
(alpha 2 M) on human chromosome 12p: cloning of the pregnancy-zone
protein gene and an alpha 2M pseudogene. Gene 81: 325-334, 1989.

5. Fukushima, Y.; Bell, G. I.; Shows, T. B.: The polymorphic human
alpha-2-macroglobulin gene (A2M) is located in chromosome region 12p12.3-p13.3.
Cytogenet. Cell Genet. 48: 58-59, 1988.

6. Gallango, M. L.; Castillo, O.: Alpha-2-macroglobulin polymorphism:
a new genetic system detected by immuno-electrophoresis. J. Immunogenet. 1:
147-151, 1974.

7. Hilliker, C.; Overbergh, L.; Petit, P.; Van Leuven, F.; Van den
Berghe, H.: Assignment of mouse alpha-2-macroglobulin gene to chromosome
6 band F1-G3. Mammalian Genome 3: 469-471, 1992.

8. Kan, C.-C.; Solomon, E.; Belt, K. T.; Chain, A. C.; Hiorns, L.
R.; Fey, G.: Nucleotide sequence of cDNA encoding human alpha-2-macroglobulin
and assignment of the chromosomal locus. Proc. Nat. Acad. Sci. 82:
2282-2286, 1985.

9. Leikola, J.; Fudenberg, H. H.; Kasukawa, R.; Milgrom, F.: A new
genetic polymorphism of human serum: alpha(2) macroglobulin (AL-M).
Am. J. Hum. Genet. 24: 134-144, 1972.

10. Marynen, P.; Bell, G. I.; Cavalli-Sforza, L. L.: Three RFLPs
associated with the human alpha-2-macroglobulin gene (A2M). Nucleic
Acids Res. 13: 8287 only, 1985.

11. Marynen, P.; Zhang, J.; Devriendt, K.; Cassiman, J.-J.: Alpha-2-macroglobulin,
pregnancy zone protein and an alpha-2-macroglobulin pseudogene map
to chromosome 12p12.2-p13.  (Abstract) Cytogenet. Cell Genet. 51:
1040 only, 1989.

12. Matthijs, G.; Devriendt, K.; Cassiman, J.-J.; van den Berghe,
H.; Marynen, P.: Structure of the human alpha-2 macroglobulin gene
and its promotor (sic). Biochem. Biophys. Res. Commun. 184: 596-603,
1992.

13. Poller, W.; Barth, J.; Voss, B.: Detection of an alteration of
the alpha-2-macroglobulin gene in a patient with chronic lung disease
and serum alpha-2-macroglobulin deficiency. Hum. Genet. 83: 93-96,
1989.

14. Poller, W.; Faber, J.-P.; Klobeck, G.; Olek, K.: Cloning of the
human alpha-2-macroglobulin gene and detection of mutations in two
functional domains: the bait region and the thiolester site. Hum.
Genet. 88: 313-319, 1992.

15. Sottrup-Jensen, L.; Stepanik, T. M.; Kristensen, T.; Lonblad,
P. B.; Jones, C. M.; Wierzbicki, D. M.; Magnusson, S.; Domdey, H.;
Wetsel, R. A.; Lundwall, A.; Tack, B. F.; Fey, G. H.: Common evolutionary
origin of alpha-2-macroglobulin and complement components C3 and C4.
Proc. Nat. Acad. Sci. 82: 9-13, 1985.

16. Umans, L.; Serneels, L.; Hilliker, C.; Stas, L.; Overbergh, L.;
De Strooper, B.; Van Leuven, F.; Van den Berghe, H.: Molecular cloning
of the mouse gene coding for alpha-2-macroglobulin and targeting of
the gene in embryonic stem cells. Genomics 22: 519-529, 1994.

*FIELD* CS

Pulmonary:
   Chronic lung disease

Lab:
   Serum A2M deficiency

Inheritance:
   Autosomal dominant (12p13.3-p12.3)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 9/12/1994
mimadm: 3/11/1994
carol: 1/15/1993
carol: 6/19/1992
supermim: 3/16/1992
carol: 2/29/1992

*RECORD*
*FIELD* NO
104000
*FIELD* TI
104000 ALOPECIA AREATA
*FIELD* TX
Lubowe (1959) described a family with affected mother and affected
daughter and son. Evidence suggests an autoimmune mechanism in this
disorder. See autoimmune diseases (109100). Stankler (1979) observed
onset in brother and sister at age 2, with regular and periodic
synchronous exacerbation thereafter. One exacerbation was after mumps.
In a white American family, Hordinsky et al. (1984) found alopecia
universalis in 2 brothers and alopecia areata in the son of one of them.
Valsecchi et al. (1985) found 6 cases in 3 generations and showed that
all affected persons had the same haplotype, HLA-Aw32,B18. In 2 Israeli
families, Zlotogorski et al. (1990) could find no linkage to HLA.
Galbraith and Pandey (1989) suggested an association between the gene
encoding the Km1 allotype of the immunoglobulin kappa light chain
determinant and a chromosome 2 gene encoding susceptibility to alopecia
areata, based on a significantly higher frequency of this allotype in
patients with the disorder than in a reference population of 105 healthy
subjects. Within the patient population, an association between the
absence of detectable serum antibody and the Km1 allotype was observed.

Among first-degree relatives of 348 severely affected patients, van der
Steen et al. (1992) found that one of the parents was affected in 7%.
Among the sibs, 3% had developed alopecia areata (AA), while AA was
present in 2% of the children. Taking into account the age of the
children, they estimated that the lifetime risk approached 6%. They
concluded that the degree of involvement observed in the probands did
not influence the frequency and type of AA present in their first-degree
relatives.

Galbraith and Pandey (1995) studied 2 polymorphic systems of tumor
necrosis factor alpha (TNFA; 191160) in 50 patients with alopecia
areata. The first bi-allelic TNFA polymorphism was detected in humans by
Wilson et al. (1992); this involved a single base change from G to A at
position -308 in the promoter region of the gene. The less common
allele, A at -308 (called T2), shows an increased frequency in patients
with IDDM, but this depends on the concurrent increase in HLADR3 with
which T2 is associated. A second TNFA polymorphism, described by
D'Alfonso and Richiardi (1994), also involves a G-to-A transition at
position -238 of the gene. In alopecia areata, Galbraith and Pandey
(1995) found that the distribution of T1/T2 phenotypes differed between
patients with the patchy form of the disease and patients with
totalis/universalis disease. There was no significant difference in the
distribution of the phenotypes for the second system. The results
suggested genetic heterogeneity between the 2 forms of alopecia areata
and suggested that the TNFA gene is a closely linked locus within the
major histocompatibility complex on chromosome 6 where this gene maps
and may play a role in the pathogenesis of the patchy form of the
disease.

*FIELD* RF
1. D'Alfonso, S.; Richiardi, P. M.: A polymorphic variation in a
putative regulation box of the TNFA promoter region. Immunogenetics 39:
150-154, 1994.

2. Galbraith, G. M. P.; Pandey, J. P.: Km1 allotype association with
one subgroup of alopecia areata. Am. J. Hum. Genet. 44: 426-428,
1989.

3. Galbraith, G. M. P.; Pandey, J. P.: Tumor necrosis factor alpha
(TNF-alpha) gene polymorphism in alopecia areata. Hum. Genet. 96:
433-436, 1995.

4. Hordinsky, M. K.; Hallgren, H.; Nelson, D.; Filipovich, A. H.:
Familial alopecia areata: HLA antigens and autoantibody formation
in an American family. Arch. Derm. 120: 464-468, 1984.

5. Lubowe, I. I.: The clinical aspects of alopecia areata, totalis,
and universalis. Ann. N.Y. Acad. Sci. 83: 458-462, 1959.

6. Stankler, L.: Synchronous alopecia areata in two siblings: a possible
viral aetiology.  (Letter) Lancet I: 1303-1304, 1979.

7. Valsecchi, R.; Vicari, O.; Frigeni, A.; Foiadelli, L.; Naldi, L.;
Cainelli, T.: Familial alopecia areata--genetic susceptibility or
coincidence?. Acta Derm. Venerol. 65: 175-177, 1985.

8. van der Steen, P.; Traupe, H.; Happle, R.; Boezeman, J.; Strater,
R.; Hamm, H.: The genetic risk for alopecia areata in first degree
relatives of severely affected patients: an estimate. Acta Derm.
Venerol. 72: 373-375, 1992.

9. Wilson, A. G.; di Giovine, F. S.; Blakemore, A. I. F.; Duff, G.
W.: Single base polymorphism in the human tumour necrosis factor
alpha (TNF-alpha) gene detectable by NcoI restriction of PCR product.
Hum. Molec. Genet. 1: 353 only, 1992.

10. Zlotogorski, A.; Weinrauch, L.; Brautbar, C.: Familial alopecia
areata: no linkage with HLA. Tissue Antigens 35: 40-41, 1990.

*FIELD* CS

Hair:
   Alopecia areata

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/17/1995
mark: 10/6/1995
mimadm: 3/11/1994
carol: 1/19/1993
carol: 3/25/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
104100
*FIELD* TI
104100 ALOPECIA CONGENITA WITH KERATOSIS PALMOPLANTARIS
*FIELD* TX
Stevanovic (1959) described a family with a dominant pattern of
inheritance who had hyperkeratosis of the palms and soles and mild
dystrophic changes of the fingernails.

*FIELD* RF
1. Stevanovic, D. V.: Alopecia congenita. The incomplete dominant
form of inheritance with varying expressivity. Acta Genet. Statist.
Med. 9: 127-132, 1959.

*FIELD* CS

Hair:
   Alopecia congenita

Skin:
   Hyperkeratosis of palms and soles

Nails:
   Mildly dystrophic fingernails

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
104110
*FIELD* TI
104110 ALOPECIA, FAMILIAL FOCAL
*FIELD* TX
Headington and Astle (1987) described a 14-year-old girl and her mother
who had patchy hair loss present from early childhood. When studied in
transverse section, biopsy specimens from both women showed marked
anagen-telogen transformation that appeared to be irreversible.
Preservation of telogen epithelium with absence of inflammation and
scarring distinguished familial focal alopecia from pseudopelade
(alopecia cicatrisata) and from localized alopecia areata. They could
find no description of similar cases.

('Anagen' refers to the growth phase of the cycle of activity of the
hair follicle. 'Telogen' refers to the resting phase of the cycle of
activity of the hair follicle. 'Catagen' refers to the involutional
phase of the cycle of activity of the hair follicle.)

*FIELD* RF
1. Headington, J. T.; Astle, N.: Familial focal alopecia: a new disorder
of hair growth clinically resembling pseudopelade. Arch. Derm. 123:
234-237, 1987.

*FIELD* CS

Hair:
   Patchy hair loss

Lab:
   Marked irreversible anagen-telogen transformation

Inheritance:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 02/20/1997

*FIELD* CD
Victor A. McKusick: 3/31/1987

*FIELD* ED
mark: 02/20/1997
terry: 2/12/1997
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 3/31/1987

*RECORD*
*FIELD* NO
104130
*FIELD* TI
*104130 ALOPECIA, PSYCHOMOTOR EPILEPSY, PYORRHEA, AND MENTAL SUBNORMALITY
*FIELD* TX
Shokeir (1977) observed this combination of abnormalities in 12 persons
in 4 generations with male-to-male transmission. The alopecia was
congenital, permanent, and universal. In those with alopecia, mental
subnormality was noted in 8 and psychomotor epilepsy in 7. Periodontal
disease was present in all. Timar et al. (1993) described a case that
presumably represented a new mutation. In addition to congenital total
permanent alopecia, psychomotor epilepsy, pyorrhea, and mental
retardation, the child had a giant pigmented nevus over the lower back
area on the left. Timar et al. (1993) suggested the designation Shokeir
syndrome, but this runs the risk of confusion with the 2 Pena-Shokeir
syndromes (208150, 214150) that already exist.

*FIELD* RF
1. Shokeir, M. H. K.: Universal permanent alopecia, psychomotor epilepsy,
pyorrhea and mental subnormality. Clin. Genet. 11: 13-17, 1977.

2. Timar, L.; Czeizel, A. E.; Koszo, P.: Association of Shokeir syndrome
(congenital universal alopecia, epilepsy, mental subnormality and
pyorrhea) and giant pigmented nevus. Clin. Genet. 44: 76-78, 1993.

*FIELD* CS

Hair:
   Congenital alopecia totalis

Skin:
   Giant pigmented nevus

Mouth:
   Periodontitis

Neuro:
   Psychomotor seizures;
   Mental retardation

Inheriance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
carol: 10/19/1993
supermim: 3/16/1992
carol: 2/27/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
104145
*FIELD* TI
*104145 AFAMIN; AFM
ALPHA-ALBUMIN; ALBA; ALB2
*FIELD* TX
Belanger et al. (1994) identified a fourth member of the albumin gene
family, the others being albumin (ALB; 103600), alpha-fetoprotein (AFP;
104150), and vitamin D-binding protein (DBP; 139200). The 'new' gene,
called alpha-albumin, was located 10 kb downstream from the AFP locus.
The gene is selectively expressed in the liver at late stages of
development. The mRNA sequence encodes a predicted secreted protein with
the typical triple domain disulfide cross-linked structure. Comparisons
of coding and promoter sequences suggested that ALBA could be a
phylogenetic intermediate between the ALB and AFP genes. The
developmental switch between ALBA gene activation and AFP gene
repression suggested new regulatory interplays at the albumin locus and
adult stage-specific ligand binding functions carried out by the ALBA
gene product.

The ALB and DBP genes diverged before the emergence of amphibians 500
Myr ago, while the AFP gene evolved slowly after the amphibian/reptile
separation 350 Myr ago. The fact that the 3 genes have remained closely
linked in single copy per haploid genome suggests a selective advantage
to their proximity, plausibly provided by shared cis-regulatory
elements. The sequence of the 3 most closely related genes is
5-prime--ALB--AFP--ALBA--3-prime.

Lichenstein et al. (1994) described the initial characterization of
afamin and its cDNA and provided evidence that AFM is a novel member of
the albumin family. This serum protein, with a molecular mass of 87,000
Da, was purified to homogeneity and subjected to amino acid sequence
analyses. These sequences were used to design oligonucleotide primers
and to isolate a full-length cDNA. The amino acid sequence encoded by
the cDNA was found to share strong similarity to albumin family members,
including the characteristic pattern of cys residues observed in that
family. The gene maps to chromosome 4 as do other members of the albumin
gene family. The mapping was performed by PCR applied to a panel of
somatic cell hybrids.

Noteworthy distinctions among ALB family members include the following:
concentrations in adult serum are 50 ng/ml for AFP, 350 microg/ml for
DBP, 40 mg/ml for ALB, and 30 microg/ml for AFM. ALB is not
N-glycosylated, AFP and DBP each have 1 potential N-glycosylation site,
and AFM has 4 potential sites. ALB expresses 1 free thiol group that has
been implicated in complex formation with cysteine, glutathione, and
mercurial and gold compounds. In contrast, the other 3 have an even
number of cys residues, are thought not to have a free thiol, and may
not bind glutathione and mercurials as does ALB.

Nishio and Dugaiczyk (1996) showed that the approximately 23-kb
alpha-albumin gene contains 15 exons, the last of which is untranslated.
The predicted protein has a 21-amino acid leader sequence followed by a
578-residue mature polypeptide. The exon structure is similar to that of
the related genes for albumin, alpha-fetoprotein, and vitamin D-binding
protein.

*FIELD* RF
1. Belanger, L.; Roy, S.; Allard, D.: New albumin gene 3-prime adjacent
to the alpha-1-fetoprotein locus. J. Biol. Chem. 269: 5481-5484,
1994.

2. Lichenstein, H. S.; Lyons, D. E.; Wurfel, M. M.; Johnson, D. A.;
McGinley, M. D.; Leidli, J. C.; Trollinger, D. B.; Mayer, J. P.; Wright,
S. D.; Zukowski, M. M.: Afamin is a new member of the albumin, alpha-fetoprotein,
and vitamin D-binding protein gene family. J. Biol. Chem. 269: 18149-18154,
1994.

3. Nishio, H.; Dugaiczyk, A.: Complete structure of the human alpha-albumin
gene, a new member of the serum albumin multigene family. Proc. Nat.
Acad. Sci. 93: 7557-7561, 1996.

*FIELD* CN
Alan F. Scott - updated: 08/21/1996

*FIELD* CD
Victor A. McKusick: 9/22/1994

*FIELD* ED
mark: 08/21/1996
marlene: 8/19/1996
carol: 9/22/1994

*RECORD*
*FIELD* NO
104150
*FIELD* TI
*104150 ALPHA-FETOPROTEIN; AFP
ALPHA-FETOPROTEIN, HEREDITARY PERSISTENCE OF, INCLUDED;;
HPAFP, INCLUDED;;
AFP DEFICIENCY, INCLUDED
*FIELD* MN
Alpha-fetoprotein (AFP) is a major plasma protein in the fetus, where it
is produced by the yolk sac and liver. It is the fetal counterpart of
serum albumin. The AFP gene maps to 4q11-q22, the same region as the
albumin gene (Harper and Dugaiczyk, 1983). In the adult the plasma
concentration of AFP is very low except when a tumor such as hepatoma or
teratoma is present.

In congenital nephrosis (256300), an autosomal recessive disorder
frequent in Finland, alpha-fetoprotein is increased in the maternal
blood and amniotic fluid--an expression of renal loss of protein. Loss
into the amniotic fluid in cases of spina bifida and anencephaly is the
basis of a screening test. AFP deficiency, which appears to be a benign
genetic trait like analbuminemia, has been recorded in infants
(Greenberg et al., 1992).

Autosomal dominant hereditary persistence of alpha-fetoprotein is a
clinically benign autosomal dominant condition characterized by
continued expression of the AFP gene in adult life. Such elevated
alpha-fetoprotein levels complicate the interpretation of findings in
patients being screened for malignancy (e.g., hepatocellular carcinoma
or teratoma) or in pregnant women being screened for neural tube defects
or Down syndrome in the fetus. In 1 family there was a G-to-A transition
at position -119 in a potential HNF1 (hepatocyte nuclear factor) binding
site, highlighting the importance of this HNF1 binding site in the
developmental regulation of the AFP gene (McVey et al., 1993).

*FIELD* ED
carol: 07/23/1996 marlene: 7/23/1996 joanna: 7/11/1996

*FIELD* CD
F. Clarke Fraser: 5/9/1996
*FIELD* TX
Alpha-fetoprotein is a major plasma protein in the fetus, where it is
produced by the yolk sac and liver. In the adult its concentration is
very low except when a tumor such as hepatoma or teratoma is present.
The similarity in physical properties of AFP and albumin (103600) and
the fact that their presence is inversely related suggested that AFP is
the fetal counterpart of serum albumin. In the mouse, the
alpha-fetoprotein and albumin genes are syntenic; presumably the same is
true in man and this may represent an ontogenically significant
arrangement with switch from AFP to albumin, comparable to the
hemoglobin F to hemoglobin A switch. Mammalian AFP and serum albumin
genes arose through duplication of an ancestral gene 300-500 Myr ago. By
means of restriction endonuclease mapping, Ingram et al. (1981) showed
that the AFP and albumin genes in the mouse are in tandem, 13.5 kb pairs
apart, with the albumin gene on the 5-prime side of the AFP gene. Thus,
they are transcribed from the same strand of DNA. The order is, however,
different from that expected by analogy with the gamma and beta globin
genes; with the presumed switch from AFP to albumin, one might expect
their position to be reversed from that observed. An overall
conservatism of 32% exists for DNA sequence of the 2 genes in the mouse
and probably about the same in man (Ruoslahti and Terry, 1976). In mice,
Tilghman and Belayew (1982) found a parallel accumulation of AFP and
albumin mRNAs before birth, followed by a selective decrease in AFP mRNA
after birth. The decrease in AFP mRNA was the result of decrease in
transcription of the AFP gene, as measured by an in vitro nuclear
transcription assay. They suggested a model for hepatic expression of
the AFP and albumin gene cluster in which transcription of the 2 genes
is activated simultaneously during differentiation and each gene is
thereafter modulated independently in committed cells. Minghetti et al.
(1985) found a high rate of silent substitutions for both
alpha-fetoprotein and albumin genes, perhaps the highest so far reported
for an expressed nuclear gene. The rates of effective substitution and
amino acid changes were also very high but, in contrast to silent
substitutions, they were found to be higher for alpha-fetoprotein than
for albumin by about 70%. For alpha-fetoprotein, the rate of effective
substitution may approach that for nonfunctional pseudogenes. This high
rate suggests that alpha-fetoprotein can tolerate a great deal of
molecular variation without its function being impaired. Hammer et al.
(1986) described enhancer elements in the 5-prime flanking region of the
mouse AFP gene. Gibbs et al. (1987) identified 4 types of repetitive
sequence elements in the introns and flanking regions of the human AFP
gene. One of these was apparently a novel structure designated Xba. The
others were Alu, X, and Kpn elements. X, Xba, and Kbn elements are not
present in the human albumin gene and Alu sequences are present in
different positions. From phylogenetic evidence, it appears that Alu
elements were inserted into the AFP gene at some time postdating the
mammalian radiation, 85 million years ago.

Direct confirmation of the assignment of the AFP gene to chromosome 4 by
in situ hybridization was provided by Harper and Dugaiczyk (1983), who
placed the gene in the q11-q22 region, the same region as the albumin
gene. Magenis et al. (1989) used in situ hybridization to localize the
ALB and the AFP genes to orangutan chromosome 3q11-q15 and gorilla
chromosome 3q11-q22. Beattie and Dugaiczyk (1982) found extensive DNA
sequence homology between human AFP and the third domain of serum
albumin. AFP appears to have evolved more rapidly than albumin.

In congenital nephrosis (256300), an autosomal recessive disorder
frequent in Finland, alpha-fetoprotein is increased in the maternal
blood and amniotic fluid--an expression of renal loss of protein. Loss
into the amniotic fluid in cases of spina bifida and anencephaly is the
basis of a screening test. Whether AFP increases in patients with
analbuminemia is apparently not known. (AFP was not increased (Motulsky,
1983) in the instance of analbuminemia reported by Boman et al. (1976).)
See 208900 for a discussion of the use of AFP in the diagnosis of
ataxia-telangiectasia. Voigtlander and Vogel (1985) commented on the
fact that not only is AFP low in maternal serum and amniotic fluid in
pregnancies with a Down syndrome fetus but also serum albumin is low
(according to most reports) in Down syndrome patients of all ages.
(Total serum protein may be normal because of an increase in gamma
globulins.) A defect in a regulatory mechanism common to the 2 proteins
was suggested. Faucett et al. (1989) and Greenberg et al. (1992)
documented AFP deficiency in 2 infants. One was found in the case of a
36-year-old woman who had amniocentesis for genetic indications;
amniotic fluid AFP levels were undetectable and chromosome analysis
showed a 46,XX pattern. The maternal serum AFP level was likewise
undetectable. A healthy, term female infant was delivered. In the cord
blood, AFP level was undetectable. The second mother had an
amniocentesis because of low maternal serum AFP levels. Amniotic fluid
AFP level was undetectable. Chromosome analysis showed a 46,XY pattern;
a normal, term male infant was delivered. This appears to be a situation
analogous to analbuminemia, and it is presumably a benign genetic trait
like analbuminemia.

Ferguson-Smith et al. (1984) reported an autosomal dominant hereditary
persistence of alpha-fetoprotein. The proband was a 38-year-old woman
found to have elevated AFP during pregnancy, as part of screening for
neural tube defects. The level of AFP in the amniotic fluid was normal;
the mother's elevation persisted after delivery. The infant and 2 of 3
other children also had elevated serum AFP. Subsequently, 21 members of
her family, including 9 males, were found to have elevated values.
Although close linkage of HPAFP with GC (139200) was originally excluded
(Ferguson-Smith et al., 1984), repeat GC typing with an improved
technique of isoelectric focusing showed several misclassifications in
the earlier study and the new calculations were consistent with linkage
(lod, 1.7; theta, 0.0) (Ferguson-Smith et al., 1985). Ferguson-Smith et
al. (1985) used a cDNA albumin probe which recognizes RFLPs at the ALB
locus. No recombination was found between an ALB polymorphism and HPAFP
(lod = 6.02; theta = 0). With the same ALB probe, in situ hybridization
confirmed assignment to 4q11-q21.

In the mouse liver, the adult basal levels of AFP mRNA is determined by
a gene called raf (regulator of alpha-fetoprotein) (Olsson et al.,
1977), and the inducibility of AFP mRNA during regeneration is regulated
by a gene termed rif (regulator of induction of alpha-fetoprotein)
(Belayew and Tilghman, 1982). (The raf regulatory locus must not be
confused with the RAF oncogene; see 164760.) The raf and rif genes are
not linked to the AFP gene or to each other (Vogt et al., 1987); it is
possible that these regulatory genes function through trans-acting
regulatory factors that interact with cis-acting elements of the AFP
gene. Watanabe et al. (1987) described experiments showing that the
5-prime flanking region of the human AFP gene contains transcription
control elements with characteristics of enhancers. Vogt et al. (1987)
identified in the mouse the transacting locus termed raf. The authors
suggested that the mutation in the Scottish kindred reported by
Ferguson-Smith et al. (1985) involves a DNA-binding sequence for the raf
product. This sequence must be contained within the proximal 7.6 kb of
DNA 5-prime to the AFP gene, as demonstrated in transgenic mouse strains
in which integrated AFP gene constructs exhibited raf regulation. The
evolutionarily related and closely linked albumin gene is not affected
by raf, nor is another oncofetal protein, gamma-glutamyl transpeptidase
(231950). However, raf does regulate the level of at least one other
structural gene termed H19 (103280). Tilghman (1992) indicated that
homologs of raf and rif had not been identified in humans. The only
regulatory mutation in AFP of which she was aware mapped to the
structural gene and resulted in persistence of AFP expression in adults.

Staples (1986) demonstrated high serum AFP in 6 members of 2 generations
of the family of a man with testicular carcinoma. Hereditary
spherocytosis (182900) was segregating independently in this family.
Staples (1986) also indicated that alcoholic steatosis of the liver can
cause reversible elevation of AFP. Rose et al. (1989) reported a third
family ascertained through a 42-year-old male who had 2 sibs and a
daughter with elevated serum alpha-fetoprotein levels. Such elevated
alpha-fetoprotein levels complicate the interpretation of findings in
patients being screened for malignancy (e.g., hepatocellular carcinoma
or teratoma) or in pregnant women being screened for neural tube defects
or Down syndrome in the fetus. Greenberg et al. (1990) reported another
family. A 33-year-old man, 2 of his sibs, and a daughter showed elevated
serum AFP levels.

*FIELD* AV
.0001
HEREDITARY PERSISTENCE OF ALPHA-FETOPROTEIN
HPAFP
AFP, G-A, -119
As part of an extensive screening program for spina bifida, a large
Scottish kindred spanning 5 generations was identified as having
hereditary persistence of alpha-fetoprotein, a clinically benign
autosomal dominant condition characterized by continued expression of
the AFP gene in adult life. Affected persons had mean serum AFP levels
23-fold higher than normal controls. These raised levels were, however,
far below the levels seen in the fetus. McVey et al. (1993) showed by
sequence analysis of the 5-prime flanking sequences of the AFP gene that
in this family a G-to-A transition at position -119 was associated with
the trait. This substitution occurs in a potential HNF I binding site
and increases the similarity of the sequence to a consensus HNF I
recognition site. In a competitive gel retardation assay, the mutant
sequence bound HNF-1-alpha (142410) more tightly than the wildtype
sequence. Furthermore, 5-prime-flanking sequences of the human AFP gene
containing the G-to-A substitution directed a higher level of
chloramphenicol acetyltransferase (CAT) expression in transfected human
hepatoma cells than the wildtype sequences. The findings not only
provide an explanation for the findings in this family, but also
highlight the importance of this HNF I binding site in the developmental
regulation of the AFP gene. The substitution is similar to those that
cause hereditary persistence of fetal hemoglobin (e.g., 142200.0026; a
G-A substitution at -117 of the HBG1 gene).

*FIELD* SA
D'Eustachio et al. (1981); Eiferman et al. (1981); Gorin and Tilghman
(1980); Jagodzinski et al. (1981); Morinaga et al. (1983); Sakai et
al. (1985); Szpirer et al. (1984); Urano et al. (1984)
*FIELD* RF
1. Beattie, W. G.; Dugaiczyk, A.: Structure and evolution of human
alpha-fetoprotein deduced from partial sequence of cloned cDNA. Gene 20:
415-422, 1982.

2. Belayew, A.; Tilghman, S. M.: Genetic analysis of alpha-fetoprotein
synthesis in mice. Molec. Cell. Biol. 2: 1427-1435, 1982.

3. Boman, H.; Hermodson, M.; Hammond, C. A.; Motulsky, A. G.: Analbuminemia
in an American Indian girl. Clin. Genet. 9: 513-526, 1976.

4. D'Eustachio, P.; Ingram, R. S.; Tilghman, S. M.; Ruddle, F. H.
: Murine alpha-fetoprotein and albumin: two evolutionarily linked
proteins encoded on the same mouse chromosome. Somat. Cell Genet. 7:
289-294, 1981.

5. Eiferman, F. A.; Young, P. R.; Scott, R. W.; Tilghman, S. M.:
Intragenic amplification and divergence in the mouse alpha-fetoprotein
gene. Nature 294: 713-718, 1981.

6. Faucett, W. A.; Greenberg, F.; Rose, E.; Alpert, E.; Bancalari,
L.; Kardon, N. B.; Mizjewski, G.; Knight, G.; Haddow, J. E.: Congenital
deficiency of alpha-fetoprotein.  (Abstract) Am. J. Hum. Genet. 45
(suppl.): A259, 1989.

7. Ferguson-Smith, M. A.; May, H. M.; Aitken, D. A.; O'Hare, E.; Yates,
J. R. W.; Gallagher, J.; Krumlauf, R.; Tilghman, S. M.: Hereditary
persistence of alphafetoprotein (HPAFP); linkage studies with chromosome
4 markers.  (Abstract) Cytogenet. Cell Genet. 37: 469, 1984.

8. Ferguson-Smith, M. A.; Yates, J. R. W.; Kelly, D.; Aitken, D. A.;
May, H. M.; Krumlauf, R.; Tilghman, S. M.: Hereditary persistence
of alphafetoprotein maps to the long arm of chromosome 4.  (Abstract) Cytogenet.
Cell Genet. 40: 628, 1985.

9. Gibbs, P. E. M.; Zielinski, R.; Boyd, C.; Dugaiczyk, A.: Structure,
polymorphism, and novel repeated DNA elements revealed by a complete
sequence of the human alpha-fetoprotein gene. Biochemistry 26:
1332-1343, 1987.

10. Gorin, M. B.; Tilghman, S. M.: Structure of the alpha-fetoprotein
gene in the mouse. Proc. Nat. Acad. Sci. 77: 1351-1355, 1980.

11. Greenberg, F.; Faucett, A.; Rose, E.; Bancalari, L.; Kardon, N.
B.; Mizejewski, G.; Haddow, J. E.; Alpert, E.: Congenital deficiency
of alpha-fetoprotein. Am. J. Obstet. Gynec. 167: 509-511, 1992.

12. Greenberg, F.; Rose, E.; Alpert, E.: Hereditary persistence of
alpha-fetoprotein. Gastroenterology 98: 1083-1085, 1990.

13. Hammer, R. E.; Krumlauf, R.; Camper, S. A.; Brinster, R. L.; Tilghman,
S. M.: Diversity of alpha-fetoprotein gene expression in mice is
generated by a combination of separate enhancer elements. Science 235:
53-58, 1986.

14. Harper, M. E.; Dugaiczyk, A.: Linkage of the evolutionarily-related
serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome
4. Am. J. Hum. Genet. 35: 565-572, 1983.

15. Ingram, R. S.; Scott, R. W.; Tilghman, S. M.: Alpha-fetoprotein
and albumin genes are in tandem in the mouse genome. Proc. Nat.
Acad. Sci. 78: 4694-4698, 1981.

16. Jagodzinski, L. L.; Sargent, T. D.; Yang, M.; Glackin, C.; Bonner,
J.: Sequence homology between RNAs encoding rat alpha-fetoprotein
and rat serum albumin. Proc. Nat. Acad. Sci. 78: 3521-3525, 1981.

17. Magenis, R. E.; Luo, X. Y.; Dugaiczyk, A.; Ryan, S. C.; Oosterhuis,
J. E.: Chromosomal localization of the albumin and alpha-fetoprotein
genes in the orangutan (Pongo pygmaeus) and gorilla (Gorilla gorilla).
(Abstract) Cytogenet. Cell Genet. 51: 1037, 1989.

18. McVey, J. H.; Michaelides, K.; Hansen, L. P.; Ferguson-Smith,
M.; Tilghman, S.; Krumlauf, R.; Tuddenham, E. G. D.: A G-to-A substitution
in an HNF I binding site in the human alpha-fetoprotein gene is associated
with hereditary persistence of alpha-fetoprotein (HPAFP). Hum. Molec.
Genet. 2: 379-384, 1993.

19. Minghetti, P. P.; Law, S. W.; Dugaiczyk, A.: The rate of molecular
evolution of alpha-fetoprotein approaches that of pseudogenes. Molec.
Biol. Evol. 2: 347-358, 1985.

20. Morinaga, T.; Sakai, M.; Wegmann, T. G.; Tamaoki, T.: Primary
structures of human alpha-fetoprotein and its mRNA. Proc. Nat. Acad.
Sci. 80: 4604-4608, 1983.

21. Motulsky, A. G.: Personal Communication. Seattle, Wash.  1983.

22. Olsson, M.; Lindahl, G.; Ruoslahti, E.: Genetic control of alpha-fetoprotein
synthesis in the mouse. J. Exp. Med. 145: 819-827, 1977.

23. Rose, E.; Greenberg, F.; Alpert, E.: Hereditary persistence of
alpha fetoprotein.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A61,
1989.

24. Ruoslahti, E.; Terry, W. D.: Alpha fetoprotein and serum albumin
show sequence homology. Nature 260: 804-805, 1976.

25. Sakai, M.; Morinaga, T.; Urano, Y.; Watanabe, K.; Wegmann, T.
G.; Tamaoki, T.: The human alpha-fetoprotein gene: sequence organization
and the 5-prime flanking region. J. Biol. Chem. 260: 5055-5060,
1985.

26. Staples, J.: Alphafetoprotein, cancer, and benign conditions.
(Letter) Lancet II: 1277, 1986.

27. Szpirer, J.; Levan, G.; Thorn, M.; Szpirer, C.: Gene mapping
in the rat by mouse-rat somatic cell hybridization: synteny of the
albumin and alpha-fetoprotein genes and assignment to chromosome 14.
Cytogenet. Cell Genet. 38: 142-149, 1984.

28. Tilghman, S. M.: Personal Communication. Princeton, N. J.
8/12/1992.

29. Tilghman, S. M.; Belayew, A.: Transcriptional control of the
murine albumin/alpha-fetoprotein locus during development. Proc.
Nat. Acad. Sci. 79: 5254-5257, 1982.

30. Urano, Y.; Sakai, M.; Watanabe, K.; Tamaoki, T.: Tandem arrangement
of the albumin and alpha-fetoprotein genes in the human genome. Gene 32:
255-261, 1984.

31. Vogt, T. F.; Solter, D.; Tilghman, S. M.: Raf, a trans-acting
locus, regulates the alpha-fetoprotein gene in a cell-autonomous manner.
Science 236: 301-303, 1987.

32. Voigtlander, T.; Vogel, F.: Low alpha-fetoprotein and serum albumin
levels in Morbus Down may point to a common regulatory mechanism.
Hum. Genet. 71: 276-277, 1985.

33. Watanabe, K.; Saito, A.; Tamaoki, T.: Cell-specific enhancer
activity in a far upstream region of the human alpha-fetoprotein gene.
J. Biol. Chem. 262: 4812-4818, 1987.

*FIELD* CS

Misc:
   Major fetal plasma protein produced by yolk sac and liver

Lab:
Elevated serum AFP with: Hepatoma;
   Teratoma;
   Alcoholic steatosis of the liver;
   Hereditary persistence of alpha-fetoprotein;
   Ataxia telangiectasia (208900);
Elevated maternal serum and amniotic fluid AFP in: Congenital nephrosis
   (256300) pregnancy;
   Spina bifida or anencephalic pregnancy;
Elevated maternal serum but normal amniotic fluid AFP in: Maternal
   hereditary persistence of AFP and normal fetus;
Low maternal serum and amniotic fluid AFP in: Down syndrome pregnancy

Inheritance:
   Autosomal dominant (4q11-q21)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 07/23/1996
carol: 7/18/1996
marlene: 7/18/1996
carol: 5/18/1996
davew: 7/19/1994
jason: 7/5/1994
mimadm: 4/14/1994
carol: 4/11/1994
warfield: 4/7/1994
carol: 10/14/1993

*RECORD*
*FIELD* NO
104155
*FIELD* TI
*104155 ALPHA-FETOPROTEIN ENHANCER-BINDING PROTEIN
AT MOTIF-BINDING FACTOR; ATBF1
*FIELD* TX
Tissue-specific expression of the human alpha-fetoprotein (AFP) gene
(104150) is strongly stimulated by an enhancer present 3.3 to 4.9 kb
upstream of the transcription initiation site. One of the enhancer
elements contains an AT-rich core sequence (AT motif). To determine the
nuclear factor in hepatoma cell lines that interacts with the human AFP
enhancer AT motif, Morinaga et al. (1991) screened a hepatoma cDNA
expression library with an AFP enhancer fragment that bore the AT motif.
They succeeded in isolating a cDNA that can code for an AT motif-binding
factor, termed ATBF1. This was the largest DNA-binding protein
identified to that time and the first protein shown to contain multiple
homeodomains and multiple zinc finger motifs. The protein had a
predicted mass of 306 kD and contained 4 homeodomains and 17 zinc finger
motifs.

By fluorescence in situ hybridization, Yamada et al. (1995) mapped the
ATBF1 gene to 16q22.3-q23.1. Yamada et al. (1996) used fluorescence in
situ hybridization to assign the Atbf1 gene to mouse chromosome 8E1.

*FIELD* RF
1. Morinaga, T.; Yasuda, H.; Hashimoto, T.; Higashio, K.; Tamaoki,
T.: A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains
four homeodomains and seventeen zinc fingers. Molec. Cell. Biol. 11:
6041-6049, 1991.

2. Yamada, K.; Ma, D.; Miura, Y.; Ido, A.; Tamaoki, T.; Yoshida, M.
C.: Assignment of the ATBF1 transcription factor gene (Atbf1) to
mouse chromosome band 8E1 by in situ hybridization. Cytogenet. Cell
Genet. 75: 30-31, 1996.

3. Yamada, K.; Mirua, Y.; Scheidl, T.; Yoshida, M. C.; Tamaoki, T.
: Assignment of the human ATBF1 transcription factor gene to chromosome
16q22.3-q23.1. Genomics 29: 552-553, 1995.

*FIELD* CD
Victor A. McKusick: 1/22/1992

*FIELD* ED
terry: 01/15/1997
mark: 10/25/1995
supermim: 3/16/1992
carol: 1/22/1992

*RECORD*
*FIELD* NO
104160
*FIELD* TI
*104160 ALPHA-GLUCOSIDASE, NEUTRAL, AB FORM; GANAB
*FIELD* TX
Human tissues contain 2 isozymes of neutral alpha-glucosidase designated
AB (GANAB) and C (GANC). Initially distinguished on the basis of
differences in electrophoretic mobility in starch gel, the two have been
shown to have other differences including those of substrate
specificity. Martiniuk et al. (1982, 1983) assigned the GANAB locus to
11q13-qter by study of mouse-man hybrid cells. Since the AB form of
mouse is not different electrophoretically from that in man, these
workers used rocket immunoelectrophoresis to distinguish the enzymes
from the 2 species.

*FIELD* RF
1. Martiniuk, F.; Smith, M.; Desnick, R.; Astrin, K.; Mitra, J.; Hirschhorn,
R.: Assignment of the gene for neutral alpha-glucosidase AB to chromosome
11.  (Abstract) Am. J. Hum. Genet. 34: 173A only, 1982.

2. Martiniuk, F.; Smith, M.; Ellenbogen, A.; Desnick, R. J.; Astrin,
K.; Mitra, J.; Hirschhorn, R.: Assignment of the gene for neutral
alpha-glucosidase AB to chromosome 11. Cytogenet. Cell Genet. 35:
110-116, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 6/16/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
104170
*FIELD* TI
*104170 ALPHA-GALACTOSIDASE B; GALB
N-ACETYL-ALPHA-D-GALACTOSAMINIDASE; NAGA
LYSOSOMAL ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, INCLUDED;;
SCHINDLER DISEASE, INCLUDED;;
NEUROAXONAL DYSTROPHY, SCHINDLER TYPE, INCLUDED;;
KANZAKI DISEASE, INCLUDED
*FIELD* TX
In a study of man-rodent somatic cell hybrids, de Groot et al. (1978)
assayed human N-acetyl-alpha-D-galactosaminidase activity and concluded
that alpha-galactosidase B and mitochondrial aconitase (ACO2; 100850),
known to be on chromosome 22, are syntenic. They also obtained evidence
for direct assignment of alpha-galactosidase B to chromosome 22.
Alpha-NAGA was thought to be a more appropriate designation for this
enzyme than alpha-galactosidase B by de Groot et al. (1978), who claimed
that there was no structural relationship between alpha-gal A (on the X
chromosome; GLA; 301500) and so-called alpha-gal B. However, DNA studies
(Wang et al., 1990; Wang and Desnick, 1991), described later, led to a
different conclusion. In man-rodent cell hybrids, Geurts van Kessel et
al. (1979, 1980) studied chronic myeloid leukemia cells to determine the
site of the break on 22q relative to markers assigned to chromosomes 22
and 9. Alpha-NAGA remained with the Ph-1 chromosome, whereas ACO2 went
with chromosome 9. Thus, the former is probably in band 22q11, whereas
the latter is between it and 22qter.

Wang et al. (1990) isolated a full-length 2.2-kb cDNA and a genomic
cosmid clone containing the entire NAGA gene. Sequence analysis revealed
striking similarities between the NAGA locus and exons 1-6 of
alpha-galactosidase A, suggesting that the 2 genes evolved by
duplication and divergence from a common ancestral locus. Wang and
Desnick (1991) also pointed to remarkable amino acid identity between
the NAGA and GLA genes.

In 2 sons of a German couple with remote consanguinity, van Diggelen et
al. (1987, 1988) described the clinical and biochemical features of
lysosomal alpha-N-acetylgalactosaminidase deficiency. The boys showed
neurologic abnormalities starting at age 9 months, followed by
progressive psychomotor deterioration. By the age of 2.5 and 4 years,
they had 'largely lost their previously acquired motor and language
skills.' Growth had been normal. Computerized tomographic scans were
normal, and there was no organomegaly, obvious coarsening of the facies,
or skeletal dysplasia. A uniquely abnormal pattern of urinary
oligosaccharides was demonstrated by thin-layer chromatography. Among
the carbohydrate-hydrolyzing lysosomal enzymes, only alpha-NAGA had not
previously been associated with a disorder. The levels of this enzyme
were very low in cultured fibroblasts, leukocytes and plasma, whereas
these levels were normal in a healthy brother. Both parents had low
normal or reduced activity. A major neutral oligosaccharide from the
urine of 1 patient was identified as the blood group A determinant, a
trisaccharide with terminal alpha-N-acetylgalactosamine. The
concentration of this product in the urine of the older boy, who was a
secretor and had blood group A, was 5 times normal. The younger boy, who
had blood group O, did not excrete this trisaccharide. Schindler et al.
(1988) described the clinical findings as consisting of severe
psychomotor retardation with myoclonic seizures, decorticate posture,
optic atrophy, blindness, marked long tract signs, and total loss of
contact with the environment. No features of other lysosomal storage
diseases were present. Ultrastructural examination of peripheral nerves
was unremarkable, whereas the rectal mucosa contained dystrophic
autonomic axons with 'tubulovesicular' material. A unique pattern of
abnormal urinary oligosaccharides/glycopeptides was found by thin layer
chromatography. Wang et al. (1988) pointed out that the brothers
reported by van Diggelen et al. (1987) had a clinical course and
neuropathologic findings similar to those in Seitelberger disease, the
infantile form of neuroaxonal dystrophy (256600). The characteristic
'spheroids' were observed histologically and ultrastructurally in
terminal exons in gray matter. This disorder, which they referred to as
Schindler disease, must represent, therefore, a form of infantile axonal
dystrophy, the first in which a specific enzymatic defect has been
identified. The disorder is autosomal recessive. Schindler et al. (1989)
also characterized the disorder as a neuroaxonal dystrophy. They pointed
out that although the disorder is caused by deficiency of a lysosomal
enzyme, no lysosomal storage could be identified. It has been proposed
that the dystrophic axons in infantile neuroaxonal dystrophy result from
defective retrograde axonal transport. How deficiency of
alpha-N-acetylgalactosaminidase might lead to a similar problem is not
clear. Using PCR amplification and sequence analysis of PCR product from
type I and type II offspring of consanguineous matings, Wang et al.
(1990) demonstrated single basepair mutations in the homozygous state in
both type I and type II. (Type I is classic Schindler disease; type II
is an adult disorder with angiokeratoma as a prominent feature
(104170.0002). Type II might appropriately be called Kanzaki disease
(Kanzaki et al., 1989).)

Keulemans et al. (1996) reported the genotypes of 5 more patients with
NAGA deficiency. One of them, related to the first reported German
family (van Diggelen et al., 1987), had classic Schindler disease and
the same homozygous mutation, i.e., glu325to-lys (104170.0001). The only
manifestations in another patient, a 5-year-old Dutch girl whose family
was clinically described by de Jong et al. (1994), were convulsions
during fever and psychomotor retardation starting after the age of 1
year. She had 2 different mutations: glu325-to-lys inherited from her
father and ser160-to-cys (104170.0004) inherited from her mother. The
same genotype was found in a clinically unaffected 3.5-year-old brother
of the proband. Keulemans et al. (1996) suggested that the brother might
be a preclinical case of NAGA deficiency detected through screening. A
homozygous nonsense mutation, glu193-to-ter, was found in 2 adult
Spanish sibs who had angiokeratoma, lymphedema, and vacuolization in
dermal cells, but no neurologic signs. These sibs, previously reported
by Chabas et al. (1994), were clinically similar to the original patient
described by Kanzaki et al. (1989). Although at the metabolic level the
patients with NAGA deficiency are similar, extreme differences between
the infantile form(s) and the adult form (Kanzaki disease) suggested to
Keulemans et al. (1996) that other factors or genes contribute to the
clinical heterogeneity.

*FIELD* AV
.0001
SCHINDLER DISEASE
NAGA, GLU325LYS
In the first cases described with Schindler disease (van Diggelen et
al., 1987, 1988), Wang et al. (1990) found a G-to-A transition at
nucleotide 973 of the NAGA gene, resulting in substitution of lysine for
glutamic acid as residue 325.

.0002
KANZAKI DISEASE
SCHINDLER DISEASE, TYPE II
LYSOSOMAL GLYCOAMINOACID STORAGE DISEASE WITH ANGIOKERATOMA CORPORIS
DIFFUSUM
NAGA, ARG329TRP
In a 46-year-old Japanese woman with disseminated angiokeratoma, Kanzaki
et al. (1989) demonstrated numerous cytoplasmic vacuoles in cells of the
kidney and skin. Enzyme activities against synthetic and natural
substrates were normal in leukocytes and fibroblasts. Her urine
contained a large amount of sialylglycoaminoacids, with predominant
excretion of an O-glycoside-linked glycoaminoacid. No information was
provided on the patient's family. The enzyme studies excluded Fabry
disease (301500), fucosidosis (230000), galactosialidosis (256540), and
the various mucolipidoses and mucopolysaccharidoses. Desnick (1991)
recounted reading an abstract by Kanzaki et al. (1988) in which the
presence of angiokeratoma attracted his attention because of his
longtime work with Fabry disease; the possibility that this disorder was
related to Schindler disease was suggested by the excretion of large
amounts of glycopeptides in the urine. A collaboration thereafter led to
the demonstration that indeed there is deficiency of alpha-galactosidase
B in Kanzaki disease also (Wang et al., 1990). Even though the disorder
was much milder, with no neurodegeneration and no neuroaxonal dystrophy,
the deficiency of enzymes seemed to be of the same order as in type I
Schindler disease. In the laboratory of Desnick (1991), a substitution
of tryptophan for arginine-329 was demonstrated as the basic defect
(Wang et al., 1994). Again, it is remarkable that a change so close to
that in Schindler disease could cause such a different phenotype. This
situation is comparable to that of the Hurler and Scheie forms of
mucopolysaccharidosis I and to the allelic mild and severe forms of many
lysosomal storage diseases. Kanzaki et al. (1991) provided further
evidence that there are 2 forms of alpha-N-acetylgalactosaminidase
deficiency with sialopeptiduria: a severe infantile-onset form of
neuroaxonal dystrophy without angiokeratoma or visceral lysosomal
inclusions, and an adult-onset form with angiokeratoma, extensive
lysosomal accumulation of sialoglycopeptides, and the absence of
detectable neurologic involvement. Kanzaki et al. (1993) gave an
extensive description of the 46-year-old Japanese woman with the adult
form of lysosomal alpha-N-acetylgalactosaminidase deficiency. The
angiokeratomas first appeared on her lower torso when she was 28 years
old and later became diffusely distributed. Her 2 unaffected children
had half-normal enzyme levels, consistent with autosomal recessive
inheritance. The woman had mild intellectual impairment and peripheral
neuroaxonal degeneration. She was the product of a first-cousin marriage
and worked in a hospital as a nurse's aide. Endoscopic examination
demonstrated telangiectasia on the gastric mucosa. Dilated blood vessels
were present on the ocular conjunctiva and dilated vessels with
corkscrewlike tortuosity were observed in the fundi.

To identify the mutation causing this phenotypically distinct
adult-onset form of NAGA deficiency, Wang et al. (1994) used reverse
transcription, amplification, and sequencing of the NAGA transcript. The
change was a C-to-T transition at nucleotide 985, resulting in an R329W
amino acid substitution. The base substitution was confirmed by
hybridization of PCR-amplified genomic DNA from family members with
allele-specific oligonucleotides. Wang et al. (1994) showed that in
transiently expressed COS-1 cells, both the E325K (infantile-onset) and
R329W (adult-onset) precursors were processed to the mature form;
however, the E325K mutant polypeptide was more rapidly degraded than the
R329W subunit, thereby providing a basis for the distinctly different
infantile- and adult-onset phenotypes.

.0003
KANZAKI DISEASE
SCHINDLER DISEASE, TYPE II
NAGA, GLU193TER
Keulemans et al. (1996) showed by PCR and sequence analysis that the
Spanish brother and sister with manifestations of Kanzaki disease
described by Chabas et al. (1994) were homozygous for an E193X mutation
in exon 5 leading to complete loss of NAGA protein.

.0004
NAGA DEFICIENCY, MILD FORM
NAGA, SER160CYS
Keulemans et al. (1996) reported that a Dutch girl with NAGA deficiency
and mild neurologic manifestations was heterozygous for the E325K
(104170.0001) mutation and a C-to-G change at nucleotide 11017
(numbering according to Yamauchi et al., 1990) in exon 4, leading to a
substitution of serine for cysteine at residue 160. The same genotype
was found in the 3-year-old asymptomatic brother of the proband, who was
presumed by the authors to be presymptomatic.

*FIELD* SA
Wang et al. (1990)
*FIELD* RF
1. Chabas, A.; Coll, M. J.; Aparicio, M.; Rodriguez Diaz, E.: Mild
phenotypic expression of alpha-N-acetylgalactosaminidase deficiency
in two adult siblings. J. Inherit. Metab. Dis. 17: 724-731, 1994.

2. de Groot, P. G.; Westerveld, A.; Meera Khan, P.; Tager, J. M.:
Localization of a gene for human alpha-galactosidase B (=N-acetyl-alpha-D-galactosaminidase)
on chromosome 22. Hum. Genet. 44: 305-312, 1978.

3. de Jong, J; van den Berg, C; Wijburg, H.; Willemsen, R.; van Diggelen,
O.; Schindler, D.; Hoevenaars, F.; Wevers, R.: Alpha-N-acetylgalactosaminidase
deficiency with mild clinical manifestations and difficult biochemical
diagnosis. J. Pediat. 125: 385-391, 1994.

4. Desnick, R. J.: Personal Communication. New York, N. Y.  1/15/1991.

5. Geurts van Kessel, A. H. M.; ten Brinke, H.; de Groot, P. G.; Hagemeijer,
A.; Westerveld, A.; Meera Khan, P.; Pearson, P. L.: Regional localization
of NAGA and ACO2 on human chromosome 22. (Abstract) Cytogenet. Cell
Genet. 25: 161 only, 1979.

6. Geurts van Kessel, A. H. M.; Westerveld, A.; de Groot, P. G.; Meera
Khan, P.; Hagemeijer, A.: Regional localization of the genes coding
for human ACO2, ARSA, and NAGA on chromosome 22. Cytogenet. Cell
Genet. 28: 169-172, 1980.

7. Kanzaki, T.; Wang, A. M.; Desnick, R. J.: Lysosomal alpha-N-acetylgalactosaminidase
deficiency, the enzymatic defect in angiokeratoma corporis diffusum
with glycopeptiduria. J. Clin. Invest. 88: 707-711, 1991.

8. Kanzaki, T.; Yokota, M.; Irie, F.; Hirabayashi, Y.; Wang, A. M.;
Desnick, R. J.: Angiokeratoma corporis diffusum with glycopeptiduria
due to deficient lysosomal alpha-N-acetylgalactosaminidase activity:
clinical, morphologic, and biochemical studies. Arch. Derm. 129:
460-465, 1993.

9. Kanzaki, T.; Yokota, M.; Mizuno, N.: Clinical and ultrastructural
studies of novel angiokeratoma corporis diffusum. (Abstract) Clin.
Res. 36: 377A only, 1988.

10. Kanzaki, T.; Yokota, M.; Mizuno, N.; Matsumoto, Y.; Hirabayashi,
Y.: Novel lysosomal glycoaminoacid storage disease with angiokeratoma
corporis diffusum. Lancet I: 875-876, 1989.

11. Keulemans, J. L. M.; Reuser, A. J. J.; Kroos, M. A.; Willemsen,
R.; Hermans, M. M. P.; van den Ouweland, A. M. W.; de Jong, J. G.
N.; Wevers, R. A.; Renier, W. O.; Schindler, D.; Coll, M. J.; Chabas,
A.; Sakuraba, H.; Suzuki, Y.; van Diggelen, O. P.: Human alpha-N-acetylgalactosaminidase
(alpha-NAGA) deficiency: new mutations and the paradox between genotype
and phenotype. J. Med. Genet. 33: 458-464, 1996.

12. Schindler, D.; Bishop, D. F.; Wallace, S.; Wolfe, D. E.; Desnick,
R. J.: Characterization of alpha-N-acetylgalactosaminidase deficiency:
a new neurodegenerative lysosomal disease. (Abstract) Pediat. Res. 23:
333A only, 1988.

13. Schindler, D.; Bishop, D. F.; Wolfe, D. E.; Wang, A. M.; Egge,
H.; Lemieux, R. U.; Desnick, R. J.: Neuroaxonal dystrophy due to
lysosomal alpha-N-acetylgalactosaminidase deficiency. New Eng. J.
Med. 320: 1735-1740, 1989.

14. van Diggelen, O. P.; Schindler, D.; Kleijer, W. J.; Huijmans,
J. G. M.; Galjaard, H.; Linden, H. U.; Peter-Katalinic, J.; Egge,
H.; Dabrowski, U.; Cantz, M.: Lysosomal alpha-N-acetylgalactosaminidase
deficiency: a new inherited metabolic disease. (Letter) Lancet II:
804 only, 1987.

15. van Diggelen, O. P.; Schindler, D.; Willemsen, R.; Boer, M.; Kleijer,
W. J.; Huijmans, J. G. M.; Blom, W.; Galjaard, H.: Alpha-N-acetylgalactosaminidase
deficiency, a new lysosomal storage disorder. J. Inherit. Metab.
Dis. 11: 349-357, 1988.

16. Wang, A. M.; Bishop, D. F.; Desnick, R. J.: Human alpha-N-acetylgalactosaminidase-molecular
cloning, nucleotide sequence, and expression of a full-length cDNA:
homology with human alpha-galactosidase A suggests evolution from
a common ancestral gene. J. Biol. Chem. 265: 21859-21866, 1990.

17. Wang, A. M.; Desnick, R. J.: Structural organization and complete
sequence of the human alpha-N-acetylgalactosaminidase gene: homology
with the alpha-galactosidase A gene provides evidence for evolution
from a common ancestral gene. Genomics 10: 133-142, 1991.

18. Wang, A. M.; Kanzaki, T.; Desnick, R. J.: The molecular lesion
in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma
corporis diffusum with glycopeptiduria. J. Clin. Invest. 94: 839-845,
1994.

19. Wang, A. M.; Schindler, D.; Bishop, D. F.; Lemieux, R. U.; Desnick,
R. J.: Schindler disease: biochemical and molecular characterization
of a new neuroaxonal dystrophy due to alpha-N-acetylgalactosaminidase
deficiency. (Abstract) Am. J. Hum. Genet. 43: A99 only, 1988.

20. Wang, A. M.; Schindler, D.; Desnick, R. J.: Schindler disease:
the molecular lesion in the alpha-N-acetylgalactosaminidase gene that
causes an infantile neuroaxonal dystrophy. J. Clin. Invest. 86:
1752-1756, 1990.

21. Wang, A. M.; Schindler, D.; Kanzaki, T.; Desnick, R. J.: Alpha-N-acetylgalactosaminidase
gene: homology with human alpha-galactosidase A, and identification
and confirmation of the mutations causing type I and II Schindler
disease. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A169 only, 1990.

22. Yamauchi, T.; Hiraiwa, M.; Kobayashi, H.; Uda, Y.; Miyatake, T.;
Tsuji, S.: Molecular cloning of two species of cDNAs for human alpha-N-acetylgalactosaminidase
and expression in mammalian cells. Biochem. Biophys. Res. Commun. 170:
231-237, 1990.

*FIELD* CS

Neuro:
   Progressive psychomotor deterioration;
   Loss of previously acquired motor and language skills;
   Abnormal pattern of urinary oligosaccharides;
   Myoclonic seizures;
   Decorticate posture;
   Marked long tract signs

Skin:
   Angiokeratoma corporis diffusum (.0002 KANZAKI DISEASE)

GI:
   Gastric mucosal telangiectasia

Eyes:
   Optic atrophy;
   Blindness;
   Dilated conjunctival blood vessels;
   Dilated corkscrewlike tortuous fundal vessels

Growth:
   Growth normal

Misc:
   Onset about age 9 months

Lab:
   Lysosomal alpha-N-acetylgalactosaminidase deficiency;
   Peripheral neuroaxonal degeneration;
   Rectal mucosal biopsy shows dystrophic autonomic axons with tubulovesicular
   material

Inheritance:
   Autosomal recessive (22q11)

*FIELD* CN
Iosif W. Lurie - updated: 7/10/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/27/1996
carol: 7/22/1996
carol: 7/10/1996
carol: 10/10/1994
jason: 6/9/1994
warfield: 4/7/1994
mimadm: 3/11/1994
carol: 6/3/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
104175
*FIELD* TI
*104175 ALPHA-1,3-GALACTOSYLTRANSFERASE
GLYCOPROTEIN, ALPHA-GALACTOSYLTRANSFERASE 1; GGTA1
*FIELD* TX
Alpha-1,3-galactosyltransferase is a Golgi membrane-bound enzyme
involved in the biosynthesis of the carbohydrate genes of glycoproteins
and glycolipids. Enzyme levels are developmentally regulated and
differentiation dependent. The enzyme is present in most mammals but
cannot be detected in man, apes, or Old World monkeys. The carbohydrate
structure produced by the enzyme is immunogenic in man, and most normal,
healthy individuals have a significant titre of a natural antibody
against the enzyme. Aberrant expression of the enzyme in man has been
implicated in autoimmune disorders and in the occurrence of certain germ
cell tumors. Joziasse et al. (1989) isolated 2 human homologs of the
gene encoding the bovine enzyme. They concluded that these most likely
represent a processed pseudogene and the inactivated remnant of the once
functional source gene. The latter, referred to as HG-10 and symbolized
GGTA1, was mapped to human chromosome 9 (Joziasse et al., 1991) by study
of human-rodent somatic cell hybrids. The processed pseudogene,
initially referred to as HGT-2 and later as GGTA1P, was mapped to human
chromosome 12 by the same method. By in situ hybridization, Shaper et
al. (1992) localized GGTA1 to 9q33-q34 and GGTA1P to 12q14-q15. It had
previously been suggested (Joziasse et al., 1991) that this enzyme is
evolutionarily related to the A and B blood group transferases; the
location of the gene in distal 9q in the proximity of the ABO locus
lends support to this hypothesis. The ABO and GGTA1 loci evolved from an
ancestral locus through duplication. Subsequently, GGTA1 gave rise to an
mRNA that, after reverse transcription, was incorporated into chromosome
12 as GGTA1P. In an even later event, the ancestral human alpha-1,3-GT
became inactivated, possibly through a mutation in an upstream
regulatory sequence, because its transcripts are no longer detected.
This situation is comparable to the loss of vitamin C synthesizing
capacity (240400) or uricase enzymatic activity (191540) in the human
even though sequences for the relevant genes can be identified in the
human genome.

*FIELD* SA
Joziasse et al. (1991)
*FIELD* RF
1. Joziasse, D. H.; Shaper, J. H.; Jabs, E. W.; Shaper, N. L.: Characterization
of an alpha-1,3-galactosyltransferase homologue on human chromosome
12 that is organized as a processed pseudogene. J. Biol. Chem. 266:
6991-6998, 1991.

2. Joziasse, D. H.; Shaper, J. H.; Van den Eijnden, D. H.; Van Tunen,
A. J.; Shaper, N. L.: Bovine alpha-1,3-galactosyltransferase: isolation
and characterization of a cDNA clone: identification of homologous
sequences in human genomic DNA. J. Biol. Chem. 264: 14290-14297,
1989.

3. Joziasse, D. H.; Shaper, N. L.; Shaper, J. H.; Kozak, C. A.: The
gene for murine alpha-1,3-galactosyltransferase is located in the
centromeric region of chromosome 2. Somat. Cell Molec. Genet. 17:
201-205, 1991.

4. Shaper, N. L.; Lin, S.; Joziasse, D. H.; Kim, D.; Yang-Feng, T.
L.: Assignment of two human alpha-1,3-galactosyltransferase gene
sequences (GGTA1 and GGTA1P) to chromosomes 9q33-q34 and 12q14-q15.
Genomics 12: 613-615, 1992.

*FIELD* CD
Victor A. McKusick: 2/24/1992

*FIELD* ED
jason: 6/9/1994
carol: 9/24/1993
carol: 3/31/1992
supermim: 3/16/1992
carol: 3/6/1992
carol: 2/26/1992

*RECORD*
*FIELD* NO
104180
*FIELD* TI
*104180 ALPHA-GLUCOSIDASE C, NEUTRAL; GANC
*FIELD* TX
Martiniuk et al. (1979, 1980) assigned a locus for this enzyme to
chromosome 15. They also found a genetic polymorphism by starch gel
electrophoresis, including a null allele. Martiniuk and Hirschhorn
(1980) concluded that a combination of starch gel electrophoresis and
isoelectric focusing permits recognition of 7 phenotypes resulting from
4 different alleles. The product of one of the alleles is 'silent,' with
an unusually high gene frequency--0.174 in whites. About one-third of
the population is heterozygous 'null.' It appears that the homozygous
state does not result in disease.

*FIELD* RF
1. Martiniuk, F.; Hirschhorn, R.: Human neutral alpha-glucosidase
C: genetic polymorphism including a 'null' allele. Am. J. Hum. Genet. 32:
497-507, 1980.

2. Martiniuk, F.; Hirschhorn, R.; Smith, M.: Assignment of human
neutral alpha-glucosidase C to chromosome 15.  (Abstract) Cytogenet.
Cell Genet. 25: 182 only, 1979.

3. Martiniuk, F.; Hirschhorn, R.; Smith, M.: Assignment of the gene
for human neutral alpha-glucosidase C to chromosome 15. Cytogenet.
Cell Genet. 27: 168-175, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987
marie: 1/7/1987

*RECORD*
*FIELD* NO
104200
*FIELD* TI
104200 ALPORT SYNDROME
HEREDITARY NEPHROPATHY AND DEAFNESS
*FIELD* TX
The classic phenotype as described by Alport (1927) is nephritis, often
progressing to renal failure, and sensorineural hearing loss affecting
both sexes in successive generations. The renal disease becomes evident
as recurrent microscopic or gross hematuria as early as childhood,
earlier in males than in females. Progression to renal failure is
gradual and usually occurs in males by the fifth decade. The nephrotic
syndrome is unusual but has been reported. The renal histology is
nonspecific; both glomerular and interstitial abnormalities, including
foam cells, occur. Some investigators (e.g., Churg and Sherman, 1973)
believe the ultrastructural changes of the glomerular basement membrane,
which is irregularly thickened and attenuated, are specific for this
condition, but controversy exists on this point. Immunofluorescence
studies have provided little evidence for an immunologic basis for renal
damage. Hearing loss, which is sensorineural and primarily affects high
tones, occurs in 30 to 50% of relatives with renal disease. The severity
of auditory and renal features do not correlate in a given individual.

Alport syndrome shows considerable heterogeneity. In addition to the
existence of X-linked and autosomal forms (which often cannot be
distinguished in individual kindreds), families differ in the age of
end-stage renal disease (ESRD) and the occurrence of deafness. Hasstedt
et al. (1986) tested for heterogeneity among 23 Utah kindreds using 2
methods developed for assay of linkage heterogeneity: C.A.B. Smith's
admixture test and Morton's predivided-sample test. The 3 phenotypes
were juvenile Alport syndrome with deafness, adult Alport syndrome with
deafness, and adult Alport syndrome without deafness or other defects.
The age of 31 years for ESRD was taken as the divide between the
juvenile and adult forms. Atkin et al. (1986) proposed the existence of
6 types of dominant Alport syndrome among kindreds reported: I, classic
juvenile Alport syndrome with deafness; II, X-linked juvenile Alport
syndrome with deafness (301050); III, X-linked adult Alport syndrome
with deafness; IV, X-linked adult Alport syndrome without deafness or
other defect, that is, purely renal disease; V, autosomal Alport
syndrome with deafness and thrombocytopathia (153650); and VI, autosomal
recessive juvenile Alport syndrome with deafness (203780). A possibly
distinct entity is hereditary nephritis without deafness (161900)
reported by Reyersbach and Butler (1954) and Dockhorn (1967). M'Rad et
al. (1992) reviewed 31 families with Alport syndrome. Though there was
clinical heterogeneity for ophthalmic signs and the age of development
of end-stage renal disease, homogeneity tests failed to show evidence of
genetic heterogeneity.

Partial sex linkage (location of the gene on the part of the X and Y
chromosomes that is homologous) was suggested on the basis of the large
Mormon kindred reported by Perkoff et al. (1958). O'Neill et al. (1978)
reexamined and extended this pedigree and provided convincing evidence
for X-linked inheritance (see 301050), and Barker et al. (1990)
demonstrated substitution of serine for cysteine in the alpha-5 chain of
type IV collagen (303630.0002). Autosomal dominant inheritance with
anomalous segregation was proposed by Shaw and Glover (1961).
Heterozygous mothers transmit the gene to more than 50% of daughters and
probably more than 50% of their sons. Evans et al. (1980) reported a
family with male-to-male transmission. The kindred reported by Ohlsson
(1963) differed from others reported in that myopia was a conspicuous
feature and the impairment of renal function in the affected males was
relatively mild even in 2 over age 30 years. Ocular abnormalities have
been observed in some patients (Arnott et al., 1966). Stanbury and
Castleman (1968) reported 7 persons in 3 generations; the proband had
hypophosphatemia, nephrocalcinosis, and unilateral deafness; foam cells
were demonstrated in the kidney. Miller et al. (1970) showed that the
vestibular neuroepithelium is involved as well as that of the cochlea.
Variability in histologic findings in the ear in Alport syndrome led
Myers and Tyler (1972) to conclude that it is a heterogeneous category.
They reported the temporal bone histology in 2 cases: both had severe
deafness but one had a histologically normal inner ear whereas the other
had a marked reduction in spinal ganglion cochlear neurons.

Miyoshi et al. (1975) found antithyroid antibodies in the serum of
multiple persons with Alport syndrome in 2 Japanese kindreds.
Hyperthyroidism was present in one and histologic changes of thyroiditis
in a second. They proposed that Alport syndrome may be an immunologic
disorder. Spear (1973) suggested that a primary structural abnormality
of basement membranes underlies the phenotype. Evidence from many
sources suggests that the glomerular basement membrane of patients with
Alport syndrome is different antigenically and therefore biochemically,
as well as morphologically, from that of normal persons (review by
Milliner et al., 1982); these authors reported successful results of
kidney transplantation in most cases. Yoshikawa et al. (1982) emphasized
'basket weave' alteration in the lamina densa of the capillary basement
membrane, demonstrated by electron microscopy, as the pathognomonic
histologic feature of Alport syndrome. The change was, furthermore,
found in all 3 children biopsied under 5 years of age. The finding
served to differentiate benign familial hematuria (141200). Yoshikawa et
al. (1982) found families with heavy proteinuria, segmented sclerosis,
foam cells, and the 'basket weave' alteration, but no deafness (see
161900). They concluded that families with and without deafness 'fall
within the spectrum of Alport syndrome, although the presence of
deafness adversely affected the prognosis.' The report of Alport (1927),
in which he first described deafness as a component of the syndrome, was
the fourth concerning this signal pedigree. The first report (Dickinson,
1875) noted hematuria in 3 generations while 2 later studies (Guthrie,
1902; Kendall and Hertz, 1912) added albuminuria and azotemia to the
spectrum of renal involvement. Patients with Alport syndrome constituted
2.3% of the transplant population at the Mayo Clinic (Milliner et al.,
1982). In the study Waldherr (1982), Alport syndrome comprised at least
a sixth of familial glomerular disease, which itself was responsible for
6.3% of his biopsy material.

In a retrospective, double-blind study, Savage et al. (1986) examined
paraffin-embedded renal biopsy sections from 44 children with hematuria
to see whether a mouse monoclonal antibody (MCA-P1) against glomerular
basement membrane (GBM) could identify a subgroup of patients with
Alport syndrome in which the Goodpasture antigen is abnormal. Strong
linear binding of MCA-P1 to GBM was found in all 29 patients without
evidence of hereditary nephritis and in 2 with possible but not definite
hereditary nephritis. In contrast, 12 of 13 patients with strong
evidence of hereditary nephritis showed no binding (9) or greatly
reduced binding (3). Thus, abnormal antigenicity of the basement
membrane in hereditary nephritis, as reported by McCoy et al. (1982), is
confirmed. Savage et al. (1987) concluded that the inherited defect in
hereditary nephritis affects Goodpasture antigen secondarily. Serum
amyloid P component (SAP; 104770) has been found to be a constituent of
normal glomerular basement membrane. Melvin et al. (1986) showed that
SAP and Goodpasture antigen are closely associated in the glomerular
basement membrane and that in patients with Alport-type hereditary
nephritis who lack Goodpasture antigen, SAP is also uniformly absent.

Yoshikawa et al. (1987) reviewed 48 children with ultrastructural
changes of the glomerular basement membrane, a characteristic of
hereditary nephritis. All had hematuria. In 30 cases, there was
hematuria in at least 1 other member of the family; in the other 18
cases, there was no familial incidence. There were no differences
between the 2 groups with regard to clinical and pathologic findings. At
the latest follow-up, 6 boys with familial hematuria and 3 boys with
nonfamilial hematuria had reduced renal function, and 9 boys with
familial hematuria and 4 boys and 1 girl with nonfamilial hematuria had
sensorineural deafness. Yoshikawa et al. (1987) suggested that the
disorder in patients with nonfamilial hematuria may represent new
mutations for hereditary nephritis. Nielsen (1978) suggested that
anterior lenticonus may be a specific sign of Alport syndrome, since all
recently reported cases (e.g., Arnott et al., 1966) had been associated
with hereditary nephropathy. Streeten et al. (1987) concluded that the
anterior capsule of the lens 'is clearly fragile in this disease,
forming the basis for the progressive lenticonus and anterior polar
cataract. These abnormalities correlate well with a defect in the type
IV collagen molecule.'

The disorder that has come to be known as Alport syndrome is
characterized by hematuria, progressive renal failure, and sensorineural
hearing loss and is frequently associated with both ocular abnormalities
(such as lenticonus and retinal anomalies) as well as the identification
of mutations in the gene encoding the basement membrane specific type IV
collagen alpha-5 chain (COL4A5; 303630), an X-linked gene. This syndrome
was definitely proven to be an X-linked dominant disorder. The
possibility of an autosomal dominant form became less likely, as most of
the cases were shown to be X-linked. There was a possibility, however,
that possible autosomal dominant Alport syndrome was, in fact,
hereditary nephropathy and deafness in association with hematologic
abnormalities, Epstein syndrome (153650), or Fechtner syndrome (153640).
Although autosomal recessive transmission had been previously considered
unlikely, this mode of transmission seemed likely in a remaining small
percentage of kindreds in which there was parental consanguinity,
absence of severe symptoms in parents, and equal severity of the disease
in males and females; see 203780. The plausibility of an autosomal form
of Alport syndrome was supported by the isolation of 2 autosomal type IV
collagen genes, COL4A3 (120070) and COL4A4 (120131), which are located
head-to-head on 2q35-q37 and are specifically expressed in the
glomerular basement membrane and the specialized ocular and inner ear
basement membranes. Demonstration of linkage analysis to chromosome 2q
in consanguineous families and of mutations in one or the other of these
2 autosomal genes provided clear evidence of the existence of the
autosomal recessive form of Alport syndrome. It remains to be determined
whether mutations in either of these genes in heterozygous state cause
abnormality.

*FIELD* SA
Beathard and Granholm (1977); Chazan et al. (1971); Chuang and Reuter
(1974); Cohen et al. (1961); Crawfurd and Toghill (1968); DiBona
(1983); Goyer et al. (1968); Kenya et al. (1977); Marin and Tyler
(1961); Mulrow et al. (1963); Perrin et al. (1980); Preus and Fraser
(1971); Purriel et al. (1970); Schneider  (1963); Sherman et al. (1974);
Spear  (1984); Spear and Slusser (1972); Spear et al. (1970); Turner
(1970); Westley  (1970); Whalen et al. (1961); Williamson  (1961)
*FIELD* RF
1. Alport, A. C.: Hereditary familial congenital hemorrhagic nephritis.
Brit. Med. J. 1: 504-506, 1927.

2. Arnott, E. J.; Crawfurd, M. D. A.; Toghill, P. J.: Anterior lenticonus
and Alport's syndrome. Brit. J. Ophthal. 50: 390-403, 1966.

3. Atkin, C. L.; Gregory, M. C.; Border, W. A.: Alport syndrome.
In: Schrier, R. W.; Gottschalk, C. W.: Strauss and Welt's Diseases
of the Kidney.  Boston: Little, Brown (pub.)  (4th ed.): 1986.

4. Barker, D. F.; Hostikka, S. L.; Zhou, J.; Chow, L. T.; Oliphant,
A. R.; Gerken, S. C.; Gregory, M. C.; Skolnick, M. H.; Atkin, C. L.;
Tryggvason, K.: Identification of mutations in the COL4A5 collagen
gene in Alport syndrome. Science 248: 1224-1227, 1990.

5. Beathard, G. A.; Granholm, N. A.: Development of the characteristic
ultrastructural lesion of hereditary nephritis during the course of
the disease. Am. J. Med. 62: 751-756, 1977.

6. Chazan, J. A.; Zacks, J.; Cohen, J. J.; Garella, S.: Hereditary
nephritis: clinical spectrum and mode of inheritance in five new kindreds.
Am. J. Med. 50: 764-771, 1971.

7. Chuang, V. P.; Reuter, S. R.: Angiographic features of Alport's
syndrome: hereditary nephritis. Am. J. Roentgen. 121: 539-543,
1974.

8. Churg, J.; Sherman, R. L.: Pathology of hereditary nephritis.
Arch. Path. 95: 374-379, 1973.

9. Cohen, M. M.; Cassady, G.; Hanna, B. L.: A genetic study of hereditary
renal dysfunction with associated nerve deafness. Am. J. Hum. Genet. 13:
379-389, 1961.

10. Crawfurd, M. D. A.; Toghill, P. J.: Alport's syndrome of hereditary
nephritis and deafness. Quart. J. Med. 37: 563-576, 1968.

11. DiBona, G. F.: Alport's syndrome: a genetic defect in biochemical
composition of basement membrane of glomerulus, lens, and inner ear?.
(Editorial) J. Lab. Clin. Med. 101: 817-820, 1983.

12. Dickinson, W. H.: Disease of the Kidney and Urinary Derangements.
Part 2..  London: Longmans, Green (pub.)  1875. Pp. 379 only.

13. Dockhorn, R. J.: Hereditary nephropathy without deafness. Am.
J. Dis. Child. 114: 135-138, 1967.

14. Evans, S. H.; Erickson, R. P.; Kelsch, R.; Pierce, J. C.: Apparently
changing patterns of inheritance in Alport's hereditary nephritis:
genetic heterogeneity versus altered diagnostic criteria. Clin.
Genet. 17: 285-292, 1980.

15. Goyer, R. A.; Reynolds, J., Jr.; Burke, J.; Burkholder, P.: Hereditary
renal disease with neurosensory hearing loss, prolinuria and ichthyosis.
Am. J. Med. Sci. 256: 166-179, 1968.

16. Guthrie, L. B.: 'Idiopathic' or congenital, hereditary and family
haematuria. Lancet I: 1243-1246, 1902.

17. Hasstedt, S. J.; Atkin, C. L.; San Juan, A. C., Jr.: Genetic
heterogeneity among kindreds with Alport syndrome. Am. J. Hum. Genet. 38:
940-953, 1986.

18. Kendall, G.; Hertz, A. F.: Hereditary familial congenital hemorrhagic
nephritis. Guy's Hosp. Rep. 66: 137-141, 1912.

19. Kenya, P. R.; Asal, N. R.; Pederson, J. A.; Lindeman, R. D.:
Hereditary (familial) renal disease: clinical and genetic studies.
Sth. Med. J. 70: 1049-1051, 1977.

20. M'Rad, R.; Sanak, M.; Deschenes, G.; Zhou, J.; Bonaiti-Pellie,
C.; Holvoet-Vermaut, L.; Heuertz, S.; Gubler, M.-C.; Broyer, M.; Grunfeld,
J.-P.; Tryggvason, K.; Hors-Cayla, M.-C.: Alport syndrome: a genetic
study of 31 families. Hum. Genet. 90: 420-426, 1992.

21. Marin, O. S. M.; Tyler, H. R.: Hereditary interstitial nephritis
associated with polyneuropathy. Neurology 11: 999-1005, 1961.

22. McCoy, R. C.; Johnson, K. H.; Stone, W. J.; Wilson, C. B.: Absence
of nephritogenic GBM antigen(s) in some patients with hereditary nephritis.
Kidney Int. 21: 642-652, 1982.

23. Melvin, T.; Kim, Y.; Michael, A. F.: Amyloid P component is not
present in the glomerular basement membrane in Alport-type hereditary
nephritis. Am. J. Path. 125: 460-464, 1986.

24. Miller, G. W.; Joseph, D. J.; Cozad, R. L.; McCabe, B. F.: Alport's
syndrome. Arch. Otolaryng. 92: 419-432, 1970.

25. Milliner, D. S.; Pierides, A. M.; Holley, K. E.: Renal transplantation
in Alport's syndrome: anti-glomerular basement membrane glomerulonephritis
in the allograft. Mayo Clin. Proc. 57: 35-43, 1982.

26. Miyoshi, K.; Suzuki, M.; Ohno, F.; Yamano, T.; Yagi, F.; Khono,
H.: Antithyroid antibodies in Alport's syndrome. Lancet II: 480-482,
1975.

27. Mulrow, P. J.; Aron, A. M.; Gathman, G. E.; Yesner, R.; Lubs,
H. A.: Hereditary nephritis: report of a kindred. Am. J. Med. 35:
737-748, 1963.

28. Myers, G. J.; Tyler, H. R.: The etiology of deafness in Alport's
syndrome. Arch. Otolaryng. 96: 333-340, 1972.

29. Nielsen, C. E.: Lenticonus anterior and Alport's syndrome. Acta
Ophthal. 56: 518-530, 1978.

30. O'Neill, W. M., Jr.; Atkin, C. L.; Bloomer, H. A.: Hereditary
nephritis: a re-examination of its clinical and genetic features.
Ann. Intern. Med. 88: 176-182, 1978.

31. Ohlsson, L.: Congenital renal disease, deafness and myopia in
one family. Acta Med. Scand. 174: 77-84, 1963.

32. Perkoff, G. T.; Nugent, C. A., Jr.; Dolowitz, D. A.; Stephens,
F. E.; Carnes, W. H.; Tyler, F. H.: A follow-up study of hereditary
chronic nephritis. Arch. Intern. Med. 102: 733-746, 1958.

33. Perrin, D.; Jungers, P.; Grunfeld, J. P.; Delons, S.; Noel, L.-H.;
Zenatti, C.: Perimacular changes in Alport's syndrome. Clin. Nephrol. 13:
163-167, 1980.

34. Preus, M.; Fraser, F. C.: Genetics of hereditary nephropathy
with deafness (Alport's disease). Clin. Genet. 2: 331-337, 1971.

35. Purriel, P.; Drets, M.; Pascale, E.; Cestau, R. S.; Borras, A.;
Ferreira, W. A.; Delucca, A.; Fernandez, L.: Familial hereditary
nephropathy (Alport's syndrome). Am. J. Med. 49: 753-773, 1970.

36. Reyersbach, G. C.; Butler, A. M.: Congenital hereditary hematuria.
New Eng. J. Med. 251: 377-380, 1954.

37. Savage, C. O. S.; Noel, L. H.; Cashman, S.; Grunfeld, J. P.; Lockwood,
C. M.: Characterisation by immunoblotting of the glomerular basement
membrane defect in hereditary nephritis.  (Abstract) Clin. Res. 35:
663A only, 1987.

38. Savage, C. O. S.; Reed, A.; Kershaw, M.; Pincott, J.; Pusey, C.
D.; Dillon, M. J.; Barratt, T. M.; Lockwood, C. M.: Use of a monoclonal
antibody in differential diagnosis of children with haematuria and
hereditary nephritis. Lancet I: 1459-1461, 1986.

39. Schneider, R. G.: Congenital hereditary nephritis with nerve
deafness. New York J. Med. 63: 2644-2648, 1963.

40. Shaw, R. F.; Glover, R. A.: Abnormal segregation in hereditary
renal disease with deafness. Am. J. Hum. Genet. 13: 89-97, 1961.

41. Sherman, R. L.; Churg, J.; Yudis, M.: Hereditary nephritis with
a characteristic renal lesion. Am. J. Med. 56: 44-51, 1974.

42. Spear, G. S.: Alport's syndrome: a consideration of pathogenesis.
Clin. Nephrol. 1: 336-337, 1973.

43. Spear, G. S.: Hereditary nephritis (Alport's syndrome)--1983.
Clin. Nephrol. 21: 3-6, 1984.

44. Spear, G. S.; Slusser, R. J.: Alport's syndrome: emphasizing
electron microscopic studies of the glomerulus. Am. J. Path. 69:
213-224, 1972.

45. Spear, G. S.; Whitworth, J. M.; Konigsmark, B. W.: Hereditary
nephritis with nerve deafness: immunofluorescent studies on the kidney,
with a consideration of discordant immunoglobulin-complement immunofluorescent
reactions. Am. J. Med. 49: 52-63, 1970.

46. Stanbury, S. W.; Castleman, B.: Nephrocalcinosis and azotemia
in a young man. New Eng. J. Med. 278: 839-846, 1968.

47. Streeten, B. W.; Robinson, M. R.; Wallace, R.; Jones, D. B.:
Lens capsule abnormalities in Alport's syndrome. Arch. Ophthal. 105:
1693-1697, 1987.

48. Turner, J. S., Jr.: Hereditary hearing loss with nephropathy
(Alport's syndrome). Acta Otolaryng. 271 (suppl.): 7-26, 1970.

49. Waldherr, R.: Familial glomerular disease. Contrib. Nephrol. 33:
104-121, 1982.

50. Westley, C. R.: Familial nephritis and associated deafness in
a southwestern Apache Indian family. Sth. Med. J. 63: 1415-1419,
1970.

51. Whalen, R. E.; Huang, S.-S.; Peschel, E.; McIntosh, H. D.: Hereditary
nephropathy, deafness and renal foam cells. Am. J. Med. 31: 171-186,
1961.

52. Williamson, D. A. J.: Alport's syndrome of hereditary nephritis
with deafness. Lancet II: 1321-1323, 1961.

53. Yoshikawa, N.; Matsuyama, S.; Ito, H.; Hajikano, H.; Matsuo, T.
: Nonfamilial hematuria associated with glomerular basement membrane
alterations characteristic of hereditary nephritis: comparison with
hereditary nephritis. J. Pediat. 111: 519-524, 1987.

54. Yoshikawa, N.; White, R. H. R.; Cameron, A. H.: Familial hematuria:
clinico-pathological correlations. Clin. Nephrol. 17: 172-182,
1982.

*FIELD* CS

GU:
   Nephritis;
   Renal failure;
   Nephrotic syndrome

Ears:
   Sensorineural hearing loss

Eyes:
   Fragile anterior lens capsule;
   Lenticonus;
   Anterior polar cataract;
   Myopia

Lab:
   Hematuria;
   Renal foam cells;
   Hypophosphatemia;
   Nephrocalcinosis;
   Proteinuria;
   Azotemia;
   Ultrastructural glomerular basement membrane changes;
   Antithyroid antibodies

Inheritance:
   Autosomal dominant form;
   6 types including X-linked form

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 6/9/1995
davew: 8/18/1994
jason: 6/16/1994
carol: 6/9/1994
mimadm: 4/17/1994
carol: 10/14/1993

*RECORD*
*FIELD* NO
104210
*FIELD* TI
*104210 ALPHA-2A-ADRENERGIC RECEPTOR; ADRA2A; ADRAR; ADRA2
ALPHA-2-ADRENERGIC RECEPTOR, PLATELET TYPE;;
ADRENOCEPTOR, ALPHA-2A
*FIELD* TX
Hormones and drugs exert their physiologic and pharmacologic effects by
interacting with specific plasma membrane receptors of responsive cells.
Adrenergic receptors fall into two major classes, alpha and beta, each
of which is subdivided into 2 subclasses, termed alpha-1 and alpha-2 and
beta-1 and beta-2. The beta-adrenergic receptors, which stimulate, and
the alpha-2 adrenergic receptors, which often inhibit adenylate cyclase,
are coupled to guanine nucleotide regulatory proteins. Using an
alpha-2-adrenergic receptor clone, Yang-Feng et al. (1987) mapped the
ADRAR locus to 10q23-q25 by somatic cell hybridization and in situ
hybridization. Kobilka et al. (1987) cloned the gene for the human
platelet alpha-2-adrenergic receptor using oligonucleotides
corresponding to the partial amino acid sequence of the purified
receptor. The deduced amino acid sequence was most similar to those of
human beta-2 and beta-1 adrenergic receptors. Similarities to the
muscarinic cholinergic receptors were also evident. Two related genes
were identified by low stringency Southern blot analysis. Hoehe et al.
(1988) identified a DraI RFLP of the ADRAR gene. By study of
interspecific backcrosses, Oakey et al. (1991) assigned the Adra2r gene
to the distal region of mouse chromosome 19.

An aspartic acid residue at position 79 is highly conserved among G
protein-coupled receptors. Surprenant et al. (1992) found that when
asp-79 was mutated to asparagine, cells transfected with the mutant
adrenoceptor showed inhibition of adenylyl cyclase and calcium currents
by agonists but did not increase potassium currents. Because distinct G
proteins appear to couple adrenoceptors to potassium and calcium
currents, the findings suggested that the mutant adrenoceptor could not
achieve the conformation necessary to activate G proteins that mediate
potassium channel activation.

*FIELD* SA
Hoehe et al. (1989)
*FIELD* RF
1. Hoehe, M.; Berrettini, W.; Leppert, M.; Lalouel, J.-M.; Byerley,
W.; Gershon, E.; White, R.: Genetic mapping of adrenergic receptor
genes.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A143 only, 1989.

2. Hoehe, M. R.; Berrettini, W. H.; Lentes, K.-U.: Dra I identifies
a two allele DNA polymorphism in the human alpha-2-adrenergic receptor
gene (ADRAR), using a 5.5 kb probe (p ADRAR). Nucleic Acids Res. 16:
9070 only, 1988.

3. Kobilka, B. K.; Matsui, H.; Kobilka, T. S.; Yang-Feng, T. L.; Francke,
U.; Caron, M. G.; Lefkowitz, R. J.; Regan, J. W.: Cloning, sequencing,
and expression of the gene coding for the human platelet alpha-2-adrenergic
receptor. Science 238: 650-656, 1987.

4. Oakey, R. J.; Caron, M. G.; Lefkowitz, R. J.; Seldin, M. F.: Genomic
organization of adrenergic and serotonin receptors in the mouse: linkage
mapping of sequence-related genes provides a method for examining
mammalian chromosome evolution. Genomics 10: 338-344, 1991.

5. Surprenant, A.; Horstman, D. A.; Akbarali, H.; Limbird, L. E.:
A point mutation of the alpha-2-adrenoceptor that blocks coupling
to potassium but not calcium currents. Science 257: 977-980, 1992.

6. Yang-Feng, T. L.; Kobilka, B. K.; Caron, M. G.; Lefkowitz, R. J.;
Francke, U.: Chromosomal assignment of genes for an alpha-adrenergic
receptor (ADRAR) and for another member of this receptor family coupled
to guanine nucleotide regulatory proteins (RG21).  (Abstract) Cytogenet.
Cell Genet. 46: 722-723, 1987.

*FIELD* CD
Victor A. McKusick: 8/31/1987

*FIELD* ED
carol: 9/9/1992
carol: 9/8/1992
carol: 4/1/1992
supermim: 3/19/1992
supermim: 3/16/1992
carol: 3/5/1992

*RECORD*
*FIELD* NO
104219
*FIELD* TI
*104219 ALPHA-1A-ADRENERGIC RECEPTOR; ADRA1A
*FIELD* TX
Lomasney et al. (1991) demonstrated that there are at least 3
alpha-1-adrenergic receptors. From in situ hybridization studies, they
concluded that the gene for the alpha-1A receptor is located on
chromosome 5 in the region q23-q32, the same region that contains the
ADRA1B gene (104220). The ADRB2 gene (109690) is also in the same area.
The close proximity of 3 adrenergic receptors on the same chromosome
suggested that this family of proteins arose by gene duplication.
However, Schwinn and Lomasney (1992) concluded from its pharmacologic
characteristics that the clone represents a further subtype designated
alpha-1D (see ADRA1D; 104222). Loftus et al. (1994) found by PCR
analysis of somatic cell hybrids that ADRA1A is in fact located on
chromosome 20. They cited work of others confirming the assignment of
ADRA1A to chromosome 20 by FISH.

Bruno et al. (1991) also cloned a human alpha-1A-adrenergic receptor.
The homologous gene in the mouse is located on chromosome 11 (Wilkie et
al., 1993), which shows homology of synteny with 5q, not chromosome 20.

*FIELD* RF
1. Bruno, J. F.; Whittaker, J.; Song, J.; Berelowitz, M.: Molecular
cloning and sequencing of a cDNA encoding a human alpha-1A adrenergic
receptor. Biochem. Biophys. Res. Commun. 179: 1485-1490, 1991.

2. Loftus, S. K.; Shiang, R.; Warrington, J. A.; Bengtsson, U.; McPherson,
J. D.; Wasmuth, J. J.: Genes encoding adrenergic receptors are not
clustered on the long arm of human chromosome 5. Cytogenet. Cell
Genet. 67: 69-74, 1994.

3. Lomasney, J. W.; Cotecchia, S.; Lorenz, W.; Leung, W.-Y.; Schwinn,
D. A.; Yang-Feng, T. L.; Brownstein, M.; Lefkowitz, R. J.; Caron,
M. G.: Molecular cloning and expression of the cDNA for the alpha-1A-adrenergic
receptor: the gene for which is located on human chromosome 5. J.
Biol. Chem. 266: 6365-6369, 1991.

4. Schwinn, D. A.; Lomasney, J. W.: Pharmacologic characterization
of cloned alpha-1-adrenoceptor subtypes: selective antagonists suggest
the existence of a fourth subtype. Europ. J. Pharm. 227: 433-436,
1992.

5. Wilkie, T. M.; Chen, Y.; Gilbert, D. J.; Moore, K. J.; Yu, L.;
Simon, M. I.; Copeland, N. G.; Jenkins, N. A.: Identification, chromosomal
location, and genome organization of mammalian G-protein-coupled receptors.
Genomics 18: 175-184, 1993.

*FIELD* CD
Victor A. McKusick: 5/13/1991

*FIELD* ED
carol: 11/10/1994
pfoster: 8/16/1994
jason: 6/9/1994
carol: 12/1/1993
carol: 11/29/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
104220
*FIELD* TI
*104220 ALPHA-1B-ADRENERGIC RECEPTOR; ADRA1B
ALPHA-1-ADRENERGIC RECEPTOR; ADRA1
*FIELD* TX
The alpha-1B-adrenergic receptor is a member of the G-protein-coupled
family of transmembrane receptors. See 104210. Yang-Feng et al. (1990)
mapped the ADRA1 gene to chromosome 5 by Southern analysis of somatic
cell hybrids and regionalized it to 5q32-q34 by in situ hybridization.
From pulsed field gel electrophoresis, they concluded that the ADRA1R
and ADRB2R (109690) loci are within 300 kb of each other. Lomasney et
al. (1991) indicated that this alpha-1 receptor is alpha-1B and that the
regional assignment is 5q23-q32. The corresponding gene in the mouse,
symbolized Adra1r, is located on proximal chromosome 11 (Oakey et al.,
1991).

From cloning and sequencing the ADRA1B gene, Ramarao et al. (1992) found
that it comprises 2 exons and a single large intron of at least 20 kb
that interrupts the coding region at the end of the putative sixth
transmembrane domain. The genomic organization of this adrenergic
receptor with a single large intron interrupting its coding region
differs from those of other adrenergic receptors as well as muscarinic
and 5-hydroxytryptamine receptors, which are intronless. The location of
the intron is also unique among those members of the G-protein-coupled
receptor family that do possess introns.

When transfected into NIH 3T3 fibroblasts and other cell lines, the
alpha-1B-adrenergic receptor induces neoplastic transformation which
identifies this normal cellular gene as a protooncogene. Allen et al.
(1991) demonstrated that mutational alteration of the receptor can lead
to activation of this protooncogene in such a way that cell lines are
constitutively activated, even though not stimulated by agonist. These
cells demonstrate an enhanced ability for tumor generation in nude mice,
with a decreased period of latency compared with cells expressing the
wildtype receptor. From these observations, Allen et al. (1991)
suggested that analogous spontaneously occurring mutations in this class
of receptor proteins could play a key role in the induction or
progression of neoplastic transformation and atherosclerosis. Indeed, a
comparable situation was demonstrated in the case of the thyrotropin
receptor, causing hyperfunctioning thyroid adenoma (275200.0002).
Furthermore, a mutation in the luteinizing hormone receptor can result
in its constitutive activation, resulting in familial male precocious
puberty (152790.0001).

Loftus et al. (1994) concluded that ADRA1B and ADRB2 are several Mb
apart rather than a few hundred kb as reported by Yang-Feng et al.
(1990).

*FIELD* RF
1. Allen, L. F.; Lefkowitz, R. J.; Caron, M. G.; Cotecchia, S.: G-protein-coupled
receptor genes as protooncogenes: constitutively activating mutation
of the alpha-1B-adrenergic receptor enhances mitogenesis and tumorigenicity.
Proc. Nat. Acad. Sci. 88: 11354-11358, 1991.

2. Loftus, S. K.; Shiang, R.; Warrington, J. A.; Bengtsson, U.; McPherson,
J. D.; Wasmuth, J. J.: Genes encoding adrenergic receptors are not
clustered on the long arm of human chromosome 5. Cytogenet. Cell
Genet. 67: 69-74, 1994.

3. Lomasney, J. W.; Cotecchia, S.; Lorenz, W.; Leung, W.-Y.; Schwinn,
D. A.; Yang-Feng, T. L.; Brownstein, M.; Lefkowitz, R. J.; Caron,
M. G.: Molecular cloning and expression of the cDNA for the alpha-1A-adrenergic
receptor: the gene for which is located on human chromosome 5. J.
Biol. Chem. 266: 6365-6369, 1991.

4. Oakey, R. J.; Caron, M. G.; Lefkowitz, R. J.; Seldin, M. F.: Genomic
organization of adrenergic and serotonin receptors in the mouse: linkage
mapping of sequence-related genes provides a method for examining
mammalian chromosome evolution. Genomics 10: 338-344, 1991.

5. Ramarao, C. S.; Kincade Denker, J. M.; Perez, D. M.; Gaivin, R.
J.; Riek, R. P.; Graham, R. M.: Genomic organization and expression
of the human alpha-1B-adrenergic receptor. J. Biol. Chem. 267:
21936-21945, 1992.

6. Yang-Feng, T. L.; Xue, F.; Zhong, W.; Cotecchia, S.; Frielle, T.;
Caron, M. G.; Lefkowitz, R. J.; Francke, U.: Chromosomal organization
of adrenergic receptor genes. Proc. Nat. Acad. Sci. 87: 1516-1520,
1990.

*FIELD* CD
Victor A. McKusick: 12/2/1987

*FIELD* ED
carol: 11/10/1994
pfoster: 8/16/1994
jason: 6/16/1994
carol: 11/16/1993
carol: 11/5/1993
carol: 1/15/1993

*RECORD*
*FIELD* NO
104221
*FIELD* TI
*104221 ALPHA-1C-ADRENERGIC RECEPTOR; ADRA1C
*FIELD* TX
Schwinn et al. (1990) cloned the gene encoding the bovine
alpha-1C-adrenergic receptor and localized its human counterpart to
human chromosome 8 by somatic cell hybridization analysis. They used an
interesting approach to demonstrate that the bovine gene is distinct
from the hamster alpha-1B-adrenergic receptor; a human homolog of the
latter gene is located on human chromosome 5 (104220). Despite the
similarities in pharmacologic profile, the bovine alpha-1-adrenergic
receptor showed differences in sensitivity to inhibition and lack of
expression in some tissues in which the alpha-1A subtype (104219)
existed. Hoehe et al. (1992) demonstrated a 2-allele PstI RFLP in the
ADRA1C gene. Using this probe for the study of DNAs from the CEPH
pedigrees, they concluded that the gene is closely linked (theta = 0.03)
to NEFL (162280) on 8p21 (maximum lod = 12).

*FIELD* RF
1. Hoehe, M. R.; Berrettini, W. H.; Schwinn, D. A.; Hsieh, W.-T.:
A two-allele PstI RFLP for the alpha-1C adrenergic receptor gene (ADRA1C).
Hum. Molec. Genet. 1: 349 only, 1992.

2. Schwinn, D. A.; Lomasney, J. W.; Lorenz, W.; Szklut, P. J.; Fremeau,
R. T., Jr.; Yang-Feng, T. L.; Caron, M. G.; Lefkowitz, R. J.; Cotecchia,
S.: Molecular cloning and expression of the cDNA for a novel alpha-1-adrenergic
receptor subtype. J. Biol. Chem. 265: 8183-8189, 1990.

*FIELD* CD
Victor A. McKusick: 5/13/1991

*FIELD* ED
carol: 9/28/1992
carol: 3/20/1992
supermim: 3/16/1992
carol: 10/1/1991
carol: 5/13/1991

*RECORD*
*FIELD* NO
104222
*FIELD* TI
*104222 ALPHA-1D-ADRENERGIC RECEPTOR; ADRA1D
*FIELD* TX
As indicated in 104219, a receptor which was previously thought to
represent the alpha-1A subtype of adrenergic receptor and to map to
chromosome 5 was characterized pharmacologically as a distinct subtype,
designated alpha-1D (Schwinn and Lomasney, 1992). Yang-Feng et al.
(1994) mapped the ADRA1D gene to chromosome 20 by analysis of a
mouse/human hybrid cell mapping panel and to 20p13 by isotopic in situ
hybridization. Is it possible that this is, in fact, the same as ADRA1A
(104219), which is located on chromosome 20?

*FIELD* RF
1. Schwinn, D. A.; Lomasney, J. W.: Pharmacologic characterization
of cloned alpha-1-adrenoceptor subtypes: selective antagonists suggest
the existence of a fourth subtype. Europ. J. Pharm. 227: 433-436,
1992.

2. Yang-Feng, T. L.; Han, H.; Lomasney, J. W.; Caron, M. G.: Localization
of the cDNA for an alpha-1-adrenergic receptor subtype (ADRA1D) to
chromosome band 20p13. Cytogenet. Cell Genet. 66: 170-171, 1994.

*FIELD* CD
Victor A. McKusick: 6/13/1994

*FIELD* ED
jason: 6/22/1994
carol: 6/13/1994

*RECORD*
*FIELD* NO
104225
*FIELD* TI
*104225 LOW DENSITY LIPOPROTEIN-RELATED PROTEIN-ASSOCIATED PROTEIN 1; LRPAP1
ALPHA-2-MACROGLOBULIN RECEPTOR-ASSOCIATED PROTEIN; A2; RAP; MRAP
*FIELD* TX
The alpha-2-macroglobulin receptor complex (107770), as purified by
affinity chromatography, contains 3 polypeptides: a 515-kD heavy chain,
an 85-kD light chain, and a 39-kD associated protein. The 515/85-kD
components are derived from a 600-kD precursor whose complete sequence
was determined by cDNA cloning (Herz et al., 1988). Strickland et al.
(1991) determined the primary structure of the 39-kD polypeptide, termed
alpha-2-macroglobulin receptor-associated protein (MRAP) by them, by
cDNA cloning. The deduced amino acid sequence contains a putative signal
sequence that precedes the 323-residue mature protein. The sequence
showed 73% identity with a rat protein reported to be a pathogenic
domain of the Heymann nephritis antigen gp 330 and 77% identity to a
mouse heparin-binding protein termed HBP-44. There are also similarities
between MRAP and apolipoprotein E (107741). Studies indicated that the
molecule is present on the cell surface, forming a complex with the
heavy and light chains of the alpha-2-macroglobulin receptor (103950).

Using a human 1.5-kb cDNA clone encoding MRAP, Korenberg et al. (1994)
performed fluorescence in situ hybridization to map the gene to human
chromosome 4p16.3. This location is in the vicinity of the 2.5-Mb
deletion associated with the Wolf-Hirschhorn syndrome (194190). The
kidney hypoplasia associated with Wolf-Hirschhorn syndrome may be
relevant in view of the high MRAP expression that is observed in this
organ. The 39-kD MRAP has been shown to copurify and bind in vitro with
high affinity to both LRP1 (107770) and LRP2 (600073). Although the
function of MRAP remains to be established, MRAP can specifically
inhibit ligand binding to both receptors. Although previous studies
localized MRAP to the cell surface, Korenberg et al. (1994) stated: 'Its
intracellular localization has led to suggestions that it might function
in the biosynthesis of gp 330 and LRP, perhaps acting as a chaperone,
preventing ligand binding during receptor trafficking.' The gene was
symbolized also as LRPAP1 (low-density lipoprotein-associated
protein-1).

Jou et al. (1994) used the direct cDNA selection approach to isolate the
LRPAP1 gene from cloned genomic DNA from the region of the Huntington
disease gene (143100) located at 4p16.3. Van Leuven et al. (1995)
assigned the LRPAP1 gene to chromosome 4 by PCR of human-hamster hybrid
cell lines and to 4p16.3 by fluorescence in situ hybridization. Using an
LRPAP1 genomic probe for fluorescence in situ hybridization, they
studied 2 patients with deletions of 4p, resulting in the
Wolf-Hirschhorn syndrome. One patient retained both copies of the gene,
whereas the other patient displayed no signal for LRPAP1 on the deleted
chromosome.

Van Leuven et al. (1995) cloned the mouse gene coding for HBP-44 from a
cosmid library and determined that its structure is very similar to that
of the LRPAP1 gene: in both species, the known coding part of the cDNA
is encoded by 8 exons and the position of the boundaries of the exons is
conserved. (HBP-44 stands for 44-kD heparin-binding protein.)

*FIELD* RF
1. Herz, J.; Hamann, U.; Rogne, S.; Myklebost, O.; Gausepohl, H.;
Stanley, K. K.: Surface location and high affinity for calcium of
a 500 kd liver membrane protein closely related to the LDL-receptor
suggest a physiological role as lipoprotein receptor. EMBO J. 7:
4119-4127, 1988.

2. Jou, Y.-S.; Goold, R. D.; Myers, R. M.: Localization of the alpha-2-macroglobulin
receptor-associated protein 1 gene (LRPAP1) and other gene fragments
to human chromosome 4p16.3 by direct cDNA selection. Genomics 24:
410-413, 1994.

3. Korenberg, J. R.; Argraves, K. M.; Chen, X.-N.; Tran, H.; Strickland,
D. K.; Argraves, W. S.: Chromosomal localization of human genes for
the LDL receptor family member glycoprotein 330 (LRP2) and its associated
protein RAP (LRPAP1). Genomics 22: 88-93, 1994.

4. Strickland, D. K.; Ashcom, J. D.; Williams, S.; Battey, F.; Behre,
E.; McTigue, K.; Battey, J. F.; Argraves, W. S.: Primary structure
of alpha-2-macroglobulin receptor-associated protein: human homologue
of a Heymann nephritis antigen. J. Biol. Chem. 266: 13364-13369,
1991.

5. Van Leuven, F.; Hilliker, C.; Serneels, L.; Umans, L.; Overbergh,
L.; De Strooper, B.; Fryns, J. P.; Van den Berghe, H.: Cloning, characterization,
and chromosomal localization to 4p16 of the human gene (LRPAP1) coding
for the alpha-2-macroglobulin receptor-associated protein and structural
comparison with the murine gene coding for the 44-kDa heparin-binding
protein. Genomics 25: 492-500, 1995.

*FIELD* CD
Victor A. McKusick: 4/12/1994

*FIELD* ED
mark: 12/31/1996
mark: 12/6/1995
carol: 3/6/1995
terry: 1/9/1995
jason: 6/16/1994
mimadm: 4/12/1994

*RECORD*
*FIELD* NO
104230
*FIELD* TI
*104230 FUCOSYLTRANSFERASE-4; FUT4
ALPHA-3-FUCOSYLTRANSFERASE; FCT3A;;
CD15;;
MYELOID-ASSOCIATED SURFACE ANTIGEN
*FIELD* TX
In human/mouse myeloid cell hybrids, Geurts van Kessel et al. (1984)
tested for reactivity with monoclonal antibodies with known myelocytic,
monocytic, or myelomonocytic specificity. Twenty antibodies, all of
which bind specifically to the surface of human myeloid cells, exhibited
similar reactivity patterns with the hybrid clones. Chromosomal analysis
showed that the gene or genes involved in the expression of the one or
more antigens recognized by these antibodies must be located on human
11q12-qter. This myeloid-associated surface antigen is designated CD15
in the 'CD system.' Using panels of somatic cell and radiation hybrids
which retained different rearrangements of chromosome 11, Reguigne et
al. (1994) assigned this gene, which they symbolized FUT4, to 11q21
between D11S388 and D11S919. Using fluorescence in situ hybridization
and a cosmid containing FUT4 sequence, McCurley et al. (1995) confirmed
the assignment of the FUT4 gene to 11q21.

Tetteroo et al. (1987) found that alpha-3-fucosyltransferase activity is
correlated with the presence of human chromosome 11 in human-mouse
myeloid cell hybrids. Also, several other myeloid-associated
carbohydrate antigens, e.g., Le(x), are associated with chromosome 11.
Tetteroo et al. (1987) concluded, therefore, that the enzyme
alpha-3-fucosyltransferase is responsible for the synthesis of these
antigens. Using human/mouse hybrid cell lines, Couillin et al. (1991)
mapped a human alpha-3-fucosyltransferase to 11q. Because the enzyme
transfers fucose onto H type 2 more efficiently than onto
sialyl-N-acetyllactosamine, Couillin et al. (1991) suggested that it is
the myeloid type of alpha-3-fucosyltransferase which creates the
3-fucosyllactosamine epitope on polymorphonuclear cells and monocytes.
(The Lewis enzyme (EC 2.4.1.65), alpha-3/4-fucosyltransferase, is coded
by a gene on chromosome 19 (111100). It is never found in plasma but is
found in human milk, digestive mucosa, and kidney. The plasma type of
alpha-3-fucosyltransferase (EC 2.4.1.152) is found in hepatocytes and
plasma; see 136835.)

Gersten et al. (1995) demonstrated that the homolog of FUT4 maps to
mouse chromosome 9 in a region of homology of synteny to 11q.

*FIELD* RF
1. Couillin, P.; Mollicone, R.; Grisard, M. C.; Gibaud, A.; Ravise,
N.; Feingold, J.; Oriol, R.: Chromosome 11q localization of one of
the three expected genes for the human alpha-3-fucosyltransferases,
by somatic hybridization. Cytogenet. Cell Genet. 56: 108-111, 1991.

2. Gersten, K. M.; Natsuka, S.; Trinchera, M.; Petryniak, B.; Kelly,
R. J.; Hiraiwa, N.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.;
Lowe, J. B.: Molecular cloning, expression, chromosomal assignment,
and tissue-specific expression of a murine alpha-(1,3)-fucosyltransferase
locus corresponding to the human ELAM-1 ligand fucosyl transferase. J.
Biol. Chem. 270: 25047-25056, 1995.

3. Geurts van Kessel, A.; Tetteroo, P.; Van Agthoven, T.; Paulussen,
R.; Van Dongen, J.; Hagemeijer, A.; Von dem Borne, A.: Localization
of human myeloid-associated surface antigen detected by a panel of
20 monoclonal antibodies to the q12-qter region of chromosome 11.
J. Immun. 133: 1265-1269, 1984.

4. McCurley, R. S.; Recinos, A., III; Olsen, A. S.; Gingrich, J. C.;
Szczepaniak, D.; Cameron, H. S.; Krauss, R.; Weston, B. W.: Physical
maps of human alpha(1,3)fucosyltransferase genes FUT3-FUT6 on chromosomes
19p13.3 and 11q21. Genomics 26: 142-146, 1995.

5. Reguigne, I.; James, M. R.; Richard, C. W., III; Mollicone, R.;
Seawright, A.; Lowe, J. B.; Oriol, R.; Couillin, P.: The gene encoding
myeloid alpha-3-fucosyltransferase (FUT4) is located between D11S388
and D11S919 on 11q21. Cytogenet. Cell Genet. 66: 104-106, 1994.

6. Tetteroo, P. A. T.; de Heij, H. T.; Van den Eijnden, D. H.; Visser,
F. J.; Schoenmaker, E.; Geurts van Kessel, A. H. M.: A GDP-fucose:(Gal-beta-1-to-4)GlcNAc
alpha-1-to-3-fucosyltransferase activity is correlated with the presence
of human chromosome 11 and the expression of the Le(x), Le(y), and
sialyl-Le(x) antigens in human-mouse cell hybrids. J. Biol. Chem. 262:
15984-15989, 1987.

*FIELD* CD
Victor A. McKusick: 6/29/1988

*FIELD* ED
terry: 06/18/1996
mark: 3/11/1996
terry: 3/6/1996
mark: 4/21/1995
jason: 6/9/1994
terry: 5/13/1994
carol: 4/20/1994
carol: 11/4/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
104240
*FIELD* TI
*104240 ALPHA-3-N-ACETYLNEURAMINYLTRANSFERASE
CMP-N-ACETYLNEURAMINATE:BETA-GALACTOSIDASE ALPHA-2,3-SIALYLTRANSFERASE;;
; CGS23; NANTA3;;
SIALYLTRANSFERASE 4; SIAT4
*FIELD* TX
Tetteroo et al. (1987) stated in an addendum that chromosome 11 codes
for an alpha-3-N-acetylneuraminyltransferase involved in the sialylation
of O-linked Gal-beta-1-to-3Gal-3GalNAc-alpha-to-R chains. The assignment
to chromosome 11 was achieved by study of somatic cell hybrids (de Heij
et al., 1988).

*FIELD* RF
1. de Heij, H. T.; Tetteroo, P. A. T.; Geurts van Kessel, A. H. M.;
Schoenmaker, E.; Visser, F. J.; van den Eijnden, D. H.: Specific
expression of a myeloid-associated CMP-NeuAc:Gal-beta-1-3GalNAc-alpha-R-alpha-2-3-sialyltransferase
and the sialyl-X determinant in myeloid human-mouse cell hybrids containing
human chromosome 11. Cancer Res. 48: 1489-1493, 1988.

2. Tetteroo, P. A. T.; de Heij, H. T.; Van den Eijnden, D. H.; Visser,
F. J.; Schoenmaker, E.; Geurts van Kessel, A. H. M.: A GDP-fucose:(Gal-beta-1-to-4)GlcNAc
alpha-1-to-3-fucosyltransferase activity is correlated with the presence
of human chromosome 11 and the expression of the Le(x), Le(y), and
sialyl-Le(x) antigens in human-mouse cell hybrids. J. Biol. Chem. 262:
15984-15989, 1987.

*FIELD* CD
Victor A. McKusick: 6/29/1988

*FIELD* ED
jason: 6/13/1994
carol: 1/11/1993
supermim: 3/16/1992
carol: 2/27/1992
carol: 6/13/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
104250
*FIELD* TI
*104250 ALPHA-2C-ADRENERGIC RECEPTOR; ADRA2C
ALPHA-2-ADRENERGIC RECEPTOR, RENAL TYPE
*FIELD* TX
Regan et al. (1988) cloned an alpha-2-adrenergic receptor subtype from a
human kidney cDNA library using the gene for the human platelet
alpha-2-adrenergic receptor as a probe. The deduced amino acid sequence
resembled the human platelet alpha-2-adrenergic receptor. The gene for
this receptor was found to be on human chromosome 4, whereas the gene
for platelet receptor (104210) is on chromosome 10. (Curiously, the
location of the gene on chromosome 4 was stated in the abstract but not
documented by results reported in the paper.) In this work, Regan et al.
(1988) achieved expression of the receptor in cultured cells, free of
other adrenergic receptor subtypes; this approach should help in
developing more selective alpha-adrenergic ligands for pharmaceutical
purposes. Hoehe et al. (1989) found close linkage between the G8 (D4S10)
marker of Huntington disease (HD; 143100) and a RFLP of the ADRA2C gene;
thus, the ADRA2C gene is presumably in band 4p16.1.

By studying cosmid clones covering the entire gene, Riess et al. (1994)
found that the ADRA2C gene is intronless. Using 2 (GT)n repeats in close
proximity to the ADRA2C gene, they analyzed its precise location.
Linkage disequilibrium studies of one microsatellite in Huntington
disease families showed strong nonrandom association to the HD mutation,
indicating tight linkage to the HD gene. The investigation of families
carrying recombinant chromosomes, pulsed-field analysis, and genomic
walking mapped the ADRA2C gene adjacent to D4S81, 500 kb proximal to the
HD gene.

*FIELD* RF
1. Hoehe, M.; Berrettini, W.; Leppert, M.; Lalouel, J.-M.; Byerley,
W.; Gershon, E.; White, R.: Genetic mapping of adrenergic receptor
genes.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A143 only, 1989.

2. Regan, J. W.; Kobilka, T. S.; Yang-Feng, T. L.; Caron, M. G.; Lefkowitz,
R. J.; Kobilka, B. K.: Cloning and expression of a human kidney cDNA
for an alpha-2-adrenergic receptor subtype. Proc. Nat. Acad. Sci. 85:
6301-6305, 1988.

3. Riess, O.; Thies, U.; Siedlaczck, I.; Potisek, S.; Graham, R.;
Theilmann, J.; Grimm, T.; Epplen, J. T.; Hayden, M. R.: Precise mapping
of the brain alpha-2-adrenergic receptor gene within chromosome 4p16.
Genomics 19: 298-302, 1994.

*FIELD* CD
Victor A. McKusick: 9/15/1988

*FIELD* ED
carol: 2/10/1994
supermim: 3/16/1992
carol: 3/5/1992
carol: 9/9/1990
supermim: 3/20/1990
carol: 12/14/1989

*RECORD*
*FIELD* NO
104260
*FIELD* TI
*104260 ALPHA-2B-ADRENERGIC RECEPTOR; ADRA2B
ALPHA-2-ADRENERGIC RECEPTOR-LIKE 1;;
ADRA2L1
*FIELD* TX
Regan et al. (1988) indicated that in addition to the platelet
alpha-2-adrenergic receptor (encoded by chromosome 10; 104210) and the
renal form of receptor (encoded by chromosome 4; 104250), a related
protein is coded by chromosome 2. Lomasney et al. (1990) also cloned the
ADRA2B gene. By hybridization with somatic cell hybrids, they showed
that the gene for this receptor is located on chromosome 2. Northern
blot analysis of various rat tissues showed expression in liver and
kidney. Unique pharmacology and tissue localization suggested that this
was a previously unidentified subtype.

*FIELD* RF
1. Lomasney, J. W.; Lorenz, W.; Allen, L. F.; King, K.; Regan, J.
W.; Yang-Feng, T. L.; Caron, M. G.; Lefkowitz, R. J.: Expansion of
the alpha-2-adrenergic receptor family: cloning and characterization
of a human alpha-2-adrenergic receptor subtype, the gene for which
is located on chromosome 2. Proc. Nat. Acad. Sci. 87: 5094-5098,
1990.

2. Regan, J. W.; Kobilka, T. S.; Yang-Feng, T. L.; Caron, M. G.; Lefkowitz,
R. J.; Kobilka, B. K.: Cloning and expression of a human kidney cDNA
for an alpha-2-adrenergic receptor subtype. Proc. Nat. Acad. Sci. 85:
6301-6305, 1988.

*FIELD* CD
Victor A. McKusick: 9/20/1988

*FIELD* ED
jason: 6/16/1994
supermim: 3/16/1992
carol: 3/5/1992
carol: 6/24/1991
carol: 9/9/1990
carol: 8/13/1990

*RECORD*
*FIELD* NO
104290
*FIELD* TI
104290 ALTERNATING HEMIPLEGIA OF CHILDHOOD
*FIELD* TX
Alternating hemiplegia of childhood is a rare syndrome of episodic hemi-
or quadriplegia lasting minutes to days. Most cases are accompanied by
dystonic posturing, choreoathetoid movements, nystagmus, other ocular
motor abnormalities, autonomic disturbances, and progressive cognitive
impairment. Mikati et al. (1992) reported what appeared to be the first
instance of familial occurrence. Inheritance appeared to be autosomal
dominant. The proband, a 9-year-old boy, presented with developmental
retardation, rare tonic-clonic seizures and frequent episodes of flaccid
alternating hemiplegia that had been presumed to represent postictal
paralysis. The hemiplegia spells, which started in his first year, did
not respond to multiple antiepileptics. Between attacks, there was
choreoathetosis and dystonic posturing. A brother, the father, a
paternal uncle, and the maternal grandmother had similar histories of
alternating hemiplegia. Investigations included negative CT and
metabolic studies. EEG and SPECT scanning failed to reveal any
significant slowing or major changes in cortical perfusion during
hemiplegia as compared with nonhemiplegic periods. The karyotype
demonstrated a balanced reciprocal translocation, 46,XY,t(3;9)(p26;q34)
in the patient, in all the affected living relatives, and in 1
apparently unaffected sib. The asymptomatic mother had a normal
karyotype. Both affected sibs were treated with and responded to
flunarizine, with a greater than 70% decrease in attack frequency.

*FIELD* RF
1. Mikati, M. A.; Maguire, H.; Barlow, C. F.; Ozelius, L.; Breakefield,
X. O.; Klauck, S. M.; Korf, B.; O'Tuama, S. L. A.; Dangond, F.: A
syndrome of autosomal dominant alternating hemiplegia: clinical presentation
mimicking intractable epilepsy; chromosomal studies; and physiologic
investigations. Neurology 42: 2251-2257, 1992.

*FIELD* CD
Victor A. McKusick: 3/16/1994

*FIELD* ED
carol: 3/16/1994

*RECORD*
*FIELD* NO
104300
*FIELD* TI
#104300 ALZHEIMER DISEASE; AD
PRESENILE AND SENILE DEMENTIA;;
ALZHEIMER DISEASE, FAMILIAL; FAD
*FIELD* MN

Alzheimer disease is by far the most common cause of dementia.
Clinically, it cannot be distinguished from Pick disease (172700).

The histopathological picture is characterized by neurofibrillary
tangles and amyloid plaques, which contain a novel amyloid protein, beta
protein. It is suggested that the amyloid in Alzheimer disease (and Down
syndrome) is formed from a precursor synthesized in neurons, where it
produces neurofibrillary tangles, and in microglial cells and brain
macrophages from which it is exuded and forms the extracellular amyloid
plaques and vascular amyloid deposits (Gajdusek, 1986).

In a study of 70 kindreds, Farrer et al. (1990) found evidence of 2
categories of families: those with mean age of onset less than 58 years
(early onset form) and those with mean age of onset greater than 58
years (late-onset form).

Early onset FAD is, in some families, due to a mutation of a gene, AD1,
near the centromere on chromosome 21q, that codes for amyloid precursor
protein (104760.0002) (Lawrence et al., 1992). Other early onset
families show linkage to markers on 14q (Van Broeckhoven et al., 1992),
and there may be a second locus on 21 (St. George-Hyslop et al., 1990).

In one representative study (van Dujin et al., 1993) the lifetime risk
(to age 90) of first degree relatives of early onset cases (less than 65
years) was about 40%; higher in females than males (56 vs. 22%) and in
parents than sibs (42 vs. 18%) compared to 14% for controls. The risk at
age 70 was about 13% for first-degree relatives versus about 7% for
controls.

The situation for late-onset AD is even more complex, involving several
loci, and perhaps polygenic and environmental contributions (Haines,
1991). Most, if not all, families with late-onset FAD have mutations on
chromosomes other than 21, particularly AD2 (104310) on chromosome 19
(Pericak-Vance et al., 1991). The recently discovered relationship of
late-onset AD to the apolipoprotein E type 4 allele on chromosome 19 may
clarify the picture (Corder et al., 1993). See 104310. In a series of 42
late-onset families, 20% of affected members had no copies of E4, 47%
had one, and 91% had two copies. Mean ages of onset were 84, 76, and 68
years, respectively.

*FIELD* TX

DESCRIPTION

A number sign (#) is used with this entry because of evidence that
mutations in at least 4 genes can cause Alzheimer disease: AD1 is caused
by mutations in the amyloid precursor gene (104760); AD2 is associated
with the APOE*4 allele on chromosome 19 (107741); AD3 is caused by
mutation in a chromosome 14 gene encoding a 7-transmembrane domain
protein (104311); and AD4 is caused by mutation in a gene on chromosome
1 that encodes a similar 7-transmembrane domain protein (600759). In
addition, evidence has been presented suggesting that mitochondrial DNA
polymorphisms may be risk factors in Alzheimer disease (502500).

Alzheimer disease, the most common cause of dementia, is inherited as an
autosomal dominant trait in some families.

Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and
pathogenetic mechanisms of Alzheimer disease as well as future research
themes in the field.

CLINICAL FEATURES

Alzheimer disease is by far the most common cause of dementia. Terry and
Davies (1980) pointed out that the presenile form (with onset before age
65) is identical to the most common form of senile dementia. Thus, they
recommended the designation senile dementia of the Alzheimer type
(SDAT). Clinically, Alzheimer disease cannot be distinguished from Pick
disease (172700).

Schottky (1932) described presenile dementia in 4 generations. The
diagnosis was confirmed at autopsy in a patient in the fourth
generation. Lowenberg and Waggoner (1934) reported a family with
unusually early onset in the father and 4 of 5 children. Postmortem
findings in 1 case were described. McMenemey et al. (1939) described 4
affected males in 2 generations with pathologic confirmation in one.

Heston et al. (1966) described a family with 19 affected in 4
generations. Dementia was coupled with conspicuous parkinsonism and long
tract signs. In a study of the families of Alzheimer disease patients,
Heston (1977) found an excess of Down syndrome and of myeloproliferative
disorders, e.g., lymphoma and leukemia. Although the mechanism is not
clear, Heston (1977) speculated that a disorder of microtubules
underlies the association. Microtubules are involved in the spatial
orientation of chromosomes and their separation in meiosis and mitosis.
Neurons of Alzheimer patients show a neurofibrillary tangle that is made
up of disordered microtubules. An identical lesion occurs in the neurons
of Down syndrome, at an earlier age than in Alzheimer disease. Leukemia
and accelerated aging are also features of Down syndrome. In a large
multicenter study of first-degree relatives of Alzheimer disease
probands and nondemented spouse controls, Silverman et al. (1994) found
only one case of Down syndrome, a relative of a spouse control. On the
basis of a study of the families of 188 Down syndrome children and 185
controls, Berr et al. (1989) found no evidence of an excess of dementia
cases with insidious onset suggestive of dementia of Alzheimer type in
the families of children with classic trisomy 21. One mechanism whereby
Alzheimer disease might occur in a parent of a Down syndrome patient is
somatic mosaicism in that parent.

Harper et al. (1979) could not confirm that a systemic microtubular
defect exists in Alzheimer disease. Cultured skin fibroblasts showed
normal tubulin networks. Nordenson et al. (1980) found an increased
frequency of acentric fragments in karyotypes from patients with
Alzheimer disease. They viewed this as consistent with defective tubulin
protein leading to erratic function of the spindle mechanism.

Rice et al. (1980) and Ball (1980) reported a kindred in which members
had the clinical features of familial Alzheimer disease but histologic
changes of spongiform encephalopathy of the Creutzfeldt-Jakob type
(123400) at autopsy. The clinical course, with dementia for as long as
10 years, was unusual for CJD. Masters et al. (1981) studied 52 families
and compared them with familial Creutzfeldt-Jakob disease. The age at
death and duration of illness was greater in AD. No maternal effect was
evident in the pattern of autosomal dominant inheritance. In 4 families
with AD, 1 or more members had died from CJD. In 17 other families with
AD, 1 or more members presented with clinical features suggesting CJD.
Although a virus causing an experimental spongiform encephalopathy was
isolated from the brain of 2 cases of familial AD, brain tissue from
most sporadic and familial cases of AD failed to cause disease when
inoculated into nonhuman primates.

In the families of 17 of 68 cases, Heyman et al. (1983) found secondary
cases in parents and sibs. The cumulative incidence in these relatives
was about 14% at age 75. A probable increase in the frequency of Down
syndrome was noted: 3.6 per 1,000 as compared with an expected rate of
1.3 per 1,000. A history of thyroid disease was unusually frequent (9 of
46; 19.6%) in the female probands. No excess of hematologic malignancy
was found in relatives. Parental age at time of birth of the probands
did not differ from the normal. Corkin et al. (1983) also could find no
difference in parental age from that in controls.

Joachim et al. (1989) presented evidence suggesting that Alzheimer
disease is not restricted to the brain but is a widespread systemic
disorder with accumulation of amyloid beta protein in nonneuronal
tissues.

In a study of 70 kindreds containing 541 affected and 1,066 unaffected
offspring of demented parents, Farrer et al. (1990) found evidence of 2
categories of families: those with mean age of onset less than 58 years
(early-onset form) and those with mean age of onset greater than 58
years (late-onset form). At-risk offspring in early-onset families had
an estimated lifetime risk for dementia of 53%, leading Farrer et al.
(1990) to suggest autosomal dominant inheritance. The lifetime risk in
late-onset families was 86%. Farrer et al. (1990) concluded that this
form may have at least 2 causes: autosomal dominant inheritance in some
families and other genetic or shared environmental factors in other
families. Farrer et al. (1990) pointed out that some early-onset
families show linkage to markers on chromosome 21, whereas there is
evidence against linkage to the same group of markers in late-onset
families. By the criteria of the analysis, the Volga Germans (Bird et
al., 1988), who are among the unlinked families, were classified as the
upper boundary of the early-onset group.

In a complex segregation analysis on 232 nuclear families ascertained
through a single proband who was referred for diagnostic evaluation of
memory disorder, Farrer et al. (1991) concluded that susceptibility to
AD is determined, in part, by a major autosomal dominant allele with an
additional multifactorial component. The frequency of the AD
susceptibility allele is estimated to be 0.038, but the major locus was
thought to account for only 24% of the 'transmission variance,'
indicating a substantial role for other genetic and nongenetic
mechanisms.

Silverman et al. (1994) used a standardized family history assessment to
study first-degree relatives of Alzheimer disease probands and
nondemented spouse controls. First-degree relatives of the probands with
Alzheimer disease had a significantly greater cumulative risk of
Alzheimer disease (24.8%) than did the relatives of spouse controls
(15.2%). The cumulative risk for the disorder among female relatives of
probands was significantly greater than that among male relatives.

BIOCHEMICAL FEATURES

Glenner and Wong (1984) identified a novel amyloid protein, called beta
protein (APP; 104760), in Alzheimer disease. The 4.2-kD polypeptide was
called beta protein because of its partial beta-pleated sheet structure.
It was identified in both amyloid plaque core and in cerebral vascular
amyloid; both have an identical 28-amino acid sequence. A cDNA for the
beta protein suggested that it is derived from a larger protein
expressed in a variety of tissues (Tanzi et al., 1987).

Kang et al. (1987) isolated and sequenced an apparently full-length cDNA
clone coding for the A4 polypeptide (the designation they used for the
major protein subunit of the amyloid fibril of tangles, plaques, and
blood vessel deposits in AD and Down syndrome). The predicted precursor
consisted of 695 residues and contained features characteristic of
glycosylated cell-surface receptors.

Abraham et al. (1988) identified one of the components of the amyloid
deposits seen in Alzheimer disease as the serine protease inhibitor
alpha-1-antichymotrypsin. Carrell (1988) speculated that plaque
formation in Alzheimer disease is a consequence of proteolysis of the
precursor protein; self-aggregation of the cleaved A4 peptides explains
the precipitated amyloid, while release of a trophic inhibitory domain
explains the interwoven neuritic development. Zubenko et al. (1987)
described a biophysical alteration of platelet membranes in Alzheimer
disease. They concluded that increased platelet membrane fluidity
identifies a subgroup of patients with early age of symptomatic onset
and rapidly progressive course.

Zubenko and Ferrell (1988) described monozygotic twins concordant for
probable Alzheimer disease and for increased platelet membrane fluid.
See 173560. Birchall and Chappell (1988) suggested that individual
vulnerability to aluminum might depend on genetic factors influencing
intake, transport or excretion, and might be a mechanism for familial
Alzheimer disease. The inositol phosphate system may be particularly
vulnerable.

Ponte et al. (1988), Tanzi et al. (1988), and Kitaguchi et al. (1988)
showed that the amyloid protein precursor contains a domain very similar
to the Kunitz family of serine protease inhibitors. All 3 groups found
the variable presence of a domain of 56 residues interpolated at residue
289, that is, in the proposed extracellular portion of the amyloid
precursor protein. The best-studied member of the protease inhibitor
family is bovine pancreatic trypsin inhibitor, also called aprotinin.
The newly found amyloid protein sequence was 50% identical to aprotinin
and also to the second inhibitory domain of the human plasma protein,
inter-alpha-trypsin inhibitor.

Yan et al. (1996) reported that the AGER protein (600214), called RAGE
(receptor for advanced glycation end products) by them, is an important
receptor for the amyloid beta peptide and that expression of this
receptor increases in Alzheimer disease. They noted that expression of
RAGE is particularly increased in neurons close to deposits of amyloid
beta peptide and to neurofibrillary tangles.

OTHER FEATURES

Gajdusek (1986) suggested that the amyloid in Alzheimer disease and Down
syndrome is formed from a precursor synthesized in neurons as well as in
microglial cells and brain macrophages: that synthesized in neurons
produces neurofibrillary tangles, and that synthesized in microglial
cells and brain macrophages is exuded from the cell and forms the
extracellular amyloid plaques and vascular amyloid deposits. Dying
neurons may also contribute to extracellular deposits.

Wolozin et al. (1988) performed immunocytochemical studies of cerebral
cortex tissue sections from normal human fetal and neonatal brain, and
of brain tissue from individuals with Down syndrome and patients with
Alzheimer disease. They used the monoclonal antibody ALZ-50, which
recognizes a 68-kD protein. The authors reported that ALZ-50-reactive
neurons are found in normal fetal and neonatal human brain as well as in
brain tissue from neonates with Down syndrome. The number of reactive
neurons decreased sharply after age 2 years, but reappeared in older
individuals with Down syndrome and in patients with Alzheimer disease.

INHERITANCE

From an extensive study in Sweden, Sjogren et al. (1952) suggested that
whereas Pick disease may be dominant with important modifier genes,
Alzheimer disease is multifactorial. However, a dominant pattern of
inheritance, more common in presenile cases than in older patients, is
well documented and accounts for about one-third of all cases of
Alzheimer disease.

Masters et al. (1981) found no maternal effect in the autosomal dominant
inheritance pattern of 52 families.

In 7 of 21 families, Powell and Folstein (1984) found evidence of
3-generation transmission. Paternal age was raised, they concluded, in
the case of new mutation cases. Age of onset varied from 25 to 85 years.
Breitner and Folstein (1984) suggested that most cases of Alzheimer
disease are familial. Fitch et al. (1988) found a familial incidence of
43%. They could detect no clinical differences between the familial and
sporadic cases. In one-third of the familial cases, the gene was not
expressed until after age 70. In a continuing longitudinal study of
family members of probands with Alzheimer disease, Breitner et al.
(1988) found that the cumulative incidence of Alzheimer disease among
relatives was 49% by age 87. The risk was similar among parents and
siblings and did not differ significantly between relatives of
presenile-onset versus senile-onset probands.

Rao et al. (1996) carried out a complex segregation analysis in 636
nuclear families of consecutively ascertained and rigorously diagnosed
probands in the Multi-Institutional Research in Alzheimer Genetic
Epidemiology study in order to derive models of disease transmission
that account for the influences of the APOE genotype of the proband and
gender. In the total group of families, models postulating sporadic
occurrence, no major gene effect, random environmental transmission, and
mendelian inheritance were rejected. Transmission of AD in families of
probands with at least 1 APOE4 allele best fitted a dominant model.
Moreover, single gene inheritance best explained clustering of the
disorder in families of probands lacking APOE4, but a more complex
genetic model or multiple genetic models may ultimately account for risk
in this group of families. The results suggested to Rao et al. (1996)
that susceptibility to AD differs between men and women regardless of
the proband's APOE status. Assuming a dominant model, AD appeared to be
completely penetrant in women, whereas only 62% to 65% of men with
predisposing genotypes developed AD. However, parameter estimates from
the arbitrary major gene model suggested that AD is expressed dominantly
in women and additively in men. These observations, taken together with
epidemiologic data, were considered consistent with the hypothesis of an
interaction between genes and other biologic factors affecting disease
susceptibility.

CYTOGENETICS

Percy et al. (1991) described 2 sisters thought to have Alzheimer
disease of late onset who also had an unusual chromosome 22-derived
marker with a greatly elongated short arm containing 2 well-separated
nucleolus organizer regions. Eleven of 24 of their biological relatives
were also found to have the marker. In the sisters' generation and in
the previous generation, 7 persons with Alzheimer disease had died. The
average age at onset of dementia was 65.8 years and the average age at
death, 74.9 years.

MAPPING

Wheelan and Race (1959) studied a family in which the mother and 5 of 10
children were affected. Possible linkage with the MNS locus was found.

In the large kindred reported by Nee et al. (1983), Weitkamp et al.
(1983) studied the transmission of HLA and Gm types and concluded that
'genes in the HLA region of chromosome 6 and perhaps also in the Gm
region of chromosome 14 are determinants of susceptibility.' The
association between immunoglobulins and the amyloid in the senile plaque
of AD was thought to be significant in this connection. The peak lod
score with Gm was 1.37 (at theta = 0.05).

Nee et al. (1983) reported the most extensively affected kindred, with
51 affected persons in 8 generations. No preponderance of affected
females and no increased incidence of Down syndrome or hematologic
malignancy were found.

Nerl et al. (1984) reported an increase in the frequency of the C4B
(120820) allele C4B2 in patients with Alzheimer disease, but Eikelenboom
et al. (1988) failed to find a significant association between C4B2
allelic frequency and AD.

Kang et al. (1987) showed by somatic cell hybrids that the gene for A4
peptide is localized to chromosome 21. They commented on the fact that
this protein shows similarities to the prion protein (PRNP; 176640)
found in the amyloid of transmissible spongiform encephalopathies (Oesch
et al., 1985). Membrane-spanning domains of both proteins may share an
amyloid-forming or amyloid-inducing potential.

St. George-Hyslop et al. (1987) studied 4 extensive kindreds with many
members affected with familial Alzheimer disease (FAD). They found
linkage to DNA markers on chromosome 21. The markers in band 21q22,
critical to the development of Down syndrome, showed negative lod
scores. Notably, the marker B21S58, which is tightly linked to SOD1
(147450), was not tightly linked. The linked markers were found to lie
on the centromere side of q22 in the region 21q11.2-21q21. Using a RFLP
of SOD1 in the study of a large family with Alzheimer disease, David et
al. (1988) concluded that SOD1 and AD are not closely linked. Goldgaber
et al. (1987) used the first 20 of the 28 amino acids in the sequence to
prepare an oligonucleotide probe for isolation of cDNA. They found that
a 3.5-kb mRNA was detectable in mammalian brains and human thymus. The
gene was found to be highly conserved in evolution and was mapped to
chromosome 21 by somatic cell hybridization.

The type of Alzheimer disease coded by chromosome 21 may be an
early-onset type; families with late onset are said not to show linkage
to chromosome 21 markers (HGM9) (Cheng et al., 1988).

Using a RFLP of the A4-amyloid gene, Van Broeckhoven et al. (1987) found
recombinants in 2 Alzheimer disease families. Two of their families were
of early onset: one with 36 cases in 6 generations of which 10 had been
histopathologically confirmed (mean age of onset, 33 years), and the
second with 22 cases in 5 generations of which 4 had been
histopathologically confirmed (mean age of onset, 34 years). All lod
scores were negative in these 2 families. In 1 of 5 families of late
onset, positive lod scores were observed. These data demonstrated that
the gene for plaque core A4-amyloid cannot be the locus of the defect
causing Alzheimer disease in these families. Tanzi et al. (1987) also
found recombination between Alzheimer disease and the amyloid protein
and came to the same conclusion.

Haines et al. (1987), who studied 4 large families with FAD, found
linkage with 2 DNA markers on chromosome 21 that had previously been
shown to be linked to each other at a distance of 8 cM. However, the
pair-wise linkage analysis showed a lod score of 2.37 at theta = 0.08
for one and 2.32 at theta = 0.00 for the other. The use of multipoint
analysis provided stronger evidence for linkage with a peak score of
4.25.

Bird et al. (1988) described 7 families with autopsy-confirmed AD, all
being descendants of a group of immigrants known as the Volga Germans,
who came to the United States between 1870 and 1920. Their ancestors had
moved from Germany to the southern Volga region of Russia in the 1760s.
All 5 were descendants of persons who originally lived in 2 small
adjacent Volga German villages and shared several surnames known to have
been present in the census records of those villages. There are more
than 300,000 American descendants of the Volga Germans. In a further
study of the 7 Volga German kindreds and in 8 other kindreds, all with
autopsy-proven AD (except for 1 of the German Volga families),
Schellenberg et al. (1988) could demonstrate no linkage to chromosome 21
markers. Other researchers have been unable to demonstrate linkage
between late-onset Alzheimer disease and chromosome 21 markers, but the
disorder in the families studied by Schellenberg et al. (1988) was of
the early-onset type. The families studied by St. George-Hyslop et al.
(1987) in which linkage with chromosome 21 markers was found had the
early-onset type. The data strongly suggest that there is at least 1
other genetically distinct form of Alzheimer disease. (Rogaev et al.
(1995) demonstrated that the mutation in the Volga Germans is located in
the presenilin-2 gene encoded by chromosome 1 (600759.0001).)

By the study of linkage to DNA markers, Van Broeckhoven et al. (1988)
concluded that the gene for early-onset familial Alzheimer disease is
located close to the centromere of chromosome 21. Pulst et al. (1989)
used a panel of aneuploid cell lines containing various regions of human
chromosome 21 to map the physical order of DNA probes linked to the FAD
locus. Van Camp et al. (1989) described the isolation of 35 chromosome
21 specific DNA probes for analysis in Alzheimer disease and Down
syndrome. Ross et al. (1989) described the isolation of cDNAs from brain
and spinal cord, mapping to chromosome 21, for investigation in
Alzheimer disease. Pericak-Vance et al. (1988) found no linkage to
chromosome 21 specific probes in studies of 13 families with FAD. The
same group (Pericak-Vance et al., 1989, 1990) presented evidence for
linkage to 2 markers on chromosome 19. When analysis was limited to the
affecteds only, a lod score of 2.5 at theta = 0 was obtained for linkage
with BCL3 (109560). Pericak-Vance et al. (1991) found evidence of both
chromosome 19 linkage in their late-onset FAD families and chromosome 21
linkage in their early-onset FAD families. When only affected persons
were used in the analysis, a high lod score was obtained also with
ATP1A3 (182350), which maps to 19q12-q13.2. Haines (1991) gave a review.

Using the exclusion mapping method of Edwards (1987) and the
affected-pedigree-member method (APM) of Weeks and Lange (1988), Roses
et al. (1989) found some suggestion of implication of chromosome 19;
predominantly late-onset families were studied.

Van Broeckhoven et al. (1989) described linkage analysis of 2 families
with Alzheimer disease by use of chromosome 21 DNA markers. With probe
D21S13, they found a lod score of 1.52 at theta = 0.09 in 1 family.
Further studies analyzing D21S13 with D21S16 and D21S1/S11, 2 markers
that had previously been linked to Alzheimer disease, found D21S13 to be
tightly linked to D21S16 with a peak lod score of 6.24 at theta = 0.
Pulsed field gel electrophoresis confirmed that the loci are separated
by a distance of approximately 400 kb.

Using pulsed field gel electrophoresis to construct a physical map of
the region of chromosome 21 around the FAD locus, Owen et al. (1989)
suggested the following order:
cen--D21S16--D21S48--D21S13--D21S46--(D21S52, D21S4)--(D21S1, D21S11).
Using genetic linkage analysis, Goate et al. (1989) found a peak lod
score of 3.3 between the FAD locus and locus D21S16.

Pulst et al. (1991) excluded the proximal portion of the long arm of
chromosome 21 as the site of the AD gene in 1 large kindred.

Because of the conflicting findings concerning linkage to chromosome 21,
St. George-Hyslop and many other members of the FAD collaborative study
group undertook a study of 5 polymorphic chromosome 21 markers in a
large unselected series of pedigrees with FAD. The results seemed to
indicate that, in many families at least, early-onset Alzheimer disease
is indeed due to a mutation on chromosome 21, whereas the late-onset
form has other causes. From the work of Goate et al. (1991), it seems
clear that 1 form of early-onset AD is caused by mutation in the gene
for amyloid precursor protein (104760.0002). The families with Alzheimer
disease mapping to chromosome 21 represent this form. Other families
with early-onset AD and probably all families with late-onset AD have
mutations on chromosomes other than chromosome 21.

Lawrence et al. (1992) reviewed the reported data on multiplex Alzheimer
pedigrees for which lod scores had been reported; the AD1 locus which
mapped to the site of the APP locus (104760) on 21q accounted for 63 +/-
11% of these pedigrees. The AD1/APP locus was placed at approximately
27.7 Mb from pter, corresponding to genetic intervals of 10.9 cM in
males and 33.9 cM in females, flanked proximally by D21S8 and distally
by D21S111. Since a much smaller proportion of pedigrees than 63% have
mutations in the cDNA for beta-amyloid, which corresponds to exons 16
and 17 of APP, it is likely that the AD1 locus spans controlling
elements near those exons. There was no evidence in this analysis for a
second locus on chromosome 21.

MOLECULAR GENETICS

Delabar et al. (1986) analyzed DNA from 4 patients with Alzheimer
disease and estimated the state of markers on chromosome 21. In all 4
cases, duplication of the ETS2 locus (164740) was found, whereas SOD1
(147450) was normal. These studies were undertaken because the patients
had a phenotype of trisomy 21 but were found to have a normal karyotype;
by chemical investigations and DNA analyses, they showed partial trisomy
due to duplication of a short segment of chromosome 21, located at the
interface between 21q21 and 21q22.1 and carrying the SOD1 and ETS2
genes.

Blanquet et al. (1987) found by molecular genetic methods that the
Alzheimer amyloid protein gene and the ETS2 oncogene are distally
located in the normal individual; surprisingly, 2 hybridization peaks
were observed for ETS2 in the Alzheimer patient, 1 at the normal site of
the oncogene and 1 at the site of the amyloid protein. Blanquet et al.
(1987) interpreted these results as indicating that Alzheimer disease is
associated with a complex rearrangement within chromosome 21, by which 2
distantly related genes come to lie in the vicinity of each other.

Overexpression of the gene in brain tissue from fetuses with Down
syndrome is explained by dosage effect since the locus encoding the beta
protein maps to chromosome 21. Regional localization of the gene by
somatic cell hybridization and with linkage to DNA markers placed it in
the vicinity of the genetic defect causing the inherited form of
Alzheimer disease. This was done with somatic cell hybridization and
with linkage to DNA markers (Tanzi et al., 1987). The 28-amino acid
sequence has a variation at position 11: glutamine in the case of the
cerebral vascular amyloid of Alzheimer disease, but glutamic acid in the
case of cerebral vascular amyloid of Down syndrome and the amyloid
plaque core of both disorders (Tanzi et al., 1987).

St. George-Hyslop et al. (1987), Tanzi et al. (1987), and Podlisny et
al. (1987) could demonstrate no evidence of duplication of chromosome 21
genes, and the amyloid beta protein gene specifically, in patients with
either familial or sporadic Alzheimer disease; thus, some other
mechanism for the brain-specific deposition of the amyloid beta protein
must be sought. Warren et al. (1987) and Murdoch et al. (1988) likewise
found no duplication of the gene in autopsy-proved cases of Alzheimer
disease.

ANIMAL MODEL

Selkoe et al. (1987) used a panel of antibodies against amyloid fibrils
and their constituent vascular amyloid in 5 other species of aged
mammals, including monkey, orangutan, polar bear, and dog. Antibodies to
the 28-amino acid peptide recognized the cortical and microvascular
amyloid of all the aged mammals examined (Selkoe et al., 1987).

Cheng et al. (1988) described the comparative mapping of DNA markers in
the region of familial Alzheimer disease on human chromosome 21 and
mouse chromosome 16. The linkage group shared by mouse chromosome 16 and
human chromosome 21 includes both the Alzheimer amyloid beta precursor
protein and markers linked to familial Alzheimer disease. The linkage
group of 6 loci extends from anonymous DNA marker D21S52 to ETS2, and
spans 39% recombination in man but only 6.4% recombination in the mouse.
A break in synteny occurs distal to ETS2, and the homolog of human
marker D21S56 maps to mouse chromosome 17.

To test whether the amyloid beta peptide in Alzheimer disease is
neurotoxic, LaFerla et al. (1995) introduced a transgene, which included
1.8 kb of 5-prime flanking DNA from the mouse neurofilament-light (NF-L)
gene, into mice to restrict expression of the peptide coding region of
the APP gene to neuronal cells. In situ hybridization and immunostaining
with amyloid beta antibodies detected extensive transgene expression and
peptide in cerebral cortex and hippocampus, and limited expression in
other areas of the brains of the transgenic mice. (Both the cerebral
cortex and hippocampus are severely affected in Alzheimer disease.) The
study showed that expression of amyloid beta is sufficient to induce a
progressive series of changes within the brains of transgenic mice,
initiating with neurodegeneration and apoptosis, followed by the
activation of secondary events such as astrogliosis, and ultimately
ending with spongiosis. Accompanying the cell death was the appearance
of clinical features including seizures and premature death, both of
which have been described in Alzheimer disease.

HISTORY

Bogerts (1993) provided a biographic sketch and photograph of Alois
Alzheimer (1864-1915). Alzheimer was a neuropathologist, clinical
psychiatrist, and chairman of psychiatry. He always considered himself a
psychiatrist. He worked with Nissl in the application of the Nissl
staining techniques for the study of the cerebral cortex in psychosis.
Alzheimer discovered the disorder that bears his name in 1906 when he
reported on 'a strange disease of the cerebral cortex' in a 56-year-old
with presenile dementia who displayed diffuse cortical atrophy, nerve
cell loss, plaques, and tangles. He was then working in Munich in the
department of Kraepelin, who coined the term 'Alzheimer's disease.'

In light of the findings of Tomita et al. (1997) concerning PS2 mutation
and altered metabolism of APP (summarized in 600759.0001), Hardy (1997)
reviewed the evidence that AD, or as he put it, the Alzheimer family of
diseases, has many etiologies but one pathogenesis. Mutations in all
known pathogenic genes have in common the fact that they alter
processing of APP, thus lending strong support to the 'amyloid cascade
hypothesis.' Hardy (1997) commented that 'genetics and molecular biology
now are revealing credible drug targets' for effective therapy.

O'Brien (1996) reported that the file on the case of Auguste D., who at
the age of 51 came under the care of Alois Alzheimer, had come to light;
it had been missing since 1910. Auguste D. came under the care of
Alzheimer at a Frankfurt hospital in 1901. The eponym 'Alzheimer
disease' was popularized by Emil Kraepelin, director of the Munich
psychiatric clinic where Alzheimer moved in 1903. On the basis of the
record some questions of whether Auguste D. had the disorder now called
Alzheimer disease were raised; namely, that autopsy findings included
arteriosclerosis noted in the smaller cerebral blood vessels. O'Brien
(1996) noted that today this is a criterion for exclusion from a
diagnosis of AD.

*FIELD* SA
Ball et al. (1985); Cohen et al. (1988); Cook and Austin (1978); Cook
et al. (1979); Corder et al. (1993); Goate et al. (1989); Goudsmit
et al. (1981); Grundke-Iqbal et al. (1979); Heston and Mastri (1977);
Heston and White (1978); McKhann et al. (1984); Prusiner  (1984);
St. George-Hyslop et al. (1990); St. George-Hyslop et al. (1987);
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95. Ward, B. E.; Cook, R. H.; Robinson, A.; Austin, J. H.: Increased
aneuploidy in Alzheimer disease. Am. J. Hum. Genet. 3: 137-144,
1979.

96. Warren, A. C.; Robakis, N. K.; Ramakrishna, N.; Koo, E. H.; Ross,
C. A.; Folstein, M. F.; Price, D. L.; Antonarakis, S. E.: Beta-amyloid
gene is not present in three copies in autopsy-validated Alzheimer's
disease. Genomics 1: 307-312, 1987.

97. Weeks, D. E.; Lange, K.: The affected-pedigree-member method
of linkage analysis. Am. J. Hum. Genet. 42: 315-326, 1988.

98. Weitkamp, L. R.; Nee, L.; Keats, B.; Polinsky, R. J.; Guttormsen,
S.: Alzheimer disease: evidence for susceptibility loci on chromosomes
6 and 14. Am. J. Hum. Genet. 35: 443-453, 1983.

99. Wheelan, L.; Race, R. R.: Familial Alzheimer's disease: note
on the linkage data. Ann. Hum. Genet. 23: 300-310, 1959.

100. White, B. J.; Crandall, C.; Goudsmit, J.; Morrow, C. H.; Alling,
D. W.; Gajdusek, D. C.; Tijio, J.-H.: Cytogenetic studies of familial
and sporadic Alzheimer disease. Am. J. Med. Genet. 10: 77-89, 1981.

101. Wolozin, B.; Scicutella, A.; Davies, P.: Reexpression of a developmentally
regulated antigen in Down syndrome and Alzheimer disease. Proc. Nat.
Acad. Sci. 85: 6202-6206, 1988.

102. Wolstenholme, G. E. W.; O'Connor, M.: Alzheimer's Disease and
Related Conditions (Ciba Foundation Symposium).  London: J. and A.
Churchill (pub.)  1970.

103. Yan, S. D.; Chen, X.; Fu, J.; Chen, M.; Zhu, H.; Roher, A.; Slattery,
T.; Zhao, L.; Nagashima, M.; Morser, J.; Migheli, A.; Nawroth, P.;
Stern, D.; Schmidt, A. M.: RAGE and amyloid-beta peptide neurotoxicity
in Alzheimer's disease. Nature 382: 685-691, 1996.

104. Zubenko, G. S.; Cohen, B. M.; Boller, F.; Malinakova, I.; Keefe,
N.; Chojnacki, B.: Platelet membrane abnormality in Alzheimer's disease. Ann.
Neurol. 22: 237-244, 1987.

105. Zubenko, G. S.; Ferrell, R. E.: Monozygotic twins concordant
for probable Alzheimer disease and increased platelet membrane fluidity. Am.
J. Med. Genet. 29: 431-436, 1988.

*FIELD* CS

Neuro:
   Presenile and senile dementia;
   Parkinsonism;
   Long tract signs

Misc:
   ? Excess of Down syndrome and myeloproliferative disorders

Lab:
   Neurofibrillary tangles composed of disordered microtubules in neurons;
   Some early-onset families due to mutation in the gene for amyloid
   precursor protein (104760.0002) on chromosome 21

Inheritance:
   Autosomal dominant allele with additional multifactorial component
   in late-onset cases

*FIELD* CN
Victor A. McKusick - updated: 04/17/1997
Moyra Smith - updated: 8/21/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 04/17/1997
terry: 4/14/1997
jamie: 2/5/1997
jamie: 11/14/1996
mark: 11/12/1996
terry: 11/8/1996
terry: 9/25/1996
mark: 8/21/1996
terry: 8/20/1996
mark: 6/20/1996
mark: 2/15/1996
mark: 8/31/1995
carol: 2/6/1995
pfoster: 1/17/1995
mimadm: 6/26/1994
jason: 6/16/1994
warfield: 4/6/1994

*RECORD*
*FIELD* NO
104310
*FIELD* TI
#104310 ALZHEIMER DISEASE-2; AD2
*FIELD* TX
A number sign (#) is used with this entry because of uncertainty as to
whether linkage to markers on proximal chromosome 19q in some families
reflects merely association with apolipoprotein E4 or mutation at a
locus separate from the APOE locus (107741).

At the time that linkage studies indicated mapping of Alzheimer disease
to proximal 21q (104300), it became clear that some families are not
linked to chromosome 21 markers. Early on, these appeared to represent
mainly families with late onset of disease. Subsequently, when the
chromosome 21-linked form of Alzheimer disease was shown to be due to
mutation in the APP gene (104760), the nonlinkage in some families was
taken to indicate that a mutation in one or more other proteins can
cause Alzheimer disease.

Pericak-Vance et al. (1988) found no linkage to chromosome 21 specific
probes in studies of 13 families with FAD. The same group (Pericak-Vance
et al., 1989, 1990) presented evidence for linkage to 2 markers on
chromosome 19. When analysis was limited to the affecteds only, a lod
score of 2.5 at theta = 0 was obtained for linkage with BCL3 (109560).
Pericak-Vance et al. (1991) found evidence of both chromosome 19 linkage
in their late-onset FAD families and chromosome 21 linkage in their
early-onset FAD families. When only affected persons were used in the
analysis, a high lod score was obtained also with ATP1A3 (182350), which
maps to 19q12-q13.2. In a study of 48 kindreds with multiple cases of
Alzheimer disease in 2 or more generations and with family age-at-onset
means ranging from 41 to 83 years, Schellenberg et al. (1991) found
negative lod scores for those families with onset after age 60, those
families with onset before age 60, and for Volga German families with
mean age of onset of 56. The early-onset non-Volga German families with
onset before age 60 had low positive lod scores. The data were taken to
indicate that it is highly unlikely that a chromosome 21 gene is
responsible for late-onset FAD and at least some forms of early-onset
FAD represented by the Volga German kindreds.

A gene for late-onset familial Alzheimer disease maps to the same region
as the gene for apolipoprotein E. APOE has 3 alleles: APOE*E2, APOE*E3,
and APOE*E4. Corder et al. (1993) found that the risk for late-onset AD
increased from 20 to 90% and mean age of onset decreased from 84 to 68
years with increasing number of APOE*E4 alleles in 42 families with
late-onset AD. Onset was early in 4 other families tested; 2 had
chromosome 21 APP mutations and 2 showed linkage to chromosome 14, thus
representing AD1 and AD3 (104311), respectively. The frequency of
APOE*E4 was not elevated in these families or in 12 other early-onset
families. Homozygosity for APOE*E4 was virtually sufficient alone to
cause AD by age 80.

*FIELD* RF
1. Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel,
D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.;
Pericak-Vance, M. A.: Gene dose of apolipoprotein E type 4 allele
and the risk of Alzheimer's disease in late onset families. Science 261:
921-923, 1993.

2. Pericak-Vance, M. A.; Bebout, J. L.; Gaskell, P. C., Jr.; Yamaoka,
L. H.; Hung, W.-Y.; Alberts, M. J.; Walker, A. P.; Bartlett, R. J.;
Haynes, C. A.; Welsh, K. A.; Earl, N. L.; Heyman, A.; Clark, C. M.;
Roses, A. D.: Linkage studies in familial Alzheimer disease: evidence
for chromosome 19 linkage. Am. J. Hum. Genet. 48: 1034-1050, 1991.

3. Pericak-Vance, M. A.; Bebout, J. L.; Haynes, C. A.; Gaskell, P.
C., Jr.; Yamaoka, L. A.; Hung, W.-Y.; Alberts, M. J.; Walker, A. P.;
Bartlett, R. J.; Welsh, K. A.; Earl, N. L.; Heyman, A.; Clark, C.
M.; Roses, A. D.: Linkage studies in familial Alzheimer's disease:
evidence for chromosome 19 linkage.  (Abstract) Am. J. Hum. Genet. 47
(suppl.): A194 only, 1990.

4. Pericak-Vance, M. A.; Yamaoka, L. H.; Bebout, J.; Gaskell, P. C.;
Clark, C.; Haynes, C. S.; Earl, N.; Welch, K.; Hung, W.-Y.; Alberts,
M. J.; Heyman, A.; Roses, A. D.: Linkage studies in familial Alzheimer's
disease.  (Abstract) Cytogenet. Cell Genet. 51: 1058-1059, 1989.

5. Pericak-Vance, M. A.; Yamaoka, L. H.; Haynes, C. S.; Speer, M.
C.; Haines, J. L.; Gaskell, P. C.; Hung, W.-Y.; Clark, C. M.; Heyman,
A. L.; Trofatter, J. A.; Eisenmenger, J. P.; Gilbert, J. R.; Lee,
J. E.; Alberts, M. J.; Dawson, D. V.; Bartlett, R. J.; Earl, N. L.;
Siddique, T.; Vance, J. M.; Conneally, P. M.; Roses, A. D.: Genetic
linkage studies in Alzheimer's disease families. Exp. Neurol. 102:
271-279, 1988.

6. Schellenberg, G. D.; Pericak-Vance, M. A.; Wijsman, E. M.; Moore,
D. K.; Gaskell, P. C., Jr.; Yamaoka, L. A.; Bebout, J. L.; Anderson,
L.; Welsh, K. A.; Clark, C. M.; Martin, G. M.; Roses, A. D.; Bird,
T. D.: Linkage analysis of familial Alzheimer disease, using chromosome
21 markers. Am. J. Hum. Genet. 48: 563-583, 1991.

*FIELD* CS

Neuro:
   Presenile and senile dementia;
   Parkinsonism;
   Long tract signs

Misc:
   Late onset

Lab:
   Neurofibrillary tangles composed of disordered microtubules in neurons

Inheritance:
   Autosomal dominant allele (19q) with additional multifactorial component
   in late-onset cases

*FIELD* CD
Victor A. McKusick: 11/4/1988

*FIELD* ED
carol: 4/6/1994
mimadm: 3/11/1994
carol: 10/4/1993
carol: 9/28/1993
carol: 11/4/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
104311
*FIELD* TI
*104311 ALZHEIMER DISEASE, FAMILIAL, TYPE 3; AD3
PRESENILIN-1; PS1;;
S182
ALZHEIMER DISEASE, EARLY-ONSET, INCLUDED
*FIELD* TX
St. George-Hyslop et al. (1992), Van Broeckhoven et al. (1992), and
Mullan et al. (1992) presented evidence of location of a mutation
responsible for early-onset familial Alzheimer disease on 14q. Mullan et
al. (1992) placed the gene proximal to that for alpha-1-antichymotrypsin
(107280), thus excluding AACT, which is a component of plaque cores and
a protease inhibitor, as a possible candidate gene for AD.

In a subset of early-onset familial Alzheimer disease (FAD), mutations
in the amyloid precursor protein (104760) have been identified; for
example, 3 have been found in codon 717. However, the majority of
early-onset FAD families do not show linkage to, or appear to have
mutations in, the APP gene. There may be an additional FAD locus on
chromosome 21 separate from the APP locus (St. George-Hyslop et al.,
1987; St. George-Hyslop et al., 1990; Tanzi et al., 1991), and a locus
on chromosome 19 seemed quite definite (Pericak-Vance et al., 1991;
Schellenberg et al., 1992). Schellenberg et al. (1992) indicated the
existence of yet another locus for early-onset Alzheimer disease on
chromosome 14; a total lod score of 9.15 at theta = 0.01 was obtained
with the marker D14S43 located at 14q24.3. A single early-onset family
yielded a lod score of 4.89 (theta = 0.0). When no assumptions were made
about age-dependent penetrance, significant results were still obtained
(maximum lod = 5.94 at theta = 0.0) despite the loss of power.

Campion et al. (1995) studied a large pedigree that included 34 subjects
with early onset progressive dementia with mean age of onset at 46 plus
or minus 3.5 years and mean age at death at 52.6. Myoclonus and
extrapyramidal signs were common; seizures were present in all affected
subjects. There were neuropathologic changes typical of Alzheimer
disease in the 2 brains examined. Campion et al. (1995) observed A lod
score of 5.48 at a recombination fraction of theta = 0.0 with the
genetic marker D14S43, confirming the location of the responsible gene
on chromosome 14q24.3.

Results for the Volga German families were either negative or
nonsignificant for markers in this region of chromosome 14. In 2 large
early-onset FAD pedigrees, Nechiporuk et al. (1993) found tight linkage
to D14S43 and D14S53. Schellenberg et al. (1993) explored the role of
chromosome 14 in late-onset FAD. They studied 49 families with a mean
age of onset of 60 years or more. No evidence of linkage was obtained,
and strong evidence against linkage to chromosome 3 markers was found.
Evidence of linkage to D14S52 was found for a subgroup of families of
intermediate age of onset, namely, older than 60 but less than 70 years
of age. They concluded that the chromosome 14 locus was not responsible
for Alzheimer disease in most late-onset FAD kindreds.

On the basis of a novel gene cotransfer technique in hybrid cells,
Ettinger et al. (1994) proposed that familial Alzheimer disease is
associated with chromosomal breakage at nonrandom sites. They found
cotransfer of HPRT and G6PD markers substantially decreased when
fibroblasts from individuals of 3 different FAD families were used as
opposed to those from age-matched, young controls. They did not specify
what linkage, if any, had been determined in these donors. They
suggested that trifunctional protein C(1)-THF synthase (172460), which
is required for oxidative conversion of 1 carbon unit attached to
coenzyme tetrahydrofolate, may be a candidate for the FAD gene. The
trifunctional protein has been mapped to chromosome 14q24 near the locus
14q24.3 that was recently assigned to familial Alzheimer disease (Rozen
et al., 1989).

By linkage mapping, Sherrington et al. (1995) defined a minimal
cosegregating region containing the AD3 gene and isolated at least 19
different transcripts encoded within the region. One of these
transcripts, designated S182 by them, corresponded to a novel gene whose
product is predicted to contain multiple transmembrane domains and
resembles an integral membrane protein. Five different missense
mutations were found that cosegregated with early-onset familial
Alzheimer disease (see 104311.0001 through 104311.0005). Because these
changes occurred in conserved domains of this gene and were not present
in normal controls, they were considered to be causative of AD3.
Sherrington et al. (1995) pointed out that the AD3 locus is associated
with the most aggressive form of Alzheimer disease, suggesting that
mutations at the locus affect a biologically fundamental process.

The Alzheimer's Disease Collaborative Group (1995) isolated full-length
cDNA clones for what they referred to as the PS1 gene. Contrary to
previous mapping data, they found that the gene maps just telomeric to
D14S77. The location at the 5-prime end of a specific YAC enabled them
to determine that the gene is oriented 5-prime/3-prime
centromere-telomere. Evidence for alternative splicing of the gene was
found. The open reading frame of PS1 is encoded by 10 exons. They
concluded that the PS2 gene, otherwise known as STM or AD4 (600759),
located on chromosome 1 has a very similar gene structure. Analyzing 40
families multiply affected by early onset AD (under 60 years of age), in
none of which any of the published mutations had been found, the
Alzheimer's Disease Collaborative Group (1995)found 6 novel missense
mutations in 13 families. None of these mutations occurred in either
elderly unaffected individuals from the families concerned, control
samples, or individuals with late onset disease. The fact that no
nonsense mutations were identified suggested that PS1 mutations cause
alteration rather than loss of function of this protein. There was
evidence that some of the mutations caused earlier onset ages than
others. For example, 3 families with the M146V mutation had onset ages
between 36 and 40 years, whereas families with the C410Y (104311.0005)
and E280A (104311.0008) mutations had mean onset ages between 45 and 50
years. All 11 of the mutations described to that time altered residues
that are conserved in the mouse homologs of PS1 and PS2. Of these
mutations, 2 occurred at each of the codons 146, 163, and 280.
Furthermore, the M146V mutation (104311.0007) had occurred, apparently
independently, in 3 pedigrees with different ethnic backgrounds. There
also appeared to be a clustering of mutations in transmembrane domain 2.
Predictions of protein secondary structure for the presenilins indicated
to the authors that there may have between 6 and 9 transmembrane domains
depending on the methods of prediction used; for this reason, the name
Seven TransMembrane protein (STM) seemed unwise. Wasco et al. (1995)
added 2 more novel PS1 mutations, bringing the total at the time to 13.

By in situ hybridization to tissues, Kovacs et al. (1996) demonstrated
that the expression patterns of PS1 and PS2 in the brain are extremely
similar to each other and that messages for both are primarily
detectable in neuronal populations. Immunochemical analyses indicated
that PS1 and PS2 are similar in size and localized to similar
intracellular compartments (endoplasmic reticulum and Golgi complex).

Identification of genes in genomic regions associated with human
diseases has been greatly facilitated by the development of techniques
such as exon trapping (Buckler et al., 1991) and cDNA selection (Parimoo
et al., 1991). Direct sequencing of disease loci has also been shown to
be one of the most effective methods of gene detection, but it requires
substantial sequencing capacity. The pufferfish (Fugu rubripes) genome
is 7- to 8-fold smaller than that of the human (~ 400 Mb compared to ~
3,000 Mb), but it appears to contain a similar complement of genes. Thus
a typical cosmid clone of genomic DNA might be expected to contain 7 to
8 Fugu genes compared to only 1 human gene. Therefore, sequencing
regions of the Fugu genome syntenic with a particular human disease
region should accelerate the identification of candidate genes. Trower
et al. (1996) used this approach to characterize 14q24.3 associated with
autosomal dominant, early onset Alzheimer disease, AD3. They
demonstrated that 3 genes that are linked to FOS (164810) on 14q in the
AD3 region have homologs in the Fugu genome adjacent to the Fugu FOS
gene: dihydrolipoamide succinyltransferase (126063), S31iii125, and
S20i15. In Fugu these 3 genes lie within a 12.4-kb region, compared to
more than 600 kb in the human AD3 locus. The results demonstrated the
conservation of synteny between the genomes of Fugu in man and
highlighted the utility of this approach for sequence-based
identification of genes in human disease genomic regions.

Duff et al. (1996) demonstrated that transgenic mice overexpressing
mutant, but not wildtype, presenilin-1 show a selective increase in
brain A-beta-42(43). These results indicated that the presenilin
mutations probably cause Alzheimer disease through a gain of deleterious
function that increases the amount of the deposited A-beta-42(43) in the
brain.

Citron et al. (1997) noted that several lines of evidence strongly
support the conclusion that progressive cerebral deposition of amyloid
beta protein is a seminal event in familial Alzheimer disease (FAD)
pathogenesis. They carried out experiments to test the hypothesis that
FAD mutations act by fostering deposition of amyloid beta protein
particularly in the highly amyloidogenic 42-residue form described by
Jarrett et al. (1993). Citron et al. (1997) established transfected cell
lines and transgenic mouse models that coexpress human presenilins PS1
or PS2 (600759) and human amyloid beta precursor and analyzed
quantitatively the effects of presenilin expression on APP processing.
They demonstrated that in both model systems, expression of wildtype
presenilin genes did not alter APP levels, alpha- and beta-secretase
activity, and beta-amyloid production. PS1 and PS2 mutations in the
transfected cells caused a highly significant increase in secretion of
amyloid beta-42 in all mutant clones. Their data raised the possibility
of an intrinsic difference in the effects of PS1 and PS2 mutations on
APP processing. The PS2 Volga mutation (600759.0001) led to a 6- to
8-fold increase in the production of total amyloid beta-42; none of the
PS1 mutations had such a dramatic effect. Citron et al. (1997) noted
that transgenic mice carrying mutant PS1 genes differed from transgenic
mice carrying wildtype PS1 genes in that the mutation-carrying
transgenic mice overproduced amyloid beta-42 in the brain, which was
detectable at 2 to 4 months of age. Citron et al. (1997) stated that
their combined in vitro and in vivo data clearly demonstrated that the
FAD-linked presenilin mutations directly or indirectly altered the level
of gamma-secretase (but not of alpha- or beta-secretase). This increase
in gamma-secretase resulted in increased proteolysis of APP at the
amyloid beta-42 site, leading to heightened amyloid beta-42 production.
They noted that elucidating the biologic mechanism of this effect could
lead to therapeutic inhibition of amyloid beta 42 production in order to
prevent or slow the progress of Alzheimer disease.

Mercken et al. (1996) produced 7 monoclonal antibodies that react with 3
nonoverlapping epitopes on the N-terminal hydrophilic tail of PS1. The
monoclonal antibodies can detect the full-size 47-kD PS1 and the more
abundant 28-kD product in membrane extracts from human brain and human
cell lines. PC12 cells transiently transfected with PS1 constructs
containing 2 different Alzheimer mutations, i.e., M146V and A246E
(104311.0003), failed to generate the 28-kD degradation product in
contrast to PC12 cells transfected with wildtype PS1. Mercken et al.
(1996) suggested that type 3 Alzheimer disease may be the result of
impaired proteolytic processing of PS1.

Page et al. (1996) described the anatomic distribution of PS1 in the
brain and its expression in AD. Using in situ hybridization in the rat
forebrain, they showed that PS1 mRNA expression is primarily in cortical
and hippocampal neurons with less expression in subcortical structures,
in a regional pattern similar to that of amyloid precursor protein
APP695. Excitotoxic lesions led to loss of PS1 signal. A neuronal
pattern of expression of PS1 mRNA was also observed in the human
hippocampal formation. AD and control levels did not differ. PS1 is
expressed to a greater extent in brain areas vulnerable to AD than in
areas spared in AD; however, PS1 expression was not sufficient to mark
vulnerable regions. Collectively, the data suggested to Page et al.
(1996) that the neuropathogenic process consequent to PS1 mutations
begins in neuronal cell populations.

*FIELD* AV
.0001
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, MET146LEU
In 2 unrelated families with chromosome 14-linked early-onset Alzheimer
disease, Sherrington et al. (1995) identified a met146-to-leu mutation
in the novel gene they isolated from the region of chromosome 14
identified by linkage studies as containing the AD3 gene. The authors
detected the mutation in affected family members but not in asymptomatic
family members aged more than 2 standard deviations beyond the mean age
of onset and not on 284 chromosomes from unrelated, neurologically
normal subjects drawn from comparable ethnic origins. The 2 families
reported by Sherrington et al. (1995) were from southern Italy. Sorbi et
al. (1995) studied 15 unrelated Italian families with necropsy-proven
early-onset familial AD and found the met146-to-leu substitution in 3.

.0002
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, HIS163ARG
In an American pedigree (#603) with chromosome 14-linked Alzheimer
disease, Sherrington et al. (1995) found a his163-to-arg substitution in
the novel gene whose product was predicted to contain multiple
transmembrane domains and resembled an integral membrane protein. The
same mutation was found in a small French-Canadian pedigree with
early-onset Alzheimer disease.

.0003
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, ALA246GLU
In a pedigree with chromosome 14-linked early-onset Alzheimer disease,
Sherrington et al. (1995) identified an ala246-to-glu mutation in the
novel gene they isolated from the region of chromosome 14 identified by
linkage studies as containing the AD3 gene.

.0004
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, LEU286VAL
In a pedigree with chromosome 14-linked early-onset Alzheimer disease,
Sherrington et al. (1995) identified a leu286-to-val mutation in the
novel gene they isolated from the region of chromosome 14 identified by
linkage studies as containing the AD3 gene.

.0005
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, CYS410TYR
In 2 pedigrees with chromosome 14-linked early-onset Alzheimer disease,
Sherrington et al. (1995) identified a cys410-to-tyr mutation in the
novel gene they isolated from the region of chromosome 14 identified by
linkage studies as containing the AD3 gene.

.0006
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, MET139VAL
In 2 families with early onset Alzheimer disease, the Alzheimer's
Disease Collaborative Group (1995) detected an M139V mutation. They
found that the mean age of onset was 39-41 years in 2 families.

.0007
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, MET146VAL
In 3 unrelated early onset AD families, the Alzheimer's Disease
Collaborative Group (1995) found an M146V mutation. See also the M146L
mutation (104311.0001). The age of onset was unusually early in these 3
families, between 36 and 40 years.

.0008
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, HIS163TYR
In a Swedish family in which 8 members had early onset Alzheimer
disease, the Alzheimer's Disease Collaborative Group (1995) identified
an H163Y mutation. The average age of onset was 47 years. See also the
H163R mutation (104311.0002).

.0009
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, GLU280ALA
In 4 families with onset of AD in their late forties, the Alzheimer's
Disease Collaborative Group (1995) found an E280A mutation in the AD3
gene.

With this and other missense mutations in the PS1 gene, increased levels
of amyloid beta-peptides ending at residue 42 are found in plasma and
skin fibroblast media of gene carriers. A-beta-42 aggregates readily and
appears to provide a nidus for the subsequent aggregations of A-beta-40,
resulting in the formation of innumerable neuritic plaques. To obtain in
vivo information about how PS1 mutations cause AD pathology at such
early ages, Lemere et al. (1996) characterized the neuropathologic
phenotype of 4 patients from a large Colombian kindred bearing the
glu280-to-ala substitution in PS1. Using antibodies specific to the
alternative C-termini of A-beta, they detected massive deposition of
A-beta-42 (the earliest and predominant form of plaque A-beta to occur
in AD) in many brain regions. Quantification revealed a significant
increase in the A-beta-42 form, but not the A-beta-40 form, in the
brains from 4 patients with the PS1 mutation compared with those from 12
sporadic AD patients. Thus, Lemere et al. (1996) concluded that the
mutant PS1 protein appears to alter the proteolytic processing of the
beta-amyloid precursor protein at the C-terminus of A-beta to favor
deposition of A-beta-42.

.0010
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, GLN280GLY
In 2 families with multiple cases of Alzheimer disease with onset in the
early forties, the Alzheimer's Disease Collaborative Group (1995) found
an E280G mutation in the AD3 gene. See also the E280A mutation
(104311.0009).

.0011
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, PRO267SER
In one AD family with a mean onset of 35 years, the Alzheimer's Disease
Collaborative Group (1995) detected a P267S mutation in the AD3 gene.

.0012
ALZHEIMER DISEASE, FAMILIAL, TYPE 3
AD3, IVS8AS, G-T, -1, EX9 DEL
Perez-Tur et al. (1995) found a heterozygous mutation changing G to T in
the splice-acceptor site for exon 9 in a family segregating Alzheimer
disease with linkage to chromosome 14. RT-PCR of cDNA isolated from
lymphoblasts of affected members demonstrated an aberrant band in the
sequence of which exon 9 was deleted inframe, removing amino acids 290
to 319. The authors suggested that since the predicted protein structure
would retain the same overall topology as the wildtype protein, exon 9
was of particular relevance to the abnormal physiology of presenilin 1
in Alzheimer disease.

*FIELD* SA
Schellenberg et al. (1992)
*FIELD* RF
1. Alzheimer's Disease Collaborative Group: The structure of the
presenilin 1 (S182) gene and identification of six novel mutations
in early onset AD families. Nature Genet. 11: 219-222, 1995.

2. Buckler, A. J.; Chang, D. D.; Graw, S. L.; Brook, J. D.; Haber,
D. A.; Sharp, P. A.; Housman, D. E.: Exon amplification: a strategy
to isolate mammalian genes based on RNA splicing. Proc. Nat. Acad.
Sci. 88: 4005-4009, 1991.

3. Campion, D.; Brice, A.; Hannequin, D.; Tardieu, S.; Dubois, B.;
Calenda, A.; Brun, E.; Penet, C.; Tayot, J.; Martinez, M.; Bellis,
M.; Mallet, J.; Agid, Y.; Clerget-Darpoux, F.: A large pedigree with
early-onset Alzheimer's disease: clinical, neuropathologic, and genetic
characterization. Neurology 45: 80-85, 1995.

4. Citron, M.; Westaway, D.; Xia, W.; Carlson, G.; Diehl, T.; Levesque,
G.; Johnson-Wood, K.; Lee, M.; Seubert, P.; Davis, A.; Kholodenko,
D.; Motter, R.; Sherrington, R.; Perry, B.; Yao, H.; Strome, R.; Lieberburg,
I.; Rommens, J.; Kim. S.; Schenk, D.; Fraser, P.; St George Hyslop,
P.; Selkoe, D. J.: Mutant presenilins of Alzheimer's disease increase
production of 42-residue amyloid beta-protein in both transfected
cells and transgenic mice. Nature Med. 3: 67-72, 1997.

5. Duff, K.; Eckman, C.; Zehr, C.; Yu, X; Prada, C.-M.; Perez-tur;
J.; Hutton, M.; Buee, L.; Harigaya, Y.; Yager, D.; Morgan, D.; Gordon,
M. N.; Holcomb, L.; Refolo, L.; Zenk, B.; Hardy, J.; Youndkin, S.
: Increased amyloid-beta-42(43) in brains of mice expressing mutant
presenilin 1. Nature 383: 710-713, 1996.

6. Ettinger, S.; Weksler, M. E.; Zhou, X.; Blass, J.; Szabo, P.:
Chromosomal fragility associated with familial Alzheimer's disease. Ann.
Neurol. 36: 190-199, 1994.

7. Jarrett, J. T.; Berger, E. P.; Lansbury, P. T.: The carboxy terminus
of the beta amyloid protein is critical for the seeding of amyloid
formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32:
4693-4697, 1993.

8. Kovacs, D. M.; Fausett, H. J.; Page, K. J.; Kim, T.-W.; Moir, R.
D.; Merriam, D. E.; Hollister, R. D.; Hallmark, O. G.; Mancini, R.;
Felsenstein, K. M.; Hyman, B. T.; Tanzi, R. E.; Wasco, W.: Alzheimer-associated
presenilins 1 and 2: neuronal expression in brain and localization
to intracellular membranes in mammalian cells. Nature Med. 2: 224-229,
1996.

9. Lemere, C. A.; Lopera, F.; Kosik, K. S.; Lendon, C. L.; Ossa, J.;
Saido, T. C.; Yamaguchi, H.; Ruiz, A.; Martinez, A.; Madrigal, L.;
Hincapie, L.; Arango, J. C.; Anthony, D. C.; Koo, E. H.; Goate, A.
M.; Selkoe, D. J.; Arango, J. C.: The E280A presenilin 1 Alzheimer
mutation produces increased A-beta-42 deposition and severe cerebellar
pathology. Nature Med. 2: 1146-1150, 1996.

10. Mercken, M.; Takahashi, H.; Honda, T.; Sato, K.; Murayama, M.;
Nakazato, Y.; Noguchi, K.; Imahori, K.; Takashima, A.: Characterization
of human presenilin 1 using N-terminal specific monoclonal antibodies:
evidence that Alzheimer mutations affect proteolytic processing. FEBS
Lett. 389: 297-303, 1996.

11. Mullan, M.; Houlden, H.; Windelspecht, M.; Fidani, L.; Lombardi,
C.; Diaz, P.; Rossor, M.; Crook, R.; Hardy, J.; Duff, K.; Crawford,
F.: A locus for familial early-onset Alzheimer's disease on the long
arm of chromosome 14, proximal to the alpha-1-antichymotrypsin gene. Nature
Genet. 2: 340-342, 1992.

12. Nechiporuk, A.; Fain, P.; Kort, E.; Nee, L. E.; Frommelt, E.;
Polinsky, R. J.; Korenberg, J. R.; Pulst, S.-M.: Linkage of familial
Alzheimer disease to chromosome 14 in two large early-onset pedigrees:
effects of marker allele frequencies on lod scores. Am. J. Med. Genet. 48:
63-66, 1993.

13. Page, K.; Hollister, R.; Tanzi, R. E.; Hyman, B. T.: In situ
hybridization analysis of presenilin 1 mRNA in Alzheimer disease and
in lesioned rat brain. Proc. Nat. Acad. Sci. 93: 14020-14024, 1996.

14. Parimoo, S.; Patanjali, S. R.; Shukla, H.; Chaplin, D. D.; Weissman,
S. M.: cDNA selection: efficient PCR approach for the selection of
cDNAs encoded in large chromosomal DNA fragments. Proc. Nat. Acad.
Sci. 88: 9623-9627, 1991.

15. Perez-Tur, J.; Froelich, S.; Prihar, G.; Crook, R.; Baker, M.;
Duff, K.; Wragg, M.; Busfield, F.; Lendon, C.; Clark, R. F.; Roques,
P.; Fuldner, R. A.; Johnston, J.; Cowburn, R.; Forsell, C.; Axelman,
K.; Lilius, L.; Houlden, H.; Karran, E.; Roberts, G. W.; Rossor, M.;
Adams, M. D.; Hardy, J.; Goate, A.; Lannfelt, L.; Hutton, M.: A mutation
in Alzheimer's disease destroying a splice acceptor site in the presenilin-1
gene. NeuroReport 7: 297-301, 1995.

16. Pericak-Vance, M. A.; Bebout, J. L.; Gaskell, P. C., Jr.; Yamaoka,
L. H.; Hung, W.-Y.; Alberts, M. J.; Walker, A. P.; Bartlett, R. J.;
Haynes, C. A.; Welsh, K. A.; Earl, N. L.; Heyman, A.; Clark, C. M.;
Roses, A. D.: Linkage studies in familial Alzheimer disease: evidence
for chromosome 19 linkage. Am. J. Hum. Genet. 48: 1034-1050, 1991.

17. Rozen, R.; Barton, D.; Du, J.; Hum, D. W.; MacKenzie, R. E.; Francke,
U.: Chromosomal localization of the gene for the human trifunctional
enzyme, methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate
cyclohydrolase-formyltetrahydrofolate synthetase. Am. J. Hum. Genet. 44:
781-786, 1989.

18. Schellenberg, G. D.; Bird, T. D.; Wijsman, E. M.; Orr, H. T.;
Anderson, L.; Nemens, E.; White, J. A.; Bonnycastle, L.; Weber, J.
L.; Alonso, M. E.; Potter, H.; Heston, L. L.; Martin, G. M.: Genetic
linkage evidence for a familial Alzheimer's disease locus on chromosome
14. Science 258: 668-671, 1992.

19. Schellenberg, G. D.; Boehnke, M.; Wijsman, E. M.; Moore, D. K.;
Martin, G. M.; Bird, T. D.: Genetic association and linkage analysis
of the apolipoprotein CII locus and familial Alzheimer's disease. Ann.
Neurol. 31: 223-227, 1992.

20. Schellenberg, G. D.; Payami, H.; Wijsman, E. M.; Orr, H. T.; Goddard,
K. A. B.; Anderson, L.; Nemens, E.; White, J. A.; Alonso, M. E.; Ball,
M. J.; Kaye, J.; Morris, J. C.; Chui, H.; Sadovnick, A. D.; Heston,
L. L.; Martin, G. M.; Bird, T. D.: Chromosome 14 and late-onset familial
Alzheimer disease (FAD). Am. J. Hum. Genet. 53: 619-628, 1993.

21. Sherrington, R.; Rogaev, E. I.; Liang, Y.; Rogaeva, E. A.; Levesque,
G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G.; Holman, K.; Tsuda, T.; Mar,
L.; Foncin, J.-F.; Bruni, A. C.; Montesi, M. P.; Sorbi, S.; Rainero,
I.; Pinessi, L.; Nee, L.; Chumakov, I.; Pollen, D.; Brookes, A.; Sanseau,
P.; Polinsky, R. J.; Wasco, W.; Da Silva, H. A. R.; Haines, J. L.;
Pericak-Vance, M. A.; Tanzi, R. E.; Roses, A. D.; Fraser, P. E.; Rommens,
J. M.; St George-Hyslop, P. H.: Cloning of a gene bearing mis-sense
mutations in early-onset familial Alzheimer's disease. Nature 375:
754-760, 1995.

22. Sorbi, S.; Nacmias, B.; Forleo, P.; Piacentini, S.; Sherrington,
R.; Rogaev, E.; St. George-Hyslop, P.; Amaducci, L.: Missense mutation
of S182 gene in Italian families with early-onset Alzheimer's disease.
(Letter) Lancet 346: 439-440, 1995.

23. St. George-Hyslop, P.; Haines, J.; Rogaev, E.; Mortilla, M.; Vaula,
G.; Pericak-Vance, M.; Foncin, J.-F.; Montesi, M.; Bruni, A.; Sorbi,
S.; Rainero, I.; Pinessi, L.; Pollen, D.; Polinsky, R.; Nee, L.; Kennedy,
J.; Macciardi, F.; Rogaeva, E.; Liang, Y.; Alexandrova, N.; Lukiw,
W.; Schlumpf, K.; Tanzi, R.; Tsuda, T.; Farrer, L.; Cantu, J.-M.;
Duara, R.; Amaducci, L.; Bergamini, L.; Gusella, J.; Roses, A.; Crapper
McLachlan, D.: Genetic evidence for a novel familial Alzheimer's
disease locus on chromosome 14. Nature Genet. 2: 330-334, 1992.

24. St. George-Hyslop, P. H.; Haines, J. L.; Farrer, L. A.; Polinsky,
R.; Van Broeckhoven, C.; Goate, A.; Crapper McLachlan, D. R.; Orr,
H.; Bruni, A. C.; Sorbi, S.; Rainero, I.; Foncin, J.-F.; Pollen, D.;
Cantu, J. M.; Tupler, R.; Voskresenskaya, N.; Mayeux, R.; Growdon,
J.; Fried, V. A.; Myers, R. H.; Nee, L.; Backhovens, H.; Martin, J.
J.; Rossor, M.; Owen, M. J.; Mullan, M.; Percy, M. E.; Karlinsky,
H.; Rich, S.; Heston, L.; Montesi, M.; Mortilla, M.; Nacmias, N.;
Gusella, J. F.; Hardy, J. A.; other members of the FAD Collaborative
Study Group: Genetic linkage studies suggest that Alzheimer's disease
is not a single homogeneous disorder. Nature 347: 194-197, 1990.

25. St. George-Hyslop, P. H.; Tanzi, R. E.; Polinsky, R. J.; Haines,
J. L.; Nee, L.; Watkins, P. C.; Myers, R. H.; Feldman, R. G.; Pollen,
D.; Drachman, D.; Growdon, J.; Bruni, A.; Foncin, J.-F.; Salmon, D.;
Frommelt, P.; Amaducci, L.; Sorbi, S.; Piacentini, S.; Stewart, G.
D.; Hobbs, W. J.; Conneally, P. M.; Gusella, J. F.: The genetic defect
causing familial Alzheimer's disease maps on chromosome 21. Science 235:
885-890, 1987.

26. Tanzi, R. E.; St. George-Hyslop, P. H.; Gusella, J. F.: Molecular
genetics of Alzheimer disease amyloid. J. Biol. Chem. 266: 20579-20582,
1991.

27. Trower, M. K.; Orton, S. M.; Purvis, I. J.; Sanseau, P.; Riley,
J.; Christodoulou, C.; Burt, D.; See, C. G.; Elgar, G.; Sherrington,
R.; Rogaev, E. I.; St. George-Hyslop, P.; Brenner, S.; Dykes, C. W.
: Conservation of synteny between the genome of the pufferfish (Fugu
rubripes) and the region on human chromosome 14 (14q24.3) associated
with familial Alzheimer disease (AD3 locus). Proc. Nat. Acad. Sci. 93:
1366-1369, 1996.

28. Van Broeckhoven, C.; Backhovens, H.; Cruts, M.; De Winter, G.;
Bruyland, M.; Cras, P.; Martin, J.-J.: Mapping of a gene predisposing
to early-onset Alzheimer's disease to chromosome 14q24.3. Nature
Genet. 2: 335-339, 1992.

29. Wasco, W.; Pettingell, W. P.; Jondro, P. D.; Schmidt, S. D.; Gurubhagaratula,
S.; Rodes, L.; DiBlasi, T.; Romano, D. M.; Guenette, S. Y.; Kovacs,
D. M.; Growdon, J. H.; Tanzi, R. E.: Familial Alzheimer's chromosome
14 mutations. (Letter) Nature Med. 1: 848, 1995.

*FIELD* CS

Neuro:
   Presenile dementia;
   Parkinsonism;
   Long tract signs

Misc:
   Early onset

Lab:
   Neurofibrillary tangles composed of disordered microtubules in neurons

Inheritance:
   Autosomal dominant (14q24.3);
   ? additional FAD locus on chromosome 21 separate from the APP locus

*FIELD* CN
Victor A. McKusick - updated: 02/03/1997
Orest Hurko - updated: 5/14/1996
Orest Hurko - updated: 1/25/1996

*FIELD* CD
Victor A. McKusick: 11/4/1992

*FIELD* ED
mark: 02/03/1997
terry: 2/3/1997
terry: 1/23/1997
mark: 1/23/1997
carol: 11/4/1996
mark: 10/25/1996
mark: 10/23/1996
terry: 10/22/1996
mark: 10/22/1996
terry: 5/17/1996
terry: 5/14/1996
terry: 4/15/1996
mark: 3/25/1996
terry: 3/18/1996
mark: 2/19/1996
mark: 2/10/1996
terry: 2/5/1996
mark: 1/25/1996
terry: 1/19/1996
mark: 12/11/1995
terry: 11/17/1995
mark: 11/2/1995
carol: 9/29/1994
mimadm: 4/12/1994
pfoster: 3/24/1994
warfield: 3/23/1994

*RECORD*
*FIELD* NO
104350
*FIELD* TI
104350 AMASTIA, BILATERAL, WITH URETERAL TRIPLICATION AND DYSMORPHISM
*FIELD* TX
Rich et al. (1987) reported this combination in a 24-year-old
primigravida and her male infant offspring. The mother had multiple
congenital anomalies including dysmorphic low-set ears, high-arched
palate, flat broad nasal bridge, ptosis, epicanthic folds with an
antimongoloid slant of the eyes and hypertelorism, congenital hip
anomaly, scoliosis, hemivertebra, bilateral syndactyly of the fingers
and toes, cubitus valgus, mitral valve prolapse, umbilical hernia, and
bilateral amastia. At the age of 18 months, left nephrectomy had been
performed for hydronephrosis. Ureteral triplication was discovered. At 5
months of gestation, her son was found to have hydrocephalus on the
left. At birth, he had dysmorphic low-set ears, flat broad nasal bridge,
high-arched palate, antimongoloid slant of the eyes with hypertelorism,
ptosis, epicanthic folds, tapered digits, cubitus valgus, pectus
excavatum, bilateral amastia, umbilical hernia, and a left flank mass
consistent with hydronephrosis. There was a 'machinery' murmur
consistent with patent ductus arteriosus.

*FIELD* RF
1. Rich, M. A.; Heimler, A.; Waber, L.; Brock, W. A.: Autosomal dominant
transmission of ureteral triplication and bilateral amastia. J.
Urol. 137: 102-105, 1987.

*FIELD* CS

Thorax:
   Amastia;
   Absent nipples;
   Pectus excavatum

GU:
   Hydronephrosis;
   Ureteral triplication

Ears:
   Dysmorphic ears;
   Low-set ears

Eyes:
   Ptosis;
   Epicanthic folds;
   Antimongoloid eye slant;
   Hypertelorism

Nose:
   Flat nasal bridge;
   Broad nasal bridge

Mouth:
   High-arched palate

Joints:
   Congenital hip anomaly

Spine:
   Scoliosis;
   Hemivertebra

Limbs:
   Syndactyly;
   Cubitus valgus;
   Tapered digits

Cardiac:
   Mitral valve prolapse;
   Patent ductus arteriosus

Abdomen:
   Umbilical hernia

Neuro:
   Hydrocephalus

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 4/16/1987

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 5/14/1987

*RECORD*
*FIELD* NO
104400
*FIELD* TI
104400 AMELIA AND TERMINAL TRANSVERSE HEMIMELIA
*FIELD* TX
Most cases are sporadic. Some families have affected relatives,
suggesting a complex genetic etiology.

*FIELD* SA
Temtamy and McKusick (1978)
*FIELD* RF
1. Temtamy, S. A.; McKusick, V. A.: The Genetics of Hand Malformations.
New York: Alan R. Liss (pub.)  1978.

*FIELD* CS

Limbs:
   Amelia;
   Terminal transverse hemimelia

Inheritance:
   Autosomal dominant vs. multifactorial;
   most cases sporadic

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/18/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
104500
*FIELD* TI
*104500 AMELOGENESIS IMPERFECTA 2, HYPOPLASTIC LOCAL, AUTOSOMAL DOMINANT;
AIH2
AMELOGENESIS IMPERFECTA-2, HYPOCALCIFICATION TYPE;;
AI, HYPOMINERALIZATION TYPE
*FIELD* TX
The enamel is of normal thickness but opaque or yellowish white without
lustre on newly erupted teeth; it is so soft that it is lost soon after
eruption, eventuating in a crown composed only of yellowish dentin. The
enamel can easily be scraped from the tooth. Both the primary and the
secondary dentitions are affected. Anterior open bite is noted in over
60% (Persson and Sundell, 1982). Chaudhry et al. (1959) reported 5
families with an autosomal dominant pattern of inheritance. Weinmann et
al. (1945) made the useful division of enamel defects into two classes:
(1) hereditary enamel hypoplasia, in which the enamel is hard but
deficient in quantity, and (2) hereditary enamel hypocalcification, in
which the enamel is soft and undercalcified but normal in quantity and
histology. See amelogenesis imperfecta in the X-linked catalog (301100,
301200). The hypocalcification type is the most frequent type of enamel
dysplasia, occurring in about 1 in 20,000 population. The existence of a
recessive form of hypocalcified amelogenesis imperfecta has not been
firmly established (Witkop and Sauk, 1976). Clinically,
radiographically, and histologically, the findings in the suspected
recessive cases were more severe than in the dominant cases.

Backman and Holmgren (1988) studied 51 families with amelogenesis
imperfecta from the county of Vasterbotten in northern Sweden. Autosomal
dominant inheritance was the likely mode of inheritance in 33 families,
although X-linked dominant inheritance was a possible alternative in 1
of these. Autosomal recessive inheritance was found likely in 6 families
(see 204650 and 204700) and X-linked recessive inheritance in 2
families. Ten probands were sporadic cases. AI was of the hypoplastic
form in 72% and of the hypomineralization form in 28% of the
individuals. Autosomal dominant inheritance was found in 89% of the
cases with the hypoplastic form and in 44% of the cases with the
hypomineralization form. In most families the type was consistent within
the family; in 3 families, however, both hypoplastic and
hypomineralization forms were seen. In the families with X-linked
inheritance, clinical manifestations were more severe in males.

Forsman et al. (1994) mapped the autosomal dominant form of amelogenesis
imperfecta to 4q. In 3 families from northern Sweden, the gene was
localized by linkage analysis and recombination data to the 17.6-cM
region between markers D4S392 and D4S395. This region also contains the
albumin gene (ALB; 103600) which was hypothesized to be a candidate gene
for the disorder. Karrman et al. (1997) constructed a detailed marker
map of the region to refine the localization of the AIH2 locus to a 4-Mb
region present on a YAC contig. The new studies excluded ALB as the
disease-causing gene. Affected members in all 6 families studied shared
the same allele haplotype, indicating a common ancestral mutation in all
families. The AIH2 critical region, as defined by their studies, spans a
physical distance of approximately 4 Mb as judged from radiation hybrid
maps. (ALB had been considered a candidate because of a possible role of
albumin in enamel maturation.)

The ameloblastin gene (AMBN; 601259) maps to the same region of 4q21 and
is a strong candidate gene for AIH2 (MacDougall et al., 1997).

*FIELD* SA
Giansanti  (1973); Sauk et al. (1972); Winter and Brook (1975)
*FIELD* RF
1. Backman, B.; Holmgren, G.: Amelogenesis imperfecta: a genetic
study. Hum. Hered. 38: 189-206, 1988.

2. Chaudhry, A. P.; Johnson, O. N.; Mitchell, D. F.; Gorlin, R. J.;
Bartholdi, W. L.: Hereditary enamel dysplasia. J. Pediat. 54: 776-785,
1959.

3. Forsman, K.; Lind, L.; Backman, B.; Westermark, E.; Holmgren, G.
: Localization of a gene for autosomal dominant amelogenesis imperfecta
(ADAI) to chromosome 4q. Hum. Molec. Genet. 3: 1621-1625, 1994.

4. Giansanti, J. S.: A kindred showing hypocalcified amelogenesis
imperfecta. J. Am. Dent. Assoc. 86: 675-678, 1973.

5. Karrman, C.; Backman, B.; Dixon, M.; Holmgren, G.; Forsman, K.
: Mapping of the locus for autosomal dominant amelogenesis imperfecta
(AIH2) to a 4-Mb YAC contig on chromosome 4q11-q21. Genomics 39:
164-170, 1997.

6. MacDougall, M.; DuPont, B. R.; Simmons, D.; Reus, B.; Krebsbach,
P.; Karrman, C.; Holmgren, G.; Leach, R. J.; Forsman, K.: Ameloblastin
gene (AMBN) maps within the critical region for autosomal dominant
amelogenesis imperfecta at chromosome 4q21. Genomics 41: 115-118,
1997.

7. Persson, M.; Sundell, S.: Facial morphology and open bite deformity
in amelogenesis imperfecta. Acta Odontol. Scand. 40: 135-144, 1982.

8. Sauk, J. J., Jr.; Cotton, W. R.; Lyon, H. W.; Witkop, C. J., Jr.
: Electron-optic analysis of hypomineralized amelogenesis imperfecta. Arch.
Oral Biol. 17: 771-780, 1972.

9. Weinmann, J. P.; Svoboda, J. F.; Woods, R. W.: Hereditary disturbances
of enamel formation and calcification. J. Am. Dent. Assoc. 32: 397-418,
1945.

10. Winter, G. B.; Brook, A. H.: Enamel hypoplasia and anomalies
of the enamel. Dent. Clin. N. Am. 19: 3-24, 1975.

11. Witkop, C. J., Jr.; Sauk, J. J., Jr.: Chapter 7. Heritable defects
of enamel.In: Stewart, R. E.; Prescott, G. H.: Oral Facial Genetics.
St. Louis: C. V. Mosby (pub.)  1976.

*FIELD* CS

Teeth:
   Soft opaque or yellowish white lusterless enamel;
   Anterior open bite

Inheritance:
   Autosomal dominant form;
   also recessive and X-linked forms

*FIELD* CN
Victor A. McKusick - updated: 04/14/1997
Victor A. McKusick - updated: 2/11/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 04/14/1997
terry: 4/10/1997
jamie: 2/18/1997
terry: 2/11/1997
terry: 2/4/1997
carol: 5/11/1994
mimadm: 3/11/1994
carol: 3/31/1992
carol: 3/23/1992
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
104510
*FIELD* TI
104510 AMELOGENESIS IMPERFECTA, HYPOMATURATION-HYPOPLASIA TYPE, WITH TAURODONTISM
*FIELD* TX
Congleton and Burkes (1979) and Crawford et al. (1988) described
amelogenesis imperfecta of the hypomaturation-hypoplasia type with
taurodontism. The dental findings were apparently identical to those of
the trichodentoosseous syndrome (190320) from which it differs only by
the lack of changes in the hair and bones. Crawford and Aldred (1990)
reviewed all reported cases of these disorders, obtaining additional
information from the original authors. They concluded that 'if the teeth
are affected in the absence of hair or bone changes, either in the
individual or within the family, then the diagnosis should be deemed to
be AI H-H T.' Seow (1993) suggested that true taurodontism, as indicated
by a change in the mandibular first permanent molar, occurs only in the
TDO syndrome and that this feature can be used to differentiate clearly
between TDO and AI.

*FIELD* RF
1. Congleton, J.; Burkes, E. J.: Amelogenesis imperfecta with taurodontism.
Oral Surg. Oral Med. Oral Path. 48: 540-544, 1979.

2. Crawford, P. J. M.; Aldred, M. J.: Amelogenesis imperfecta with
taurodontism and the tricho-dento-osseous syndrome: separate conditions
or a spectrum of disease?. Clin. Genet. 38: 44-50, 1990.

3. Crawford, P. J. M.; Evans, R. D.; Aldred, M. J.: Amelogenesis
imperfecta: autosomal dominant hypomaturation-hypoplasia type with
taurodontism. Brit. Dent. J. 164: 71-73, 1988.

4. Seow, W. K.: Taurodontism of the mandibular first permanent molar
distinguishes between the tricho-dento-osseous (TDO) syndrome and
amelogenesis imperfecta. Clin. Genet. 43: 240-246, 1993.

*FIELD* CS

Teeth:
   Amelogenesis imperfecta, hypomaturation-hypoplasia type;
   Taurodontism

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 8/20/1990

*FIELD* ED
mimadm: 3/11/1994
carol: 11/5/1993
supermim: 3/16/1992
carol: 8/20/1990

*RECORD*
*FIELD* NO
104530
*FIELD* TI
*104530 AMELOGENESIS IMPERFECTA, HYPOPLASTIC TYPE
MICRODONTIA, GENERALIZED, INCLUDED
*FIELD* TX
There may be more than one distinct form of autosomal dominant
hypoplastic amelogenesis imperfecta. For example, Witkop and Rao (1971)
list smooth, rough and pitted forms, as well as a local form. These
might be allelic disorders, comparable to the hemoglobin variants which
have various changes in the beta chain. In the smooth hypoplastic type,
many teeth fail to erupt and multiple calcifications of the pulp often
occur, even in unerupted teeth. Numerous enameloid conglomerates are
found histologically in areas of unerupted teeth. Witkop and Sauk (1976)
enumerated six forms of hypoplastic amelogenesis imperfecta. Four--the
pitted, local, smooth and rough forms--are autosomal dominant. In
addition, there is probably an autosomal recessive rough type and an
X-linked smooth type (301200). The dental anomaly designated generalized
microdontia by Steinberg et al. (1961) is the hypoplastic type of
amelogenesis imperfecta. The pedigree of the family they reported is
consistent with either autosomal or X-linked dominant inheritance.

*FIELD* SA
Gertzman et al. (1979); Weyers  (1977); Winter and Brook (1975)
*FIELD* RF
1. Gertzman, G. B. R.; Gaston, G.; Quinn, I.: Amelogenesis imperfecta:
local hypoplastic type with pulpal calcification. J. Am. Dent. Assoc. 99:
637-639, 1979.

2. Steinberg, A. G.; Warren, J. F.; Warren, L. M.: Hereditary generalized
microdontia. J. Dent. Res. 40: 58-62, 1961.

3. Weyers, H.: Ein besonderer Typ dominant erblicher Schmelzdysplasie?.
Dtsch. Zahnaerztl. Z. 32: 243-247, 1977.

4. Winter, G. B.; Brook, A. H.: Enamel hypoplasia and anomalies of
the enamel. Dent. Clin. N. Am. 19: 3-24, 1975.

5. Witkop, C. J., Jr.; Rao, S. R.: Inherited defects in tooth structure.
Birth Defects Orig. Art. Ser. VII(7): 153-184, 1971.

6. Witkop, C. J., Jr.; Sauk, J. J., Jr.: Chapter 7. Heritable defects
of enamel. In: Stewart, R. E.; Prescott, G. H.: Oral Facial Genetics.
St. Louis: C. V. Mosby (pub.)  1976.

*FIELD* CS

Teeth:
   Hypoplastic amelogenesis imperfecta;
   Generalized microdontia

Inheritance:
Autosomal dominant (Four types: pitted, local, smooth and rough);
   also autosomal recessive rough type and an X-linked smooth type (301200)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987

*RECORD*
*FIELD* NO
104570
*FIELD* TI
*104570 AMELOONYCHOHYPOHIDROTIC SYNDROME
*FIELD* TX
Witkop et al. (1975) described a kindred segregating for a syndrome
comprising hypocalcified-hypoplastic enamel, onycholysis with subungual
hyperkeratosis, and hypohidrosis. Witkop and Sauk (1976) observed a
second kindred. The affected persons included father-son pairs. No
further cases have been reported (Witkop, 1982).

*FIELD* RF
1. Witkop, C. J., Jr.: Personal Communication. Minneapolis, Minn.
1982.

2. Witkop, C. J., Jr.; Brearley, L. J.; Gentry, W. C., Jr.: Hypoplastic
enamel, onycholysis, and hypohidrosis inherited as an autosomal dominant
trait: a review of ectodermal dysplasia syndromes. Oral Surg. 39:
71-86, 1975.

3. Witkop, C. J., Jr.; Sauk, J. J., Jr.: Heritable defects of enamel.
In: Stewart, R. E.; Prescott, G. H.: Oral Facial Genetics.  St.
Louis: C. V. Mosby (pub.)  1976. Pp. 194-197.

*FIELD* CS

Teeth:
   Hypocalcified-hypoplastic enamel

Nails:
   Onycholysis;
   Subungual hyperkeratosis

Skin:
   Hypohidrosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
104600
*FIELD* TI
104600 AMENORRHEA-GALACTORRHEA SYNDROME
*FIELD* TX
The association of secondary amenorrhea and galactorrhea is generally
thought to occur in 2 distinct syndromes: the Forbes-Albright syndrome,
in which amenorrhea and galactorrhea are accompanied by a pituitary
tumor, with or without prior pregnancy, and the Chiari-Frommel syndrome,
in which amenorrhea and galactorrhea commence after pregnancy, without
associated pituitary tumor. This distinction may be artificial (Rimoin
and Schimke, 1971), because the pituitary adenoma may be too small to
identify clinically and progression from the benign to the neoplastic
syndrome has been documented (Young et al., 1967). Linquette et al.
(1967) described mother and daughter with amenorrhea-galactorrhea
associated with pituitary adenoma. The mother first developed clinical
signs after a pregnancy, whereas the daughter was never pregnant and
amenorrhea followed emotional trauma. The sella turcica was enlarged in
both and tumor was confirmed by craniotomy. The tumors resembled
chromophobe adenomas, but there was fine eosinophilic granulation on
tetrachrome staining, as seen in prolactin cells. Since the
amenorrhea-galactorrhea syndrome has been described as a part of a
multiple endocrine adenomatosis syndrome, it is not certain that the
ailment in the mother and daughter reported by Linquette et al. (1967)
represented a distinct entity.

*FIELD* RF
1. Linquette, M.; Herlant, M.; Laine, E.; Fossati, P.; Dupont-Lecompte,
M.: Adenome prolactive chez une jeune fille dont la mere etait porteuse
d'un adenome hypophysaire avec amenorrhee-galactorrhee. Ann. Endocr. 28:
773-780, 1967.

2. Rimoin, D. L.; Schimke, R. N.: Genetic Disorders of the Endocrine
Glands.  St. Louis: C. V. Mosby (pub.)  1971.

3. Young, R. L.; Bradley, E. M.; Goldzieher, J. W.; Myers, P. W.;
Lecocq, F. R.: Spectrum of nonpuerperal galactorrhea: report of two
cases evolving through the various syndromes. J. Clin. Endocr. 27:
461-466, 1967.

*FIELD* CS

GU:
   Secondary amenorrhea

Thorax:
   Galactorrhea

Oncology:
   Pituitary adenoma

Radiology:
   Enlarged sella turcica

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/15/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
104610
*FIELD* TI
*104610 AMILORIDE-BINDING PROTEIN-1; ABP1
DIAMINE OXIDASE; DAO
*FIELD* TX
Amiloride acts as a diuretic via the closure of epithelial sodium ion
channels. Phenamil, an analog of the diuretic amiloride, is a potent
blocker of the epithelial sodium channel. Barbry et al. (1990) used
phenamil to purify the porcine kidney amiloride-binding protein. They
then used synthetic oligonucleotides derived from partial sequences to
screen a human kidney cDNA library and to isolate the cDNA encoding the
human amiloride-binding protein. Using this cDNA, Barbry et al. (1990)
mapped the corresponding structural gene to 7q34-q36 by in situ
hybridization. This region flanks the location (7q32) of the cystic
fibrosis (219700) gene. From studies of association between the ABP gene
and cystic fibrosis by means of RFLPs, Barbry et al. (1990) excluded the
gene from involvement in that disorder.

On the basis of its primary structure, the amiloride-binding protein (EC
1.4.3.6) is 713 amino acids long, with a 19-amino acid signal peptide.
Expressed in cultured cells, the mRNA yields a glycoprotein that binds
amiloride and amiloride analogs with affinities similar to the amiloride
receptor associated with the apical Na+ channel in pig kidney membranes
and is immunoprecipitated with monoclonal antibodies raised against pig
kidney amiloride-binding protein. Barbry et al. (1990) pointed out that
amiloride-sensitive Na+ channels are also present in airway epithelia,
where they play an important role in fluid secretion. Amiloride inhibits
the excessive absorption of Na+ and liquid that takes place in airway
epithelia of patients with cystic fibrosis, and amiloride aerosol
therapy has been tried for the treatment of lung disease in CF.

Novotny et al. (1994) demonstrated that ABP is an amiloride-sensitive
diamine oxidase. Chassande et al. (1994) analyzed the organization of
the ABP/DAO gene. The cDNA corresponded to a 751-residue polypeptide.

*FIELD* SA
Barbry et al. (1990)
*FIELD* RF
1. Barbry, P.; Champe, M.; Chassande, O.; Munemitsu, S.; Champigny,
G.; Lingueglia, E.; Maes, P.; Frelin, C.; Tartar, A.; Ullrich, A.;
Lazdunski, M.: Human kidney amiloride-binding protein: cDNA structure
and functional expression. Proc. Nat. Acad. Sci. 87: 7347-7351,
1990.

2. Barbry, P.; Simon-Bouy, B.; Mattei, M.-G.; Le Guern, E.; Jaume-Roig,
B.; Chassande, O.; Ullrich, A.; Lazdunski, M.: Localization of the
gene for amiloride binding protein on chromosome 7 and RFLP analysis
in cystic fibrosis families. Hum. Genet. 85: 587-589, 1990.

3. Chassande, O.; Renard, S.; Barbry, P.; Lazdunski, M.: The human
gene for diamine oxidase, an amiloride binding protein: molecular
cloning, sequencing, and characterization of the promoter. J. Biol.
Chem. 269: 14484-14489, 1994.

4. Novotny, W. F.; Chassande, O.; Baker, M.; Lazdunski, M.; Barbry,
P.: Diamine oxidase is the amiloride-binding protein and is inhibited
by amiloride analogues. J. Biol. Chem. 269: 9921-9925, 1994.

*FIELD* CD
Victor A. McKusick: 11/26/1990

*FIELD* ED
jason: 7/13/1994
carol: 6/28/1994
supermim: 3/16/1992
carol: 8/6/1991
carol: 12/4/1990
carol: 11/26/1990

*RECORD*
*FIELD* NO
104613
*FIELD* TI
*104613 CHAPERONIN CONTAINING T-COMPLEX SUBUNIT 6; CCT6
T-COMPLEX HOMOLOG TCP-20; TCP20;;
HISTIDINE TRANSPORT REGULATOR-3; HTR3;;
AMINO ACID TRANSPORT DEFECT COMPLEMENTING
*FIELD* TX
Segel et al. (1992) used complementation of yeast to isolate a member of
a class of genes that carry out the probable function of protecting a
regulator protein from indigenous degradation. Although yeast cells
normally synthesize amino acids, mutants with biosynthetic defects
require uptake of exogenous amino acids for growth. Yeast can import a
wide range of amino acids by the general amino acid permease (GAP)
which, however, can be repressed with ammonium sulfate. Thus,
Saccharomyces cerevisiae with a defect in histidine biosynthesis and
histidine uptake does not grow on histidine-containing medium when GAP
is repressed by ammonium. Human cDNA clones can directly complement the
synthetic or transport defects or indirectly prevent the ammonium
repression. The deduced amino acid sequence encoded by one of these cDNA
clones in the experiments of Segel et al. (1992) suggested that a
chaperonin-like protein was responsible for complementation by
preventing ammonium repression. The amino acid sequence encoded by this
cDNA clone, designated HTR3 by them (presumably for 'histidine transport
regulator'), was related to that of the T-complex proteins (e.g.,
186980). However, further studies by Li et al. (1994) revealed that the
lack of ammonium repression of general amino acid permease also involved
secondary mutations which arose in the yeast transformant. Thus the
specific action of HTR3 on the yeast amino acid permease was uncertain.

Segel et al. (1992) proposed that HTR3, TCP1 (186980), and others
constituted a class of chaperonins that are cytoplasmic proteins.
Although a distinct class, the cytoplasmic chaperonins have a weak but
significant sequence similarity to the chaperonin proteins (e.g.,
118190).

Li et al. (1994) reported the nucleotide and amino acid sequences of the
human homolog of yeast Tcp20. They found that the TCP20 protein
(previously designated HTR3 by them) shows approximately 30% identity to
TCP1, a known subunit of the hetero-oligomeric TRiC (see, for example,
600114). Western blot analysis of purified bovine TRiC with a
TCP20-specific antibody indicated that TCP20 is also a subunit of TRiC.
Gene disruption studies showed that Tcp20, like Tcp1, is an essential
gene in yeast.

*FIELD* RF
1. Li, W.-Z.; Lin, P.; Frydman, J.; Boal, T. R.; Cardillo,  T. S.;
Richard, L. M.; Toth, D.; Lichtman, M. A.; Hartl, F.-U.; Sherman,
F.; Segel, G. B.: Tcp20, a subunit of the eukaryotic TRiC chaperonin
from humans and yeast. J. Biol. Chem. 269: 18616-18622, 1994.

2. Segel, G. B.; Boal, T. R.; Cardillo, T. S.; Murant, F. G.; Lichtman,
M. A.; Sherman, F.: Isolation of a gene encoding a chaperonin-like
protein by complementation of yeast amino acid transport mutants with
human cDNA. Proc. Nat. Acad. Sci. 89: 6060-6064, 1992.

*FIELD* CN
Andre K. Cheng: 4/17/1996

*FIELD* CD
Victor A. McKusick: 8/17/1992

*FIELD* ED
mark: 04/17/1996
mark: 4/17/1996
mark: 3/7/1996
carol: 4/6/1994
carol: 8/17/1992

*RECORD*
*FIELD* NO
104614
*FIELD* TI
*104614 SOLUTE CARRIER FAMILY 3, MEMBER 1; SLC3A1
AMINO ACID TRANSPORTER 1; ATR1;;
D2H
*FIELD* TX
Absorption of amino acids in the kidney and small intestine appears to
be mediated by transporters with well-defined specificities, although
little is known about these proteins at the molecular level. By
expression cloning in Xenopus oocytes, Wells and Hediger (1992) isolated
kidney- and intestine-specific DNA clones in the rat, designated D2. The
cDNA induced the high affinity uptake into oocytes of a broad spectrum
of amino acids, including cystine and dibasic and neutral amino acids.
Unlike most known transporters, D2 was found to be a type II membrane
glycoprotein. It had a low but significant degree of similarity to
alpha-glucosidases and to the 4F2 cell surface antigen heavy chain
(158070). Out of an interest in the possible role of this gene and its
protein product in human inherited disorders of transport such as
cystinuria (220100) and Hartnup disorder (234500), Lee et al. (1993)
isolated a D2-like cDNA (D2H) from a human kidney library. They
presented functional data showing that D2H, like D2, induces the uptake
of a broad spectrum of amino acids into oocytes. The D2H cDNA was 2,284
bp long and encoded a 663-amino acid protein that was 80% identical to
rat D2. By Southern blot analysis of genomic DNA from a panel of
mouse/human somatic cell hybrids, Lee et al. (1993) showed that the
human gene is on chromosome 2. One of the hybrid clones that they
analyzed retained an X/2 translocation chromosome containing the
2q32.3-qter region. This clone was negative for D2H, indicating that the
D2H locus is in the 2pter-q32.3 region.

Yan et al. (1994) isolated and sequenced the promoter region of the rat
kidney neutral and basic amino acid transporter gene, which they
symbolized NBAT. The major transcription initiation site was mapped by
primer extension. Positive and negative regulatory elements in the
promoter region were observed. Yan et al. (1994) used a human genomic
clone of the transporter to localize the NBAT gene to 2p21 by
fluorescence in situ hybridization (FISH). By the same method, Zhang et
al. (1994) confirmed the assignment to 2p21. On other hand, Calonge et
al. (1995) mapped SLC3A1 and 2 linked markers, D2S119 and D2S177, to
2p16.3, also by FISH. This was the location identified when FISH was
performed either with Alu-PCR-amplified sequences of a YAC containing
the SLC3A1 gene or with SLC3A1-specific PCR-amplified genomic fragments.
To correlate this physical information with the genetic information on
cystinuria, they performed FISH with combinations of Alu-PCR-amplified
sequences from YACs containing SLC3A1 or the D2S119 and D2S177 loci. In
all cases, a fused signal was obtained demonstrating their close
physical location. Calonge et al. (1995) also referred to the SLC3A1
gene as rBAT.

Because the protein product of the SLC3A1 gene is involved in cystine
and dibasic and neutral amino acid transport, which is defective in
cystinuria, Pras et al. (1994) focused attention on 2p as the possible
site of the gene for cystinuria. Using DNA markers, they demonstrated
linkage to a site on 2p in the same general area as the SLC3A1 gene.
Affected offspring of inbred families showed a high rate of homozygosity
for linked markers. They found no evidence for locus heterogeneity in a
study of 17 families. Calonge et al. (1994) focused on SLC3A1 (which
they called the rBAT gene) as a likely site of the defect of the
mutation(s) in cystinuria. They used illegitimate transcription and
RT-PCR to isolate the SLC3A1 gene from cystinuric patients. They sampled
affected individuals from 8 different families and found a total of 6
missense mutations, accounting for 30% of the cystinuria chromosomes.
Homozygosity for the most common mutation (104614.0001) was detected in
3 cystinuric sibs.

Three types of classic cystinuria have been described (see 220100). Type
I heterozygotes show normal amino acididuria, whereas type II and type
III heterozygotes show high and moderate hyperexcretion of cystine and
dibasic amino acids, respectively. In contrast to types I and II
homozygotes, type III homozygotes show a nearly normal increase in
cystine plasma levels after oral cystine administration. These types had
been thought to be due to allelism of the same gene, although
involvement of 2 distinct genetic loci for type I and type III
cystinuria had been suggested by Goodyer et al. (1993). To resolve this
question, Calonge et al. (1995) did a linkage study of type I and/or
type III cystinuria families (N = 22) using the SLC3A1 gene and its
nearest marker, D2S119. They were able to demonstrate homogeneity for
linkage to SLC3A1 in type I/I families, whereas types I/III and III/III
were not linked.

Pras et al. (1995) brought to 10 the number of cystinuria-associated
mutations in the SLC3A1 gene. Horsford et al. (1996) performed
mutational analysis of the D2H gene in 13 cystinuric patients identified
primarily through the Quebec newborn urinary screening program.
Mutations were identified on 7 of 25 alleles; all of these 7 mutant
alleles were associated with type I cystinuria. Four of the mutations (a
large deletion, a 5-prime-splice site mutation, a 2-bp deletion, and a
nonsense mutation) had not been previously reported. The findings
suggested that abnormalities in the D2H gene may account for only type I
cystinuria and that this subtype can be caused by a wide variety of
population-specific mutations. They provided an illustration of the
location of 18 mutations that had been identified to that time.

Bisceglia et al. (1996) investigated the entire coding region of the
cystinuria disease gene, including all intron/exon boundaries and some
intron sequences (50-bp on each side of the exons on average) in a
sample of 54 type 1 cystinuria chromosomes. They considered the method
of choice to be SSCP of PCR transcripts (RNA-SSCP). When electrophoretic
bands showed altered mobility, the corresponding transcripts were
sequenced. Bisceglia et al. (1996) identified 4 new mutations, 1 large
deletion, and a polymorphism. Bisceglia et al. (1996) tabulated the
frequency of mutations in the gene. They noted that the M467T occurred
with the highest frequency (0.26) (104614.0001) in their population.
Comparison of their data with those for other populations revealed that
only 4 mutated alleles, M467T, R270X, E483X, and T216M, were detected
more than once.

Analysis of the genomic structure and organization of the SLC3A1 gene
was also reported by Pras et al. (1996). They found that the gene spans
about 45-kb of genomic DNA and is composed of 10 exons. Pras et al.
(1996) published primer sequences for amplification of exons and their
boundaries from genomic DNA. They sequenced 700 bp from the promoter
region and detected a number of potential regulatory sites, including
multiple gamma-interferon response elements. They reported that in a
substantial number of cystinuria patients mutations were not found in
the coding region of the gene. They attributed this to possible locus
heterogeneity in cystinuria or to the possible presence of mutations in
the promoter region or in intronic regulatory sequences.

*FIELD* AV
.0001
CYSTINURIA
SLC3A1, MET467THR
Calonge et al. (1994) detected a met467-to-thr mutation in the SLC3A1
gene in 3 cystinuric sibs. The mutation nearly abolished the amino acid
transport activity induced by the SLC3A1 gene in Xenopus oocytes.
Bisceglia et al. (1996) noted that this was the most common allele
detected in the Spanish and Italian population analyzed by them.

.0002
CYSTINURIA
SLC3A1, MET467LYS
Calonge et al. (1994) found a met467-to-lys mutation in a cystinuric
patient who was a compound heterozygote for this and an L678P mutation
(104614.0003). It is of interest that this mutation is in the same codon
and, indeed, in the same nucleotide, T1400, as the M467T mutation
(104614.0001).

.0003
CYSTINURIA
SLC3A1, LEU678PRO
See 104614.0002.

.0004
CYSTINURIA
SLC3A1, ARG181GLN
In a patient with cystinuria, Calonge et al. (1994) found compound
heterozygosity for 2 mutations, R181Q and T652R (104614.0005).

.0005
CYSTINURIA
SLC3A1, THR652ARG
See 104614.0004.

.0006
CYSTINURIA
SLC3A1, PRO615THR
In a patient with cystinuria, Calonge et al. (1994) demonstrated a P615T
mutation in the SLC3A1 gene.

*FIELD* SA
Calonge et al. (1995)
*FIELD* RF
1. Bisceglia, L.; Calonge, M. J.; Strologo, L. D.; Rizzoni, G.; de
Sanctis, L.; Gallucci, M.; Beccia, E.; Testar, X.; Zorzano, A.; Estivill,
X.; Zelante, L.; Palacin, M.; Gasparini, P.; Nunes, V.: Molecular
analysis of the cystinuria disease gene: identification of four new
mutations, one large deletion, and one polymorphism. Hum. Genet. 98:
447-451, 1996.

2. Calonge, M. J.; Gasparini, P.; Chillaron, J.; Chillon, M.; Gallucci,
M.; Rousaud, F.; Zelante, L.; Testar, X.; Dallapiccola, B.; Di Silverio,
F.; Barcelo, P.; Estivill, X.; Zorzano, A.; Nunes, V.; Palacin, M.
: Cystinuria caused by mutations in rBAT, a gene involved in the transport
of cystine. Nature Genet. 6: 420-425, 1994.

3. Calonge, M. J.; Nadal, M.; Calvano, S.; Testar, X.; Zelante, L.;
Zorzano, A.; Estivill, X.; Gasparini, P.; Palacin, M.; Nunes, V.:
Assignment of the gene responsible for cystinuria (rBAT) and of markers
D2S119 and D2S177 to 2p16 by fluorescence in situ hybridization. Hum.
Genet. 95: 633-636, 1995.

4. Calonge, M. J.; Volpini, V.; Bisceglia, L.; Rousaud, F.; De Sanctis,
L.; Beccia, E.; Zelante, L.; Testar, X.; Zorzano, A.; Estivill, X.;
Gasparini, P.; Nunes, V.; Palacin, M.: Genetic heterogeneity in cystinuria:
the SLC3A1 gene is linked to type I but not to type III cystinuria. Proc.
Nat. Acad. Sci. 92: 9667-9671, 1995.

5. Goodyer, P. R.; Clow, C.; Reade, T.; Girardin, C.: Prospective
analysis and classification of patients with cystinuria identified
in a newborn screening program. J. Pediat. 122: 568-572, 1993.

6. Horsford, J.; Saadi, I.; Raelson, J.; Goodyer, P. R.; Rozen, R.
: Molecular genetics of cystinuria in French Canadians: identification
of four novel mutations in type I patients. Kidney Int. 49: 1401-1406,
1996.

7. Lee, W.-S.; Wells, R. G.; Sabbag, R. V.; Mohandas, T. K.; Hediger,
M. A.: Cloning and chromosomal localization of a human kidney cDNA
involved in cystine, dibasic, and neutral amino acid transport. J.
Clin. Invest. 91: 1959-1963, 1993.

8. Pras, E.; Arber, N.; Aksentijevich, I.; Katz, G.; Schapiro, J.
M.; Prosen, L.; Gruberg, L.; Harel, D.; Liberman, U.; Weissenbach,
J.; Pras, M.; Kastner, D. L.: Localization of a gene causing cystinuria
to chromosome 2p. Nature Genet. 6: 415-419, 1994.

9. Pras, E.; Raben, N.; Golomb, E.; Arber, N.; Aksentijevich, I.;
Schapiro, J. M.; Harel, D.; Katz, G.; Liberman, U.; Pras, M.; Kastner,
D. L.: Mutations in the SLC3A1 transporter gene in cystinuria. Am.
J. Hum. Genet. 56: 1297-1303, 1995.

10. Pras, E.; Sood, R.; Raben, N.; Aksentijevich, I.; Chen, X.; Kastner,
D. L.: Genomic organization of SLC3A1, a transporter gene mutated
in cystinuria. Genomics 36: 163-167, 1996.

11. Wells, R. G.; Hediger, M. A.: Cloning of a rat kidney cDNA that
stimulates dibasic and neutral amino acid transport and has sequence
similarity to glucosidases. Proc. Nat. Acad. Sci. 89: 5596-5600,
1992.

12. Yan, N.; Mosckovitz, R.; Gerber, L. D.; Mathew, S.; Murty, V.
V. V. S.; Tate, S. S.; Udenfriend, S.: Characterization of the promoter
region of the gene for the rat neutral and basic amino acid transporter
and chromosomal localization of the human gene. Proc. Nat. Acad.
Sci. 91: 7548-7552, 1994.

13. Zhang, X.-X.; Rozen, R.; Hediger, M. A.; Goodyer, P.; Eydoux,
P.: Assignment of the gene for cystinuria (SLC3A1) to human chromosome
2p21 by fluorescence in situ hybridization. Genomics 24: 413-414,
1994.

*FIELD* CN
Moyra Smith - updated: 12/31/1996
Moyra Smith - updated: 9/13/1996

*FIELD* CD
Victor A. McKusick: 6/4/1993

*FIELD* ED
mark: 12/31/1996
mark: 9/13/1996
terry: 9/12/1996
terry: 9/4/1996
mark: 5/2/1996
mark: 3/26/1996
mark: 3/15/1996
terry: 3/11/1996
terry: 11/7/1995
mark: 7/7/1995
carol: 1/9/1995
carol: 6/8/1993
carol: 6/4/1993

*RECORD*
*FIELD* NO
104615
*FIELD* TI
*104615 AMINO ACID TRANSPORTER, CATIONIC; ATRC1
CATIONIC AMINO ACID TRANSPORTER-1
*FIELD* TX
Susceptibility to murine ecotropic retroviruses is attributed to the
binding of the virus envelope to the membrane receptor encoded by the
Rec-1 gene. The protein was identified as the principal transporter of
the cationic amino acids, arginine, lysine, and ornithine in mouse cells
(Kim et al., 1991). Oie et al. (1978), Ruddle et al. (1978), and Kozak
et al. (1990) mapped the Rec-1 gene to mouse chromosome 5 by analysis of
murine-hamster somatic cell hybrids. Using a human cDNA obtained by
homology to Rec-1, Albritton et al. (1992) determined the location of
the human cationic amino acid transporter by somatic cell genetics, in
situ hybridization, and RFLP linkage analysis. The studies indicated
that ATRC1 is located at 13q12-q14, closely linked to ATP1AL1 (182360).
The CEPH consortium linkage map of chromosome 13 published by Bowcock et
al. (1993) showed ATRC1 to be distal to ATP1AL1.

*FIELD* RF
1. Albritton, L. M.; Bowcock, A. M.; Eddy, R. L.; Morton, C. C.; Tseng,
L.; Farrer, L. A.; Cavalli-Sforza, L. L.; Shows, T. B.; Cunningham,
J. M.: The human cationic amino acid transporter (ATRC1): physical
and genetic mapping to 13q12-q14. Genomics 12: 430-434, 1992.

2. Bowcock, A. M.; Gerken, S. C.; Barnes, R. I.; Shiang, R.; Jabs,
E. W.; Warren, A. C.; Antonarakis, S.; Retief, A. E.; Vergnaud, G.;
Leppert, M.; Lalouel, J.-M.; White, R. L.; Cavalli-Sforza, L. L.:
The CEPH consortium linkage map of human chromosome 13. Genomics 16:
486-496, 1993.

3. Kim, J. W.; Closs, E. I.; Albritton, L. M.; Cunningham, J. M.:
Transport of cationic amino acids by the mouse ecotropic retrovirus
receptor. Nature 352: 725-728, 1991.

4. Kozak, C. A.; Albritton, L. M.; Cunningham, J. M.: Genetic mapping
of a cloned sequence responsible for susceptibility to ecotropic murine
leukemia viruses. J. Virol. 64: 3119-3121, 1990.

5. Oie, H. K.; Gazdar, A. F.; Lalley, P. A.; Russell, E. K.; Minna,
J. D.; DeLarco, J.; Todaro, G. J.; Francke, U.: Mouse chromosome
5 codes for ecotropic murine leukaemia virus cell-surface receptor.
Nature 274: 60-62, 1978.

6. Ruddle, N. H.; Conta, B. S.; Leinwand, L.; Kozak, C.; Ruddle, F.;
Besmer, P.; Baltimore, D.: Assignment of the receptor for ecotropic
murine leukemia virus to mouse chromosome 5. J. Exp. Med. 148:
451-465, 1978.

*FIELD* CD
Victor A. McKusick: 2/20/1992

*FIELD* ED
jason: 6/9/1994
carol: 5/26/1993
supermim: 3/16/1992
carol: 3/6/1992
carol: 2/21/1992
carol: 2/20/1992

*RECORD*
*FIELD* NO
104620
*FIELD* TI
*104620 AMINOACYLASE-1; ACY1
N-ACYL-L-AMINO-ACID AMIDOHYDROLASE;;
ACYLASE
*FIELD* TX
Aminoacylase-1 (EC 3.5.1.14) is a homodimeric zinc-binding
metalloenzyme. Naylor et al. (1979) developed a novel method for
visualizing isozymes of cultured somatic cells after zone
electrophoresis ('bioautography') and applied it in the study of
interspecific cell hybrids to assign the gene for aminoacylase-1 to
chromosome 3. Aminoacylase-1, a cytosolic enzyme with a wide range of
tissue expression, cleaves acylated L-amino acids (except L-aspartate)
into L-amino acids and an acyl group. L-aspartate derivatives are
cleaved by aminoacylase-2 (aspartoacylase; EC 3.5.1.15; 271900). A
genetic polymorphism of this enzyme was demonstrated in the mouse
(Naylor et al., 1979). The principle of bioautography is the
visualization of an enzyme by a zone of bacterial growth that results
when an auxotrophic bacterium is supplied a required product by the
enzyme. Voss et al. (1980) confirmed the assignment to chromosome 3.
They also described a method of colorimetric-enzymatic determination on
electrophoresis. They showed that ACY1 hydrolyzes both acetyl-methionine
and acetyl-glutamate. They suggested that the most likely site of the
locus is 3p21-3pter. By studying recombinant inbred strains of mice,
Naylor et al. (1982) found that aminoacylase-1 and beta-galactosidase A
are 10.7 map units apart (on mouse chromosome 9). Since transferrin is
closely linked to these 2 loci in the mouse, they suggested that the
human transferrin gene may be on chromosome 3, which is known to carry
ACY1 and GLB1. Nadeau (1986) demonstrated that the mouse homologs for
the human genes TF, ACY1, and GLB1 are in that order on mouse chromosome
9. He took this to mean that aminoacylase-1 and beta-galactosidase mark
a chromosomal segment that has been conserved since divergence of
lineages leading to man and mouse. Whereas normally aminoacylase-1 is
expressed in all nucleated human cells (it is not expressed in
erythrocytes), Miller et al. (1989) found that the enzyme was
undetectable in 4 of 29 small cell lung cancer (SCLC) cell lines and in
1 of 8 SCLC tumors (182280). The finding supports the hypothesis that
inactivation of both alleles of specific chromosome 3p genes occurs in
SCLC in a fashion analogous to RB gene inactivation in retinoblastoma
and suggests that the ACY1 gene may be closely linked to the putative
SCLC tumor suppressor gene. Using a panel of monoclonal antibodies
specific for aminoacylase-1, Miller et al. (1989, 1990) isolated a cDNA
from a lambda gt11 expression library. Using a panel of somatic cell
hybrids containing fragments of chromosome 3, they localized the gene to
distal 3p21.1. An additional restriction fragment to which the probe
hybridized was assigned to chromosome 18 and appeared to be expressed as
an mRNA species. Jones et al. (1991) compared this enzyme with
acylpeptide hydrolase (APH; 102645), which also maps to 3p21 and shares
functional features. By pulsed field gel electrophoretic (PFGE) studies,
Gemmill et al. (1991) showed that ACY1 is physically linked to D3S2
within a 2.5-Mb region in 3p21.1, but DNF15S2, a marker for acylpeptide
hydrolase, was shown by Boldog et al. (1989), also by PFGE studies, not
to be linked to D3S2. Ginzinger et al. (1992) suggested that ACY1 (at
3p21.1) may be an 'ancestral copy' of the APH gene at 3p21.3.

Cook et al. (1993) isolated an ACY1 cDNA of 1,438 bp with an open
reading frame of 1,224 bp coding for a putative protein of 408 amino
acids with a predicted molecular mass of 45,882 Da. Sequence analysis
demonstrated no homology to previously reported cDNA or protein
sequences and established ACY1 as the first member of a new family of
zinc-binding enzymes. The subcellular localization of ACY1 was
established to be cytosolic by flow cytometry. Southern and Northern
analyses of ACY1 in SCLC cell lines failed to demonstrate any gross
abnormalities of the ACY1 structural gene or instances of absent or
aberrantly sized mRNA, respectively.

*FIELD* SA
Miller et al. (1989)
*FIELD* RF
1. Boldog, F.; Erlandsson, R.; Klein, G.; Sumegi, J.: Long-range
restriction enzyme maps of DNF15S2, D3S2 and c-raf1 loci on the short
arm of human chromosome 3. Cancer Genet. Cytogenet. 42: 295-306,
1989.

2. Cook, R. M.; Burke, B. J.; Buchhagen, D. L.; Minna, J. D.; Miller,
Y. E.: Human aminoacylase-1: cloning, sequence, and expression analysis
of a chromosome 3p21 gene inactivated in small cell lung cancer. J.
Biol. Chem. 268: 17010-17017, 1993.

3. Gemmill, R. M.; Varella-Garcia, M.; Smith, D. I.; Erickson, P.;
Golembieski, W.; Miller, Y.; Coyle-Morris, J.; Tommerup, N.; Drabkin,
H. A.: A 2.5 Mb physical map within 3p21.1 spans the breakpoint associated
with Greig cephalopolysyndactyly syndrome. Genomics 11: 93-102,
1991.

4. Ginzinger, D. G.; Shridhar, V.; Baldini, A.; Taggart, R. T.; Miller,
O. J.; Smith, D. I.: The human loci DNF15S2 and D3S94 have a high
degree of sequence similarity to acyl-peptide hydrolase and are located
at 3p21.3. Am. J. Hum. Genet. 50: 826-833, 1992.

5. Jones, W. M.; Scaloni, A.; Bossa, F.; Popowicz, A. M.; Schneewind,
O.; Manning, J. M.: Genetic relationship between acylpeptide hydrolase
and acylase, two hydrolytic enzymes with similar binding but different
catalytic specificities. Proc. Nat. Acad. Sci. 88: 2194-2198, 1991.

6. Miller, Y. E.; Drabkin, H.; Jones, C.; Fisher, J. H.: Aminoacylase-1:
cDNA isolation, regional assignment to chromosome 3p21.1 and identification
of a cross-hybridizing sequence on chromosome 18.  (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A28 only, 1989.

7. Miller, Y. E.; Drabkin, H.; Jones, C.; Fisher, J. H.: Human aminoacylase-1:
cloning, regional assignment to distal chromosome 3p21.1, and identification
of a cross-hybridizing sequence on chromosome 18. Genomics 8: 149-154,
1990.

8. Miller, Y. E.; Minna, J. D.; Gazdar, A. F.: Lack of expression
of aminoacylase-1 in small cell lung cancer: evidence for inactivation
of genes encoded by chromosome 3p. J. Clin. Invest. 83: 2120-2124,
1989.

9. Nadeau, J. H.: A chromosomal segment conserved since divergence
of lineages leading to man and mouse: the gene order of aminoacylase-1,
transferrin, and beta-galactosidase on mouse chromosome 9. Genet.
Res. 48: 175-178, 1986.

10. Naylor, S. L.; Elliott, R. W.; Brown, J. A.; Shows, T. B.: Mapping
of aminoacylase-1 and beta-galactosidase-A to homologous regions of
human chromosome 3 and mouse chromosome 9 suggests location of additional
genes. Am. J. Hum. Genet. 34: 235-244, 1982.

11. Naylor, S. L.; Shows, T. B.; Klebe, R. J.: Bioautographic visualization
of aminoacylase-1: assignment of the structural gene ACY-1 to chromosome
3 in man. Somat. Cell Genet. 5: 11-21, 1979.

12. Voss, R.; Lerer, I.; Povey, S.; Solomon, E.; Bobrow, M.: Confirmation
and further regional assignment of aminoacylase 1 (ACY-1) on human
chromosome 3 using a simplified detection method. Ann. Hum. Genet. 44:
1-10, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 3/19/1994
carol: 6/8/1992
carol: 6/5/1992
supermim: 3/16/1992
carol: 3/25/1991
carol: 9/8/1990

*RECORD*
*FIELD* NO
104640
*FIELD* TI
*104640 AMPHIREGULIN; AREG
SCHWANNOMA-DERIVED GROWTH FACTOR; SDGF
*FIELD* TX
Shoyab et al. (1988) isolated a novel glycoprotein termed amphiregulin
which inhibits growth of certain human tumor cells and stimulates
proliferation of human fibroblasts and other normal and tumor cells.
Shoyab et al. (1989) determined the complete amino acid sequence. The
truncated form contains 78 amino acids, whereas a larger form contains 6
additional amino acids at the amino-terminal end. The carboxyl-terminal
half, residues 46 to 84, exhibited striking homology to the epidermal
growth factor (EGF) family of proteins. Amphiregulin binds to the EGF
receptor but not as well as EGF does. Disteche et al. (1989) used a
combination of in situ hybridization and somatic cell hybrid methods to
map the amphiregulin gene to human chromosome 4q13-q21. Pathak et al.
(1995) demonstrated that the Areg gene maps to mouse chromosome 5, where
it is tightly linked to the gene for Btc (600345).

To identify new growth factors important to the development of the
nervous system, Kimura et al. (1990) screened serum-free
growth-conditioned media from many clonal cell lines for the presence of
mitogens for CNS glial cells. A cell line secreting a potent glial
mitogen was established from a schwannoma of the sciatic nerve. The
cells of the tumor, named JS1 cells, were adapted to clonal culture and
identified as Schwann cells. Schwann cells secrete an autocrine mitogen
and human schwannoma extracts have mitogenic activity on glial cells.
Kimura et al. (1990) reported the purification and characterization of
the mitogenic molecule, designated schwannoma-derived growth factor
(SDGF), from the growth-conditioned medium of the JS1 Schwann cell line.
SDGF belongs to the epidermal growth factor family and is an autocrine
growth factor as well as a mitogen for astrocytes, Schwann cells, and
fibroblasts.

*FIELD* RF
1. Disteche, C. M.; Plowman, G. D.; Gronwald, R. G. K.; Kelly, J.;
Bowen-Pope, D.; Adler, D. A.; Murray, J. C.: Mapping of the amphiregulin
and the platelet-growth factor receptor alpha genes to the proximal
long arm of chromosome 4. (Abstract) Cytogenet. Cell Genet. 51:
990 only, 1989.

2. Kimura, H.; Fischer, W. H.; Schubert, D.: Structure, expression
and function of a schwannoma-derived growth factor. Nature 348:
257-260, 1990.

3. Pathak, B. G.; Gilbert, D. J.; Harrison, C. A.; Luetteke, N. C.;
Chen, X.; Klagsbrun, M.; Plowman, G. D.; Copeland, N. G.; Jenkins,
N. A.; Lee, D. C.: Mouse chromosomal location of three EGF receptor
ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding
EGF (Hegfl). Genomics 28: 116-118, 1995.

4. Shoyab, M.; McDonald, V. L.; Bradley, J. G.; Todaro, G. J.: Amphiregulin:
a bifunctional growth-modulating glycoprotein produced by the phorbol
12-myristate 13-acetate-treated human breast adenocarcinoma cell line
MCF-7. Proc. Nat. Acad. Sci. 85: 6528-6532, 1988.

5. Shoyab, M.; Plowman, G. D.; McDonald, V. L.; Bradley, J. G.; Todaro,
G. J.: Structure and function of human amphiregulin: a member of
the epidermal growth factor family. Science 243: 1074-1076, 1989.

*FIELD* CN
Alan F. Scott - edited: 01/08/1997

*FIELD* CD
Victor A. McKusick: 4/4/1989

*FIELD* ED
mark: 01/08/1997
mark: 8/17/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
carol: 6/1/1989

*RECORD*
*FIELD* NO
104650
*FIELD* TI
*104650 AMYLASE, PANCREATIC, A; AMY2A
*FIELD* TX
Polymorphism was determined by agar gel electrophoresis. Data on gene
frequencies of allelic variants were tabulated by Roychoudhury and Nei
(1988).

Kamaryt et al. (1971) assigned the locus to chromosome 1 by study of
linkage with the 'uncoiler' chromosomal variant (1qh+) used by Donahue
et al. (1968) in assigning the Duffy blood group locus (110700) to
chromosome 1. Hill et al. (1972) demonstrated probable linkage between
the AMY2 locus and the Duffy blood group locus. In the mouse, Hjorth et
al. (1980) concluded that at least 4 structural gene loci code for
pancreatic amylase, whereas only a single gene, different from any of
the pancreatic genes, codes for salivary amylase. These genes are on
mouse chromosome 3. Young et al. (1981) showed that in the mouse two
different tissue-specific mRNAs are coded by a single gene. Using a
human genomic DNA segment that hybridizes with rat pancreatic amylase
cDNA to study human-mouse somatic cell hybrids, Tricoli and Shows (1984)
assigned the amylase gene(s) to region 1p22-p21. The human cell studied
in the hybrid had a translocation involving chromosome 1. RFLPs at the
amylase loci were described. Groot et al. (1988) suggested that there
are 2 pancreatic amylase genes in the human genome, designated AMY2A and
AMY2B (104660). Pronk et al. (1982) presented evidence they interpreted
as indicating duplication of the salivary amylase locus also. In a full
exposition of the structure of the part of the genome containing the
alpha-amylase multigene family, Groot et al. (1989) described 2
haplotypes consisting of different numbers of salivary amylase genes:
the short haplotype contains 2 pancreatic genes, termed by them AMY2A
and AMY2B, and 1 salivary amylase gene, termed by them AMY1C, arranged
in the order 2B-2A-1C and encompassing a total length of approximately
100 kb. The long haplotype spans about 300 kb and contains 6 additional
genes arranged in 2 repeats, each of which consists of 2 salivary
amylase genes, designated AMY1A and AMY1B, and a pseudogene lacking the
first 3 exons (AMYP1). The order of the amylase genes within the repeat
is 1A-1B-P1. All genes are in a head-to-tail orientation except AMY1B,
which has a reverse orientation with respect to the other genes. A
general designation 2B-2A-(1A-1B-P)n-1C can describe these haplotypes, n
being 0 and 2 for the short and long haplotypes, respectively. Groot et
al. (1989) presented evidence for the existence of additional
haplotypes. Groot et al. (1990) proposed that the alpha-amylase
multigene family evolved through unequal, homologous, inter- and
intrachromosomal crossovers. Groot et al. (1991) reported observations
on polymorphic DNA patterns and interpreted them in light of this
hypothesis.

Brock et al. (1988), Jorgensen et al. (1984), and Sjolund et al. (1991)
reported familial selective deficiency of pancreatic amylase. The
patients of Sjolund et al. (1991) were unrelated women aged 49 and 38
years. In the second woman reduced levels of serum amylase were found in
a sister and her only son. The sister had a daughter with 'slightly
reduced pancreatic amylase activity in serum.' In young children,
physiologically low levels of pancreatic amylase activity are observed.
The adult level of activity in the duodenal juice is reached at the age
of 18 months and in serum at about age 7 years, although delayed
maturation has been described.

*FIELD* SA
Carfagna et al. (1976); Merritt et al. (1973); Merritt et al. (1973);
Merritt et al. (1972); Rosenblum and Merritt (1978); Spence et al.
(1977)
*FIELD* RF
1. Brock, A.; Mortensen, P. B.; Mortensen, B. B.; Roge, H. R.: Familial
occurrence of diminished pancreatic amylase in serum--a 'silent' Amy-2
allelic variant?. Clin. Chem. 34: 1516-1517, 1988.

2. Carfagna, M.; Gaudio, L.; Patricolo, M. R.; Spadacenta, F.: Pancreatic
amylase polymorphism: another example of a distinctive gene frequency
among Sardinians. Hum. Hered. 26: 59-65, 1976.

3. Donahue, R. P.; Bias, W. B.; Renwick, J. H.; McKusick, V. A.:
Probable assignment of the Duffy blood group locus to chromosome 1
in man. Proc. Nat. Acad. Sci. 61: 949-955, 1968.

4. Groot, P. C.; Bleeker, M. J.; Pronk, J. C.; Arwert, F.; Mager,
W. H.; Planta, R. J.; Eriksson, A. W.; Frants, R. R.: Human pancreatic
amylase is encoded by two different genes. Nucleic Acids Res. 16:
4724 only, 1988.

5. Groot, P. C.; Bleeker, M. J.; Pronk, J. C.; Arwert, F.; Mager,
W. H.; Planta, R. J.; Eriksson, A. W.; Frants, R. R.: The human alpha-amylase
multigene family consists of haplotypes with variable numbers of genes.
Genomics 5: 29-42, 1989.

6. Groot, P. C.; Mager, W. H.; Frants, R. R.: Interpretation of polymorphic
DNA patterns in the human alpha-amylase multigene family. Genomics 10:
779-785, 1991.

7. Groot, P. C.; Mager, W. H.; Henriquez, N. V.; Pronk, J. C.; Arwert,
F.; Planta, R. J.; Eriksson, A. W.; Frants, R. R.: Evolution of the
human alpha-amylase multigene family through unequal, homologous,
and inter- and intrachromosomal crossovers. Genomics 8: 97-105,
1990.

8. Hill, C. J.; Rowe, S. I.; Lovrien, E. W.: Probable genetic linkage
between human serum amylase (AMY-2) and Duffy blood groups. Nature 235:
162-163, 1972.

9. Hjorth, J. P.; Lusis, A. J.; Nielsen, J. T.: Multiple structural
genes for mouse amylase. Biochem. Genet. 18: 281-302, 1980.

10. Jorgensen, H. R.; Kristensen, B.; Mortensen, P. B.: Familial
incidence of reduced activity of pancreas correlated with amylase-isoenzyme
in the serum. Ugeskr. Laeger 146: 657-659, 1984.

11. Kamaryt, J.; Adamek, R.; Vrba, M.: Possible linkage between uncoiler
chromosome Un 1 and amylase polymorphism Amy 2 loci. Humangenetik 11:
213-220, 1971.

12. Merritt, A. D.; Lovrien, E. W.; Rivas, M. L.; Conneally, P. M.
: Human amylase loci: genetic linkage with the Duffy blood group locus
and assignment to linkage group I. Am. J. Hum. Genet. 25: 523-538,
1973.

13. Merritt, A. D.; Rivas, M. L.; Bixler, D.; Newell, R.: Salivary
and pancreatic amylase: electrophoretic characterizations and genetic
studies. Am. J. Hum. Genet. 25: 510-522, 1973.

14. Merritt, A. D.; Rivas, M. L.; Ward, J. C.: Evidence for close
linkage of human amylase loci. Nature N.B. 239: 243-244, 1972.

15. Pronk, J. C.; Frants, R. R.; Jansen, W.; Eriksson, A. W.; Tonino,
G. J. M.: Evidence for duplication of the human salivary amylase
gene. Hum. Genet. 60: 32-35, 1982.

16. Rosenblum, B. B.; Merritt, A. D.: Human pancreatic alpha-amylase:
phenotypic codominance and new electrophoretic variants. Am. J.
Hum. Genet. 30: 434-441, 1978.

17. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

18. Sjolund, K.; Haggmark, A.; Ihse, I.; Skude, G.; Karnstrom, U.;
Wikander, M.: Selective deficiency of pancreatic amylase. Gut 32:
546-548, 1991.

19. Spence, M. A.; Sparkes, R. S.; Heckenlively, J. R.; Pearlman,
J. T.; Zedalis, D.; Sparkes, M.; Crist, M.; Tideman, S.: Probable
genetic linkage between autosomal dominant retinitis pigmentosa (RP)
and amylase (AMY-2): evidence of an RP locus on chromosome 1. Am.
J. Hum. Genet. 29: 397-404, 1977.

20. Tricoli, J. V.; Shows, T. B.: Regional assignment of human amylase
(AMY) to p22-p21 of chromosome 1. Somat. Cell Molec. Genet. 10:
205-210, 1984.

21. Young, R. A.; Hagenbuchle, O.; Schibler, U.: A single mouse alpha-amylase
gene specifies two different tissue-specific mRNAs. Cell 23: 451-458,
1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
pfoster: 5/12/1994
mimadm: 4/26/1994
warfield: 3/23/1994
supermim: 3/16/1992
carol: 2/18/1992
carol: 7/24/1991

*RECORD*
*FIELD* NO
104660
*FIELD* TI
*104660 AMYLASE, PANCREATIC, B; AMY2B
*FIELD* TX
See 104650.

*FIELD* CD
Victor A. McKusick: 9/15/1988
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 9/15/1988
*RECORD*
*FIELD* NO
104700
*FIELD* TI
*104700 AMYLASE, SALIVARY; AMY1
AMYLASE, SALIVARY, A; AMY1A
*FIELD* TX
The alpha-amylases hydrolyze alpha-1,4-glucoside bonds in polymers of
glucose units. Kamaryt and Laxova (1965, 1966) found 2 amylase
isoenzymes in serum, one produced by the salivary gland and the second
by the pancreas. In 11 of 120 children, a duplication of pancreatic
enzyme band was found on starch gel electrophoresis and in each case 1
parent also showed the duplication. In the mouse the salivary and
pancreatic amylases are determined by genes at closely linked loci (Sick
and Nielsen, 1964). The separate loci in the human were designated AMY1
(salivary) and AMY2 (pancreatic). Polymorphism of both the salivary and
the pancreatic serum amylases has been demonstrated in man. Ward et al.
(1971) studied amylase in saliva and identified electrophoretic
variants. Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

By in situ hybridization combined with high resolution cytogenetics,
Zabel et al. (1983) assigned the amylase gene to 1p21, the POMC gene to
2p23, and the somatostatin gene to 3q28. Pronk et al. (1982) presented
evidence they interpreted as indicating duplication of the salivary
amylase locus. Using amylase DNA probes in somatic cell hybrids, Tricoli
and Shows (1984) mapped the amylase genes to the 1p22.1-p21 region.
Nishide et al. (1986) showed that the human salivary alpha-amylase gene
is about 10 kb long and has 10 introns. Gumucio et al. (1988) isolated
cosmid clones containing 250 kb of genomic DNA from the human amylase
gene cluster. These clones were found to contain 7 distinct amylase
genes: 2 pancreatic amylase genes, 3 salivary amylase genes, and 2
truncated pseudogenes. Intergenic distances of 17 to 22 kb separated the
amylase gene copies. Dracopoli and Meisler (1990) used a (CA)n repeat
sequence immediately upstream from the gamma-actin pseudogene associated
with the AMY2B gene (104660) in a study of 40 CEPH families. By PCR
amplification of genomic DNA, they identified 6 alleles with (CA)n
lengths of 16 to 21 repeats. The average heterozygosity was 0.70.
Multipoint linkage analysis showed that the amylase gene cluster is
located distal to NGFB (162030). Groot et al. (1990) presented
structural analyses of the human amylase gene cluster that allowed them
to construct a model for the evolution of this family of genes by a
number of consecutive events involving inter- and intrachromosomal
crossovers.

*FIELD* SA
de Soyza  (1978); Ishizaki et al. (1985); McGeachin  (1968); Muenke
et al. (1984); Pronk et al. (1984); Tricoli and Shows (1984); Wiebauer
et al. (1985)
*FIELD* RF
1. de Soyza, K.: Polymorphism of human salivary amylase: a preliminary
communication. Hum. Genet. 45: 189-192, 1978.

2. Dracopoli, N. C.; Meisler, M. H.: Mapping the human amylase gene
cluster on the proximal short arm of chromosome 1 using a highly informative
(CA)n repeat. Genomics 7: 97-102, 1990.

3. Groot, P. C.; Mager, W. H.; Henriquez, N. V.; Pronk, J. C.; Arwert,
F.; Planta, R. J.; Eriksson, A. W.; Frants, R. R.: Evolution of the
human alpha-amylase multigene family through unequal, homologous,
and inter- and intrachromosomal crossovers. Genomics 8: 97-105,
1990.

4. Gumucio, D. L.; Wiebauer, K.; Caldwell, R. M.; Samuelson, L. C.;
Meisler, M. H.: Concerted evolution of human amylase genes. Molec.
Cell. Biol. 8: 1197-1205, 1988.

5. Ishizaki, K.; Noda, A.; Ikenaga, M.; Ida, K.; Omoto, K.; Nakamura,
Y.; Matsubara, K.: Restriction fragment length polymorphism detected
by human salivary amylase cDNA. Hum. Genet. 71: 261-262, 1985.

6. Kamaryt, J.; Laxova, R.: Amylase heterogeneity: some genetic and
clinical aspects. Humangenetik 1: 579-586, 1965.

7. Kamaryt, J.; Laxova, R.: Amylase heterogeneity variants in man. Humangenetik 3:
41-45, 1966.

8. McGeachin, R. L.: Multiple molecular forms of amylase. Ann. N.Y.
Acad. Sci. 151: 208-212, 1968.

9. Muenke, M.; Lindgren, V.; de Martinville, B.; Francke, U.: Comparative
analysis of mouse-human hybrids with rearranged chromosomes 1 by in
situ hybridization and Southern blotting: high resolution mapping
of NRAS, NGFB, and AMY on chromosome 1. Somat. Cell Molec. Genet. 10:
589-599, 1984.

10. Nishide, T.; Nakamura, Y.; Emi, M.; Yamamoto, T.; Ogawa, M.; Mori,
T.; Matsubara, K.: Primary structure of human salivary alpha-amylase
gene. Gene 41: 299-304, 1986.

11. Pronk, J. C.; Frants, R. R.; Jansen, W.; Eriksson, A. W.; Tonino,
G. J. M.: Evidence for duplication of the human salivary amylase
gene. Hum. Genet. 60: 32-35, 1982.

12. Pronk, J. C.; Jansen, W. J.; Pronk, A.; Pol, C. F. A. M.; Frants,
R. R.; Eriksson, A. W.: Salivary protein polymorphism in Kenya: evidence
for a new AMY1 allele. Hum. Hered. 34: 212-216, 1984.

13. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

14. Sick, K.; Nielsen, J. T.: Genetics of amylase isozymes in the
mouse. Hereditas 51: 291-296, 1964.

15. Tricoli, J. V.; Shows, T. B.: Assignment of alpha-amylase genes
to the p22.1-p21 region of chromosome 1. (Abstract) Cytogenet. Cell
Genet. 37: 597 only, 1984.

16. Tricoli, J. V.; Shows, T. B.: Regional assignment of human amylase
(AMY) to p22-p21 of chromosome 1. Somat. Cell Molec. Genet. 10:
205-210, 1984.

17. Ward, J. C.; Merritt, A. D.; Bixler, D.: Human salivary amylase:
genetics of electrophoretic variants. Am. J. Hum. Genet. 23: 403-409,
1971.

18. Wiebauer, K.; Gumucio, D. L.; Jones, J. M.; Caldwell, R. M.; Hartle,
H. T.; Meisler, M. H.: A 78-kilobase region of mouse chromosome 3
contains salivary and pancreatic amylase genes and a pseudogene. Proc.
Nat. Acad. Sci. 82: 5446-5449, 1985.

19. Zabel, B. U.; Naylor, S. L.; Sakaguchi, A. Y.; Bell, G. I.; Shows,
T. B.: High-resolution chromosomal localization of human genes for
amylase, proopiomelanocortin, somatostatin, and a DNA fragment (D3S1)
by in situ hybridization. Proc. Nat. Acad. Sci. 80: 6932-6936, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/27/1996
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 2/27/1992
carol: 10/21/1991
carol: 12/14/1990
carol: 12/6/1990

*RECORD*
*FIELD* NO
104701
*FIELD* TI
*104701 AMYLASE, SALIVARY, B; AMY1B
*FIELD* TX
To investigate the genomic organization of the human alpha-amylase
genes, Groot et al. (1989) isolated the pertinent genes from a cosmid
library constructed of DNA from an individual expressing 3 different
salivary amylase allozymes. From the restriction maps of the overlapping
cosmids and a comparison of these maps with the restriction enzyme
patterns of DNA from the donor and family members, they were able to
identify 2 haplotypes consisting of very different numbers of salivary
amylase genes. The short haplotype contained 2 pancreatic genes, AMY2A
and AMY2B, and 1 salivary amylase gene, AMY1C, arranged in the order
2B--2A--1C, encompassing a total length of approximately 100 kb. The
long haplotype spanned about 300 kb and contained 6 additional genes
arranged in 2 repeats, each one consisting of 2 salivary genes, AMY1A
and AMY1B, and a pseudogene lacking the first 3 exons, AMYP1. The order
of the amylase genes within the repeat was 1A--1B--P1. All of the genes
were in a head-to-tail orientation except AMY1B, which had the reverse
orientation with respect to the other genes.

*FIELD* RF
1. Groot, P. C.; Bleeker, M. J.; Pronk, J. C.; Arwert, F.; Mager,
W. H.; Planta, R. J.; Eriksson, A. W.; Frants, R. R.: The human alpha-amylase
multigene family consists of haplotypes with variable numbers of genes.
Genomics 5: 29-42, 1989.

*FIELD* CD
Victor A. McKusick: 10/21/1991

*FIELD* ED
supermim: 3/16/1992
carol: 1/10/1992
carol: 10/21/1991

*RECORD*
*FIELD* NO
104702
*FIELD* TI
*104702 AMYLASE, SALIVARY, C; AMY1C
*FIELD* TX
See 104701.

*FIELD* CD
Victor A. McKusick: 10/21/1991
*FIELD* ED
supermim: 3/16/1992
carol: 10/21/1991
*RECORD*
*FIELD* NO
104740
*FIELD* TI
*104740 AMYLOID BETA A4 PRECURSOR PROTEIN-LIKE; APPL1
*FIELD* TX
Jenkins et al. (1987) used single-stranded beta-amyloid cDNA as a probe
for in situ chromosome hybridization in Epstein-Barr virus transformed
lymphoblastoid cells from 3 patients with familial Alzheimer disease
(from 2 different families). Although a concentration of grains was
found on chromosome 21, a significantly increased number of grains were
found on chromosome 9 in the region 9q31-qter. The functional
significance of the hybridizing sequence is not known; hence, the
designation 'like.'

*FIELD* RF
1. Jenkins, E. C.; Devine-Gage, E. A.; Yao, X.-L.; Houck, G. E., Jr.;
Brown, W. T.; Wisniewski, H. M.; Robakis, N. K.: In-situ hybridisation
of the beta-amyloid protein probe to chromosome 9 in patients with
familial Alzheimer's disease.  (Letter) Lancet II: 1155-1156, 1987.

*FIELD* CD
Victor A. McKusick: 9/21/1988

*FIELD* ED
carol: 10/15/1993
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/27/1990
ddp: 10/26/1989
root: 9/27/1988

*RECORD*
*FIELD* NO
104750
*FIELD* TI
*104750 SERUM AMYLOID A1; SAA1
AMYLOID A, SERUM; SAA
*FIELD* TX
The serum amyloid A proteins are chemically and antigenically related to
the A proteins of secondary amyloidosis and are associated with the
plasma high-density lipoproteins. Bausserman et al. (1980) isolated 6
polymorphic forms of SAA that have an identical molecular weight and
COOH-terminal sequence but different electrophoretic mobilities at
alkaline pH. In further studies of 4 of the 6, Bausserman et al. (1982)
demonstrated differences in the NH2-terminal residues of certain ones
and interpreted this as indicating that some of the SAA polymorphs are
products of different genes. Serum amyloid A is the proteolytic cleavage
product of an acute phase reactant. Upon cleavage from the parent
product, called SAAL (L = liver), AA can aggregate into insoluble
antiparallel beta-pleated sheet fibrils which cause the systemic
complications known as amyloidosis. Sack (1983) cloned the human genes
for SAAL. Kluve-Beckerman et al. (1986) cloned human SAA-specific cDNAs
and determined their nucleotide sequence. An SAA gene has been assigned
to mouse chromosome 7 by study of recombinant inbred strains (Taylor and
Rowe, 1984). By means of a cDNA probe for Southern analysis of DNA from
human/mouse somatic cell hybrids, Kluve-Beckerman et al. (1986) assigned
the SAA gene to 11pter-p11. They demonstrated RFLPs of the gene. The
distal part of 11p has homology of synteny with mouse 7, whereas the
proximal part has homology with mouse 2. The most proximal locus
homologous on mouse 7 is LDHA (150000) which is located on
11p12.08-p12.03. The most distal locus homologous on mouse 2 is acid
phosphatase-1 (171650) at 11p12-p11. Possibly the assignment can be
narrowed a bit, to 11pter-p12. Sack et al. (1989) confirmed the
assignment of the SAA gene to the short arm of chromosome 11 and
concluded that the SAA gene family comprises at least 3 members in the
haploid human genome. Strachan et al. (1989) presented evidence for 2
SAA loci. See SAA2 (104751). Stevens et al. (1993) indicated that cDNA
probe pSAA82 detects 3 serum amyloid A loci on chromosome 11p. SAA1 and
SAA2 have 90% nucleotide identity in exon and intron sequences (Betts et
al., 1991), whereas SAA3 has an average of 70% identity with SAA1 and
SAA2 (Kluve-Beckerman et al., 1991). SAA3 is a pseudogene, while SAA4
(104752) is a low-level, constitutively expressed gene. Stevens et al.
(1993) described a HindIII RFLP in the SAA1 gene and found distinctive
allele frequencies in Negroids and San (formerly 'Bushmen') in South
Africa.

Sellar et al. (1994) used a combination of physical and genetic mapping
techniques to demonstrate that the SAA gene superfamily comprises a
cluster of closely linked genes localized to 11p15.1. Pulsed field gel
electrophoresis placed SAA1 within 350 kb of the previously linked SAA2
and SAA4 (104752) genes. Fluorescence in situ hybridization using a
cosmid probe carrying the SAA2 and SAA4 genes refined the localization
of the genes to 11p15.1. A highly polymorphic (CA)n dinucleotide repeat
within the SAA3 pseudogene was typed in the CEPH reference families and
found to map also in the 11p15.1 region, proximal to the parathyroid
hormone gene (PTH; 168450) and distal to D11S455.

Watson et al. (1994) used fluorescence in situ hybridization analysis
and PCR amplification of DNA from 17 somatic cell hybrids carrying all
or part of chromosome 11 as their only human component to demonstrate
that the entire SAA superfamily is located at 11p15. Furthermore, they
demonstrated that SAA1, SAA2, and SAA4, i.e., all of the functional
genes of the superfamily, map within the region 11p15.4-p15.1.
Kluve-Beckerman and Song (1995) showed that the SAA1 and SAA2 genes are
arranged in a head-to-head transcriptional orientation about 18 kb
apart. SAA4, the third functional serum amyloid locus, is 11 kb from
SAA2 and in the same orientation. A fifth SAA clone isolated from this
library was noncontiguous with the other 4 and contained the SAA3
pseudogene.

Sellar et al. (1994) demonstrated that the human SAA gene family
encompasses approximately 150 kb. SAA1 and SAA2 are 15-20 kb apart and
are arranged in divergent transcriptional orientations. SAA4 is 9 kb
downstream of SAA2 and in the same orientation. SAA3 is 110 kb
downstream of SAA4; its relative orientation could not be determined.
Using interphase fluorescence in situ hybridization, Sellar et al.
(1994) found the following gene order:
cen--LDHC--LDHA--SAA1--SAA2--SAA4--SAA3--TPH--D11SA8--KCNC1--MYOD1--pter.

See 249100 for discussion of a possible relationship of the SAA gene to
familial Mediterranean fever--a relationship (at least as the primary
defect) later disproven.

*FIELD* AV
.0001
SERUM AMYLOID A VARIANT
SAA1, GLY72ASP
In a family of Turkish origin, an acidic variant of SAA was identified
by isoelectrofocusing. Kluve-Beckerman et al. (1991) demonstrated that a
G-to-A transition in codon 72 had resulted in substitution of aspartic
acid for glycine. Beach et al. (1992) found the same gly72-to-asp
allelic variant.

*FIELD* SA
Kluve-Beckerman et al. (1991); Kluve-Beckerman et al. (1986); Sack
(1988); Sellar et al. (1994); Sipe et al. (1985)
*FIELD* RF
1. Bausserman, L. L.; Herbert, P. N.; McAdam, K. P. W. J.: Heterogeneity
of human serum amyloid A proteins. J. Exp. Med. 152: 641-656, 1980.

2. Bausserman, L. L.; Saritelli, A. L.; Herbert, P. N.; McAdam, K.
P. W. J.; Shulman, R. S.: NH2-terminal analysis of four of the polymorphic
forms of human serum amyloid A proteins. Biochim. Biophys. Acta 704:
556-559, 1982.

3. Beach, C. M.; De Beer, M. C.; Sipe, J. D.; Loose, L. D.; De Beer,
F. C.: Human serum amyloid A protein: complete amino acid sequence
of a new variant. Biochem. J. 282: 615-620, 1992.

4. Betts, J. C.; Edbrooke, M. R.; Thakker, R. V.; Woo, P.: The human
acute-phase serum amyloid A gene family: structure, evolution and
expression in hepatoma cells. Scand. J. Immun. 34: 471-482, 1991.

5. Kluve-Beckerman, B.; Drumm, M. L.; Benson, M. D.: Nonexpression
of the human serum amyloid A three (SAA3) gene. DNA Cell Biol. 10:
651-661, 1991.

6. Kluve-Beckerman, B.; Long, G. L.; Benson, M. D.: DNA sequence
evidence for polymorphic forms of human serum amyloid A (SAA). Biochem.
Genet. 24: 795-803, 1986.

7. Kluve-Beckerman, B.; Malle, E.; Vitt, H.; Pfeiffer, C.; Benson,
M.; Steinmetz, A.: Characterization of an isoelectric focusing variant
of SAA1 (asp-72) in a family of Turkish origin. Biochem. Biophys.
Res. Commun. 181: 1097-1102, 1991.

8. Kluve-Beckerman, B.; Naylor, S. L.; Marshall, A.; Gardner, J. C.;
Shows, T. B.; Benson, M. D.: Localization of human SAA gene(s) to
chromosome 11 and detection of DNA polymorphisms. Biochem. Biophys.
Res. Commun. 137: 1196-1204, 1986.

9. Kluve-Beckerman, B.; Song, M.: Genes encoding human serum amyloid
A proteins SAA1 and SAA2 are located 18 kb apart in opposite transcriptional
orientations. Gene 159: 289-290, 1995.

10. Sack, G. H., Jr.: Molecular cloning of human genes for serum
amyloid A. Gene 21: 19-24, 1983.

11. Sack, G. H., Jr.: Serum amyloid A (SAA) gene variations in familial
Mediterranean fever. Molec. Biol. Med. 5: 61-67, 1988.

12. Sack, G. H., Jr.; Talbot, C. C., Jr.; Seuanez, H.; O'Brien, S.
J.: Molecular analysis of the human serum amyloid A (SAA) gene family.
Scand. J. Immun. 29: 113-119, 1989.

13. Sellar, G. C.; Jordon, S. A.; Bickmore, W. A.; Fantes, J. A.;
van Heyningen, V.; Whitehead, A. S.: The human serum amyloid A protein
(SAA) superfamily gene cluster: mapping to chromosome 11p15.1 by physical
and genetic linkage analysis. Genomics 19: 221-227, 1994.

14. Sellar, G. C.; Oghene, K.; Boyle, S.; Bickmore, W. A.; Whitehead,
A. S.: Organization of the region encompassing the human serum amyloid
A (SAA) gene family on chromosome 11p15.1. Genomics 23: 492-495,
1994.

15. Sipe, J. D.; Colten, H. R.; Goldberger, G.; Edge, M. D.; Tack,
B. F.; Cohen, A. S.; Whitehead, A. S.: Human serum amyloid A (SAA):
biosynthesis and postsynthetic processing of preSAA and structural
variants defined by complementary DNA. Biochemistry 24: 2931-2936,
1985.

16. Stevens, G.; Ramsay, M.; Kluve-Beckerman, B.; Jenkins, T.: A
new Negroid-specific HindIII polymorphism in the serum amyloid A1
(SAA1) gene increases the usefulness of the SAA locus in linkage studies.
Genomics 15: 242-243, 1993.

17. Strachan, A. F.; Brandt, W. F.; Woo, P.; van der Westhuyzen, D.
R.; Coetzee, G. A.; de Beer, M. C.; Shephard, E. G.; de Beer, F. C.
: Human serum amyloid A protein: the assignment of the six major isoforms
to three published gene sequences and evidence for two genetic loci.
J. Biol. Chem. 264: 18368-18373, 1989.

18. Taylor, B. A.; Rowe, L.: Genes for serum amyloid A proteins map
to chromosome 7 in the mouse. Molec. Gen. Genet. 195: 491-499,
1984.

19. Watson, G.; See, C. G.; Woo, P.: Use of somatic cell hybrids
and fluorescence in situ hybridization to localize the functional
serum amyloid A (SAA) genes to chromosome 11p15.4-p15.1 and the entire
SAA superfamily to chromosome 11p15. Genomics 23: 694-696, 1994.

*FIELD* CN
Alan F. Scott - updated: 8/8/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 06/06/1996
mark: 4/18/1996
terry: 4/17/1996
mark: 1/21/1996
terry: 11/17/1995
mark: 9/27/1995
carol: 4/12/1994
carol: 2/17/1993
carol: 6/8/1992

*RECORD*
*FIELD* NO
104751
*FIELD* TI
*104751 SERUM AMYLOID A2; SAA2
AMYLOID A, SERUM, 2
*FIELD* TX
Dwulet et al. (1988) isolated from one individual 3 distinct serum
amyloid A (SAA) proteins, each present in 2 forms (+/- the
amino-terminal arginine), and fully sequenced them. The 6 sequences,
referred to as SAA1, SAA1 des Arg, SAA2-alpha, SAA2-alpha des Arg,
SAA2-beta, and SAA2-beta des Arg, are resolved by electrofocusing into 6
isoforms. SAA1 is the product of one gene, while SAA2-alpha and
SAA2-beta, which differ by only a single amino acid, represent allelic
sequences of a second gene. Although the first reported AA protein
corresponded to SAA2-beta, subsequent analyses showed that the vast
majority of the protein isolated from amyloid deposits is derived from
SAA1 (104750). This gene product also represents the predominant SAA
form isolated from or detected in the plasma of patients experiencing an
acute phase response.

The acute phase reactant serum amyloid A is a polymorphic apolipoprotein
encoded by a family of highly homologous and closely linked genes--SAA1,
SAA2, and SAA3. There is strong evidence that SAA3 is a pseudogene
(review by Steel et al., 1993). Sellar and Whitehead (1993) demonstrated
that the SAA1, SAA2, and SAA3 genes, as well as a fourth gene, SAA4
(104752), are linked on 11p. By fluorescence in situ hybridization using
a cosmid probe containing the SAA2 and SAA4 genes, Sellar et al. (1994)
localized these genes (and the closely situated SAA1 gene) to 11p15.1.
Sellar et al. (1994) used an NcoI RFLP in the SAA2 gene to analyze for
linkage in the CEPH reference panel. They found lod = 10.82 at theta =
0.001 for linkage between SAA3 and SAA2. Kluve-Beckerman and Song (1995)
showed that the SAA1 and SAA2 genes are arranged in a head-to-head
transcriptional orientation about 18 kb apart. SAA4, the third
functional serum amyloid locus, is 11 kb from SAA2 and in the same
orientation.

*FIELD* RF
1. Dwulet, F. E.; Wallace, D. K.; Benson, M. D.: Amino acid structures
of multiple forms of amyloid-related serum protein SAA from a single
individual. Biochemistry 27: 1677-1682, 1988.

2. Kluve-Beckerman, B.; Song, M.: Genes encoding human serum amyloid
A proteins SAA1 and SAA2 are located 18 kb apart in opposite transcriptional
orientations. Gene 159: 289-290, 1995.

3. Sellar, G. C.; Jordon, S. A.; Bickmore, W. A.; Fantes, J. A.; van
Heyningen, V.; Whitehead, A. S.: The human serum amyloid A protein
(SAA) superfamily gene cluster: mapping to chromosome 11p15.1 by physical
and genetic linkage analysis. Genomics 19: 221-227, 1994.

4. Sellar, G. C.; Whitehead, A. S.: Localization of four human serum
amyloid A (SAA) protein superfamily genes to chromosome 11p: characterization
of a fifth SAA-related gene sequence. Genomics 16: 774-776, 1993.

5. Steel, D. M.; Sellar, G. C.; Uhlar, C. M.; Simon, S.; DeBeer, F.
C.; Whitehead, A. S.: A constitutively expressed serum amyloid A
protein gene (SAA4) is closely linked to, and shares structural similarities
with, an acute-phase serum amyloid A protein gene (SAA1). Genomics 16:
447-454, 1993.

*FIELD* CN
Alan F. Scott - updated: 8/8/1995

*FIELD* CD
Victor A. McKusick: 2/17/1992

*FIELD* ED
terry: 06/06/1996
terry: 4/17/1996
mark: 3/7/1996
terry: 9/7/1995
carol: 4/12/1994
carol: 6/24/1993
carol: 5/21/1993
carol: 3/9/1993

*RECORD*
*FIELD* NO
104752
*FIELD* TI
*104752 SERUM AMYLOID A4; SAA4 AMYLOID A, SERUM, 4
AMYLOID A, SERUM, 4;;
SERUM AMYLOID A4, CONSTITUTIVE
*FIELD* TX
See also SAA1 (104750). Studying the protein and the cDNA, Whitehead et
al. (1992) identified a new member of the serum amyloid A protein
superfamily, designated SAA4, as constitutive apolipoprotein of high
density lipoprotein. Watson et al. (1992) analyzed the structure of the
gene and the derived protein structure. Steel et al. (1993) demonstrated
that the SAA4 gene is located 9 kb downstream of the SAA2 gene (104751)
on chromosome 11. Furthermore, it shares the same 5-prime to 3-prime
orientation and has the characteristic 4-exon structure of the other
members of the SAA superfamily. By fluorescence in situ hybridization
using a cosmid probe carrying the SAA2 and SAA4 genes, Sellar et al.
(1994) localized these genes to 11p15.1. de Beer et al. (1996) found
that in the mouse the Saa4 gene is linked to the serum amyloid A gene
family on chromosome 7.

*FIELD* RF
1. de Beer, M. C.; de Beer, F. C.; Gerardot, C. J.; Cecil, D. R.;
Webb, N. R.; Goodson M. L.; Kindy, M. S.: Structure of the mouse
Saa4 gene and its linkage to the serum amyloid A gene family. Genomics 34:
139-142, 1996.

2. Sellar, G. C.; Jordon, S. A.; Bickmore, W. A.; Fantes, J. A.; van
Heyningen, V.; Whitehead, A. S.: The human serum amyloid A protein
(SAA) superfamily gene cluster: mapping to chromosome 11p15.1 by physical
and genetic linkage analysis. Genomics 19: 221-227, 1994.

3. Steel, D. M.; Sellar, G. C.; Uhlar, C. M.; Simon, S.; DeBeer, F.
C.; Whitehead, A. S.: A constitutively expressed serum amyloid A
protein gene (SAA4) is closely linked to, and shares structural similarities
with, an acute-phase serum amyloid A protein gene (SAA1). Genomics 16:
447-454, 1993.

4. Watson, G.; Coade, S.; Woo, P.: Analysis of the genomic and derived
protein structure of a novel human serum amyloid A gene, SAA4. Scand.
J. Immun. 36: 703-712, 1992.

5. Whitehead, A. S.; DeBeer, M. C.; Steel, D. M.; Rits, M.; Lelias,
J. M.; Lane, W. S.; DeBeer, F. C.: Identification of novel members
of the serum amyloid A protein superfamily as constitutive apolipoproteins
of high density lipoprotein. J. Biol. Chem. 267: 3862-3867, 1992.

*FIELD* CD
Victor A. McKusick: 3/9/1993

*FIELD* ED
terry: 06/05/1996
terry: 6/3/1996
mark: 8/8/1995
carol: 4/12/1994
carol: 5/21/1993
carol: 3/23/1993
carol: 3/9/1993

*RECORD*
*FIELD* NO
104760
*FIELD* TI
*104760 AMYLOID BETA A4 PRECURSOR PROTEIN; APP
ALZHEIMER DISEASE 1; AD1, FORMERLY;;
AMYLOID OF AGING AND ALZHEIMER DISEASE; AAA;;
CEREBRAL VASCULAR AMYLOID PEPTIDE; CVAP
PROTEASE NEXIN II; PN2, INCLUDED
*FIELD* TX
Masters et al. (1985) purified and characterized the cerebral amyloid
protein that forms the plaque core in Alzheimer disease (AD; 104300) and
in older persons with Down syndrome. The protein consists of multimeric
aggregates of a polypeptide of about 40 residues (4 kD). The amino acid
composition, molecular mass, and NH2-terminal sequence of this amyloid
protein were found to be almost identical to those described for the
amyloid deposited in the congophilic angiopathy of Alzheimer disease and
Down syndrome. Using computer-enhanced imaging of immunocytochemical
stains of Alzheimer disease prefrontal cortex, Majocha et al. (1988)
described the distribution of amyloid protein deposits exclusive of
other senile plaque components.

APP has several isoforms generated by alternative splicing of a 19-exon
gene: exons 1-13, 13a, and 14-18 (Yoshikai et al., 1990). The
predominant transcripts are APP695 (exons 1-6, 9-18, not 13a), APP751
(exons 1-7, 9-18, not 13a) and APP770 (exons 1-18, not 13a). All of
these encode multidomain proteins with a single membrane-spanning
region. They differ in that APP751 and APP770 contain exon 7, which
encodes a serine protease inhibitor domain. APP695 is a predominant form
in neuronal tissue, whereas APP751 is the predominant variant elsewhere.
Beta-amyloid is derived from that part of the protein encoded by parts
of exons 16 and 17.

By in situ hybridization, Robakis et al. (1987) showed that the
beta-amyloid probe maps to the proximal part of 21q21. (See 104300 for a
discussion of the mapping of Alzheimer disease to approximately the same
region of chromosome 21, 21q11.2-q21.) Additional, but weaker
hybridization was observed on chromosome 20 within band 20p12, a region
in which the gene for prion protein (176640) is located. Tanzi et al.
(1987) mapped the amyloid beta protein gene to 21q11.2-q21 by analysis
of somatic cell hybrid cDNAs. They also observed putative crossovers
between the CVAP gene and familial Alzheimer disease. Zabel et al.
(1987) mapped the A4 precursor gene within band 21q21 by in situ
hybridization. They placed it near or in the 21q21-q22.1 segment, a
somewhat more distal location than that suggested by Robakis et al.
(1987). By studies of DNA from a panel of somatic cell hybrids, Lovett
et al. (1987) demonstrated that the homologous gene in the mouse is on
chromosome 16, and Cheng et al. (1987) mapped the amyloid beta protein
gene to mouse chromosome 16 by genetic linkage studies. Using a cDNA
probe for the gene encoding the beta-amyloid protein of Alzheimer
disease, Delabar et al. (1987) found that leukocyte DNA from 3 patients
with sporadic Alzheimer disease and 2 patients with karyotypically
normal Down syndrome contained 3 copies of this gene. Because a small
region of chromosome 21 containing the ETS2 gene (164740) was duplicated
in patients with Alzheimer disease as well as in karyotypically normal
Down syndrome, they suggested that duplication of a subsection of the
critical segment of chromosome 21 that is duplicated in Down syndrome
might be the genetic defect in Alzheimer disease. On the other hand,
Tanzi et al. (1987) found that the amyloid gene was not duplicated in
sporadic Alzheimer disease.

Van Broeckhoven et al. (1987) studied 2 large pedigrees in which
Alzheimer disease was inherited in a clearly autosomal dominant manner.
One pedigree contained 36 patients in 6 generations; in 10, the
diagnosis had been histologically confirmed. The second pedigree showed
22 patients in 5 generations with 5 histopathologically confirmed cases.
In 5 families the disease manifested a juvenile form; mean age of onset
was 33.1 years in 1 family and 34.4 years in the other. Four nuclear
families with senile onset after age 65 were incorporated in the linkage
calculation. All lod scores for linkage of A4 amyloid cDNA clone and
Alzheimer disease were negative. In 2 of the families a recombinant was
found, proving that the amyloid protein is not the site of the mutation
causing Alzheimer disease. In 1 of the patients in whom Delabar et al.
(1987) demonstrated an apparent duplication of the CVAP gene, an
86-year-old female Alzheimer patient, and in a normal 86-year-old female
control, Blanquet et al. (1987) studied in situ hybridization using a
cDNA probe. These results allowed assignment of the locus to the
mid-part of 21q near the interface of q21 and q22, i.e., subbands q21.3
and q22.11. There was absence of hybridization elsewhere in the genome.
The grain counts in the patient and the control were compatible with
gene dosage due to duplication of the gene in Alzheimer disease. In an
attempt to define more precisely the region of chromosome 21q containing
the beta amyloid gene, Jenkins et al. (1988) used in situ hybridization
and Southern blot techniques on skin fibroblast lines carrying
translocations involving chromosome 21. Their findings concur with the
previous report of Robakis et al. (1987) and indicate that the gene is
within the region 21q11.2-q21.05. By means of somatic cell hybrid
mapping panel, in situ hybridization, and transverse-alternating-field
electrophoresis, Patterson et al. (1988) showed that the APP gene is
located very near the 21q21/21q22 border and probably within the region
of chromosome 21 that, when trisomic, results in Down syndrome. On the
other hand, Korenberg et al. (1989) concluded that the APP gene is
located outside the minimal region producing the classic phenotypic
features of Down syndrome.

Tanzi et al. (1992) reported on the findings of a multicenter,
multifaceted study to evaluate the possible role of APP mutations in
familial and sporadic Alzheimer disease. Their final conclusion was that
APP gene mutations account for a very small portion of familial
Alzheimer disease. Although mutations of APP have been detected in a few
FAD families (see 104760.0002, 104760.0003, and 104760.0004), obligate
crossovers between APP and FAD have been reported in several pedigrees
including FAD4, a large kindred in which Tanzi et al. (1987) found
highly suggestive evidence for linkage of the disorder to chromosome 21.
No mutations were found in the APP gene when the entire coding region
was sequenced in family FAD4 and also in FAD1, a second large kindred.
Thus in at least one chromosome 21-linked FAD pedigree, the gene defect
is not accounted for by a mutation in the known coding region of the APP
gene. Furthermore, none of 25 well characterized early- and late-onset
FAD pedigrees yielded positive lod scores at a recombination fraction of
0.0 for linkage to the APP gene. Tanzi et al. (1992) also sequenced
exons 16 and 17 (which code for the beta-A4 domain of APP) in 30 (20
early- and 10 late-onset) FAD kindreds and in 11 sporadic AD cases, and
screened 56 FAD kindreds and 81 cases of sporadic AD for the presence of
the originally reported FAD-associated mutation val717-to-ile, using
BclI digestion. No APP gene mutation was found in any of the families or
sporadic cases examined. A collaborative study similar to that of Tanzi
et al. (1992) was reported by Kamino et al. (1992), who used linkage and
mutational analysis to arrive at the same conclusion, namely, that APP
mutations account for AD in only a small fraction of FAD kindreds.

Three separate mutations in codon 717 of the APP transcript have been
found in familial Alzheimer disease: val717-to-ile (104760.0002),
val717-to-phe (104760.0003), and val717-to-gly (104760.0004). The
location of these mutations and that of the double mutation discussed in
104760.0008 suggested to Suzuki et al. (1994) that they may cause
Alzheimer disease by altering beta-APP processing in a way that is
amyloidogenic. They found that the APP-717 mutations were consistently
associated with a 1.5- to 1.9-fold increase in the percentage of longer
fragments generated and that the longer fragments formed insoluble
amyloid fibrils more rapidly than did the shorter ones.

The major protein subunit (A4) of the amyloid fibril of tangles,
plaques, and blood vessel deposits is a polypeptide identified as the
cleavage product of a larger precursor protein with features of a cell
surface receptor (Kang et al., 1987). Van Nostrand et al. (1989)
presented evidence that protease nexin-II, a protease inhibitor that is
synthesized and secreted by various cultured extravascular cells, is
identical to APP. Smith et al. (1990) showed that the platelet inhibitor
of coagulation factor XI (264900) is a secreted form of Alzheimer
amyloid precursor protein. Schmaier et al. (1993) provided biochemical
evidence that PN-2 may serve as a cerebral anticoagulant. Schmaier et
al. (1993) found that PN-2 is also a potent inhibitor of factor IXa
(306900) and that it forms a complex with factor IXa as detected by gel
filtration and ELISA. They suggested that this fact may explain the
spontaneous intracerebral hemorrhages seen in patients with hereditary
cerebral hemorrhage with amyloidosis of the Dutch type in which there is
extensive accumulation of PN-2/APP-beta in cerebral blood vessels
(104760.0001).

Adler et al. (1991) used the process of cellular senescence as a model
to study the role of beta-amyloid precursor protein in biologic aging.
They demonstrated a dramatic increase in amyloid mRNA production and a
more modest increase in the protein synthesized in senescent cultured
fibroblasts compared with early-passage proliferating fibroblasts. They
found, moreover, that induction of quiescence by serum deprivation may
reversibly induce an increase in amyloid mRNA and protein levels. The
investigators hypothesized that the beta-amyloid precursor protein may
play an important role in the cellular growth and metabolic responses to
serum and growth factors under both physiologic and pathologic
conditions. Bakker et al. (1991) described the use of a
mutation-specific oligonucleotide in the diagnosis of this disorder. The
normal cellular function of APP is unknown.

Multhaup et al. (1996) demonstrated that the amyloid precursor protein
is involved in copper reduction. They postulated that copper-mediated
toxicity may contribute to neurodegeneration in Alzheimer disease,
possibly by increased production of hydroxyl radicals.

Yan et al. (1996) reported that the AGER protein (600214), called RAGE
(receptor for advanced glycation end products) by them, is an important
receptor for the amyloid beta peptide and that expression of this
receptor increases in Alzheimer disease. They noted that expression of
RAGE is particularly increased in neurons close to deposits of amyloid
beta peptide and to neurofibrillary tangles.

Kaneko et al. (1995) demonstrated that nanomolar concentrations of
various synthetic beta amyloids specifically impaired mitochondrial
succinate dehydrogenase, and speculated that one of the primary targets
of beta amyloids is the mitochondrial electron transport chain.

Alternative splicing of transcripts from the single APP gene results in
at least 10 isoforms of the gene product (Sandbrink et al., 1994), of
which APP(695) is preferentially expressed in neuronal tissues. In 3
mutations valine-642 in the transmembrane domain of APP(695) is replaced
by isoleucine (104760.0002), phenylalanine (104760.0003), or glycine
(104760.0004) in association with dominantly inherited familial
Alzheimer disease. (According to an earlier numbering system, val642 was
numbered 717 and the 3 mutations were V717I, V717F, and V717G,
respectively.) Yamatsuji et al. (1996) stated that these 3 mutations
account for most, if not all, of the chromosome 21-linked Alzheimer
disease. In transgenic mice, overexpression of such mutants mimics the
neuropathology of AD. Yamatsuji et al. (1996) demonstrated that
expression of any 1 of these 3 mutant proteins, but not of normal
APP(695), induced nucleosomal DNA fragmentation in cultured neuronal
cells. Induction of DNA fragmentation required the cytoplasmic domain of
the mutants and appeared to be mediated by heterotrimeric guanosine
triphosphate-binding proteins (G proteins).

ANIMAL MODEL

Games et al. (1995) created a mouse model for Alzheimer disease by
producing transgenic mice overexpressing the V717F beta-amyloid
precursor protein. The brains showed typical pathologic findings of AD,
including numerous extracellular thioflavin S-positive A-beta deposits,
neuritic plaques, synaptic loss, astrocytosis, and microgliosis.

Hsiao et al. (1996) produced transgenic mice overexpressing the
695-amino acid isoform of human APP containing a K670N, M671L double
mutation which was described by Mullan et al. (1992) in a large Swedish
family with early-onset Alzheimer disease. Transgenic mice
overexpressing this protein had normal learning and memory in spatial
reference and alternation tasks at 3 months of age but showed impairment
by 9 to 10 months of age. Hsiao et al. (1996) reported that a 5-fold
increase in the concentration of the beta amyloid derivatives was found
in the brains of the older transgenic mice. Classic senile plaques with
dense amyloid cores were present in mice with elevated brain beta
amyloid. The results reported by Hsiao et al. (1996) demonstrated the
feasibility of creating transgenic mice with robust behavioral and
pathologic features of Alzheimer disease.

Citron et al. (1997) noted that several lines of evidence strongly
support the conclusion that progressive cerebral deposition of amyloid
beta protein is a seminal event in familial Alzheimer disease (FAD)
pathogenesis. They carried out experiments to test the hypothesis that
FAD mutations act by fostering deposition of amyloid beta protein
particularly in the highly amyloidogenic 42-residue form described by
Jarrett et al. (1993). Citron et al. (1997) established transfected cell
lines and transgenic mouse models that coexpress human presenilins PS1
(104311) or PS2 (600759) and human amyloid beta precursor and analyzed
quantitatively the effects of presenilin expression on APP processing.
They demonstrated that in both model systems, expression of wildtype
presenilin genes did not alter APP levels, alpha- and beta-secretase
activity, and beta amyloid production. PS1 and PS2 mutations in the
transfected cells caused a highly significant increase in secretion of
amyloid beta-42 in all mutant clones. Their data raised the possibility
of an intrinsic difference in the effects of PS1 and PS2 mutations on
APP processing. The PS2 Volga mutation (600759.0001) led to a 6- to
8-fold increase in the production of total amyloid beta-42; none of the
PS1 mutations had such a dramatic effect. Citron et al. (1997) noted
that transgenic mice carrying mutant PS1 genes differed from transgenic
mice carrying wildtype PS1 genes in that the mutation-carrying
transgenic mice overproduced amyloid beta-42 in the brain, which was
detectable at 2 to 4 months of age. Citron et al. (1997) stated that
their combined in vitro and in vivo data clearly demonstrated that the
FAD-linked presenilin mutations directly or indirectly altered the level
of gamma-secretase (but not of alpha- or beta-secretase). This increase
in gamma-secretase resulted in increased proteolysis of APP at the
amyloid beta-42 site, leading to heightened amyloid beta-42 production.
They noted that elucidating the biologic mechanism of this effect could
lead to therapeutic inhibition of amyloid beta 42 production in order to
prevent or slow the progress of Alzheimer disease.

*FIELD* AV
.0001
AMYLOIDOSIS, CEREBROARTERIAL, DUTCH TYPE
AMYLOIDOSIS VIB
APP, GLU22GLN AND GLU693GLN
In 2 generations and 5 sibships of a Dutch family reported by
Wattendorff et al. (1982), 11 persons suffered cerebral and cerebellar
hemorrhage and infarction at ages ranging from 44 to 58 years. The
principal clinical characteristic was recurring cerebral hemorrhages,
sometimes preceded by migrainous headaches or mental changes. In 6
autopsied cases and 1 biopsy specimen, hyaline thickening of the walls
of cortical arterioles was found. The arteries of the arachnoid showed
marked tortuosity, concentric proliferation, and focal hyalinization.
Amyloid was demonstrated in the hyalinized vessels but was not found
outside the nervous system. The kindred of Wattendorff et al. (1982) was
from Scheveningen. Luyendijk and Bots (1986) wrote: 'As the hereditary
disease is well-known to the co-members of the respective families they
usually inform the doctors on the probable diagnosis themselves, when
such a patient is admitted into the hospital. Besides which they usually
add all kinds of genealogical information.' In studies of the Dutch form
of hereditary cerebral hemorrhage with amyloidosis, van Duinen et al.
(1987) demonstrated that the vascular amyloid deposits are related to
the beta-protein associated with Alzheimer disease and Down syndrome;
thus there are at least 2 forms of hereditary cerebral hemorrhage with
amyloidosis: the Icelandic type (105150), due to a defect in gamma-trace
(cystatin C), and the Dutch type, due to a defect in CVAP. Luyendijk et
al. (1988) described 136 patients with hereditary cerebral hemorrhage,
all belonging to families originally resident in Katwijk, The
Netherlands. No genealogic connection has been established between the
Dutch and Icelandic pedigrees The findings in all of the Dutch cases are
identical and differ from the findings in the Icelandic cases. Icelandic
patients suffer the first stroke at the mean age of 27 years, whereas
the Dutch patients are approximately 25 years older; the level of
cystatin C in the cerebrospinal fluid of Icelandic patients is decreased
as compared to Dutch patients and healthy persons; and
immunohistochemically, intense staining for cystatin C is found in
diseased Icelandic blood vessels, whereas in the Dutch material only
weak or dubious staining is found. Luyendijk et al. (1988) had 78 males
and 58 females in their series; the sex ratio for the proven cases was
nearly equal (29 males and 26 females). There were numerous examples of
father-to-son transmission. By linkage analysis (Van Broeckhoven et al.,
1990) and by demonstration of a specific intragenic lesion (Levy et al.,
1990), the amyloid beta-protein precursor gene has been shown to be the
site of the mutation in the Dutch form of cerebroarterial amyloidosis.
The amyloid precursor proteins in the Dutch and Icelandic forms of
cerebroarterial amyloidosis are both protease inhibitors and both have
been found to have a substitution in their genes that give rise to a
substitution of glutamine. In 2 patients from presumably unrelated Dutch
families, Levy et al. (1990) demonstrated a guanine-to-cytosine change
at nucleotide 1852 resulting in a substitution of glutamine for glutamic
acid at position 22 of the amyloid protein (codon 693 of APP). Prelli et
al. (1990) demonstrated that both the normal and the variant alleles are
expressed in vascular amyloid in this disorder. Haan et al. (1990) found
that all 16 patients they examined with the Dutch type of hereditary
cerebral hemorrhage with amyloidosis had psychiatric abnormalities;
dementia was present in 12. Three patients tested twice at an interval
of some years exhibited progressive intellectual deterioration and
memory disturbance; in 2 of them there was no evidence of intercurrent
strokes. Fernandez-Madrid et al. (1991) identified the mutation in a
woman of Dutch extraction living in the United States. The patient was a
normotensive 63-year-old woman who was well until age 47 when she began
to have attacks approximately every 2 weeks. Graffagnino et al. (1994)
failed to find the amyloid mutation in any of 48 consecutive patients
with intracerebral hemorrhage admitted to Duke University Hospital. No
pathologic examinations were made to determine if any of these patients
had amyloid deposition.

.0002
ALZHEIMER DISEASE, FAMILIAL
APP, VAL717ILE
In 2 families with Alzheimer disease, Goate et al. (1991) found a C-to-T
transition at base 2149 in exon 17 of the APP gene causing a
valine-to-isoleucine change at amino acid 717. This valine residue is
conserved in rodents. The mutation may have involved a CpG dinucleotide.
The substitution created a BclI restriction site which allowed detection
of the corresponding change within the PCR product. This finding
required reexamination of previous work mapping Alzheimer disease to
chromosome 21. In some families the AD gene appeared to be close to the
APP gene, but the genes were thought to be distinct because of
recombinants in some families. In general, however, late-onset families
did not show linkage to chromosome 21 markers, and even some families
with early-onset disease did not show that linkage. Other mutations in
the APP gene may be identified as the basis of Alzheimer disease. The
occurrence of pathologic changes of Alzheimer disease in trisomy 21
suggests that these mutations need not be in the coding region but may
also be in controlling elements, leading to overexpression of APP. In
the first family studied by Goate et al. (1991), the average age of
onset was 57 +/- 5 years. It is noteworthy that exon 17 is the site of
the mutation in the Dutch type of cerebral arterial amyloidosis. The
same mutation was found by Naruse et al. (1991) in 2 separate Japanese
cases of familial early-onset Alzheimer disease, and Yoshioka et al.
(1991) found it in a third Japanese family in the course of studying 6
FAD families and 3 sporadic early-onset AD patients. On the other hand,
van Duijn et al. (1991) failed to find the mutation in any of 100
early-onset patients. They concluded that at a confidence level of 95%
this finding suggested that the val717-to-ile mutation accounts for less
than 3.6% of all cases with early-onset AD. Schellenberg et al. (1991)
sought the val717-to-ile mutation in 76 families with familial Alzheimer
disease, in 127 subjects with presumably sporadic Alzheimer disease, in
16 Down syndrome cases, and in 256 normal controls; none was positive.
In the same cases they also found no example of the mutation associated
with the Dutch type of cerebroarterial amyloidosis (104760.0001).

Karlinsky et al. (1992) stated that 8 pedigrees with the val717-to-ile
mutation had been reported and that this mutation accounts for only
about 3% of familial Alzheimer disease and for none of sporadic
Alzheimer disease. They studied in detail a family from Toronto in which
the Koch postulates were satisfied: 1) presence and cosegregation of the
mutation with the disease in affected members; 2) absence of the
mutation from unaffected members; and 3) re-creation of the phenotype in
transgenic or transfection models. (The third postulate was not
addressed in their report.) The disorder in this family was presenile in
onset, with earliest manifestations related to deficits in memory,
cognitive processing speed, and attention to complex cognitive sets. The
family immigrated to Canada from the British Isles in the 18th century.
Relationship to one or both of the pedigrees with the val717-to-ile
mutation reported by Goate et al. (1991) could not be excluded. St.
George-Hyslop et al. (1994) pointed out that the family contained one
member who had the val717-to-ile mutation but remained clinically
healthy with no sign of disease on neurologic or neuropsychologic tests
or on computerized axial tomography or magnetic resonance imaging scans
at an age 2 standard deviations beyond the mean age of onset in this
pedigree. They suggested that this might be due to the fact that this
individual lacked the E4 allele at the APOE locus (107741), his genotype
being E2/E3. All 3 living clinically affected family members with the
val717-to-ile mutation were considerably younger and had the E3/E4
genotype. St. George-Hyslop et al. (1994) suggested that there is an
interaction between the development of Alzheimer disease due to
mutations in the APP gene and the E4 allele. In contrast, they observed
no relationship between the APOE genotype and age of onset or other
clinical features in affected members of a large pedigree in which
familial AD was linked to chromosome 14 (104311).

Maruyama et al. (1996) explored the significance of the fact that 3
mutations in the val717 residue of APP (to ile, phe, or gly) have been
found in familial Alzheimer disease and that these mutations increase
secretion of A-beta-42(43). To study the specificity of the effects of
these mutations on APP processing, they transiently expressed APP genes
with mutations of val717 to lys, ser, glu, or cys in COS cells. The 3
mutations associated with FAD increased the levels or ratios of
A-beta-42(43), whereas the secretion of A-beta-40 was decreased. Other
mutations irrelevant to FAD, except val717lys, had little effect on the
ratio of beta-42(43). Substitution to lys decreased the secretion of
beta-42. Overall, the results suggested a specific role of the val717
residue in APP processing and, especially, in gamma-cleavage.

.0003
ALZHEIMER DISEASE, FAMILIAL
APP, VAL717PHE
In DNA from affected members of a family with autopsy-proven Alzheimer
disease, Murrell et al. (1991) found substitution of phenylalanine for
valine at position 717. This position is the same as that of the
valine-to-isoleucine substitution found by Goate et al. (1991) in
another family with early-onset hereditary Alzheimer disease. It is 2
residues beyond the carboxyl terminus of the beta-amyloid peptide
subunit isolated from amyloid fibrils. The mutation specifically
involved change of GTC (val) to TTC (phe). Zeldenrust et al. (1993)
found 9 examples of the phe717 mutation among 34 at-risk members of the
original Indiana FAD kindred. Zeldenrust et al. (1993) tested for the 3
known mutations at codon 717 of APP in 145 FAD subjects and found none
positive for a mutation in that position. Farlow et al. (1994) reviewed
the clinical characteristics of the disorder in the family reported by
Murrell et al. (1991). Recent memory, information-processing speed,
sequential tracking, and conceptual reasoning were the earliest
cognitive functions affected. Language and visuoperceptual skills were
largely spared early in the course of the disease. Later there were
progressive cognitive deficits and inability to perform the activities
of daily living. Death occurred, on average, 6 years after onset. The
family was Romanian, many of its members having migrated to Indiana. The
mean age of onset of dementia was 43 years.

.0004
ALZHEIMER DISEASE, FAMILIAL
APP, VAL717GLY
Chartier-Harlin et al. (1991) demonstrated a third mutation in codon 717
in a family with Alzheimer disease with onset at an average age of 59
+/- 4 years. Linkage analysis had shown a peak lod score of 3.02 at
theta = 0.0 between the disease and marker D21S210 which is located
close to the APP gene. Sequencing of exon 17 showed a T-to-G
transversion at basepair 2150, changing valine to glycine at codon 717
of the APP transcript.

.0005
DEMENTIA, PRESENILE, AND CEREBROARTERIAL AMYLOIDOSIS
APP, ALA692GLY
In a 4-generation Dutch family, Hendriks et al. (1992) identified an
ACG-to-AGG mutation at codon 692 which cosegregated with presenile
dementia and cerebral hemorrhage due to cerebral amyloid angiopathy. The
ala692-to-gly mutation was in the same exon of the APP gene as the 3
mutations in codon 717.

.0006
SCHIZOPHRENIA
APP, ALA713VAL
Among 105 patients with definite or probable Alzheimer disease or
atypical dementia and chronic schizophrenia, Jones et al. (1992)
identified a single abnormality of APP in a chronic schizophrenic with
cognitive defects. A C-to-T transition resulted in substitution of
valine for alanine-713. The mutation was not detected in other members
of the patient's family (other affected individuals were deceased) nor
in a further 100 chronic schizophrenics and 100 nondemented controls.
Nonetheless, the position of the mutation at a critical portion of the
APP gene 4 codons removed from the site of 3 Alzheimer mutations
suggests possible significance. The conclusion that the ala713-to-val
substitution in APP is causally related to schizophrenia was refuted by
Mant et al. (1992) who conducted an analysis of linkage between
schizophrenia and APP markers as well as single-strand conformation
analysis of exon 17 of the APP gene in schizophrenic subjects; it was
also refuted by Carter et al. (1993) who did DGGE analysis in 104
unrelated schizophrenic subjects. In studies of 86 unrelated chronic
schizophrenics who had a first-degree relative with chronic
schizophrenia or chronic schizoaffective disorder, Coon et al. (1993)
likewise were unable to find additional cases with the codon 713
mutation.

.0007
APP POLYMORPHISM
APP, NT2124, C-T
In 2 out of 12 AD patients, in 1 out of 60 non-AD patients, and in 1 out
of 30 healthy persons, Balbin et al. (1992) found a C-to-T transition at
nucleotide 2124 in exon 17 of the APP gene. The mutation was silent at
the protein level. The mutation could be used as a marker for linkage
studies involving the APP gene; whether it represented a risk factor for
the development of AD required further study.

.0008
ALZHEIMER DISEASE, FAMILIAL
APP, LYS670ASN AND MET671LEU
In 2 large Swedish families linked by genealogy and containing multiple
cases of Alzheimer disease, Mullan et al. (1992) found a double mutation
in exon 16: 2 nucleotide transversions, G to T and A to C, were observed
in affected persons at codons 670 and 671, respectively. These changes
predicted lysine to asparagine and methionine to leucine substitutions
in the intact protein. Mullan et al. (1992) suggested that this
mutation, which occurs at the amino terminal of beta-amyloid, may be
pathogenic because it occurs at or close to the endosomal/lysosomal
cleavage site of the molecule. Linkage analysis showed the mutation to
be linked to the disease with a lod score of 4.36 with no recombination.
Citron et al. (1992) reported that cultured cells that express an APP
cDNA bearing this double mutation produce 6 to 8 times more amyloid
beta-protein than cells expressing the normal APP gene. They showed that
the met596-to-leu mutation was principally responsible for the increase.
(MET596LEU in the APP-695 transcript is the equivalent of MET671LEU in
the APP-770 transcript which was the basis of the numbering system used
by Mullan et al. (1992).) These findings established a direct link
between an FAD genotype and the clinicopathologic phenotype.

Citron et al. (1994) conducted blinded analyses of beta-APP metabolism
in primary skin fibroblasts from affected members of a Swedish FAD
pedigree and their unaffected sibs or spouses. These fibroblasts
continuously secreted a homogeneous population of beta-amyloid molecules
starting at asp-1 (D672 of beta-APP). Citron et al. (1994) found a
consistent and significant elevation of approximately 3-fold of
beta-amyloid release from all biopsied skin fibroblasts bearing the FAD
mutation. No significant alterations of other metabolic derivatives of
beta-APP were detected. The elevated beta-amyloid levels were found in
cells from both patients with clinical Alzheimer disease and
presymptomatic subjects, thus indicating that it is not a secondary
event and may play a causal role in the development of the disease.
Haass et al. (1995) showed that the increased production of amyloid-beta
peptide associated with the 'Swedish mutation' (actually the Swedish
double mutation) results from a cellular mechanism which differs
substantially from that responsible for the production of amyloid-beta
peptide from the wild type gene. In the latter case, A-beta generation
requires reinternalization and recycling of the precursor protein. In a
case of the Swedish mutation, the N-terminal beta-secretase cleavage of
A-beta occurs in golgi-derived vesicles, most likely within secretory
vesicles. Therefore, this cleavage occurs in the same compartment as the
alpha-secretase cleavage, which normally prevents A-beta production,
explaining the increased A-beta generation by a competition between
alpha- and beta-secretase.

.0009
ALZHEIMER DISEASE, FAMILIAL
APP, ALA713THR
In a study of 130 early-onset AD patients from hospitals throughout
France, Carter et al. (1992) found 1 patient with 2 G-to-A transitions
in the APP gene: one at codon 713 and the other at codon 715. These
resulted in an ala713-to-thr missense substitution and a silent change
at val715. The 713 mutation changes residue 42 of the beta-amyloid
protein, considered to be the penultimate or terminal amino acid of this
molecule, and thus could potentially alter both endosomal/lysosomal
cleavage and the C-terminal sequence of the resulting beta-peptide. The
double mutation was present also in 4 healthy sibs and a paternal aunt
who was also healthy at age 88. (The ala713-to-val mutation found in a
schizophrenic patient (104760.0006) involves the same residue.) This
experience may represent reduced penetrance; additional environmental
factors may be necessary for expression of the disorder or an
independent genetic factor absent in the affected sib may suppress
amyloid formation in the unaffected members of the kindred.

.0010
ALZHEIMER DISEASE, LATE-ONSET
APP, GLN665ASP
Peacock et al. (1994) used reverse transcription-polymerase chain
reaction, denaturing gradient gel electrophoresis, and direct DNA
sequencing to analyze APP exons 16 and 17 from patients with
histologically confirmed Alzheimer disease. (Amyloid plaques in
Alzheimer disease contain beta-amyloid, encoded by portions of exons 16
and 17 of the APP gene.) In a patient with late-onset Alzheimer disease,
they found a novel point mutation, a C-to-G transversion at nucleotide
2119 (770 in the mRNA transcript). The substitution deleted a BglII site
and substituted aspartate for glutamine at codon 665. Hitherto, no
evidence had been forthcoming that APP mutations are involved in
late-onset or sporadic Alzheimer disease. The proposita had died at age
92. A sister had died with dementia between 80 and 85 years of age. The
same mutation was present in a nondemented relative older than 65 years.
Thus, although the mutation was not found in 40 control subjects and 127
dementia patients, its relationship to Alzheimer disease remains
uncertain.

*FIELD* SA
Robakis et al. (1987); Tanzi et al. (1987)
*FIELD* RF
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N. N.: Increased gene expression of Alzheimer disease beta-amyloid
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Sci. 88: 16-20, 1991.

2. Bakker, E.; van Broeckhoven, C.; Haan, J.; Voorhoeve, E.; van Hul,
W.; Levy, E.; Lieberburg, I.; Carman, M. D.; van Ommen, G. J. B.;
Frangione, B.; Roos, R. A. C.: DNA diagnosis for hereditary cerebral
hemorrhage with amyloidosis (Dutch type). Am. J. Hum. Genet. 49:
518-521, 1991.

3. Balbin, M.; Abrahamson, M.; Gustafson, L.; Nilsson, K.; Brun, A.;
Grubb, A.: A novel mutation in the beta-protein coding region of
the amyloid beta-protein precursor (APP) gene. Hum. Genet. 89: 580-582,
1992.

4. Blanquet, V.; Goldgaber, D.; Turleau, C.; Creau-Goldberg, N.; Delabar,
J.; Sinet, P. M.; Roudier, M.; de Grouchy, J.: In situ hybridization
of the beta amyloid protein (APP) cDNA to the vicinity of the interface
of 21q21 and q22 in normal and Alzheimer's disease individuals.(Abstract) Cytogenet.
Cell Genet. 46: 582 only, 1987.

5. Carter, D.; Campion, D.; d'Amato, T.; Jay, M.; Brice, A.; Bellis,
M.; Mallet, J.; Agid, Y.: No mutation in codon 713 of the amyloid
precursor gene in schizophrenic patients. Hum. Molec. Genet. 2:
321, 1993.

6. Carter, D. A.; Desmarais, E.; Bellis, M.; Campion, D.; Clerget-Darpoux,
F.; Brice, A.; Agid, Y.; Jaillard-Serradt, A.; Mallet, J.: More missense
in amyloid gene.(Letter) Nature Genet. 2: 255-256, 1992.

7. Chartier-Harlin, M.-C.; Crawford, F.; Houlden, H.; Warren, A.;
Hughes, D.; Fidani, L.; Goate, A.; Rossor, M.; Roques, P.; Hardy,
J.; Mullan, M.: Early-onset Alzheimer's disease caused by mutations
at codon 717 of the beta-amyloid precursor protein gene. Nature 353:
844-846, 1991.

8. Cheng, S. V.; Nadeau, J. H.; Tanzi, R. E.; Watkins, P. C.; Sacchi,
N.; Neve, R. L.; Gusella, J. F.: Synteny in man and mouse of DNA
markers from the chromosomal region linked to familial Alzheimer's
disease and Down syndrome.(Abstract) Am. J. Hum. Genet. 41: A161
only, 1987.

9. Citron, M.; Oltersdorf, T.; Haass, C.; McConlogue, L.; Hung, A.
Y.; Seubert, P.; Vigo-Pelfrey, C.; Lieberburg, I.; Selkoe, D. J.:
Mutation of the beta-amyloid precursor protein in familial Alzheimer's
disease increases beta-protein production. Nature 360: 672-674,
1992.

10. Citron, M.; Vigo-Pelfrey, C.; Teplow, D. B.; Miller, C.; Schenk,
D.; Johnston, J.; Winblad, B.; Venizelos, N.; Lannfelt, L.; Selkoe,
D. J.: Excessive production of amyloid beta-protein by peripheral
cells of symptomatic and presymptomatic patients carrying the Swedish
familial Alzheimer disease mutation. Proc. Nat. Acad. Sci. 91: 11993-11997,
1994.

11. Citron, M.; Westaway, D.; Xia, W.; Carlson, G.; Diehl, T.; Levesque,
G.; Johnson-Wood, K.; Lee, M.; Seubert, P.; Davis, A.; Kholodenko,
D.; Motter, R.; Sherrington, R.; Perry, B.; Yao, H.; Strome, R.; Lieberburg,
I.; Rommens, J.; Kim. S.; Schenk, D.; Fraser, P.; St George Hyslop,
P.; Selkoe, D. J.: Mutant presenilins of Alzheimer's disease increase
production of 42-residue amyloid beta-protein in both transfected
cells and transgenic mice. Nature Med. 3: 67-72, 1997.

12. Coon, H.; Hoff, M.; Holik, J.; Delisi, L. E.; Crowe, T.; Freedman,
R.; Shields, G.; Boccio, A. M.; Lerman, M.; Gershon, E. S.; Gejman,
P. V.; Leppert, M.; Byerley, W.: C to T nucleotide substitution in
codon 713 of amyloid precursor protein gene not found in 86 unrelated
schizophrenics from multiplex families. Am. J. Med. Genet. 48: 36-39,
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13. Delabar, J.-M.; Goldgaber, D.; Lamour, Y.; Nicole, A.; Huret,
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14. Farlow, M.; Murrell, J.; Ghetti, B.; Unverzagt, F.; Zeldenrust,
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15. Fernandez-Madrid, I.; Levy, E.; Marder, K.; Frangione, B.: Codon
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36. Mant, R.; Asherson, P.; Gill, M.; McGuffin, P.; Owen, M.: Schizophrenia
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38. Masters, C. L.; Simms, G.; Weinman, N. A.; Multhaup, G.; McDonald,
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39. Mullan, M.; Crawford, F.; Axelman, K.; Houlden, H.; Lilius, L.;
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40. Mullan, M.; Crawford, F.; Axelman, K.; Houlden, H.; Lilius, L.;
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41. Multhaup, G.; Schlicksupp, A.; Hesse, L.; Beher, D.; Ruppert,
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42. Murrell, J.; Farlow, M.; Ghetti, B.; Benson, M. D.: A mutation
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43. Naruse, S.; Igarashi, S.; Kobayashi, H.; Aoki, K.; Inuzuka, T.;
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44. Patterson, D.; Gardiner, K.; Kao, F.-T.; Tanzi, R.; Watkins, P.;
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45. Peacock, M. L.; Murman, D. L.; Sima, A. A. F.; Warren, J. T.,
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46. Prelli, F.; Levy, E.; van Duinen, S. G.; Bots, G. T. A. M.; Luyendijk,
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47. Robakis, N. K.; Ramakrishna, N.; Wolfe, G.; Wisniewski, H. M.
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and the neuritic plaque amyloid peptides. Proc. Nat. Acad. Sci. 84:
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48. Robakis, N. K.; Wisniewski, H. M.; Jenkins, E. C.; Devine-Gage,
E. A.; Houck, G. E.; Yao, X.-L.; Ramakrishna, N.; Wolfe, G.; Silverman,
W. P.; Brown, W. T.: Chromosome 21q21 sublocalisation of gene encoding
beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques
of people with Alzheimer disease and Down syndrome.(Letter) Lancet I:
384-385, 1987.

49. Sandbrink, R.; Masters, C. L.; Beyreuther, K.: Beta A4-amyloid
protein precursor mRNA isoforms without exon 15 are ubiquitously expressed
in rat tissues including brain, but not in neurons. J. Biol. Chem. 269:
1510-1517, 1994.

50. Schellenberg, G. D.; Anderson, L.; O'dahl, S.; Wisjman, E. M.;
Sadovnick, A. D.; Ball, M. J.; Larson, E. B.; Kukull, W. A.; Martin,
G. M.; Roses, A. D.; Bird, T. D.: APP-717, APP-693, and PRIP gene
mutations are rare in Alzheimer disease. Am. J. Hum. Genet. 49:
511-517, 1991.

51. Schmaier, A. H.; Dahl, L. D.; Rozemuller, A. J. M.; Roos, R. A.
C.; Wagner, S. L.; Chung, R.; Van Nostrand, W. E.: Protease nexin-2/amyloid-beta
protein precursor: a tight-binding inhibitor of coagulation factor
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52. Smith, R. P.; Higuchi, D. A.; Broze, G. J., Jr.: Platelet coagulation
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53. St. George-Hyslop, P.; Crapper McLachlan, D.; Tuda, T.; Rogaev,
E.: Alzheimer's disease and possible gene interaction.(Letter) Science 263:
537 only, 1994.

54. Suzuki, N.; Cheung, T. T.; Cai, X.-D.; Odaka, A.; Otvos, L., Jr.;
Eckman, C.; Golde, T. E.; Younkin, S. G.: An increased percentage
of long amyloid beta protein secreted by familial amyloid beta protein
precursor (beta-APP-717) mutants. Science 264: 1336-1340, 1994.

55. Tanzi, R.; St. George-Hyslop, P.; Haines, J.; Neve, R.; Polinsky,
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Alzheimer's disease and chromosome 21.(Abstract) Cytogenet. Cell
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56. Tanzi, R. E.; Bird, E. D.; Latt, S. A.; Neve, R. L.: The amyloid
beta protein gene is not duplicated in brains from patients with Alzheimer's
disease. Science 238: 666-669, 1987.

57. Tanzi, R. E.; St. George-Hyslop, P. H.; Haines, J. L.; Polinsky,
R. J.; Nee, L.; Foncin, J.-F.; Neve, R. L.; McClatchey, A. I.; Conneally,
P. M.; Gusella, J. F.: The genetic defect in familial Alzheimer's
disease is not tightly linked to the amyloid beta-protein gene. Nature 329:
156-157, 1987.

58. Tanzi, R. E.; Vaula, G.; Romano, D. M.; Mortilla, M.; Huang, T.
L.; Tupler, R. G.; Wasco, W.; Hyman, B. T.; Haines, J. L.; Jenkins,
B. J.; Kalaitsidaki, M.; Warren, A. C.; McInnis, M. C.; Antonarakis,
S. E.; Karlinsky, H.; Percy, M. E.; Connor, L.; Growdon, J.; Crapper-McLachlan,
D. R.; Gusella, J. F.; St. George-Hyslop, P. H.: Assessment of amyloid
beta-protein precursor gene mutations in a large set of familial and
sporadic Alzheimer disease cases. Am. J. Hum. Genet. 51: 273-282,
1992.

59. Van Broeckhoven, C.; Backhovens, H.; Raeymaekers, P.; Wehnert,
A.; Horsthemke, B.; Beyreuther, K.; Genthe, A.; Barton, A.; Hardy,
J.; Irving, N.; Williamson, R.; Vandenberghe, A.: Linkage study between
the amyloid gene and familial Alzheimer disease.(Abstract) Cytogenet.
Cell Genet. 46: 708 only, 1987.

60. Van Broeckhoven, C.; Haan, J.; Bakker, E.; Hardy, J. A.; Van Hul,
W.; Wehnert, A.; Vegter-Van der Vlis, M.; Roos, R. A. C.: Amyloid
beta protein precursor gene and hereditary cerebral hemorrhage with
amyloidosis (Dutch). Science 248: 1120-1122, 1990.

61. van Duijn, C. M.; Hendriks, L.; Cruts, M.; Hardy, J. A.; Hofman,
A.; Van Broeckhoven, C.: Amyloid precursor protein gene mutation
in early-onset Alzheimer's disease.(Letter) Lancet 337: 978 only,
1991.

62. van Duinen, S. G.; Castano, E. M.; Prelli, F.; Bots, G. T. A.
B.; Luyendijk, W.; Frangione, B.: Hereditary cerebral hemorrhage
with amyloidosis in patients of Dutch origin is related to Alzheimer
disease. Proc. Nat. Acad. Sci. 84: 5991-5994, 1987.

63. Van Nostrand, W. E.; Wanger, S. L.; Suzuki, M.; Choi, B. H.; Farrow,
J. S.; Geddes, J. W.; Cotman, C. W.; Cunningham, D. D.: Protease
nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein
precursor. Nature 341: 546-549, 1989.

64. Wattendorff, A. R.; Bots, G. T. A. M.; Went, L. N.; Endtz, L.
J.: Familial cerebral amyloid angiopathy presenting as recurrent
cerebral haemorrhage. J. Neurol. Sci. 55: 121-135, 1982.

65. Yamatsuji, T.; Matsui, T.; Okamoto, T.; Komatsuzaki, K.; Takeda,
S.; Fukumoto, H.; Iwatsubo, T.; Suzuki, N.; Asami-Odaka, A.; Ireland,
S.; Kinane, T. B.; Giambarella, U.; Nishimoto, I.: G protein-mediated
neuronal DNA fragmentation induced by familial Alzheimer's disease-associated
mutants of APP. Science 272: 1349-1352, 1996.

66. Yan, S. D.; Chen, X.; Fu, J.; Chen, M.; Zhu, H.; Roher, A.; Slattery,
T.; Zhao, L.; Nagashima, M.; Morser, J.; Migheli, A.; Nawroth, P.;
Stern, D.; Schmidt, A. M.: RAGE and amyloid-beta peptide neurotoxicity
in Alzheimer's disease. Nature 382: 685-691, 1996.

67. Yoshikai, S.; Sasaki, H.; Doh-ura, K.; Furuya, H.; Sakaki, Y.
: Genomic organization of the human amyloid beta-protein precursor
gene. Gene 87: 257-263, 1990.

68. Yoshioka, K.; Miki, T.; Katsuya, T.; Ogihara, T.; Sakaki, Y.:
The 717-val-to-ile substitution in amyloid precursor protein is associated
with familial Alzheimer's disease regardless of ethnic groups. Biochem.
Biophys. Res. Commun. 178: 1141-1146, 1991.

69. Zabel, B. U.; Salbaum, J. M.; Multhaup, G.; Master, C. L.; Bohl,
J.; Beyreuther, K.: Sublocalization of the gene for the precursor
of Alzheimer's disease amyloid A4 protein on chromosome 21.(Abstract) Cytogenet.
Cell Genet. 46: 725-726, 1987.

70. Zeldenrust, S. R.; Murrell, J.; Farlow, M.; Ghetti, B.; Roses,
A. D.; Benson, M. D.: RFLP analysis for APP 717 mutations associated
with Alzheimer's disease. J. Med. Genet. 30: 476-478, 1993.

*FIELD* CN
Victor A. McKusick - updated: 02/03/1997
Moyra Smith - updated: 1/23/1997
Moyra Smith - updated: 10/3/1996
Moyra Smith - updated: 8/21/1996
Orest Hurko - updated: 5/8/1996
Moyra Smith - updated: 3/7/1996

*FIELD* CD
Victor A. McKusick: 12/15/1986

*FIELD* ED
mark: 02/03/1997
terry: 2/3/1997
mark: 1/23/1997
terry: 1/23/1997
mark: 11/18/1996
terry: 11/14/1996
jamie: 10/25/1996
mark: 10/3/1996
mark: 8/21/1996
terry: 8/20/1996
terry: 6/21/1996
mark: 6/20/1996
mark: 6/18/1996
terry: 6/13/1996
mark: 5/8/1996
terry: 5/2/1996
mark: 3/7/1996
terry: 3/7/1996
mark: 2/23/1996
mark: 2/16/1996
mark: 2/15/1996
terry: 2/27/1995
carol: 1/20/1995
jason: 6/14/1994
mimadm: 4/19/1994
warfield: 4/6/1994
carol: 12/10/1993

*RECORD*
*FIELD* NO
104770
*FIELD* TI
*104770 AMYLOID P COMPONENT, SERUM; APCS
SERUM AMYLOID P; SAP
*FIELD* TX
Mantzouranis et al. (1985) isolated cDNA for the P component of human
serum amyloid, determined the complete sequence of the precursor, and
assigned the gene to chromosome 1 by studies of somatic cell hybrids.
The gene is probably closely situated to that for C-reactive protein
(CRP; 123260) with which it shows homology. By in situ hybridization,
the assignment was made to segment 1q12-q23 (Floyd-Smith et al., 1985,
1986). Ionasescu et al. (1987) found a maximum lod score of 3.26 at
theta = 0.05 for linkage of APCS with the Duffy blood group locus
(110700). A RFLP marker of APCS was used. The linkage is consistent with
the physical assignment of the 2 loci. Woo et al. (1987) found a genetic
marker for susceptibility to amyloidosis in juvenile arthritis: an
8.8-kb RFLP band determined by a polymorphic DNA site 5-prime to the SAP
gene. Homozygosity for the alternative 5.6-kb band was found in none of
28 amyloid patients. Among 19 juvenile arthritic patients without
amyloidosis, the distribution of the polymorphism was the same as that
in the normal group. With a RFLP of the cloned mouse Sap gene, Whitehead
et al. (1988) demonstrated that the gene maps to chromosome 1 in the
same region specified by quantitative variation in Sap levels. They
thought it might be significant that the same region includes CRP, SAP,
and histone genes, all of which have products that interact with DNA.

*FIELD* SA
Mortensen et al. (1985); Prelli et al. (1985)
*FIELD* RF
1. Floyd-Smith, G. A.; Whitehead, A. S.; Colten, H. R.; Francke, U.
: Human serum amyloid P component (SAP) is located on the proximal
long arm of chromosome 1.  (Abstract) Cytogenet. Cell Genet. 40:
631 only, 1985.

2. Floyd-Smith, G. A.; Whitehead, A. S.; Colten, H. R.; Francke, U.
: The human C-reactive protein gene (CRP) and serum amyloid P component
gene (APCS) are located on the proximal long arm of chromosome 1.
Immunogenetics 24: 171-176, 1986.

3. Ionasescu, V.; Burns, T.; Searby, C.; Ionasescu, R.: Linkage between
the loci for Duffy (FY) and serum amyloid P component (APCS) on human
chromosome 1. Cytogenet. Cell Genet. 45: 240-241, 1987.

4. Mantzouranis, E. C.; Dowton, S. B.; Whitehead, A. S.; Edge, M.
D.; Bruns, G. A. P.; Colten, H. R.: Human serum amyloid P component:
cDNA isolation, complete sequence of pre-serum amyloid P component,
and localization of the gene to chromosome 1. J. Biol. Chem. 260:
7752-7756, 1985.

5. Mortensen, R. F.; Le, P. T.; Taylor, B. A.: Mouse serum amyloid
P-component (SAP) levels controlled by a locus on chromosome 1. Immunogenetics 22:
367-375, 1985.

6. Prelli, F.; Pras, M.; Frangione, B.: The primary structure of
human tissue amyloid P component from a patient with primary idiopathic
amyloidosis. J. Biol. Chem. 260: 12895-12898, 1985.

7. Whitehead, A. S.; Rits, M.; Michaelson, J.: Molecular genetics
of mouse serum amyloid P component (SAP): cloning and gene mapping.
Immunogenetics 28: 388-390, 1988.

8. Woo, P.; O'Brien, J.; Robson, M.; Ansell, B. M.: A genetic marker
for systemic amyloidosis in juvenile arthritis. Lancet I: 767-769,
1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 3/23/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 11/15/1988
marie: 3/25/1988

*RECORD*
*FIELD* NO
104775
*FIELD* TI
*104775 AMYLOID PRECURSOR-LIKE PROTEIN; APLP
AMYLOID BETA A4 PRECURSOR-LIKE PROTEIN 1; APLP1
*FIELD* TX
Wasco et al. (1992) isolated a cDNA from a mouse brain library that
encodes a protein whose predicted amino acid sequence is 42% identical
and 64% similar to that of the amyloid beta protein precursor (APP;
104760). This 653-amino acid amyloid precursor-like protein (APLP) was
also similar to APP in overall structure. Wasco et al. (1993) studied a
panel of DNAs from human/rodent somatic cell lines to determine that the
APLP locus is located on chromosome 19. Further study of somatic cell
hybrids containing parts of chromosome 19 excluded the short arm of
chromosome 19 as the site of APLP and placed it between the centromere
and 19q13.2. The finding was of interest because of the existence of
some families with late-onset (more than 65 years of age) Alzheimer
disease that mapped to chromosome 19 and the fact that at least some
families with Alzheimer disease have a mutation in the APP gene on
chromosome 21.

*FIELD* RF
1. Wasco, W.; Brook, J. D.; Tanzi, R. E.: The amyloid precursor-like
protein (APLP) gene maps to the long arm of human chromosome 19. Genomics 15:
237-239, 1993.

2. Wasco, W.; Bupp, K.; Magendantz, M.; Gusella, J. F.; Tanzi, R.
E.; Solomon, F.: Identification of a mouse brain cDNA that encodes
a protein related to the Alzheimer-associated amyloid beta-protein
precursor. Proc. Nat. Acad. Sci. 89: 10758-10762, 1992.

*FIELD* CD
Victor A. McKusick: 7/9/1990

*FIELD* ED
carol: 4/26/1993
carol: 2/24/1993
carol: 2/17/1993
carol: 7/12/1991
carol: 7/9/1990

*RECORD*
*FIELD* NO
104776
*FIELD* TI
*104776 AMYLOID BETA A4 PRECURSOR-LIKE PROTEIN 2; APLP2
AMYLOID PRECURSOR-LIKE PROTEIN-2;;
CDEI-BINDING PROTEIN; CDEBP
*FIELD* TX
The human amyloid precursor-like protein APLP2 is a highly conserved
homolog of a sequence-specific DNA-binding mouse protein with an
important function in the cell cycle. It also shows extensive sequence
homology with conserved domain structures of the amyloid precursor
protein (APP; 104760). The mouse amyloid precursor-like protein Aplp1
has 42% sequence identity to mouse App; the human homolog of APLP1
(104775) maps to 19q11-q13.2 (Wasco et al., 1993). By study of somatic
cell hybrids segregating human chromosomes, von der Kammer et al. (1994)
mapped the APLP2 gene to chromosome 11; by fluorescence in situ
hybridization, the assignment was confirmed and further localized to
11q23-q25.

Using interspecific mouse backcross mapping, von Koch et al. (1995)
localized the mouse Aplp2 gene to the proximal region of mouse
chromosome 9, syntenic with the region of human 11q.

Yang et al. (1996) isolated the homologous mouse gene, which has also
been called Cdebp. The protein binds to the DNA motif GTCACATG, which is
identical to the yeast centromeric element, CDEI. The mouse gene
contains 18 exons and is organized similarly to human APP. The promoter
region was characterized and shown to lack either TATA or CAAT boxes.
The gene was regionally mapped by in situ hybridization to the A2-B
region of mouse chromosome 9.

*FIELD* RF
1. von der Kammer, H.; Loffler, C.; Hanes, J.; Klaudiny, J.; Scheit,
K. H.; Hansmann, I.: The gene for the amyloid precursor-like protein
APLP2 is assigned to human chromosome 11q23-25. Genomics 10: 308-311,
1994.

2. von Koch, C. S.; Lahiri, D. K.; Mammen, A. L.; Copeland, N. G.;
Gilbert, D. J.; Jenkins, N. A.; Sisodia, S. S.: The mouse APLP2 gene:
chromosomal localization and promoter characterization. J. Biol.
Chem. 270: 25475-25480, 1995.

3. Wasco, W.; Brook, J. D.; Tanzi, R. E.: The amyloid precursor-like
protein (APLP) gene maps to the long arm of human chromosome 19. Genomics 15:
237-239, 1993.

4. Yang, Y.; Martin, L.; Cuzin, F.; Mattei, M.-G.; Rassoulzadegan,
M.: Genomic structure and chromosomal localization of the mouse CDEI-binding
protein CDEBP (APLP2) gene and promoter sequences. Genomics 35:
24-29, 1996.

*FIELD* CN
Alan F. Scott - updated: 08/22/1996

*FIELD* CD
Victor A. McKusick: 4/4/1994

*FIELD* ED
mark: 08/22/1996
marlene: 8/20/1996
mark: 1/28/1996
terry: 1/23/1996
pfoster: 9/12/1994
carol: 4/4/1994

*RECORD*
*FIELD* NO
105120
*FIELD* TI
#105120 AMYLOIDOSIS V
FINNISH TYPE AMYLOIDOSIS;;
MERETOJA TYPE AMYLOIDOSIS;;
AMYLOID CRANIAL NEUROPATHY WITH LATTICE CORNEAL DYSTROPHY;;
AMYLOIDOSIS DUE TO MUTANT GELSOLIN
LATTICE CORNEAL DYSTROPHY, TYPE II, INCLUDED;;
CORNEAL DYSTROPHY, LATTICE TYPE II, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the causative mutation
is now known to reside in the gelsolin gene (137350).

The unique features of this variety of systemic amyloidosis are corneal
lattice dystrophy and cranial neuropathy, manifesting, for example, by
facial paresis. (Corneal lattice dystrophy due to local amyloid
deposition (122200) occurs as an isolated dominant.) In a massive
investigation in Finland, Meretoja (1973) identified 207 affected
persons. Two patients, whose parents were affected and who were more
severely affected than the others, were thought to represent
homozygosity. A few of the patients developed nephrotic syndrome and
renal failure and some had cardiac involvement. Amyloid involvement was
rather widespread at autopsy. Meretoja et al. (1978) collected 307
patients in Finland. Three Czechoslovakian sisters with bulbar palsy,
'cutis hyperelastica,' and lattice dystrophy of the cornea, reported by
Klaus et al. (1959), may have had this disorder. Cases were reported
from the United States by Sack et al. (1981), Purcell et al. (1983),
Darras et al. (1986), and Starck et al. (1991); from Holland by
Winkelman et al. (1971); and from Denmark by Boysen et al. (1979). One
man had onset of facial paralysis, which began as inability to control a
drooping lower lip, at the age of about 56; the lip became strikingly
protuberant and everted with exposure of the lower gingival mucosa (Sack
et al., 1981). Five years after onset he could not wrinkle his forehead
and there was an intermittent twitch of the right side of the lower lip.
The extraocular muscles were affected only minimally and there was no
ptosis. A striking feature was laxity of the skin, which raised the
question of cutis laxa. Slit-lamp examination showed a lattice type of
corneal opacity bilaterally. The mother had the identical disorder
beginning at about the same stage of life. The proband had bulbar
manifestations. Melkersson syndrome (155900) might be considered in the
differential diagnosis. Kiuru (1992) reported the clinical findings of
30 patients. Signs of cranial neuropathy especially affecting the facial
nerve were found in all, and peripheral polyneuropathy mainly affecting
vibration and touch senses was demonstrated in 26 patients. Kiuru et al.
(1994) studied the autonomic nervous system and heart in 30 patients.
Minor autonomic nervous system dysfunction was found in most patients,
but clinically significant autonomic dysfunction or cardiopathy was not
characteristic.

It appears that amyloidosis V results from deposition of gelsolin (see
137350.0001). Maury et al. (1990) studied amyloid fibrils isolated from
the kidney of a patient with the Finnish form. The amino acid sequence
determined for part of the protein was identical to that deduced for
plasma gelsolin in the region of amino acids 235-269. Haltia et al.
(1990) likewise showed that the amyloid in this disorder is
antigenically and structurally related to gelsolin. The same mutation in
gelsolin (asp187-to-asn) has been found in all Finnish families studied
to date (Maury, 1991; Paunio et al., 1992; de la Chapelle et al., 1992;
Haltia et al., 1992); furthermore, it was found also in the affected son
of the proband of the Scottish-American family reported by Sack et al.
(1981); see de la Chapelle et al., (1992).

Maury (1993) reported the findings in 2 sisters who, by molecular
studies, were shown to be homozygous for the asp187-to-asn mutation in
gelsolin. In both, the disease was unusually severe, manifesting with
nephrotic syndrome and end-stage renal failure. Immunohistochemical
studies of the kidneys demonstrated heavy glomerular deposits of
gelsolin-derived amyloid. Immunostaining also demonstrated gelsolin in
the tubular epithelium, where it was Congo-red negative.

Akiya et al. (1996) reported a Japanese brother and half-sister with
lattice corneal dystrophy as part of the Finnish type amyloidosis. They
referred to the Finnish-type as FAP type IV. The patients were 70 and 68
years old, respectively.

*FIELD* SA
Meretoja  (1973)
*FIELD* RF
1. Akiya, S.; Nishio, Y.; Ibi, K.; Uozumi, H.; Takahashi, H.; Hamada,
T.; Onishi, A.; Ishiguchi, H.; Hoshii, Y.; Nakazato, M.: Lattice
corneal dystrophy type II associated with familial amyloid polyneuropathy
type IV. Ophthalmology 103: 1106-1110, 1996.

2. Boysen, G.; Galassi, G.; Kamieniecka, Z.; Schlaeger, J.; Trojaborg,
W.: Familial amyloidosis with cranial neuropathy and corneal lattice
dystrophy. J. Neurol. Neurosurg. Psychiat. 42: 1020-1030, 1979.

3. Darras, B. T.; Adelman, L. S.; Mora, J. S.; Rodziner, R. A.; Munsat,
T. L.: Familial amyloidosis with cranial neuropathy and corneal lattice
dystrophy. Neurology 36: 432-435, 1986.

4. de la Chapelle, A.; Kere, J.; Sack, G. H., Jr.; Tolvanen, R.; Maury,
C. P. J.: Familial amyloidosis, Finnish type: G654-to-A mutation
of the gelsolin gene in Finnish families and an unrelated American
family. Genomics 13: 898-901, 1992.

5. Haltia, M.; Ghiso, J.; Prelli, F.; Gallo, G.; Kiuru, S.; Somer,
H.; Palo, J.; Frangione, G.: Amyloid in familial amyloidosis, Finnish
type, is antigenically and structurally related to gelsolin. Am.
J. Path. 136: 1223-1228, 1990.

6. Haltia, M.; Levy, E.; Meretoja, J.; Fernandez-Madrid, I.; Koivunen,
O.; Frangione, B.: Gelsolin gene mutation--at codon 187--in familial
amyloidosis, Finnish: DNA-diagnostic assay. Am. J. Med. Genet. 42:
357-359, 1992.

7. Kiuru, S.: Familial amyloidosis of the Finnish type (FAF): a clinical
study of 30 patients. Acta Neurol. Scand. 86: 346-353, 1992.

8. Kiuru, S.; Matikainen, E.; Kupari, M.; Haltia, M.; Palo, J.: Autonomic
nervous system and cardiac involvement in familial amyloidosis, Finnish
type (FAF). J. Neurol. Sci. 126: 40-48, 1994.

9. Klaus, E.; Freyberger, E.; Kavka, G.; Vodicka, F.: Familial occurrence
of a bulbar paralytic form of amyotrophic lateral sclerosis with reticular
corneal dystrophy and cutis hyperelastica in 3 sisters. Psychiat.
Neurol. 138: 79-97, 1959.

10. Maury, C. P. J.: Personal Communication. Helsinki, Finland
10/23/1991.

11. Maury, C. P. J.: Homozygous familial amyloidosis, Finnish type:
demonstration of glomerular gelsolin-derived amyloid and non-amyloid
tubular gelsolin. Clin. Nephrol. 40: 53-56, 1993.

12. Maury, C. P. J.; Alli, K.; Baumann, M.: Finnish hereditary amyloidosis:
amino acid sequence homology between the amyloid fibril protein and
human plasma gelsoline. FEBS Lett. 260: 85-87, 1990.

13. Meretoja, J.: Genetic aspects of familial amyloidosis with corneal
lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185,
1973.

14. Meretoja, J.: Inherited Systemic Amyloidosis with Lattice Corneal
Dystrophy.  Acad. Dissertation: Helsinki (pub.)  1973.

15. Meretoja, J.; Hollmen, T.; Meretoja, T.; Penttinen, R.: Partial
characterization of amyloid proteins in inherited amyloidosis with
lattice corneal dystrophy and in secondary amyloidosis. Med. Biol. 56:
17-22, 1978.

16. Paunio, T.; Kiuru, S.; Hongell, V.; Mustonen, E.; Syvanen, A.-C.;
Bengtstrom, M.; Palo, J.; Peltonen, L.: Solid-phase minisequencing
test reveals asp187-to-asn (G654-to-A) mutation of gelsolin in all
affected individuals with Finnish type of familial amyloidosis. Genomics 13:
237-239, 1992.

17. Purcell, J. J., Jr.; Rodrigues, M.; Chishti, M. I.; Riner, R.
N.; Dooley, J. M.: Lattice corneal dystrophy associated with familial
systemic amyloidosis (Meretoja's syndrome). Ophthalmology 90: 1512-1517,
1983.

18. Sack, G. H., Jr.; Dumars, K. W.; Gummerson, K. S.; Law, A.; McKusick,
V. A.: Three forms of dominant amyloid neuropathy. Johns Hopkins
Med. J. 149: 239-247, 1981.

19. Starck, T.; Kenyon, K. R.; Hanninen, L. A.; Beyer-Machule, C.;
Fabian, R.; Gorn, R. A.; McMullan, F. D.; Baum, J.; McAdam, K. P.
W. J.: Clinical and histopathologic studies of two families with
lattice corneal dystrophy and familial systemic amyloidosis (Meretoja
syndrome). Ophthalmology 98: 1197-1206, 1991.

20. Winkelman, J. E.; Delleman, J. W.; Ansink, B. J. J.: Ein hereditaeres
Syndrom, bestehend aus peripherer Polyneuropathie, Hautveraenderungen
und gittriger Dystrophie der Hornhaut. Klin. Mbl. Augenheilk. 159:
618-623, 1971.

*FIELD* CS

Skin:
   Cutis laxa

Eye:
   Lattice corneal dystrophy

Neuro:
   Cranial neuropathy, esp. facial paresis;
   Bulbar palsy;
   Peripheral polyneuropathy, esp. vibration and touch loss;
   Autonomic dysfunction does not occur

GI:
   Gastrointestinal symptoms are inconstant

GU:
   Nephrotic syndrome;
   Renal failure

Cardiac:
   Amyloid cardiomyopathy

Misc:
   Onset in third decade

Lab:
   Generalized amyloid deposition;
   Mutant gelsolin gene (137350)

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/26/1996
terry: 10/18/1996
joanna: 2/26/1996
carol: 1/19/1995
davew: 6/8/1994
mimadm: 4/18/1994
warfield: 4/7/1994
carol: 11/9/1993
carol: 1/28/1993

*RECORD*
*FIELD* NO
105150
*FIELD* TI
*105150 AMYLOIDOSIS VI
CEREBRAL ARTERIAL TYPE AMYLOIDOSIS;;
ICELANDIC TYPE AMYLOIDOSIS;;
CEREBRAL HEMORRHAGE, FAMILIAL;;
HEREDITARY CEREBRAL HEMORRHAGE WITH AMYLOIDOSIS; HCHWA;;
CEREBRAL HEMORRHAGE, HEREDITARY, WITH AMYLOIDOSIS;;
GAMMA-TRACE, DEFECT IN METABOLISM OF;;
CEREBRAL AMYLOID ANGIOPATHY
CYSTATIN 3; CST3, INCLUDED;;
CYSTATIN C, INCLUDED
*FIELD* MN
Cerebral amyloid angiopathy is recognized as a cause of sporadic
intracerebral hemorrhage in Icelandic families (Jensson et al., 1989).
Inheritance is autosomal dominant. Over 80% of those who died from this
disease were less than 40 years of age. Cerebral arteries show
thickening of the walls with deposition of material with the
characteristics of amyloid. Characteristically, nonhypertensive,
previously healthy persons suffer sudden catastrophic, often multifocal
cerebral hemorrhages from intraparencymal and/or meningeal vessels
extensively infiltrated with amyloid (Cohen et al., 1983). None have
systemic amyloidosis. Amyloid proteins deposited in the cerebral
arteries show amino-terminal sequences similar to those of the protein
cystatin C (123855), which is a potent inhibitor of several human
cysteine proteinases. The cystatin C gene (CST3) and probably 7 other
members of the cystatin gene family are clustered within a 1.2-Mb
segment on chromosome 20p11.2 (Schnittger et al., 1993). The CST3 gene
contains 3 exons and 2 introns spanning 4.3 kb of genomic DNA. A
mutation in codon 68 that abolishes an AluI restriction site and results
in a leu68-to-gln amino acid substitution is the cause of the disorder
(Palsdottir et al., 1988). Abrahamson et al. (1992) described a rapid
and simple method of molecular diagnosis.

Two fishermen populations along the Dutch North Sea Coast are the only
groups other than Icelanders recognized as having the familial form
(Jensson et al., 1986). Abnormally low cystatin C in the cerebral spinal
fluid is a characteristic that can be used in identifying asymptomatic
affected Icelandic persons. In the Dutch patients, however, the cystatin
C was found to be normal in the cerebral spinal fluid. The forms of
HCHWA in the Netherlands and in Iceland represent fundamentally separate
diseases (van Duinen et al., 1987); see 104760.0001. Differences
include:earlier age at the first stroke in Icelandic patients (mean age
of 27 years, vs.52); lower level of cystatin C in the cerebral spinal
fluid of Icelandic patients than in Dutch patients or in healthy
persons; more intense staining for cystatin C in diseased Icelandic
brain vessels, vs. only weak or dubious stainingin the Dutch. In the
Dutch form the vascular amyloid deposits have immunohistochemical
characteristics of Alzheimer disease-related beta-protein (104760).

See also Abrahamson and Grubb (1994); Huh et al. (1995).

*FIELD* ED
jamie: 02/19/1997 joanna: 11/25/1996 joanna: 11/23/1996

*FIELD* CD
F. Clarke Fraser: 7/1/1996
*FIELD* TX
Arnason (1935) described 10 Icelandic families with a high incidence of
cerebral hemorrhage and concluded that a hereditary form of the disease
was present in these families. Also in Iceland, Gudmundsson et al.
(1972) studied a kindred in which 18 persons in 3 generations had
cerebral hemorrhage, some of them at a young age. Cerebral arteries
showed thickening of the walls with deposition of material with the
characteristics of amyloid. Amyloid was not found in other arteries
except in a case of long-standing tuberculosis. Male-to-male
transmission was observed. Cohen et al. (1983) stated that 75 cases of
HCHWA had been identified in the Icelandic kindred. Characteristically,
nonhypertensive, previously healthy persons suffer sudden catastrophic,
often multifocal cerebral hemorrhages from intraparendymal and/or
meningeal vessels extensively infiltrated with amyloid. Cohen et al.
(1983) analyzed the amyloid proteins deposited in the cerebral arteries
of 3 young Icelandic patients who died of cerebral hemorrhage.
Amino-terminal sequencing showed the proteins to be similar to a
recently described human protein called gamma-trace. The amyloid
deposits in all 3 patients stained with rabbit anti-gamma-trace
antiserum. Grubb et al. (1984) found low levels of gamma-trace in 9
patients with the cerebrovascular form of amyloidosis. The CSF
concentration of beta-2-microglobulin, a microprotein of about the same
size as gamma-trace, did not differ from the normal. No structural
abnormality of gamma-trace in the CSF of patients could be demonstrated.
Grubb et al. (1984) concluded, therefore, that the basic defect in this
disease is an abnormality in the catabolic processing of gamma-trace.
The findings provide a diagnostic index of high sensitivity and
specificity.

The microprotein gamma-trace is present in a number of neuroendocrine
cells and its concentration in the CSF is 5.5 times that in plasma of
healthy adults (Lofberg and Grubb, 1979; Lofberg et al., 1981; Grubb and
Lofberg, 1982; Lofberg et al., 1983). It was amino-acid sequenced by
Grubb and Lofberg (1982). Also called cystatin C, it is a potent
inhibitor of several human cysteine proteinases (Barrett et al., 1984).
Abrahamson (1988) reported the isolation and characterization of 6 human
cysteine proteinase inhibitors, including cystatin C.

Mandybur and Bates (1978) recognized cerebral amyloid angiopathy as a
cause of sporadic intracerebral hemorrhage. Cosgrove et al. (1985)
reviewed 24 cases of autopsy-proven cerebral amyloid angiopathy. In 16,
death was caused by intracranial hemorrhage. None had systemic
amyloidosis. Surgery is difficult (Torack, 1975). The clinical features
of cerebral amyloid angiopathy in sporadic cases are becoming more
familiar (Smith et al., 1985; Roosen et al., 1985). Graffagnino et al.
(1994) failed to find the Icelandic cystatin C mutation in any of 48
consecutive patients with intracerebral hemorrhage admitted to Duke
University Hospital. No pathology was reported on any of these cases.
Two fishermen populations along the Dutch North Sea Coast (Katwijk and
Scheveningen) are the only groups other than Icelanders recognized as
having the familial form (Luyendijk and Bots, 1986). In these cases, the
amyloid was said to react with antisera against gamma-trace in the same
way found in the Icelandic patients, but this was obviously in error
(see 104760.0001). Jensson et al. (1986) suggested that certain
differences of the disorders in Dutch patients (Wattendorff et al.,
1982) indicate that these are 2 separate mutations in cystatin C. This
proved, however, to be locus heterogeneity rather than allelic
heterogeneity. By 1986, the Icelandic experience included 128 affected
members in 8 families originating from the same geographic area of
Iceland (Jensson et al., 1986). Over 80% of those who died from this
disease were less than 40 years of age. Abnormally low cystatin C in the
cerebral spinal fluid is a characteristic that can be used in
identifying asymptomatic affected persons. In the Dutch patients,
however, the cystatin C was found to be normal in the cerebral spinal
fluid. Palsdottir et al. (1988) referred to the disorder in Icelandic
patients as hereditary cystatin C amyloid angiopathy (HCCAA).

Abrahamson et al. (1987) isolated recombinant cystatin C-producing
clones from a human placenta lambda-gt11 cDNA library. The cDNA insert
of 1 of the clones, containing 777 basepairs, encoded the 120 amino
acids of the complete mature cystatin C and a hydrophobic leader
sequence of 26 amino acids. (The presence of the leader sequence
suggests an extracellular function for cystatin C. It may serve as a
physiologically important extracellular cysteine proteinase inhibitor,
for example in seminal fluid which of all biologic fluids has the
highest concentration of cystatin C.) The deduced protein sequence
confirmed the protein sequence of cystatin C isolated from human urine,
but expectedly differed in 1 position from the sequence of the cystatin
C fragment deposited as amyloid in HCHWA. Lofberg et al. (1987) found
that amyloid angiopathy characterized by an immunoreactivity of cystatin
C was present in a submandibular lymph node in addition to small
arteries in the cerebrum, cerebellum, and leptomeninges. All 9 persons
investigated showed low CSF cystatin C. The cystatin C in the CSF of
these patients had an isoelectric point identical to that of normal
persons. Fibroblasts and glial cells secrete cystatin C into tissue
culture fluids (Palsdottir et al., 1988).

The forms of HCHWA in the Netherlands and in Iceland represent
fundamentally separate diseases (van Duinen et al., 1987); see
104760.0001. Differences that have been noted between the 2 forms
include the following: Icelandic patients suffer the first stroke at a
mean age of 27 years, whereas the Dutch patients are approximately 25
years older; the level of cystatin C in the cerebral spinal fluid of
Icelandic patients is lower than that in Dutch patients or in healthy
persons; and, immunohistochemically, intense staining for cystatin C is
found in diseased Icelandic brain vessels, whereas in the Dutch material
only weak or dubious staining is found. There is no evidence of
genealogic connection between the Dutch and Icelandic families. A
critical piece of evidence indicating a difference between the 2
diseases is the finding by van Duinen et al. (1987) that in the Dutch
form of the disease the vascular amyloid deposits have
immunohistochemical characteristics of Alzheimer disease-related
beta-protein (104760). Jensson et al. (1989) reviewed the history of the
Icelandic variety in an article appropriately called 'The saga of the
cystatin C mutation causing amyloid angiopathy and brain hemorrhage.'
They pointed out that the patients show cystatin C amyloid as a regular
histopathologic finding in lymphoid tissue, spleen, salivary glands, and
seminal vesicles. A biopsy of these tissues can be used in confirmation
of the diagnosis. Geographic distribution of the cases demonstrated 2
clusters in Iceland. Jensson et al. (1989) also gave a listing of
autosomal dominant, autosomal recessive and X-linked disorders that have
been identified and studied in Iceland.

By means of hybridization of a cDNA probe to DNA from human-rodent
somatic cell hybrids, Abrahamson et al. (1989) showed that the cystatin
C gene (CST3) is located on chromosome 20. The CST3 gene contains 3
exons and 2 introns spanning 4.3 kb of genomic DNA (Abrahamson et al.,
1990). Using Southern analysis, pulsed field gel electrophoresis (PFGE),
and both radioactive and fluorescence in situ hybridization, Gopal Rao
et al. (1991) confirmed the assignment of CST3 and the other family II
cystatins to chromosome 20. PFGE with a cystatin-C-specific probe showed
a single 300-kb BssHII fragment and in situ hybridization mapped the
locus specifically to 20p11. This location was found to be proximal to
the breakpoint in a patient with Alagille syndrome (118450). From the
results of fluorescence in situ hybridization, Southern blot, and PFGE
studies, Schnittger et al. (1993) concluded that CST3 and probably 7
other members of the cystatin gene family are clustered within a 1.2-Mb
segment on chromosome 20p11.2.

Balbin and Abrahamson (1991) demonstrated 3 point mutations in a 220-bp
fragment from the promoter region of the CST3 gene. One resulted in the
generation of a novel SstII restriction site and another in the loss of
the commonly occurring SstII restriction site. The polymorphism
displayed mendelian inheritance and should be useful for linkage
studies. It apparently involves 3 linked mutations, since alleles
carrying only 1 of the 3 base changes have not been found. The mutant
allele called B had a frequency of 0.29 (A = 0.71).

Huh et al. (1995) determined the structure of the mouse Cst3 gene by
sequencing a 6.1-kb genomic DNA containing the entire gene, as well as
0.9 kb of the 5-prime flanking region and 1.7 kb of the 3-prime flanking
region. The sequence revealed an overall organization very similar to
that of the human CST3 gene. Huh et al. (1995) mapped the gene to distal
mouse chromosome 2.

*FIELD* AV
.0001
AMYLOIDOSIS, CEREBROARTERIAL, ICELANDIC TYPE
CEREBRAL AMYLOID ANGIOPATHY, ICELANDIC TYPE
CST3, LEU68GLN
Ghiso et al. (1986) presented high performance liquid chromatography
(HPLC) tryptic fingerprint analyses that showed differences between
normal cystatin C and its variant in Icelandic amyloidosis. Only 1 amino
acid substitution was found (gln for leu at residue 58). Ghiso et al.
(1986) acknowledged the difficulty in knowing whether the gln for leu
change is a normal variation or the mutation responsible for the
formation of amyloid. In an addendum they stated that the cystatin C
gene had been cloned using a synthetic oligonucleotide. In the amyloid
protein deposited in the Icelandic type of amyloidosis, Jensson et al.
(1987) found differences from the 120-amino acid sequence of cystatin C:
first, 10 amino acids are missing from the amino terminal, and second,
there is an amino acid substitution at position 58 (glutamine for
leucine) which corresponds to position 68 in cystatin C. Abrahamson et
al. (1987) cloned and sequenced the cystatin-C gene, deduced the amino
acid sequence of the normal protein, and demonstrated the change of
leucine-68 to glutamine that results from a CTG-to-CAG change in
nucleotides 357-359. Since the mutation in codon 68 abolishes an AluI
restriction site, Palsdottir et al. (1988) used this marker to trace the
mutation through 8 families, establishing incontrovertibly that the
mutation is the cause of the disorder because it was found only in
affected individuals. Abrahamson et al. (1992) described a rapid and
simple method of diagnosis, based on oligonucleotide-directed enzymatic
amplification of a 275-bp genomic DNA segment containing exon 2 of the
cystatin C gene from a blood sample, followed by digestion of the
amplification product with AluI. Loss of an AluI recognition site in the
amplified DNA segment from patients results in a deviating band-pattern
on agarose gel electrophoresis. They sequenced amplified DNA segments
from 4 different families and found that all had the single T-to-A
transversion in codon 68. Abrahamson and Grubb (1994) produced normal
and L68Q cystatin C in an Escherichia coli expression system. Parallel
physicochemical and functional investigations of the two proteins
revealed that both effectively inhibit the cysteine protease cathepsin B
(116810) but differ considerably in their tendency to dimerize and form
aggregates. While wildtype cystatin C was monomeric and functionally
active even after prolonged storage at elevated temperatures, L68Q
cystatin C started to dimerize and lose biologic activity immediately
after it was transferred to a nondenaturing buffer. The dimerization was
highly temperature-dependent, with a rise in incubation temperature from
37 to 40 degrees centigrade resulting in a 150% increase in dimerization
rate. The aggregation at physiologic concentrations was increased at 40
degrees compared to 37 degrees centigrade, by approximately 60%. Medical
intervention to abort febrile periods in carriers of the disease trait
might reduce the in vivo formation of L68Q cystatin C aggregates.

*FIELD* SA
Ghiso et al. (1986); Gray et al. (1985); Hochwald and Thorbecke (1985);
Kidd and Cumings (1947); Stefansson et al. (1980)
*FIELD* RF
1. Abrahamson, M.: Human cysteine proteinase inhibitors: isolation,
physiological importance, inhibitory mechanism, gene structure and
relation to hereditary cerebral hemorrhage. Scand. J. Clin. Lab.
Invest. 48 (suppl. 191): 21-31, 1988.

2. Abrahamson, M.; Grubb, A.: Increased body temperature accelerates
aggregation of the leu68-to-gln mutant cystatin C, the amyloid-forming
protein in hereditary cystatin C amyloid angiopathy. Proc. Nat. Acad.
Sci. 91: 1416-1420, 1994.

3. Abrahamson, M.; Grubb, A.; Olafsson, I.; Lundwall, A.: Molecular
cloning and sequence analysis of cDNA coding for the precursor of
the human cysteine proteinase inhibitor cystatin C. FEBS Lett. 216:
229-233, 1987.

4. Abrahamson, M.; Islam, M. Q.; Szpirer, J.; Szpirer, C.; Levan,
G.: The human cystatin C gene (CST3), mutated in hereditary cystatin
C amyloid angiopathy, is located on chromosome 20. Hum. Genet. 82:
223-226, 1989.

5. Abrahamson, M.; Jonsdottir, S.; Olafsson, I.; Jensson, O.; Grubb,
A.: Hereditary cystatin C amyloid angiopathy: identification of the
disease-causing mutation and specific diagnosis by polymerase chain
reaction based analysis. Hum. Genet. 89: 377-380, 1992.

6. Abrahamson, M.; Olafsson, I.; Palsdottir, A.; Ulvsback, M.; Lundwall,
A.; Jensson, O.; Grubb, A.: Structure and expression of the human
cystatin C gene. Biochem. J. 268: 287-294, 1990.

7. Arnason, A.: Apoplexie und ihre Vererbung. Acta Psychiat. Neurol. 7
(suppl.): 1-180, 1935.

8. Balbin, M.; Abrahamson, M.: SstII polymorphic sites in the promoter
region of the human cystatin C gene. Hum. Genet. 87: 751-752, 1991.

9. Barrett, A. J.; Davies, M. E.; Grubb, A.: The place of human gamma-trace
(cystatin C) amongst the cysteine proteinase inhibitors. Biochem.
Biophys. Res. Commun. 120: 631-636, 1984.

10. Cohen, D. H.; Feiner, H.; Jensson, O.; Frangione, B.: Amyloid
fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA)
is related to the gastroentero-pancreatic neuroendocrine protein,
gamma trace. J. Exp. Med. 158: 623-628, 1983.

11. Cosgrove, G. R.; Leblanc, R.; Meagher-Villemure, K.; Ethier, R.
: Cerebral amyloid angiopathy. Neurology 35: 625-631, 1985.

12. Ghiso, J.; Jensson, O.; Frangione, B.: Amyloid fibrils in hereditary
cerebral hemorrhage with amyloidosis of Icelandic type is a variant
of gamma-trace basic protein (cystatin C). Proc. Nat. Acad. Sci. 83:
2974-2978, 1986.

13. Ghiso, J.; Pons-Estel, B.; Frangione, B.: Hereditary cerebral
amyloid angiopathy: the amyloid fibrils contain a protein which is
a variant of cystatin C, an inhibitor of lysosomal cysteine proteases. Biochem.
Biophys. Res. Commun. 136: 548-554, 1986.

14. Gopal Rao, V. V.; Schnittger, S.; Abrahamson, M.; Hansmann, I.
: Cystatin-C (CST3), the candidate gene for the hereditary cystatin-C
amyloid angiopathy (HCCAA) maps to or close to human chromosome 20p11.22.
(Abstract) Cytogenet. Cell Genet. 58: 2029, 1991.

15. Graffagnino, C.; Herbstreith, M. H.; Roses, A. D.; Alberts, M.
J.: A molecular genetic study of intracerebral hemorrhage. Arch.
Neurol. 51: 981-984, 1994.

16. Gray, F.; Dubas, F.; Roullet, E.; Escourolle, R.: Leukoencephalopathy
in diffuse hemorrhagic cerebral amyloid angiopathy. Ann. Neurol. 18:
54-59, 1985.

17. Grubb, A.; Jensson, O.; Gudmundsson, G.; Arnason, A.; Lofberg,
H.; Malm, J.: Abnormal metabolism of gamma-trace alkaline microprotein:
the basic defect in hereditary cerebral hemorrhage with amyloidosis. New
Eng. J. Med. 311: 1547-1549, 1984.

18. Grubb, A.; Lofberg, H.: Human gamma-trace, a basic microprotein:
amino acid sequence and presence in the adenohypophysis. Proc. Nat.
Acad. Sci. 79: 3024-3027, 1982.

19. Gudmundsson, G.; Hallgrimsson, J.; Jonasson, T. A.; Bjarnason,
O.: Hereditary cerebral haemorrhage with amyloidosis. Brain 95:
387-404, 1972.

20. Hochwald, G. M.; Thorbecke, G. J.: Abnormal metabolism or reduced
transport of CSF gamma-trace microprotein in hereditary cerebral hemorrhage
with amyloidosis. (Letter) New Eng. J. Med. 312: 1127-1128, 1985.

21. Huh, C.; Nagle, J. W.; Kozak, C. A.; Abrahamson, M.; Karlsson,
S.: Structural organization, expression and chromosomal mapping of
the mouse cystatin-C-encoding gene (Cst3). Gene 152: 221-226, 1995.

22. Jensson, O.; Arnason, A.; Thorsteinsson, L.; Petursdottir, I.;
Gudmundsson, G.; Blondal, H.; Grubb, A.; Lofberg, H.; Luyendijk, W.;
Bots, G. T. A. M.; Frangione, B.: Cystatin C (gamma-trace) amyloidosis.In:
Turk, V.: Cysteine Proteinases and their Inhibitors.  New York:
Walter de Gruyter and Co. (pub.)  1986.

23. Jensson, O.; Gudmundsson, G.; Arnason, A.; Blondal, H.; Petursdottir,
I.; Thorsteinsson, L.; Grubb, A.; Lofberg, H.; Cohen, D.; Frangione,
B.: Hereditary cystatin C (gamma-trace) amyloid angiopathy of the
CNS causing cerebral hemorrhage. Acta Neurol. Scand. 76: 102-114,
1987.

24. Jensson, O.; Palsdottir, A.; Thorsteinsson, L.; Arnason, A.:
The saga of cystatin C gene mutation causing amyloid angiopathy and
brain hemorrhage--clinical genetics in Iceland. Clin. Genet. 36:
368-377, 1989.

25. Kidd, H. A.; Cumings, J. N.: Cerebral angiomata in an Icelandic
family. Lancet I: 747-748, 1947.

26. Lofberg, H.; Grubb, A.; Davidsson, L.; Kjellander, B.; Stromblad,
L.-G.; Tibblin, S.; Olsson, S.-O.: Occurrence of gamma-trace in the
calcitonin-producing C-cells of simian thyroid gland. Acta Endocr. 104:
69-76, 1983.

27. Lofberg, H.; Grubb, A. O.: Quantitation of gamma-trace in human
biological fluids: indications for production in the central nervous
system. Scand. J. Clin. Lab. Invest. 39: 619-626, 1979.

28. Lofberg, H.; Grubb, A. O.; Nilsson, E. K.; Jensson, O.; Gudmundsson,
G.; Blondal, H.; Arnason, A.; Thorsteinsson, L.: Immunohistochemical
characterization of the amyloid deposits and quantitation of pertinent
cerebrospinal fluid proteins in hereditary cerebral hemorrhage with
amyloidosis. Stroke 18: 431-440, 1987.

29. Lofberg, H.; Stromblad, L.-G.; Grubb, A. O.; Olsson, S.-O.: Demonstration
of gamma-trace in normal and neoplastic endocrine A-cells of the pancreatic
islets: an immunohistochemical study in monkey, rat and man. Biomed.
Res. 2: 527-535, 1981.

30. Luyendijk, W.; Bots, G. T. A. M.: Hereditary cerebral haemorrhage.
(Letter) Scand. J. Clin. Lab. Invest. 46: 391, 1986.

31. Mandybur, T. I.; Bates, S. R. D.: Fatal massive intracerebral
hemorrhage complicating cerebral amyloid angiopathy. Arch. Neurol. 35:
246-248, 1978.

32. Palsdottir, A.; Abrahamson, M.; Thorsteinsson, L.; Arnason, A.;
Olafsson, I.; Grubb, A.; Jensson, O.: Mutation in cystatin C gene
causes hereditary brain haemorrhage. Lancet II: 603-604, 1988.

33. Roosen, N.; Martin, J.-J.; De La Porte, C.; Van Vyve, M.: Intracerebral
hemorrhage due to cerebral amyloid angiopathy: case report. J. Neurosurg. 63:
965-969, 1985.

34. Schnittger, S.; Gopal Rao, V. V. N.; Abrahamson, M.; Hansmann,
I.: Cystatin C (CST3), the candidate gene for hereditary cystatin
C amyloid angiopathy (HCCAA), and other members of the cystatin gene
family are clustered on chromosome 20p11.2. Genomics 16: 50-55,
1993.

35. Smith, D. B.; Hitchcock, M.; Philpott, P. J.: Cerebral amyloid
angiopathy presenting as transient ischemic attacks: case report. J.
Neurosurg. 63: 963-964, 1985.

36. Stefansson, K.; Antel, J. P.; Oger, J.; Burns, J.; Noronha, A.
B. C.; Roos, R. P.; Arnason, B. G. W.; Gudmundsson, G.: Autosomal
dominant cerebrovascular amyloidosis: properties of peripheral blood
lymphocytes. Ann. Neurol. 7: 436-440, 1980.

37. Torack, R. M.: Congophilic angiopathy complicated by surgery
and massive hemorrhage. Am. J. Path. 81: 349-366, 1975.

38. van Duinen, S. G.; Castano, E. M.; Prelli, F.; Bots, G. T. A.
M.; Luyendijk, W.; Frangione, B.: Hereditary cerebral hemorrhage
with amyloidosis in patients of Dutch origin is related to Alzheimer
disease. Proc. Nat. Acad. Sci. 84: 5991-5994, 1987.

39. Wattendorff, A. R.; Bots, G. T. A. M.; Went, L. N.; Endtz, L.
J.: Familial cerebral amyloid angiopathy presenting as recurrent
cerebral haemorrhage. J. Neurol. Sci. 55: 121-135, 1982.

*FIELD* CS

Neuro:
   Cerebral artery involvement with cerebral hemorrhage;
   Peripheral neuropathy does not occur;
   Autonomic dysfunction does not occur

GI:
   Gastrointestinal symptoms are inconstant

Lab:
   Generalized amyloid deposition;
   Abnormally low cerebral spinal fluid cystatin C

Inheritance:
   Autosomal dominant (20p11)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/31/1997
terry: 3/28/1997
mark: 3/21/1996
mark: 3/20/1995
carol: 1/26/1995
warfield: 4/6/1994
mimadm: 3/11/1994
carol: 10/18/1993
carol: 10/14/1993

*RECORD*
*FIELD* NO
105200
*FIELD* TI
#105200 AMYLOIDOSIS, FAMILIAL VISCERAL
AMYLOIDOSIS VIII;;
OSTERTAG TYPE AMYLOIDOSIS;;
GERMAN TYPE AMYLOIDOSIS;;
AMYLOIDOSIS, FAMILIAL RENAL;;
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
*FIELD* TX
A number sign (#) is used with this entry because of the evidence that
systemic nonneuropathic amyloidosis is the result of mutation in the
apolipoprotein A-I gene (APOA1, 107680), the fibrinogen alpha-chain gene
(FGA, 134820), the lysozyme gene (LYZ, 153450), or perhaps other genes.

Ostertag (1932, 1950) reported on a family with visceral amyloidosis. A
woman, 3 of her children, and 1 of her grandchildren were affected with
chronic nephropathy, arterial hypertension, and hepatosplenomegaly.
Albuminuria, hematuria and pitting edema were early signs. The age of
onset was variable. Death occurred about 10 years after onset. The
visceral involvement by amyloid was found to be extensive. Maxwell and
Kimbell (1936) described 3 brothers who died of visceral, especially
renal, amyloidosis in their 40s. Chronic weakness, edema, proteinuria,
and hepatosplenomegaly were features. I have followed up on the family
reported by Maxwell and Kimbell (1936). The father of the 3 affected
brothers died at age 72 after an automobile accident and their mother
died suddenly at age 87 after being in apparent good health. A son of
one of the brothers had frequent bouts of unexplained fever in childhood
(as did his father and 2 uncles), accompanied at times by nonspecific
rash. At the age of 35, proteinuria was discovered and renal amyloidosis
was diagnosed by renal biopsy. For 2 years thereafter he displayed the
nephrotic syndrome, followed in the next 2 years by uremia from which he
died at age 39. Autopsy revealed amyloidosis, most striking in the
kidneys but also involving the adrenal glands and spleen. Although some
features of the family of Maxwell and Kimbell (1936) are similar to
those of urticaria, deafness and amyloidosis (191900), no deafness was
present in their family. Weiss and Page (1974) reported a family with 2
definite and 4 probable cases in 3 generations. Mornaghi et al. (1981,
1982) reported rapidly progressive biopsy-proved renal amyloidosis in 3
brothers, aged 49, 52 and 55, of Irish-American origin. None had
evidence of a plasma cell dyscrasia, a monoclonal serum or urine
protein, or any underlying chronic disease. Immnoperoxidase staining of
1 pulmonary and 1 renal biopsy specimen was negative for amyloid A (AA),
amyloid L (AL) and prealbumin. The authors concluded that the disorder
in the 3 brothers closely resembles that described by Ostertag (1932).
Studying the proband of a kindred with the familial amyloidosis of
Ostertag, Lanham et al. (1982) demonstrated permanganate-sensitive
congophilia of the amyloid but found no immunofluorescent staining for
amyloid A or prealbumin. They concluded that this amyloid may be
chemically distinct from previously characterized forms. Libbey and
Talbert (1987) described a case of nephropathic amyloidosis, presumably
of the Ostertag type. In their case, the amyloid showed no staining for
light chains or prealbumin. Involvement of the liver was associated with
cholestasis. In the kindred reported by Lanham et al. (1982), 6 members
in 2 generations showed the onset of renal disease between ages 23 and
45 years. The deposition of amyloid is characteristically interstitial
rather than glomerular as seen in other forms of amyloidosis. The
proband had the sicca syndrome. The details of their patient's family
history were not given by Libbey and Talbert (1987). Zalin et al. (1991)
described yet another family with the Ostertag type of familial
nephropathic nonneuropathic amyloidosis. Petechial skin rash was a
striking feature, and petechial hemorrhages were induced by minimal
abrasion. Extensive amyloid deposition in the lungs was illustrated.
Zalin et al. (1991) reported that the amyloid deposits contained
apolipoprotein A-I; however, it was later shown that the disorder in
this family was caused by a mutation in lysozyme (see 153450.0001). A
second mutation in the APOA1 gene has been demonstrated in autosomal
dominant nonneuropathic systemic amyloidosis: leu60-to-arg
(107680.0016).

*FIELD* SA
Alexander and Atkins (1975); Weiss and Page (1973)
*FIELD* RF
1. Alexander, F.; Atkins, E. L.: Familial renal amyloidosis: case
reports, literature review and classification. Am. J. Med. 59:
121-128, 1975.

2. Lanham, J. G.; Meltzer, M. L.; de Beer, F. C.; Hughes, G. R. V.;
Pepys, M. B.: Familial amyloidosis of Ostertag. Quart. J. Med. 51:
25-32, 1982.

3. Libbey, C. A.; Talbert, M. L.: A 43-year-old woman with hepatic
failure after renal transplantation because of amyloidosis. New
Eng. J. Med. 317: 1520-1531, 1987.

4. Maxwell, E. S.; Kimbell, I.: Familial amyloidosis with case reports.
Med. Bull. Vet. Admin. 12: 365-369, 1936.

5. Mornaghi, R.; Rubinstein, P.; Franklin, E. C.: Studies of the
pathogenesis of a familial form of renal amyloidosis. Trans. Assoc.
Am. Phys. 94: 211-216, 1981.

6. Mornaghi, R.; Rubinstein, P.; Franklin, E. C.: Familial renal
amyloidosis: case reports and genetic studies. Am. J. Med. 73:
609-614, 1982.

7. Ostertag, B.: Demonstration einer eigenartigen familiaeren Paramyloidose.
Zbl. Path. 56: 253-254, 1932.

8. Ostertag, B.: Familiaere Amyloid-erkrankung. Z. Menschl. Vererb.
Konstitutionsl. 30: 105-115, 1950.

9. Weiss, S. W.; Page, D. L.: Amyloid nephropathy of Ostertag with
special reference to renal glomerular giant cells. Am. J. Path. 72:
447-460, 1973.

10. Weiss, S. W.; Page, D. L.: Amyloid nephropathy of Ostertag: report
of a kindred. Birth Defects Orig. Art. Ser. X(4): 67-68, 1974.

11. Zalin, A. M.; Jones, S.; Fitch, N. J. S.; Ramsden, D. B.: Familial
nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry
and chemistry. Quart. J. Med. 81: 945-956, 1991.

*FIELD* CS

GI:
   Hepatomegaly;
   Cholestasis;
   Splenomegaly

GU:
   Nephropathy with hematuria;
   Nephrotic syndrome;
   Uremia

Endocrine:
   Hypertension

Skin:
   Pitting edema;
   Petechial skin rash

Neuro:
   Nonneuropathic

Misc:
   Chronic weakness

Lab:
   Generalized amyloid deposition;
   Proteinuria;
   Hematuria

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 4/6/1994
mimadm: 3/11/1994
carol: 5/17/1993
carol: 5/12/1993
carol: 5/6/1993
carol: 3/22/1993

*RECORD*
*FIELD* NO
105210
*FIELD* TI
*105210 AMYLOIDOSIS VII
OCULOLEPTOMENINGEAL TYPE AMYLOIDOSIS;;
OHIO TYPE AMYLOIDOSIS
*FIELD* TX
In a Hessian (German) kindred living in Ohio, Goren et al. (1980)
described a form of autosomal dominant amyloidosis with manifestations
limited to central nervous and ocular dysfunction: dementia, seizures,
strokes, coma, and visual deterioration. The cerebrospinal fluid was
xanthochromic with lymphocytic pleocytosis and elevated protein.
Neurologic dysfunction was episodic, suggesting transient cortical
ischemia. The seizures were attributed to small, superficial cortical
infarcts resulting from occluded subarachnoid vessels. Obtundation and
headache were attributed to intermittent hydrocephalus. Pathologic
examinations showed severe, diffuse amyloidosis of the leptomeninges and
subarachnoid vessels associated with patchy fibrosis and obliteration of
the subarachnoid space. Amyloid deposits were prominent on the ependymal
surfaces. Severe and diffuse neuronal loss and generalized subpial
gliosis were found in the cerebrum and cerebellum, as well as occasional
superficial brain infarcts. Amyloid was also found in the vitreous, the
retinal internal limiting membrane and the retinal vessels, particularly
those in the nerve fiber layer. Only minimal amyloid deposition was
found elsewhere. At least 5 instances of male-to-male transmission were
observed. Uitti et al. (1988) described an Italian family with this form
of amyloidosis. The clinical features were hemiplegic migraine, periodic
obtundation, psychiatric symptoms, seizures, intracerebral hemorrhage,
visual impairment, deafness, myelopathy, and polyneuropathy.
Histopathologic findings were mainly amyloid deposition in the
leptomeningeal and retinal vessels, in the vitreous humor, and in
perivascular tissue throughout the body. Evaluation of the amyloid
showed it to be derived from transthyretin. The 3 affected members of
the family were twin brothers and the son of 1 of them. Uitti et al.
(1988) pointed to cases reported by Hamburg (1971) and by Okayama et al.
(1978) as representing probable cases of oculoleptomeningeal
amyloidosis.

*FIELD* RF
1. Goren, H.; Steinberg, M. C.; Farboody, G. H.: Familial oculoleptomeningeal
amyloidosis. Brain 103: 473-495, 1980.

2. Hamburg, A.: Unusual cause of vitreous opacities: primary familial
amyloidosis. Ophthalmologica 162: 173-177, 1971.

3. Okayama, M.; Goto, I.; Ogata, J.; Omae, T.; Yoshida, I.; Inomata,
H.: Primary amyloidosis with familial vitreous opacities: an unusual
case and family. Arch. Intern. Med. 138: 105-111, 1978.

4. Uitti, R. J.; Donat, J. R.; Rozdilsky, B.; Schneider, R. J.; Koeppen,
A. H.: Familial oculoleptomeningeal amyloidosis: report of a new
family with unusual features. Arch. Neurol. 45: 1118-1122, 1988.

*FIELD* CS

Eye:
   Decreased vision

Neuro:
   Dementia;
   Seizures;
   Stroke;
   Coma;
   Intermittent hydrocephalus;
   Headache;
   Hemiplegic migraine;
   Periodic obtundation;
   Psychiatric symptoms;
   Myelopathy;
   Polyneuropathy

Ears:
   Deafness

Skin:
   Cutis laxa

Lab:
   Amyloid deposition in vitreous, retinal vessels, leptomeninges and
   subarachnoid vessels;
   Generalized subpial gliosis and neuronal loss;
   Ependymal amyloid deposits

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
carol: 10/14/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 12/19/1988

*RECORD*
*FIELD* NO
105250
*FIELD* TI
*105250 AMYLOIDOSIS, PRIMARY CUTANEOUS
PRIMARY LOCALIZED CUTANEOUS AMYLOIDOSIS; PLCA;;
FAMILIAL LICHEN AMYLOIDOSIS;;
AMYLOIDOSIS IX;;
AMYLOIDOSIS, FAMILIAL CUTANEOUS LICHEN
*FIELD* TX
Sagher and Shanon (1963) found 3 cases of primary cutaneous amyloidosis
in 3 generations of a Russian-Jewish family. Tay (1971) reported
affected mother and daughter. Rajagopalan and Tay (1972) reported 19
persons in 4 successive generations of a Chinese family in Malaysia.
Onset was around the age of puberty. The extent of cutaneous involvement
increased with age but no systemic involvement occurred. There are at
least 2 reports of affected sibs. The disorder seems to be much more
frequent in South America and Asia than in Europe or North America. Eng
et al. (1976) described brother and sister with amyloid of the skin of a
type possibly different from that in the other reports. Newton et al.
(1985) described a British family. The subtlety of physical signs
contrasted with the severity of the associated pruritus. Transepidermal
elimination of amyloid was a characteristic histologic feature. When
scratching, patients were able to remove the 'core' of the papules with
consequent reduction in pruritus. Four generations and by inference a
fifth were affected. PLCA has been described in association with
multiple endocrine neoplasia type IIA (MEN2A; 171400) and with familial
medullary thyroid carcinoma (MTC; 155240). Thus, any families with PLCA
should be scrutinized for these potentially more serious aspects.

The cutaneous lichen amyloidosis that occurs in MEN2A is associated with
pruritus and occurs particularly in the interscapular region. It is
thought to be a form of 'friction amyloidosis' and to be related to
notalgia paresthetica, a neuropathy of the posterior dorsal nerve rami.
A cys634-to-tyr missense mutation (164761.0004) was demonstrated in
affected members of one family with MEN2A and cutaneous lichen
amyloidosis (Ceccherini et al., 1994).

Primary cutaneous amyloidosis is a relatively common skin disease in
Southeast Asia, South America, and the Republic of China. Some patients
have a family history. Since some patients with multiple endocrine
neoplasia type 2A have the clinical picture of primary cutaneous
amyloidosis, Lee et al. (1996) carried out linkage analysis in 7
families with cutaneous amyloidosis using 4 dinucleotide repeat markers
from the RET region. Negative lod scores and all recombination
frequencies were obtained. They thus concluded that there is no evidence
for linkage between Chinese families with primary cutaneous amyloidosis
of the pericentromeric region of chromosome 10.

Hofstra et al. (1996) screened 3 pedigrees with familial cutaneous
lichen amyloidosis for RET mutations and found none in the RET coding
and flanking intronic sequences. They interpreted this as indicating
that skin amyloidosis found in some MEN2A families and familial
cutaneous lichen amyloidosis are different conditions. Consequently,
patients with apparent familial cutaneous lichen amyloidosis do not
appear to be at risk for MEN2A. On the other hand, families with
multiple cases in which MEN2A and primary cutaneous lichen amyloidosis
have been described, e.g., by Seri et al. (1997). It appears that the
cys634gly mutation of the RET gene (164761.0003) is particularly likely
to be associated with cutaneous lichen amyloidosis.

*FIELD* SA
De Pietro  (1981); Ozaki  (1984); Shanon and Sagher (1970)
*FIELD* RF
1. Ceccherini, I.; Romei, C.; Barone, V.; Pacini, F.; Martino, E.;
Loviselli, A.; Pinchera, A.; Romeo, G.: Identification of the cys634-to-tyr
mutation of the RET proto-oncogene in a pedigree with multiple endocrine
neoplasia type 2A and localized cutaneous lichen amyloidosis. J.
Endocr. Invest. 17: 201-204, 1994.

2. De Pietro, W. P.: Primary familial cutaneous amyloidosis: a study
of HLA antigens in a Puerto Rican family. Arch. Derm. 117: 639-642,
1981.

3. Eng, A. M.; Cogan, L.; Gunnar, R. M.; Blekys, I.: Familial generalized
dyschromic amyloidosis cutis. J. Cutan. Path. 3: 102-108, 1976.

4. Hofstra, R. M. W.; Sijmons, R. H.; Stelwagen, T.; Stulp, R. P.;
Kousseff, B. G.; Lips, C. J. M.; Steijlen, P. M.; Van Voorst Vader,
P. C.; Buys, C. H. C. M.: RET mutation screening in familial cutaneous
lichen amyloidosis and in skin amyloidosis associated with multiple
endocrine neoplasia. J. Invest. Derm. 107: 215-218, 1996.

5. Lee, D.-D.; Huang, J.-Y.; Wong, C.-K.; Gagel, R. F.; Tsai, S.-F.
: Genetic heterogeneity of familial primary cutaneous amyloidosis:
lack of evidence for linkage with the chromosome 10 pericentromeric
region in Chinese families. J. Invest. Derm. 107: 30-33, 1996.

6. Newton, J. A.; Jagjivan, A.; Bhogal, B.; McKee, P. H.; McGibbon,
D. H.: Familial primary cutaneous amyloidosis. Brit. J. Derm. 112:
201-208, 1985.

7. Ozaki, M.: Familial lichen amyloidosis. Int. J. Derm. 23: 190-193,
1984.

8. Rajagopalan, K. V.; Tay, C. H.: Familial lichen amyloidosis: report
of 19 cases in 4 generations of a Chinese family in Malaysia. Brit.
J. Derm. 87: 123-129, 1972.

9. Sagher, F.; Shanon, J.: Amyloidosis cutis: familial occurrence
in three generations. Arch. Derm. 87: 171-175, 1963.

10. Seri, M.; Celli, I.; Betsos, N.; Claudiani, F.; Camera, G.; Romeo,
G.: A cys634gly substitution of the RET proto-oncogene in a family
with recurrence of multiple endocrine neoplasia type 2A and cutaneous
lichen amyloidosis. Clin. Genet. 51: 86-90, 1997.

11. Shanon, J.; Sagher, F.: Interscapular cutaneous amyloidosis. Arch.
Derm. 102: 195-198, 1970.

12. Tay, C. H.: Genodermatosis in Singapore. Asian J. Med. 7: 413
only, 1971.

*FIELD* CS

Eyes:
   Lattice corneal dystrophy

Skin:
   Papular rash;
   Pruritus;
   Cutis laxa

Neuro:
   Cranial neuropathy;
   No peripheral neuropathy;
   No autonomic dysfunction

Misc:
   Onset in third decade

Lab:
   Localized amyloid deposition

Inheritance:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 05/01/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 05/01/1997
terry: 4/28/1997
terry: 11/15/1996
terry: 11/4/1996
carol: 9/23/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/20/1991
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
105300
*FIELD* TI
105300 AMYOTROPHIC DYSTONIC PARAPLEGIA
*FIELD* TX
Gilman and Horenstein (1964) described dystonia, progressive amyotrophy,
mental retardation, nystagmus, and incontinence of bowel and bladder in
association with spastic paraplegia. Twelve members of 3 generations
were involved to an extent varying from an asymptomatic condition to a
severely disabling one beginning in late childhood.

*FIELD* RF
1. Gilman, S.; Horenstein, S.: Familial amyotrophic dystonic paraplegia.
Brain 87: 51-66, 1964.

*FIELD* CS

Neuro:
   Dystonia;
   Spastic paraplegia;
   Amyotrophy;
   Mental retardation;
   Bowel incontinence;
   Bladder incontinence;
   Nystagmus

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
105400
*FIELD* TI
#105400 AMYOTROPHIC LATERAL SCLEROSIS; ALS
ALS1
*FIELD* TX
A number sign (#) is used with this entry because of evidence that 15 to
20% of individuals with a familial form of amyotrophic lateral
sclerosis, indicated here as type 1 (ALS1), are associated with
mutations in the superoxide dismutase-1 gene (147450). Sporadic cases of
ALS are sometimes due to new mutations in the SOD1 gene (Jones et al.,
1993).

About 10% of amyotrophic lateral sclerosis is familial. Horton et al.
(1976) concluded that at least 3 forms of familial ALS exist, each
inherited as an autosomal dominant. The first is characterized by
rapidly progressive loss of motor function with predominantly lower
motor neuron manifestations and a course of less than 5 years.
Pathologic changes are limited to the anterior horn cells and pyramidal
tracts. The second type is clinically identical to the first, but at
autopsy additional changes are found in the posterior columns, Clarke
column and spinocerebellar tracts. The third type is similar to the
second except for a much longer survival (usually beyond 10 and often 20
years). Examples of type 1 include the families of Green (1960), Poser
et al. (1965) and Thomson and Alvarez (1969). Examples of type 2 include
the families of Kurland and Mulder (1955) and Engel et al. (1959). This
disorder is sometimes referred to as Lou Gherig disease after a famous
1960s American baseball player who was aflicted with it.

Engel et al. (1959) described 2 American families, one of which was of
Pennsylvania Dutch stock with at least 11 members of 4 generations
affected with what was locally and popularly termed 'Pecks disease.'
Examples of type 3 include the families of Amick et al. (1971) and
Alberca et al. (1981). In the Spanish kindred reported by Alberca et al.
(1981), early onset and persistence of muscle cramps, unilateral
proximal segmental myoclonus, and early abolition of ankle jerks were
conspicuous clinical features. Gardner and Feldmahn (1966) described ALS
in 15 members of 7 generations. Alter and Schaumann (1976) reported 14
cases in 2 families and attempted a refinement of the classification of
hereditary ALS. This disorder appears to be different from that reported
in cases found on Guam (Espinosa et al., 1962; Husquinet and Franck,
1980), in which the histology is different and dementia and parkinsonism
complicate the clinical picture (see 105500). Also see amyotrophic
lateral sclerosis with dementia (105550). In Germany, Haberlandt (1963)
concluded that ALS (and its equivalent, progressive bulbar palsy) is an
irregular autosomal dominant in many instances. Progressive bulbar palsy
of childhood (Fazio-Londe disease) is more likely to be recessive
(211500). Engel (1976) suggested that the 'Wetherbee ail' and the Farr
family disease (see 158700) were the same as ALS. In a kindred with an
apparently 'new' microcephaly-cataract syndrome (212540), reported by
Scott-Emuakpor et al. (1977), 10 persons had died of a seemingly
unrelated genetic defect--amyotrophic lateral sclerosis.

In a family reported by Wilkins et al. (1977), X-linked dominant
inheritance was suggested by the late onset in females and the lack of
male-to-male transmission. Husquinet and Franck (1980) reported a family
suggesting autosomal dominant inheritance with incomplete penetrance.
Twelve men and 6 women were affected; four unaffected members of the
family transmitted the disease. The first signs of the disease, which
ran its course in 5 to 6 years, were in either the arms or the legs. As
in most cases of ALS, death was caused by bulbar paralysis. Mean age at
death was about 57 years. Hudson (1981) stated that posterior column
disease is found in association with ALS in 80% of familial cases.
Siddique et al. (1987) did linkage studies in a family with 13 affected
persons in 4 generations. There was no instance of male-to-male
transmission. Veltema et al. (1990) described adult ALS in 18
individuals from 6 generations of a Dutch family. Onset occurred between
ages 19 and 46; duration of disease averaged 1.7 years. The clinical
symptoms were predominantly those of initial shoulder girdle and
ultimate partial bulbar muscle involvement.

Siddique et al. (1989) presented preliminary data from genetic linkage
analysis in 150 families with familial ALS. Two regions of possible
linkage were identified on chromosomes 11 and 21. The highest lod score
observed was 1.46, obtained with D21S13 at theta = 0.20. The next
highest lod score was observed with marker D11S21 (lod score = 1.05 at
maximum theta of 0.001).

Siddique et al. (1991) presented evidence for linkage of familial ALS to
markers on chromosome 21. The maximum lod score, 5.03, was obtained 10
cM telomeric to the DNA marker D21S58. The markers used in this study
were located in the region 21q22.1-q22.2. The ALS1 locus is presumably
in the distal part of this segment. Tests for heterogeneity in these
families yielded a probability of less than 0.0001 that of genetic-locus
heterogeneity, i.e., a low probability of homogeneity. Mapping of the
gene opens the way for 'positional cloning'; elucidation of the
mechanism of the disorder in familial cases may help in the
understanding of nonfamilial cases. Iwasaki et al. (1991) reported a
Japanese family in which members in at least 3 generations had ALS. At
least 2 individuals in the family also had Ribbing disease, which is
probably the same as Engelmann disease (131300), a skeletal dysplasia
that was presumably unrelated to the ALS.

Glutamate, the primary excitatory neurotransmitter in the brain, can
exert specific neurotoxic effects and can induce neuronal degeneration
in vivo and in vitro. Because of studies suggesting that the metabolism
of glutamate is abnormal in patients with ALS, Rothstein et al. (1992)
hypothesized that the high-affinity glutamate transporter (133550) is
the site of the defect. The primary mechanism for the inactivation of
glutamate and aspartate is their removal from the extracellular space by
a sodium-dependent transport system in astrocytes and neurons. This
transport system has both high-affinity and low-affinity carriers for
the 2 molecules. The low-affinity carrier subserves general metabolic
activities. The high-affinity carrier is a component of the glutamate
neurotransmitter system and is responsible for clearance of
neurotransmitter glutamate from the synaptic cleft. This carrier cannot
distinguish between glutamate and aspartate. The inhibition of glutamate
transport has been shown experimentally to be toxic to neurons, probably
because of the persistent elevation of extracellular glutamate. A
possible mechanism for the elevated cerebrospinal fluid concentrations
of glutamate and aspartate in patients with ALS could be deficient
transport into cells. Studying synaptosomes from neural tissue obtained
from 13 patients with ALS as well as from controls, Rothstein et al.
(1992) found that the ALS patients showed a marked decrease in the
maximal velocity of transport for high-affinity glutamate uptake in
synaptosomes from spinal cord, motor cortex, and somatosensory cortex,
but not in those from visual cortex, striatum, or hippocampus. Affinity
of the transporter for glutamate was not altered. Neurodegenerative
disorders did not show this defect. Transport of other molecules
(gamma-aminobutyric acid and phenylalanine) was normal in patients with
ALS.

The murine Mnd mutation (for 'motor neuron degeneration') causes a
late-onset, progressive degeneration of upper and lower motor neurons.
Using endogenous retroviruses as markers, Messer et al. (1992) mapped
the Mnd gene in the mouse to proximal chromosome 8. Messer et al. (1992)
suggested that examination of human chromosome 8, which shows homology
of synteny, in human kindreds with ALS as well as related hereditary
neurologic diseases might be fruitful. They presented evidence
suggesting that a combination of genetic and environmental modifiers can
alter the time course of the phenotypic expression in the mouse model.

Rosen et al. (1993) reported tight genetic linkage between ALS1 and the
gene for Cu/Zn-binding superoxide dismutase (SOD1). Given this linkage
and the potential role of free radical toxicity in neurodegenerative
disorders, they investigated SOD1 as a candidate gene in ALS1 and
identified 11 different SOD1 missense mutations in 13 different ALS
families. Other workers failed to find linkage to chromosome 21 loci;
for example, see the study by King et al. (1993) in 8 families in the
U.K. This is to be expected because of the recognized heterogeneity in
ALS, including familial ALS; see juvenile ALS (205100) due to mutation
in a gene on 2q. Jones et al. (1993) demonstrated that mutation in the
SOD1 gene can also be responsible for sporadic cases of ALS. They found
the ile113-to-thr mutation (147450.0011) in 3 patients among 56 cases of
ALS drawn from a population-based study in Scotland. Pramatarova et al.
(1995) estimated that approximately 10% of ALS cases are inherited as an
autosomal dominant and that SOD1 mutations are responsible for at least
13% of familial ALS cases.

In a review of a familial ALS, de Belleroche et al. (1995) gave a
listing of 30 missense mutations of the SOD1 gene and 1 deletion of 2
nucleotides. They indicated that there is incomplete penetrance; by age
85 years about 80% of carriers have manifested the disorder. It is,
therefore, not uncommon to see obligate carriers in a family who died
without manifesting the disease. Phenotypic heterogeneity is also common
within families, for example, age of onset varying over 30 years within
a family and duration of illness varying from 6 months to 5 years. Signs
at onset may be variable. The initiation of the disease is usually focal
and asymmetric, wasting of muscles of 1 hand with spreading of the
disorder in a contiguous manner. Lower motor neuron involvement is
usually conspicuous, whereas involvement of upper motor neurons is less
marked. They pointed out that the his46-to-arg mutation of the SOD1 gene
(147450.0013) is associated with a benign form of the disease with
average duration of 17 years and only slightly reduced levels of SOD1
enzyme activity. They referred to a family with an ile113-to-thr
mutation of SOD1 (147450.0011)in which 1 affected member of the family
died after a short progression and another member survived more than 20
years.

Siddique and Deng (1996) reviewed the genetics of ALS. They included a
tabulation of SOD1 mutations in FALS. They pointed out that both
dominant (symbolized DFALS by them) and recessive (symbolized RFALS by
them) familial ALS have more than 1 locus in the genome. RFALS is rare
and has been observed in relatively high prevalence in Tunisia (see
205100). The symptoms of sporadic ALS and DFALS do not occur before the
age of 10 years and rarely before the age of 20. The mean age at onset
of symptoms in RFALS, on the other hand, is 12, ranging from 3 to 23
years, and the duration of the disease ranges from 15 to 20 years.

*FIELD* SA
Bias  (1978); Gimenez-Roldan and Esteban (1977); Haberlandt  (1961);
Hirano et al. (1967); Phillips et al. (1978); Swerts and Van den Bergh
(1976); Takahashi et al. (1972)
*FIELD* RF
1. Alberca, R.; Castilla, J. M.; Gil-Peralta, A.: Hereditary amyotrophic
lateral sclerosis. J. Neurol. Sci. 50: 201-206, 1981.

2. Alter, M.; Schaumann, B.: Hereditary amyotrophic lateral sclerosis:
a report of two families. Europ. Neurol. 14: 250-265, 1976.

3. Amick, L. D.; Nelson, J. W.; Zellweger, H.: Familial motor neuron
disease, non-Chamorro type: report of kinship. Acta Neurol. Scand. 47:
341-349, 1971.

4. Bias, W. B.: Personal Communication. Baltimore, Md.  1978.

5. de Belleroche, J.; Orrell, R.; King, A.: Familial amyotrophic
lateral sclerosis/motor neurone disease (FALS): a review of current
developments. J. Med. Genet. 32: 841-847, 1995.

6. Engel, W. K.: Personal Communication. Bethesda, Md.  1976.

7. Engel, W. K.; Kurland, L. T.; Klatzo, I.: An inherited disease
similar to amyotrophic lateral sclerosis with a pattern of posterior
column involvement: an intermediate form?. Brain 82: 203-220, 1959.

8. Espinosa, R. E.; Okihiro, M. M.; Mulder, D. W.; Sayre, G. P.:
Hereditary amyotrophic lateral sclerosis: a clinical and pathologic
report with comments on classification. Neurology 12: 1-7, 1962.

9. Gardner, J. H.; Feldmahn, A.: Hereditary adult motor neuron disease. Trans.
Am. Neurol. Assoc. 91: 239-241, 1966.

10. Gimenez-Roldan, S.; Esteban, A.: Prognosis in hereditary amyotrophic
lateral sclerosis. Arch. Neurol. 34: 706-708, 1977.

11. Green, J. B.: Familial amyotrophic lateral sclerosis occurring
in 4 generations. Neurology 10: 960-962, 1960.

12. Haberlandt, W. F.: Ergebnisse einer neurologisch-genetischen
Studie im nordwestdeutschen Raum.. (Abstract) Proc. 2nd Int. Cong.
Hum. Genet., Rome, Sept. 6-12, 1961 3: 1645-1651, 1963.

13. Haberlandt, W. F.: Aspects genetiques de la sclerose laterale
amyotrophique. World Neurol. 2: 356-365, 1961.

14. Hirano, A.; Kurland, L. T.; Sayre, G. P.: Familial amyotrophic
lateral sclerosis: a subgroup characterized by posterior and spinocerebellar
tract involvement and hyaline inclusions in the anterior horn cells. Arch.
Neurol. 16: 232-243, 1967.

15. Horton, W. A.; Eldridge, R.; Brody, J. A.: Familial motor neuron
disease: evidence for at least three different types. Neurology 26:
460-465, 1976.

16. Hudson, A. J.: Amyotrophic lateral sclerosis and its association
with dementia, parkinsonism and other neurological disorders: a review. Brain 104:
217-247, 1981.

17. Husquinet, H.; Franck, G.: Hereditary amyotrophic lateral sclerosis
transmitted for five generations. Clin. Genet. 18: 109-115, 1980.

18. Iwasaki, Y.; Kinoshita, M.; Ikeda, K.: Concurrence of familial
amyotrophic lateral sclerosis with Ribbing's disease. Int. J. Neurosci. 58:
289-292, 1991.

19. Jones, C. T.; Brock, D. J. H.; Chancellor, A. M.; Warlow, C. P.;
Swingler, R. J.: Cu/Zn superoxide dismutase (SOD1) mutations and
sporadic amyotrophic lateral sclerosis. Lancet 342: 1050-1051, 1993.

20. King, A.; Houlden, H.; Hardy, J.; Lane, R.; Chancellor, A.; de
Belleroche, J.: Absence of linkage between chromosome 21 loci and
familial amyotrophic lateral sclerosis. J. Med. Genet. 30: 318,
1993.

21. Kurland, L. T.; Mulder, D. W.: Epidemiologic investigations of
amyotrophic lateral sclerosis. 2. Familial aggregations indicative
of dominant inheritance. Neurology 5: 182-196 and 249-268, 1955.

22. Messer, A.; Plummer, J.; Maskin, P.; Coffin, J. M.; Frankel, W.
N.: Mapping of the motor neuron degeneration (Mnd) gene, a mouse
model of amyotrophic lateral sclerosis (ALS). Genomics 13: 797-802,
1992.

23. Phillips, J.; Pyeritz, R.; Brooks, B.; Rosenthal, G.; Weintraub,
A.; Weinblatt, J.: Familial amyotrophic lateral sclerosis: an evaluation
of genetic counseling. (Abstract) Am. J. Hum. Genet. 30: 63A, 1978.

24. Poser, C. M.; Johnson, M.; Bunch, L. D.: Familial amyotrophic
lateral sclerosis. Dis. Nerv. Syst. 26: 697-702, 1965.

25. Pramatarova, A.; Figlewicz, D. A.; Krizus, A.; Han, F. Y.; Ceballos-Picot,
I.; Nicole, A.; Dib, M.; Meininger, V.; Brown, R. H.; Rouleau, G.
A.: Identification of new mutations in the Cu/Zn superoxide dismutase
gene of patients with familial amyotrophic lateral sclerosis. Am.
J. Hum. Genet. 56: 592-596, 1995.

26. Rosen, D. R.; Siddique, T.; Patterson, D.; Figlewicz, D. A.; Sapp,
P.; Hentati, A.; Donaldson, D.; Goto, J.; O'Regan, J. P.; Deng, H.-X.;
Rahmani, Z.; Krizus, A.; McKenna-Yasek, D.; Cayabyab, A.; Gaston,
S. M.; Berger, R.; Tanzi, R. E.; Halperin, J. J.; Herzfeldt, B.; Van
den Bergh, R.; Hung, W.-Y.; Bird, T.; Deng, G.; Mulder, D. W.; Smyth,
C.; Laing, N. G.; Soriano, E.; Pericak-Vance, M. A.; Haines, J.; Rouleau,
G. A.; Gusella, J. S.; Horvitz, H. R.; Brown, R. H., Jr.: Mutations
in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic
lateral sclerosis. Nature 362: 59-62, 1993.

27. Rothstein, J. D.; Martin, L. J.; Kuncl, R. W.: Decreased glutamate
transport by the brain and spinal cord in amyotrophic lateral sclerosis. New
Eng. J. Med. 326: 1464-1468, 1992.

28. Scott-Emuakpor, A. B.; Heffelfinger, J.; Higgins, J. V.: A syndrome
of microcephaly and cataracts in four siblings: a new genetic syndrome?. Am.
J. Dis. Child. 131: 167-169, 1977.

29. Siddique, T.; Deng, H.-X.: Genetics of amyotrophic lateral sclerosis. Hum.
Molec. Genet. 5: 1465-1470, 1996.

30. Siddique, T.; Figlewicz, D. A.; Pericak-Vance, M. A.; Haines,
J. L.; Rouleau, G.; Jeffers, A. J.; Sapp, P.; Hung, W.-Y.; Bebout,
J.; McKenna-Yasek, D.; Deng, G.; Horvitz, H. R.; Gusella, J. F.; Brown,
R. H., Jr.; Roses, A. D.; et al.: Linkage of a gene causing familial
amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus
heterogeneity. New Eng. J. Med. 324: 1381-1384, 1991.

31. Siddique, T.; Pericak-Vance, M. A.; Brooks, B. R.; Bias, W.; Walker,
N.; Siddique, N.; Hung, W.-Y.; Roses, A. D.: Linkage in familial
amyotrophic lateral sclerosis (ALS). (Abstract) Cytogenet. Cell Genet. 46:
692, 1987.

32. Siddique, T.; Pericak-Vance, M. A.; Brooks, B. R.; Roos, R. P.;
Tandan, R.; Nicholson, G.; Noore, F.; Antel, J. P.; Munsat, T. L.;
Phillips, K. L.; Hung, W.-Y.; Warner, K. L.; Bebout, J.; Bias, W.;
Roses, A. D.: Genetic linkage analysis in familial amyotrophic lateral
sclerosis. (Abstract) Cytogenet. Cell Genet. 51: 1080, 1989.

33. Swerts, L.; Van den Bergh, R.: Sclerose laterale amyotrophique
familiale: etude d'une famille atteinte sur trois generations (Familial
amyotrophic lateral sclerosis: a study of a family suffering from
this disease for three generations). J. Genet. Hum. 24: 247-255,
1976.

34. Takahashi, K.; Nakamura, H.; Okada, E.: Hereditary amyotrophic
lateral sclerosis: histochemical and electron microscopic study of
hyaline inclusions in motor neurons. Arch. Neurol. 27: 292-299,
1972.

35. Thomson, A. F.; Alvarez, F. A.: Hereditary amyotrophic lateral
sclerosis. J. Neurol. Sci. 8: 101-110, 1969.

36. Veltema, A. N.; Roos, R. A. C.; Bruyn, G. W.: Autosomal dominant
adult amyotrophic lateral sclerosis: a six generation Dutch family. J.
Neurol. Sci. 97: 93-115, 1990.

37. Wilkins, L. E.; Winter, R. M.; Myer, E. C.; Nance, W. E.: Dominantly
inherited amyotrophic lateral sclerosis (motor neuron disease). Med.
Coll. Va. Quart. 13(4): 182-186, 1977.

*FIELD* CS

Neuro:
   Progressive motor function loss;
   Lower motor neuron manifestations;
   Unilateral proximal segmental myoclonus;
   Early abolition of ankle jerks;
   Bulbar paralysis

Muscle:
   Muscle weakness;
   Muscle cramps

Lab:
   Mutant superoxide dismutase-1 (SOD1);
   Pathologic changes in anterior horn cells, pyramidal tracts, posterior
   columns, Clarke column and spinocerebellar tracts

Inheritance:
   Autosomal dominant (21q22.1-q22.2);
   also a recessive juvenile form

*FIELD* CN
Orest Hurko - updated: 5/8/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 03/12/1997
mark: 1/29/1997
jenny: 12/23/1996
terry: 12/18/1996
terry: 5/10/1996
mark: 5/8/1996
terry: 5/3/1996
mark: 2/22/1996
mark: 1/31/1996
terry: 1/26/1996
mark: 3/29/1995
davew: 8/16/1994
carol: 6/8/1994
warfield: 4/21/1994
mimadm: 4/14/1994
pfoster: 3/25/1994

*FIELD* MN
At least 3 forms of familial ALS exist, each inherited as an autosomal
dominant (Horton et al., 1976). The first is characterized by rapidly
progressive loss of motor function with predominantly lower motor neuron
manifestations and a course of less than 5 years. Pathologic changes are
limited to the anterior horn cells and pyramidal tracts. The second type
is clinically identical to the first, but at autopsy additional changes
are found in the posterior columns, Clarke column and spinocerebellar
tracts. The third type is similar to the second except for a much longer
survival (usually beyond 10 and often 20 years). Death is caused by
bulbar paralysis. There may be incomplete penetrance (Husquinet and
Franck, 1980). Posterior column disease is found in association with ALS
in 80% of familial cases (Hudson, 1981). This disorder appears to be
different from that reported in cases found on Guam (see 105500) and
amyotrophic lateral sclerosis with dementia (105550). Progressive bulbar

palsy of childhood is more likely to be recessive (211500).

Given the potential role of free radical toxicity in neurodegenerative
disorders, it is not surprising to find mutations in the gene for
Cu/Zn-binding superoxide dismutase (SOD1), in the region 21q22.1-q22.2,
accounting for some familial cases of ALS (Rosen et al., 1993). Mutation
in the SOD1 gene can also be responsible for sporadic cases (Jones et
al., 1993). Approximately 10% of ALS cases are inherited as an autosomal
dominant and SOD1 mutations are responsible for at least 13% of familial
ALS cases (Pramatarova et al., 1995). See also juvenile ALS (205100) due

to mutation in a gene on 2q.

*FIELD* ED

jamie: 02/19/1997 joanna: 11/23/1996

*FIELD* CD
F. Clarke Fraser: 7/1/1996

*RECORD*
*FIELD* NO
105500
*FIELD* TI
105500 AMYOTROPHIC LATERAL SCLEROSIS-PARKINSONISM/DEMENTIA COMPLEX OF GUAM;
ALS-PD
GUAM DISEASE
*FIELD* TX
ALS-PD occurs in unusually high incidence among the Chamorro people of
Guam. Both ALS and parkinsonism-dementia are chronic, progressive, and
uniformly fatal disorders in this population. Both diseases are known to
occur in the same kindred, the same sibship, and even the same
individual. Plato et al. (1969) found about the same level of inbreeding
in affected sibships as in unaffected sibships and interpreted this as
an argument against recessive inheritance. Their finding that affected
sibships were more closely related to each other than to the 'general
population' suggested dominant transmission, although a communicable
factor could not be excluded. Segregation analysis adjusted for age was
consistent with the conclusion that the disorder on Guam is autosomal
dominant with complete penetrance in males but only about 50% penetrance
in females. On the whole, the evidence for a mendelian basis is minimal.
Garruto et al. (1983) and Blake et al. (1983) found no marker system
associated with this disorder, and concluded that 'local environmental
factors are most likely involved in pathogenesis.' The authors appear to
view ALS and parkinsonism-dementia as separate disorders even though
they occur in the same family, the same sibship, and the same
individual. Beginning with a 59-year-old man who died after a 14-year
course of an illness characterized by progressive dementia,
parkinsonism, and ALS, Schmitt et al. (1984) studied a family in which 9
other members had ALS or parkinsonism-dementia or both. The affected
persons were rather widely separated in the family, suggesting to the
authors recessive inheritance 'with genetic epistasis.' The pathologic
features in their case were also different from those of Guam disease
and consisted particularly of Alzheimer neurofibrillary tangles in many
areas. Guam disease has also been observed in one area of Japan and in
southwest New Guinea; occasional cases have been found in other parts of
the world. Garruto et al. (1985) reported a striking decline in the
incidence rates of ALS and PD among the Chamorros of Guam so that the
rates are now only slightly higher than those in the continental United
States. They suggested that the change is consistent with the
pathogenetic sequence of low calcium and magnesium intake in water and
vegetables, secondary hyperparathyroidism, increased intestinal
absorption of toxic metals, and the deposition of calcium and other
metals in the CNS. ALS and PD have disappeared with the change in
dietary habits and loss of exclusive dependence on locally grown food.
Guiroy et al. (1987) found that the amyloid of neurofibrillary tangles
of Guamanian parkinsonism-dementia has an identical amino acid sequence
to that of Alzheimer disease and Down syndrome. Gajdusek (1986)
presented evidence that the deposition of calcium aluminum silicon in
neurons leads to paired helical filaments identical to those in patients
with Down syndrome or Alzheimer disease (104300). The high incidence of
ALS/PD in Guam and other locations disappears when isolation is
disrupted and travel and economic changes lead to food and water sources
from the outside. Spencer et al. (1987) investigated the role of the
neurotoxic plant Cycas circinalis, a traditional source of food and
medicine that has been used less by the Chamorro people since the
Americanization that occurred after World War II. Macaques fed a
constituent of Cycas developed clinical and histopathologic changes
similar to those of Guam ALS-parkinsonism-dementia. In records from 1944
through 1985, Zhang et al. (1990) found documented clinical descriptions
of this disorder in 363 Chamorros and 3 Filipino immigrants who had
lived on Guam before onset of the disorder. After 1980, new cases
occurred only among persons over 50 years of age, whereas a younger age
of onset had been noted previously. The critical age of exposure to the
unknown factor in the environment on Guam appeared to have been
adolescence or early adulthood. Bailey-Wilson et al. (1993) concluded
that purely environmental, mendelian dominant, and mendelian recessive
hypotheses of causation could be rejected; however, a 2-allele additive
major locus hypothesis could not be rejected. Stone (1993) reviewed the
progressive disappearance of Guam disease.

Majoor-Krakauer et al. (1994) investigated the hypothesis that there may
be shared genetic susceptibility between classic amyotrophic lateral
sclerosis with Parkinson disease and dementia in non-Guamanian
individuals. They compared the family histories of 151 newly diagnosed
ALS patients (7 of whom were familial) with 140 controls to examine
cumulative incidence of ALS, Parkinson disease, and dementia in parents,
siblings, and grandparents. The risk for dementia was significantly
higher in relatives of ALS patients than in those of controls and was
similar for relatives of probands with sporadic or familial ALS. The
risk of Parkinson disease was higher in relatives of patients with
familial ALS than in patients with sporadic ALS, but these differences
were not considered statistically significant. Their findings suggested
that ALS, dementia, and Parkinson disease occur within families more
often than expected by chance, suggesting that there may be a shared
genetic susceptibility to these disorders.

*FIELD* SA
Garruto et al. (1980); Hirano et al. (1961)
*FIELD* RF
1. Bailey-Wilson, J. E.; Plato, C. C.; Elston, R. C.; Garruto, R.
M.: Potential role of an additive genetic component in the cause
of amyotrophic lateral sclerosis and parkinsonism-dementia in the
Western Pacific. Am. J. Med. Genet. 45: 68-76, 1993.

2. Blake, N. M.; Kirk, R. L.; Wilson, S. R.; Garruto, R. M.; Gajdusek,
D. C.; Gibbs, C. J., Jr.; Hoffman, P.: Search for a red cell enzyme
or serum protein marker in amyotrophic lateral sclerosis and parkinsonism-dementia
of Guam. Am. J. Med. Genet. 14: 299-305, 1983.

3. Gajdusek, D. C.: Calcium aluminum silicon deposits in neurons
lead to paired helical filaments identical to those of AD and Down's
patients. Neurobiol. Aging 7: 555-556, 1986.

4. Garruto, R. M.; Gajdusek, D. C.; Chen, K.-M.: Amyotrophic lateral
sclerosis among Chamorro migrants from Guam. Ann. Neurol. 8: 612-619,
1980.

5. Garruto, R. M.; Plato, C. C.; Myrianthopoulos, N. C.; Schanfield,
M. S.; Gajdusek, D. C.: Blood groups, immunoglobulin allotypes and
dermatoglyphic features of patients with amyotrophic lateral sclerosis
and parkinsonism-dementia of Guam. Am. J. Med. Genet. 14: 289-298,
1983.

6. Garruto, R. M.; Yanagihara, R.; Gajdusek, D. C.: Disappearance
of high-incidence amyotrophic lateral sclerosis and parkinsonism-dementia
on Guam. Neurology 35: 193-198, 1985.

7. Guiroy, D. C.; Miyazaki, M.; Multhaup, G.; Fischer, P.; Garruto,
R. M.; Beyreuther, K.; Masters, C. L.; Simms, G.; Gibbs, C. J., Jr.;
Gajdusek, D. C.: Amyloid of neurofibrillary tangles of Guamanian
parkinsonism-dementia and Alzheimer disease share identical amino
acid sequence. Proc. Nat. Acad. Sci. 84: 2073-2077, 1987.

8. Hirano, A.; Kurland, L. T.; Krooth, R. S.; Lessell, S.: Parkinsonism-dementia
complex, an endemic disease on the Island of Guam. Brain 84: 642-661,
1961.

9. Majoor-Krakauer, D.; Ottman, R.; Johnson, W. G.; Rowland, L. P.
: Familial aggregation of amyotrophic lateral sclerosis, dementia,
and Parkinson's disease: evidence of shared genetic susceptibility.
Neurology 44: 1872-1877, 1994.

10. Plato, C. C.; Cruz, M. T.; Kurland, L. T.: Amyotrophic lateral
sclerosis-Parkinsonism dementia complex of Guam: further genetic investigations.
Am. J. Hum. Genet. 21: 133-141, 1969.

11. Schmitt, H. P.; Emser, W.; Heimes, C.: Familial occurrence of
amyotrophic lateral sclerosis, parkinsonism, and dementia. Ann.
Neurol. 16: 642-648, 1984.

12. Spencer, P. S.; Nunn, P. B.; Hugon, J.; Ludolph, A. C.; Ross,
S. M.; Roy, D. N.; Robertson, R. C.: Guam amyotrophic lateral sclerosis-parkinsonism-dementia
linked to a plant excitant neurotoxin. Science 237: 517-522, 1987.

13. Stone, R.: Guam: deadly disease dying out. Science 261: 424-426,
1993.

14. Zhang, Z.; Anderson, D. W.; Lavine, L.; Mantel, N.: Patterns
of acquiring parkinsonism-dementia complex on Guam: 1944 through 1985.
Arch. Neurol. 47: 1019-1024, 1990.

*FIELD* CS

Neuro:
   Amyotrophic lateral sclerosis;
   Parkinsonism-dementia;
   Progressive motor function loss;
   Lower motor neuron manifestations;
   Bulbar paralysis

Muscle:
   Muscle weakness;
   Muscle cramps

Misc:
   Chronic, progressive, and fatal

Inheritance:
   ? Two-allele major locus;
   ? environmental factor(s)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 1/13/1995
davew: 6/8/1994
warfield: 4/6/1994
mimadm: 3/11/1994
carol: 8/23/1993
carol: 3/26/1993

*RECORD*
*FIELD* NO
105550
*FIELD* TI
105550 AMYOTROPHIC LATERAL SCLEROSIS WITH DEMENTIA
*FIELD* TX
Pinsky et al. (1975) described amyotrophic lateral sclerosis with
dementia as an entity distinct from that listed as 105400 because in the
latter condition dementia is absent and the characteristic pathologic
findings of sporadic ALS are accompanied by degeneration of Clark's
column and demyelination of the posterior columns and spinocerebellar
tracts. They found considerable intrafamilial variability. Lesions in
the cerebral cortex had a distinctive frontotemporal distribution.
Another family was reported by Finlayson et al. (1973) and the families
reported by Dazzi and Finizio (1969) and by Robertson (1953) may have
had the same condition. See 205200.

*FIELD* RF
1. Dazzi, P.; Finizio, F. S.: Sulla sclerosa laterale amiotrofica
familiare. Contributo clinico. G. Psychiat. Neuropat. 97: 299-337,
1969.

2. Finlayson, M. H.; Guberman, A.; Martin, J. B.: Cerebral lesions
in familial amyotrophic lateral sclerosis and dementia. Acta Neuropath. 26:
237-246, 1973.

3. Pinsky, L.; Finlayson, M. H.; Libman, I.; Scott, B. H.: Familial
amyotrophic lateral sclerosis with dementia: a second Canadian family.
Clin. Genet. 7: 186-191, 1975.

4. Robertson, E. E.: Progressive bulbar paralysis showing heredofamilial
incidence and intellectual impairment. Arch. Neurol. Psychiat. 69:
197-207, 1953.

*FIELD* CS

Neuro:
   Amyotrophic lateral sclerosis;
   Dementia;
   Progressive motor function loss;
   Lower motor neuron manifestations;
   Bulbar paralysis

Lab:
   Frontotemporal cerebral cortex lesions

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
warfield: 4/6/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
105563
*FIELD* TI
105563 ANAL SPHINCTER DYSPLASIA; ASDP
*FIELD* TX
Zorzi et al. (1991) pointed out that anal sphincter dysplasia, a
congenital malformation of the anal canal, is often familial. Hitherto,
it had been poorly represented in the literature, where it was usually
referred to as anteriorly or ventrally displaced anus. The range of
symptoms included chronic constipation, severe straining at defecation,
encopresis, and chronic paradoxical diarrhea with fecal incontinence. A
dysplasia was associated with either absent (type I) or incomplete (type
II) fixation of the sphincter complex to the coccyx. Both could be
demonstrated by computerized tomography (CT) as well as by
intraoperative dissection of the sphincter muscles. There is also
shortening of the ectodermal segment of the anal canal which is
responsible for the disturbed stool sensation. Posterior butterfly
anoplasty combined with fixation of the sphincter complex to the coccyx
usually led to prompt improvement in the disturbances of defecation.
Genetic study of 42 patients, aged 1 to 52 years, operated on for anal
sphincter dysplasia, supported autosomal dominant inheritance with
variable expression and probably incomplete penetrance. Of the 42
patients, 17 were apparently sporadic and 25 had a family history of
disturbance in defecation. Studies in 11 of the 25 families involved 27
persons, of whom 22 were found to have a disorder of defecation by
history. Further investigation demonstrated sphincter dysplasia in 17 of
these. In her thesis, Zorzi (1990) presented the full data.

*FIELD* RF
1. Zorzi, A.: Analsphinkterdysplasie als Ursache chronischer Defaekationsstoerungen:
eine klinische und genetische Studie.  Thesis: Univ. Zurich (pub.)
1990.

2. Zorzi, A.; Schinzel, A.; Hirsig, J.: Analsphinkterdysplasie als
Ursache chronischer Defakationsstoerungen: eine klinische und genetische
Studie. Schweiz. Med. Wschr. 121: 1567-1575, 1991.

*FIELD* CS

GI:
   Congenital anal canal malformation;
   Chronic constipation;
   Straining at defecation;
   Encopresis;
   Chronic paradoxical diarrhea;
   Fecal incontinence

Radiology:
   Absent (type I) or incomplete (type II) fixation of the sphincter
   complex to the coccyx on CT scan

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/9/1993

*FIELD* ED
davew: 8/9/1994
mimadm: 3/11/1994
carol: 1/27/1994
carol: 3/9/1993

*RECORD*
*FIELD* NO
105565
*FIELD* TI
105565 ANAL SPHINCTER MYOPATHY, INTERNAL
PROCTALGIA FUGAX DUE TO ANAL SPHINCTER MYOPATHY
*FIELD* TX
Kamm et al. (1991) described a family in which at least 1 member in each
of 5 successive generations had severe proctalgia fugax beginning in the
third to fifth decades of life. They studied in detail 3 members of the
family demonstrating a 'new' myopathy of the internal anal sphincter.
Each affected member had severe pain intermittently during the day and
hourly during the night. Clinically the internal anal sphincter was
thickened and of decreased compliance. The maximum anal canal pressure
was usually increased with marked ultraslow wave activity. One patient
showed marked improvement with strip myectomy of the internal anal
sphincter; a second was relieved of constipation but had only slight
improvement of pain. The hypertrophied muscle showed unique myopathic
changes, consisting of vacuolar changes with periodic
acid-Schiff-positive polyglycosan bodies in the smooth muscle fibers and
increased endomysial fibrosis. Celik et al. (1995) described anorectal
ultrasonography, manometry and sensory testing in 3 affected persons
from a family with autosomal dominant inheritance of proctalgia fugax.
Two affected members had hypertension as well as proctalgia fugax;
treatment with the calcium antagonist nifedipine reduced anal tone,
decreased the frequency and intensity of anal pain, and returned blood
pressure to the normal range.

('Proctalgia fugax' means fleeting pain in the rectum. The same Latin
root, fugere (to flee), appears in 'fugitive' and 'centrifugal.')

*FIELD* RF
1. Celik, A. F.; Katsinelos, P.; Read, N. W.; Khan, M.I.; Donnelly,
T. C.: Hereditary proctalgia fugax and constipation:report of a second
family. Gut 36: 581-584, 1995.

2. Kamm, M. A.; Hoyle, C. H. V.; Burleigh, D. E.; Law, P. J.; Swash,
M.; Martin, J. E.; Nicholls, R. J.; Northover, J. M. A.: Hereditary
internal anal sphincter myopathy causing proctalgia fugax and constipation:
a newly identified condition. Gastroenterology 100: 805-810, 1991.

*FIELD* CS

GI:
   Proctalgia fugax;
   Intermittent severe rectal pain;
   Constipation;
   Internal anal sphincter myopathy

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 8/5/1991

*FIELD* ED
mark: 7/6/1995
clair: 5/12/1995
mimadm: 3/11/1994
carol: 3/23/1992
supermim: 3/16/1992
carol: 2/29/1992

*RECORD*
*FIELD* NO
105570
*FIELD* TI
105570 ANDROSTENONE, ABILITY TO SMELL
*FIELD* TX
Human sensory perception of androstenone, a C19 androgen with a
distinctive odor, exhibits great individual variation. Among adults,
about 50% report no odor, even at high concentrations. About 15% detect
a subtle odor, are not offended by it, and may even find it pleasant.
The remaining 35% are exquisitely sensitive to androstenone, detecting
less than 200 parts per trillion in air, and ascribe a foul odor to the
steroid, usually that of stale urine or strong sweat. Wysocki and
Beauchamp (1984) concluded that there is a genetic component of
variation in sensitivity to this odor, based on a finding of a greater
correlation for MZ twins than for DZ twins. Whether this difference in
the ability to smell androstenone is based on differences in a specific
peripheral receptor or in central processing is not certain. The same
study examined the ability to smell pyridine and found no difference
between MZ and DZ twins. Wysocki et al. (1989) reported that the ability
to perceive androstenone was induced in 10 of 20 initially insensitive
subjects who were systematically exposed to androstenone. Since
olfactory neurons of the olfactory epithelium undergo periodic
replacement from differentiating basal cells, and assuming the induction
of sensitivity to be peripheral, it is possible that apparently anosmic
humans do in fact possess olfactory neurons with specific receptors for
androstenone. Such neurons may undergo clonal expansion, or selection of
lineages with more receptors or receptors of higher affinity, in
response to androstenone stimulation, much in the manner of lymphocytes
responding to antigenic stimulation. Provisionally, Wysocki et al.
(1989) envisaged 3 categories of human subjects, the truly anosmic, the
inducible, and those who are either constitutionally sensitive or have
already experienced incidental induction.

*FIELD* SA
Cagan and Kare (1981)
*FIELD* RF
1. Cagan, R. H.; Kare, M. R.: Biochemistry of Taste and Olfaction.
New York: Academic Press (pub.)  1981.

2. Wysocki, C. J.; Beauchamp, G. K.: Ability to smell androstenone
is genetically determined. Proc. Nat. Acad. Sci. 81: 4899-4902,
1984.

3. Wysocki, C. J.; Dorries, K. M.; Beauchamp, G. K.: Ability to perceive
androstenone can be acquired by ostensibly anosmic people. Proc.
Nat. Acad. Sci. 86: 7976-7978, 1989.

*FIELD* CS

Neuro:
   Ability to smell androstenone

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 6/9/1994
pfoster: 3/25/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/2/1990

*RECORD*
*FIELD* NO
105580
*FIELD* TI
105580 ANAL CANAL CARCINOMA
CLOACOGENIC CARCINOMA, INCLUDED
*FIELD* TX
Squamous carcinoma of the anal canal is a relatively uncommon tumor.
Most of these carcinomas develop from squamous epithelium, but some
arise from the transitional zone between the columnar epithelium of the
rectum and the squamous epithelium of the anal canal. The latter type is
called cloacogenic or transitional carcinoma. In a cytogenetic study of
8 cases of anal canal cancer (1 cloacogenic and 7 squamous cell),
Muleris et al. (1987) found that all had chromosomal abnormalities. A
rearrangement involving the long arm of chromosome 11 was found in all
instances. Rearrangements of chromosome 3, detected in 6 tumors, led to
a deletion of the short arm in 5 cases. The smallest common deleted
segments were 11q22-qter and 3p22. The authors pointed out that this may
be a situation comparable to that in retinoblastoma (180200), Wilms
tumor (194070), osteosarcoma (259500), and acoustic neurinoma (101000).

*FIELD* RF
1. Muleris, M.; Salmon, R.-J.; Girodet, J.; Zafrani, B.; Dutrillaux,
B.: Recurrent deletions of chromosomes 11q and 3p in anal canal carcinoma.
Int. J. Cancer 39: 595-598, 1987.

*FIELD* CS

Oncology:
   Anal canal squamous carcinoma

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/17/1987

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 8/10/1987

*RECORD*
*FIELD* NO
105590
*FIELD* TI
*105590 ANAPLASTIC LYMPHOMA KINASE; ALK
*FIELD* TX
Large-cell lymphomas comprise approximately 25% of all non-Hodgkin
lymphomas in children and young adults, and approximately one-third of
these tumors have a t(2;5)(p23;q35) translocation. By a positional
cloning strategy, Morris et al. (1994) demonstrated that the
rearrangement fused the nucleophosmin gene (NPM1; 164040), located on
5q35, to a previously unidentified protein tyrosine kinase gene, which
they called anaplastic lymphoma kinase (ALK), located on 2p23. In the
predicted hybrid protein, the amino terminus of nucleophosmin is linked
to the catalytic domain of ALK. Expressed in the small intestine,
testis, and brain but not in normal lymphoid cells, ALK shows greatest
sequence similarity to the insulin receptor subfamily of kinases (see
INSR; 147670). Unscheduled expression of the truncated ALK was thought
to contribute to malignant transformation in these lymphomas. Mathew et
al. (1995) mapped the murine homolog to mouse chromosome 17 by
interspecific backcross analysis, thus confirming the homology between
the portion of distal mouse 17 and the short arm of human chromosome 2.

*FIELD* RF
1. Mathew, P.; Morris, S. W.; Kane, J. R.; Shurtleff, S. A.; Pasquini,
M.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.: Localization
of the murine homolog of the anaplastic lymphoma kinase (Alk) gene
on mouse chromosome 17. Cytogenet. Cell Genet. 70: 143-144, 1995.

2. Morris, S. W.; Kirstein, M. N.; Valentine, M. B.; Dittmer, K. G.;
Shapiro, D. N.; Saltman, D. L.; Look, A. T.: Fusion of a kinase gene,
ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
Science 263: 1281-1284, 1994.

*FIELD* CD
Victor A. McKusick: 6/21/1994

*FIELD* ED
mark: 7/11/1995
jason: 6/21/1994

*RECORD*
*FIELD* NO
105600
*FIELD* TI
*105600 ANEMIA WITH MULTINUCLEATED ERYTHROBLASTS
DYSERYTHROPOIETIC ANEMIA, CONGENITAL, TYPE III;;
CDA III; CDAN3; CDA3
ERYTHRORETICULOSIS, HEREDITARY BENIGN, INCLUDED
*FIELD* TX
In a mother and all 3 of her children, Wolff and Van Hofe (1951)
described mild anemia, macrocytosis in the peripheral blood, and giant
multinuclear erythroblasts in the bone marrow. This was probably the
first report of this class of dyserythropoietic anemia, which is
distinct from the 2 recessively inherited forms (224100 and 224120).
Bergstrom and Jacobsson (1962) reported 15 cases in 1 family (calling
the disorder hereditary benign erythroreticulosis) and established
autosomal dominant inheritance. Weatherly et al. (1974) described a form
of congenital dyserythropoietic anemia in a Filipino mother and 2 of her
daughters. There were no serologic abnormalities and the proband's red
cells showed a lipid abnormality not previously described in CDA.
Bjorksten et al. (1978) stated that, including the reports of Clauvel et
al. (1972) and Goudsmit et al. (1972), only 23 cases of CDA III in 4
families had been reported. Some electron-microscopic differences from
CDA I were reported by Bjorksten et al. (1978), who studied a mother and
daughter from the kindred reported by Bergstrom and Jacobsson (1962).
Holmgren (1985) stated that 17 cases had been identified in this family,
all living in northern Sweden. In a study of 2 affected members in a
Swedish family with CDA III transmitted as an autosomal dominant,
Wickramasinghe et al. (1993) found unusual features: hemosiderinuria,
grossly disorganized erythroblast nuclei, differences in the
ultrastructural appearance of individual nuclei within the same
multinucleate erythroblast, and intraerythroblastic inclusions
resembling precipitated globin chains. In both cases, the giant
mononucleate erythroblasts and the multinucleate erythroblasts had total
DNA contents up to 28 and 48 times, respectively, the haploid DNA
content. They commented that the findings were similar to those that
occur in autosomal recessive CDA III (Wickramasinghe et al., 1982). Lind
et al. (1993) performed linkage studies in the same large Swedish
kindred which could be traced back to a couple born in northern Sweden
in the last century. They pointed out that affected members of the
family displayed mild-to-moderate anemia, multinuclear erythroblasts,
and elevated levels of serum thymidine kinase. Furthermore, a
significant number of the affected individuals showed myeloma or
monoclonal gammopathy, conditions that had not been found in unaffected
relatives. Using microsatellite markers, they found linkage to 15q21,
where the CDAN3 locus was thought to be situated between D15S125 and
D15S114. The lod scores were 6.0 or greater with both markers.

See 141900 for a dominantly inherited form of dyserythropoietic anemia,
the Irish or Weatherall type, which is in fact a form of inclusion body
beta-thalassemia. Ohisalo et al. (1988) also reported what they
suggested is a 'new' type of CDA in father and daughter. The father's
case had been described by Koskinen et al. (1962). He became icteric at
the age of 10 years and anemia was established at the age of 23. The
bone marrow showed highly hyperplastic erythropoiesis, and reticulocyte
counts ranged from 4.2 to 28.5%. Constitutional anomalies included
dome-shaped head and slightly protruding eyes with high and sharply
arched palate. He had hemolysis and died of hemochromatosis at the age
of 37 years. Massive heterotopia of bone marrow simulated mediastinal
tumor. The daughter had been icteric from the age of 8 months.
Cholecystectomy was performed at the age of 13 years. Mild anemia and
marked hypercellularity of the bone marrow were found. The concentration
of bilirubin was lowered markedly by administration of phenobarbital.

Lind et al. (1995) performed linkage studies in an extensively affected
Swedish kindred with known affected members in 5 generations and by
inference in a sixth. The pedigree pattern was typical of an autosomal
dominant disorder. The condition in this family was characterized by
macrocytic anemia, bone marrow erythroid hyperplasia, and giant
multinucleate erythroblasts. In this family, which had been studied by
Bjorksten et al. (1978) and Wickramasinghe et al. (1993), they showed an
unusual concurrence of type III CDA with myeloma or benign monoclonal
gammopathy. Among 20 CDA III patients examined (Sandstrom et al., 1994),
1 had multiple myeloma and 3 had monoclonal gammopathy of undetermined
significance (MGUS), whereas the healthy relatives did not show any sign
of gammopathy. A deceased member of the family had had both CDA III and
myeloma, whereas no signs of gammopathy had been recorded among family
members not affected by CDA III. Lind et al. (1995) demonstrated close
linkage of the CDAN3 locus to microsatellite markers within an 11-cM
interval within 15q21-q25.

*FIELD* RF
1. Bergstrom, I.; Jacobsson, L.: Hereditary benign erythroreticulosis.
Blood 19: 296-303, 1962.

2. Bjorksten, B.; Holmgren, G.; Roos, G.; Stenling, R.: Congenital
dyserythropoietic anaemia type III: an electron microscopic study.
Brit. J. Haemat. 38: 37-42, 1978.

3. Clauvel, J. P.; Cosson, A.; Breton-Gorius, J.; Flandrin, G.; Faille,
A.; Bonnet-Gajdos, M.; Turpin, F.; Bernard, J.: Dyserythropoiese
congenitale: etude de 6 observations. Nouv. Rev. Franc. Hemat. 12:
635-672, 1972.

4. Goudsmit, R.; Beckers, D.; De Bruijne, J. I.; Engelfriet, C. P.;
James, J.; Morselt, A. F. W.; Reynierse, T.: Congenital dyserythropoietic
anaemia, type III. Brit. J. Haemat. 23: 97-105, 1972.

5. Holmgren, G.: Personal Communication. Umea, Sweden  1/15/1985.

6. Koskinen, P. J.; Kurkipaa, M.; Airaksinen, K.: Massive heterotopia
of bone marrow simulating mediastinal tumour. Ann. Med. Int. Fenn. 51:
145-149, 1962.

7. Lind, L.; Sandstrom, H.; Wahlin, A.; Eriksson, M.; Nilsson-Sojka,
B.; Sikstrom, C.; Holmgren, G.: Localization of the gene for congenital
dyserythropoietic anemia type III, CDAN3, to chromosome 15q21-q25.
Hum. Molec. Genet. 4: 109-112, 1995.

8. Lind, L.; Sikstrom, C.; Sandstrom, H.; Wahlin, A.; Eriksson, M.;
Nilsson, B.; Holmgren, G.: The locus for congenital dyserythropoietic
anemia type III (CDA III), associated with monoclonal gammopathy and
myeloma, is localized on chromosome 15q21.  (Abstract) Am. J. Hum.
Genet. 53 (suppl.): A1035 only, 1993.

9. Ohisalo, J. J.; Viitala, J.; Lintula, R.; Ruutu, T.: A new congenital
dyserythropoietic anaemia. Brit. J. Haemat. 68: 111-114, 1988.

10. Sandstrom, H.; Wahlin, A.; Eriksson, M.; Bergstrom, I.; Wickramasinghe,
S. N.: Intravascular haemolysis and increased prevalence of myeloma
and monoclonal gammopathy in congenital dyserythropoietic anaemia,
type III. Europ. J. Haemat. 52: 42-46, 1994.

11. Weatherly, T. L.; Flannery, E. P.; Doyle, W. F.; Shohet, S. B.;
Garratty, G.: Congenital dyserythropoietic anemia (CDA) with increased
red cell lipids. Am. J. Med. 57: 912-919, 1974.

12. Wickramasinghe, S. N.; Parry, T. E.; Williams, C.; Bond, A. N.;
Hughes, M.; Crook, S.: A new case of congenital dyserythropoietic
anaemia, type III: studies of the cell cycle distribution and ultrastructure
of erythroblasts and of nucleic acid synthesis in marrow cells. J.
Clin. Path. 35: 1103-1109, 1982.

13. Wickramasinghe, S. N.; Wahlin, A.; Anstee, D.; Parsons, S. F.;
Stopps, G.; Bergstrom, I.; Eriksson, M.; Sandstrom, H.; Shiels, S.
: Observations on two members of the Swedish family with congenital
dyserythropoietic anaemia, type III. Europ. J. Haemat. 50: 213-221,
1993.

14. Wolff, J. A.; Van Hofe, F. M.: Familial erythroid multinuclearity.
Blood 6: 1274-1283, 1951.

*FIELD* CS

Heme:
   Congenital dyserythropoietic anemia;
   Macrocytosis;
   Giant bone marrow multinuclear erythroblasts

Skin:
   Jaundice

Misc:
   Increased frequency of myeloma or monoclonal gammopathy

Lab:
   Hemosiderinuria;
   Grossly disorganized erythroblast nuclei;
   Intraerythroblastic inclusions;
   Highly polyploid giant mononucleate erythroblasts;
   Elevated levels of serum thymidine kinase

Inheritance:
   Autosomal dominant;
   also two recessive forms

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/6/1995
jason: 6/9/1994
mimadm: 3/11/1994
carol: 10/13/1993
carol: 9/29/1993
carol: 7/9/1993

*RECORD*
*FIELD* NO
105650
*FIELD* TI
*105650 ANEMIA, CONGENITAL HYPOPLASTIC, OF BLACKFAN AND DIAMOND
BLACKFAN-DIAMOND SYNDROME; BDS
*FIELD* TX
Falter and Robinson (1972) described affected mother and daughter. Only
the mother had aminoaciduria, suggesting that it was unrelated to the
hematologic disorder. Forare (1963) described this disorder in 2
children with the same father and different mothers. (Forare (1963)
referred to these as step-siblings; they accurately should be called
half-siblings (or half-sibs, according to my preference of usage). A
step-brother is a son of 1 step-parent by a former marriage. Step-sibs
are not biologically related.) Mott et al. (1969) reported a similar
situation, namely, 3 affected children from 2 mothers and the same
father. Families with possible autosomal dominant transmission were also
reported by Hunter and Hakami (1972), Gray (1982), and Viskochil et al.
(1990). The kindred reported by Viskochil et al. (1990) had 7 affected
members in 4 sibships in 3 generations and several instances of
male-to-male transmission. See 205900. Hurst et al. (1991) described a
mother and son with congenital hypoplastic anemia; the son had a right
radial club hand with absent thumb and conjoined radius and ulna on the
right with small, useless thumb on the left. Gojic et al. (1994)
reported a family in which 4 males in 3 successive generations had
congenital hypoplastic anemia. None of these individuals had
malformations. Specifically, the thumbs and radii were normal. Two
brothers were of short stature: 162 and 156 cm.

McLennan et al. (1996) made the prenatal diagnosis of congenital
hypoplastic anemia causing hydrops fetalis in a child born to a
26-year-old woman with steroid-dependent Blackfan-Diamond syndrome. In
the mother the diagnosis of BDS had been made at the age of 2 years
following investigation of short stature and failure to thrive. From the
age of 4 years, she had been treated with steroids, titrated to maintain
a hemoglobin level between 7 and 8.5 g/dl. There was no relevant family
history. Her first pregnancy ended in a spontaneous abortion at 8 weeks.
In the second pregnancy, failure to visualize cardiac structures
adequately at 22 weeks led to referral to a tertiary center.
Cardiomegaly and a small pericardial effusion with structurally normal
heart were demonstrated. By 33 weeks severe ascites and enlargement of
the heart, which occupied nearly the entire chest, were found.
Cordocentesis at that time confirmed severe fetal anemia, and
transfusion of packed red cells was undertaken. The infant was delivered
by caesarean section at 34 weeks. No physical anomalies were found
except for proximal and superior displacement of the first
metatarsophalangeal joint of an otherwise normal left great toe. Mild
cardiac failure had resolved by day 14. Bone marrow at 3 months of age
showed a cellular marrow with normal megakaryocytes and myeloid
differentiation but virtual absence of red cell precursors. Prednisolone
was introduced at that stage without any significant response over the
next 2 months. At 14 months of age, the baby was being managed with
intermittent transfusions and continued steroid administration.

*FIELD* RF
1. Falter, M. L.; Robinson, M. G.: Autosomal dominant inheritance
and amino aciduria in Blackfan-Diamond anemia. J. Med. Genet. 9:
64-66, 1972.

2. Forare, S. A.: Pure red cell anemia in step siblings. Acta Paediat. 52:
159-160, 1963.

3. Gojic, V.; van't Veer-Korthof, E. T.; Bosch, L. J.; Puyn, W. H.;
van Haeringen, A.: Congenital hypoplastic anemia: another example
of autosomal dominant transmission. Am. J. Med. Genet. 50: 87-89,
1994.

4. Gray, P.: Pure red-cell aplasia. Med. J. Aust. 1: 519-521, 1982.

5. Hunter, R. E.; Hakami, N.: The occurrence of congenital hypoplastic
anemia in half brothers. J. Pediat. 81: 346-348, 1972.

6. Hurst, J. A.; Baraitser, M.; Wonke, B.: Autosomal dominant transmission
of congenital erythroid hypoplastic anemia with radial abnormalities. Am.
J. Med. Genet. 40: 482-484, 1991.

7. McLennan, A. C.; Chitty, L. S.; Rissik, J.; Maxwell, D. J.: Prenatal
diagnosis of Blackfan-Diamond syndrome: case report and review of
the literature. Prenatal Diag. 16: 349-353, 1996.

8. Mott, M. G.; Apley, J.; Raper, A. B.: Congenital (erythroid) hypoplastic
anaemia: modified expression in males. Arch. Dis. Child. 44: 757-760,
1969.

9. Viskochil, D. H.; Carey, J. C.; Glader, B. E.; Rothstein, G.; Christensen,
R. D.: Congenital hypoplastic (Diamond-Blackfan) anemia in seven
members of one kindred. Am. J. Med. Genet. 35: 251-256, 1990.

*FIELD* CS

Heme:
   Congenital hypoplastic anemia

Growth:
   Growth retardation

Cardiac:
   Congestive heart failure

Limbs:
   Abnormal thumbs

Skin:
   Infantile pallor

Lab:
   Reticulocytopenia;
   Macrocytosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 08/22/1996
marlene: 8/2/1996
terry: 7/29/1996
jason: 6/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 9/27/1991
supermim: 3/20/1990
supermim: 2/28/1990

*RECORD*
*FIELD* NO
105800
*FIELD* TI
*105800 ANEURYSM, INTRACRANIAL BERRY
ANEURYSMAL SUBARACHNOID HEMORRHAGE, FAMILIAL
*FIELD* TX
Ullrich and Sugar (1960) reported 4 families, in each of which 2 members
had cerebral aneurysms. I observed a 34-year-old man and his 13-year-old
daughter, both of whom died of intracranial berry aneurysm (McKusick,
1964). Graf (1966) reported 2 pairs of affected sibs. Beumont (1968)
described 3 affected sisters. Thierry et al. (1972) reviewed 10 reports
and documented autosomal dominant inheritance. Brisman and Abbassioun
(1971) raised the question of prophylactic investigations in a family
with a high frequency of mortality from ruptured aneurysms. Edelsohn et
al. (1972) reported a family with affected father and 3 affected
daughters and an affected son. Toglia and Samii (1972) suggested that
familial aneurysms may have favored locations and that multiple
aneurysms may be more often familial than are single aneurysms. They
reported 2 families: 2 black sisters and 2 white brothers with
intracranial aneurysms. One sister, aged 38, developed 6 intracranial
aneurysms, the largest at the left middle cerebral artery. Her sister
suffered an aneurysm at the right anterior cerebral artery at age 43. In
the second family, a 31-year-old male developed an aneurysm at the
bifurcation of the basilar artery. His brother, at age 34, developed an
aneurysm at the same site, as well as a smaller one at the left middle
cerebral artery. Their father died of a subarachnoid hemorrhage at age
39. Berry aneurysm appears to have a lower frequency in blacks than in
whites in the U.S. and elsewhere.

Fox and Ko (1980) found that in a sibship of thirteen, 6 had proven
intracranial aneurysm and 5 had normal finding on cerebral
arteriography; 2 refused arteriography. The parents and other relatives
were not known to be affected. The authors reasoned that 'it is hard to
escape the strong possibility of a dominant inheritance' in this family.
Although this may well be true, observation of several cases in a single
sibship is not supportive of their conclusion. One of the sibs who
refused elective angiography (Fox and Ko, 1980) was the subject of a
report by Fox (1982): the 57-year-old woman suffered subarachnoid
hemorrhage, was found to have 2 aneurysms by arteriography, and died
suddenly 3 days before the scheduled surgery to clip them. Thus, 7 of 12
sibs had aneurysm; the status of the 13th sib was unknown. Ronkainen et
al. (1993) investigated the frequency of either aneurysmal subarachnoid
hemorrhage or incidental intracranial aneurysms in the relatives of
1,150 subarachnoid hemorrhage patients from east Finland who had proven
intracranial aneurysms. They found a 10% incidence of familial
intracranial aneurysm.

Bromberg et al. (1995) found a higher relative risk for poor outcome in
patients with familial subarachnoid hemorrhage from those of sporadic
cases. Of their 14 families, 2 were segregating autosomal dominant
polycystic kidney disease. The mean age of subarachnoid hemorrhage in
familial cases in their series was 44.7 years compared to 53.4 years in
sporadic cases. The authors recommended screening individuals at risk
for familial intercranial aneurysms with catheter and angiography
between the ages of 40 and 60 and with MR angiography between the ages
of 20 and 70. Leblanc et al. (1995) found higher than expected
concordance of the age at rupture in a prospective study of 30
individuals in 13 families with multiple affected individuals. A
specific pattern of inheritance could not be ascertained from these
pedigrees nor was there an abnormality demonstrated in type 3 collagen
in any of these patients.

Berry aneurysm may have an increased frequency in persons with the
Ehlers-Danlos syndrome. It also occurs in some cases of polycystic
kidneys (Jankowicz et al., 1971) and with coarctation of the aorta.
Ostergaard and Oxlund (1987) sampled the middle cerebral artery and
brachial artery postmortem in 14 patients who died following rupture of
intracranial saccular aneurysms and from a control group of 14 age- and
sex-matched patients who died of causes unrelated to aneurysm rupture.
In 6 of the 14 patients, deficiency of type III collagen (120180) was
demonstrated in the specimens from the middle cerebral artery. De Paepe
et al. (1988) proposed that a defect in type III collagen
(COL3A1;120180) may be responsible for familial multiple intracranial
aneurysms, perhaps with few signs suggesting Ehlers-Danlos syndrome type
IV (130050). The same suggestion had been made by Pope et al. (1981).
The experience of Kuivaniemi et al. (1993), however, suggested that
mutations in the COL3A1 gene are not a common cause of intracranial
aneurysms or of cervical artery dissections. They studied type III
collagen cDNA from 58 patients of 7 different nationalities with one or
the other of these diagnoses. Among the patients studied were 3 pairs of
relatives; among the others 29 had at least 1 blood relative with either
an intracranial artery aneurysm or a cervical artery dissection. The age
of the patients at the time of diagnosis ranged from 15 to 68 years. The
study group consisted of 25 males and 33 females. Mutations in the
coding sequence for the triple-helical domain were excluded in 40
individuals with intracranial aneurysms and 18 individuals with cervical
artery dissections. Mutations that markedly decreased expression from 1
allele were also excluded in 42 of the 58 individuals. Majamaa et al.
(1994) investigated the familial aggregation of cervical artery
dissection and cerebral aneurysm in 22 consecutively diagnosed patients
with spontaneous carotid artery dissection and 38 randomly selected
controls. Of the sibs of dissection patients, 3.5% had either an
intracranial aneurysm or carotid artery dissection, compared with only 1
of 189 sibs of control patients. This suggested to the authors that
spontaneous carotid dissection in cerebral aneurysms may have a common
pathogenetic factor.

Schievink et al. (1994) reported a 3-generation family in which there
were 7 individuals affected with intracranial aneurysms with
male-to-male transmission. They also reviewed the literature of familial
intracranial aneurysms and found 238 families with 560 affected members,
of which 56% were female and 44% were male. The most common affected
kinship was among siblings. Segregation analysis revealed several
patterns of inheritance with no single mendelian model showing a best
overall fit. Schievink et al. (1994) suggested that genetic
heterogeneity may be important. Twenty-two percent of siblings of male
probands had an intracranial aneurysm compared with 9% of siblings of
female probands. Angiographic screening in 12 families detected an
intracranial aneurysm in 29% of 51 asymptomatic relatives.

In a complete survey of the families of patients with aneurysmal
subarachnoid hemorrhage in Rochester, Minnesota, between 1970 and 1979,
Schievink et al. (1995) found that 15 of 76 patients (20%) had a first-
or second-degree relative with aneurysmal subarachnoid hemorrhage. The
number of observed first-degree relatives with aneurysmal subarachnoid
hemorrhage was 11, compared to an expected number of 2.66, giving a
relative risk of 4.14.

*FIELD* SA
Acosta-Rua  (1978); Bannerman et al. (1970); Chakravorty and Gleadhill
(1966); Halal et al. (1983); Hashimoto  (1977); Kak et al. (1970);
Nagae et al. (1972); Patrick and Appleby (1983)
*FIELD* RF
1. Acosta-Rua, G. J.: Familial incidence of ruptured intracranial
aneurysms: report of 12 cases. Arch. Neurol. 35: 675-677, 1978.

2. Bannerman, R. M.; Ingall, G. B.; Graf, C. J.: The familial occurrence
of intracranial aneurysms. Neurology 20: 283-292, 1970.

3. Beumont, P. J.: The familial occurrence of berry aneurysm. J.
Neurol. Neurosurg. Psychiat. 31: 399-402, 1968.

4. Brisman, R.; Abbassioun, K.: Familial intracranial aneurysms. J.
Neurosurg. 34: 678-681, 1971.

5. Bromberg, J. E. C.; Rinkel, J. E.; Algra, A.; Limburg, M.; van
Gijn, J.: Outcome in familial subarachnoid hemorrhage. Stroke 26:
961-963, 1995.

6. Chakravorty, B. G.; Gleadhill, C. A.: Familial incidence of cerebral
aneurysms. Brit. Med. J. 1: 147-148, 1966.

7. De Paepe, A.; Van Landeghem, W.; De Keyser, F.; Pope, F. M.; Matton,
M.: Collagen type III deficiency associated with multiple intracranial
aneurysms. (Abstract) Clin. Genet. 33: 462, 1988.

8. Edelsohn, L.; Caplan, L.; Rosenbaum, A. E.: Familial aneurysms
and infundibular widening. Neurology 22: 1056-1060, 1972.

9. Fox, J. L.: Familial intracranial aneurysms: case report. J.
Neurosurg. 57: 416-417, 1982.

10. Fox, J. L.; Ko, J. P.: Familial intracranial aneurysms: six cases
among 13 siblings. J. Neurosurg. 52: 501-503, 1980.

11. Graf, C. J.: Familial intracranial aneurysms: report of four
cases. J. Neurosurg. 25: 304-308, 1966.

12. Halal, F.; Mohr, G.; Toussi, T.; Martinez, S. N.: Intracranial
aneurysms: a report of a large pedigree. Am. J. Med. Genet. 15:
89-95, 1983.

13. Hashimoto, I.: Familial intracranial aneurysms and cerebral vascular
anomalies. J. Neurosurg. 46: 419-427, 1977.

14. Jankowicz, E.; Banach, S.; Pikiel, L.: Intracranial familial
aneurysms associated with polycystic kidneys. Neurol. Neurochir.
Pol. 5: 263-265, 1971.

15. Kak, V. K.; Gleadhill, C. A.; Bailey, I. C.: The familial incidence
of intracranial aneurysms. J. Neurol. Neurosurg. Psychiat. 33: 29-33,
1970.

16. Kuivaniemi, H.; Prockop, D. J.; Wu, Y.; Madhatheri, S. L.; Kleinert,
C.; Earley, J. J.; Jokinen, A.; Stolle, C.; Majamaa, K.; Myllyla,
V. V.; Norrgard, O.; Schievink, W. I.; Mokri, B.; Fukawa, O.; ter
Berg, J. W. M.; De Paepe, A.; Lozano, A. M.; Leblanc, R.; Ryynanen,
M.; Baxter, B. T.; Shikata, H.; Ferrell, R. E.; Tromp, G.: Exclusion
of mutations in the gene for type III collagen (COL3A1) as a common
cause of intracranial aneurysms or cervical artery dissections: results
from sequence analysis of the coding sequences of type III collagen
from 55 unrelated patients. Neurology 43: 2652-2658, 1993.

17. Leblanc, R.; Melanson, D.; Tampieri, D.; Guttmann, R. D.: Familial
cerebral aneurysms: a study of 13 families. Neurosurgery 37: 633-639,
1995.

18. Majamaa, K.; Portimojarvi, H.; Sotaniemi, K. A.; Myllyla, V. V.
: Familial aggregation of cervical artery dissection and cerebral
aneurysm. (Letter) Stroke 25: 1704-1705, 1994.

19. McKusick, V. A.: Intracranial aneurysm and heredity. (Letter) J.A.M.A. 190:
791, 1964.

20. Nagae, K.; Goto, I.; Ueda, K.; Morotomi, Y.: Familial occurrence
of multiple intracranial aneurysms: case report. J. Neurosurg. 37:
364-367, 1972.

21. Ostergaard, J. R.; Oxlund, H.: Collagen type III deficiency in
patients with rupture of intracranial saccular aneurysms. J. Neurosurg. 67:
690-696, 1987.

22. Patrick, D.; Appleby, A.: Familial intracranial aneurysm and
infundibular widening. Neuroradiology 25: 329-334, 1983.

23. Pope, F. M.; Nicholls, A. C.; Narcisi, P.; Bartlett, J.; Neil-Dwyer,
G.; Doshi, B.: Some patients with cerebral aneurysms are deficient
in type III collagen. Lancet I: 973-975, 1981.

24. Ronkainen, A.; Hernesniemi, J.; Ryynanen, M.: Familial subarachnoid
hemorrhage in east Finland, 1977-1990. Neurosurgery 33: 787-797,
1993.

25. Schievink, W. I.; Schaid, D. J.; Michels, V. V.; Piepgras, D.
G.: Familial aneurysmal subarachnoid hemorrhage: a community-based
study. J. Neurosurg. 83: 426-429, 1995.

26. Schievink, W. I.; Schaid, D. J.; Rogers, H. M.; Piepgras, D. G.;
Michels, V. V.: On the inheritance of intracranial aneurysms. Stroke 25:
2028-2037, 1994.

27. Thierry, A.; Ballivet, J.; Dumas, R.: Les cas familiaux d'aneurysmes
intra-craniens. Neurochirgia 18: 267-276, 1972.

28. Toglia, J. U.; Samii, A. R.: Familial intracranial aneurysms. Dis.
Nerv. Syst. 33: 611-613, 1972.

29. Ullrich, D. P.; Sugar, O.: Familial cerebral aneurysms including
one extracranial internal carotid aneurysm. Neurology 10: 288-294,
1960.

*FIELD* CS

Neuro:
   Cerebral aneurysm, often multiple;
   Intracranial hemorrhage

Inheritance:
   Autosomal dominant

*FIELD* CN
Orest Hurko - updated: 4/1/1996
Orest Hurko - updated: 1/25/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/21/1997
terry: 4/15/1996
mark: 4/2/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 1/25/1996
terry: 1/22/1996
mark: 11/1/1995
carol: 1/20/1995
terry: 7/18/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
105805
*FIELD* TI
105805 ANEURYSM OF INTERVENTRICULAR SEPTUM
*FIELD* TX
Chen et al. (1991) found a congenital aneurysm of the interventricular
septum of the heart in a 29-year-old man and his 4-year-old son. Both
were symptom free. Echocardiography demonstrated the aneurysm in the
mid-muscular trabecular portion of the ventricular septum with
considerable paradoxical motion of the aneurysmal segment. Otherwise,
abnormality of structure or function of the heart was not found. Such
aneurysms are rare (Fasoli et al., 1988; Magherini et al., 1988), and
the familial cases reported by Chen et al. (1991) may be unique.

*FIELD* RF
1. Chen, M.-R.; Rigby, M. L.; Redington, A. N.: Familial aneurysms
of the interventricular septum. Brit. Heart J. 65: 104-106, 1991.

2. Fasoli, G.; Della Valentina, P.; Scognamiglio, R.: Echocardiographic
findings in left ventricular septal aneurysm. Int. J. Cardiol. 18:
441-443, 1988.

3. Magherini, A.; Schmidtlein, C.; Urciuolo, A.; Tomassini, C. R.;
Calzolari, A.; Rorani, C.; Machetti, G.; Martinelli, R.; Vizzoni,
L.; Bartolozzi, G.: Congenital aneurysm of the interventricular muscular
septum with rupture into the right ventricle in a child. Am. Heart
J. 116: 185-187, 1988.

*FIELD* CS

Cardiac:
   Congenital aneurysm of interventricular septum

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/13/1991

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 1/31/1992
carol: 3/13/1991

*RECORD*
*FIELD* NO
105830
*FIELD* TI
#105830 ANGELMAN SYNDROME; AS
ANGELMAN SYNDROME CHROMOSOME REGION; ANCR;;
HAPPY PUPPET SYNDROME
*FIELD* MN
The 'happy puppet' syndrome is a condition with features of severe motor
and intellectual retardation, microcephaly, ataxia, frequent jerky limb
movements and flapping of the arms and hands, hypotonia, hyperactivity,
hypopigmentation (39%), seizures, absence of speech, frequent smiling
and episodes of paroxysmal laughter, and an unusual facies characterized
by macrostomia, a large mandible and open-mouthed expression, a great
propensity for protruding the tongue ('tongue thrusting'), and an
occipital groove (Clayton-Smith, 1993) (Buntinx et al., 1995). The
eponym Angelman syndrome is preferred because the term 'happy puppet'
may appear derisive to the patient's family. The diagnosis may be
difficult in the first years of life (Dorries et al., 1988). The
electroencephalogram is useful in the early diagnosis (Boyd et al,
1988).

A visible chromosomal change occurs in half of AS patients (Fryns et
al., 1989). A deletion of band 15q11-q13 may be found both in patients
with Angelman syndrome (Buxton et al., 1994), and with Prader-Willi
syndrome. The origin of the deleted chromosome is maternal in AS and
paternal in PWS. This suggests imprinting, i.e., changes in the
chromosome according to the parent of origin, with resulting
consequences for early development (Williams et al., 1990). The
imprinted gene responsible for the PWS phenotype is proximal to that
responsible for the AS phenotype (Greger et al., 1993). Studies using
DNA markers specific to 15q11-q13 identified three classes of deletions:
in class I, deletion of 2 markers was detected; in class II, deletion of
1 marker; and in class III no deletion was detected (Knoll et al.,
1990). There was complete concordance between the presence of a
cytogenetic deletion and a molecular deletion.

Alternatively, uniparental paternal disomy may occur, with absence of
the maternal 15q. Of the possible mechanisms for uniparental disomy, one
is gamete complementation, i.e., the gamete from one parent containing
both chromosomes of the pair and that from the other parent containing
neither. A second mechanism is so-called trisomy rescue or correction.
It is expected that the remaining pair, after loss of the extra homolog,
will be biparental in two-thirds of cases and uniparental in one-third.
In such instances, as in gamete complementation, isodisomy may or may
not be present. A third mechanism is akin to the second; the abnormal
initial zygotic situation is monosomy rather than trisomy and the
abnormality is 'corrected' through duplication of the single available
homolog (Engel, 1993). Finally, nondeletion AS can result from a genetic
mutation in 15q11-q13, when transmitted by the mother, but not the
father (Wagstaff et al., 1993).

In summary, Angelman syndrome results from a lack of maternal
contribution from chromosome 15q11-q13, arising from de novo deletion in
most cases or from uniparental disomy in rare cases. Most families are
associated with a low recurrence risk. Deletion has almost never been
found in the minority of families with more than one child affected. The
mode of inheritance in these families is autosomal dominant modified by
imprinting. Thus sporadic cases with no observable deletion pose a
counseling dilemma. A diagnostic strategy is proposed by Chan et al.
(1993). On the basis of molecular and cytogenetic findings on 61
patients, Saitoh et al. (1994) found that 70% of sporadic cases had a
molecular deletion, maternal in origin; 1 of 8 familial cases had a
molecular deletion involving only 2 marker loci, which defined the
critical region for the AS phenotype; the 7 remaining familial cases
were presumably mutational. Among sporadic and familial cases without
deletion, no uniparental disomy was found. Of patients with a normal
karyotype, 43% showed a molecular deletion. Familial cases with
submicroscopic deletion were not associated with hypopigmentation,
suggesting that a gene for hypopigmentation is located outside the
critical region of AS and is not imprinted.

Kishino et al. (1997) and Matsuura et al. (1997) demonstrated that
mutation of the gene E6-AP ubiquitin-protein ligase (UEB3A;601623) is
one cause of Angelman syndrome.

*FIELD* ED
jamie: 02/19/1997 joanna: 2/13/1997

*FIELD* CD
F. Clarke Fraser: 7/3/1996
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
cause resides in the E6-associated protein ubiquitin-protein ligase gene
(UBE3A; 601623).

Bower and Jeavons (1967) coined the name 'happy puppet' syndrome for a
condition with features of severe motor and intellectual retardation,
ataxia, hypotonia, epilepsy, absence of speech, and unusual facies
characterized by a large mandible and open-mouthed expression revealing
the tongue. They reported 2 patients. The French refer to the syndrome
as that of the 'marionette joyeuse' (Halal and Chagnon, 1976) or 'pantin
hilare' (Pelc et al., 1976). Williams and Frias (1982) suggested use of
the eponym Angelman syndrome because the term 'happy puppet' may appear
derisive and even derogatory to the patient's family. (Harry Angelman
pronounces his name as though it means 'male angel;' in other words, he
uses a 'long a' and a 'soft g.') Angelman (1965) had reported 3 'puppet
children,' as he called them. Berg and Pakula (1972) reported a case and
reviewed those reported by Angelman (1965) and Bower and Jeavons (1967).
All of the patients demonstrated excessive laughter, an occipital
groove, a great facility for protruding the tongue (tongue thrusting'),
abnormal choroidal pigmentation, and characteristic electroencephalogram
(EEG) discharges. Of the 3 patients reported by Angelman (1965), at
least 1 developed optic atrophy. Two patients showed jerky movements and
had trouble walking. The walking problem may be due to poor balance.
One, a 9-year-old boy who was noticed as an infant to be 'floppy,' could
take only a few steps without support. Both patients had major
convulsions and showed periods of flapping their arms up and down with
the elbows flexed. The EEG pattern seen in these 2 cases and in the
cases of Bower and Jeavons (1967) consisted of high amplitude bilateral
spike-and-wave activity which was symmetrical, synchronous, and most
often monorhythmic, having a slow wave component at 2 cycles per sec.
Normal karyotype was found in the 5 patients studied. Viani et al.
(1995) found electroencephalographic evidence of transient myoclonic
status epilepticus in 9 of 18 Angelman patients. This may account for
recurrent jerky abnormal movements that have been previously observed in
these patients. In addition, 7 patients had partial seizures with eye
deviation and vomiting similar to those of childhood occipital
epilepsies. The patient reported by Berg and Pakula (1972) had an
unaffected sib who, however, showed abnormal EEG patterns. Williams and
Frias (1982) demonstrated unilateral cerebellar atrophy by computerized
axial tomography in 1 patient. Angelman (1965) emphasized the abnormal
cranial shape and suggested that the depressed occiput may reflect a
cerebellar abnormality. Boyd et al. (1988) pointed out the usefulness of
the electroencephalogram in the early diagnosis of Angelman syndrome.
Dorries et al. (1988) described 7 cases and concluded that the diagnosis
is difficult in the first years of life. Robb et al. (1989) reviewed the
clinical features in 36 children. Episodes of paroxysmal laughter was a
feature, and tongue thrusting was common. The movement disorder
consisted of a wide-based, ataxic gait with frequent jerky limb
movements and flapping of the hands. Scheffer et al. (1990) pointed out
the possible confusion with Rett syndrome (312750). Fryburg et al.
(1991) described the clinical features in 4 patients diagnosed at less
than 2 years of age. One of their patients had oculocutaneous albinism,
and all were hypopigmented compared to their first-degree relatives. All
4 had choroidal pigment hypoplasia, severe to profound global
developmental delay and microcephaly of postnatal onset, seizures,
hypotonia, hyperreflexia, and hyperkinesis. Clayton-Smith (1993)
reported on observations concerning 82 affected individuals. All of them
had absent speech or spoke less than 6 words. Thirty-nine percent were
hypopigmented compared to the family. Frequent smiling was present in
96%. King et al. (1993) concluded from the study of 6 individuals with
AS that hypopigmentation characterized by light skin, reduced retinal
pigment, low hairbulb tyrosinase activity, and incomplete melanization
of melanosomes is part of the phenotype of AS, and is similar to that
found in Prader-Willi syndrome (PWS; 176270). Reish and King (1995)
established the diagnosis of Angelman syndrome in a 50-year-old woman.
She had been healthy without seizures and had a history of pelvic
fracture resulting from her unbalanced gait. She was born to a
40-year-old mother. Her height was 148 cm and her IQ was measured at
less than 20. She did not speak and had frequent bursts of laughter.
Reish and King (1995) demonstrated a 15q11.2-q12 deletion by karyotypic
examination and fluorescence in situ hybridization.

Buntinx et al. (1995) compared the main manifestations of Angelman
syndrome in 47 patients at different ages. Most patients between the
ages of 2 and 16 years showed at least 8 of the major characteristics of
the syndrome (bursts of laughter, happy disposition, hyperactivity,
micro- and brachycephaly, macrostomia, tongue protrusion, prognathism,
widely spaced teeth, puppetlike movements, wide-based gait) in addition
to mental retardation and absence of speech. Most patients (80.8%) had
epileptic seizures, starting after the age of 10 months. In children
under the age of 2 years, bursts of laughter was found in 42.8% and
macrostomia in only 13.3%, but protruding tongue was a constant feature.
In patients over 16 years of age, protruding tongue was found in 38.8%,
whereas prognathism and macrostomia were almost constant findings. A
cytogenetic deletion was found in 61% and a molecular deletion in 73% of
the patients. No case of paternal disomy was found. Buntinx et al.
(1995) found no differences between patients with or without deletion.
The diagnosis of Angelman syndrome may be hampered in young children
because of the absence of some typical manifestations and in older
patients because of the changing behavioral characteristics.

Angelman syndrome is not typically mendelian. The disorder could
represent a dominant mutation. However, paternal age was not remarkable
in the patients of Williams and Frias (1982). Pashayan et al. (1982)
reported Angelman syndrome in 2 brothers, and Kuroki et al. (1980)
reported 2 affected sisters. Pashayan et al. (1982) found reports of 27
sporadic cases with a sex ratio of M1:F1. Dijkstra et al. (1986)
reported brother and sister with the Angelman syndrome. Hersh et al.
(1981) reported affected monozygotic twins. Fisher et al. (1987)
reported affected brother and sister. Baraitser et al. (1987) reported 7
cases of Angelman syndrome from 3 families: 2 brothers in the first
family, 3 sisters in the second, and 2 brothers in the third. The EEG
changes were striking in all 7 patients. Willems et al. (1987) reported
what they believed to be the fourth family with affected sibs out of a
total of 52 cases in the literature. This suggests a low but not
negligible recurrence risk. Robb et al. (1989) observed 3 sibships with
more than 1 affected sib: 3 affected sisters, 2 affected brothers, and 2
affected sisters. Clayton-Smith et al. (1992) studied 11 patients and
their parents from 5 families using high resolution chromosome analysis
and molecular probes from the region 15q11-q13. No deletions were
detected. All sets of sibs inherited the same maternal chromosome 15,
whereas in 3 families sibs inherited different paternal 15s. Polymorphic
DNA markers gave the same conclusion. Thus, autosomal recessive
inheritance is very unlikely and maternal transmission of a mutation
within 15q11-q13 is much more tenable.

Magenis et al. (1987) described 2 unrelated girls with a deletion of the
proximal part of 15q. The girls showed none of the typical features of
the Prader-Willi syndrome, a disorder with which this deletion is
sometimes associated. The clinical features were more like those of
Angelman syndrome; specifically, ataxia-like incoordination, frequent,
unprovoked and prolonged bouts of laughter, and a facial appearance
compatible with that diagnosis. Magenis et al. (1988) studied 15q
deletion in 6 Angelman syndrome patients and an equal number of
Prader-Willi syndrome patients. In all patients, band 15q11 appeared to
be deleted; however, the deletion appeared larger in the patients with
Angelman syndrome and also included band q12. Magenis et al. (1988)
suggested that genes in band 15q12 are responsible for the greater
severity of mental retardation and speech in Angelman syndrome and that
these genes also suppress or alter the presumed hypothalamic abnormality
that results in the uncontrolled appetite and obesity of Prader-Willi
syndrome. Magenis et al. (1990) did high-resolution cytogenetic studies
of 7 patients with Prader-Willi syndrome and 10 patients with Angelman
syndrome. The same proximal band was deleted (15q11.2) in both
syndromes. In general, the deletion in patients with Angelman syndrome
was larger, though variable, and included bands q12 and part of q13.
Magenis et al. (1990) confirmed the maternal origin of the deleted
chromosome, contrasting with the predominant paternal origin of the
deletion in patients with Prader-Willi syndrome. All 4 of the patients
described by Fryburg et al. (1991) had deletions in the 15q11.2-q13
region. Parental chromosomes were available for study in 3 of these
cases; in all 3 the deleted chromosome 15 was maternally derived. By
molecular analyses, Donlon (1988) and Knoll et al. (1989) showed that
similar deletions of 15q11.2 were present in patients with the
Prader-Willi syndrome and the Angelman syndrome. He proposed a
hypothesis to explain the seemingly paradoxical findings. Whereas the
deleted chromosome is of paternal origin in the Prader-Willi syndrome,
it is the maternal chromosome that is partially deleted in Angelman
syndrome (Williams et al., 1988). Otherwise, the deletions in Angelman
syndrome and the Prader-Willi syndrome are indistinguishable
cytogenetically or by molecular genetic methods. This has been
interpreted as indicating imprinting of chromosomes, i.e., changes in
the chromosome according to the parent of origin, with resulting
consequences for early development. Using RFLPs, Knoll et al. (1989)
demonstrated maternal inheritance of the deleted chromosome 15 in 4
Angelman syndrome patients. Knoll et al. (1990) studied DNA of 19
patients, including 2 sib pairs, using 4 DNA markers specific to
15q11-q13. Three classes were identified: in class I, deletion of 2
markers was detected; in class II, deletion of 1 marker; and in class
III, including both sib pairs, no deletion was detected. High resolution
cytogenetic data were available on 16 of the patients, and complete
concordance between the presence of a cytogenetic deletion and a
molecular deletion was observed. No submicroscopic deletions were
detected by the DNA studies. DNA samples from the parents of 10 patients
with either a class I or a class II deletion were available for study.
In 7 of the 10 families, RFLPs were informative as to the parental
origin of the deletion, and in all, the deleted chromosome was of
maternal origin. Knoll et al. (1991) concluded, however, that
uniparental disomy may be infrequent in Angelman syndrome: by
qualitative hybridization with chromosome 15q11-q13-specific DNA
markers, they examined the DNA from 10 AS patients (at least 7 of whom
were familial cases) with no cytogenetic or molecular deletion of
chromosome 15q11-q13. In each case, 1 maternal copy and 1 paternal copy
of 15q11-q13 was observed. Malcolm et al. (1991) found evidence of
uniparental paternal disomy in 2 patients. Engel (1991), who introduced
the concept of uniparental disomy in 1980 (Engel, 1980), took Knoll et
al. (1991) to task for their conclusion that uniparental disomy may be
rare in this disorder and urged further studies. Paternal uniparental
disomy was demonstrated by Freeman et al. (1993) in a child with a
balanced 15;15 translocation. DNA polymorphisms demonstrated that the
patient was homozygous at all loci for which the father was
heterozygous, suggesting that the structural rearrangement was an
isochromosome 15q and not a Robertsonian translocation.

Engel (1993) reviewed the possible mechanisms for uniparental disomy.
One possibility is gamete complementation, i.e., the gamete from one
parent containing both chromosomes of the pair and that from the other
parent containing neither. When gamete complementation is the mechanism,
the centromeres of the resulting pair will be heterodisomic if resulting
from a meiosis 1 error, and isodisomic if resulting from a meiosis 2
error. Beyond that, meiosis 1 UPD, depending on crossingover and
segregation, may be wholly heterodisomic (holo-heterodisomy) or
partially isodisomic (mero-isodisomy); meiosis 2 UPD should always
result in an element of isodisomy embodied in the 2 segments of the
nonseparated chromatids left unaffected by crossingover. This unaffected
segment, of course, tends to be juxtacentromeric. Gametic
complementation UPD was reported by Wang et al. (1991), who found
paternal heterodisomy for chromosome 14 in a 45,XX,t(13q14q)der pat
proposita, whose 2 parents were balanced heterozygotes for a
translocation involving chromosome 14. This situation is analogous to
the effects of biparental translocation as in the mouse experiments of
Cattanach and Kirk (1985). A second mechanism of UPD is so-called
trisomy rescue or correction. It is expected that the remaining pair,
after loss of the extra homolog, will be biparental in two-thirds of
cases and uniparental in one-third of cases. In such instances, as in
gamete complementation, isodisomy may or may not be present. Cases of
UPD in Prader-Willi syndrome whose chromosomal 15 maternal disomy could
be traced to a placental mosaicism for trisomy 15 documented at the time
of choriocentesis (chorion villus sampling) performed for advanced
maternal age were reported by Cassidy et al. (1992) and Purvis-Smith et
al. (1992). A third situation is akin to the second; the abnormal
initial zygotic situation is monosomy rather than trisomy and the
abnormality is 'corrected' through duplication of the single available
homolog. The case of cystic fibrosis with maternal chromosome 7
isodisomy and growth delay reported by Spence et al. (1988) may have
been of this type, although there is at least one other explanation.
Donnai (1993) pointed out that Robertsonian translocations, occurring
with a frequency of about 1 in 10,000 live births, may be an important
cause of UPD; such has been demonstrated to be the case for 13/15,
13/14, 14/14, and 22/22 translocations. Dysmorphologic features and/or
mental retardation are clinical clues for uniparental disomy in
apparently balanced offspring of translocation carriers. Among abortion
products of balanced Robertsonian translocation carriers, an excess of
'normal balanced' conceptions has been noted. Robertsonian
translocations involving chromosomes 13 and/or 21 are frequently
ascertained through a trisomic child. Among those ascertained through a
mentally retarded but nontrisomic proband, there appears to be
overrepresentation of translocations involving chromosome 14. Since
nonmosaic trisomy 14 is nonviable, such a conception would survive a
pregnancy only by reducing to disomy.

In line with other reports, Smith et al. (1992) found the deletion of
band 15q12 to be of maternal origin in all of 25 cases. The parental
origin was determined using cytogenetic markers in 13 of the cases, by
the pattern of inheritance of RFLPS in 9, and by both techniques in 3.
Tonk et al. (1992) found cytogenetic deletion of 15q12 in 3 cases of AS
and by heteromorphism studies showed that the deleted chromosome was
maternal in all 3. Meijers-Heijboer et al. (1992) reported findings in
an usually large pedigree with segregation of AS through maternal
inheritance and apparent asymptomatic transmission through several male
ancestors. Deletion and paternal disomy at 15q11-q13 were excluded;
however, the genetic defect was located in this region because they
found a maximum lod score of 5.40 for linkage to GABRB3 (137192) and the
DNA marker D15S10. The size of the pedigree allowed calculation of an
odds ratio in favor of genomic imprinting of 9.25 x 10(5).

After discovering 2 unrelated patients with a small deletion of proximal
15q, Pembrey et al. (1988, 1989) reassessed 10 further patients. Four
showed a deletion within 15q11-q13, 1 showed an apparent pericentric
inversion with breakpoints at 15q11 and q13 inherited from the mother,
and 5 showed no discernible abnormality. Of the 5 children without
discernible chromosome change, 1 had a definitely affected sib and 1 had
a possibly affected sib. Of the 4 sets of parents studied, 3 had normal
chromosomes, and in 1 the mother had a deletion of 15q11.2 but not
15q12. Kaplan et al. (1987) also described deletion in 15q11-q12 in a
child with Angelman syndrome. By flow karyotype analysis on
lymphoblastoid cell lines, Cooke et al. (1988, 1989) confirmed the
presence of a de novo 15q deletion in a child with Angelman syndrome.
The deleted segment represented 6.1 to 9.5% of chromosome 15, or
approximately 6-9.3 million base pairs. Cytogenetic evidence suggested
that the deleted chromosome was derived from the smaller chromosome 15
homolog of the mother. Like Pembrey et al. (1989), Fryns et al. (1989)
found a visible chromosomal change in half of the patients they studied.
No deletion was found in 2 affected sisters. In 6 out of 8 children,
aged 3 to 10 years, Dickinson et al. (1988) found an association of
striking deficiency of choroidal pigment with normal foveal reflexes.
All 6 had light blue irides with normal iris architecture. All were
isolated cases born to healthy, unrelated parents. The presence or
absence of 15q microdeletions did not correlate with the ocular
findings. Imaizumi et al. (1990) described 6 patients, including 2 sibs,
with Angelman syndrome. The 4 sporadic cases showed a microdeletion in
the proximal part of 15q. The affected sibs had no visible deletion. No
clinical difference between the sporadic cases and the sib cases was
discerned. Using 2 DNA probes that detect a molecular deletion in most
patients with Prader-Willi syndrome, they found by densitometry that 2
patients had only 1 copy of each probe, whereas the other 4, including
the sibs, had 2 copies of each sequence. Thus, the segment causing
Angelman syndrome may be different from that causing Prader-Willi
syndrome, although closely adjacent. Williams et al. (1990) studied 6
persons with Angelman syndrome and de novo deletions of 15q11-q13. In 4
of the patients, cytogenetic studies were informative of parental
origin; in all, the deletion was inherited from the mother. Genomic
imprinting was suggested. Malcolm et al. (1990) studied 37 typical
cases. A 15q11-q13 deletion was observed in 18 of 24 isolated cases. No
deletion was observed in 13 cases from 6 families with more than 1
affected child. In 11 cases it was possible to elucidate the parental
origin of the deleted chromosome and these were shown to be
predominantly maternal.

Greenstein (1990) presented a kindred in which both the Prader-Willi and
Angelman syndromes were found; the inheritance pattern was consistent
with genetic imprinting. Hulten et al. (1991) reported an extraordinary
family showing segregation of a balanced translocation t(15;22)(q13;q11)
and 2 cases of Prader-Willi syndrome and 1 of Angelman syndrome. It
appeared that the females carrying the balanced translocation had a high
risk of having children with AS, while their brothers had a high risk of
having children with PWS. Wagstaff et al. (1992) presented observations
on a family demonstrating that nondeletion, nonuniparental disomy can
result from a genetic alteration in 15q11-q13, when transmitted by the
mother, and that the loci responsible for PWS and AS, although closely
linked, are distinct. In the instructive family they described, 3
sisters had given birth to 4 AS offspring who had no evidence of
deletion or paternal disomy. Wagstaff et al. (1992) showed that the
inferred mutation had been transmitted by the grandfather to 3 of his
offspring without phenotypic effects. Wagstaff et al. (1993) indicated
that this was the first instance in which the origin of a new mutation
in nondeletion AS could be pinpointed. A sister of the grandfather had
transmitted the same AS-associated haplotype to 4 of her children, all
of whom were phenotypically normal. Therefore, either there was germline
mosaicism in the grandfather, with the mutation transmitted to at least
3 of his 5 children, or the grandfather inherited a new AS mutation from
his father. Hamabe et al. (1991) described transmission of a
submicroscopic deletion in a 3-generation family which resulted in AS
only upon maternal transmission of the deletion. No clinical phenotype
was associated with paternal transmission. Greger et al. (1993) cloned
and sequenced the breakpoint of this submicroscopic deletion. Among
other things, their findings suggested that the imprinted gene
responsible for the PWS phenotype is proximal to that responsible for
the AS phenotype. In studies reported by Robinson et al. (1993), most
cases of paternal UPD(15) leading to Angelman syndrome were meiosis II
errors or, more likely, mitotic errors. On the other hand, in more than
82% of cases of maternal UPD(15) leading to Prader-Willi syndrome, the
extra chromosome was due to a meiosis I nondisjunction event. A similar
observation has been made for trisomy 21: the majority (78%) of maternal
errors leading to trisomy 21 are attributable to meiosis I events,
whereas most paternal errors are attributed to either meiosis II or
mitotic events (40% and 33%, respectively) (Antonarakis et al., 1993).
In summary, Angelman syndrome results from a lack of maternal
contribution from chromosome 15q11-q13, arising from de novo deletion in
most cases or from uniparental disomy in rare cases. Most families are
associated with a low recurrence risk. With the exception of the family
reported by Hamabe et al. (1991) (see earlier), no deletion has been
found in the minority of families with more than one child affected. The
mode of inheritance in these families is autosomal dominant modified by
imprinting. Sporadic cases with no observable deletion pose a counseling
dilemma.

Chan et al. (1993) presented a series of 93 Angelman syndrome patients,
showing the relative contribution of the various genetic mechanisms.
Sporadic cases accounted for 81 AS patients, while 12 cases came from 6
families. Deletions in 15q11-q13 were detected in 60 cases by use of a
set of highly polymorphic (CA)n repeat markers and conventional RFLPs.
In 10 sporadic cases and in all 12 familial cases, no deletion was
detectable. In addition, 2 cases of de novo deletions occurred in a
chromosome 15 carrying a pericentric inversion. In one of these the AS
child had a cousin with Prader-Willi syndrome arising from a de novo
deletion in an inverted chromosome 15 inherited from his father. The
other case arose from a maternal balanced t(9;15)(p24;q15)
translocation. There were 3 cases of uniparental disomy. In the familial
cases, all affected sibs inherited the same maternal chromosome 15
markers for the region 15q11-q13. Cytogenetic analysis detected only 42
of the 60 deletion cases. Cytogenetic analysis is still essential,
however, to detect chromosomal abnormalities other than deletions such
as inversions and balanced translocations, both of which have an
increased risk for deletions.

Beuten et al. (1996) reported an extraordinary, highly inbred, extended
Dutch kindred in which 3 cases, 2 males and 1 female with Angelman
syndrome, occurred in 3 separate sibships in the kindred sharing common
ancestral couples through all 6 parents. High resolution chromosome
analysis combined with DNA analysis using 14 marker loci from the
15q11-q13 region failed to detect a deletion in any of the 3 patients.
Paternal uniparental disomy of chromosome 15 was detected in 1 case,
while the other 2 patients had abnormal methylation of D15S9, D15S63,
and SNRPN (182279). Although the 3 patients were distantly related, the
chromosome 15q11-q13 haplotypes were different, again suggesting that
independent mutations gave rise to AS in this family.

On the basis of molecular and cytogenetic findings, Saitoh et al. (1994)
classified 61 Angelman syndrome patients into 4 groups: familial cases
without deletion, familial cases with submicroscopic deletion, sporadic
cases with deletion, and sporadic cases without deletion. Among 53
sporadic cases, 37 (70%) had molecular deletion, which commonly extended
from D15S9 to D15S12, although not all deletions were identical. Of 8
familial cases, 3 sibs from 1 family had a molecular deletion involving
only 2 loci, D15S10 and GABRB3, which defined the critical region for AS
phenotypes. The deletion, both in sporadic and familial cases, was
exclusively maternal in origin, consistent with the genomic imprinting
hypothesis. Among sporadic and familial cases without deletion, no
uniparental disomy was found. Of 23 patients with a normal karyotype, 10
(43%) showed a molecular deletion. Except for hypopigmentation of skin
or hair, neurologic signs and facial characteristics were not
distinctive in a particular group. Familial cases with submicroscopic
deletion were not associated with hypopigmentation, suggesting that a
gene for hypopigmentation is located outside the critical region of AS
and is not imprinted.

Bundey et al. (1994) reported a boy with ataxia, mental retardation,
infantile autism, and seizures, who had an extensive interstitial
duplication of 15q11-q13, including the critical regions for the
Prader-Willi and Angelman syndromes, on the maternally derived
chromosome. Analysis by FISH and conventional Southern blot analysis, as
well as genotyping for (CA)n repeat markers by PCR amplification,
demonstrated duplication of all markers from D15S11 to D15S24. Among the
duplicated genes were GABRA5 (137142) and GABRB3 (137192), and the
authors speculated that these duplications may have contributed to the
phenotype. Clayton-Smith et al. (1993) had earlier reported a patient
with a less extensive duplication, which included the Angelman critical
region, who had ataxia and moderate developmental delay, particularly of
language, but neither epilepsy nor behavior problems.

Before the study of Buxton et al. (1994), the AS region had been
narrowed to approximately 1.5 Mb, as defined by an affected family
carrying a small inherited deletion (Kuwano et al., 1992) and another
patient with an unbalanced translocation (Reis et al., 1993). Buxton et
al. (1994) identified an individual with typical features of AS who had
a deletion of the maternal chromosome shown to be less than 200-kb in
size.

Unlike the usual cause of loss of maternal genetic material through
deletion of 15q11-q13 of paternal uniparental disomy of chromosome 15,
Burke et al. (1996) reported a case of Angelman syndrome resulting from
an unbalanced cryptic translocation with a breakpoint at 15q11.2. The
proband was diagnosed clinically as having Angelman syndrome but no
cytogenetic deletion was detected. Fluorescence in situ hybridization
detected a deletion of D15S11, with an intact GABRB3 locus. Subsequent
studies of the proband's mother and sister detected a cryptic reciprocal
translocation between chromosomes 14 and 15 with the breakpoint being
between SNRPN (182279) and D15S10. The proband was found to have
inherited an unbalanced form, being monosomic from 15pter through SNRPN
and trisomic for 14pter-q11.2. DNA methylation studies showed that the
proband had a paternal-only DNA methylation pattern at SNRPN, D15S63 and
ZNF127. The mother and unaffected sister, both having the balanced
translocation, demonstrated normal DNA methylation patterns at all 3
loci. These data suggested to Burke et al. (1996) that the gene for AS
most likely lies proximal to D15S10, in contrast to the previously
published position, although a less likely possibility is that the
maternally inherited imprinting center acts in trans in the unaffected
balanced translocation carrier sister.

Clayton-Smith and Pembrey (1992) provided a review. Smith et al. (1996)
reviewed the clinical features of 27 Australasian patients with AS, all
with a DNA deletion involving 15q11-q13 and spanning markers from D15S9
to D15S12 (approximately 3.5 Mb of DNA). There were 9 males and 18
females, all sporadic, ranging in age from 3 to 34 years, and all
ataxic, severely retarded, and lacking in recognizable speech. Head
circumference at birth was normal in all but skewed in distribution,
with 62.5% at the tenth centile. Epilepsy was present in 96% with onset
during the third year of life in 20 of 26 patients. Hypopigmentation was
present in 19 (73%). One patient had ocular cutaneous albinism. A happy
disposition was noted in infancy in 95% and they all had a large, wide
mouth.

The American Society of Human Genetics/American College of Medical
Genetics Test and Technology Transfer Committee (1996) reviewed
diagnostic testing for Prader-Willi syndrome and Angelman syndrome.

Kishino et al. (1997) and Matsuura et al. (1997) demonstrated that the
gene for E6-AP ubiquitin-protein ligase (UBE3A; 601623) is one cause of
Angelman syndrome. Matsuura et al. (1997) identified de novo truncating
mutations in patients with Angelman syndrome, indicating that UBE3A is
the AS gene and suggesting the possibility of a maternally expressed
gene product in addition to the biallelically expressed transcript of
the UBE3A gene. Kishino et al. (1997) found novel UBE3A mutations in
nondeletion/nonunipaternal disomy/nonimprinting mutation AS patients.
These mutations also were predicted to cause a frameshift and premature
termination of translation. This suggested that AS is the first
recognized example of genetic disorder of the ubiquitin-dependent
proteolytic pathway in mammals. It also may represent an example of a
human genetic disorder associated with a locus producing functionally
distinct imprinted and biallelically expressed gene products. Precedent
for the production of imprinted and nonimprinted transcripts from a
single locus exists for insulin growth factor-2 (IGF2; 147470), where 4
promoters, 3 imprinted and 1 biallelically expressed, account for
differential expression.

As indicated earlier, Angelman syndrome most frequently results from
large de novo deletions of 15q11-q13. The deletions are exclusively of
maternal origin, and a few cases of paternal uniparental disomy of
chromosome 15 have been identified as the cause of AS. The findings
indicate that AS is caused by absence of a maternal contribution to the
imprinted 15q11-q13 region. Cases of AS resulting from translocations or
pericentric inversions had been observed to be associated with
deletions, and no confirmed reports of balanced rearrangements had been
reported in AS until the patient described by Greger et al. (1997).
Their patient had a paracentric inversion with a breakpoint located
approximately 25 kb proximal to the reference marker D15S10. This
inversion was inherited from a phenotypically normal mother. No deletion
was evident by molecular analysis in this case, by use of cloned
fragments mapped to within approximately 1 kb of the inversion
breakpoint. Among the possible explanations for the AS phenotype put
forth by Greger et al. (1997) was the possibility that the inversion
disrupted the UBE3A gene (601623).

*FIELD* SA
Dooley et al. (1981); Moore and Jeavons (1973)
*FIELD* RF
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syndrome in infants. Am. J. Med. Genet. 38: 58-64, 1991.

34. Fryns, J. P.; Kleczkowska, A.; Decock, P.; Van den Berghe, H.
: Angelman's syndrome and 15q11-13 deletions. (Letter) J. Med. Genet. 26:
538, 1989.

35. Greenstein, M. A.: Prader-Willi and Angelman syndromes in one
kindred with expression consistent with genetic imprinting. (Abstract) Am.
J. Hum. Genet. 47 (suppl.): A59, 1990.

36. Greger, V.; Knoll, J. H. M.; Wagstaff, J.; Woolf, E.; Lieske,
P.; Glatt, H.; Benn, P. A.; Rosengren, S. S.; Lalande, M.: Angelman
syndrome associated with an inversion of chromosome 15q11.2q24.3. Am.
J. Hum. Genet. 60: 574-580, 1997.

37. Greger, V.; Woolf, E.; Lalande, M.: Cloning of the breakpoints
of a submicroscopic deletion in an Angelman syndrome patient. Hum.
Molec. Genet. 2: 921-924, 1993.

38. Halal, F.; Chagnon, J.: Le syndrome de la 'marionette joyeuse.'. Un.
Med. Canada 105: 1077-1083, 1976.

39. Hamabe, J.; Kuroki, Y.; Imaizumi, K.; Sugimoto, T.; Fukushima,
Y.; Yamaguchi, A.; Izumikawa, Y.; Niikawa, N.: DNA deletion and its
parental origin in Angelman syndrome patients. Am. J. Med. Genet. 41:
64-68, 1991.

40. Hersh, J. H.; Bloom, A. S.; Zimmerman, A. W.; Dinno, N. D.; Greenstein,
R. M.; Weisskopf, B.; Reese, A. H.: Behavioral correlates in the
happy puppet syndrome: a characteristic profile?. Dev. Med. Child
Neurol. 23: 792-800, 1981.

41. Hulten, M.; Armstrong, S.; Challinor, P.; Gould, C.; Hardy, G.;
Leedham, P.; Lee, T.; McKeown, C.: Genomic imprinting in an Angelman
and Prader-Willi translocation family. (Letter) Lancet 338: 638-639,
1991.

42. Imaizumi, K.; Takada, F.; Kuroki, Y.; Naritomi, K.; Hamabe, J.;
Niikawa, N.: Cytogenetic and molecular study of the Angelman syndrome. Am.
J. Med. Genet. 35: 314-318, 1990.

43. Kaplan, L. C.; Wharton, R.; Elias, E.; Mandell, F.; Donlon, T.;
Latt, S. A.: Clinical heterogeneity associated with deletions in
the long arm of chromosome 15: report of 3 new cases and their possible
genetic significance. Am. J. Med. Genet. 28: 45-53, 1987.

44. King, R. A.; Wiesner, G. L.; Townsend, D.; White, J. G.: Hypopigmentation
in Angelman syndrome. Am. J. Med. Genet. 46: 40-44, 1993.

45. Kishino, T.; Lalande, M.; Wagstaff, J.: UBE3A/E6-AP mutations
cause Angelman syndrome. Nature Genet. 15: 70-73, 1997.

46. Knoll, J. H. M.; Glatt, K. A.; Nicholls, R. D.; Malcolm, S.; Lalande,
M.: Chromosome 15 uniparental disomy is not frequent in Angelman
syndrome. Am. J. Hum. Genet. 48: 16-21, 1991.

47. Knoll, J. H. M.; Nicholls, R. D.; Magenis, R. E.; Glatt, K.; Graham,
J. M., Jr.; Kaplan, L.; Lalande, M.: Angelman syndrome: three molecular
classes identified with chromosome 15q11q13-specific DNA markers. Am.
J. Hum. Genet. 47: 149-155, 1990.

48. Knoll, J. H. M.; Nicholls, R. D.; Magenis, R. E.; Graham, J. M.,
Jr.; Lalande, M.; Latt, S. A.: Angelman and Prader-Willi syndromes
share a common chromosome 15 deletion but differ in parental origin
of the deletion. Am. J. Med. Genet. 32: 285-290, 1989.

49. Kuroki, Y.; Matsui, I.; Yamamoto, Y.; Ieshima, A.: The 'happy
puppet' syndrome in two siblings. Hum. Genet. 56: 227-229, 1980.

50. Kuwano, A.; Mutirangura, A.; Dittrich, B.; Buiting, K.; Horsthemke,
B.; Saitoh, S.; Niikawa, N.; Ledbetter, S. A.; Greenberg, F.; Chinault,
A. C.; Ledbetter, D. H.: Molecular dissection of the Prader-Willi/Angelman
syndrome region (15q11-13) by YAC cloning and FISH analysis. Hum.
Molec. Genet. 1: 417-425, 1992.

51. Magenis, R. E.; Brown, M. G.; Lacy, D. A.; Budden, S.; LaFranchi,
S.: Is Angelman syndrome an alternate result of del(15)(q11q13)?. Am.
J. Med. Genet. 28: 829-838, 1987.

52. Magenis, R. E.; Toth-Fejel, S.; Allen, L. J.; Black, M.; Brown,
M. G.; Budden, S.; Cohen, R.; Friedman, J. M.; Kalousek, D.; Zonana,
J.; Lacy, D.; LaFranchi, S.; Lahr, M.; Macfarlane, J.; Williams, C.
P. S.: Comparison of the 15q deletions in Prader-Willi and Angelman
syndromes: specific regions, extent of deletions, parental origin,
and clinical consequences. Am. J. Med. Genet. 35: 333-349, 1990.

53. Magenis, R. E.; Toth-Fejel, S.; Allen, L. J.; Cohen, R.; Lahr,
M.; Macfarlane, J.; Black, M.; Lacy, D.; Brown, M.: Angelman happy
puppet and Prader Willi syndromes: do they share an identical deletion?.
(Abstract) Am. J. Hum. Genet. 43: A113, 1988.

54. Malcolm, S.; Clayton-Smith, J.; Nichols, M.; Robb, S.; Webb, T.;
Armour, J. A. L.; Jeffreys, A. J.; Pembrey, M. E.: Uniparental paternal
disomy in Angelman's syndrome. Lancet 337: 694-697, 1991.

55. Malcolm, S.; Webb, T.; Rutland, P.; Middleton-Price, H. R.; Pembrey,
M. E.: Molecular genetic studies of Angelman's syndrome. (Abstract) J.
Med. Genet. 27: 205, 1990.

56. Matsuura, T.; Sutcliffe, J. S.; Fang, P.; Galjaard, R.-J.; Jiang,
Y.; Benton, C. S.; Rommens, J. M.; Beaudet, A. L.: De novo truncating
mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman
syndrome. Nature Genet. 15: 74-77, 1997.

57. Meijers-Heijboer, E. J.; Sandkuijl, L. A.; Brunner, H. G.; Smeets,
H. J. M.; Hoogeboom, A. J. M.; Deelen, W. H.; van Hemel, J. O.; Nelen,
M. R.; Smeets, D. F. C. M.; Niermeijer, M. F.; Halley, D. J. J.:
Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting
in familial Angelman syndrome. J. Med. Genet. 29: 853-857, 1992.

58. Moore, J. R.; Jeavons, P. M.: The 'happy puppet' syndrome: two
new cases and a review of five previous cases. Neuropaediatrie 4:
172-179, 1973.

59. Pashayan, H. M.; Singer, W.; Bove, C.; Eisenberg, E.; Seto, B.
: The Angelman syndrome in two brothers. Am. J. Med. Genet. 13:
295-298, 1982.

60. Pelc, S.; Levy, J.; Point, G.: 'Happy puppet' syndrome ou syndrome
du 'pantin hilare.'. Helv. Paediat. Acta 31: 183-188, 1976.

61. Pembrey, M.; Fennell, S. J.; van den Berghe, J.; Fitchett, M.;
Summers, D.; Butler, L.; Clarke, C.; Griffiths, M.; Thompson, E.;
Super, M.; Baraitser, M.: The association of Angelman's syndrome
with deletions within 15q11-13. J. Med. Genet. 26: 73-77, 1989.

62. Pembrey, M.; Fennell, S. J.; van den Berghe, J.; Fitchett, M.;
Summers, D.; Butler, L.; Clarke, C.; Griffiths, M.; Thompson, E.;
Super, M.; Baraitser, M.: The association of Angelman syndrome and
deletions within 15q11-13. (Abstract) J. Med. Genet. 25: 274, 1988.

63. Purvis-Smith, S. G.; Saville, T.; Manass, S.; Yip, M.-Y.; Lam-Po-Tang,
P. R. L.; Duffy, B.; Johnston, H.; Leigh, D.; McDonald, B.: Uniparental
disomy 15 resulting from 'correction' of an initial trisomy 15. (Letter) Am.
J. Hum. Genet. 50: 1348-1350, 1992.

64. Reis, A.; Kunze, J.; Ladanyi, L.; Enders, H.; Klein-Vogler, U.;
Niemann, G.: Exclusion of the GABA(A)-receptor beta-3 subunit gene
as the Angelman's syndrome gene. (Letter) Lancet 341: 122-123, 1993.

65. Reish, O.; King, R. A.: Angelman syndrome at an older age. (Letter) Am.
J. Med. Genet. 57: 510-511, 1995.

66. Robb, S. A.; Pohl, K. R. E.; Baraitser, M.; Wilson, J.; Brett,
E. M.: The 'happy puppet' syndrome of Angelman: review of the clinical
features. Arch. Dis. Child. 64: 83-86, 1989.

67. Robinson, W. P.; Bernasconi, F.; Mutirangura, A.; Ledbetter, D.
H.; Langlois, S.; Malcolm, S.; Morris, M. A.; Schinzel, A. A.: Nondisjunction
of chromosome 15: origin and recombination. Am. J. Hum. Genet. 53:
740-751, 1993.

68. Saitoh, S.; Harada, N.; Jinno, Y.; Hashimoto, K.; Imaizumi, K.;
Kuroki, Y.; Fukushima, Y.; Sugimoto, T.; Renedo, M.; Wagstaff, J.;
Lalande, M.; Mutirangura, A.; Kuwano, A.; Ledbetter, D. H.; Niikawa,
N.: Molecular and clinical study of 61 Angelman syndrome patients. Am.
J. Med. Genet. 52: 158-163, 1994.

69. Scheffer, I.; Brett, E. M.; Wilson, J.; Baraitser, M.: Angelman's
syndrome. (Letter) J. Med. Genet. 27: 275-277, 1990.

70. Smith, A.; Wiles, C.; Haan, E.; McGill, J.; Wallace, G.; Dixon,
J.; Selby, R.; Colley, A.; Marks, R.; Trent, R. J.: Clinical features
in 27 patients with Angelman syndrome resulting from DNA deletion. J.
Med. Genet. 33: 107-112, 1996.

71. Smith, J. C.; Webb, T.; Pembrey, M. E.; Nichols, M.; Malcolm,
S.: Maternal origin of deletion 15q11-13 in 25/25 cases of Angelman
syndrome. Hum. Genet. 88: 376-378, 1992.

72. Spence, J. E.; Perciaccante, R. G.; Greig, G. M.; Willard, H.
F.; Ledbetter, D. H.; Hejtmancik, J. F.; Pollack, M. S.; O'Brien,
W. E.; Beaudet, A. L.: Uniparental disomy as a mechanism for human
genetic disease. Am. J. Hum. Genet. 42: 217-226, 1988.

73. Tonk, V.; Wyandt, H. E.; Michand, L.; Milunsky, A.: Deletion
of 15q12 in Angelman syndrome: report of 3 new cases. Clin. Genet. 42:
229-233, 1992.

74. Viani, F.; Romeo, A.; Viri, M.; Mastrangelo, M.; Lalatta, F.;
Selicorni, A.; Gobbi, G.; Lanzi, G.; Bettio, D.; Briscioli, V.; Di
Segni, M.; Parini, R.; Terzoli, G.: Seizure and EEG patterns in Angelman's
syndrome. J. Child Neurol. 10: 467-471, 1995.

75. Wagstaff, J.; Knoll, J. H. M.; Glatt, K. A.; Shugart, Y. Y.; Sommer,
A.; Lalande, M.: Maternal but not paternal transmission of 15q11-13-linked
nondeletion Angelman syndrome leads to phenotypic expression. Nature
Genet. 1: 291-294, 1992.

76. Wagstaff, J.; Shugart, Y. Y.; Lalande, M.: Linkage analysis in
familial Angelman syndrome. Am. J. Hum. Genet. 53: 105-112, 1993.

77. Wang, J.-C. C.; Passage, M. B.; Yen, P. H.; Shapiro, L. J.; Mohandas,
T. K.: Uniparental heterodisomy for chromosome 14 in a phenotypically
abnormal familial balanced 13/14 Robertsonian translocation carrier. Am.
J. Hum. Genet. 48: 1069-1074, 1991.

78. Willems, P. J.; Dijkstra, I.; Brouwer, O. F.; Smit, G. P. A.:
Recurrence risk in the Angelman ('happy puppet') syndrome. Am. J.
Med. Genet. 27: 773-780, 1987.

79. Williams, C. A.; Donlon, T. A.; Gray, B. A.; Stone, J. W.; Hendrickson,
J. E.; Cantu, E. S.: Incidence of 15q deletions in the Angelman syndrome:
a survey of 14 affected persons. (Abstract) Am. J. Hum. Genet. 43:
A75, 1988.

80. Williams, C. A.; Frias, J. L.: The Angelman ('happy puppet')
syndrome. Am. J. Med. Genet. 11: 453-460, 1982.

81. Williams, C. A.; Zori, R. T.; Stone, J. W.; Gray, B. A.; Cantu,
E. S.; Ostrer, H.: Maternal origin of 15q11-13 deletions in Angelman
syndrome suggests a role for genomic imprinting. Am. J. Med. Genet. 35:
350-353, 1990.

*FIELD* CS

Facies:
   Peculiar facies;
   Large mandible;
   Open-mouthed expression;
   Tongue thrusting;
   Macrostomia

Neuro:
   Mental retardation;
   Motor retardation;
   Arm flapping with flexed elbows;
   Ataxia;
   Hypotonia;
   Seizures;
   Hyperreflexia;
   Hyperkinesis;
   Absent speech;
   Paroxysmal laughter

Teeth:
   Wide spaced teeth

Eyes:
   Abnormal choroidal pigmentation

Lab:
   Characteristic electroencephalogram (EEG) discharges;
   Mild cortical atrophy on CT or MRI

Head:
   Postnatal microbrachycephaly;
   Flat occiput

Skin:
   Hypopigmentation

Misc:
   Usually low recurrence risk

Inheritance:
   Lack of maternal 15q11-q13 by de novo deletion or uniparental disomy;
   some families autosomal dominant modified by imprinting

*FIELD* CN
Victor A. McKusick - updated: 03/14/1997
Iosif W. Lurie - updated: 7/21/1996
Orest Hurko - updated: 4/3/1996

*FIELD* CD
Victor A. McKusick: 10/9/1992

*FIELD* ED
terry: 03/14/1997
joanna: 2/13/1997
jenny: 1/14/1997
terry: 1/8/1997
carol: 7/22/1996
carol: 7/21/1996
terry: 4/29/1996
mark: 4/27/1996
terry: 4/22/1996
terry: 4/15/1996
mark: 4/3/1996
terry: 3/23/1996
mark: 2/22/1996
terry: 2/20/1996
mark: 8/18/1995
carol: 10/18/1994
davew: 8/17/1994
terry: 7/18/1994
pfoster: 3/24/1994
mimadm: 3/11/1994

*FIELD* MN
The 'happy puppet' syndrome is a condition with features of severe motor
and intellectual retardation, microcephaly, ataxia, frequent jerky limb
movements and flapping of the arms and hands, hypotonia, hyperactivity,
hypopigmentation (39%), seizures, absence of speech, frequent smiling
and episodes of paroxysmal laughter, and an unusual facies characterized
by macrostomia, a large mandible and open-mouthed expression, a great
propensity for protruding the tongue ('tongue thrusting'), and an
occipital groove (Clayton-Smith, 1993) (Buntinx et al., 1995). The
eponym Angelman syndrome is preferred because the term 'happy puppet'
may appear derisive to the patient's family. The diagnosis may be
difficult in the first years of life (Dorries et al., 1988). The
electroencephalogram is useful in the early diagnosis (Boyd et al,

1988).

A visible chromosomal change occurs in half of AS patients (Fryns et
al., 1989). A deletion of band 15q11-q13 may be found both in patients
with Angelman syndrome (Buxton et al., 1994), and with Prader-Willi
syndrome. The origin of the deleted chromosome is maternal in AS and
paternal in PWS. This suggests imprinting, i.e., changes in the
chromosome according to the parent of origin, with resulting
consequences for early development (Williams et al., 1990). The
imprinted gene responsible for the PWS phenotype is proximal to that
responsible for the AS phenotype (Greger et al., 1993). Studies using
DNA markers specific to 15q11-q13 identified three classes of deletions:
in class I, deletion of 2 markers was detected; in class II, deletion of
1 marker; and in class III no deletion was detected (Knoll et al.,
1990). There was complete concordance between the presence of a

cytogenetic deletion and a molecular deletion.

Alternatively, uniparental paternal disomy may occur, with absence of
the maternal 15q. Of the possible mechanisms for uniparental disomy, one
is gamete complementation, i.e., the gamete from one parent containing
both chromosomes of the pair and that from the other parent containing
neither. A second mechanism is so-called trisomy rescue or correction.
It is expected that the remaining pair, after loss of the extra homolog,
will be biparental in two-thirds of cases and uniparental in one-third.
In such instances, as in gamete complementation, isodisomy may or may
not be present. A third mechanism is akin to the second; the abnormal
initial zygotic situation is monosomy rather than trisomy and the
abnormality is 'corrected' through duplication of the single available
homolog (Engel, 1993). Finally, nondeletion AS can result from a genetic
mutation in 15q11-q13, when transmitted by the mother, but not the

father (Wagstaff et al., 1993).

In summary, Angelman syndrome results from a lack of maternal
contribution from chromosome 15q11-q13, arising from de novo deletion in
most cases or from uniparental disomy in rare cases. Most families are
associated with a low recurrence risk. Deletion has almost never been
found in the minority of families with more than one child affected. The
mode of inheritance in these families is autosomal dominant modified by
imprinting. Thus sporadic cases with no observable deletion pose a
counseling dilemma. A diagnostic strategy is proposed by Chan et al.
(1993). On the basis of molecular and cytogenetic findings on 61
patients, Saitoh et al. (1994) found that 70% of sporadic cases had a
molecular deletion, maternal in origin; 1 of 8 familial cases had a
molecular deletion involving only 2 marker loci, which defined the
critical region for the AS phenotype; the 7 remaining familial cases
were presumably mutational. Among sporadic and familial cases without
deletion, no uniparental disomy was found. Of patients with a normal
karyotype, 43% showed a molecular deletion. Familial cases with
submicroscopic deletion were not associated with hypopigmentation,
suggesting that a gene for hypopigmentation is located outside the

critical region of AS and is not imprinted.

Kishino et al. (1997) and Matsuura et al. (1997) demonstrated that
mutation of the gene E6-AP ubiquitin-protein ligase (UEB3A;601623) is

one cause of Angelman syndrome.

*FIELD* ED

jamie: 02/19/1997 joanna: 2/13/1997

*FIELD* CD
F. Clarke Fraser: 7/3/1996

*RECORD*
*FIELD* NO
105835
*FIELD* TI
105835 ANGEL-SHAPED PHALANGOEPIPHYSEAL DYSPLASIA; ASPED
*FIELD* TX
Bachman and Norman (1967) reported the cases of mother and 2 children
with what they referred to as peripheral dysostosis (170700). The
47-year-old mother, 61.5 inches tall, had marked hyperextensibility of
the fingers and precocious osteoarthritis of the hips. A son and
daughter had very flexible fingers and, on x-rays of the hands, delay in
carpal ossification, proximal pseudoepiphyses of metacarpals 2-5,
cone-cup-epiphyses-metaphyses, and widened joint spaces. Other joints
showed extensive changes with widening of joint spaces and irregular
epiphyses. The mother's mother and several relatives on her side also
had hyperextensibility of the fingers and premature osteoarthritis of
the fingers. I had suggested earlier that this was probably the Fairbank
type of multiple epiphyseal dysplasia (see 132400). Giedion et al.
(1993) noted a characteristic change in the middle phalanges which they
called 'angel-shaped phalanx.' The change results from the combined
disturbance of development affecting epiphysis, diaphysis, and
metaphysis and leads to an appearance resembling the little angels used
in the decoration of Christmas trees. The wings are formed by a
diaphyseal cuff, the skirt by a cone-shaped epiphysis, and the head by
the distal pseudoepiphysis. Based on this and another family, as well as
2 isolated patients with similar radiographic and clinical findings,
Giedion et al. (1993) delineated a probable autosomal dominant disorder
which they called angel-shaped phalango-epiphyseal dysplasia, or ASPED.
The angel-shaped phalanges became brachydactyly after closure of the
epiphyses. (As pointed out by Giedion et al. (1993), brachydactyly is
relatively inconspicuous; see their figure 4.) Severe osteoarthritic
changes of the hips (coxarthrosis) developed at an early age.
Hyperextensibility of the interphalangeal joints was present in 7 of
their 9 cases and hypodontia in 4 of 7 patients.

*FIELD* RF
1. Bachman, K.; Norman, A. P.: Hereditary peripheral dysostosis (3
cases). Proc. Roy. Soc. Med. 60: 21-22, 1967.

2. Giedion, A.; Prader, A.; Fliegel, C.; Krasikov, N.; Langer, L.;
Poznanski, A.: Angel-shaped phalango-epiphyseal dysplasia (ASPED):
identification of a new genetic bone marker. Am. J. Med. Genet. 47:
765-771, 1993.

*FIELD* CD
Victor A. McKusick: 11/4/1993

*FIELD* ED
carol: 4/6/1994
carol: 11/5/1993
carol: 11/4/1993

*RECORD*
*FIELD* NO
105850
*FIELD* TI
*105850 ANGIOGENIN; ANG
*FIELD* TX
The cellular and molecular events that result in neovascularization can
be elicited by a variety of tissue-produced mediators. One of these,
angiogenin, an exceedingly potent mediator of new blood vessel
formation, was isolated from growth medium conditioned by human colon
cancer cells. Rybak et al. (1987) demonstrated that angiogenin mRNA is
expressed in a wide spectrum of cells and is not correlated to a
particular cell phenotype. Strydom et al. (1985) determined the complete
amino acid sequence of angiogenin, and Kurachi et al. (1985) determined
the nucleotide sequence of the gene. Weremowicz et al. (1989, 1990)
assigned the human angiogenin gene to chromosome 14q11 by study of
somatic cell hybrids and in situ hybridization. By study of cells
containing a translocation t(11;14), they showed that the angiogenin
gene is proximal to the translocation breakpoint, which is within the
T-cell receptor alpha/delta locus (186880, 186810). Steinhelper and
Field (1992) mapped the Ang gene to mouse chromosome 14 by use of a
PCR-RFLP mapping technique in connection with recombinant inbred
strains.

Angiogenin is a homolog of pancreatic ribonuclease (RNS1; 180440) which,
like angiogenin, is encoded by a gene on chromosome 14. As an initial
step toward investigating the in vivo functional role of angiogenin via
gene disruption, Brown et al. (1995) isolated the Ang gene from mouse
strain 129. Unexpectedly, screening of a genomic library with an Ang
gene probe obtained previously from the BALB/c strain yielded not Ang
itself but 2 new genes closely similar to Ang. One of the genes encodes
a protein with 78% sequence identity to angiogenin and was designated
Angrp for 'angiogenin-related protein.' The ribonucleolytic active site
of angiogenin, which is critical for angiogenic activity, was completely
conserved in Angrp, whereas a second essential site, thought to bind
cellular receptors, was considerably different. Thus, the Angrp product
may have a function distinct from that of angiogenin. The second gene
was a pseudogene that contained a frameshift mutation in the early part
of the coding region. Although the Ang gene was not isolated from the
BALB/c library, it was possible to amplify this gene from a strain 129
mouse genomic DNA by PCR. Sequence analysis showed that the strain 129
Ang gene is identical to the BALB/c gene throughout the coding region.

*FIELD* RF
1. Brown, W. E.; Nobile, V.; Subramanian, V.; Shapiro, R.: The mouse
angiogenin gene family: structures of an angiogenin-related protein
gene and two pseudogenes. Genomics 29: 200-206, 1995.

2. Kurachi, K.; Davie, E. W.; Strydom, D. J.; Riordan, J. F.; Vallee,
B. L.: Sequence of the cDNA and gene for angiogenin, a human angiogenesis
factor. Biochemistry 24: 5495-5499, 1985.

3. Rybak, S. M.; Fett, J. W.; Yao, Q.-Z.; Vallee, B. L.: Angiogenin
mRNA in human tumor and normal cells. Biochem. Biophys. Res. Commun. 146:
1240-1248, 1987.

4. Steinhelper, M. E.; Field, L. J.: Assignment of the angiogenin
gene to mouse chromosome 14 using a rapid PCR-RFLP mapping technique.
Genomics 12: 177-179, 1992.

5. Strydom, D. J.; Fett, J. W.; Lobb, R. R.; Alderman, E. M.; Bethune,
J. L.; Riordan, J. F.; Vallee, B. L.: Amino acid sequence of human
tumor derived angiogenin. Biochemistry 24: 5486-5495, 1985.

6. Weremowicz, S.; Fox, E. A.; Morton, C. C.: Assignment of human
angiogenin gene to chromosome 14q11-q13.  (Abstract) Cytogenet. Cell
Genet. 51: 1107 only, 1989.

7. Weremowicz, S.; Fox, E. A.; Morton, C. C.; Vallee, B. L.: Localization
of the human angiogenin gene to chromosome band 14q11, proximal to
the T cell receptor alpha/delta locus. Am. J. Hum. Genet. 47: 973-981,
1990.

*FIELD* CD
Victor A. McKusick: 4/25/1988

*FIELD* ED
mark: 10/3/1995
supermim: 3/16/1992
carol: 1/6/1992
carol: 11/6/1991
carol: 2/11/1991
carol: 12/19/1990

*RECORD*
*FIELD* NO
106050
*FIELD* TI
106050 ANGIOMA SERPIGINOSUM
*FIELD* TX
This uncommon dermatosis was first described by Jonathan Hutchinson
(1889) in Plate IX of Vol. 1 of his Archives of Surgery. More common in
females, the condition begins before puberty as pin-sized capillary
puncta affecting any part of the body surface except the palms and soles
and sparing also mucous membranes. Marriott et al. (1975) reported 2
kindreds with several affected individuals, consistent with dominant
inheritance and reduced penetrance; no male-to-male transmission was
observed.

*FIELD* RF
1. Hutchinson, J.: . Arch. Surg. 1: 1889. Note: Plate IX.

2. Marriott, P. J.; Munro, D. D.; Ryan, T.: Angioma serpiginosum--familial
incidence. Brit. J. Derm. 93: 701-706, 1975.

*FIELD* CS

Skin:
   Pin-sized capillary puncta

Misc:
   More common in females;
   Palms, soles and mucous membranes spared

Inheritance:
   Autosomal dominant with reduced penetrance

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
pfoster: 9/7/1994
davew: 7/21/1994
mimadm: 3/28/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
106070
*FIELD* TI
*106070 ANGIOMA, HEREDITARY NEUROCUTANEOUS
SPINAL ARTERIAL VENOUS MALFORMATIONS WITH CUTANEOUS HEMANGIOMAS, INCLUDED;;
HEMANGIOMATOSIS, DISSEMINATED, INCLUDED
*FIELD* TX
Zaremba et al. (1979) reported 4 affected persons in 3 generations,
including a father and his 2 sons. One patient died at age 28 of
multiple dilated thin-walled vessels in the cerebral substance; an
extensive, irregularly shaped, pink hemangioma planum, which faded on
pressure, was present on the skin of the left shoulder, arm and forearm.
His brother developed left hemiparesis at age 13 and died at age 19
after an unsuccessful attempt was made to resect a spinal angioma in the
C6-T1 region (producing the Horner syndrome and the Brown-Sequard
syndrome). He had an angioma in the left frontotemporal area and a
second over the right mastoid process. Their father developed left
hemiparesis at age 58 and had episodes of urinary and gastrointestinal
bleeding. Angiomas were present on the chest and left thigh. A daughter
of the oldest of his sons (who died at age 28) had 3 angiomas in the
lumbosacral area and 1 on the left palm. None of the patients had
retinal angiomas or telangiectases typical of Osler-Rendu-Weber
syndrome. The involvement of the central nervous system resembled that
in the Icelandic family reported by Kidd and Cumings (1947) but that
family had no skin angiomas. Burke et al. (1964) described 2 unrelated
infants with a large number of small hemangiomata in many areas of the
skin and also in the brain. Kaplan et al. (1976) described a
16-month-old girl with cutaneomeningospinal angiomatosis leading to
paraplegia because of intraspinal AV malformation. Skin hemangiomas
occurred in 3 generations of the family (with no instance of
male-to-male transmission). Hemangioma of the skin in the same dermatome
as the symptoms of a space-occupying spinal lesion can be a clue to
early diagnosis of the nature of the latter. Foo et al. (1980) reported
the case of a 33-year-old man who developed cervical anterior cord
syndrome from spontaneous bleeding of an arteriovenous malformation in
the cervical epidural space. Follow-up (Foo et al., 1980) revealed
cutaneous vascular malformations in 3 generations. The proband's mother
had 4 hemangiomas removed (from the neck, back, right thigh and face). A
maternal aunt had a left ankle hemangioma removed at age 20. One of his
younger sisters had a hemangioma resected from the right shoulder at age
15 and another from the pelvis at 31. This sister passed the gene to her
2 sons; one son had a hemangioma removed from the forehead at age 2, and
the other had a hemangioma removed from the left side of the head at age
3. The proband's brother had a hemangioma removed from above the right
ear at age 10. Hurst and Baraitser (1988) reported 2 families with this
disorder. In 1 family there was father-to-son transmission; the father
had cutaneous hemangiomata of the nose, arm, and trunk, and the son had
a temporal lobe arteriovenous malformation. Four generations and 5
individuals were affected in the other family. Although the evidence is
not ironclad, this syndrome of hereditary neurocutaneous angioma is
probably distinct from familial cavernous malformations of the CNS and
retina (116860).

*FIELD* SA
Foo et al. (1980)
*FIELD* RF
1. Burke, E. C.; Winkelmann, R. K.; Strickland, M. K.: Disseminated
hemangiomatosis: the newborn with central nervous system involvement.
Am. J. Dis. Child. 108: 418-424, 1964.

2. Foo, D.; Chang, Y. C.; Rossier, A. B.: Spontaneous cervical epidural
hemorrhage, anterior cord syndrome, and familial vascular malformation:
case report. Neurology 30: 308-311, 1980.

3. Foo, D.; Chang, Y. C.; Rossier, A. B.: Spontaneous cervical epidural
hemorrhage, anterior cord syndrome, and familial vascular malformation.
(Letter) Neurology 30: 1253-1254, 1980.

4. Hurst, J.; Baraitser, M.: Hereditary neurocutaneous angiomatous
malformations: autosomal dominant inheritance in two families. Clin.
Genet. 33: 44-48, 1988.

5. Kaplan, P.; Hollenberg, R. D.; Fraser, F. C.: A spinal arteriovenous
malformation with hereditary cutaneous hemangiomas. Am. J. Dis.
Child. 130: 1329-1331, 1976.

6. Kidd, H. A.; Cumings, J. N.: Cerebral angiomata in an Icelandic
family. Lancet I: 747-748, 1947.

7. Zaremba, J.; Stepien, M.; Jelowicka, M.; Ostrowska, D.: Hereditary
neurocutaneous angioma: a new genetic entity?. J. Med. Genet. 16:
443-447, 1979.

*FIELD* CS

Neuro:
   Multiple dilated thin-walled cerebral vessels;
   Spinal angioma;
   Horner syndrome;
   Hemiparesis

Skin:
   Large irregular flat hemangiomas

GU:
   Episodic hematuria

GI:
   Gastrointestinal bleeding

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/30/1988
marie: 3/25/1988

*RECORD*
*FIELD* NO
106100
*FIELD* TI
*106100 ANGIONEUROTIC EDEMA, HEREDITARY; HANE
ANGIOEDEMA, HEREDITARY; HAE
COMPLEMENT COMPONENT 1 INHIBITOR; C1NH, INCLUDED;;
C1 ESTERASE INHIBITOR, DEFICIENCY OF; C1I, INCLUDED
*FIELD* MN
Hereditary angioneurotic edema (HANE) is an autosomal dominant disorder
characterized by episodic local subcutaneous edema and submucosal edema
involving the upper respiratory and gastrointestinal tracts. It is
caused by deficiency of activated C1 esterase inhibitor (C1NH). Edema of
the larynx and other portions of the airways is the most fearsome
feature of this disorder. Trauma, as in attempted tracheal intubation,
can precipitate or aggravate such edema. Visceral involvement with
abdominal pain can lead to unnecessary laparotomy. Recurrent abdominal
pain, nausea, diarrhea, and vomiting may (rarely) be the only
manifestation (Weinstock et al., 1987). Polycystic ovaries (PCO
syndrome; 184700) or multifollicular ovaries occur with unusually high
frequency in women with HANE (Perricone et al., 1992).

A low level of C4 (120810, 120820) and normal levels of C1 (120550) are
characteristic of HANE. The low levels of C4 are responsible for the
impressively increased frequency of SLE (152700), glomerulonephritis,
and vasculitis in patients with HANE (Muhlemann et al., 1987). The basis
for the edema is not entirely clear.

From immunofluorescence studies, Johnson et al. (1971) concluded that
defective hepatic synthesis of C1 inhibitor causes the deficiency of
plasma inhibitor.

Three types of C1 esterase inhibitor were described by Rosen et al.
(1971) in different families with angioneurotic edema. Immunologically,
one group had levels of inhibitor (an alpha-2 neuraminoglycoprotein)
17.5% of normal (type I), a second group had levels 111% of normal (type
II), and a third group represented by a single kindred had levels more
than 400% of normal. Although immunologically identical, the 3 types of
(functionally deficient) inhibitor differed in electrophoretic and other
characteristics from the normal and from each other.

C1 inhibitor is a highly glycosylated serum protein, synthesized in the
liver. It regulates the first component of complement (C1) by inhibition
of the proteolytic activity of its subcomponents C1r and C1s. This
prevents activation of C4 and C2 by C1s. The synthesis of half-normal
levels of C1 inhibitor in the type I heterozygotes permits the
activation of C1, which in its activated form complexes with the
inhibitor. The level of inhibitor in the circulation assumes a new
equilibrium level of 10 to 20% of normal (Cicardi et al., 1982).

The human C1 inhibitor gene has been localized to chromosome 11q11-q13.1
(Theriault et al., 1990).

Many kindreds with angioneurotic edema transmitted in a typical
autosomal dominant pattern have been described (Rosen et al., 1965).
(See cold hypersensitivity (120100) for related condition.) Probably
each family with type I hereditary angioedema carries a unique variant
of the C1 inhibitor gene, which, once identified, lends itself to
prenatal or early diagnosis of the disease (Stoppa-Lyonnet et al.,
1987). Patients with HANE type I appear to have a deletion of the C1
inhibitor gene or a truncated transcript because of a stop codon,
whereas patients with HANE type II have a single base substitution.

There appear to be multiple levels of control of C1-INH synthesis in
type I HANE. Pretranslational regulation results in less than 50% of the
mutant truncated 1.9-kb mRNA; translational regulation results in
decreased synthesis of both wildtype and mutant proteins (Kramer et al.,
1993).

Apparently effective prophylaxis with testosterone has been described
(Dennehy, 1970), and epsilon aminocaproic acid is efficacious in
treatment (Frank et al., 1972). The therapeutic benefit of Danazol, an
'impeded' androgen, is of interest from the point of view of the basic
defect in this disorder (Gelfand et al., 1976). The reason impeded
androgen is effective in all cases is that it works on the normal allele
to stimulate increased levels of C1 inhibitor. Concentrates of C1
inhibitor are found effective and without side effects in the treatment
of severe acute attacks (Cicardi et al., 1982). Androgen derivatives are
useful for longterm prophylaxis. It is suggested that prophylaxis
against attacks should not be used during pregnancy because of its
potential taratogenicity and that severe attacks should be treated with
purified C1-INH concentrate (Chappatte and De Swiet, 1988). For a
comprehensive review of clinical features and therapy of HANE, see
Winkelstein and Colten (1989). See Cox and Holdcroft (1995) for a
discussion of management during pregnancy and delivery.

*FIELD* ED
jenny: 02/04/1997 jamie: 1/6/1997

*FIELD* TX

DESCRIPTION

Hereditary angioneurotic edema (HANE) is an autosomal dominant disorder
characterized by episodic local subcutaneous edema and submucosal edema
involving the upper respiratory and gastrointestinal tracts. It is
caused by deficiency of activated C1 esterase inhibitor (C1NH).

CLINICAL FEATURES

Edema of the larynx and other portions of the airways is the most
fearsome feature of this disorder. Trauma, as in attempted tracheal
intubation, can precipitate or aggravate such edema. Visceral
involvement with abdominal pain can lead to unnecessary laparotomy. In
type I, representing 85% of patients, serum levels of C1NH are 5 to 30%
of normal. In type II, the levels are normal or elevated. The two types
are clinically indistinguishable.

Muhlemann et al. (1987) found an increased frequency of thyroglobulin
antibodies and thyroid microsomal antibodies in patients with hereditary
angioedema. They reported the occurrence of systemic lupus erythematosus
and glomerulonephritis in patients with this disorder.

Fearon (1987) discussed the lower than expected levels of C1NH as well
as the effectiveness of impeded androgen in therapy of this disorder.
Laurent et al. (1988) showed that sonographic demonstration of fluid in
the abdomen in association with an attack of abdominal pain could be
used in diagnosis. A low level of C4 (120810, 120820) and normal levels
of C1 (120550) are characteristic of HANE. The low levels of C4 are
responsible for the impressively increased frequency of SLE (152700),
glomerulonephritis, and vasculitis in patients with HANE. All of these
disorders are frequent in persons homozygous for primary C4 deficiency.

Weinstock et al. (1987) described a family in which lifelong abdominal
pain was the only manifestation of hereditary angioedema. A 40-year-old
man, 2 of his brothers, his mother, and his daughter were affected. In
addition to abdominal pain, nausea, diarrhea and vomiting occurred, but
there were no cutaneous, oropharyngeal, or respiratory manifestations.
Barium studies during painful attacks showed transient intestinal wall
edema.

Angioedema due to acquired C1-inhibitor deficiency has always been
associated with benign or malignant B-cell lymphoproliferative disorders
such as chronic lymphatic leukemia, multiple myeloma, or essential
cryoglobulinemia (Gelfand et al., 1979) and is due not to defective
synthesis but to markedly increased catabolism of the C1-inhibitor
protein (C1I).

Perricone et al. (1992)concluded that polycystic ovaries (PCO syndrome;
184700) or multifollicular ovaries occur with unusually high frequency
in women with HANE. Weidenbach et al. (1993) reported a 25-year-old
woman, with no family history of the disorder, in whom infectious
mononucleosis appeared to precipitate the acute onset of HAE.

Jackson et al. (1986), Alsenz et al. (1987), and Malbran et al. (1988)
described patients with acquired C1-inhibitor deficiency resulting from
anti-C1-inhibitor autoantibodies. These patients had no evidence of an
underlying disease, followed a benign course, and showed variable
responses to therapy. Frigas (1989) described a patient with acquired
C1-inhibitor deficiency who had no evidence of underlying disease 11
years after onset. A second patient had angioedema associated with a
B-cell lymphoproliferative disorder that became evident 9 months after
C1-INH deficiency was diagnosed.

BIOCHEMICAL FEATURES

Three types of C1 esterase inhibitor were described by Rosen et al.
(1971) in different families with angioneurotic edema. Immunologically,
one group had levels of inhibitor (an alpha-2 neuraminoglycoprotein)
17.5% of normal, a second group had levels 111% of normal, and a third
group represented by affected persons in a single kindred had levels
more than 400% of normal. Although immunologically identical, the three
types of inhibitor differed in electrophoretic and other characteristics
from the normal and from each other.

From immunofluorescence studies, Johnson et al. (1971) concluded that
deficient hepatic synthesis of C1 inhibitor is the basis of the
deficiency in plasma inhibitor.

Cicardi et al. (1982) reported on 104 cases in 31 families. In 22%,
functionally defective C1 esterase inhibitor was present. In 78%, both
antigen levels and functional activity of C1 esterase inhibitor were
low. Quastel et al. (1983) studied the catabolism of C1-inhibitor in
HANE I. The fact that serum concentrations of a structurally normal
C1-inhibitor is 5 to 31% of normal rather than the 50% expected in
heterozygotes is explained, the authors suggested, by the presence of
only one functional gene and increased catabolism of the protein,
perhaps related to activation of C1 or other proteases.

Functional levels of the inhibitor in the serum of type I patients range
from 5 to 30% of normal rather than the expected 50% for the
heterozygous state. This was interpreted by Quastel et al. (1983), on
the basis of in vivo turnover studies, as indicating that at half-normal
concentration of the inhibitor, there is activation of C1 and/or other
enzyme systems in which this protein acts as an inhibitor. This, in
turn, could lead to consumption of normal C1 inhibitor that falls below
normal. Although the hepatocyte is the main site of synthesis of the
inhibitor, cultured human peripheral blood monocytes also synthesize and
secrete this protein. Cicardi et al. (1987) found that in the
supernatant of such cells, the inhibitor was present at levels of about
20% of normal, whereas intracellular reduction approached 50%. The
Northern blot analysis showed inhibitor mRNA to be present at about
half-normal concentrations. One of the patients showed a genetically
abnormal mRNA (1.9 kb) in addition to the normal mRNA (2.1 kb).

With 35% carbohydrate by weight, C1 inhibitor is the most highly
glycosylated serum protein. It is synthesized in the liver as a single
amino acid chain. It regulates the first component of complement (C1) by
inhibition of the proteolytic activity of its subcomponents C1r and C1s.
This prevents activation of C4 and C2 by C1s. C1I also inhibits several
other serine proteinases including plasmin, kallikrein, and coagulation
factors XIa and XIIa (Davis et al., 1986).

The synthesis of half-normal levels of C1 inhibitor in the heterozygotes
permits the activation of C1, which in its activated form complexes with
the inhibitor. The level of inhibitor in the circulation assumes a new
equilibrium level of 10 to 20% of normal. The reason impeded androgen is
effective in all cases is that it is working on the normal allele to
stimulate increased synthesis of C1 inhibitor.

Bock et al. (1986) determined that the single chain moiety of
C1-inhibitor has 478 residues accounting for little more than half the
molecular weight of the molecule. It is heavily glycosylated. Comparison
of the amino acid and cDNA sequences showed that secretion is mediated
by a 22-residue signal peptide and that further proteolytic processing
does not occur.

INHERITANCE

A considerable number of kindreds with angioneurotic edema transmitted
in a typical autosomal dominant pattern have been described. In the
family studied by Trigg (1961) about twice as many males as females were
affected. It is curious that this 'deficiency' is expressed in the
heterozygote. A family studied by Donaldson and Rosen (1964) had
previously been reported by Heiner and Blitzer (1957). Cohen (1961)
described a family with many cases in 5 generations. Although reported
as giant urticaria, the same family was studied by Rosen et al. (1965)
and shown to have a defect in a component of complement. (See cold
hypersensitivity (120100) for related condition.) Episodic angioedema
with eosinophilia (Gleich et al., 1984) is a distinct disorder which is
not mendelian; in addition to angioedema, urticaria, which is not a
feature of HANE, occurs.

MAPPING

Robson et al. (1979) demonstrated that HANE is not linked to HLA or PGM1
on chromosome 6 and not linked to C6, which had not been assigned.
Linkage to markers on 1p (Rh), 4q (MNSs), 9q (ABO), 16q (Hp), and 7 (Km)
was also excluded. Furthermore, HANE was not linked to Gm. Linkage to
HLA was excluded by Eggert et al. (1982). In family linkage studies,
Olaisen et al. (1985) obtained 'a clear hint' that the HANE locus may be
distal to F13A (134570) on 6p. The maximum lod score with F13A was 1.0
at a recombination fraction of 10%. By study of hybrids between human
fetal liver and rat hepatoma cells, Cox and Francke (1985) concluded
that the C1 esterase inhibitor gene is on chromosome 4, 8, 12, 20, or
21.

Bock et al. (1986) assigned the gene to 11p11.2-q13 by Southern blot
analysis of DNA of mouse-human hybrid cells, some containing chromosomal
rearrangements. In 4 HANE kindreds, no obvious deletions or
rearrangements of the C1-inhibitor locus were found. RFLPs useful in
linkage studies were defined. By means of a cDNA probe in somatic cell
hybrids, Cohen-Haguenauer et al. (1986) confirmed the assignment to
chromosome 11. Theriault et al. (1989, 1990) used in situ hybridization
to obtain a more precise localization of the human C1 inhibitor gene to
chromosome 11q11-q13.1.

Davis et al. (1986) demonstrated that the C1I gene is on chromosome 11,
by using the cDNA clone to study hybrid cells.

MOLECULAR GENETICS

Stoppa-Lyonnet et al. (1987) studied DNA from multiple members of 2
families with hereditary angioedema and from 6 unrelated patients. Using
a cDNA probe, they identified in the larger of the 2 families a cluster
of 4 distinctive restriction sites. The strict cosegregation of these
markers with a low C1 inhibitor level indicated that a defective
structural gene was responsible for the disease. In this family they
found alterations in the 5-prime half of the C1 inhibitor gene. In 2
other instances, structural changes appeared to reside in that part of
the gene. They concluded that probably each family with type I
hereditary angioedema carries a unique variant of the C1 inhibitor gene,
which, once identified, lends itself to prenatal or early diagnosis of
the disease. In 1 subject in family 1, the C1 inhibitor level determined
at birth in cord blood was inconclusive. Later the measurement showed a
level in agreement with the diagnosis predicted by DNA analysis.
Patients with HANE type I appear to have a deletion of the C1 inhibitor
gene or a truncated transcript because of a stop codon, whereas patients
with HANE type II have a single base substitution. The two forms are
clinically indistinguishable. In contrast, Cicardi et al. (1987)
concluded from Northern and Southern blot analyses that the defect (or
defects) in type I HANE is pretranslational but is not due to a deletion
or to a major chromosomal rearrangement.

Shokeir (1973) suggested that the mutation is in a repressor which fails
to bind an inducer so that the operator site remains repressed. He
suggested that the repressor molecule has a very high affinity for the
operator site so that the amount of unbound repressor present in the
heterozygote suffices for repression of both operators. Shokeir (1973)
encountered greater difficulty in explaining the 'genetic variant' form
of angioedema. He presented the possibility that these persons are
heterozygous for an enzyme which attaches an auxiliary group to the
molecule (e.g., neuraminic acid), thereby altering its biologic but not
its immunologic properties. If true, this hypothesis points to the
existence of at least two loci at which mutation can lead to angioedema.

C1 inhibitor is a member of a large serine protease inhibitor (serpin)
gene family. Davis et al. (1986) characterized a cDNA clone that
represents about half the coding sequence of the protein. In the region
sequenced, C1I showed about 22% identity with antithrombin III (107300),
26% with alpha-1-antitrypsin (107400) and alpha-1-antichymotrypsin
(107280), and 18% with angiotensinogen.

Cicardi et al. (1987) found RFLPs in only 2 of 24 type I families and in
1 of 5 type II families. They interpreted these findings as indicating
that most of the mutations are point mutations or other 'minor' defects
and not major deletions or rearrangements. In 2 families with C1
inhibitor deficiency, Ariga et al. (1990) found that deletions were the
consequence of recombination of 2 Alu repetitive DNA elements. In 1
family with a deletion measuring approximately 2 kb and including exon
7, Alu repeat sequences from introns 6 and 7 combined to make a novel
Alu; in a second family, Alu sequences in introns 3 and 6 were spliced
to make a new Alu with a resulting deletion measuring approximately 8.5
kb and including exons 4-6. Unequal crossingover seemed the likely
mechanism of these mutations.

Using 38 restriction enzymes, McPhaden et al. (1991) found a different
unique disease-related RFLP in 1 allele of the C1NH gene in 4 of 12
kindreds with HANE. The 4 mutations affected exons 4, 6, 7, and 8;
mutations in exons 6 and 8 had not previously been described. The C1NH
gene contains unusually dense clusters of Alu repeats in various
orientations. Among patients belonging to 45 unrelated families,
Stoppa-Lyonnet et al. (1991) found 8 partial C1NH gene deletions and a
partial duplication. Four deletions had one of the boundaries within the
gene and the other in extragenic regions--in 3 cases 5-prime of the gene
and in 1 case 3-prime of the gene. The boundaries of the partial
duplication and of the remaining 4 deletions mapped instead within a few
kilobases of exon 4. In each of these 5 rearrangements, one of the
breakpoints was in Alu 1, the first of 3 tandem Alu repeats preceding
exon 4. Moreover, these recombination breakpoints were spread over the
entire length of Alu 1, in contrast with the tight clustering observed
near the 5-prime end of Alu sequences rearranged in other human genes.
Stoppa-Lyonnet et al. (1991) suggested that a region of potential Z-DNA
structure, located 1.7 kb upstream of Alu 1, may contribute to these
peculiarities.

To ascertain the mechanism for decreased synthesis of C1 inhibitor in
certain patients with type I HANE, Kramer et al. (1993) studied
expression of C1-INH in fibroblasts in which the mutant and wildtype
mRNA and protein could be distinguished because of deletion of exon 7
(106100.0001). In the mutant cells, the amount of wildtype mRNA was
expressed at 52% of normal, whereas the mutant mRNA was 27% of normal.
Rates of synthesis of both wildtype and mutant proteins were lower than
predicted from the mRNA levels. There was no evidence of increased
C1-INH protein catabolism. Thus, there appear to be multiple levels of
control of C1-INH synthesis in type I HANE. Pretranslational regulation
results in less than 50% of the mutant truncated 1.9-kb mRNA;
translational regulation results in decreased synthesis of both wildtype
and mutant proteins. These data suggested a transinhibition of wildtype
C1-INH translation by mutant mRNA and/or protein.

CLINICAL MANAGEMENT

Spaulding (1960) and Dennehy (1970) described apparently effective
prophylaxis with testosterone, and Frank et al. (1972) reported that
epsilon aminocaproic acid is efficacious in treatment. The therapeutic
benefit of Danazol, an 'impeded' androgen, is of interest from the point
of view of the basic defect in this disorder (Gelfand et al., 1976;
Fearon, 1987). Danazol also raises the levels of the deficient protein
in alpha-1-antitrypsin deficiency (Gadek et al., 1980) and in
hemophilias A and B (Gralnick and Rick, 1983). Cicardi et al. (1982)
found concentrates of C1 inhibitor to be effective and without side
effects in the treatment of severe acute attacks. Androgen derivatives
were useful for longterm prophylaxis.

Chappatte and De Swiet (1988) gave an account of pregnancy in 2 patients
with HANE. They suggested that prophylaxis against attacks should not be
used during pregnancy and that severe attacks should be treated with
purified C1-INH concentrate.

For a comprehensive review of clinical features and therapy of HANE, see
Winkelstein and Colten (1989). Cox and Holdcroft (1995) discussed the
management of pregnancy and delivery in a 20-year-old primiparous woman
with a history of type I HAE first diagnosed at age 12. She had been
treated with an attenuated androgen in low dose (danazol and then
amicar), which raised her C1 esterase inhibitor level and controlled her
symptoms. Danazol rendered the patient oligomenorrheic. Since it is also
teratogenic (Duck and Katayama, 1981), it was withdrawn under hospital
observation when she decided to start a family. The recurrent symptoms
were controlled with intravenous administration of C1 esterase
inhibitor. Vaginal delivery in HAE may be impeded by perineal edema and
abdominal pain may obscure obstetric disorders. In this case, successful
spontaneous vaginal delivery was achieved using prophylactic C1 esterase
inhibitor and epidural analgesia.

Waytes et al. (1996) concluded that infusions of vapor-heated C1
inhibitor concentrate are a safe and effective means of both preventing
attacks of hereditary angioedema and treating acute attacks. The
concentrate was vapor-heated to inactivate hepatitis and human
immunodeficiency viruses. In an accompanying editorial, Cicardi and
Agostoni (1996) viewed the pathophysiology of hereditary angioedema with
an instructive diagram. Agostoni and Cicardi (1992) pointed out that in
more than 20% of those with hereditary angioedema, the mutations are de
novo and therefore there is no family history of the disease. In rare
patients the deficiency is acquired, with symptoms first emerging well
into adulthood.

HISTORY

Quincke (1882) first described (and named) angioneurotic edema. Osler
(1888), while in Philadelphia, was first to describe the hereditary
form.

Dennehy (1970) called attention to the fact that Nathaniel Hawthorne was
apparently familiar with this disorder for in his 'House of the Seven
Gables' he described a family with members who gurgled in the throat and
chest when excited and who would sometimes die this way, ever since a
curse to choke on blood had been placed on 1 of their ancestors. Dennehy
(1970) interpreted the following passage as an indication that Hawthorne
recognized that a hereditary disease, not a curse, was responsible for
the deaths: 'This mode of death has been an idiosyncrasy with his
family, for generations past....Old Maule's prophecy was probably
founded on a knowledge of this physical predisposition in the Pyncheon
race.'

Six years before Quincke (1882) introduced the term angioneurotic edema,
Milton (1876) described 1 of his patients with angioedema in the
following words: 'So soon as ever she came into the room I recognized
the affection, for there lay, across the face from temple to temple, an
oblong tumor almost closing both eyes.'

*FIELD* AV
.0001
ANGIOEDEMA, HEREDITARY, TYPE I
C1NH, EX7DEL
In a patient with type I HANE, Ariga et al. (1989) found 2 classes of
mRNA, one abnormally short and one normal. Restriction analysis
suggested that exon 7 and portions of both flanking introns were deleted
in the mutant gene. This was confirmed by further studies involving PCR
amplification. Deletions in either exon 4 or exon 7 have been identified
in some type I kindreds (Cicardi et al., 1987; Stoppa-Lyonnet et al.,
1987; Ariga et al., 1989).

.0002
ANGIOEDEMA, HEREDITARY, TYPE II
C1NH, ALA436THR
In 2 unrelated families, Levy et al. (1990) demonstrated a G-to-A change
in codon 436 resulting in replacement of alanine with a threonine
residue. This position is 9 amino acid residues amino-terminal to the
reactive-center arginylthreonine peptide bond. Previously defined
mutations in type II HANE resulted in replacement of the reactive-center
arginine. Davis et al. (1992) showed that the dysfunction demonstrated
by this mutation results from a block in the interaction with target
protease.

.0003
ANGIOEDEMA, HEREDITARY, TYPE II
C1NH, ARG444HIS
This and the arg444-to-cys mutation occur in the reactive center and
represent a change in the arginine codon (CGC) to either TGC (cysteine)
or CAC (histidine). These presumably result from deamination of
5-methylcytosine to thymidine within the CpG dinucleotide in either the
coding or the noncoding strand. See Aulak et al. (1988).

.0004
ANGIOEDEMA, HEREDITARY, TYPE II
C1NH, ARG444CYS
See Skriver et al. (1989).

.0005
ANGIOEDEMA, HEREDITARY, TYPE II
C1NH, ARG444SER
Aulak et al. (1990) identified a CGC-to-AGC mutation in codon 444 in a
case of type II hereditary angioedema. The mutation is in the
reactive-center P1 residue. The arginine codon CGC can give rise to 6
possible products: pro, gly, leu, ser, his, and cys. Previously observed
mutations have been restricted either to histidine or to cysteine. This
limited mutational variability may be explained by the hypermutability
of the CpG dinucleotide, generating CpA (hence CAC, histidine) or TpG
(hence TGC, cysteine) dinucleotides.

.0006
ANGIOEDEMA, HEREDITARY, TYPE I
C1NH, 1-BP INS, A INS, NT1304, FS, TER
In affected members of 2 unrelated families with type I hereditary
angioedema accompanied by elevated levels of C1NH mRNA, Frangi et al.
(1991) found normal and mutant transcripts. Single base mutations near
the 3-prime end of the coding sequence were identified in affected
members of each family. One mutation consisted of insertion of an
adenosine at position 1304 which created a premature termination codon
(TAA), whereas the second consisted of deletion of thymidine-1298 which
created a premature termination codon (TGA) 23 nucleotides downstream
(106100.0007). These mutations were located approximately 250
nucleotides upstream of the natural termination codon. The elevation in
the levels of the mutant transcript was ascribed to decreased
catabolism.

.0007
ANGIOEDEMA, HEREDITARY, TYPE I
C1NH, 1-BP DEL, T1298 DEL
See 106100.0006.

.0008
ANGIOEDEMA, HEREDITARY, TYPE I
C1NH, IVS6DS, G-T, +1
In a family with type I hereditary angioedema, Siddique et al. (1991)
identified a single base substitution (G-to-T) at nucleotide 8863. The
mutation destroyed the 5-prime donor splice site recognition motif of
the sixth intron.

.0009
ANGIOEDEMA, HEREDITARY, TYPE I
C1NH, 1-BP DEL, C11698 DEL, FS, TER
Siddique et al. (1992) found deletion of a single base, C11698, from the
eighth exon of the C1NH gene. The mutation altered the reading frame and
generated a premature translation termination codon.

.0010
ANGIOEDEMA, HEREDITARY, TYPE II
C1NH, VAL432GLU
In a patient heterozygous for a mutant dysfunctional C1 inhibitor
protein, Davis et al. (1992) identified a 'hinge' region mutation in C1
inhibitor: an A to T substitution at position 1396 producing a
val-to-glu replacement at residue 432. Recombinant C1 inhibitor with the
val432-to-glu mutation did not form stable complexes with fluid phase
C1s or kallikrein. The val432-to-glu mutant form was cleaved to a 96-K
form by C1s. Thus the mutation results in dysfunction, converting the
inhibitor to a substrate. Davis et al. (1992) demonstrated that this
mutation and the ala436-to-thr mutation (106100.0002) result in
dysfunction by different mechanisms.

.0011
ANGIOEDEMA, HEREDITARY, TYPE II
C1NH, 3-BP INS, TGT, NT16749
In a 47-year-old male with type II HANE, Siddique et al. (1993) used PCR
and nucleotide sequence analysis to characterize a 3-nucleotide (TGT)
insertion between nucleotides 16749 and 16750 in exon 8 of the C1NH
gene. The insertion caused a change at amino acid 431 from polar glycine
to nonpolar valine as well as the insertion of an additional tryptophan
residue. This was the first report of a nucleotide insertion in the C1NH
gene causing type II HANE.

.0012
COMPLEMENT COMPONENT-4, PARTIAL DEFICIENCY OF, DUE TO DYSFUNCTIONAL
C1 INHIBITOR
C1NH, ALA443VAL
Zahedi et al. (1995) demonstrated an ala443-to-val mutation in the C1NH
gene, resulting in a dysfunctional C1 inhibitor, in 11 members of a
5-family kindred spanning 3 generations. The pattern of inheritance was
autosomal dominant, and there was no HLA linkage. The proband had
systemic lupus erythematosus, but no member had had angioedema. Serum C4
levels in affected members were less than 10 mg/dl (less than 33% of
pooled normal human serum) and did not fluctuate. Serum C2 levels
measured by hemolytic titration had always been normal. A mutant C1
inhibitor containing the ala443-to-val mutation, constructed by
site-directed mutagenesis and expressed in COS-1 cells, failed to
complex completely with C1r and showed impaired complexing with C1s. The
mutant inhibitor also formed a complex with trypsin, a serine protease
that normally cleaves, and is not inhibited by, C1 inhibitor. The
ala443-to-val mutation therefore converts C1 inhibitor from a substrate
to an inhibitor of trypsin.

.0013
ANGIOEDEMA, HEREDITARY, AUTOSOMAL RECESSIVE
C1NH, C-T, -103
In 36 unrelated angioedema patients, Verpy et al. (1996) performed a
complete mutational scan of the C1NH gene, compromising all 8 exons and
adjacent intron sequences and the 550 bp preceding the transcription
start site, by using fluorescence-assisted mismatched analysis (FAMA).
Mutations accounting for C1 inhibitor deficiency were identified in 34
patients; the 2 failures turned out to be spurious cases resulting from
the development of antibodies against the C1 inhibitor (in one case, an
acquired form of the disorder). Homozygosity for a promoter mutation, a
C-to-T transition at position -103, was found in 2 members of a family.
The mutation occurred in a putative CAAT box and was the first promoter
mutation reported in the C1NH gene. In this family homozygosity
correlated with low C1 inhibitor levels and severe HAE. In contrast,
heterozygous individuals had C1 inhibitor levels within the normal
range, although often at its lower level, and were free of angioedema
attacks. No other idiomorphic nucleotide change was found in this
kindred to account for the angioedema.

*FIELD* SA
Alper  (1978); Austen and Sheaffer (1965); Blumenthal et al. (1978);
Bock et al. (1986); Carter et al. (1988); Cicardi et al. (1987); DeMarchi
et al. (1973); Donaldson and Evans (1963); Gadek et al. (1980); Harrington
et al. (1984); Hartmann  (1983); Landerman  (1962); Ohela et al. (1977);
Pickering et al. (1969); Schwarz et al. (1981); Sheffer et al. (1972);
Small and Frenkiel (1983); Stewart et al. (1979); Van Dellen and Myers
(1980); Young et al. (1980); Zuraw and Curd (1986)
*FIELD* RF
1. Agostoni, A.; Cicardi, M.: Hereditary and acquired C1-inhibitor
deficiency: biological and clinical characteristics in 235 patients. Medicine 71:
206-215, 1992.

2. Alper, C. A.: The 'cure' of an inherited disease. (Editorial) J.
Lab. Clin. Med. 92: 497-500, 1978.

3. Alsenz, J.; Bork, K.; Loos, M.: Autoantibody-mediated acquired
deficiency of C1 inhibitor. New Eng. J. Med. 316: 1360-1366, 1987.

4. Ariga, T.; Carter, P. E.; Davis, A. E., III: Recombinations between
Alu repeat sequences that result in partial deletions within the C1
inhibitor gene. Genomics 8: 607-613, 1990.

5. Ariga, T.; Igarashi, T.; Ramesh, N.; Parad, R.; Cicardi, M.; Davis,
A. E., III: Type I C1 inhibitor deficiency with a small messenger
RNA resulting from deletion of one exon. J. Clin. Invest. 83: 1888-1893,
1989.

6. Aulak, K. S.; Cicardi, M.; Harrison, R. A.: Identification of
a new P1 residue mutation (444arg-to-ser) in a dysfunctional C1 inhibitor
protein contained in a type II hereditary angioedema plasma. FEBS
Lett. 266: 13-16, 1990.

7. Aulak, K. S.; Pemberton, P. A.; Rosen, F. S.; Carrell, R. W.; Lachmann,
P. J.; Harrison, R. A.: Dysfunctional C1-inhibitor (At), isolated
from a type II hereditary angiooedema plasma, contains a P1 'reactive
centre' (arg444-to-his) mutation. Biochem. J. 253: 615-618, 1988.

8. Austen, K. F.; Sheaffer, A. L.: Detection of hereditary angioneurotic
edema by demonstration of a reduction in the second component of human
complement. New Eng. J. Med. 272: 649-656, 1965.

9. Blumenthal, M. N.; Dalmasso, A. P.; Roitman, B.; Kelly, J.; Noreen,
H.; Emmy, L.; Mendell, N. R.; Yunis, E. J.: Lack of linkage between
hereditary angioedema and the A and B loci of the HLA system. Vox
Sang. 35: 132-136, 1978.

10. Bock, S. C.; Harrinan, J. A.; Radziejewska, E.; Donaldson, V.
H.: Structure of the normal human C1 inhibitor gene and preliminary
analysis of C1 inhibitor genes from patients with hereditary angioneurotic
edema. (Abstract) Am. J. Hum. Genet. 39: A189 only, 1986.

11. Bock, S. C.; Skriver, K.; Nielsen, E.; Thogersen, H.-C.; Wiman,
B.; Donaldson, V. H.; Eddy, R. L.; Marrinan, J.; Radziejewska, E.;
Huber, R.; Shows, T. B.; Magnusson, S.: Human C1 inhibitor: primary
structure, cDNA cloning, and chromosomal localization. Biochemistry 25:
4292-4301, 1986.

12. Carter, P. E.; Dunbar, B.; Fothergill, J. E.: Genomic and cDNA
cloning of the human C1 inhibitor: intron-exon junctions and comparison
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Eng. J. Med. 334: 1666-1667, 1996.

15. Cicardi, M.; Bergamaschini, L.; Marasini, B.; Boccassini, G.;
Tucci, A.; Agostoni, A.: Hereditary angioedema: an appraisal of 104
cases. Am. J. Med. Sci. 284: 2-9, 1982.

16. Cicardi, M.; Igarashi, T.; Kim, M. S.; Frangi, D.; Agostoni, A.;
Davis, A. E., III: Restriction fragment length polymorphism of the
C1 inhibitor gene in hereditary angioneurotic edema. J. Clin. Invest. 80:
1640-1643, 1987.

17. Cicardi, M.; Igarashi, T.; Rosen, F. S.; Davis, A. E., III: Molecular
basis for the deficiency of complement 1 inhibitor in type I hereditary
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19. Cohen-Haguenauer, O.; Tosi, M.; Meo, T.; Van Cong, N.; Frezal,
J.: Assignment of human complement C1r and C1s genes to chromosome
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Int. Cong. Hum. Genet., Berlin 617 only, 1986.

20. Cox, D. W.; Francke, U.: Direct assignment of orosomucoid to
human chromosome 9 and alpha-2-HS-glycoprotein to chromosome 3 using
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1985.

21. Cox, M.; Holdcroft, A.: Hereditary angioneurotic oedema: current
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22. Davis, A. E., III; Aulak, K.; Parad, R. B.; Stecklein, H. P.;
Eldering, E.; Hack, C. E.; Kramer, J.; Strunk, R. C.; Bissler, J.;
Rosen, F. S.: C1 inhibitor hinge region mutations produce dysfunction
by different mechanisms. Nature Genet. 1: 354-358, 1992.

23. Davis, A. E., III; Whitehead, A. S.; Harrison, R. A.; Dauphinais,
A.; Bruns, G. A. P.; Cicardi, M.; Rosen, F. S.: Human inhibitor of
the first component of complement, C1: characterization of cDNA clones
and localization of the gene to chromosome 11. Proc. Nat. Acad. Sci. 83:
3161-3165, 1986.

24. DeMarchi, M. J.; Jacot-Guillarmod, H.; Reesa, T. G.; Carbonara,
A. O.: Hereditary angioedema: report of a large kindred with a rare
genetic variant of C-prime-1-esterase inhibitor. Clin. Genet. 4:
229-235, 1973.

25. Dennehy, J. J.: Hereditary angioneurotic edema: report of a large
kindred with defect in C-prime-1 esterase inhibitor and review of
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26. Donaldson, V. H.; Evans, R. R.: A biochemical abnormality in
hereditary angioneurotic edema: absence of serum inhibitor C-prime-1-esterase. Am.
J. Med. 35: 37-44, 1963.

27. Donaldson, V. H.; Rosen, F. S.: Action of complement in hereditary
angioneurotic edema: the role of C-prime-1-esterase. J. Clin. Invest. 43:
2204-2213, 1964.

28. Duck, S. C.; Katayama, K. P.: Danazol may cause female pseudohermaphroditism. Fertil.
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29. Eggert, J.; Zachariae, H.; Svejgaard, E.; Svejgaard, A.; Kissmeyer-Nielsen,
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30. Fearon, D. T.: Personal Communication. Baltimore, Md.  10/3/1987.

31. Frangi, D.; Cicardi, M.; Sica, A.; Colotta, F.; Agostoni, A.;
Davis, A. E., III: Nonsense mutations affect C1 inhibitor messenger
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Clin. Invest. 88: 755-759, 1991.

32. Frank, M. M.; Sergent, J. S.; Kane, M. A.; Alling, D. W.: Epsilon
aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind
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33. Frigas, E.: Angioedema with acquired deficiency of the C1 inhibitor:
a constellation of syndromes. Mayo Clin. Proc. 64: 1269-1275, 1989.

34. Gadek, J. E.; Fulmer, J. D.; Gelfand, J. A.; Frank, M. M.; Petty,
T. L.; Crystal, R. G.: Danazol-induced augmentation of serum alpha-1-antitrypsin
levels in individuals with marked deficiency of this antiprotease. J.
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35. Gadek, J. E.; Hosea, S. W.; Gelfand, J. A.; Santaella, M.; Wickerhauser,
M.; Triantaphyllopoulos, D. C.; Frank, M. M.: Replacement therapy
in hereditary angioedema: successful treatment of acute episodes of
angioedema with partly purified C1 inhibitor. New Eng. J. Med. 302:
542-546, 1980.

36. Gelfand, J. A.; Boss, G. R.; Conley, C. L.; Reinhart, R.; Frank,
M. M.: Acquired C1 esterase inhibitor deficiency and angioedema:
a review. Medicine 58: 321-328, 1979.

37. Gelfand, J. A.; Sherins, R. J.; Alling, D. W.; Frank, M. M.:
Treatment of hereditary angioedema with Danazol: reversal of clinical
and biochemical abnormalities. New Eng. J. Med. 295: 1444-1448,
1976.

38. Gleich, G. J.; Schroeter, A. L.; Marcoux, J. P.; Sachs, M. I.;
O'Connell, E. J.; Kohler, P. F.: Episodic angioedema associated with
eosinophilia. New Eng. J. Med. 310: 1621-1626, 1984.

39. Gralnick, H. R.; Rick, M. E.: Danazol increases factor VIII and
factor IX in classic hemophilia and Christmas disease. New Eng. J.
Med. 308: 1393-1395, 1983.

40. Harrington, T. M.; Torretti, D.; Pytko, V. F.; Plotkin, G. R.
: Hereditary angioedema and coronary arteritis. Am. J. Med. Sci. 287:
50-52, 1984.

41. Hartmann, L.: L'oedeme angioneurotique hereditaire a propos de
185 malades et 40 families. Bull. Acad. Nat. Med. 167: 343-351,
1983.

42. Heiner, D. C.; Blitzer, J. R.: Familial paroxysmal dysfunction
of the autonomic nervous system (a periodic disease), often precipitated
by emotional stress. Pediatrics 20: 782-793, 1957.

43. Jackson, J.; Sim, R. B.; Whelan, A.; Feighery, C.: An IgG autoantibody
which inactivates C1-inhibitor. Nature 323: 722-724, 1986.

44. Johnson, A. M.; Alper, C. A.; Rosen, F. S.; Craig, J. M.: C-prime-1
inhibitor: evidence for decreased hepatic synthesis in hereditary
angioneurotic edema. Science 173: 553-554, 1971.

45. Kramer, J.; Rosen, F. S.; Colten, H. R.; Rajczy, K.; Strunk, R.
C.: Transinhibition of C1 inhibitor synthesis in type I hereditary
angioneurotic edema. J. Clin. Invest. 91: 1258-1262, 1993.

46. Landerman, N. S.: Hereditary angioneurotic edema. I. Case reports
and a review of the literature. J. Allergy 33: 316-329, 1962.

47. Laurent, J.; Toulet, R.; Lagrue, G.: Ultrasonography in the diagnosis
of hereditary angioneurotic oedema. (Letter) Lancet I: 761 only,
1988.

48. Levy, N. J.; Ramesh, N.; Cicardi, M.; Harrison, R. A.; Davis,
A. E., III: Type II hereditary angioneurotic edema that may result
from a single nucleotide change in the codon for alanine-436 in the
C1 inhibitor gene. Proc. Nat. Acad. Sci. 87: 265-268, 1990.

49. Malbran, A.; Hammer, C. H.; Frank, M. M.; Fries, L. F.: Acquired
angioedema: observations on the mechanism of action of autoantibodies
directed against C1 esterase inhibitor. J. Allergy Clin. Immun. 81:
1199-1204, 1988.

50. McPhaden, A. R.; Birnie, G. D.; Whaley, K.: Restriction fragment
length polymorphism analysis of the C1-inhibitor gene in hereditary
C1-inhibitor deficiency. Clin. Genet. 39: 161-171, 1991.

51. Milton, J. L.: On giant urticaria. Edinb. Med. J. 22: 513-526,
1876.

52. Muhlemann, M. F.; Macrae, K. D.; Smith, A. M.; Beck, P.; Hine,
I.; Hegde, U.; Milford-Ward, A.; Carter, G. D.; Wise, P. H.; Cream,
J. J.: Hereditary angioedema and thyroid autoimmunity. J. Clin.
Path. 40: 518-523, 1987.

53. Ohela, K.; Tiilikainen, A.; Kaakinen, A.; Rasanen, J.: Hereditary
angioneurotic edema (HANE): lack of close linkage between HLA haplotypes
and C1 esterase inhibitor deficiency. Tissue Antigens 9: 90-95,
1977.

54. Olaisen, B.; Gedde-Dahl, T., Jr.; Nielsen, A.: Hereditary angioneurotic
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55. Osler, W.: Hereditary angio-neurotic oedema. Am. J. Med. Sci. 95:
362-367, 1888.

56. Perricone, R.; Pasetto, N.; De Carolis, C.; Vaquero, E.; Noccioli,
G.; Panerai, A. E.; Fontana, L.: Cystic ovaries in women affected
with hereditary angioedema. Clin. Exp. Immun. 90: 401-404, 1992.

57. Pickering, R. J.; Kelly, J. R.; Good, R. A.; Gewurz, H.: Replacement
therapy in hereditary angioedema: successful treatment of two patients
with fresh frozen plasma. Lancet I: 326-330, 1969.

58. Quastel, M.; Harrison, R.; Cicardi, M.; Alper, C. A.; Rosen, F.
S.: Behavior in vivo of normal and dysfunctional C1 inhibitor in
normal subjects and patients with hereditary angioneurotic edema. J.
Clin. Invest. 71: 1041-1046, 1983.

59. Quincke, H.: Concerning the acute localized oedema of the skin. Monatsh.
Prakt. Dermat. 1: 129-131, 1882. Note: Alternate: Major, R. H.: Classic
Descriptions of Disease. 3rd ed., Springfield, Ill.: Charles C Thomas,
1945. Pp. 624-625.

60. Robson, E. B.; Lachmann, P. J.; Hobart, M. J.; Johnston, A. W.
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347-350, 1979.

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V. H.: Genetically determined heterogeneity of the C-prime-1 esterase
inhibitor in patients with hereditary angioneurotic edema. J. Clin.
Invest. 50: 2143-2158, 1971.

62. Rosen, F. S.; Charache, P.; Pensky, J.; Donaldson, V. H.: Hereditary
angioneurotic edema: two genetic variants. Science 148: 957-958,
1965.

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64. Sheffer, A. L.; Austen, K. F.; Rosen, F. S.: Tranexamic acid
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Genet. 4: 494-499, 1973.

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RNA splice site mutation in the C1-inhibitor gene causes type I hereditary
angio-oedema. Hum. Genet. 88: 231-232, 1991.

67. Siddique, Z.; McPhaden, A. R.; McCluskey, D.; Whaley, K.: A single
base deletion from the C1-inhibitor gene causes type I hereditary
angio-oedema. Hum. Hered. 42: 231-234, 1992.

68. Siddique, Z.; McPhaden, A. R.; Whaley, K.: C1-inhibitor gene
nucleotide insertion causes type II hereditary angio-oedema. Hum.
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73. Stoppa-Lyonnet, D.; Duponchel, C.; Meo, T.; Laurent, J.; Carter,
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G.; Lagrue, G.; Lesavre, P.; Lopez-Trascasa, M.; Misiano, G.; Moraine,
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74. Stoppa-Lyonnet, D.; Tosi, M.; Laurent, J.; Sobel, A.; Lagrue,
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75. Theriault, A.; Whaley, K.; Bock, S. C.; Boyd, E.; Connor, J. M.
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80. Waytes, A. T.; Rosen, F. S.; Frank, M. M.: Treatment of hereditary
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83. Winkelstein, J. A.; Colten, H. R.: Genetically determined disorders
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in hereditary angioneurotic edema and systemic lupus erythematosus. Arch.
Intern. Med. 140: 127-128, 1980.

85. Zahedi, R.; Bissler, J. J.; Davis, A. E., III; Andreadis, C.;
Wisnieski, J. J.: Unique C1 inhibitor dysfunction in a kindred without
angioedema. II. Identification of an ala443-to-val substitution and
functional analysis of the recombinant mutant protein. J. Clin. Invest. 95:
1299-1305, 1995.

86. Zuraw, B. L.; Curd, J. G.: Demonstration of modified inactive
first component of complement (C1) inhibitor in the plasmas of C1
inhibitor-deficient patients. J. Clin. Invest. 78: 567-575, 1986.

*FIELD* CS

Skin:
   Angioedema;
   Episodic nonpuritic, nonurticarial, nonpitting edema

Pulm:
   Laryngeal edema

GI:
   Abdominal pain with visceral edema;
   Nausea;
   Diarrhea;
   Vomiting

Misc:
   Trauma can precipitate or aggravate edema;
   Onset precipitated by mononucleosis;
   Increased frequency of thyroglobulin antibodies, thyroid microsomal
   antibodies and polycystic ovaries syndrome;
Male:female ratio 0.85

Lab:
   C1 esterase inhibitor deficiency;
   Low level of C4 and normal level of C1;
   Leukocytosis

Inheritance:
   Autosomal dominant (11p11.2-q13)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jamie: 10/23/1996
jamie: 10/16/1996
mark: 9/10/1996
terry: 9/3/1996
mark: 8/19/1996
mark: 8/14/1996
terry: 7/24/1996
terry: 10/30/1995
mark: 6/11/1995
jason: 6/17/1994
warfield: 4/7/1994
carol: 4/5/1994
mimadm: 2/21/1994

*RECORD*
*FIELD* NO
106150
*FIELD* TI
*106150 ANGIOTENSIN I; AGT
ANGIOTENSINOGEN, INCLUDED;;
ANGIOTENSIN II, INCLUDED
*FIELD* TX
Human angiotensin I has an amino acid sequence of 14 residues which is
identical to that of the horse. Angiotensin is formed from a precursor
angiotensinogen which is produced by the liver and found in the
alpha-globulin fraction of plasma. The lowering of blood pressure is a
stimulus to secretion of renin by the kidney into the blood. Renin
cleaves from angiotensinogen a terminal decapeptide, angiotensin I. This
is further altered by the enzymatic removal of a dipeptide to form
angiotensin II. Ohkubo et al. (1983) determined the sequence of the
cloned rat angiotensinogen gene. The human angiotensinogen molecule has
a molecular weight of about 50,000. The angiotensin I decapeptide is
located in its amino-terminal part. Kageyama et al. (1984) reported the
complete nucleotide sequence of human angiotensinogen mRNA. Similarly,
Kunapuli et al. (1987) isolated cDNA clones for human angiotensinogen
from a human liver library. The determined nucleotide sequence
corroborated that published by Kageyama et al. (1984), with the
exception of a single nucleotide change which may represent a simple
genetic polymorphism. Kunapuli et al. (1987) constructed a full-length
angiotensinogen cDNA which enabled the in vitro synthesis of human
angiotensinogen in E. coli. Gaillard et al. (1989) found that the human
angiotensinogen gene contains 5 exons. The primary amino acid sequence
showed similarities to that of alpha-1-antitrypsin (107400) and
antithrombin III (107300). The angiotensinogen gene showed identical
organization with the AAT gene but was different from the AT3 gene.

By in situ hybridization, Gaillard-Sanchez et al. (1990) assigned the
angiotensinogen gene to 1q4 in the same region as the renin gene
(179820). Isa et al. (1989, 1990) used a human angiotensinogen cDNA
plasmid probe to localize the gene by nonisotopic in situ hybridization;
the location was determined to be 1q42-q43. By screening a panel of
human-mouse somatic cell hybrids, Abonia et al. (1993) confirmed the
assignment of the AGT locus to chromosome 1. They showed, furthermore,
that the homologous gene in the mouse is on the distal end of chromosome
8; a short region of conserved linkage homology between mouse chromosome
8 and human chromosome 1 was indicated by the mapping also of the
skeletal alpha-actin locus (102610) to mouse chromosome 8 and human
chromosome 1.

Jeunemaitre et al. (1992) reported results from a collaborative study of
AGT in 215 sibships, each with 2 or more hypertensive subjects
ascertained from American and French study populations, a total of 379
sib pairs. The study provided evidence for involvement of AGT in the
pathogenesis of essential hypertension (145500). In each of the samples,
they found genetic linkage between essential hypertension and AGT in
affected sibs, association between hypertension and certain molecular
variants of AGT as revealed by a comparison between cases and controls,
and increased concentrations of plasma angiotensinogen in hypertensive
subjects who carry a common variant of AGT strongly associated with
hypertension. Among the 15 molecular variants of AGT that had been
identified, significant association with hypertension was observed with
2 amino acid substitutions, M235T (106150.0001) and T174M. These 2
variants exhibited complete linkage disequilibrium, as T174M occurred on
a subset of the haplotypes carrying the M235T variant, and both
haplotypes were observed at higher frequency among hypertensives.
Several interpretations can be proposed to account for this observation:
M235T directly mediates a predisposition to hypertension; an
unidentified risk factor is common to both haplotypes; or each haplotype
harbors a distinct risk factor. Caulfield et al. (1994) could find no
association between essential hypertension and either the M235T or the
T174M variant. On the other hand, studies in a distinct, ethnically
homogeneous population, namely Japanese, showed that the same variant,
T235, is associated with essential hypertension (Hata et al., 1994). In
the Japanese study, the population frequency of the T235 variant was
found to be higher than among Caucasian subjects. Because of the
involvement of angiotensinogen in salt homeostasis, T235 may be a marker
for a salt-sensitive form of essential hypertension. Epidemiologic
studies documented a striking gradient of increasing prevalence of
hypertension and stroke mortality from south to north Japan (Takahashi
et al., 1957), which correlates with a parallel rise in average daily
salt intake (Sasaki, 1964).

Hypertrophy is a fundamental adaptive process occurring in postmitotic
cardiac and skeletal muscle in response to mechanical load. Using an in
vitro model of load-induced cardiac hypertrophy, Sadoshima et al. (1993)
demonstrated that mechanical stress causes release of angiotensin II
from cardiac myocytes and that angiotensin II acts as an initial
mediator of the hypertrophic response. The results not only provided
direct evidence for the autocrine mechanism in load-induced growth of
cardiac muscle cells, but also defined a pathophysiologic role of the
local (cardiac) renin-angiotensin system.

The observation that plasma and angiotensinogen levels correlate with
blood pressure and track through families suggested that angiotensinogen
may have a role in essential hypertension. Caulfield et al. (1994)
therefore investigated linkage between the AGT gene and essential
hypertension in 63 white European families in which 2 or more members
had essential hypertension. To test for linkage they used a dinucleotide
repeat marker flanking the gene on 1q42-q43 and adopted the
affected-pedigree-member method of linkage analysis (Weeks and Lange,
1988). In this approach, a t-statistic is computed that tests whether
affected relatives share alleles at the AGT locus more often than would
be expected by chance. Linkage was detected (t = 5.00, P less than
0.001).

Among the Hutterites, a North American religious genetic isolate
(Hostetler, 1974), Hegele et al. (1994) tested for association between
variation in systolic and diastolic blood pressures and the
insertion/deletion polymorphism of ACE (106180) and 2 protein
polymorphisms of AGT, namely, M235T and T174M. The genotypes of AGT
codon 174 were significantly associated with variation in systolic blood
pressure in men and accounted for 3.1% of the total variation. Hegele et
al. (1996) provided further information on this association and that of
the genotype of apoB codon 4154 (107730) in association with variation
in systolic blood pressure in Hutterites.

Tanimoto et al. (1994) generated angiotensinogen-deficient mice by
homologous recombination in mouse embryonic stem cells. These mice do
not produce angiotensinogen in the liver, resulting in the complete loss
of plasma immunoreactive angiotensin I. The systolic blood pressure of
the homozygous mutant mice was 66.9 +/- 4.1 mmHg, as compared with 100.4
+/- 4.4 mm Hg in wildtype mice. The findings demonstrated an
indispensable role for the renin-angiotensin system in maintaining blood
pressure.

In a study in African Caribbeans from St. Vincent and the Grenadines,
Caulfield et al. (1995) tested for linkage between the AGT gene and
hypertension by analyzing 63 affected sib pairs for an excess of allele
sharing, using an AGT dinucleotide repeat sequence as an indicator.
There was significant support for linkage (P = 0.001) and association (P
less than 0.001) of AGT to hypertension. However, they found no
association of the M235T variant (106150.0001) with hypertension in this
study of African Caribbeans.

In a New Zealand study of 422 patients with documented coronary heart
disease and 406 controls without known CHD (matched to cases by age and
sex), Katsuya et al. (1995) concluded that the T225 of AGT is an
independent risk factor that carries an approximately 2-fold increased
risk of CHD. In that study, however, ACE DD (106180.0001) is not
associated with any detectable increase in CHD risk.

As outlined earlier, the strongest evidence implicating a gene as the
cause of human essential hypertension is for the AGT gene (Jeunemaitre
et al., 1992), Davisson et al. (1997) reported studies designed to
determine whether elements of the human renin-angiotensin system (RAS)
could functionally replace elements of the mouse RAS by complementing
the reduced survival and renal abnormalities observed in mice carrying a
gene-targeted deletion of the mouse angiotensinogen gene (mAgt). These
studies established that the human renin and angiotensinogen genes can
functionally replace the mouse angiotensinogen gene, and provided proof
in principle that one can examine the regulation of elements of the
human RAS, and test the significance of human RAS gene variants, by a
combined transgenic and gene-targeting approach.

*FIELD* AV
.0001
HYPERTENSION, ESSENTIAL, PREDISPOSITION TO
PREECLAMPSIA, PREDISPOSITION TO
AGT, MET235THR
By 3 sets of observations--genetic linkage, allelic associations, and
differences in plasma angiotensinogen concentrations among AGT
genotypes--in a sample of families from 2 different populations, Salt
Lake City and Paris, Jeunemaitre et al. (1992) demonstrated involvement
of the AGT gene in essential hypertension. Hypertension showed
association with 2 distinct amino acid substitutions, M235T and T174M.
The 2 variants showed complete linkage disequilibrium; T174M occurred on
a subset of the haplotypes carrying the M235T variant, and both
haplotypes were observed at higher frequency among hypertensives.
Whether M235T directly mediates a predisposition to hypertension, or an
unidentified risk factor is common to both haplotypes, or each haplotype
harbors a distinct factor is uncertain. In a series of Caucasian women
with pregnancy-induced hypertension, Ward et al. (1993) observed
significant association of preeclampsia with the M235T variant. The
finding was corroborated in a sample ascertained in Japan. Arngrimsson
et al. (1993) studied involvement of the ATG gene in preeclampsia and
eclampsia by linkage studies with a highly informative dinucleotide
repeat from the 3-prime flanking region of the ATG gene. They used a
nonparametric method, i.e., one in which the mode of inheritance, gene
frequency, and penetrance did not have to be specified. Their results
supported the findings of Ward et al. (1993). Lifton et al. (1993) found
the M235T variant to be very frequent among African Americans who as a
group have a high prevalence of hypertension. The frequency of T235
homozygotes was 70%, with 28% for T235 heterozygotes and only 2% for
M235 homozygotes; the corresponding figures were 12%, 46%, and 42% in
Caucasians.

Lifton et al. (1993) suggested that the T235 allele may have been the
ancestral form, and, in an earlier period of salt scarcity, increased
salt and water retention associated with T235 may have been an
advantage. After the Diaspora from Africa to salt-rich areas, M235 may
have become fixed or had some advantage. Russ et al. (1993) described a
rapid method for detection of the M235T polymorphism.

It is well known that blood pressure increases faster over time in black
children than in white children and that in adults, hypertension is more
prevalent in blacks. In a study of 148 white and 62 black normotensive
children, Bloem et al. (1995) found that the frequency of the T235
allele was 0.81 in blacks and 0.42 in whites. The mean angiotensinogen
level was 19% higher in blacks than in whites. This racial difference in
the renin-angiotensin system may contribute to the disparity in blood
pressure levels in white and black young people.

In Rochester, Minnesota, Fornage et al. (1995) studied a
population-based sample consisting of 104 subjects diagnosed with
hypertension before age 60 and 195 matched normotensive individuals to
determine the relationship between M235T and essential hypertension. The
authors used 2 methods: contingency chi-square analysis of association
and a multivariable conditional logistic regression for variation at the
M235T polymorphism as a significant predictor of the probability of
having essential hypertension. They detected no statistically
significant association in either gender or in a subset of severely
hypertensive subjects requiring 2 or more antihypertensive medications.
Furthermore, variation in the number of M235T alleles made no
significant contribution to predicting the probability of having
hypertension, either alone or in conjunction with other predictor
variables.

*FIELD* SA
Arakawa et al. (1968)
*FIELD* RF
1. Abonia, J. P.; Abel, K. J.; Eddy, R. L.; Elliott, R. W.; Chapman,
V. M.; Shows, T. B.; Gross, K. W.: Linkage of Agt and Actsk-1 to
distal mouse chromosome 8 loci: a new conserved linkage. Mammalian
Genome 4: 25-32, 1993.

2. Arakawa, K.; Minohara, A.; Yamada, J.; Nakamura, M.: Enzymatic
degradation and electrophoresis of human angiotensin I. Biochim.
Biophys. Acta 168: 106-112, 1968.

3. Arngrimsson, R.; Purandare, S.; Connor, M.; Walker, J. J.; Bjornsson,
S.; Soubrier, F.; Kotelevtsev, Y. V.; Geirsson, R. T.; Bjornsson,
H.: Angiotensinogen: a candidate gene involved in preeclampsia?.
(Letter) Nature Genet. 4: 114-115, 1993.

4. Bloem, L. J.; Manatunga, A. K.; Tewksbury, D. A.; Pratt, J. H.
: The serum angiotensinogen concentration and variants of the angiotensinogen
gene in white and black children. J. Clin. Invest. 95: 948-953,
1995.

5. Caulfield, M.; Lavender, P.; Farrall, M.; Munroe, P.; Lawson, M.;
Turner, P.; Clark, A. J. L.: Linkage of the angiotensinogen gene
to essential hypertension. New Eng. J. Med. 330: 1629-1633, 1994.

6. Caulfield, M.; Lavender, P.; Newell-Price, J.; Farrall, M.; Kamdar,
S.; Daniel, H.; Lawson, M.; De Freitas, P.; Fogarty, P.; Clark, A.
J. L.: Linkage of the angiotensinogen gene locus to human essential
hypertension in African Caribbeans. J. Clin. Invest. 96: 687-692,
1995.

7. Davisson, R. L.; Kim, H.-S.; Krege, J. H.; Lager, D. J.; Smithies,
O.; Sigmund, C. D.: Complementation of reduced survival, hypotension,
and renal abnormalities in angiotensinogen-deficient mice by the human
renin and human angiotensinogen genes. J. Clin. Invest. 99: 1258-1264,
1997.

8. Fornage, M.; Turner, S. T.; Sing, C. F.; Boerwinkle, E.: Variation
at the M235T locus of the angiotensinogen gene and essential hypertension:
a population-based case-control study from Rochester, Minnesota. Hum.
Genet. 96: 295-300, 1995.

9. Gaillard, I.; Clauser, E.; Corvol, P.: Structure of human angiotensinogen
gene. DNA 8: 87-99, 1989.

10. Gaillard-Sanchez, I.; Mattei, M. G.; Clauser, E.; Corvol, P.:
Assignment by in situ hybridization of the angiotensinogen gene to
chromosome band 1q4, the same region as the human renin gene. Hum.
Genet. 84: 341-343, 1990.

11. Hata, A.; Namikawa, C.; Sasaki, M.; Sato, K.; Nakamura, T.; Tamura,
K.; Lalouel, J.-M.: Angiotensinogen as a risk factor for essential
hypertension in Japan. J. Clin. Invest. 93: 1285-1287, 1994.

12. Hegele, R. A.; Brunt, J. H.; Connelly, P. W.: Genetic and biochemical
factors associated with variation in blood pressure in a genetic isolate. Hypertension 27:
308-312, 1996.

13. Hegele, R. A.; Brunt, J. H.; Connelly, P. W.: A polymorphism
of the angiotensinogen gene associated with variation in blood pressure
in a genetic isolate. Circulation 90: 2207-2212, 1994.

14. Hostetler, J. A.: Hutterite Society.  Baltimore: Johns Hopkins
Univ. Press (pub.)  1974.

15. Isa, M. N.; Boyd, E.; Morrison, N.; Harrap, S.; Clauser, E.; Connor,
J. M.: Assignment of the human angiotensin gene to chromosome 1q42-q43
by nonisotopic in situ hybridization. Genomics 8: 598-600, 1990.
Note: Erratum: Genomics 10: 1110 only, 1991

16. Isa, M. N.; Boyd, E.; Morrison, N.; Theriault, A.; Connor, J.
M.; Harrap, S.; Clauser, E.: Regional chromosomal localization of
the human angiotensinogen gene to 1q4.42-4.43 band. (Abstract) Am.
J. Hum. Genet. 45: A144, 1989.

17. Jeunemaitre, X.; Soubrier, F.; Kotelevtsev, Y. V.; Lifton, R.
P.; Williams, C. S.; Charru, A.; Hunt, S. C.; Hopkins, P. N.; Williams,
R. R.; Lalouel, J.-M.; Corvol, P.: Molecular basis of human hypertension:
role of angiotensinogen. Cell 71: 7-20, 1992.

18. Kageyama, R.; Ohkubo, H.; Nakanishi, S.: Primary structure of
human preangiotensinogen deduced from the cloned cDNA sequence. Biochemistry 23:
3603-3609, 1984.

19. Katsuya, T.; Koike, G.; Yee, T. W.; Sharpe, N.; Jackson, R.; Norton,
R.; Horiuchi, M.; Pratt, R. E.; Dzau, V. J.; MacMahon, S.: Association
of angiotensinogen gene T235 variant with increased risk of coronary
heart disease. Lancet 345: 1600-1603, 1995.

20. Kunapuli, S. P.; Prasad, G. L.; Kumar, A.: Expression of human
angiotensinogen cDNA in Escherichia coli. J. Biol. Chem. 262: 7672-7675,
1987.

21. Lifton, R. P.; Warnock, D.; Acton, R. T.; Harman, L.; Lalouel,
J. M.: High prevalence of hypertension-associated angiotensinogen
variant T235 in African Americans. (Abstract) Clin. Res. 260A, 1993.

22. Ohkubo, H.; Kageyama, R.; Ujihara, M.; Hirose, T.; Inayama, S.;
Nakanishi, S.: Cloning and sequence analysis of cDNA for rat angiotensinogen. Proc.
Nat. Acad. Sci. 80: 2196-2200, 1983.

23. Russ, A. P.; Maerz, W.; Ruzicka, V.; Stein, U.; Gross, W.: Rapid
detection of the hypertension-associated met235-to-thr allele of the
human angiotensinogen gene. Hum. Molec. Genet. 2: 609-610, 1993.

24. Sadoshima, J.; Xu, Y.; Slayter, H. S.; Izumo, S.: Autocrine release
of angiotensin II mediates stretch-induced hypertrophy of cardiac
myocytes in vitro. Cell 75: 977-984, 1993.

25. Sasaki, N.: The relationship of salt intake to hypertension in
the Japanese. Geriatrics 19: 735-744, 1964.

26. Takahashi, E.; Sasaki, N.; Takeda, J.; Ito, H.: The geographic
distribution of cerebral hemorrhage and hypertension in Japan. Hum.
Biol. 29: 139-166, 1957.

27. Tanimoto, K.; Sugiyama, F.; Goto, Y.; Ishida, J.; Takimoto, E.;
Yagami, K.; Fukamizu, A.; Murakami, K.: Angiotensinogen-deficient
mice with hypotension. J. Biol. Chem. 269: 31334-31337, 1994.

28. Ward, K.; Hata, A.; Jeunemaitre, X.; Helin, C.; Nelson, L.; Namikawa,
C.; Farrington, P. F.; Ogasawara, M.; Suzumori, K.; Tomoda, S.; Berrebi,
S.; Sasaki, M.; Corvol, P.; Lifton, R. P.; Lalouel, J.-M.: A molecular
variant of angiotensinogen associated with preeclampsia. Nature Genet. 4:
59-61, 1993.

29. Weeks, D. E.; Lange, K.: The affected-pedigree-member method
of linkage analysis. Am. J. Hum. Genet. 42: 315-326, 1988.

*FIELD* CN
Victor A. McKusick - updated: 04/28/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 04/28/1997
terry: 4/25/1997
mark: 10/11/1996
mark: 3/28/1996
terry: 3/20/1996
mark: 9/19/1995
carol: 1/30/1995
jason: 7/14/1994
pfoster: 3/25/1994
mimadm: 2/11/1994
carol: 12/16/1993

*RECORD*
*FIELD* NO
106160
*FIELD* TI
106160 ANGIOTENSIN II BINDING PROTEIN
*FIELD* TX
Angiotensin II, an octapeptide hormone, is the biologically active
component of the renin-angiotensin system. It mediates vasoconstriction
and aldosterone secretion through specific interaction with angiotensin
II receptors present on vascular smooth muscle and adrenal glands,
respectively. The binding protein, with molecular weight 66,000, has
been purified by several methods (e.g., that used by Elton et al.,
1988). (Angiotensin II is derived from angiotensin I, which in turn is
synthesized as angiotensinogen; see 106150.)

*FIELD* RF
1. Elton, T. S.; Dion, L. D.; Bost, K. L.; Oparil, S.; Blalock, J.
E.: Purification of an angiotensin II binding protein by using antibodies
to a peptide encoded by angiotensin II complementary RNA. Proc.
Nat. Acad. Sci. 85: 2518-2522, 1988.

*FIELD* CD
Victor A. McKusick: 5/12/1988

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 5/12/1988

*RECORD*
*FIELD* NO
106165
*FIELD* TI
*106165 ANGIOTENSIN II RECEPTOR, VASCULAR TYPE 1; AT2R1
ANGIOTENSIN RECEPTOR 1; AGTR1; AGTR1A
*FIELD* TX
Angiotensin II is an important effector controlling blood pressure and
volume in the cardiovascular system. Its importance is reflected by the
efficacy of angiotensin-converting enzyme inhibitors in the treatment of
hypertension and congestive heart failure. Angiotensin II interacts with
2 pharmacologically distinct subtypes of cell-surface receptors, types 1
and 2 (AGTR2; 600350). Type 1 receptors seem to mediate the major
cardiovascular effects of angiotensin II. By expression cloning, Murphy
et al. (1991) isolated a cDNA encoding the type 1 receptor. Hydropathic
modeling of the deduced protein suggested that it shares the
7-transmembrane-region motif with the G protein-coupled receptor
superfamily. Sasaki et al. (1991) isolated the corresponding bovine
gene. Takayanagi et al. (1992) cloned and sequenced a cDNA encoding this
receptor in the human, and by Northern blot analysis they demonstrated
its expression in human liver, lung, adrenal, and adrenocortical
adenomas, but not in pheochromocytomas. Bergsma et al. (1992) and Mauzy
et al. (1992) also cloned and characterized a human AGTR1 cDNA. Furuta
et al. (1992) studied the genomic sequence and demonstrated that the
coding region is contained in a single exon. By comparing genomic DNA
and cDNA sequences, Guo et al. (1994) demonstrated that the AGTR1 gene
consists of at least 5 exons and spans more than 55 kb of genomic DNA.
The size of the exons ranged from 59 to 2,014 bp. Four of the exons
encoded 5-prime untranslated sequences. Multiple transcription
initiation sites were observed by primer extension experiments.

In the rat, Elton et al. (1992) identified 2 distinct type I angiotensin
II receptor genes. The first of these corresponded to the published rat
vascular cDNA sequence; the second corresponded to a novel receptor not
previously described. By Southern blot analysis of somatic cell hybrids,
Szpirer et al. (1993) showed that in the rat there are 2 nonsyntenic
genes, one on chromosome 17 and the other on chromosome 2.

Curnow et al. (1992) mapped the AGTR1 gene to 3q by PCR analysis of DNA
from a panel of human-hamster somatic cell hybrids. In an analysis of
cDNA and genomic clones, variation was found, making these clones
potentially useful in testing the hypothesis that genetic variations in
AGTR1 function are associated with a tendency to develop hypertension.
Using a somatic cell hybrid regional mapping panel, the AGTR1 gene was
further regionalized to 3q21-q25 (Gemmill and Drabkin, 1991). By
Southern blot analysis of somatic cell hybrids, Szpirer et al. (1993)
likewise mapped the human AGTR1 gene to chromosome 3.

Ito et al. (1995) examined the physiologic and genetic functions of the
type 1A receptor for angiotensin II by disrupting the mouse gene
encoding this receptor in embryonic stem cells by gene targeting.
Agtr1a-null mice were born in expected numbers and the histomorphology
of their kidneys, heart, and vasculature was normal. Type 1
receptor-specific angiotensin II binding was not detected in the kidneys
of homozygous mutant animals, and heterozygotes exhibited a reduction in
renal type 1 receptor-specific binding to approximately 50% of wildtype
levels. Pressor responses to infused angiotensin II were virtually
absent in homozygous mice and were altered in heterozygotes. Compared
with wildtype controls, systolic blood pressure was reduced by 12 mmHg
in heterozygous mice and by 24 mmHg in homozygous mutant mice. The 2
subtypes of angiotensin II type 1 receptors, 1A and 1B (AGTR1B; 600015),
have been identified in human, rat, and mouse. These receptors are
products of separate genes, share substantial sequence homology, and
have wide tissue distributions. The angiotensin II 1A receptor seems to
predominate in most tissues except the adrenal gland and the anterior
pituitary and expression of the 2 types of receptors may be
differentially regulated in the heart and the adrenals. This
differential tissue distribution and regulation of angiotensin II
receptor subtypes may serve to modulate the biologic effects of
angiotensin II. Variants in the human AGTR1A gene may affect blood
pressure in the human. Bonnardeaux et al. (1994) identified an
association between several AGTR1A gene polymorphisms and hypertension.
Specifically, an A-to-C variant, located in the 3-prime untranslated
region at nucleotide 1166, showed a significantly elevated frequency in
206 Caucasian patients with essential hypertension. Wang et al. (1997)
did a case-control study of the 1166A-C variant in 108 Caucasian
hypertensive subjects with a strong family history (2 affected parents)
and early onset disease. The frequency of the 1166C allele was 0.40 in
hypertensives and 0.29 in normotensives.

Pharmacologic agents that either block the formation of angiotensin II
or interrupt its action by antagonizing the AT1-receptor are highly
successful in the treatment of angiotensin II-dependent hypertension.
Most notable among these agents is losartan, an AT1-receptor antagonist
that has been found to be an effective anti-hypertension drug without
the usual side effects. This, coupled with the demonstration that
polymorphism in the AGTR1 gene is associated with hypertension
(Bonnardeaux et al., 1994), further supports the notion that the AT1
receptor is an important target for the control of angiotensin
II-dependent hypertension. In spite of the availability of excellent
drugs for the control of hypertension, Iyer et al. (1996) explored the
possibility that gene therapy could be used. They demonstrated that the
delivery of angiotension type 1 receptor antisense by a
retrovirally-mediated delivery system resulted in a selective
attenuation of the cellular actions of angiotensin II in the neurons of
the spontaneously hypertensive (SH) rat model. A single injection
normalized blood pressure in the SH rat on a longterm basis. The use of
this approach in patients was proposed.

*FIELD* RF
1. Bergsma, D. J.; Ellis, C.; Kumar, C.; Nuthulaganti, P.; Kersten,
H.; Elshourbagy, N.; Griffin, E.; Stadel, J. M.; Aiyar, N.: Cloning
and characterization of a human angiotensin II type 1 receptor. Biochem.
Biophys. Res. Commun. 183: 989-995, 1992.

2. Bonnardeaux, A.; Davies, E.; Jeunemaitre, X.; Fery, I.; Charru,
A.; Clauser, E.; Tiret, L.; Cambien, F.; Corvol, P.; Soubrier, F.
: Angiotensin II type 1 receptor gene polymorphisms in human essential
hypertension. Hypertension 24: 63-69, 1994.

3. Curnow, K. M.; Pascoe, L.; White, P. C.: Genetic analysis of the
human type-1 angiotensin II receptor. Molec. Endocr. 6: 1113-1118,
1992.

4. Elton, T. S.; Stephan, C. C.; Taylor, G. R.; Kimball, M. G.; Martin,
M. M.; Durand, J. N.; Oparil, S.: Isolation of two distinct type
I angiotensin II receptor genes. Biochem. Biophys. Res. Commun. 184:
1067-1073, 1992.

5. Furuta, H.; Guo, D.-F.; Inagami, T.: Molecular cloning and sequencing
of the gene encoding human angiotensin II type 1 receptor. Biochem.
Biophys. Res. Commun. 183: 8-13, 1992.

6. Gemmill, R. M.; Drabkin, H. A.: Report of The Second International
Workshop on Human Chromosome 3 Mapping. Cytogenet. Cell Genet. 57:
162-166, 1991.

7. Guo, D.-F.; Furuta, H.; Mizukoshi, M.; Inagami, T.: The genomic
organization of human angiotensin II type 1 receptor. Biochem. Biophys.
Res. Commun. 200: 313-319, 1994.

8. Ito, M.; Oliverio, M. I.; Mannon, P. J.; Best, C. F.; Maeda, N.;
Smithies, O.; Coffman, T. M.: Regulation of blood pressure by type
1A angiotensin II receptor gene. Proc. Nat. Acad. Sci. 92: 3521-3525,
1995.

9. Iyer, S. N.; Lu, D.; Katovich, M. J.; Raizada, M. K.: Chronic
control of high blood pressure in the spontaneously hypertensive rat
by delivery of angiotensin type 1 receptor antisense. Proc. Nat.
Acad. Sci. 93: 9960-9965, 1996.

10. Mauzy, C. A.; Hwang, O.; Egloff, A. M.; Wu, L.-H.; Chung, F.-Z.
: Cloning, expression, and characterization of a gene encoding the
human angiotensin II type 1A receptor. Biochem. Biophys. Res. Commun. 186:
277-284, 1992.

11. Murphy, T. J.; Alexander, R. W.; Griendling, K. K.; Runge, M.
S.; Bernstein, K. E.: Isolation of a cDNA encoding the vascular type-1
angiotensin II receptor. Nature 351: 233-236, 1991.

12. Sasaki, K.; Yamano, Y.; Bardhan, S.; Iwai, N.; Murray, J. J.;
Hasegawa, M.; Matsuda, Y.; Inagami, T.: Cloning and expression of
a complementary DNA encoding a bovine adrenal angiotensin II type-1
receptor. Nature 351: 230-233, 1991.

13. Szpirer, C.; Riviere, M.; Szpirer, J.; Levan, G.; Guo, D. F.;
Iwai, N.; Inagami, T.: Chromosomal assignment of human and rat hypertension
candidate genes: type 1 angiotensin II receptor genes and the SA gene. J.
Hypertension 11: 919-925, 1993.

14. Takayanagi, R.; Ohnaka, K.; Sakai, Y.; Nakao, R.; Yanase, T.;
Haji, M.; Inagami, T.; Furuta, H.; Gou, D.-F.; Nakamuta, M.; Nawata,
H.: Molecular cloning, sequence analysis and expression of a cDNA
encoding human type-1 angiotensin II receptor. Biochem. Biophys.
Res. Commun. 183: 910-916, 1992.

15. Wang, W. Y. S.; Zee, R. Y. L.; Morris, B. J.: Association of
angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin.
Genet. 51: 31-34, 1997.

*FIELD* CN
Victor A. McKusick: 04/24/1997

*FIELD* CD
Victor A. McKusick: 6/24/1991

*FIELD* ED
terry: 04/24/1997
terry: 4/24/1997
terry: 4/21/1997
mark: 11/18/1996
terry: 10/23/1996
mark: 5/8/1995
jason: 7/1/1994
carol: 11/3/1993
carol: 3/25/1993
carol: 1/6/1993
carol: 11/5/1992

*RECORD*
*FIELD* NO
106180
*FIELD* TI
*106180 DIPEPTIDYL CARBOXYPEPTIDASE-1; DCP1
ANGIOTENSIN I CONVERTING ENZYME; ACE;;
ACE1;;
KININASE II
ANGIOTENSIN I CONVERTING ENZYME, TESTICULAR, INCLUDED;;
ANGIOTENSIN I CONVERTING ENZYME, PLASMA LEVEL OF, INCLUDED
*FIELD* TX
Angiotensin I converting enzyme (EC 3.4.15.1), a widely distributed
metallopeptidase, plays an important role in blood pressure regulation
and electrolyte balance by hydrolyzing angiotensin I into angiotensin
II, a potent vasopressor, and aldosterone-stimulating peptide. The
enzyme is also able to inactivate bradykinin, a potent vasodilator.
Mattei et al. (1989) assigned the ACE gene to 17q23 by in situ
hybridization. Using a DNA marker at the hGH locus (139250), which they
characterized as 'extremely polymorphic' and which showed no
recombination with ACE, Jeunemaitre et al. (1992) mapped ACE to
17q22-q24, consistent with the in situ hybridization mapping to 17q23. A
demonstration of linkage between the ACE locus and elevated blood
pressure in a rat model of hypertension (see 145500) pointed to ACE as a
candidate gene in human hypertension. In studies of hypertensive
families, they found no evidence to support linkage between the ACE
locus and the disease, however.

The testis contains a unique, androgen-dependent ACE isozyme of unknown
function. Ehlers et al. (1989) determined the cDNA sequence for human
testicular ACE. The predicted protein is identical, from residue 37 to
its C terminus, to the second half or C-terminal domain of the
endothelial ACE sequence. The inferred protein sequence consisted of a
732-residue preprotein including a 31-residue signal peptide. The mature
polypeptide had a molecular weight of 80,073.

The angiotensin I converting enzyme, or kininase II, is a dipeptidyl
carboxypeptidase that hydrolyzes angiotensin I in the circulation and
converts it into the pressor peptide angiotensin II. It also inactivates
bradykinin. The importance of ACE in circulatory homeostasis is well
documented. Besides being present as a membrane-bound enzyme on the
surface of vascular endothelial cells, ACE also circulates in plasma.
The plasma enzyme may be synthesized in vascular endothelium. In normal
individuals, plasma ACE levels can show as much as a 5-fold
interindividual variation; on the other hand, intraindividual variation
is small. Singer et al. (1996) provided a review of the clinical
literature.

Cambien et al. (1988) studied familial resemblance for plasma ACE
activity in 87 healthy families. The mean levels were 34.1, 30.7, and
43.1 in fathers, mothers, and offspring, respectively. Plasma ACE was
uncorrelated with age, height, weight, or blood pressure in the parents,
but a negative correlation with age was observed in offspring. Results
of genetic analysis suggested that a major gene may affect the
interindividual variability of plasma ACE. Okabe et al. (1985) described
a family in which an abnormal elevation in plasma ACE levels was
transmitted apparently as an autosomal dominant trait. Plasma ACE levels
in affected individuals in this kindred were much higher than the values
observed in the 87 families studied by Cambien et al. (1988). After the
ACE gene was cloned, it was shown that 50% of the interindividual
variability of plasma ACE concentration is determined by an insertion
(I)/deletion (D) polymorphism situation in intron 16 of the ACE gene and
known as the ACE/ID polymorphism; see 106180.0001. Ohishi et al. (1993)
presented data indicating that the DD genotype is associated with an
increased risk of restenosis after percutaneous transluminal angioplasty
(PTCA) for widening the lumen of coronary arteries stenosed by
atherosclerotic lesions. Schachter et al. (1994) undertook a
case-control study of 338 centenarians in comparison with adults aged 20
to 70 years. Surprisingly, they found that the DD genotype, which
predisposes to coronary heart disease, has an increased frequency in
centenarians. Ruiz et al. (1994) compared the frequency of the deletion
polymorphism in 132 unrelated individuals with noninsulin-dependent
diabetes mellitus (NIDDM) who had had myocardial infarction or
significant coronary stenoses and 184 NIDDM individuals with no history
of coronary heart disease. They found that the D allele was a strong and
independent risk factor for coronary heart disease in NIDDM patients. It
was associated with early-onset coronary heart disease in NIDDM,
independently of hypertension and lipid values. A progressively
increasing relative risk was observed in individuals heterozygous and
homozygous for the D allele, suggesting a codominant effect. The
percentage of coronary heart disease attributable to the ACE deletion
allele was 24% in this NIDDM population. Evans et al. (1994) determined
the frequency of the ACE I/D polymorphism in 313 fatal cases of definite
and possible myocardial infarction that came to autopsy in the Belfast,
Northern Ireland area. In comparison to controls from the same
population, the autopsy cases had an increased frequency of the ACE D
allele (p less than 0.02). The overall odds ratios were 2.2 for DD vs
II, and 1.8 for ID vs II.

Berge and Berg (1994) found no evidence of association between genotypes
in the insertion/deletion polymorphism and level of systolic or
diastolic blood pressure. In 2 series of monozygotic twin pairs, there
was no difference between genotypes in within-pair variation in systolic
or diastolic blood pressure. On the other hand, Schunkert et al. (1994)
found an association between left ventricular hypertrophy, as assessed
by electrocardiographic criteria, and the DD genotype of ACE.
Epidemiologic studies had shown that left ventricular hypertrophy is
often found in the absence of an elevated cardiac workload. The
association with the DD genotype was stronger in men than in women and
was more prominent when blood pressure measurements were normal. The
findings suggest that the DD genotype is a genetic marker associated
with an elevated risk of left ventricular hypertrophy in middle-aged
men. Lindpaintner et al. (1996) were unable to confirm an association
between electrocardiographically determined left ventricular mass
(determined by echocardiography) and left ventricular hypertrophy
(adjusted for clinical covariates) in an analysis of 2,439 subjects from
the Framingham Heart Study.

The ACE gene codes for both a somatic and a testis isoenzyme. A
testis-specific form of ACE has its own promoter within intron 12
(Howard et al., 1990), is encoded by the 3-prime region of the gene, and
is found only in postmeiotic spermatogenic cells and sperm. Its function
is unknown.

Lindpaintner et al. (1995) were unable to confirm the association
between the D allele and increased risk of ischemic heart disease or
myocardial infarction in a large, prospectively followed population of
U.S. male physicians.

Krege et al. (1995) investigated the role of the ACE gene in blood
pressure control and reproduction using mice generated to carry an
insertional mutation that was designed to inactivate both forms of Ace.
All homozygous female mutants were found to be fertile, but the
fertility of homozygous male mutants was greatly reduced. Heterozygous
males but not females had blood pressures that were 15 to 20 mm Hg less
than normal, although both male and female heterozygotes had reduced
serum Ace activity.

Yoshida et al. (1995) presented evidence suggesting that the deletion
polymorphism in the ACE gene, particularly the homozygote DD, is a risk
factor for progression to chronic renal failure in IgA nephropathy
(161950). Moreover, this deletion polymorphism appeared to predict the
therapeutic efficacy of ACE inhibition on proteinuria and, potentially,
on progressive deterioration of renal function in that disorder.

On the other hand, in a study of 388 white Italian patients of whom 255
had proven coronary atherosclerosis and 133 had angiographically normal
coronary arteries, Arbustini et al. (1995) found that the deletion
allele, whether homozygous or heterozygous, was the strongest risk
factor for atherosclerosis, and that the D allele was significantly
associated with the risk of infarction (although to a lesser extent than
with permanent atherosclerosis). Hypertension proved to be unrelated
with the ACE genotype.

In an angiographically defined study sample, Winkelmann et al. (1996)
failed to find an association between ACE I/D gene polymorphism although
an effect on plasma ACE activity could be demonstrated.

*FIELD* AV
.0001
MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO
DCP1, INS/DEL
Factors involved in the pathogenesis of atherosclerosis, thrombosis, and
vasoconstriction contribute to the development of coronary heart
disease. In a study comparing patients after myocardial infarction (MI)
with controls, Cambien et al. (1992) found association between coronary
heart disease and a polymorphism, ACE/ID, in the ACE gene. Rigat et al.
(1990) had found that the polymorphism is strongly associated with the
level of circulating enzyme. This enzyme plays a key role in the
production of angiotensin II and in the catabolism of bradykinin, 2
peptides involved in the modulation of vascular tone and in the
proliferation of smooth muscle cells. Cambien et al. (1988) had shown
that about 50% of the interindividual variability of plasma ACE
concentration is determined by a major gene effect. Soubrier et al.
(1988) cloned the ACE gene and Tiret et al. (1992) demonstrated that
this major gene effect is associated with an insertion (I)/deletion (D)
polymorphism involving about 250 bp situated in intron 16 of the ACE
gene, the so-called ACE/ID polymorphism. The mean plasma ACE level of DD
subjects was about twice that of II subjects, with ID subjects having
intermediate levels (Rigat et al., 1990). The frequency of the ACE/DD
genotype in the 'general population' is approximately 0.27. The ACE
polymorphism is unrelated to blood pressure and hypertension. Cambien et
al. (1992) estimated that in the low-risk group, i.e., those without
tobacco usage, high blood pressure, diabetes, obesity, or
hypercholesterolemia, the ACE/DD genotype may account for 35% of cases
of myocardial infarction. The results of these studies correlate with
those of Pfeffer et al. (1992) which showed that administration of an
ACE inhibitor not only decreased the risk of developing heart failure
but also reduced the risk for recurrent myocardial infarction.
Experimental studies had shown that ACE gene expression is increased in
myocardial tissue after coronary artery occlusion. Among 185 male and 49
female survivors of myocardial infarction below 56 and 61 years of age,
respectively, Bohn et al. (1993) failed to find results similar to those
reported by Cambien et al. (1992). They offered several possible
explanations for the different results. Bohn et al. (1993) also studied
the possible association between premature parental myocardial
infarction (before age 61 in mothers and/or before age 56 years in
fathers) and the I/D polymorphism in the ACE gene in 181 male and 48
female myocardial infarction survivors. In the total series, the
frequency of premature parental MI was 14% in DD, 10.6% in ID, and 6.1%
in II individuals. Thus, the ACE polymorphism may be an important
genetic marker of MI risk and contribute to clustering of premature MI
in families.

Oike et al. (1995) suggested that the DD genotype relates to a greater
risk for myocardial infarction in patients with coronary artery spasm
(CAS). This would explain the greater risk for myocardial infarction of
persons with the D allele, especially persons normally considered to be
at low risk. Coronary artery spasm is considered to be one mechanism for
developing MI. Oike et al. (1995) studied 150 angiographically assessed
Japanese males, all more than 60 years of age. Coronary artery spasm was
detected using intracoronary injection of ergonovine maleate. The
subjects were divided into 3 groups: those with CAS, those without CAS
but with fixed organic stenosis, and those without CAS and no organic
stenosis. DD subjects were significantly represented in group 1 when
compared with groups 2 and 3.

*FIELD* SA
Bohn et al. (1993); Kurtz  (1992); Rigat et al. (1992)
*FIELD* RF
1. Arbustini, E.; Grasso, M.; Fasani, R.; Klersy, C.; Diegoli, M.;
Porcu, E.; Banchieri, N.; Fortina, P.; Danesino, C.; Specchia, G.
: Angiotensin converting enzyme gene deletion allele is independently
and strongly associated with coronary atherosclerosis and myocardial
infarction. Brit. Heart J. 74: 584-591, 1995.

2. Berge, K. E.; Berg, K.: No effect of insertion/deletion polymorphism
at the ACE locus on normal blood pressure level or variability. Clin.
Genet. 45: 169-174, 1994.

3. Bohn, M.; Berge, K. E.; Bakken, A.; Erikssen, J.; Berg, K.: Insertion/deletion
(I/D) polymorphism at the locus for angiotensin I-converting enzyme
and parental history of myocardial infarction. Clin. Genet. 44:
298-301, 1993.

4. Bohn, M.; Berge, K. E.; Bakken, A.; Erikssen, J.; Berg, K.: Insertion/deletion
(I/D) polymorphism at the locus for angiotensin I-converting enzyme
and myocardial infarction. Clin. Genet. 44: 292-297, 1993.

5. Cambien, F.; Alhenc-Gelas, F.; Herbeth, B.; Andre, J. L.; Rakotovao,
R.; Gonzales, M. F.; Allegrini, J.; Bloch, C.: Familial resemblance
of plasma angiotensin-converting enzyme level: the Nancy study. Am.
J. Hum. Genet. 43: 774-780, 1988.

6. Cambien, F.; Poirier, O.; Lecerf, L.; Evans, A.; Cambou, J.-P.;
Arveiler, D.; Luc, G.; Bard, J.-M.; Bara, L.; Ricard, S.; Tiret, L.;
Amouyel, P.; Alhenc-Gelas, F.; Soubrier, F.: Deletion polymorphism
in the gene for angiotensin-converting enzyme is a potent risk factor
for myocardial infarction. Nature 359: 641-644, 1992.

7. Ehlers, M. R. W.; Fox, E. A.; Strydom, D. J.; Riordan, J. F.:
Molecular cloning of human testicular angiotensin-converting enzyme:
the testis isozyme is identical to the C-terminal half of endothelial
angiotensin-converting enzyme. Proc. Nat. Acad. Sci. 86: 7741-7745,
1989.

8. Evans, A. E.; Poirier, O.; Kee, F.; Lecerf, L.; McCrum, E.; Falconer,
T.; Crane, J.; O'Rourke, D. F.; Cambien, F.: Polymorphisms of the
angiotensin-converting-enzyme gene in subjects who die from coronary
heart disease. Quart. J. Med. 87: 211-214, 1994.

9. Howard, T. E.; Shai, S. Y.; Langford, K. G.; Martin, B. M.; Bernstein,
K. E.: Transcription of testicular angiotensin-converting enzyme
(ACE) is initiated within the 12th intron of the somatic ACE gene. Molec.
Cell. Biol. 10: 4294-4302, 1990.

10. Jeunemaitre, X.; Lifton, R. P.; Hunt, S. C.; Williams, R. R.;
Lalouel, J.-M.: Absence of linkage between the angiotensin converting
enzyme locus and human essential hypertension. Nature Genet. 1:
72-75, 1992.

11. Krege, J. H.; John, S. W. M.; Langenbach, L. L.; Hodgin, J. B.;
Hagaman, J. R.; Bachman, E. S.; Jennette, J. C.; O'Brien, D. A.; Smithies,
O.: Male-female differences in fertility and blood pressure in ACE-deficient
mice. Nature 375: 146-148, 1995.

12. Kurtz, T. W.: The ACE of hearts. Nature 359: 588-589, 1992.

13. Lindpaintner, K.; Lee, M.; Larson, M. G.; Rao, V. S; Pfeffer,
M. A.; Ordovas, J. M.; Schaefer, E. J.; Wilson, A. F.; Wilson, P.
W. F.; Vasan, R. S.; Myers, R. H.; Levy, D.: Absence of association
or genetic linkage between the angiotensin-converting-enzyme gene
and left ventricular mass. New Eng. J. Med. 334: 1023-1028, 1996.

14. Lindpaintner, K.; Pfeffer, M. A.; Kreutz, R.; Stampfer, M. J.;
Grodstein, F.; LaMotte, F.; Buring, J.; Hennekens, C. H.: A prospective
evaluation of an angiotensin-converting-enzyme gene polymorphism and
the risk of ischemic heart disease. New Eng. J. Med. 332: 706-711,
1995.

15. Mattei, M.-G.; Hubert, C.; Alhenc-Gelas, F.; Roeckel, N.; Corvol,
P.; Soubrier, F.: Angiotensin-I converting enzyme gene is on chromosome
17. (Abstract) Cytogenet. Cell Genet. 51: 1041, 1989.

16. Ohishi, M.; Fujii, K.; Minamino, T.; Hagaki, J.; Kamitani, A.;
Rakugi, H.; Zhao, Y.; Mikami, H.; Miki, T.; Ogihara, T.: A potent
genetic risk factor for restenosis. (Letter) Nature Genet. 5: 324-325,
1993.

17. Oike, Y.; Hata, A.; Ogata, Y.; Numata, Y.; Shido, K.; Kondo, K.
: Angiotensin converting enzyme as a genetic risk factor for coronary
artery spasm: implication in the pathogenesis of myocardial infarction. J.
Clin. Invest. 96: 2975-2979, 1995.

18. Okabe, T.; Fusisawa, M.; Yotsumoto, M.; Takaru, F.; Lanzillo,
J. J.; Fanburg, B. L.: Familial elevation of serum angiotensin-converting
enzyme. Quart. J. Med. 216: 55-61, 1985.

19. Pfeffer, M. A.; Braunwald, E.; Moye, L. A.; Basta, L.; Brown,
E. J., Jr.; Cuddy, T. E.; Davis, B. R.; Geltman, E. M.; Goldman, S.;
Flaker, G. C.; Klein, M.; Lamas, G. A.; Packer, M.; Rouleau, J.; Rouleau,
J. L.; Rutherford, J.; Wertheimer, J. H.; Hawkins, C. M.: Effect
of captopril on mortality and morbidity in patients with left ventricular
dysfunction after myocardial infarction: results of the survival and
ventricular enlargement trial. New Eng. J. Med. 327: 669-677, 1992.

20. Rigat, B.; Hubert, C.; Alhenc-Gelas, F.; Cambien, F.; Corvol,
P.; Soubrier, F.: An insertion/deletion polymorphism in the angiotensin
I-converting enzyme gene accounting for half the variance of serum
enzyme levels. J. Clin. Invest. 86: 1343-1346, 1990.

21. Rigat, B.; Hubert, C.; Corvol, P.; Soubrier, F.: PCR detection
of the insertion/deletion polymorphism of the human angiotensin converting
enzyme gene (DCP1) (dipeptidylcarboxypeptidase 1). Nucleic Acids
Res. 20: 1433, 1992.

22. Ruiz, J.; Blanche, H.; Cohen, N.; Velho, G.; Cambien, F.; Cohen,
D.; Passa, P.; Froguel, P.: Insertion/deletion polymorphism of the
angiotensin-converting enzyme gene is strongly associated with coronary
heart disease in non-insulin-dependent diabetes mellitus. Proc. Nat.
Acad. Sci. 91: 3662-3665, 1994.

23. Schachter, F.; Faure-Delanef, L.; Guenot, F.; Rouger, H.; Froguel,
P.; Lesueur-Ginot, L.; Cohen, D.: Genetic associations with human
longevity at the APOE and ACE loci. Nature Genet. 6: 29-32, 1994.

24. Schunkert, H.; Hense, H.-W.; Holmer, S. R.; Stender, M.; Perz,
S.; Keil, U.; Lorell, B. H.; Riegger, G. A. J.: Association between
a deletion polymorphism of the angiotensin-converting-enzyme gene
and left ventricular hypertrophy. New Eng. J. Med. 330: 1634-1638,
1994.

25. Singer, D. R. J.; Missouris, C. G.; Jeffery, S.: Angiotensin-converting
enzyme gene polymorphism: what to do about all the confusion? (Editorial) Circulation 94:
236-239, 1996.

26. Soubrier, F.; Alhenc-Gelas, F.; Hubert, C.; Allegrini, J.; John,
M.; Tregear, G.; Corvol, P.: Two putative active centers in human
angiotensin I-converting enzyme revealed by molecular cloning. Proc.
Nat. Acad. Sci. 85: 9386-9390, 1988.

27. Tiret, L.; Rigat, B.; Visvikis, S.; Breda, C.; Corvol, P.; Cambien,
F.; Soubrier, F.: Evidence, from combined segregation and linkage
analysis, that a variant of the angiotensin I-converting enzyme (ACE)
gene controls plasma ACE levels. Am. J. Hum. Genet. 51: 197-205,
1992.

28. Winkelmann, B. R.; Nauck, M.; Klein, B.; Russ, A. P.; Bohm, B.
O.; Siekmeier, R.; Ihnken, K.; Verho, M.; Gross, W.; Marz, W.: Deletion
polymorphism of the angiotensin I-converting enzyme gene is associated
with increased plasma angiotensin-converting enzyme activity but not
with increased risk for myocardial infarction and coronary artery
disease. Ann. Intern. Med. 125: 19-25, 1996.

29. Yoshida, H.; Mitarai, T.; Kawamura, T.; Kitajima, T.; Miyazaki,
Y.; Nagasawa, R.; Kawaguchi, Y.; Kubo, H.; Ichikawa, I.; Sakai, O.
: Role of the deletion polymorphism of the angiotensin converting
enzyme gene in the progression and therapeutic responsiveness of IgA
nephropathy. J. Clin. Invest. 96: 2162-2169, 1995.

*FIELD* CN
Cynthia K. Ewing - updated: 10/11/1996

*FIELD* CD
Victor A. McKusick: 6/14/1989

*FIELD* ED
terry: 11/04/1996
jamie: 10/23/1996
jamie: 10/16/1996
jamie: 10/11/1996
mark: 4/29/1996
terry: 4/24/1996
mark: 3/14/1996
terry: 3/5/1996
mark: 1/27/1996
terry: 1/26/1996
terry: 1/19/1996
mark: 1/5/1996
terry: 1/3/1996
mark: 6/15/1995
carol: 9/9/1994
jason: 7/19/1994
carol: 12/17/1993
carol: 1/19/1993
carol: 1/7/1993

*RECORD*
*FIELD* NO
106190
*FIELD* TI
106190 ANHIDROSIS, FAMILIAL GENERALIZED, WITH NORMAL SWEAT GLANDS
*FIELD* TX
Dann et al. (1990) reported the case of a young man with generalized
anhidrosis rendering him heat intolerant. His reaction to muscarinic
stimulation of sweat glands was 10% of normal. On biopsy, the sweat
glands were morphologically intact and cardiovascular autonomic
responses were normal. The patient's mother reported reduced sweating
and her response to muscarinic stimulation was 50% of normal, but the
father and 2 sisters sweated normally. A postganglionic defect was
postulated. The sketchy information on the family is consistent with
autosomal dominant inheritance but also with X-linked inheritance since
the deficiency in the mother appears to have been less severe than that
in the son. Ingber (1990) commented that there are 3 types of
generalized anhidrosis: (1) ectodermal dysplasia with generalized
anhidrosis, and hair, sweat gland and dental anomalies with or without
additional congenital defects; (2) ectodermal dysplasia with generalized
anhidrosis, with no other defects but with morphologic and functional
abnormalities of sweat glands; and (3) ectodermal dysplasia with
generalized anhidrosis, with no other defects and with no morphologic
sweat gland anomalies.

*FIELD* RF
1. Dann, E. J.; Epstein, Y.; Sohar, E.: Familial generalized anhidrosis.
Israel J. Med. Sci. 26: 451-453, 1990.

2. Ingber, A.: Familial generalized anhidrosis. Israel J. Med.
Sci. 26: 457-458, 1990.

*FIELD* CS

Skin:
   Generalized anhidrosis

Misc:
   Heat intolerance

Lab:
   Reduced reaction to muscarinic sweat gland stimulation;
   No morphologic sweat gland anomalies

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/25/1991

*FIELD* ED
mimadm: 4/18/1994
supermim: 3/16/1992
carol: 3/25/1991

*RECORD*
*FIELD* NO
106195
*FIELD* TI
*106195 SOLUTE CARRIER FAMILY 4, ANION EXCHANGER, MEMBER 3; SLC4A3
SLC2C;;
ANION EXCHANGER-3; AE3;;
ANION EXCHANGER, NEURONAL
*FIELD* TX
Kopito et al. (1989) isolated AE3, a novel gene expressed primarily in
brain neurons and in heart. The predicted AE3 polypeptide shared a high
degree of identity with the anion exchange and cytoskeletal binding
domains of the erythrocyte band 3 protein (EPB3; 109270), also known as
AE1 or the erythrocyte anion exchanger. Expression of AE3 cDNA in COS
cells led to chronic cytoplasmic acidification and to chloride- and
bicarbonate-dependent changes in intracellular pH, confirming that this
gene product is an anion exchanger. Characterization of an AE3 mutant
lacking the NH2-terminal 645 amino acids demonstrated that the
COOH-terminal half of the polypeptide is both necessary and sufficient
for correct insertion into the plasma membrane and for anion exchange
activity. The NH2-terminal domain may play a role in regulating the
activity of the exchanger and may be involved in the structural
organization of the cytoskeleton in neurons.

The cardiac anion exchanger (AE3) cDNA was cloned from a human
heart-specific cDNA library and the gene was mapped to 2q35-q37.2 by in
situ hybridization (Raney, 1993). Su et al. (1994) isolated and
partially sequenced the AE3 gene (approved gene symbol, SLC4A3).
Oligonucleotide primers based on this sequence were used in a PCR to
specifically amplify a segment of the human gene from a panel of
human/rodent somatic cell hybrids, allowing the assignment of the gene
to chromosome 2. By fluorescence in situ hybridization, the gene was
mapped to 2q36. A polymorphic dinucleotide (GT/CA)n repeat marker was
typed on a subset of the CEPH families; multipoint linkage analysis
placed the SLC2C gene between D2S128 and D2S126. The homologous gene in
the mouse, Ae3, was mapped to chromosome 1 by analysis of recombinant
inbred strains (White et al., 1994).

*FIELD* RF
1. Kopito, R. R.; Lee, B. S.; Simmons, D. M.; Lindsey, A. E.; Morgans,
C. W.; Schneider, K.: Regulation of intracellular pH by a neuronal
homolog of the erythrocyte anion exchanger. Cell 59: 927-937, 1989.

2. Raney, H. M.: Personal Communication. San Diego, Calif.  8/9/1993.

3. Su, Y. R.; Klanke, C. A.; Houseal, T. W.; Linn, S. C.; Burk, S.
E.; Varvil, T. S.; Otterud, B. E.; Shull, G. E.; Leppert, M. F.; Menon,
A. G.: Molecular cloning and physical and genetic mapping of the
human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36. Genomics 22:
605-609, 1994.

4. White, R. A.; Geissler, E. N.; Adkison, L. R.; Dowler, L. L.; Alper,
S. L.; Lux, S. E.: Chromosomal location of the murine anion exchanger
genes encoding AE2 and AE3. Mammalian Genome 5: 827-829, 1994.

*FIELD* CD
Victor A. McKusick: 3/9/1993

*FIELD* ED
terry: 05/16/1996
carol: 2/20/1995
terry: 7/5/1994
warfield: 4/7/1994
carol: 9/2/1993
carol: 3/9/1993

*RECORD*
*FIELD* NO
106200
*FIELD* TI
#106200 ANIRIDIA; AN1
*FIELD* TX
Because of information (Lyons et al., 1992) indicating that a form of
aniridia is not linked to markers on 2p as previously thought, a number
sign (#) is used with this entry. There probably is no form of autosomal
dominant aniridia other than that which maps to 11p13 and was designated
AN2 (106210).

Shaw et al. (1960) ascertained 176 cases of aniridia in the lower
Michigan peninsula. Forty isolated cases were considered mutants. The
frequency in Michigan was about 1.8 x 10(-5) and the mutation rate about
4 x 10(-6) per gamete per generation. Affected persons may be visually
handicapped because of nystagmus, cataract or glaucoma. The ratio of
affected to normal among the offspring of an affected parent was 38 to
62, a significant difference from 50 to 50. Undoubtedly more than one
'cause' of aniridia exists. In an economically depressed area of eastern
Canada, Gove et al. (1961) identified 77 cases of aniridia descended
from an affected woman born in 1824. The aniridias showed approximately
a 20% elevation of reproductive activity as compared with the rest of
the community, and this community was in turn nearly twice as fertile as
the rest of Canada. Delleman and Winkelman (1973) emphasized that
atypical colobomata and slitlike defects of the iris stroma may be
partial expressions of aniridia. Heterogeneity in aniridia was suggested
by the studies of Elsas et al. (1977). Vision was well preserved in one
form, whereas more commonly the affected persons have a poor prognosis
for ocular function because of a high incidence of cataracts, glaucoma,
corneal pannus, nystagmus, and foveal hypoplasia. In addition to the two
types suggested by these differences, they suggested the existence of a
third type associated with mental retardation (Delay and Pichot, 1946;
Grebe, 1954; Gillespie, 1965) and a fourth type associated with Wilms
tumor, genital abnormalities, and deletion of 11p13 (WAGR syndrome;
194072). Since the last form sometimes has mental retardation as a
feature, the earlier reported cases of type 3 may have been instances of
11p13 deletion.

Ferrell et al. (1980) studied a large kindred with aniridia and found
evidence of linkage to ACP1, which is on chromosome 2. Aniridia was
segregating with the B allele at the ACP1 locus (171500). The lod score
varied from 1.81 to 3.45 at theta 0.00, depending on the scoring of
certain persons as to aniridia phenotype. Indeed, marked phenotypic
variability was found in this family with many persons being unaware of
the presence of the trait because they had round pupils and good vision
in at least one eye. Thinning of the iris was a manifestation. The fact
that another aniridia syndrome (AN2) is linked to ACP2 (171650) on 11p,
taken with this evidence, is of great evolutionary interest. Ferrell et
al. (1987) confirmed linkage of AN1 to ACP1 in a study of an additional
16 members of the family they reported in 1980 (Ferrell et al., 1987).
An analysis of the updated pedigree gave a maximal lod score of 3.030 at
theta = 0.078. Lyons et al. (1992) updated and expanded the kindred
segregating for autosomal dominant aniridia on the basis of which
Ferrell et al. (1980, 1987) had suggested linkage to ACP1. The new data
excluded linkage up to theta = 0.17 with lod = -2. Linkage of other 2p
markers to aniridia was excluded. On the other hand, markers from 11p13
showed evidence of linkage. The PvuII RFLP at the D11S323 locus showed
no recombinants with a maximum lod score of Z = 6.97 at theta = 0.00.
The basis of the earlier error was in part due to diagnostic
difficulties; diagnosis, especially at an early age, may be difficult in
patients with round and central pupils. Both normal and affected irides
of such at-risk family members transilluminate in early infancy and do
not transilluminate at maturation. This is consistent with the
hypothesis that aniridia is a disease of the neuroectoderm with normal
acquisition of iris epithelial pigmentation and pupillary musculature,
but secondary faulty induction of the 3 neural crest mesenchymal waves
into the corneal endothelium and trabecular meshwork, corneal stroma,
and iris stroma. The variability in phenotype and the resulting
diagnostic difficulties were commented on by Shaw et al. (1960) and
Hittner et al. (1980).

*FIELD* SA
Balmer and Zografos (1980)
*FIELD* RF
1. Balmer, A.; Zografos, L.: Aniridie, une famille a degre de penetrance
faible. J. Genet. Hum. 28: 195-200, 1980.

2. Delay, J.; Pichot, P.: Sur un maladie familiale characterisee
par l'association d'oligophrenie, d'aniridie et de cataracte congenitale.
Ann. Med. Psychol. 104: 233 only, 1946.

3. Delleman, J. W.; Winkelman, J. E.: Die Bedeutung der atypischen
Kolobome und Defekte der Iris fuer die Erkennung des hereditaeren
Aniridie-Syndroms. Klin. Mbl. Augenheilk. 163: 528-542, 1973.

4. Elsas, F. J.; Maumenee, I. H.; Kenyon, K. R.; Yoder, F.: Familial
aniridia with preserved ocular function. Am. J. Ophthal. 83: 718-724,
1977.

5. Ferrell, R. E.; Chakravarti, A.; Antonarakis, S.; Antoszyk, J.
H.; Hittner, H. M.: Aniridia 1 update of linkage to ACP.  (Abstract) Cytogenet.
Cell Genet. 46: 614 only, 1987.

6. Ferrell, R. E.; Chakravarti, A.; Hittner, H. M.; Riccardi, V. M.
: Autosomal dominant aniridia: probable linkage to acid phosphatase-1
on chromosome 2. Proc. Nat. Acad. Sci. 77: 1580-1582, 1980.

7. Gillespie, F. D.: Aniridia, cerebellar ataxia, and oligophrenia
in siblings. Arch. Ophthal. 73: 338-341, 1965.

8. Gove, J. H.; Shaw, M. W.; Bourque, G.: A family study of aniridia.
Arch. Ophthal. 65: 81-94, 1961.

9. Grebe, H.: Aniridie et oligophrenie--un syndrome hereditaire.
J. Genet. Hum. 3: 269-283, 1954.

10. Hittner, H. M.; Riccardi, V. M.; Ferrell, R. E.; Borda, R. R.;
Justice, J.: Variable expressivity in autosomal dominant aniridia
by clinical, electrophysiology, and angiographic criteria. Am. J.
Ophthal. 89: 531-539, 1980.

11. Lyons, L. A.; Martha, A.; Mintz-Hittner, H. A.; Saunders, G. F.;
Ferrell, R. E.: Resolution of the two loci for autosomal dominant
aniridia, AN1 and AN2, to a single locus on chromosome 11p13. Genomics 13:
925-930, 1992.

12. Shaw, M. W.; Falls, H. F.; Neel, J. V.: Congenital aniridia.
Am. J. Hum. Genet. 12: 389-415, 1960.

*FIELD* CS

Eyes:
   Aniridia;
   Decreased vision;
   Cataract;
   Glaucoma;
   Nystagmus;
   Atypical colobomata;
   Slitlike iris stromal defects;
   Corneal pannus;
   Foveal hypoplasia;
   Optic nerve hypoplasia;
   Thinned iris

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 6/8/1994
carol: 5/10/1994
warfield: 4/6/1994
mimadm: 3/11/1994
carol: 10/5/1992
carol: 8/17/1992

*RECORD*
*FIELD* NO
106210
*FIELD* TI
*106210 ANIRIDIA, TYPE II; AN2
PAIRED BOX HOMEOTIC GENE 6; PAX6, INCLUDED
*FIELD* TX
As indicated in 106200, at least 2 distinct types of aniridia were
thought to exist on the basis of linkage differences and possibly
phenotypic differences. The designation AN1 was used for the aniridia
locus thought to be on chromosome 2 and AN2 for the locus on chromosome
11. However, Lyons et al. (1992) restudied the family on which mapping
of an aniridia locus to 2p was based (Ferrell et al., 1980). They
excluded linkage to markers in the terminal portion of 2p; contrariwise,
strong indication of linkage to markers in the 11p13 region was found.

Although entitled aniridia, this disorder is a panocular one taking its
name from the noticeable iris hypoplasia seen in most cases. This
feature can range from a readily visible, almost complete absence of the
iris, through enlargement and irregularity of the pupil mimicking a
coloboma, to small slitlike defects in the anterior layer seen only on
transillumination with a slit-lamp. The effect on vision is similarly
variable. Elsas et al. (1977) described a large pedigree in which visual
acuity of affected members was nearly normal. By contrast, the presence
of one or more of the associated ocular abnormalities--cataract, lens
dislocation, foveal dysplasia, optic nerve hypoplasia, and
nystagmus--contributes to severe reduction in visual acuity. About half
of cases develop glaucoma which causes severe ocular pain and, if not
treated successfully, can destroy residual vision. In the Gillespie
syndrome (206700), aniridia is associated with cerebellar ataxia and
mental retardation in a combination that may be inherited as an
autosomal recessive. Approximately a third of all cases of aniridia are
sporadic and these are often found to have cytogenetically detectable
deletions involving 11p13, which, if extensive enough, cause the WAGR
contiguous gene syndrome (see 194072).

Simola et al. (1983, 1984) described a family with aniridia in 3
generations and an apparently balanced chromosomal translocation,
t(4;11)(q22;p13). The 3 affected persons were otherwise clinically
normal, had no signs of Wilms tumor, and had normal red cell catalase
levels. Simola et al. (1983) suggested that aniridia in this family was
caused by a submicroscopic deletion at the translocation breakpoint
11p13 or by a position effect on the same chromosome segment. The
observations indicated that the loci for aniridia and Wilms tumor
susceptibility are separate. Turleau et al. (1984) also suggested that
the determinant of aniridia may be separate from that for
nephroblastoma, on the basis of a boy with deletion of most of 11p13,
low catalase, nephroblastoma, chordee and cryptorchidism but normal
irides and no mental retardation. The authors pointed out that in all
published cases with aniridia the distal half of 11p13 is deleted
whereas in their presently reported case there was 'a tiny residual
distal segment.' The observation might suggest the order: cen--CAT
(115503)--WILMS--aniridia--tel; however, Narahara et al. (1984) placed
the catalase locus distal to the WAGR locus. Riccardi et al. (1982)
reported a patient with Wilms tumor and iris dysplasia, not aniridia.
Moore et al. (1986) observed a kindred like that of Simola et al.
(1983). Isolated aniridia was associated with an apparently balanced
translocation, t(11;22)(p13;q12.2). Of the 11 affected persons in 5
generations, 8 who were studied karyologically had the translocation,
whereas 4 unaffected persons had normal karyotypes. In 4 of the 8,
aniridia was associated with glaucoma and cataracts. No Wilms tumor or
genitourinary abnormalities were found in the family and restriction
enzyme analysis showed no abnormality of the catalase gene. They
reviewed data suggesting that the order is centromere--CAT--FSHB
(136530)--Wilms tumor (194070)--AN2--pter.

From a review of many reported cases, Moore et al. (1986) concluded that
single breaks are associated with isolated aniridia whereas deletion of
11p13 results in the WAGR syndrome. The association of a disorder with
seemingly balanced autosomal reciprocal translocation of several other
types has been observed (see, for example, 101200, 115650, 127300,
157900, 175700, 182900, 268800). Some of these may be dominant mutations
created at the breakpoint in one or the other chromosome. Others may
represent 'uncovering' of heterozygosity (e.g., Sandhoff disease,
268800). (The association of Duchenne muscular dystrophy (310200) with
X-autosome translocation in females, with the break in the X chromosome
at Xp21, gave the first indication of the location of that gene; the
fact that the normal X chromosome is inactive in most cells renders the
female liable to the effects of the break at Xp21. Several other
X-linked genes have been regionalized by this approach.) Rutledge et al.
(1986) found a neurologic disorder in a semisterile male mouse
translocation carrier found among the offspring of male mice treated
with triethylenemelamine. Breeding and cytogenetic findings showed
complete concordance between the neurologic disorder and translocation
heterozygosity.

Lyon (1988) suggested that 'Small eye' (Sey) in the mouse, which is on
chromosome 2, may be homologous to aniridia-2 inasmuch as there is a
region of conserved homology of synteny between human 11p and mouse
chromosome 2. This suggestion was corroborated by van der Meer-de Jong
et al. (1990) who found through interspecies backcrosses for linkage
mapping that the Sey gene lies between Fshb and Cas-1. In the human, AN2
lies between the 2 cognate genes, FSHB and CAT. Glaser et al. (1990)
studied the Sey mutation by localizing in an interspecies backcross
between Mus musculus/domesticus and Mus spretus, the region on mouse
chromosome 2 carrying 9 evolutionarily conserved DNA clones from
proximal human 11p. In Dickie's 'Small eye,' they found deletion of 3
clones that encompass the aniridia (AN2) and Wilms tumor susceptibility
genes in man. Unlike their human counterparts, the heterozygous Dickie's
Small-eye mice do not develop nephroblastomas. The homology of Sey and
AN2 was established by the cloning of the AN2 gene in the human and its
homolog in the mouse, and the demonstration of mutations in 3
independent Sey alleles (Hill et al., 1991). The mutations would
predictably disrupt the function of the gene, which belongs to the Pax
multigene family. This family of developmental genes was first described
in Drosophila. A Pax gene referred to as Pax6 is identical to the mouse
homolog of the candidate aniridia gene. Matsuo et al. (1993) found an
internal deletion of about 600 bp in the Pax-6 gene in rats homozygous
for the 'Small eye' mutation. Deletion was due to a single base
insertion that generated an abnormal 5-prime donor splice site. They
showed that anterior midbrain crest cells in the homozygous embryos
reached the eye rudiments but did not migrate any further to the nasal
rudiments, suggesting that the Pax-6 gene is involved in conducting
migration of neural crest cells from the anterior midbrain.

Davis et al. (1988) identified 2 new anonymous DNA segments from the
WAGR region of 11p13. Both probes identified a cytologically
undetectable deletion associated with a balanced chromosome
translocation inherited by a patient with familial aniridia but not
Wilms tumor. The same 2 DNA segments were also included in the distal
11p14.1-p13 deletion of another patient who had aniridia, Wilms tumor,
and hypogonadism, but they were not included in the 11p13-p12 deletion
of a third patient who had Wilms tumor but not aniridia. These 2 DNA
segments, labeled D11S93 and D11S95, map between the catalase and
FSH-beta loci, either very near to or within the aniridia gene. They
should prove to be valuable tools in the identification of the genes in
the WAGR complex, beginning with the aniridia gene. Gessler et al.
(1989) studied 2 families in which familial aniridia was associated with
chromosome translocations involving 11p13. In 1 kindred the
translocation was associated with a deletion; probes for this region
were used to identify and clone the breakpoints of the translocation in
the second kindred. Comparison of phage restriction maps excluded the
presence of any sizable deletion in this case. Sequences at the 11p13
breakpoint were found to be conserved in multiple species, suggesting
that the translocation fell within the AN2 gene. Initial sequence
analysis of the breakpoint showed that the translocation occurred within
an open reading frame that was flanked by consensus splice donor and
acceptor sites, suggesting that it may represent an exon. Pettenati et
al. (1989) reported a fourth instance of a break at 11p13 in association
with aniridia: a father and daughter with isolated aniridia were found
to have an apparently balanced, reciprocal translocation involving
chromosomes 5 and 11 [t(5;11)(q13.1;p13)]. Mannens et al. (1989) found
close linkage between autosomal dominant aniridia and the CAT locus;
maximum lod = 7.27 at theta = 0.00. In the large Dutch family studied,
they excluded linkage between aniridia and a marker at 2p25 that is
linked to ACP1 (171500). Fukushima et al. (1993) described familial
aniridia associated with a cryptic inversion within 11p13.

Fantes et al. (1992) described a mother and son with aniridia associated
with a submicroscopic 11p13 deletion. This was a rare case of an
inherited WAGR deletion; the family was ascertained through the son who
presented with Wilms tumor in a horseshoe kidney. Fluorescence in situ
hybridization with biotin-labeled probes supported the Pax-6 homolog as
a strong candidate for the AN2 gene. FISH with cosmid probes was found
to be a fast and reliable technique for the molecular analysis of
deletions.

Based on the map location of the AN2 locus, Ton et al. (1991) cloned a
candidate cDNA (D11S812E) that was completely or partially deleted in 2
patients with aniridia. The smallest region of overlap between the 2
deletions, comprising less than 70 kb, encompassed the 3-prime coding
region of the cDNA. This cDNA, which spanned over 50 kb of genomic DNA,
detected a 2.7-kb message specifically within all tissues affected in
aniridia. The predicted polypeptide product possessed a paired domain, a
homeodomain, and a serine/threonine-rich carboxy-terminal domain, all
structural motifs characteristic of certain transcription factors. All
evidence pointed to D11S812E as being the AN2 gene. Ton et al. (1992)
isolated a structurally homologous murine embryonic cDNA. It detected a
2.7-kb transcript in the adult mouse eye and cerebellum and in human
glioblastomas, suggesting a neuroectodermal involvement in the
pathogenesis of Sey/AN (see earlier). There was more than 92% identity
in nucleotide sequence and virtually complete identity at the predicted
amino acid level. The gene is clearly the human homolog of the mouse
Pax-6 gene (Walther and Gruss, 1991).

Hanson et al. (1993) described 4 PAX6 point mutations in aniridia
patients, both sporadic and familial. They suggested that the frequency
at which PAX6 mutations are found is an indication that lesions in PAX6
account for most cases of aniridia.

Hanson et al. (1994) presented evidence that PAX6 is involved in other
anterior segment malformations than merely aniridia. They described a
child with Peters anomaly, a major error in the embryonic development of
the eye with corneal clouding with variable iridolenticulocorneal
adhesions (see 261540), in whom one copy of PAX6 was deleted. They also
found that affected members in a family with dominantly inherited
anterior malformations, including Peters anomaly, were heterozygous for
an R26G mutation (106210.0004) in the PAX6 gene. In addition, they
pointed out that a proportion of 'Small eye' mice, heterozygous for a
nonsense mutation in murine Pax-6, have an ocular phenotype resembling
Peters anomaly.

Quiring et al. (1994) isolated a Drosophila gene that contains both a
paired box and a homeo box and has extensive sequence homology to the
mouse Pax-6 gene that is mutant in 'Small eye.' They found that the
Drosophila gene mapped to chromosome IV in a region close to the
'eyeless' locus (ey). Two spontaneous mutations contained transposable
element insertions into the cloned gene and affected gene expression,
particularly in the eye primordia, thus establishing that the cloned
gene encodes 'ey.' The finding that ey of drosophila, Small eye of the
mouse, and human aniridia are encoded by homologous genes suggests that
eye morphogenesis is under similar genetic control in both vertebrates
and insects, in spite of the large differences in eye morphology and
mode of development. Zuker (1994) noted that in his book 'On the Origin
of Species,' Darwin dealt with the difficulties in explaining the
evolution of organs of extreme perfection and complication and focused
on the eye. Furthermore, Salvini-Plawen and Mayr (1977), in their study
of the evolution of eyes, commented: 'It requires little persuasion to
become convinced that the lens eye of a vertebrate and the compound eye
of an insect are independent evolutionary developments.' The Drosophila
compound eye is composed of 800 facets or ommatidia, each containing
photoreceptor neurons, accessory cells, and a lens.

Glaser et al. (1994) described the first example of homozygosity
(actually compound heterozygosity) for a human paired box gene. They
characterized 2 PAX6 mutations in a family segregating for aniridia and
a milder syndrome consisting of congenital cataracts and late-onset
corneal dystrophy. Two nonsense mutations, at codons 103 and 353,
truncated PAX6 within the N-terminal paired and C-terminal PST domains,
respectively. (The PST domain is the 152-amino acid C-terminal region
rich in proline, serine, and threonine.) They showed that the PST domain
functions as a transcriptional activator and that the mutant form has
partial activity. A compound heterozygote had severe craniofacial and
central nervous system defects and no eyes. The head was small with
disproportionately large ears. The nose was malformed with a flattened
bridge, pinpoint external nares, and choanal atresia. Born by caesarean
section at 43 weeks' gestation the infant died on the eighth day of
life. The mother had defects characteristic of aniridia, including
essentially absent irides, bilateral cataracts, decreased visual acuity
in both eyes, an irregular searching nystagmus, small corneal diameters,
and foveal hypoplasia with extension of blood vessels through the
central retinal region. She had no intellectual or neurologic
impairment. Similar findings were present in her mother and
half-brother. The father had developed bilateral cataracts shortly after
birth, which progressed and were extracted at ages 38 and 40. A
circumferential corneal pannus was first noted at age 50. The iris in
each eye had a large post-surgical defect but was otherwise normal. The
foveas appeared well developed. The brain was small and misshapen. The
cerebral hemispheres were thin and widely separated with a single open
ventricular system. Midline fusion occurred focally in the anterior
septal area, but the corpus callosum was otherwise absent. Glaser et al.
(1994) demonstrated that the pattern of malformations was similar to
that in the homozygous Sey mouse and suggested that PAX6 plays a
critical role in controlling the migration and differentiation of
specific neuronal progenitor cells in the brain.

Schedl et al. (1996) generated YAC transgenic mice carrying the human
PAX6 locus. When crossed onto the 'Small eye' background, the transgene
rescued the mutant phenotype. Strikingly, mice carrying multiple copies
on a wildtype background showed specific developmental abnormalities of
the eye, but not of other tissues expressing the gene. Schedl et al.
(1996) commented on the occurrence of abnormalities of the eye in
patients with duplication of part of chromosome 11 including the PAX6
locus. The fact that simple overexpression of the human gene in
transgenic mice causes abnormalities is encouraging for the generation
of mouse models for human trisomies. They noted that generation of
transgenics carrying large fragments of DNA should make it possible to
narrow it down and identify genes responsible for particular aspects of
trisomic phenotypes.

Fantes et al. (1995) studied 2 aniridia pedigrees in which the disease
segregated with chromosomal rearrangements that involved 11p13 but did
not disrupt the PAX6 gene. They isolated YAC clones that encompass the
PAX6 locus and found that, in both pedigrees, the chromosomal breakpoint
is at least 85 kb distal to the 3-prime end of PAX6. In addition, the
open reading frame of PAX6 was apparently free of mutations. Fantes et
al. (1995) proposed that the PAX6 gene on the rearranged chromosome 11
is in an inappropriate chromatin environment for normal expression, and
therefore that a 'position effect' is the underlying mechanism of the
anomaly in these families. Crolla et al. (1996) described another case
which also suggested position effect: sporadic aniridia with a
translocation t(7;11). By fluorescence in situ hybridization they showed
that the breakpoint in 11p13 lay between the PAX6 locus and a region
approximately 100 kb distal to PAX6. No detectable deletion was found
within PAX6, suggesting that the aniridia may have resulted from the
distal chromatin domain containing either enhancers or regulators.
Position effect variegation was reviewed by Karpen (1994).

In the guinea pig, zeta-crystallin (123691) achieves high expression
specifically in lens through use of an alternative promoter. Richardson
et al. (1995) showed that the PAX6 protein binds a site in this promoter
that is essential for lens-specific expression. Lens and lens-derived
cells exhibited a tissue-specific pattern of alternative splicing of
PAX6 transcripts, and PAX6 was expressed in adult lens and cells that
support zeta-crystallin expression. These results suggested that
zeta-crystallin is a natural target gene for PAX6 and that this PAX
family member has a direct role in the continuing expression of
tissue-specific genes.

Martha et al. (1995) found 4 different mutations in PAX6 in 1 sporadic
and 5 familial cases of aniridia: a previously reported mutation and 3
'new' ones. In one family with an affected 32-year-old woman and a
10-year-old daughter, the mother had bilateral erosion of the cornea and
blood vessels on the corneas with bilateral cataracts and also had very
thin irides (106210.0008). In another family with affected father and
son, the father had aniridia, glaucoma, cataracts, and macular agenesis
(106210.0009). In yet another family with affected mother and daughter,
the mother but not the daughter also had anosmia (106210.0010). In all 6
of the aniridia cases, the mutations were predicted to generate
incomplete PAX6 proteins and supported the theory that aniridia is
caused by haploinsufficiency of PAX6.

Hanson and Van Heyningen (1995) reviewed the work on PAX6 in man, mouse,
and Drosophila. A chronology was provided, beginning with identification
of the 'paired' gene as a key regulator of segmentation in Drosophila in
1980 to the discovery by Halder et al. (1995) that ectopic expression of
Drosophila Pax6 induces ectopic eye development.

Autosomal dominant keratitis (148190) is an eye disorder characterized
chiefly by corneal opacification and vascularization and by foveal
hypoplasia. The clinical findings overlap with those of aniridia. For
this reason, Mirzayans et al. (1995) used the candidate-gene approach to
investigate whether mutations in the PAX6 gene are also responsible for
this disorder. Significant linkage was found between 2 polymorphic loci
in the PAX6 region and ADK in a family with 15 affected members in 4
generations; peak lod score = 4.45 at theta = 0.00 with D11S914. By SSCP
analysis and direct sequencing, a mutation was found at the
splice-acceptor site of PAX6 exon 11 (106210.0011). The predicted
consequence was incorrect splicing resulting in truncation of the PAX6
proline-serine-threonine activation domain. The Sey(Neu) mouse results
from a mutation in the Pax-6 exon 10 splice-donor site that produces a
PAX6 protein truncated from the same point as occurred in the family
reported by Mirzayans et al. (1995). Therefore, the Sey(Neu) mouse is an
authentic animal model of ADK. The finding that mutations in PAX6
underlie both ADK and Peters anomaly (106210.0004) implicated PAX6
broadly in human anterior segment malformations.

*FIELD* AV
.0001
ANIRIDIA
PAX6, 2BP INS, FS
In a sporadic case of aniridia, Jordan et al. (1992) demonstrated
insertion of 2 extra bases, AG, resulting in frameshift and producing a
stop codon, TAA, in the next exon. This was predicted to result in
truncation of the protein with exclusion of the remaining C-terminal
portion. The inserted bases created a new restriction site for the
enzyme HinfI which led to the production of additional fragments on
digestion of both DNA and RNA PCR products.

.0002
ANIRIDIA
PAX6, EXON G DEL
In a sporadic case of aniridia (cell line RUBAI), Jordan et al. (1992)
identified a T-to-A transversion at position -6 of the splice acceptor
site immediately 5-prime of exon G. Exon G was missing from the
processed RNA, with exon F joined directly to exon H.

.0003
ANIRIDIA
PAX6, GLN116TER
Davis and Cowell (1993) performed an SSCP analysis exon-by-exon of all
14 exons of the PAX6 gene in 6 aniridia families. In each family, band
shifts were observed on the SSCP gels for only 1 exon, and direct
PCR-sequencing revealed mutations in each case. Two mutations involved
C-to-T transitions in CGA (arg) codons in exons 9 and 11, converting the
codon to stop. Another C-to-T transition converted a CAG (gln) to a TAG
(stop) in exon 7. A 2-bp insertion in exon 5 and a 1-bp insertion in
exon 10 resulted in frameshift and premature termination in 2 further
families. One of the 6 families showed an A-to-T mutation in the fourth
position of the splice donor sequence in intron 5. This was the only
mutation that was not identified by SSCP.

.0004
PETERS ANOMALY
PAX6, ARG26GLY
In a family with dominantly inherited anterior segment malformations
with variable expression, including typical Peters anomaly (family 3 of
Holmstrom et al., 1991), Hanson et al. (1994) found a C-to-G
transversion in nucleotide 438 (numbering according to Ton et al., 1991)
in exon 5 of the PAX6 gene. (The C-to-G change was given as nucleotide
438 in the text, but nucleotide 439 in figure 4 of Hanson et al.
(1994).) The predicted result of this change would be the
nonconservative replacement of arg26 with glycine. In the proband, the
phenotype was that of Peters anomaly, while the phenotype of 2 other
members of the family, his mother and his sister, most closely resembled
the Rieger anomaly (see 180500). Hanson et al. (1994) pointed to
published pedigrees illustrating the considerable variations in
expressivity of both aniridia and anterior segment defects. Stone et al.
(1976) and Beauchamp (1978) each reported a case of a child with an
aniridia-like phenotype in one eye and a Peters-like phenotype in the
other. A profusion of terms is used to describe these anterior segment
malformations, e.g., anterior cleavage anomalies, mesenchymal
dysgenesis, and anterior segment dysgenesis.

.0005
ANIRIDIA
PAX6, ARG103TER
In a family in which a severely affected compound heterozygote was
identified, Glaser et al. (1994) demonstrated that the mother, who had
classic aniridia, had a CGA (arg103)-to-TGA (stop) mutation in exon 6,
which was expected to truncate PAX6 within the C-terminal half of the
paired domain. The resulting 102-amino acid polypeptide could
potentially bind DNA via the N-terminal half of the paired domain, but
would lack the homeo- and PST-domains and therefore would almost
certainly be nonfunctional. The mutation occurred within a CpG
dinucleotide.

.0006
CATARACTS, CONGENITAL, WITH LATE-ONSET CORNEAL DYSTROPHY
PAX6, SER353TER
The father of a child with compound heterozygosity for 2 PAX6 genes and
a very severe ocular, craniofacial, and CNS malformation (Glaser et al.,
1994) had bilateral cataracts evident shortly after birth, which
progressed and were extracted at ages 38 and 40. A circumferential
corneal pannus was first noted at age 50. The man was found to have a
TCA (ser353)-to-TGA (stop) mutation in exon 12, which was expected to
truncate PAX6 in the middle of the PST domain.

.0007
ANIRIDIA
PAX6, IVS12DS G-C, -1
In affected members of a family in which the father and 2 children
showed aniridia, Hanson et al. (1995) found a G-to-C transversion in the
last nucleotide of exon 12 leading to abnormality of splicing and
skipping of exon 12. The wildtype exon 12 splice donor already differed
from the consensus at position 3 and position 6; presumably the
patient's mutation reduced the complementarity further so that the
splice site was no longer recognized by the snRNA.

.0008
ANIRIDIA
PAX6, ARG203TER
Martha et al. (1995) found a C-to-T transition in exon 8 causing an
arg203-to-ter change in codon 203 in a mother and daughter. The mother
had corneal changes.

.0009
ANIRIDIA
ARG240TER
In a father and son with aniridia, Martha et al. (1995) found a C-to-T
transition in exon 9 changing arginine-240 to a stop codon. The father
was said to have macular agenesis in addition to glaucoma and cataracts.

.0010
ANIRIDIA
PAX6, IVS11DS, A-G, -2
In a sporadic case of aniridia and in a family in which a mother and
daughter were analyzed, Martha et al. (1995) found the same mutation in
the 5-prime splice acceptor site between intron 11 and exon 12. This
mutation was predicted to result in deletion of exon 12 of the PAX6
gene. The mutation was an A-to-G transition at position -2.

.0011
KERATITIS, AUTOSOMAL DOMINANT
PAX6, IVS10AS, A-T, -2
In a family with autosomal dominant keratitis in 4 generations,
Mirzayans et al. (1995) found an A-to-T transversion in the exon 11
splice-acceptor site, predicted to result in aberrant splicing and the
skipping of exon 11. The direct joining of exons 10 and 12 would result
in exon 12 being read out of frame, producing a short nonsense peptide
and premature stop. A mutant PAX6 protein truncated for 117 amino acids
from the C-terminus. PAX6 proline-serine-threonine (PST) domain was
expected in affected members of the family.

.0012
FOVEAL HYPOPLASIA, ISOLATED
PAX6, ARG125CYS
Whereas foveal hypoplasia with decreased visual acuity and congenital
nystagmus is a common feature of albinism (203100) and aniridia,
isolated foveal hypoplasia (136520), unassociated with other known
ocular abnormalities, is rare and sporadic (Curran and Robb, 1976,
Oliver et al., 1987). In a family with autosomal dominant isolated
foveal hypoplasia which may be the same as that reported by O'Donnell
and Pappas (1982), Azuma et al. (1996) found that isolated foveal
hypoplasia was associated with a missense mutation in the PAX6 gene. The
mutations occurred in the C-terminal part of the paired domain and was
thought to be the first mutation identified in this region in any member
of the PAX gene family. Affected members of the family were heterozygous
for a mutation in exon 7, a C-to-T transition at nucleotide 799 which
caused an arg125-to-cys substitution (R125C). All affected family
members had poorly defined foveal regions with normal appearing anterior
segments including the iris. The foveal reflex was totally absent and
retinal vessels were noted to cross the presumed foveal region.

*FIELD* SA
Funderburk et al. (1977)
*FIELD* RF
1. Azuma, N.; Nishina, S.; Yanagisawa, H.; Okuyama, T.; Yamada, M.
: PAX6 missense mutation in isolated foveal hypoplasia.(Letter) Nature
Genet. 13: 141-142, 1996.

2. Beauchamp, G. R.: Anterior segment dysgenesis keratolenticular
adhesion and aniridia. J. Pediat. Ophthal. Strabismus 17: 55-58,
1978.

3. Crolla, J. A.; Cross, I.; Atkey, N.; Wright, M.; Oley, C. A.:
FISH studies in a patient with sporadic aniridia and t(7;11)(q31.2;p13). J.
Med. Genet. 33: 66-68, 1996.

4. Curran, R. E.; Robb, R. M.: Isolated foveal hypoplasia. Arch.
Ophthal. 94: 48-50, 1976.

5. Davis, A.; Cowell, J. K.: Mutations in the PAX6 gene in patients
with hereditary aniridia. Hum. Molec. Genet. 2: 2093-2097, 1993.

6. Davis, L. M.; Stallard, R.; Thomas, G. H.; Couillin, P.; Junien,
C.; Nowak, N. J.; Shows, T. B.: Two anonymous DNA segments distinguish
the Wilms' tumor and aniridia loci. Science 241: 840-842, 1988.

7. Elsas, F. J.; Maumenee, I. H.; Kenyon, K. R.; Yoder, F.: Familial
aniridia with preserved ocular function. Am. J. Ophthal. 83: 718-724,
1977.

8. Fantes, J.; Redeker, B.; Breen, M.; Boyle, S.; Brown, J.; Fletcher,
J.; Jones, S.; Bickmore, W.; Fukushima, Y.; Mannens, M.; Danes, S.;
van Heyningen, V.; Hanson, I.: Aniridia-associated cytogenetic rearrangements
suggest that a position effect may cause the mutant phenotype. Hum.
Molec. Genet. 4: 415-422, 1995.

9. Fantes, J. A.; Bickmore, W. A.; Fletcher, J. M.; Ballesta, F.;
Hanson, I. M.; van Heyningen, V.: Submicroscopic deletions at the
WAGR locus, revealed by nonradioactive in situ hybridization. Am.
J. Hum. Genet. 51: 1286-1294, 1992.

10. Ferrell, R. E.; Chakravarti, A.; Hittner, H. M.; Riccardi, V.
M.: Autosomal dominant aniridia: probable linkage to acid phosphatase-1
on chromosome 2. Proc. Nat. Acad. Sci. 77: 1580-1582, 1980.

11. Fukushima, Y.; Hoovers, J.; Mannens, M.; Wakui, K.; Ohashi, H.;
Ohno, T.; Ueoka, Y.; Niikawa, N.: Detection of a cryptic paracentric
inversion within band 11p13 in familial aniridia by fluorescence in
situ hybridization. Hum. Genet. 91: 205-209, 1993.

12. Funderburk, S. J.; Spence, M. A.; Sparkes, R. S.: Mental retardation
associated with 'balanced' chromosome rearrangements. Am. J. Hum.
Genet. 29: 136-141, 1977.

13. Gessler, M.; Simola, K. O. J.; Bruns, G. A. P.: Cloning of breakpoints
of a chromosome translocation identifies the AN2 locus. Science 244:
1575-1578, 1989.

14. Glaser, T.; Jepeal, L.; Edwards, J. G.; Young, S. R.; Favor, J.;
Maas, R. L.: PAX6 gene dosage effect in a family with congenital
cataracts, aniridia, anophthalmia and central nervous system defects. Nature
Genet. 7: 463-471, 1994.

15. Glaser, T.; Lane, J.; Housman, D.: A mouse model of the aniridia-Wilms
tumor deletion syndrome. Science 250: 823-827, 1990.

16. Halder, G.; Callaerts, P.; Gehring, W. J.: Induction of ectopic
eyes by targeted expression of the eyeless gene in Drosophila. Science 267:
1788-1792, 1995.

17. Hanson, I.; Brown, A.; van Heyningen, V.: A new PAX6 mutation
in familial aniridia. J. Med. Genet. 32: 488-489, 1995.

18. Hanson, I.; Van Heyningen, V.: Pax6: more than meets the eye. TIG 11:
268-272, 1995.

19. Hanson, I. M.; Fletcher, J. M.; Jordon, T.; Brown, A.; Taylor,
D.; Adams, R. J.; Punnett, H. H.; van Heyningen, V.: Mutations at
the PAX6 locus are found in heterogeneous anterior segment malformations
including Peters' anomaly. Nature Genet. 6: 168-173, 1994.

20. Hanson, I. M.; Seawright, A.; Hardman, K.; Hodgson, S.; Zaletayev,
D.; Fekete, G.; van Heyningen, V.: PAX6 mutations in aniridia. Hum.
Molec. Genet. 2: 915-920, 1993.

21. Hill, R. E.; Favor, J.; Hogan, B. L. M.; Ton, C. C. T.; Saunders,
G. F.; Hanson, I. M.; Prosser, J.; Jordan, T.; Hastie, N. D.; van
Heyningen, V.: Mouse small eye results from mutations in a paired-like
homeobox-containing gene. Nature 354: 522-525, 1991.

22. Holmstrom, G. E.; Reardon, W. P.; Baraitser, M.; Elston, J. S.;
Taylor, D. S.: Heterogeneity in dominant anterior segment malformations.. Brit.
J. Ophthal. 75: 591-597, 1991.

23. Jordan, T.; Hanson, I.; Zaletayev, D.; Hodgson, S.; Prosser, J.;
Seawright, A.; Hastie, N.; van Heyningen, V.: The human PAX6 gene
is mutated in two patients with aniridia. Nature Genet. 1: 328-332,
1992.

24. Karpen, G. H.: Position effect variegation and the new biology
of heterochromatin. Curr. Opin. Genet. Dev. 4: 281-291, 1994.

25. Lyon, M. F.: Personal Communication. Harwell, England  6/9/1988.

26. Lyons, L. A.; Martha, A.; Mintz-Hittner, H. A.; Saunders, G. F.;
Ferrell, R. E.: Resolution of the two loci for autosomal dominant
aniridia, AN1 and AN2, to a single locus on chromosome 11p13. Genomics 13:
925-930, 1992.

27. Mannens, M.; Bleeker-Wagemakers, E. M.; Bliek, J.; Hoovers, J.;
Mandjes, I.; van Tol, S.; Frants, R. R.; Heyting, C.; Westerveld,
A.; Slater, R. M.: Autosomal dominant aniridia linked to the chromosome
11p13 markers catalase and D11S151 in a large Dutch family. Cytogenet.
Cell Genet. 52: 32-36, 1989.

28. Martha, A.; Strong, L. C.; Ferrell, R. E.; Saunders, G. F.: Three
novel aniridia mutations in the human PAX6 gene. Hum. Mutat. 6:
44-49, 1995.

29. Matsuo, T.; Osumi-Yamashita, N.; Noji, S.; Ohuchi, H.; Koyama,
E.; Myokai, F.; Matsuo, N.; Taniguchi, S.; Doi, H.; Iseki, S.; Ninomiya,
Y.; Fujiwara, M.; Watanabe, T.; Eto, K.: A mutation in the Pax-6
gene in rat small eye is associated with impaired migration of midbrain
crest cells. Nature Genet. 3: 299-304, 1993.

30. Mirzayans, F.; Pearce, W. G.; MacDonald, I. M.; Walter, M. A.
: Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am.
J. Hum. Genet. 57: 539-548, 1995.

31. Moore, J. W.; Hyman, S.; Antonarakis, S. E.; Mules, E. H.; Thomas,
G. H.: Familial isolated aniridia associated with a translocation
involving chromosomes 11 and 22 [t(11;22)(p13;q12.2)]. Hum. Genet. 72:
297-302, 1986.

32. Narahara, K.; Kikkawa, K.; Kimira, S.; Kimoto, H.; Ogata, M.;
Kasai, R.; Hamawaki, M.; Matsuoka, K.: Regional mapping of catalase
and Wilms tumor--aniridia, genitourinary abnormalities, and mental
retardation triad loci to the chromosome segment 11p1305-p1306. Hum.
Genet. 66: 181-185, 1984.

33. O'Donnell, F. E., Jr.; Pappas, H. R.: Autosomal dominant foveal
hypoplasia and presenile cataracts: a new syndrome. Arch. Ophthal. 100:
279-281, 1982.

34. Oliver, M. D.; Dotan, S. A.; Chemke, J.; Abraham, F. A.: Isolated
foveal hypoplasia. Brit. J. Ophthal. 71: 926-930, 1987.

35. Pettenati, M. J.; Weaver, R. G.; Burton, B. K.: Translocation
t(5;11)(q13.1;p13) associated with familial isolated aniridia. Am.
J. Med. Genet. 34: 230-232, 1989.

36. Quiring, R.; Walldorf, U.; Kloter, U.; Gehring, W. J.: Homology
of the eyeless gene of Drosophila to the small eye gene in mice and
aniridia in humans. Science 265: 785-789, 1994.

37. Riccardi, V. M.; Hittner, H. M.; Strong, L. C.; Fernbach, D. J.;
Lebo, R.; Ferrell, R. E.: Wilms tumor with aniridia/iris dysplasia
and apparently normal chromosomes. J. Pediat. 100: 574-577, 1982.

38. Richardson, J.; Cvekl, A.; Wistow, G.: Pax-6 is essential for
lens-specific expression of zeta-crystallin. Proc. Nat. Acad. Sci. 92:
4676-4680, 1995.

39. Rutledge, J. C.; Cain, K. T.; Cacheiro, N. L. A.; Cornett, C.
V.; Wright, C. G.; Generoso, W. M.: A balanced translocation in mice
with a neurological defect. Science 231: 395-397, 1986.

40. Salvini-Plawen, L.; Mayr, E.: On the evolution of photoreceptors
and eyes.In: Hecht, M. K.; Steere, W.; Wallace, B.: Evolutionary
Biology.  New York: Plenum Pub. (pub.)  10: 1977. Pp. 207-263.

41. Schedl, A.; Ross, A.; Lee, M.; Engelkamp, D.; Rashbass, P.; van
Heyningen, V.; Hastie, N. D.: Influence of PAX6 gene dosage on development:
overexpression causes severe eye abnormalities. Cell 86: 71-82,
1996.

42. Simola, K. O. J.; Knuutila, S.; Kaitila, I.; de la Chapelle, A.
: A separate gene for aniridia at 11p13.(Abstract) Cytogenet. Cell
Genet. 37: 584, 1984.

43. Simola, K. O. J.; Knuutila, S.; Kaitila, I.; Pirkola, A.; Pohja,
P.: Familial aniridia and translocation t(4;11)(q22;p13) without
Wilms' tumor. Hum. Genet. 63: 158-161, 1983.

44. Stone, D. L.; Kenyon, K. R.; Green, W. R.; Ryan, S. J.: Congenital
central corneal leukoma (Peters' anomaly). Am. J. Ophthal. 81: 173-193,
1976.

45. Ton, C. C. T.; Hirvonen, H.; Miwa, H.; Weil, M. M.; Monaghan,
P.; Jordan, T.; van Heyningen, V.; Hastie, N. D.; Meijers-Heijboer,
H.; Drechsler, M.; Royer-Pokora, B.; Collins, F.; Swaroop, A.; Strong,
L. C.; Saunders, G. F.: Positional cloning and characterization of
a paired box- and homeobox-containing gene from the aniridia region. Cell 67:
1059-1074, 1991.

46. Ton, C. C. T.; Miwa, H.; Saunders, G. F.: Small eye (Sey): cloning
and characterization of the murine homolog of the human aniridia gene. Genomics 13:
251-256, 1992.

47. Turleau, C.; de Grouchy, J.; Nihoul-Fekete, C.; Dufier, J. L.;
Chavin-Colin, F.; Junien, C.: Del11p13/nephroblastoma without aniridia. Hum.
Genet. 67: 455-456, 1984.

48. van der Meer-de Jong, R.; Dickinson, M. E.; Woychik, R. P.; Stubbs,
L.; Hetherington, C.; Hogan, B. L. M.: Location of the gene involving
the small eye mutation on mouse chromosome 2 suggests homology with
human aniridia 2 (AN2). Genomics 7: 270-275, 1990.

49. Walther, C.; Gruss, P.: Pax-6, a murine paired box gene, is expressed
in the developing CNS. Development 113: 1435-1449, 1991.

50. Zuker, C. S.: On the evolution of eyes: would you like it simple
or compound? Science 265: 742-743, 1994.

*FIELD* CS

Eyes:
   Aniridia;
   Decreased vision;
   Cataract;
   Glaucoma;
   Nystagmus;
   Atypical colobomata;
   Slitlike iris stromal defects;
   Corneal pannus;
   Foveal hypoplasia;
   Optic nerve hypoplasia;
   Thinned iris

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/03/1996
terry: 11/7/1996
terry: 6/11/1996
mark: 5/30/1996
terry: 5/29/1996
mark: 2/17/1996
mark: 2/12/1996
mark: 1/31/1996
mark: 10/2/1995
terry: 8/3/1995
mimadm: 6/26/1994
carol: 5/10/1994
carol: 8/17/1993
carol: 6/25/1993

*RECORD*
*FIELD* NO
106220
*FIELD* TI
106220 ANIRIDIA AND ABSENT PATELLA
*FIELD* TX
Mirkinson and Mirkinson (1975) reported this combination in a boy, his
father, and his paternal grandmother. In the grandmother, bilateral
cataracts and glaucoma complicated the aniridia. The patella was either
hypoplastic or aplastic.

*FIELD* RF
1. Mirkinson, A. E.; Mirkinson, N. K.: A familial syndrome of aniridia
and absence of the patella. Birth Defects Orig. Art. Ser. XI(5):
129-131, 1975.

*FIELD* CS

Eyes:
   Aniridia;
   Cataracts;
   Glaucoma

Skel:
   Absent/hypoplastic patella

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/28/1988

*RECORD*
*FIELD* NO
106230
*FIELD* TI
106230 ANIRIDIA, MICROCORNEA, AND SPONTANEOUSLY REABSORBED CATARACT
*FIELD* TX
Yamamoto et al. (1988) observed this combination in 3 generations of a
family and possibly in a fourth. Although autosomal dominant inheritance
is suggested, there was no male-to-male transmission.

*FIELD* RF
1. Yamamoto, Y.; Hayasaka, S.; Setogawa, T.: Family with aniridia,
microcornea, and spontaneously reabsorbed cataract. Arch. Ophthal. 106:
502-504, 1988.

*FIELD* CS

Eyes:
   Aniridia;
   Microcornea;
   Spontaneously reabsorbed cataract

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 9/21/1988

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 9/21/1988

*RECORD*
*FIELD* NO
106240
*FIELD* TI
106240 ANISOCORIA
*FIELD* TX
Unequal pupil size without associated features of the Horner syndrome
(143000) or any other abnormality has been observed in a dominant
pedigree pattern. We have observed one such family (P14104). Cheng and
Catalano (1990) described uniocular, fatigue-induced mydriasis of the
left pupil in a 36-year-old man and his 7-year-old daughter. The father
dated the onset of his disorder to childhood, and it had been noted in
his daughter for at least 2 years. Anisocoria consistently developed in
both subjects after about 17 hours of wakefulness and resolved after
about 2 hours of sleep. The father had a history of migraine headaches.
The internal ophthalmoplegia that is occasionally seen in patients with
ophthalmoplegic migraine typically follows or accompanies ocular or
periocular pain. Furthermore, the paralysis usually lasts longer than 2
hours.

*FIELD* RF
1. Cheng, M. M. P.; Catalano, R. A.: Fatigue-induced familial anisocoria.
(Letter) Am. J. Ophthal. 109: 480-481, 1990.

*FIELD* CS

Eyes:
   Unequal pupil size;
   Uniocular, fatigue-induced mydriasis

Neuro:
   Normal neurologic examination

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 7/11/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
106250
*FIELD* TI
106250 ANKYLOBLEPHARON FILIFORME ADNATUM AND CLEFT PALATE
*FIELD* TX
Cleft palate and/or cleft lip, together with congenital filiform fusion
of the eyelids, has been observed in families. Khanna (1957) described
affected sisters, one of whom had cleft lip and palate. Other familial
cases were reported by Ehlers and Jensen (1970) and by Lemtis and
Neubauer (1959). Since clefts and ankyloblepharon occur together in the
syndrome of cleft lip-palate, paramedian mucous pits of the lower lip,
popliteal pterygium, etc. (119500), it is not certain that this
represents a separate mutation. Filiform fusion of the eyelids has been
concordant in identical twins (Howe and Harcourt, 1974). There have been
about 30 case reports of the eyelid anomaly and less than 10 cases with
the binary combination (Gorlin, 1982). Evans et al. (1990) reported 3
cases of Edwards syndrome (trisomy 18) with ankyloblepharon filiforme
adnatum.

*FIELD* SA
Akkermans and Stern (1979)
*FIELD* RF
1. Akkermans, C. H.; Stern, L. M.: Ankyloblepharon filiforme adnatum.
Brit. J. Ophthal. 63: 129-131, 1979.

2. Ehlers, N.; Jensen, I. K.: Ankyloblepharon filiforme congenitum
associated with harelip and cleft palate. Acta Ophthal. 48: 465-467,
1970.

3. Evans, D. G. R.; Evans, I. D.; Donnai, D.; Lindenbaum, R. H.:
Ankyloblepharon filiforme adnatum in trisomy 18 Edwards syndrome.
J. Med. Genet. 27: 720-721, 1990.

4. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.  1982.

5. Howe, J.; Harcourt, B.: Ankyloblepharon filiforme adnatum affecting
identical twins. Brit. J. Ophthal. 58: 630-632, 1974.

6. Khanna, V. N.: Ankyloblepharon filiforme adnatum. Am. J. Ophthal. 43:
774-777, 1957.

7. Lemtis, H.; Neubauer, H.: Ankyloblepharon filiforme et membraniforme
adnatum. Klin. Mbl. Augenheilk. 135: 510-516, 1959.

*FIELD* CS

Eyes:
   Congenital filiform eyelid fusion

Mouth:
   Cleft lip/palate

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
mimadm: 3/11/1994
carol: 7/9/1993
carol: 3/23/1992
supermim: 3/16/1992
carol: 11/27/1990

*RECORD*
*FIELD* NO
106260
*FIELD* TI
106260 ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE
AEC SYNDROME;;
HAY-WELLS SYNDROME
*FIELD* TX
Hay and Wells (1976) described 7 individuals from 4 families with an
uncommon disorder characterized by congenital ectodermal dysplasia with
coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp
infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary
hypoplasia; and cleft lip/palate. Speigel and Colton (1985) reported
affected mother and son. Both had cleft lip and palate. The eyelashes
were rudimentary, and in the son there was fusion of the right upper and
lower eyelids at birth. Greene et al. (1987) described 2 isolated cases.
Weiss et al. (1992) described an isolated case. They reported 2 other
patients with ankyloblepharon filiforme adnatum who had chromosomal
abnormalities and 1 patient who had the abnormality as an isolated
finding. Seres-Santamaria et al. (1993) reported a family in which 2
sibs showed cleft palate, ankyloblepharon, and ectodermal defects and,
in addition, had congenital adhesions between the upper and lower jaws
(alveolar synechiae). Neither parent had any features of the syndrome,
suggesting this is either a recessive form of Hay-Wells syndrome with
additional features or should be viewed as a separate entity. It is
possible, of course, that the family reported by Seres-Santamaria et al.
(1993) represented an instance of germinal mosaicism for the dominant
mutation in one of the normal parents.

*FIELD* RF
1. Greene, S. L.; Michels, V. V.; Doyle, J. A.: Variable expression
in ankyloblepharon-ectodermal defects-cleft lip and palate syndrome.
Am. J. Med. Genet. 27: 207-212, 1987.

2. Hay, R. J.; Wells, R. S.: The syndrome of ankyloblepharon, ectodermal
defects and cleft lip and palate: an autosomal dominant condition.
Brit. J. Derm. 94: 287-289, 1976.

3. Seres-Santamaria, A.; Arimany, J. L.; Muniz, F.: Two sibs with
cleft palate, ankyloblepharon, alveolar synechiae, and ectodermal
defects: a new recessive syndrome?. J. Med. Genet. 30: 793-795,
1993.

4. Speigel, J.; Colton, A.: AEC syndrome: ankyloblepharon, ectodermal
defects, and cleft lip and palate. J. Am. Acad. Derm. 12: 810-815,
1985.

5. Weiss, A. H.; Riscile, G.; Kousseff, B. G.: Ankyloblepharon filiforme
adnatum. Am. J. Med. Genet. 42: 369-373, 1992.

*FIELD* CS

Eyes:
   Congenital filiform eyelid fusion

Skin:
   Congenital ectodermal dysplasia;
   Slight hypohidrosis;
   Scalp infections

Mouth:
   Cleft lip/palate;
   Alveolar ridge synechiae

Hair:
   Coarse, wiry, sparse hair;
   Rudimentary eyelashes

Nails:
   Dystrophic nails

Teeth:
   Hypodontia

Facies:
   Maxillary hypoplasia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 5/19/1987

*FIELD* ED
mark: 11/1/1995
mimadm: 3/11/1994
carol: 11/3/1993
carol: 11/2/1993
carol: 10/29/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
106280
*FIELD* TI
106280 ANKYLOGLOSSIA
'@TONGUE-TIE'
*FIELD* TX
Keizer (1952) described a Dutch family in which 13 persons in 3
generations had ankyloglossia. There were many instances of male-to-male
transmission.

*FIELD* RF
1. Keizer, D.: Casuistische mededelingen dominant erfeljik ankyloglosson.
Nederl. T. Geneesk. 96: 2203-2205, 1952.

*FIELD* CS

Mouth:
   Ankyloglossia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 2/25/1988

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 2/25/1988

*RECORD*
*FIELD* NO
106300
*FIELD* TI
*106300 ANKYLOSING SPONDYLITIS; AS
MARIE-STRUMPELL SPONDYLITIS;;
BECHTEREW SYNDROME
*FIELD* TX
Karten et al. (1962) demonstrated familial aggregation. Rheumatoid
arthritis and positive tests for rheumatoid factor were found no more
often in the relatives of spondylitics than in those of controls,
suggesting that rheumatoid arthritis and ankylosing spondylitis are
distinct entities. De Blecourt et al. (1961) found spondylitis 22.6
times more frequently in the relatives of spondylitic patients than in
the relatives of controls. They suggested autosomal dominant inheritance
with greater penetrance in males than in females. O'Connell (1959)
arrived at the same conclusion. The familial incidence was higher when
the proband was female. Kornstad and Kornstad (1960) described 2
families in which only females were affected. Emery and Lawrence (1967)
presented data that they interpreted as indicating multifactorial
inheritance, however. Linkage data were published by Kornstad and
Kornstad (1960) and earlier by Riecker et al. (1950). Schlosstein et al.
(1973) found HLA specificity w27 in 35 of 40 cases of ankylosing
spondylitis and in only 8% of normal controls. The HLA findings brought
thinking about the genetics full-circle. Autosomal dominant inheritance
with reduced penetrance seemed to be established.

The finding of B27 in 16 of 17 AS cases in India and in 2 of 60 controls
(Sengupta et al., 1977) appears to exclude genetic linkage as the basis
of the association. Calin et al. (1983) studied 499 available
first-degree relatives of 79 HLA-B27-positive patients with ankylosing
spondylitis and 69 HLA-B27-positive healthy blood donors. The rate of
ankylosing spondylitis cases was estimated to be 10.6% as compared with
1.9% in B27-positive relatives of healthy persons (p less than 0.025).
This suggested a genetic difference between B27-positive diseased
persons and B27-positive healthy persons. It was thought that complete
sequencing of HLA-B27 cDNA might help identify whether this polymorphic
marker is directly related in the etiology of AS and, if so, what the
mechanism of that involvement is (Szots et al., 1986). Calin and Elswood
(1989) analyzed 42 sib pairs concordant for ankylosing spondylitis. They
found that the correlation coefficient was not significant for age at
onset but was much higher, reaching a level of significance at the 0.01
level, for calendar year of onset. This was interpreted as consistent
with environmental factors playing a greater role in the timing of
onset. Concordance with the presence or absence of uveitis was only 43%,
again suggesting that genetic factors are less significant than
environment. Conversely, genetic factors appear to be more important
than environment in influencing prognosis as measured by a disability
and pain index and by the severity of radiologic findings. James (1991)
suggested an ingenious explanation for the fact that, in conditions
suspected of multifactorial inheritance, the sex ratio (proportion of
males) of randomly ascertained probands is more extreme than that of
their affected relatives. He used a simple model, based on
multifactorial inheritance with liability varying by sex, and the
following assumptions: (1) the variances of male and female liability
are equal; (2) the variances of liability in male and female sibs of
probands take the same value; and (3) the difference between the mean
liabilities of males and females in the general population is equal to
the difference between the mean liabilities of male and female sibs of
cases. With a pair of diagrams, one for the male and female
distributions in the general population and one for the relatives of
probands, he demonstrated that the proportion of males above the
threshold is less markedly different from the proportion of females in
the case of relatives. The other conditions with unusual sex ratio that
were studied included infantile pyloric stenosis (179010), otosclerosis
(166800), congenital dislocation of the hip (142700), and systemic lupus
erythematosus (152700).

Despite the strong association between HLA-B27 and ankylosing
spondylitis, linkage of this phenotype to the MHC region had not been
established before the study of Rubin et al. (1992, 1994) involving 15
multiplex AS families. Among affected family members, 13 of 15 females
and 46 of 49 males were B27 positive, as compared with 22 of 43
unaffected females and 16 of 40 unaffected males. The linkage analysis
was based on a genetic model with a frequency of the AS gene of 1.8%;
the risk of AS for homozygotes was placed at 99.5% and for heterozygotes
at 43% with a sporadic risk of 0.1%. Analysis showed linkage with the
MHC region, with a lod score of 3.36 at no recombination. The B27
haplotype did not consistently segregate with disease in 2 families, but
both families still supported linkage. In a second analysis in which the
population association of HLA-B27 with AS was taken into account, the
maximum lod score was 7.5 at theta = 0.05. Identity-by-descent analyses
showed a significant departure from random segregation among affected
avuncular (uncle/nephew-niece) and cousin pairs. The presence of HLA-B40
in HLA-B27 positive individuals increased the risk for disease more than
3-fold, confirming previous reports. Disease susceptibility modeling
suggested an autosomal dominant pattern of inheritance with penetrance
of approximately 20%. In this study, which involved families from
Toronto and Newfoundland, B27 alleles were detected by hybridization
with sequence-specific oligonucleotide probes (SSOP) after amplification
of genomic DNA by PCR.

Mahowald et al. (1988) analyzed the features of murine progressive
ankylosis, an autosomal recessive mutation first described by Sweet and
Green (1981). Peripheral joints were inflamed initially, then became
ankylosed in a predictable sequence from distal to proximal. Axial joint
involvement produced severe spinal ankylosis. Vertebral syndesmophytes
produced a 'bamboo' spine. Mahowald et al. (1988) suggested that this is
a useful animal model for study of the human spondyloarthropathies.

Scofield et al. (1993) used protein sequence databases to test a series
of hypotheses: first, they asked whether the primary amino acid sequence
of the hypervariable regions of HLA-B27 shares short sequences with the
proteins of gram-negative enteric bacteria. They found that, unique
among the HLA-B molecules, the hypervariable regions of HLA-B27 shared
short peptide sequences with proteins from these bacteria, indicating
the possibility of antigen mimicry. Second, they asked whether the
enteric proteins satisfy the structural requirements for peptide binding
to B27. This hypothesis also tended to be true. Scofield et al. (1993)
concluded that HLA-B27 and enteric gram-negative bacteria have undergone
convergent evolution. The regions of the enteric bacterial proteins that
are contiguous with the short sequences shared with B27 tend to have
structures that are also predicted to bind B27. The observation
suggested a mechanism for autoimmunity and led to the prediction that
the B27-associated diseases are mediated by a subset of T-cell
receptors, B27, and the peptides bound by B27.

HLA-B27 shares sequence with proteins from enteric bacteria. Scofield et
al. (1995) pointed out that the B*2705 sequence contains a nonapeptide
(LRRYLENGK) predicted to bind in the binding cleft of B27. Some
nonapeptides from enteric organisms that share sequence with this
nonapeptide of B27 also bind B27. Thus, peptides that both mimic and
bind B27 may constitute the molecular components of a mechanism for
spondyloarthropathies.

Kidd et al. (1995) described a family in which 7 of 12 members had early
onset oligo- or polyarthritis, enthesitis, or both, and fulfilled
established criteria for spondyloarthropathy, although none had
radiologic evidence of sacroiliitis. The mean age at first symptom was
22 years, with only 1 individual having the first symptom beyond the age
of 30 years. All subjects were rheumatoid factor negative.
Histocompatibility showed association with HLA-B7. None had psoriasis or
inflammatory bowel disease.

Gran and Husby (1995) expressed the view that the HLA-B27 test is of
limited usefulness. It cannot, in their view, be used for confirming a
diagnosis of spondyloarthropathy or predicting the prognosis in patients
with an established diagnosis of inflammatory rheumatic disease. The
test can be used in 3 ways: first, if the likelihood of
spondyloarthropathy based on symptoms and signs is greater than 50%, a
B27-positive test result significantly increases the chance for correct
diagnosis. A high pretest likelihood, however, required reliable
diagnostic criteria. Secondly, in patients with back pain and stiffness,
a negative B27 test result very strongly indicates that the complaints
are caused by disorders other than AS. In the absence of concurrent
psoriasis or inflammatory bowel disease, a negative B27 test result
virtually excludes a diagnosis of AS. Third, a positive B27 test in
children with established inflammatory joint disease may help the
physician focus on the possible development of seronegative
spondyloarthropathy.

*FIELD* SA
Brewerton  (1976); Brewerton et al. (1973); Caffrey and James (1973);
Calin and Fries (1975); Falace et al. (1978); Gofton et al. (1975);
Lockshin et al. (1975); Moller and Berg (1983); Moller and Berg (1984);
Russell and Percy (1975); Woodrow and Eastmond (1978)
*FIELD* RF
1. Brewerton, D. A.: HLA-B27 and the inheritance of susceptibility
to rheumatic disease. Arthritis Rheum. 19: 656-668, 1976.

2. Brewerton, D. A.; Hart, F. D.; Nicholls, A.; Caffrey, M.; James,
D. C. O.; Sturrock, R. D.: Ankylosing spondylitis and HL-27. Lancet I:
904-907, 1973.

3. Caffrey, M. F. P.; James, D. C. O.: Human lymphocyte antigen association
in ankylosing spondylitis. Nature 242: 121 only, 1973.

4. Calin, A.; Elswood, J.: Relative role of genetic and environmental
factors in disease expression: sib pair analysis in ankylosing spondylitis.
Arthritis Rheum. 32: 77-81, 1989.

5. Calin, A.; Fries, J. F.: Striking prevalence of ankylosing spondylitis
in 'healthy' W27 positive males and females: a controlled study. New
Eng. J. Med. 293: 835-839, 1975.

6. Calin, A.; Marder, A.; Becks, E.; Burns, T.: Genetic differences
between B27 positive patients with ankylosing spondylitis and B27
positive healthy controls. Arthritis Rheum. 26: 1460-1464, 1983.

7. De Blecourt, J. J.; Polman, A.; De Blecourt-Meindersma, T.: Hereditary
factors in rheumatoid arthritis and ankylosing spondylitis. Ann.
Rheum. Dis. 20: 215-220, 1961.

8. Emery, A. E. H.; Lawrence, J. S.: Genetics of ankylosing spondylitis.
J. Med. Genet. 4: 239-244, 1967.

9. Falace, P.; Ruderman, R. J.; Ward, F. E.; Swift, M.: Histocompatibility
typing and the counseling of families with ankylosing spondylitis.
Clin. Genet. 13: 380-383, 1978.

10. Gofton, J. P.; Chalmers, A.; Price, G. E.; Reeve, C. E.: HL-A27
and ankylosing spondylitis in B.C. Indians. J. Rheum. 2: 314-318,
1975.

11. Gran, J. T.; Husby, G.: HLA-B27 and spondyloarthropathy: value
for early diagnosis?. J. Med. Genet. 32: 497-501, 1995.

12. James, W. H.: The sex ratios of probands and of secondary cases
in conditions of multifactorial inheritance where liability varies
with sex. J. Med. Genet. 28: 41-43, 1991.

13. Karten, I.; Ditata, D.; McEwen, C.; Tanner, M. S.: A family study
of rheumatoid (ankylosing) spondylitis. Arthritis Rheum. 5: 131-143,
1962.

14. Kidd, B. L.; Wilson, P. J.; Evans, P. R.; Cawley, M. I. D.: Familial
aggregation of undifferentiated spondyloarthropathy associated with
HLA-B7. Ann. Rheum. Dis. 54: 125-127, 1995.

15. Kornstad, A. M. G.; Kornstad, L.: Ankylosing spondylitis in two
families showing involvement of female members only, with a search
for linkage to genes determining blood group antigens. Acta Rheum.
Scand. 6: 59-64, 1960.

16. Lockshin, M. D.; Fotino, M.; Gough, W. W.; Litwin, S. D.: Ankylosing
spondylitis and HL-A: a genetic disease plus?. Am. J. Med. 58:
695-703, 1975.

17. Mahowald, M.; Krug, H.; Taurog, J.: Progressive ankylosis in
mice: an animal model of spondylarthropathy. I. Clinical and radiographic
findings. Arthritis Rheum. 31: 1390-1399, 1988.

18. Moller, P.; Berg, K.: Family studies in Bechterew's syndrome
(ankylosing spondylitis). III. Genetics. Clin. Genet. 24: 73-89,
1983.

19. Moller, P.; Berg, K.: Ankylosing spondylitis is part of a multifactorial
syndrome: hereditary multifocal relapsing inflammation (HEMRI). Clin.
Genet. 26: 187-194, 1984.

20. O'Connell, D.: Heredity in ankylosing spondylitis. Ann. Intern.
Med. 50: 1115-1121, 1959.

21. Riecker, H. H.; Nell, J. V.; Test, A. R.: The inheritance of
spondylitis rhizomelique (ankylosing spondylitis) in the K family.
Ann. Intern. Med. 33: 1254-1273, 1950.

22. Rubin, L. A.; Amos, C. I.; Wade, J. A.; Martin, J. R.; Bale, S.
J.; Little, A. H.; Gladman, D. D.; Bonney, G. E.; Rubenstein, J. D.;
Siminovitch, K. A.: Investigating the genetic basis for ankylosing
spondylitis: linkage studies with the major histocompatibility complex
region. Arthritis Rheum. 37: 1212-1220, 1994.

23. Rubin, L. R.; Amos, C. I.; Falk-Wade, J.; Martin, J.; Bonney,
G. E.; Bale, S. J.; Gladman, D.; Siminovitch, K.; Little, H.; Rubinstein,
J.: Linkage studies of class I MHC region genes in ankylosing spondylitis.
(Abstract) Am. J. Hum. Genet. 51 (suppl.): A34 only, 1992.

24. Russell, A. S.; Percy, J. S.: Prevalence of ankylosing spondylitis.
New Eng. J. Med. 292: 1352 only, 1975.

25. Schlosstein, L.; Terasaki, P. I.; Bluestone, R.; Pearson, C. M.
: High association of an HL-A antigen, W27, with ankylosing spondylitis.
New Eng. J. Med. 288: 704-706, 1973.

26. Scofield, R. H.; Kurien, B.; Gross, T.; Warren, W. L.; Harley,
J. B.: HLA-B27 binding of peptide from its own sequence and similar
peptides from bacteria: implications for spondyloarthropathies. Lancet 345:
1542-1544, 1995.

27. Scofield, R. H.; Warren, W. L.; Koelsch, G.; Harley, J. B.: A
hypothesis for the HLA-B27 immune dysregulation in spondyloarthropathy:
contributions from enteric organisms, B27 structure, peptides bound
by B27, and convergent evolution. Proc. Nat. Acad. Sci. 90: 9330-9334,
1993.

28. Sengupta, S.; Sehgal, S.; Aikat, B. K.; Deodhar, S. D.; James,
D. C. O.: HLA B27 in ankylosing spondylitis in India.  (Letter) Lancet I:
1209-1210, 1977.

29. Sweet, H. O.; Green, M. C.: Progressive ankylosis, a new skeletal
mutation in the mouse. J. Hered. 72: 87-93, 1981.

30. Szots, H.; Riethmuller, G.; Weiss, E.; Meo, T.: Complete sequence
of HLA-B27 cDNA identified through the characterization of structural
markers unique to the HLA-A, -B, and -C allelic series. Proc. Nat.
Acad. Sci. 83: 1428-1432, 1986.

31. Woodrow, J. C.; Eastmond, C. J.: HLA B-27 and the genetics of
ankylosing spondylitis. Ann. Rheum. Dis. 37: 504-509, 1978.

*FIELD* CS

Skel:
   Ankylosing spondylitis

Spine:
   Back pain and stiffness

Eyes:
   Iridocyclitis

Cardiac:
   AV block;
   Aortic insufficiency

Radiology:
   Sacroiliitis;
   Bamboo spine

Lab:
   HLA-B27 haplotype association

Inheritance:
   Autosomal dominant with greater penetrance in males

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 11/6/1995
terry: 9/13/1995
mimadm: 3/11/1994
carol: 11/9/1993
carol: 10/18/1993
carol: 10/29/1992

*RECORD*
*FIELD* NO
106400
*FIELD* TI
106400 ANKYLOSING VERTEBRAL HYPEROSTOSIS WITH TYLOSIS
DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS, INCLUDED;;
DISH, INCLUDED
*FIELD* TX
Beardwell (1969) described a family of Greek Cypriot extraction in which
at least 8 persons in 4 sibships in 2 generations were known to have a
combination of ankylosing vertebral hyperostosis and tylosis (144200).
The tylosis was a punctate hyperkeratosis of the soles and palms. In
addition, 6 persons had tylosis alone; thus, these may have been 2
independent genetic traits in this kindred. (This condition is sometimes
called Forestier disease, although Forestier described senile ankylosing
hyperostosis (Forestier and Rotes-Querol, 1950) and, before Beardwell's
paper, familial occurrence had never been noted.) The family contained
instances of male-to-male transmission. No member had the spinal disease
without tylosis. No further families were known to Beardwell (1978).
Involvement of the appendicular skeleton was recognized by Resnick et
al. (1975), who proposed the designation diffuse idiopathic skeletal
hyperostosis (DISH). The prevalence of DISH was studied in various
population groups by Utsinger (1985). Although DISH was thought to be
less common in American blacks as compared to Caucasians, Cassim et al.
(1990) found it rather frequent among hospitalized blacks in Africa.

*FIELD* RF
1. Beardwell, A.: Familial ankylosing vertebral hyperostosis with
tylosis. Ann. Rheum. Dis. 28: 518-523, 1969.

2. Beardwell, A.: Personal Communication. Barking, Essex, England
1978.

3. Cassim, B.; Mody, G. M.; Rubin, D. L.: The prevalence of diffuse
idiopathic skeletal hyperostosis in African blacks. Brit. J. Rheum. 29:
131-132, 1990.

4. Forestier, J.; Rotes-Querol, J.: Senile ankylosing hyperostosis
of the spine. Ann. Rheum. Dis. 9: 321-330, 1950.

5. Resnick, D.; Shaul, S. R.; Robins, J. M.: Diffuse idiopathic skeletal
hyperostosis (DISH): Forestier's disease with extraspinal manifestations.
Radiology 115: 513-524, 1975.

6. Utsinger, P. D.: Diffuse idiopathic skeletal hyperostosis. Clin.
Rheum. Dis. 11: 325-351, 1985.

*FIELD* CS

Spine:
   Ankylosing vertebral hyperostosis

Skin:
   Tylosis;
   Punctate palmar and solar hyperkeratosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
mimadm: 3/11/1994
carol: 12/4/1992
carol: 10/29/1992
carol: 10/22/1992
carol: 10/21/1992

*RECORD*
*FIELD* NO
106410
*FIELD* TI
*106410 ANKYRIN, NONERYTHROID
ANKYRIN-2; ANK2;;
ANKYRIN, BRAIN;;
ANKYRIN-B
*FIELD* TX
Tse et al. (1991) studied immunoreactive isoforms of erythrocyte ankyrin
found in nonerythroid tissues. Using an erythrocyte ankyrin cDNA clone
as a hybridization probe, they isolated a clone from a human genomic
library that hybridized at low but not at high stringency. Further
studies suggested that the clone represented part of a gene for
nonerythroid ankyrin, which they designated ANK2. By analysis of somatic
cell hybrids and by fluorescence in situ hybridization, they assigned
ANK2 to 4q25-q27. Otto et al. (1991) isolated and sequenced cDNAs
related to 2 brain ankyrin isoforms and showed that they are produced
through alternative splicing of the mRNA from a single gene. By analysis
of human/rodent cell hybrids, Otto et al. (1991) assigned the brain
ankyrin gene to chromosome 4.

*FIELD* RF
1. Otto, E.; Kunimoto, M.; McLaughlin, T.; Bennett, V.: Isolation
and characterization of cDNAs encoding human brain ankyrins reveal
a family of alternatively spliced genes. J. Cell Biol. 114: 241-253,
1991.

2. Tse, W. T.; Menninger, J. C.; Yang-Feng, T. L.; Francke, U.; Sahr,
K. E.; Lux, S. E.; Ward, D. C.; Forget, B. G.: Isolation and chromosomal
localization of a novel non-erythroid ankyrin gene. Genomics 10:
858-866, 1991.

*FIELD* CD
Victor A. McKusick: 5/15/1991

*FIELD* ED
mark: 3/20/1995
carol: 4/7/1993
carol: 10/23/1992
supermim: 3/16/1992
carol: 8/8/1991
carol: 5/15/1991

*RECORD*
*FIELD* NO
106490
*FIELD* TI
*106490 ANNEXIN III; ANX3
LIPOCORTIN III
*FIELD* TX
The annexins are a family of calcium-dependent phospholipid-binding
proteins. The family consists of at least 10 distinct members, each of
which contains 4 or 8 copies of an 80-amino acid repeating unit first
identified in lipocortin/annexin I. Annexin III was previously
identified as inositol 1,2-cyclic phosphate 2-phosphohydrolase (EC
3.1.4.36), an enzyme of inositol phosphate metabolism, and also as
placental anticoagulant protein III, lipocortin III, calcimedin
35-alpha, and an abundant neutrophil cytoplasmic protein. Tait et al.
(1991) localized the ANX3 gene to 4q21 (q13-q22) by PCR analysis of a
human-rodent hybrid cell panel, confirmed by genomic Southern blot
analysis of the same panel with a cDNA probe, and by in situ
hybridization with a cDNA probe.

The mature annexin III protein contains 322 amino acids and, like other
annexins, consists primarily of 4 copies of a 70- to 80-amino-acid
repeat unit. Characterizing the gene from directly amplified genomic DNA
and from 6 genomic clones in phage lambda, Tait et al. (1993) determined
that the transcribed region spans 58 kb and contains 12 introns ranging
from 0.3 to 19.1 kb and 13 exons ranging from 53 to 374 bases. Northern
blot showed a single mRNA species with approximately 1.7 kb in all
tissues examined.

*FIELD* RF
1. Tait, J. F.; Frankenberry, D. A.; Miao, C. H.; Killary, A. M.;
Adler, D. A.; Disteche, C. M.: Chromosomal localization of the human
annexin III (ANX3) gene. Genomics 10: 441-448, 1991.

2. Tait, J. F.; Smith, C.; Xu, L.; Cookson, B. T.: Structure and
polymorphisms of the human annexin III (ANX3) gene. Genomics 18:
79-86, 1993.

*FIELD* CD
Victor A. McKusick: 6/17/1991

*FIELD* ED
mark: 11/27/1996
joanna: 2/5/1996
mimadm: 3/11/1994
carol: 10/13/1993
supermim: 3/16/1992
carol: 6/17/1991

*RECORD*
*FIELD* NO
106491
*FIELD* TI
*106491 ANNEXIN IV; ANX4
PLACENTAL ANTICOAGULANT PROTEIN II
*FIELD* TX
The annexins, or lipocortins, are a family of calcium-dependent
phospholipid-binding proteins whose normal function is uncertain.
Annexin IV, otherwise known as placental anticoagulant protein II, was
one of the 4 annexins isolated from human placenta on the basis of their
in vitro anticoagulant activity. Grundmann et al. (1988) reported a cDNA
clone for annexin IV. Hauptmann et al. (1989) showed that annexin IV has
45 to 59% identity with other members of the annexin family. By PCR
analysis of somatic cell hybrids and in situ hybridization with a cDNA
probe, Tait et al. (1992) mapped the human ANX4 gene to 2p13. Genomic
Southern blotting with a cDNA probe indicated a gene size of 18-56 kb.
DNA sequence analysis demonstrated a single intron with exon-intron
boundaries in exactly the same position as in the mouse annexin I and
annexin II genes. Barrow et al. (1994) demonstrated that the Anx4 gene
is located on mouse chromosome 6 in a region of conserved synteny with
human chromosome 2.

*FIELD* RF
1. Barrow, L. L.; Simin, K.; Jones, J. M.; Lee, D. C.; Meisler, M.
H.: Conserved linkage of early growth response 4, annexin 4, and
transforming growth factor alpha on mouse chromosome 6. Genomics 19:
388-390, 1994.

2. Grundmann, U.; Amann, E.; Abel, K.-J.; Kupper, H. A.: Isolation
and expression of cDNA coding for a new member of the phospholipase
A2 inhibitor family. Behring Inst. Mitt. 82: 59-67, 1988.

3. Hauptmann, R.; Maurer-Fogy, I.; Krystek, E.; Bodo, G.; Andree,
H.; Reutelingsperger, C. P. M.: Vascular anticoagulant beta, a novel
human Ca(2+)/phospholipid binding protein that inhibits coagulation
and phospholipase A-2 activity: its molecular cloning, expression
and comparison with VAC-alpha. Europ. J. Biochem. 185: 63-71, 1989.

4. Tait, J. F.; Smith, C.; Frankenberry, D. A.; Miao, C. H.; Adler,
D. A.; Disteche, C. M.: Chromosomal mapping of the human annexin
IV (ANX4) gene. Genomics 12: 313-318, 1992.

*FIELD* CD
Victor A. McKusick: 2/1/1992

*FIELD* ED
mark: 12/29/1996
joanna: 2/5/1996
mimadm: 3/11/1994
carol: 2/15/1994
supermim: 3/16/1992
carol: 2/26/1992
carol: 2/18/1992
carol: 2/1/1992

*RECORD*
*FIELD* NO
106500
*FIELD* TI
106500 ANNULAR ERYTHEMA
*FIELD* TX
Beare et al. (1966) described an Irish family in which 4 persons in 3
generations suffered from annular erythema.

*FIELD* RF
1. Beare, J. M.; Froggatt, P.; Jones, J. H.; Neill, D. W.: Familial
annular erythema, an apparently new dominant mutation. Brit. J.
Derm. 78: 59-68, 1966.

*FIELD* CS

Skin:
   Annular erythema

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
106600
*FIELD* TI
*106600 ANODONTIA, PARTIAL
HYPODONTIA;;
TOOTH AGENESIS, SELECTIVE;;
TOOTH AGENESIS, FAMILIAL
*FIELD* TX
Erwin and Cockern (1949) described absent second bicuspids and third
molars in 9 members of 3 generations. (Partial anodontia is an obsolete
term (Salinas, 1978). Hypodontia is the presently preferred term.) The
defect in this kindred may be the same as that in the family reported by
Vastardis et al. (1996) as showing linkage to 4p and showing a point
mutation in the MSX1 gene (142983). Vastardis et al. (1996) referred to
the disorder in their family as selective tooth agenesis.

Gorlin (1982) pointed out that about a third of the general population
are missing one or more of the third molars and that premolars are, next
to the third molars, the teeth most often missing. See 114600, 150400,
194100, 302400.

Lyngstadaas et al. (1996) observed an increase in the number of
congenitally missing teeth in the offspring of affected subjects from 2
unrelated Norwegian families. This suggested to them that the disorder
was due to allelic mutations at a single gene locus, or alternatively,
that incompletely penetrant nonallelic genes were showing a synergistic
effect. Brittle nails, delayed growth of hair, and delayed teething in
the probands supported the grouping of the condition among the
ectodermal dysplasias.

*FIELD* RF
1. Erwin, W. G.; Cockern, R. W.: A pedigree of partial anodontia. J.
Hered. 40: 215-218, 1949.

2. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.  1982.

3. Lyngstadaas, S. P.; Nordbo, H.; Gedde-Dahl, T., Jr.; Thrane, P.
S.: On the genetics of hypodontia and microdontia: synergism or allelism
of major genes in a family with six affected members. J. Med. Genet. 33:
137-142, 1996.

4. Salinas, C. F.: Personal Communication. Charleston, S. C.  10/8/1978.

5. Vastardis, H.; Karimbux, N.; Guthua, S. W.; Seidman, J. G.; Seidman,
C. E.: A human MSX1 homeodomain missense mutation causes selective
tooth agenesis. Nature Genet. 13: 417-421, 1996.

*FIELD* CS

Teeth:
   Hypodontia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 08/07/1996
terry: 7/30/1996
mark: 6/7/1996
terry: 6/6/1996
warfield: 4/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
106700
*FIELD* TI
*106700 ANOMALOUS PULMONARY VENOUS RETURN; APVR
TOTAL ANOMALOUS PULMONARY VENOUS RETURN;;
TAPVR;;
TAPVR1
*FIELD* TX
Neill et al. (1960) described father and daughter with hypoplastic right
lung with systemic arterial supply and venous drainage. They referred to
the disorder as the 'scimitar syndrome' because of the radiographic
appearance created by the anomalous vein draining the right lower lung
and connecting with the inferior vena cava. The father was asymptomatic
but had been rejected for military service because his heart was said to
be on the right side. The daughter had severe pulmonary hypertension,
frequent respiratory infections, and marked hypoplasia of the right lung
with dextroposition of the heart. Vinh et al. (1968) described a brother
and sister, offspring of nonconsanguineous parents, with total
infradiaphragmatic pulmonary venous return. In 2 brothers and a male
paternal first cousin, Paz and Castilla (1971) observed total anomalous
pulmonary venous return. Kaufman et al. (1972) described total anomalous
pulmonary venous return of the figure-of-eight type in 2 sisters and a
daughter of their maternal uncle. Chelius et al. (1962) described
partial anomalous pulmonary venous return in 2 brothers whose maternal
grandmother died at age 42 of congenital heart disease. Solymar et al.
(1987) reported 3 pairs of sibs with total anomalous pulmonary venous
connection. Four of the affected persons were male. Even in the same
family, the connection was supracardial in one and infracardial in the
other, indicating that genetic regulation deals with the left atrial
connection to the intrapulmonary veins. Having failed to establish this
connection, the intrapulmonary veins attach themselves to any adjacent
venous structure; hence, the variety of connections found at birth.
Raisher et al. (1991) reported total anomalous pulmonary venous
connections in a father and his son and daughter. There was no known
consanguinity in the family.

In total anomalous pulmonary venous return (TAPVR), a cyanotic form of
congenital heart defect, the pulmonary veins fail to enter the left
atrium and instead drain into the right atrium or one of the venous
tributaries. Bleyl et al. (1993) and Bleyl et al. (1994) reported a
large Utah-Idaho family in which nonsyndromic TAPVR appeared to be
inherited as an autosomal dominant with incomplete penetrance and
variable expression. The family contained 14 affected individuals. By
linkage mapping with polymorphic microsatellite markers, Bleyl et al.
(1994, 1995) localized the TAPVR1 locus to a 30-cM interval on 4p13-q12;
maximum lod = 6.51 at theta = 0.0. A vascular epithelial growth factor
receptor, thought to have a role in vasculogenesis, also mapped near the
centromere and therefore was considered a candidate for the TAPVR gene.
Kinase insert domain receptor (KDR; 191306) and its mouse homolog, fetal
liver kinase-1, bind vascular endothelial growth factor with high
affinity in vitro and are expressed early in development by endothelial
cell precursors. The mouse homolog has been implicated in the
development of blood and blood vessels. KDR maps to 4q12.

Ward (1996) observed 10 families with multiple cases of TAPVR in Utah
for which 4 failed to show linkage to 4q12-q13. The original family and
others that derived from Scotland had the same haplotype. The region of
mapping is one of very low recombination.

*FIELD* SA
Bleyl et al. (1994)
*FIELD* RF
1. Bleyl, S.; Nelson, L.; Byme, J. L. B.; Ward, K.: Familial total
anomalous pulmonary venous return: characterization of a large Utah
family.    (Abstract) Am. J. Hum. Genet. 53 (suppl.): A404, 1993.

2. Bleyl, S.; Nelson, L.; Odelberg, S. J.; Ruttenberg, H. D.; Otterud,
B.; Leppert, M.; Ward, K.: A gene for familial total anomalous pulmonary
venous return maps to chromosome 4p13-q12. Am. J. Hum. Genet. 56:
408-415, 1995.

3. Bleyl, S.; Nelson, L.; Otterud, B.; Leppert, M.; Ward, K.: A gene
for total anomalous pulmonary venous return (TAPVR-1) maps to the
centromere of chromosome 4.    (Abstract) Am. J. Hum. Genet. 55
(suppl.): A181, 1994.

4. Bleyl, S.; Ruttenberg, H. D.; Carey, J. C.; Ward, K.: Familial
total anomalous pulmonary venous return: a large Utah-Idaho family.
Am. J. Med. Genet. 52: 462-466, 1994.

5. Chelius, C. J.; Rowe, G. C.; Grumpton, C. W.: Familial aspects
of congenital heart disease. Am. J. Cardiol. 9: 508-514, 1962.

6. Kaufman, R. L.; Boynton, R. C.; Hartmann, A. F.; Morgan, B. C.;
McAlister, W. H.: Family studies in congenital heart disease. III.
Total anomalous venous connection in two sisters and their female
maternal first cousin. Birth Defects Orig. Art. Ser. VIII(5): 88-91,
1972.

7. Neill, C. A.; Ferencz, C.; Sabiston, D. C.; Sheldon, H.: The familial
occurrence of hypoplastic right lung with systemic arterial supply
and venous drainage 'scimitar syndrome.'. Bull. Johns Hopkins Hosp. 107:
1-21, 1960.

8. Paz, J. E.; Castilla, E. E.: Familial total anomalous pulmonary
venous return. J. Med. Genet. 8: 312-314, 1971.

9. Raisher, B. D.; Dowton, S. B.; Grant, J. W.: Father and two children
with total anomalous pulmonary venous connection. Am. J. Med. Genet. 40:
105-106, 1991.

10. Solymar, L.; Sabel, K.-G.; Zetterqvist, P.: Total anomalous pulmonary
venous connection in siblings: report on three families. Acta Paediat.
Scand. 76: 124-127, 1987.

11. Vinh, L. T.; Duc, T. V.; Aicardi, J.; Thieffry, S.: Retour veineux
pulmonaire anormal total infra-diaphragmatique familiale. Arch.
Franc. Pediat. 25: 1141-1149, 1968.

12. Ward, K.: Personal Communication. Salt Lake City, Utah  2/24/1996.

*FIELD* CS

Lung:
   Hypoplastic right lung;
   Pulmonary hypertension;
   Frequent respiratory infections

Radiology:
   Scimitar appearance of anomalous right lower pulmonary vein

Cardiac:
   Cardiac dextroposition

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/03/1996
terry: 2/27/1996
terry: 5/25/1995
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/19/1991
carol: 6/26/1991
carol: 8/23/1990

*RECORD*
*FIELD* NO
106750
*FIELD* TI
106750 ANONYCHIA WITH FLEXURAL PIGMENTATION
*FIELD* TX
Verbov (1975) described this combination in a mother and her son and
daughter. A brother of the mother was said to be affected. In the
axillae and groin both hyperpigmentation and hypopigmentation were
found. The skin of the soles and palms was dry.

*FIELD* RF
1. Verbov, J.: Anonychia with bizarre flexural pigmentation--an autosomal
dominant dermatosis. Brit. J. Derm. 92: 469-474, 1975.

*FIELD* CS

Nails:
   Anonychia

Skin:
   Axillary and groin hyperpigmentation and hypopigmentation;
   Dry skin of soles and palms

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
106900
*FIELD* TI
106900 ANONYCHIA-ECTRODACTYLY
*FIELD* TX
Lees et al. (1957) described a condition of absence of some or all
fingernails with variable absence of some phalanges and metacarpals. A
suggestion of linkage with the Lutheran locus was presented. The
distinctness from the EEC syndrome (129900), which combines ectrodactyly
with ectodermal abnormalities and cleft lip-palate, is problematic.

*FIELD* RF
1. Lees, D. H.; Lawler, S. D.; Renwick, J. H.; Thoday, J. M.: Anonychia
with ectrodactyly: clinical and linkage data. Ann. Hum. Genet. 22:
69-79, 1957.

*FIELD* CS

Skin:
   Ectodermal dysplasia

Nails:
   Anonychia

Limbs:
   Ectrodactyly;
   Absent phalanges;
   Absent metacarpals

Inheritance:
   Autosomal dominant;
   ? same as EEC syndrome (129900)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986

*RECORD*
*FIELD* NO
106990
*FIELD* TI
106990 ANONYCHIA-ONYCHODYSTROPHY WITH BRACHYDACTYLY TYPE B AND ECTRODACTYLY
*FIELD* TX
Kumar and Levick (1986) reported a family in which members in 5
generations appeared to have had anonychia-onychodystrophy in
association with hypoplasia of metacarpals, metatarsals, and distal
phalanges and, in at least 2 individuals, absent metacarpals and
phalanges. No male-to-male transmission was observed.

*FIELD* RF
1. Kumar, D.; Levick, R. K.: Autosomal dominant onychodystrophy and
anonychia with type B brachydactyly and ectrodactyly. Clin. Genet. 30:
219-225, 1986.

*FIELD* CS

Skin:
   Ectodermal dysplasia

Nails:
   Anonychia;
   Onychodystrophy

Limbs:
   Ectrodactyly;
   Absent/hypoplastic metacarpals;
   Absent/hypoplastic distal phalanges;
   Hypoplastic metatarsals

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 1/7/1987

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 1/7/1987

*RECORD*
*FIELD* NO
106995
*FIELD* TI
*106995 ANONYCHIA-ONYCHODYSTROPHY WITH HYPOPLASIA OR ABSENCE OF DISTAL PHALANGES
COOKS SYNDROME
*FIELD* TX
Cooks et al. (1985) described a kindred in which 7 individuals in 2
generations with one instance of male-to-male transmission had a
disorder characterized by onychodystrophy, anonychia, brachydactyly of
the fifth finger, and digitalization of the thumbs, with absence or
hypoplasia of the distal phalanges of the hands and feet. Cooks et al.
(1985) stated that the disorder differed from autosomal dominant
anonychia-onychodystrophy (107000) in which there is progressive nail
hypoplasia from the fifth digit to the thumb, with anonychia often
present in the second and third digits while in their family they
observed nail hypoplasia in the thumb progressing to total nail absence
in the fourth and fifth digits. Moreover, in dominant
anonychia-onychodystrophy, no bone changes had been described. In
autosomal dominant brachydactyly with absence of middle phalanges and
hypoplastic nails (112900), the changes in the middle phalanges are
distinctive. Relatively bizarre, asymmetric digital anomalies, including
absence of one or more digits, distinguish anonychia with ectrodactyly
(106900). In '20-nail dystrophy' (161050), dystrophy of the nails
progresses with age, while in the family of Cooks et al. (1985) the nail
findings were present from birth.

Nevin et al. (1995) described a second family of the condition they
called Cooks syndrome in 4 members of 3 successive generations with an
instance of male-to-male transmission. There was bilateral nail
hypoplasia of digits 1-3, with absence of nails of digits 4-5 of the
hands, and total absence of toenails. In addition, there was
absence/hypoplasia of the distal phalanges of the hands and feet.

*FIELD* RF
1. Cooks, R. G.; Hertz, M.; Bat Miriam Katznelson, M.; Goodman, R.
M.: A new nail dysplasia syndrome with onychonychia (sic) and absence
and/or hypoplasia of distal phalanges. Clin. Genet. 27: 85-91,
1985.

2. Nevin, N. C.; Thomas, P. S.; Eedy, D. J.; Shepherd, C.: Anonychia
and absence/hypoplasia of distal phalanges (Cooks syndrome): report
of a second family. J. Med. Genet. 32: 638-641, 1995.

*FIELD* CS

Nails:
   Onychodystrophy;
   Anonychia

Limbs:
   Fifth finger brachydactyly;
   Digitalization of thumbs;
   Absent/hypoplastic distal phalanges of hands and feet

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 1/28/1994

*FIELD* ED
mark: 9/22/1995
warfield: 3/31/1994
mimadm: 3/11/1994
carol: 1/28/1994

*RECORD*
*FIELD* NO
107000
*FIELD* TI
107000 ANONYCHIA-ONYCHODYSTROPHY
*FIELD* TX
Timerman et al. (1969) described affected persons in at least 4
generations with male-to-male transmission. Some digits showed absent
nails while others showed dystrophic nails. In some reported families
absence of some or all nails apparently occurred without associated
manifestations of the nail-patella syndrome (161200) and without absence
of digits as in the anonychia-ectrodactyly syndrome (106900). Recessive
anonychia has also been described (see 206800). Ahlgren et al. (1988)
described a family with autosomal dominant onychodystrophy; congenital
dislocation of the hips was found concordantly in 3 of 4 affected sibs.

*FIELD* SA
Charteris  (1918); Hobbs  (1935); Vogel and Dorn (1964)
*FIELD* RF
1. Ahlgren, S.; Elmros, T.; Mamoun, I.; Mitelman, F.; Said, S.: Congenital
hip dislocation and onychodystrophy in a family. Saudi Med. J. 9:
165-168, 1988.

2. Charteris, F.: A case of partial hereditary anonychia. Glasgow
Med. J. 89: 207-209, 1918.

3. Hobbs, M. E.: Hereditary onychial dysplasia. Am. J. Med. Sci. 190:
200-206, 1935.

4. Timerman, I.; Museteanu, C.; Simionescu, N. N.: Dominant anonychia
and onychodystrophy. J. Med. Genet. 6: 105-106, 1969.

5. Vogel, F.; Dorn, H.: Anonychia congenita. In: Becker, P. E.:
Humangenetik.  Stuttgart: Georg Thieme Verlag (pub.)  4: 1964.
Pp. 489-490.

*FIELD* CS

Nails:
   Anonychia;
   Onychodystrophy

Limbs:
   No ectrodactyly

Joints:
   Congenital hip dislocation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
pfoster: 4/4/1994
mimadm: 3/11/1994
carol: 5/21/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
107100
*FIELD* TI
107100 ANORECTAL ANOMALIES
*FIELD* TX
Van Gelder and Kloepfer (1961) observed 4 sibs with anorectal stenosis
or imperforate anus. Although the parents were unaffected the authors
pointed out that failure of expression of a recent dominant mutation,
carried by one parent, is a possibility. Kaijser and Malmstrom-Groth
(1957) described imperforate anus with rectovaginal fistula in a mother
and her 2 daughters. From the findings of Cozzi and Wilkinson (1968),
anal stenosis seems particularly liable to familial occurrence, probably
as an irregular dominant. Anorectal malformation was combined with
nephritis and nerve deafness (?Alport syndrome) in a dominant pedigree
pattern in the family reported by Lowe et al. (1983).

*FIELD* RF
1. Cozzi, F.; Wilkinson, A. W.: Familial incidence of congenital
anorectal anomalies. Surgery 64: 669-671, 1968.

2. Kaijser, K.; Malmstrom-Groth, A.: Anorectal abnormalities as a
congenital familial incidence. Acta Paediat. 46: 199-200, 1957.

3. Lowe, J.; Kohn, G.; Cohen, O.; Mogilner, M.; Schiller, M.: Dominant
ano-rectal malformation, nephritis and nerve-deafness: a possible
new entity?. Clin. Genet. 24: 191-193, 1983.

4. Van Gelder, D. W.; Kloepfer, H. W.: Familial anorectal anomalies.
Pediatrics 27: 334-336, 1961.

*FIELD* CS

GI:
   Anorectal stenosis;
   Imperforate anus

GU:
   Rectovaginal fistula

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107200
*FIELD* TI
107200 ANOSMIA, CONGENITAL
*FIELD* TX
In a Japanese kindred, Yamamoto et al. (1966) found tremor and/or
anosmia or hyposmia in 14 persons. They suggested that the two traits
are independent dominants. Their findings may be equally consistent with
the pleiotropic and variable effects of a single gene. In the Faroe
Islands, Lygonis (1969) found a large kindred in which 9 males and 19
females in 4 generations had anosmia with no other abnormality.
Male-to-male transmission was observed several times. Singh et al.
(1970) observed anosmia in 6 males in 3 generations. One male who
transmitted the trait had only partial anosmia. Dominant inheritance was
recorded by Mainland (1945) and Joyner (1963). Several instances of
male-to-male transmission were observed. Singh et al. (1970) observed
anosmia or hyposmia in 6 males in 3 consecutive generations. One of the
patients of Hockaday (1966) with anosmia-hypogonadism had father and a
brother with anosmia alone. See Kallmann syndrome (147950, 244200,
308700).

*FIELD* SA
Wenzel  (1948)
*FIELD* RF
1. Hockaday, T. D. R.: Hypogonadism and life-long anosmia. Postgrad.
Med. J. 42: 572-574, 1966.

2. Joyner, R. E.: Olfactory acuity in an industrial population. J.
Occup. Med. 5: 37-42, 1963.

3. Lygonis, C. S.: Familial absence of olfaction. Hereditas 61:
413-415, 1969.

4. Mainland, R. C.: Absence of olfactory sensation. J. Hered. 36:
143-144, 1945.

5. Singh, N.; Grewal, M. S.; Austin, J. H.: Familial anosmia. Arch.
Neurol. 22: 40-44, 1970.

6. Wenzel, B. M.: Techniques in olfactometry: a critical review of
the last one hundred years. Psychol. Bull. 45: 231 only, 1948.

7. Yamamoto, K.; Ito, K.; Yamaguchi, M.: A family showing smell disturbance
and tremor. Jpn. J. Hum. Genet. 11: 36-38, 1966.

*FIELD* CS

Neuro:
   Congenital anosmia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/11/1988

*RECORD*
*FIELD* NO
107240
*FIELD* TI
*107240 ANTIGEN MSK39 IDENTIFIED BY MONOCLONAL ANTIBODY 5.1H11; MSK39
*FIELD* TX
Using serologic analysis of a panel of rodent-human somatic cell
hybrids, Rettig (1989) showed that the cell surface antigen defined by
monoclonal antibody 5.1H11 is encoded by chromosome 11q13-qter. Rettig
(1989) concluded that the antigen is distinct from several other cell
surface antigens encoded by the long arm of human chromosome 11.

*FIELD* RF
1. Rettig, W. J.: Chromosome assignment of the human 5.1H11 and E3
cell surface antigens.  (Abstract) Cytogenet. Cell Genet. 51: 1065-1066,
1989.

*FIELD* CD
Victor A. McKusick: 6/14/1989

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
carol: 6/14/1989

*RECORD*
*FIELD* NO
107250
*FIELD* TI
*107250 ANTERIOR SEGMENT OCULAR DYSGENESIS; ASOD
ANTERIOR SEGMENT MESENCHYMAL DYSGENESIS; ASMD
*FIELD* TX
Hittner et al. (1981) identified a kindred in which an autosomal
dominant anterior segment dysgenesis of the eye (ASOD) with variable
expression affected members of at least 8 generations. (Hittner (1981)
preferred the designation 'anterior segment mesenchymal dysgenesis,'
arguing that 'anterior segment' can refer only to the eye, making
'ocular' redundant and that 'mesenchymal' conveys important additional
information on the nature of the disorder.) Clinical findings ranged
from an anterior Schwalbe line with mild cataract to severe corneal
opacification with moderate cataract, while visual acuity varied from
20/20 to hand motion only. The proband had corneal transplant and
cataract extraction of one eye at age 6 weeks. Microscopic studies of
the cornea showed basal epithelial cell protrusions into a thickened
Bowman layer, 'activated' keratocytes throughout the entire stroma, no
Descemet layer or endothelial cells, and an aggregation of keratocytes
posteriorly. The lens showed focal aggregations of vesicles in cortical
fibers with extensive epithelial atrophy. Probable linkage of ASOD and
MNSs (111300) was indicated by a lod score of 3.48 (Ferrell et al.,
1982). Such a linkage would place the ASMD locus on 4q; MNSs is located
on 4q28-q31. Whether ASMD is distinct from Rieger syndrome (180500) must
be considered. A relationship is further suggested by the fact that
interstitial deletion of 4q has been found in association with Rieger
syndrome (Ligutic et al., 1981).

*FIELD* RF
1. Ferrell, R. E.; Hittner, H. M.; Kretzer, F. L.; Antoszyk, J. H.
: Anterior segment mesenchymal dysgenesis: probable linkage to the
MNS blood group on chromosome 4. Am. J. Hum. Genet. 34: 245-249,
1982.

2. Hittner, H. M.: Personal Communication. Houston, Texas  7/28/1981.

3. Hittner, H. M.; Ferrell, R. E.; Antoszyk, J. H.; Kretzer, F. L.
: Autosomal dominant anterior segment dysgenesis with variable expressivity:
probable linkage to MNS blood group on chromosome 4.  (Abstract) Pediat.
Res. 15: 563 only, 1981.

4. Ligutic, I.; Brecevic, L.; Petkovic, I.; Kalogjera, T.; Rajic,
Z.: Interstitial deletion 4q and Rieger syndrome. Clin. Genet. 20:
323-327, 1981.

*FIELD* CS

Eyes:
   Anterior segment ocular dysgenesis;
   Cataract;
   Corneal opacity;
   Normal/reduced visual acuity

Lab:
   Abnormal cornea and lens histology

Inheritance:
   Autosomal dominant (4q28-q31);
   ? same as Rieger syndrome (180500)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 7/5/1994
warfield: 4/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
107253
*FIELD* TI
*107253 ANTIGEN MDF1 IDENTIFIED BY MONOCLONAL ANTIBODY A-3A4; MDF1
*FIELD* TX
The antigen identified by monoclonal antibody A-3A4 (approximately
45,000 Mr) is a novel cell surface molecule expressed on all
hematopoietic cell lines tested. Peters et al. (1984) mapped the gene to
human chromosome 4 by study of human-mouse somatic cell hybrids.
Expression of the antigen was quantitated by indirect immunofluorescence
and fluorescence-activated cell sorter analysis.

*FIELD* RF
1. Peters, P. M.; Kamarck, M. E.; Hemler, M. E.; Strominger, J. L.;
Ruddle, F. H.: Genetic and biochemical characterization of human
lymphocyte cell surface antigens: the A-1A5 and A-3A4 determinants.
(Abstract) J. Exp. Med. 159: 1441-1454, 1984.

*FIELD* CD
Victor A. McKusick: 9/12/1991

*FIELD* ED
supermim: 3/16/1992
carol: 9/12/1991

*RECORD*
*FIELD* NO
107254
*FIELD* TI
*107254 ANTIGEN MIC12 IDENTIFIED BY MONOCLONAL ANTIBODY 30.2A8; MIC12
*FIELD* TX
Walsh et al. (1985) produced monoclonal antibody 30.2A8 by a hybridoma
made by fusing cells from rats that had been immunized with rat-human
muscle cell hybrids. The 30.2A8 reacts with a differentiation antigen in
human skeletal muscle that is synthesized by myoblasts but not myotubes.
By analysis of somatic cell hybrids, Walsh et al. (1985) found that the
gene controlling synthesis of this antigen, designated MIC12, is located
on human chromosome 15.

*FIELD* RF
1. Walsh, F. S.; Quinn, C. A.; Pym, B.; Goodfellow, P. N.: Cell surface
differentiation antigen of human muscle encoded by a gene (MIC12)
on chromosome 15. Cytogenet. Cell Genet. 39: 51-56, 1985.

*FIELD* CD
Victor A. McKusick: 10/1/1991

*FIELD* ED
supermim: 3/16/1992
carol: 10/1/1991

*RECORD*
*FIELD* NO
107257
*FIELD* TI
*107257 ANTIGEN MSK3 IDENTIFIED BY MONOCLONAL ANTIBODY M68; MSK3
*FIELD* TX
By means of mouse monoclonal antibodies derived after immunization with
human tumor cells or melanocytes, Dracopoli et al. (1984) identified 2
cell surface antigens (MSK4; MSK7) that mapped to 12q, and 1 (MSK3) that
mapped to 12p. They could distinguish these from cell surface molecules
previously mapped to chromosome 12 (e.g., MIC3, 143030). (The
development of the monoclonal antibodies at the Sloan-Kettering Cancer
Center is responsible for the designations.)

*FIELD* RF
1. Dracopoli, N. C.; Rettig, W. J.; Goetzger, T. A.; Houghton, A.
N.; Spengler, B. A.; Oettgen, H. F.; Biedler, J. L.; Old, L. J.:
Three human cell surface antigen systems determined by genes on chromosome
12. Somat. Cell Molec. Genet. 10: 475-481, 1984.

*FIELD* CD
Victor A. McKusick: 3/6/1992

*FIELD* ED
supermim: 3/16/1992
carol: 3/6/1992

*RECORD*
*FIELD* NO
107260
*FIELD* TI
*107260 ANTIGEN MSK41 IDENTIFIED BY MONOCLONAL ANTIBODY E3; MSK41
*FIELD* TX
Using serologic analysis of a panel of rodent-human somatic cell
hybrids, Rettig (1989) showed that the cell surface antigen defined by
monoclonal antibody E3 maps to human chromosome 22 and differs from at
least 1 cell surface antigen previously assigned to that chromosome.

*FIELD* RF
1. Rettig, W. J.: Chromosome assignment of the human 5.1H11 and E3
cell surface antigens.  (Abstract) Cytogenet. Cell Genet. 51: 1065-1066,
1989.

*FIELD* CD
Victor A. McKusick: 6/14/1989

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
carol: 6/14/1989

*RECORD*
*FIELD* NO
107265
*FIELD* TI
*107265 ANTIGEN CD19
B-LYMPHOCYTE ANTIGEN CD19; CD19
*FIELD* TX
CD19 is a cell surface molecule expressed only by B-lymphocytes and
follicular dendritic cells of the hematopoietic system. It is the
earliest of the B-lineage-restricted antigens to be expressed and is
present on most pre-B cells and most non-T-cell acute lymphocytic
leukemia cells and B-cell type chronic lymphocytic leukemia cells. The
CD19 molecule has a molecular weight of about 95,000. Tedder and Isaacs
(1989) isolated cDNA clones that encode CD19 from a human tonsilar cDNA
library and determined the amino acid sequence. The amino acid sequence
showed no significant homology with other known proteins, but the
putative extracellular region contained 2 Ig-like domains, indicating
that CD19 is a new member of the Ig superfamily. Carter and Fearon
(1992) described the role of CD19 in helping the B cell resolve its
dilemma, the conflict between broad specificity and sensitivity. The
former is met by low-affinity antigen receptors, which precludes
achieving the latter with high-affinity receptors. Coligation of CD19
with the antigen receptor of B lymphocytes decreases the threshold for
antigen receptor-dependent stimulation by 2 orders of magnitude. Thus, B
lymphocytes proliferate when approximately 100 antigen receptors per
cell, 0.03% of the total, are ligated with CD19.

Ord et al. (1994) assigned the CD19 gene to 16p11.2 by in situ
hybridization and by PCR analysis of a panel of human/hamster somatic
cell hybrid DNAs. The mouse gene was mapped to bands F3-F4 of chromosome
7 by in situ hybridization. Segregation analysis in interspecific
backcross progeny showed linkage to loci previously mapped to the same
region of mouse chromosome 7 in a region of conserved synteny with human
chromosome 16.

*FIELD* RF
1. Carter, R. H.; Fearon, D. T.: CD19: lowering the threshold for
antigen receptor stimulation of B lymphocytes. Science 256: 105-107,
1992.

2. Ord, D. C.; Edelhoff, S.; Dushkin, H.; Zhou, L.-J.; Beier, D. R.;
Disteche, C.; Tedder, T. F.: CD19 maps to a region of conservation
between human chromosome 16 and mouse chromosome 7. Immunogenetics 39:
322-328, 1994.

3. Tedder, T. F.; Isaacs, C. M.: Isolation of cDNAs encoding the
CD19 antigen of human and mouse B lymphocytes: a new member of the
immunoglobulin superfamily. J. Immun. 143: 712-717, 1989.

*FIELD* CD
Victor A. McKusick: 7/10/1990

*FIELD* ED
terry: 7/28/1994
carol: 4/6/1994
carol: 1/12/1993
carol: 12/17/1992
carol: 12/4/1992
carol: 8/11/1992

*RECORD*
*FIELD* NO
107266
*FIELD* TI
*107266 ANTIGEN CD22
B-CELL ANTIGEN CD22
*FIELD* TX
The human B-lymphocyte-restricted antigen CD22 is expressed early in
B-cell development in pro-B cells, as a cytoplasmic protein, and later
in B-cell development, at the late pre-B-cell stage, as a cell surface
protein. Once expressed as a membrane protein, CD22 persists on B cells
until they differentiate into plasma cells. The presence of cytoplasmic
CD22 is a useful marker for B-cell precursor acute lymphocytic leukemia.
CD22 appears to be a heterodimer consisting of 130- and 140-kD
glycoproteins with protein cores of 80 and 100 kD, respectively. The 2
subunits are thought to be independently transported to the surface and
originate from 2 separate precursor molecules. Studies of the structure
of the 2 proteins and cDNA cloning suggested that the 2 proteins arise
from differential RNA processing of the same gene, with the larger
subunit being composed of an extracellular portion of 7 immunoglobulin
domains, 1 V-like and 6 C-like, and a smaller subunit of 5 Ig domains, 1
V-like and 4 C-like. The CD22 polypeptide is structurally related to
myelin-associated glycoprotein (MAG; 159460), neural cell adhesion
molecule (NCAM; 116930), and carcinoembryonic antigen (CEA; 114890).
Consistent with the structural similarities to the adhesion molecules,
CD22 participates in adhesion between B cells and other cell types.
Wilson et al. (1993) used a nearly full-length cDNA clone of CD22 to
isolate genomic clones that spanned the gene. The gene covers 22 kb of
DNA and comprises 15 exons. By fluorescence in situ hybridization, they
showed that the CD22 locus is located within band 19q13.1.

O'Keefe et al. (1996) made observations in mice with a targeted
disruption of the CD22 gene, indicating that CD22 is a negative
regulator of antigen receptor signaling whose onset of expression at the
mature B cell stage may serve to raise the antigen concentration
threshold required for B cell triggering. Splenic B cells from CD22
knockout mice were found to be hyperresponsive to receptor signaling.
Heightened calcium fluxes and cell proliferation were obtained at lower
ligand concentrations. The mice gave augmented immune response, had an
expanded peritoneal B-1 cell population, and contained increased serum
titers of autoantibody.

*FIELD* SA
Wilson et al. (1991)
*FIELD* RF
1. O'Keefe, T. L.; Williams, G. T.; Davies, S. L.; Neuberger, M. S.
: Hyperresponsive B cells in CD22-deficient mice. Science 274: 798-801,
1996.

2. Wilson, G. L.; Fox, C. H.; Fauchi, A. S.; Kehrl, J. H.: cDNA cloning
of the B cell membrane protein CD22: a mediator of B-B cell interactions. J.
Exp. Med. 173: 137-146, 1991.

3. Wilson, G. L.; Najfeld, V.; Kozlow, E.; Menniger, J.; Ward, D.;
Kehrl, J. H.: Genomic structure and chromosomal mapping of the human
CD22 gene. J. Immun. 150: 5013-5024, 1993.

*FIELD* CD
Victor A. McKusick: 6/28/1993

*FIELD* ED
jenny: 12/09/1996
terry: 12/6/1996
jason: 7/5/1994
carol: 5/31/1994
carol: 7/1/1993
carol: 6/28/1993

*RECORD*
*FIELD* NO
107269
*FIELD* TI
*107269 CD44 ANTIGEN; CD44
HERMES ANTIGEN;;
Pgp-1;;
MDU3
*FIELD* TX
CD44 is an integral cell membrane glycoprotein with a postulated role in
matrix adhesion lymphocyte activation and lymph node homing. The
nucleotide sequence of CD44 cDNAs predicts a 37-kD polypeptide with
homology to cartilage link protein (115435) in a phylogenetically
conserved amino-terminal domain. Aruffo et al. (1990) demonstrated that
CD44 is the main cell surface receptor for hyaluronate. Mature
lymphocytes in the circulation migrate selectively from the bloodstream
to different lymphatic tissues through specialized high endothelial
venules (HEV). Molecules on the surface of lymphocytes called homing
receptors interact specifically with HEV and play a central role in the
migration. The mouse monoclonal antibody Hermes-3 recognizes the 85-95
kD human lymphocyte homing receptor. Using mouse-human T-lymphocyte
hybrids and hybrids of Chinese hamster ovary cells with human amniotic
fibroblasts, Ala-Kapee et al. (1989) found that Hermes-3 expression, as
demonstrated by indirect immunofluorescence and immunoprecipitation, was
determined by 11pter-p13. Forsberg et al. (1989) refined the assignment
of the lymphocyte homing receptor gene to 11pter-p13 by study of Chinese
hamster-human cell hybrids in which the human parent cells had various
deletions of human chromosome 11. Stefanova et al. (1989) demonstrated
that the lymphocyte homing receptor is identical to the human leukocyte
surface glycoprotein called CDw44, on the basis of studies at the Third
International Workshop on Human Leukocyte Differentiation Antigens. It
also appears to be identical to the Pgp-1 glycoprotein of Omary et al.
(1988).

Telen et al. (1983) used a murine monoclonal antibody (A3D8) to identify
an erythrocyte antigen inhibited by the In(Lu) gene. Telen et al. (1984)
showed that the A3D8 antigenic property resides on an 80-kD red cell
membrane protein which is present in only trace amounts in In(Lu)
Lu(a-b-) red cells (INLU; 111150). Francke et al. (1983) showed that the
antigens defined by monoclonal antibodies A3D8 and A1G3 are determined
by genes on 11p. Haynes (1986) had evidence that the A1G3 and A3D8
monoclonal antibodies bind to different epitopes on the same 80-kD
molecule. The monoclonal antibody A3D8 recognized an antigen officially
called MDU3--'monoclonal Duke University, 3,' or CD44. Telen (1992) knew
of no evidence that the INLU and CD44 (MDU3) genes are the same.

Cianfriglia et al. (1992) mapped a drug-sensitivity marker, MC56, to
11pter-p13. Identity of the protein to the CD44 antigen, suggested on
other grounds, was supported by the map location.

Although CD44 may have function as a lymphocyte homing receptor, the
gene that maps to chromosome 11 is distinct from the lymph node homing
receptor located on chromosome 1 (153240) (Seldin, 1990). In the mouse,
the corresponding gene has been referred to as Ly-24.

Screaton et al. (1992) found that the CD44 gene contains 19 exons
spanning some 50 kb of genomic DNA. They identified 10 alternatively
spliced exons within the extracellular domain, including 1 exon that had
not previously been reported. In addition to the inclusion or exclusion
of whole exons, additional diversity was generated through the
utilization of internal splice donor and acceptor sites within 2 of the
exons. A variation in the cytoplasmic domain was shown to result from
the alternative splicing of 2 exons. Thus the genomic structure of CD44
is remarkably complex, and alternative splicing is the basis of its
structural and functional diversity. Splice variants of the glycoprotein
CD44 may be associated with metastases and therefore may be useful in
the early detection of metastatic potential in surgical biopsy
specimens, as well as in the early diagnosis of cancer in screening
programs, assessment of remaining disease, and early detection of
recurrence (Matsumura and Tarin, 1992). Mayer et al. (1993) found that
expression of CD44, which is not found in normal gastric mucosa and is
found in only 49% of primary tumors, was associated with distant
metastases at time of diagnosis and with tumor recurrence and increased
mortality from gastric cancer.

Weber et al. (1996) noted that the CD44 gene encodes a transmembrane
protein that is expressed as a family of molecular isoforms generated
from alternative RNA splicing and posttranslational modifications.
Certain CD44 isoforms that regulate activation and migration of
lymphocytes and macrophages may also enhance local growth and metastatic
spread of tumor cells. One ligand of CD44 is hyaluronic acid, binding of
which to the NH2-terminal domain of CD44 enhances cellular aggregation
and tumor cell growth. (Krainer et al. (1991) referred to CD44 as a
'hyaladherin' -- see 601269.) Weber et al. (1996) demonstrated that
another ligand is osteopontin (166490). Osteopontin induces cellular
chemotaxis but not homotypic aggregation of cells, whereas the inverse
is true for the interaction between CD44 and hyaluronate. The
alternative responses to CD44 ligation may be exploited by tumor cells
to allow OPN-mediated metastatic spread and hyaluronate-dependent growth
in newly colonized tissues in the process of tumor metastasis.

A table of all the CD antigens was provided by Schlossman et al. (1994)
with a list of the common names, the size in kilodaltons, and the nature
of the protein (adhesion, myeloid, platelet, and B cell, T cell, etc.).

*FIELD* SA
Forsberg et al. (1989)
*FIELD* RF
1. Ala-Kapee, M.; Forsberg, U. H.; Jalkanen, S.; Schroder, J.: Mapping
of gene for human lymphocyte homing receptor to the short arm of chromosome
11.    (Abstract) Cytogenet. Cell Genet. 51: 948-949, 1989.

2. Aruffo, A.; Stamenkovic, I.; Melnick, M.; Underhill, C. B.; Seed,
B.: CD44 is the principal cell surface receptor for hyaluronate.
Cell 61: 1303-1313, 1990.

3. Cianfriglia, M.; Viora, M.; Tombesi, M.; Merendino, N.; Esposito,
G.; Samoggia, P.; Forsberg, U. H.; Schroder, J.: The gene encoding
for MC56 determinant (drug-sensitivity marker) is located on the short
arm of human chromosome 11. Int. J. Cancer 52: 585-587, 1992.

4. Forsberg, U. H.; Ala-Kapee, M. M.; Jalkanen, S.; Andersson, L.
C.; Schroder, J.: The gene for human lymphocyte homing receptor is
located on chromosome 11. Europ. J. Immun. 19: 409-412, 1989.

5. Forsberg, U. H.; Jalkanen, S.; Schroder, J.: Assignment of the
human lymphocyte homing receptor gene to the short arm of chromosome
11. Immunogenetics 29: 405-407, 1989.

6. Francke, U.; Foellmer, B. E.; Haynes, B. F.: Chromosome mapping
of human cell surface molecules: monoclonal anti-human lymphocyte
antibodies 4F2, A3D8, and A1G3 define antigens controlled by different
regions of chromosome 11. Somat. Cell Genet. 9: 333-344, 1983.

7. Haynes, B. F.: Personal Communication. Durham, N. C.  2/28/1986.

8. Krainer, A. R.; Mayeda, A.; Kozak, D.; Binns, G.: Functional expression
of cloned human splicing factor SF2: homology to RNA-binding proteins,
U1 70K, and Drosophila splicing regulators. Cell 66: 383-394, 1991.

9. Matsumura, Y.; Tarin, D.: Significance of CD44 gene products for
cancer diagnosis and disease evaluation. Lancet 340: 1053-1058,
1992.

10. Mayer, B.; Jauch, K. W.; Gunthert, U.; Figdor, C. G.; Schildberg,
F. W.; Funke, I.; Johnson, J. P.: De-novo expression of CD44 and
survival in gastric cancer. Lancet 342: 1019-1022, 1993.

11. Omary, M. B.; Trowbridge, I. S.; Letarte, M.; Kagnoff, M. F.;
Isacke, C. M.: Structural heterogeneity of human Pgp-1 and its relationship
with p85. Immunogenetics 27: 460-464, 1988.

12. Schlossman, S. F.; Boumsell, L.; Gilks, W.; Harlan, J. M.; Kishimoto,
T.; Morimoto, C.; Ritz, J.; Shaw, S.; Silverstein, R. L.; Springer,
T. A.; Tedder, T. F.; Todd, R. F.: CD antigens 1993. Immun. Today 15:
98-99, 1994.

13. Screaton, G. R.; Bell, M. V.; Jackson, D. G.; Cornelis, F. B.;
Gerth, U.; Bell, J. I.: Genomic structure of DNA encoding the lymphocyte
homing receptor CD44 reveals at least 12 alternatively spliced exons.
Proc. Nat. Acad. Sci. 89: 12160-12164, 1992.

14. Seldin, M. F.: Personal Communication. Durham, N. C.  9/19/1990.

15. Stefanova, I.; Hilgert, I.; Bazil, V.; Kristofova, H.; Horejsi,
V.: Human leucocyte surface glycoprotein CDw44 and lymphocyte homing
receptor are identical molecules. Immunogenetics 29: 402-404, 1989.

16. Telen, M. J.: Personal Communication. Durham, N. C.  12/30/1992.

17. Telen, M. J.; Eisenbarth, G. S.; Haynes, B. F.: Human erythrocyte
antigens: regulation of expression of a novel erythrocyte surface
antigen by the inhibitor Lutheran In(Lu) gene. J. Clin. Invest. 71:
1878-1886, 1983.

18. Telen, M. J.; Palker, T. J.; Haynes, B. F.: Human erythrocyte
antigens: II. The In(Lu) gene regulates expression of an antigen on
an 80-kilodalton protein of human erythrocytes. Blood 64: 599-606,
1984.

19. Weber, G. F.; Ashkar, S.; Glimcher, M. J.; Cantor, H.: Receptor-ligand
interaction between CD44 and osteopontin (Eta-1). Science 271: 509-512,
1996.

*FIELD* CN
Alan F. Scott - updated: 05/21/1996

*FIELD* CD
Victor A. McKusick: 9/25/1990

*FIELD* ED
mark: 05/21/1996
terry: 5/21/1996
mark: 5/20/1996
mark: 2/10/1996
terry: 2/7/1996
terry: 7/29/1994
carol: 4/11/1994
warfield: 4/7/1994
carol: 9/8/1993
carol: 1/14/1993
carol: 1/13/1993

*RECORD*
*FIELD* NO
107270
*FIELD* TI
*107270 ANTIGEN CD38 OF ACUTE LYMPHOBLASTIC LEUKEMIA CELLS; CD38
ADP-RIBOSYL CYCLASE/CYCLIC ADP-RIBOSE HYDROLASE
*FIELD* TX
Katz et al. (1983) used hybrids formed between human acute lymphoblastic
leukemia (ALL) cells and mouse myeloma cells to determine the
chromosomal location of genes required for the expression of several
monoclonal antibody-defined cell surface antigens on ALL cells. Two
antigens could definitely be mapped: OKT10/p45 (CD38) to chromosome 4
and BA-2/p24 (CD9) to chromosome 12. The latter monoclonal reacted with
the same protein as did another monoclonal antibody designated 609-29,
an antiteratocarcinoma antibody (see 143030). Thus, this is a confirmed
assignment.

By fluorescence in situ hybridization, Nakagawara et al. (1995) mapped
the CD38 gene to 4p15. Cyclic ADP-ribose is generated in pancreatic
islets by glucose stimulation, serving as a second messenger for Ca(2+)
mobilization in the endoplasmic reticulum for secretion of insulin
(Takasawa et al., 1993). Takasawa et al. (1993) demonstrated the
synthesis and hydrolysis of cADPR by CD38, which had previously been
used as a human leukocyte differentiation marker.

*FIELD* SA
Takasawa et al. (1993)
*FIELD* RF
1. Katz, F.; Povey, S.; Parkar, M.; Schneider, C.; Sutherland, R.;
Stanley, K.; Solomon, E.; Greaves, M.: Chromosome assignment of monoclonal
antibody-defined determinants on human leukemic cells. Europ. J.
Immun. 13: 1008-1013, 1983.

2. Nakagawara, K.; Mori, M.; Takasawa, S.; Nata, K.; Takamura, T.;
Berlova, A.; Tohgo, A.; Karasawa, T.; Yonekura, H.; Takeuchi, T.;
Okamoto, H.: Assignment of CD38, the gene encoding human leukocyte
antigen CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase), to
chromosome 4p15. Cytogenet. Cell Genet. 69: 38-39, 1995.

3. Takasawa, S.; Nata, K.; Yonekura, H.; Okamoto, H.: Cyclic ADP-ribose
in insulin secretion from pancreatic beta cells. Science 259: 370-373,
1993.

4. Takasawa, S.; Tohgo, A.; Noguchi, N.; Koguma, T.; Nata, K.; Sugimoto,
T.; Yonekura, H.; Okamoto, H.: Synthesis and hydrolysis of cyclic
ADP-ribose by human leukocyte antigen CD38 and inhibition of the hydrolysis
by ATP. J. Biol. Chem. 268: 26052-26054, 1993.

*FIELD* CD
Victor A. McKusick: 3/22/1989

*FIELD* ED
mark: 4/4/1995
supermim: 3/16/1992
carol: 10/1/1991
supermim: 3/20/1990
ddp: 10/26/1989
root: 5/30/1989

*RECORD*
*FIELD* NO
107271
*FIELD* TI
*107271 CD59 ANTIGEN P18-20; CD59
PROTECTIN
CD59 DEFICIENCY, INCLUDED
*FIELD* TX
The CD59 antigen recognized by monoclonal antibody MEM-43 is an 18- to
25-kD glycoprotein expressed on all human peripheral blood leukocytes,
erythrocytes, and several human cell lines. A close relationship to Ly-6
of the mouse has been demonstrated. Antigens encoded by both Ly-6 and
CD59 genes are important to T-cell and NK-cell function. CD59 is also
known as protectin. Its function is to restrict lysis of human
erythrocytes and leukocytes by homologous complement. By directly
incorporating protectin into membranes of heterologous cells, Meri et
al. (1990) found that protectin does not prevent perforin-mediated
killing (see 170280), whereas complement killing is effectively
restricted. Thus, cell-mediated killing is unaffected by protectin. Meri
et al. (1990) described the functional characteristics of protectin.
Much attention has been focused on the Ly-6 proteins because they may be
involved in lymphocyte activation, and expression of some of them occurs
at critical times in the differentiation of lymphocytes.

Forsberg et al. (1989) used indirect immunofluorescence and
immunoblotting with MEM-43 antibody to demonstrate expression of CD59 in
Chinese hamster-human cell hybrids. CD59 was found to segregate with
hybrids containing part of the short arm of human chromosome 11 but not
with hybrids containing the long arm. They specifically assigned the
gene to 11p14-p13. Heckl-Ostreicher et al. (1993) used chromosomal in
situ hybridization and pulsed field gel electrophoresis to map the CD59
gene to 11p13, distal to the breakpoint of acute T-cell leukemia (TCL2;
151390) and proximal to the Wilms tumor gene (WT1; 194070). Ly-6 is on
mouse chromosome 15 (LeClair et al., 1987). Indeed, the Ly-6 multigene
family is clustered in a region closely linked to the Sis (190040) and
Myc (190080) protooncogenes (Huppi et al., 1988). Kamiura et al. (1992)
used the combined techniques of field-inversion gel electrophoresis
(FIGE), phage and cosmid genomic library screening, and 2-dimensional
DNA electrophoresis to construct a physical map of the entire Ly-6
complex. The map spanned approximately 1,600 kb. Bickmore et al. (1993)
assigned the CD59 gene to 11p13 by study of somatic cell hybrids and by
pulsed field gel electrophoresis, as well as by the fact that the gene
is often deleted in WAGR individuals. This region of chromosome 11 shows
homology of synteny with mouse chromosome 2. This suggested that CD59 is
not a homolog of the mouse Ly-6 gene on mouse chromosome 15, but rather
is a related gene. A possibility of identity to MIC11 (143065) was
suggested by the fact that both mapped to the same region.

Petranka et al. (1992) demonstrated that the CD59 gene consists of 4
exons spanning 20 kb. The untranslated first exon is preceded by a
G+C-rich promoter region that lacks a consensus TATA or CAAT motif. The
second exon encodes the hydrophobic leader sequence of the protein, and
the third exon encodes the amino-terminal portion of the mature protein.
The fourth exon encodes the remainder of the mature protein, including
the hydrophobic sequence necessary for glycosylphosphatidylinositol
(GPI) anchor attachment. They found that the structure of the CD59 gene
is very similar to that encoding Ly-6. Similarity in gene structure
suggests that the 2 proteins belong to a superfamily of proteins that
may also include the urokinase plasminogen activator receptor (173391).
Tone et al. (1992) reported that the CD59 gene is more than 27 kb long
and comprises one 5-prime-untranslated exon and 3 coding exons. Northern
blot analysis using 6 different probes located in the 3-prime region of
the gene showed that more than 4 different CD59 mRNA molecules are
generated by alternative polyadenylation. Three of these polyadenylation
sites were predicted from previously published cDNA sequences.

Okada et al. (1989) described a novel membrane inhibitor of the membrane
attack complexes (MACs). A protein of molecular weight 20,000, its
function is the same as that of HRF, which has a molecular weight of
65,000. Therefore, they termed the new protein HRF20. HRF20 was also
found to be identical to membrane-attack-complex inhibitory factor
(MACIF) and CD59 (Davies et al., 1989); the sequences of cDNA encoding
the 3 were essentially identical. By means of flow cytometric analysis,
HRF20 was found to be expressed on most leukocytes and erythrocytes,
indicating that it may have a role in preventing complement attack in
the circulation.

Walsh et al. (1992) reviewed information on CD59, which they
characterized as a multifunctional molecule with a role particularly in
inhibition of formation of membrane attack complex. They raised the
possibility that Ly-6 is not a homolog and that the true MAC-inhibiting
murine homolog of CD59 had yet to be found.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease
resulting from unusual susceptibility of erythrocytes to the lytic
action of complement. The abnormal erythrocytes are thought to originate
from the clonal proliferation of bone marrow progenitors altered by
somatic mutation (Rosse and Parker, 1985). In this disorder, there is a
generalized, clonal defect of GPI anchoring of multiple proteins in the
cell membrane. Since many complement regulatory proteins that protect
cells against complement lysis are linked to the membrane by GPI anchors
(Low and Saltiel, 1988), deficiency of GPI-linked proteins appears to
play a central role in the pathogenesis of the disorder. Mahoney et al.
(1992) found that in 10 patients with PNH the granulocytes had no
detectable surface expression of glycosylphosphatidylinositol-anchored
proteins and concluded that there was a defect in the synthesis of GPI.

Yamashina et al. (1990) found that the erythrocytes from a patient
thought to have paroxysmal nocturnal hemoglobinuria were devoid of HRF20
and that those of his parents were deficient in the protein, compatible
with the heterozygous state. The patient, previously described by Ono et
al. (1990), was a 22-year-old man with intermittent pallor and hematuria
of 9 years' duration. Paroxysmal nocturnal hemoglobinuria had been
diagnosed at the age of 13 when he had an episode of hemolytic anemia
and hemoglobinuria. During the subsequent 9 years, Ham and sucrose
hemolysis tests were consistently positive and 9 episodes of hemolysis
occurred, with a cerebral infarction during the third and ninth
episodes. His father and mother were cousins, but neither had a history
of hemolytic anemia or hemoglobinuria. Rosse (1993) pointed out that,
although the patient had hemolytic anemia and thrombosis typical of PNH
caused by CD59 deficiency, he did not have PNH, which is due to
deficiency of PIGA (311770), the molecule that anchors CD59 and several
other molecules to the cell surface. Rother et al. (1994) demonstrated
that retroviral transduction with a recombinant transmembrane form of
CD59 of mouse L cells deficient in GPI anchoring resulted in surface
expression of the CD59 protein and resistance of these cells to human
complement-mediated membrane damage. Furthermore, a GPI
anchoring-deficient complement-sensitive B-cell line derived from a PNH
patient was successfully transduced with the particular form of
recombinant CD59, resulting in surface expression of the protein. These
cells were protected against classic complement-mediated membrane damage
by human serum. The findings suggested that retroviral gene therapy with
this molecule could provide a treatment for PNH patients.

Mao et al. (1996) described a 'new' gene, called RIGE (601384) by them,
which they suggested is the closest human homolog of the murine LY-6
gene family.

*FIELD* AV
.0001
CD59 DEFICIENCY
CD59, 1BP DEL, FS54TER
In the 23-year-old Japanese male with inherited complete deficiency of
CD59 reported by Ono et al. (1990) and Yamashina et al. (1990), Motoyama
et al. (1992) found single nucleotide deletions in codon 16 (GCC to GC)
and codon 96 (GCA to CA). Deletion in codon 16 resulted in a frameshift
and introduced a stop codon at position 54. The parents, who are
cousins, were found to be heterozygous for the change which was present
in homozygous state in the proband. One sister was also heterozygous; a
brother was homozygous normal. Presumably it was the deletion in codon
16 that was responsible for the effects on the protein resulting in CD59
deficiency. The patient had hemolytic anemia and thrombosis causing
cerebral infarction but did not have other features of paroxysmal
nocturnal hemoglobinuria (Rosse, 1993), which is a disorder of PIGA.

*FIELD* SA
Harada et al. (1990); Meri et al. (1990)
*FIELD* RF
1. Bickmore, W. A.; Longbottom, D.; Oghene, K.; Fletcher, J. M.; van
Heyningen, V.: Colocalization of the human CD59 gene to 11p13 with
the MIC11 cell surface antigen. Genomics 17: 129-135, 1993.

2. Davies, A.; Simmons, D. L.; Hale, G.; Harrison, R. A.; Tighe, H.;
Lachmann, P. J.; Waldmann, H.: CD59, an LY-6-like protein expressed
in human lymphoid cells, regulates the action of the complement membrane
attack complex on homologous cells. J. Exp. Med. 170: 637-654, 1989.

3. Forsberg, U. H.; Bazil, V.; Stefanova, I.; Schroder, J.: Gene
for human CD59 (likely Ly-6 homologue) is located on the short arm
of chromosome 11. Immunogenetics 30: 188-193, 1989.

4. Harada, R.; Okada, N.; Fujita, T.; Okada, H.: Purification of
1F5 antigen that prevents complement attack on homologous cell membranes. J.
Immun. 144: 1823-1828, 1990.

5. Heckl-Ostreicher, B.; Ragg, S.; Drechsler, M.; Scherthan, H.; Royer-Pokora,
B.: Localization of the human CD59 gene by fluorescence in situ hybridization
and pulsed-field gel electrophoresis. Cytogenet. Cell Genet. 63:
144-146, 1993.

6. Huppi, K.; Duncan, R.; Potter, M.: Myc-1 is centromeric to the
linkage group Ly-6-Sis-Gdc-1 on mouse chromosome 15. Immunogenetics 27:
215-219, 1988.

7. Kamiura, S.; Nolan, C. M.; Meruelo, D.: Long-range physical map
of the Ly-6 complex: mapping the Ly-6 multigene family by field-inversion
and two-dimensional gel electrophoresis. Genomics 12: 89-105, 1992.

8. LeClair, K. P.; Rabin, M.; Nesbitt, M. N.; Pravtcheva, D.; Ruddle,
F. H.; Palfree, R. G. E.; Bothwell, A.: Murine Ly-6 multigene family
is located on chromosome 15. Proc. Nat. Acad. Sci. 84: 1638-1642,
1987.

9. Low, M. G.; Saltiel, A. R.: Structural and functional roles of
glycosyl-phosphatidylinositol in membranes. Science 239: 268-275,
1988.

10. Mahoney, J. F.; Urakaze, M.; Hall, S.; DeGasperi, R.; Chang, H.-M.;
Sugiyama, E.; Warren, C. D.; Borowitz, M.; Nicholson-Weller, A.; Rosse,
W. F.; Yeh, E. T. H.: Defective glycosylphosphatidylinositol anchor
synthesis in paroxysmal nocturnal hemoglobinuria granulocytes. Blood 79:
1400-1403, 1992.

11. Mao, M.; Yu, M.; Tong, J.-H.; Ye, J.; Zhu, J.; Huang, Q.-H.; Fu,
G.; Yu, L.; Zhao, S.-Y.; Waxman, S.; Lanotte, M.; Wang, Z.-Y.; Tan,
J.-Z.; Chan, S.-J.; Chen, Z.: RIG-E, a human homolog of the murine
Ly-6 family, is induced by retinoic acid during the differentiation
of acute promyelocytic leukemia cell. Proc. Nat. Acad. Sci. 93:
5910-5914, 1996.

12. Meri, S.; Morgan, B. P.; Davies, A.; Daniels, R. H.; Olavesen,
M. G.; Waldmann, H.; Lachmann, P. J.: Human protectin (CD59), an
18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8
catalysed insertion of C9 into lipid bilayers. Immunology 71: 1-9,
1990.

13. Meri, S.; Morgan, B. P.; Wing, M.; Jones, J.; Davies, A.; Podack,
E.; Lachmann, P. J.: Human protectin (CD59), an 18-20-kD homologous
complement restriction factor, does not restrict perforin-mediated
lysis. J. Exp. Med. 172: 367-370, 1990.

14. Motoyama, N.; Okada, N.; Yamashina, M.; Okada, H.: Paroxysmal
nocturnal hemoglobinuria due to hereditary nucleotide deletion in
the HRF20 (CD59) gene. Europ. J. Immun. 22: 2669-2673, 1992.

15. Okada, N.; Harada, R.; Fujiita, T.; Okada, H.: A novel membrane
glycoprotein capable of inhibiting membrane attack by homologous complement. Int.
Immun. 1: 205-208, 1989.

16. Ono, H.; Kuno, Y.; Tanaka, H.; Yamashina, M.; Tsuyoshi, T.; Kondo,
N.; Orii, T.: A case of paroxysmal nocturnal hemoglobinuria without
deficiency of decay-accelerating factor on erythrocytes. Blood 75:
1746-1747, 1990.

17. Petranka, J. G.; Fleenor, D. E.; Sykes, K.; Kaufman, R. E.; Rosse,
W. F.: Structure of the CD59-encoding gene: further evidence of a
relationship to murine lymphocyte antigen Ly-6 protein. Proc. Nat.
Acad. Sci. 89: 7876-7879, 1992.

18. Rosse, W. F.: Personal Communication. Durham, N. C.  6/3/1993.

19. Rosse, W. F.; Parker, C. J.: Paroxysmal nocturnal hemoglobinuria. Clin.
Haemat. 14: 105-125, 1985.

20. Rother, R. P.; Rollins, S. A.; Mennone, J.; Chodera, A.; Fidel,
S. A.; Bessler, M.; Hillmen, P.; Squinto, S. P.: Expression of recombinant
transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells
confers resistance to human complement. Blood 84: 2604-2611, 1994.

21. Tone, M.; Walsh, L. A.; Waldmann, H.: Gene structure of human
CD59 and demonstration that discrete mRNAs are generated by alternative
polyadenylation. J. Molec. Biol. 227: 971-976, 1992.

22. Walsh, L. A.; Tone, M.; Thiru, S.; Waldmann, H.: The CD59 antigen--a
multifunctional molecule. Tissue Antigens 40: 213-220, 1992.

23. Yamashina, M.; Ueda, E.; Kinoshita, T.; Takami, T.; Ojima, A.;
Ono, H.; Tanaka, H.; Kondo, N.; Orii, T.; Okada, N.; Okada, H.; Inoue,
K.; Kitani, T.: Inherited complete deficiency of 20-kilodalton homologous
restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. New
Eng. J. Med. 323: 1184-1189, 1990.

*FIELD* CD
Victor A. McKusick: 12/12/1989

*FIELD* ED
terry: 08/21/1996
terry: 7/16/1996
mark: 7/8/1996
carol: 1/24/1995
warfield: 4/7/1994
carol: 7/13/1993
carol: 7/6/1993
carol: 6/9/1993
carol: 6/8/1993

*RECORD*
*FIELD* NO
107272
*FIELD* TI
*107272 ANTIGEN CD72; CD72
Lyb-2, HUMAN HOMOLOG OF
*FIELD* TX
By means of monoclonal antibodies, Von Hoegen et al. (1991) demonstrated
identity of CD72 to the human homolog of mouse Lyb-2 and localized the
gene to the short arm of human chromosome 9 by study of mouse/human
somatic cell hybrids. The mouse Lyb-2 gene had previously been mapped to
chromosome 4. Expression of Lyb-2 is restricted to B-lineage cells and
is turned off in antibody-secreting plasma cells in both mice and
humans. The protein may be involved in signals for B-cell proliferation.

*FIELD* RF
1. Von Hoegen, I.; Hsieh, C.-L.; Scharting, R.; Francke, U.; Parnes,
J. R.: Identity of human Lyb-2 and CD72 and localization of the gene
to chromosome 9. Europ. J. Immun. 21: 1425-1431, 1991.

*FIELD* CD
Victor A. McKusick: 10/21/1991

*FIELD* ED
supermim: 3/16/1992
carol: 10/25/1991
carol: 10/21/1991

*RECORD*
*FIELD* NO
107273
*FIELD* TI
*107273 ANTIGEN CD69; CD69
EARLY T-CELL ACTIVATION ANTIGEN p60
*FIELD* TX
The activation of T lymphocytes, both in vivo and in vitro, induces the
expression of CD69. This molecule, which appears to be the earliest
inducible cell surface glycoprotein acquired during lymphoid activation,
is involved in lymphocyte proliferation and functions as a signal
transmitting receptor in lymphocytes, natural killer (NK) cells, and
platelets. Cambiaggi et al. (1992) produced and characterized
interspecies somatic cell hybrids between human activated mature T cells
and mouse BW5147 thymoma cells. A preferential segregation of human
chromosomes was observed in the hybrids. They found in clones a
coexpression of CD4 and CD69 antigens. Molecular and karyotypic studies
of the hybrids demonstrated that the locus encoding CD69 maps to human
chromosome 12 as does that for CD4 (186940). Although the expression of
CD69 antigen is an early event after T-lymphocyte activation and rapidly
declines in the absence of exogenous stimuli, in the hybrids they
developed the expression was constitutive, similar to what is found in
early thymocyte precursors and mature thymocytes. The finding suggested
a dominant influence of the thymus-derived mouse tumor cell genome in
controlling the constitutive expression of CD69.

Lopez-Cabrera et al. (1993) demonstrated that a cDNA for CD69 showed a
single open reading frame of 597 bp, predicting a 199-amino acid protein
of type II membrane topology. The CD69 clone hybridized to a 1.7-kb mRNA
species, which was rapidly induced and degraded after lymphocyte
stimulation, consistent with the presence of rapid degradation signals
at the 3-prime untranslated region. By somatic cell hybrid DNA analysis
and fluorescence in situ hybridization, Lopez-Cabrera et al. (1993)
assigned the CD69 gene to 12p13-p12. Protein sequence homology search
demonstrated that CD69 is a member of the same superfamily of type II
transmembrane receptors as natural killer cell lectin (NKG2; 161555),
which also maps to chromosome 12.

*FIELD* RF
1. Cambiaggi, C.; Scupoli, M. T.; Cestari, T.; Gerosa, F.; Carra,
G.; Tridente, G.; Accolla, R. S.: Constitutive expression of CD69
in interspecies T-cell hybrids and locus assignment to human chromosome
12. Immunogenetics 36: 117-120, 1992.

2. Lopez-Cabrera, M.; Santis, A. G.; Fernandez-Ruiz, E.; Blacher,
R.; Esch, F.; Sanchez-Mateos, P.; Sanchez-Madrid, F.: Molecular cloning,
expression, and chromosomal localization of the human earliest lymphocyte
activation antigen AIM/CD69, a new member of the C-type animal lectin
superfamily of signal-transmitting receptors. J. Exp. Med. 178:
537-547, 1993.

*FIELD* CD
Victor A. McKusick: 9/16/1992

*FIELD* ED
carol: 11/9/1993
carol: 9/16/1992

*RECORD*
*FIELD* NO
107280
*FIELD* TI
*107280 ALPHA-1-ANTICHYMOTRYPSIN; AACT
ANTICHYMOTRYPSIN, ALPHA-1; ACT
*FIELD* TX
Alpha-1-antichymotrypsin is a plasma protease inhibitor synthesized in
the liver. It is a single glycopeptide chain of about 68,000 daltons and
belongs to the class of serine protease inhibitors. In man, the normal
serum level is about one-tenth that of alpha-1-antitrypsin (PI; 107400),
with which it shares nucleic acid and protein sequence homology (Chandra
et al., 1983). Both are major acute phase reactants; their
concentrations in plasma increase in response to trauma, surgery, and
infection. Antithrombin III, which also is structurally similar to
alpha-1-antitrypsin, shows less sequence homology to antichymotrypsin
and is not an acute phase reactant. It would be of interest to know the
signals in the genes that evoke the acute phase response. The homology
of AACT and alpha-1-antitrypsin is at a level comparable to that between
chymotrypsin and trypsin.

Rabin et al. (1985) found by in situ hybridization that the AACT gene
maps to 14q31-q32.3, which overlaps the region to which PI has been
mapped (14q24.3-q32.1) by study of somatic cell hybrids. PI and AACT may
constitute a gene cluster: in situ hybridization shows that both map to
the 14q31-q32.3 region (Rabin et al., 1986). Indeed, Sefton et al.
(1989) demonstrated that the PI and the AACT genes are located on the
same 360-kb MluI restriction fragment by pulsed field gel
electrophoresis. Sefton et al. (1990) concluded that the PI-PIL gene
cluster is only 220 kb away from the AACT gene and that it is oriented
in the opposite direction. The comparatively short interval between the
genes came as a surprise given previous estimates of the level of
genetic recombination between them.

Eriksson et al. (1986) studied levels of antichymotrypsin in 229
patients with liver disease verified by biopsy. In a small subgroup with
seronegative, chronic, active hepatitis, they found low ACT values. In 1
of these patients they found equally low AACT levels among first-degree
relatives, prompting a study of other cases of partial deficiency, i.e.,
those with approximately 50% of normal plasma levels. Six of 8
AACT-deficient individuals, over 25 years of age, had liver
manifestations and 3 of 8 had pulmonary defects, varying from severe
disease to subtle laboratory abnormalities. The abnormal gene was
inherited in an autosomal dominant manner, and its frequency was
estimated to be 0.003. Kelsey et al. (1988) cloned and analyzed the AACT
gene, partly because of the possibility that genetic variation in other
protease inhibitors may influence the prognosis in AAT deficiency. They
isolated the AACT gene on a series of cosmid clones, with restriction
mapping of about 70 kb around the gene. A common TaqI polymorphism was
found to be tightly linked to the PI gene (maximum lod score in males =
2.29 at theta = 0; in females 6.11 at theta = 0.032). PI-AACT haplotypes
in 31 families ascertained through subjects with the PI*Z allele did not
show any linkage disequilibrium, and the distribution of RFLP alleles in
16 unrelated PI*Z patients presenting with childhood liver disease and 5
unrelated PI*Z patients with adult chest disease did not differ
significantly from each other.

One form of Alzheimer disease (AD3; 104311), like AACT, maps to 14q.
Because of a somewhat different location on 14q, it was thought that ACT
could be excluded as a candidate gene. However, Kamboh et al. (1995)
presented evidence that a polymorphism of AACT (107280.0005) in
combination with the APOE4 allele (107741.0016) increases susceptibility
to Alzheimer disease. The polymorphism discussed by Kamboh et al. (1995)
results in the presence of either an alanine (the A allele, symbolized
ACT*A by them) or threonine (the T allele, symbolized ACT*T by them) at
residue -15 of the AACT signal peptide.

Morgan et al. (1997) found that a dinucleotide microsatellite allele in
the 5-prime-flanking sequence of the ACT gene, designated A10, in
association with APOE*4 significantly increased the risk of developing
sporadic Alzheimer disease (104300).

*FIELD* AV
.0001
CEREBROVASCULAR DISEASE, OCCLUSIVE
ANTICHYMOTRYPSIN ISEHARA-1
AACT, MET389VAL
By PCR-single strand conformation polymorphism (SSCP) analysis, Tsuda et
al. (1992) identified a point mutation in exon 5 of the AACT gene
resulting in substitution of met by val at codon 389. The mutation, an
A-to-G transition at basepair 1252, was found in heterozygous state in 6
patients; 4 of the 6 (aged 38, 43, 69, and 80 years) had occlusive
cerebrovascular disease.

.0002
ANTICHYMOTRYPSIN ISEHARA-2
AACT, 2-BP DEL
Tsuda et al. (1992) used PCR-SCCP and direct sequencing to demonstrate a
variant AACT: deletion of 2 bases (AA) from codon 391 (AAA for lys) led
to a frameshift, a change in the amino acid sequence downstream of the
deletion, and elongation of the peptide chain by 10 amino acids. The
subject was a 26-year-old asymptomatic male. The concentration of serum
AACT was about 40% of the normal level, suggesting that the variant
molecule is not secreted from the liver or is rapidly degraded.

.0003
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
COPD ANTICHYMOTRYPSIN BOCHUM-1
AACT, LEU55PRO
Using denaturing gradient gel electrophoresis and direct sequencing of
amplified genomic DNA, Poller et al. (1993) identified 2 defective
mutants of the human AACT gene associated with COPD. A CTG (leu) to CCG
(pro) transition in codon 55 was found in affected members in 3
successive generations.

.0004
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
COPD ANTICHYMOTRYPSIN BONN-1
AACT, PRO229ALA
In 4 patients with COPD and a positive family history for COPD, Poller
et al. (1993) observed a CCT (pro)-to-GCT (ala) transversion in codon
229. (Poller et al. (1992) referred to this mutation as PRO227ALA.)
Samilchuk and Chuchalin (1993) failed to find this mutation among 102
COPD patients treated in Moscow hospitals.

.0005
ANTICHYMOTRYPSIN SIGNAL PEPTIDE POLYMORPHISM
AACT, ALA-15THR
The polymorphism discussed by Kamboh et al. (1995) results in the
presence of either an alanine (the A allele, symbolized ACT*A by them)
or threonine (the T allele, symbolized ACT*T by them) at residue -15 of
the AACT signal peptide; their 'AA' genotype is biallelic for ACT*A,
while genotypes 'AT' and 'TT' have 1 and no ACT*A alleles, respectively.
The frequency of the 2 alleles ACT*A and ACT*T was approximately equal
in the control population and 0.57 and 0.43, respectively, in a group of
Alzheimer disease patients. The combination of AA homozygosity with
homozygosity of APOE4 (107741.0016) had a frequency of 1/17 in the AD
group compared to 1/313 in the general population control. Possible
mechanisms for the apparent dependent effect of APOE4 on the AACT signal
peptide polymorphism were proposed by Kamboh et al. (1995): the ACT*A
allele in the signal peptide may be in strong linkage disequilibrium
with a functional mutation affecting an amino acid substitution in the
mature AACT protein which possibly enhances the binding of the AACT
protein to amyloid beta protein or interacts with APOE to alter binding
to microtubular elements. Alternatively, amino acid changes in a signal
peptide could affect hydrophobicity and alter the posttranslational
protein structure.

Haines et al. (1996) were, however, unable to confirm any effect of the
AA/TT polymorphism, either alone or in combination with the APOE4
allele, in a large set of Alzheimer disease families and sporadic
Alzheimer cases. Kamboh et al. (1997) felt that the data of Haines et
al. (1996) were at least not inconsistent with their own as reported in
Kamboh et al. (1995). Haines et al. (1997) retorted and pointed out that
3 additional reports had failed to confirm the findings of Kamboh et al.
(1995). Haines et al. (1997) concluded that, in toto, the results
suggest that any effect of the ACT signal peptide polymorphism on AD, if
it exists at all, is very small.

*FIELD* SA
Tsuda et al. (1992)
*FIELD* RF
1. Chandra, T.; Stackhouse, R.; Kidd, V. J.; Robson, K. J. H.; Woo,
S. L. C.: Sequence homology between human alpha-1-antichymotrypsin,
alpha-1-antitrypsin, and antithrombin III. Biochemistry 22: 5055-5061,
1983.

2. Eriksson, S.; Lindmark, B.; Lilia, H.: Familial alpha-1-antichymotrypsin
deficiency. Acta Med. Scand. 220: 447-453, 1986.

3. Haines, J. L.; Pritchard, M. L.; Saunders, A. M.; Schildkraut,
J. M.; Growdon, J. H.; Gaskell, P. C.; Farrer, L. A.; Auerbach, S.
A.; Gusella, J. F.; Locke, P. A.; Rosi, B. L.; Yamaoka, L.; Small,
G. W.; Conneally, P. M.; Roses, A. D.; Pericak-Vance, M. A.: No genetic
effect of alpha-1-antichymotrypsin in Alzheimer disease. Genomics 33:
53-56, 1996.

4. Haines, J. L.; Scott, W. K.; Pericak-Vance, M. A.: Reply to 'Genetic
effect of alpha-1-antichymotrypsin on the risk of Alzheimer disease.'
(Letter) Genomics 40: 384-385, 1997.

5. Kamboh, M. I.; Aston, C. E.; Ferrell, R. E.; Dekosky, S. T.: Genetic
effect of alpha-1-antichymotrypsin on the risk of Alzheimer disease.
(Letter) Genomics 41: 382-385, 1997.

6. Kamboh, M. I.; Sanghera, D. K.; Ferrell, R. E.; DeKosky, S. T.
: APOE*4-associated Alzheimer's disease risk is modified by alpha-1-antichymotrypsin
polymorphism. Nature Genet. 10: 486-488, 1995.

7. Kelsey, G. D.; Abeliovich, D.; McMahon, C. J.; Whitehouse, D.;
Corney, G.; Povey, S.; Hopkinson, D. A.; Wolfe, J.; Mieli-Vergani,
G.; Mowat, A. P.: Cloning of the human alpha-1 antichymotrypsin gene
and genetic analysis of the gene in relation to alpha-1 antitrypsin
deficiency. J. Med. Genet. 25: 361-368, 1988.

8. Morgan, K.; Morgan, L.; Carpenter, K.; Lowe, J.; Lam, L.; Cave,
S.; Xuereb, J.; Wischik, C.; Harrington, C.; Kalsheker, N. A.: Microsatellite
polymorphism of the alpha-1-antichymotrypsin gene locus associated
with sporadic Alzheimer's disease. Hum. Genet. 99: 27-31, 1997.

9. Poller, W.; Faber, J.-P.; Scholz, S.; Weidinger, S.; Bartholome,
K.; Olek, K.; Eriksson, S.: Mis-sense mutation of alpha-1-antichymotrypsin
gene associated with chronic lung disease. (Letter) Lancet 339:
1538, 1992.

10. Poller, W.; Faber, J.-P.; Weidinger, S.; Tief, K.; Scholz, S.;
Fischer, M.; Olek, K.; Kirchgesser, M.; Heidtmann, H.-H.: A leucine-to-proline
substitution causes a defective alpha-1-antichymotrypsin allele associated
with familial obstructive lung disease. Genomics 17: 740-743, 1993.

11. Rabin, M.; Watson, M.; Breg, W. R.; Kidd, V.; Woo, S. L. C.; Ruddle,
F. H.: Human alpha-1-antichymotrypsin and alpha-1-antitrypsin (PI)
genes map to the same region on chromosome 14. (Abstract) Cytogenet.
Cell Genet. 40: 728, 1985.

12. Rabin, M.; Watson, M.; Kidd, V.; Woo, S. L. C.; Breg, W. R.; Ruddle,
F. H.: Regional location of alpha-1-antichymotrypsin and alpha-1-antitrypsin
genes on human chromosome 14. Somat. Cell Molec. Genet. 12: 209-214,
1986.

13. Samilchuk, E. I.; Chuchalin, A. G.: Mis-sense mutation of alpha-1-antichymotrypsin
gene and chronic lung disease. (Letter) Lancet 342: 624, 1993.

14. Sefton, L.; Kearney, P.; Kelsey, G.; Povey, S.; Wolfe, J.: Physical
linkage of the genes PI and AACT. (Abstract) Cytogenet. Cell Genet. 51:
1076, 1989.

15. Sefton, L.; Kelsey, G.; Kearney, P.; Povey, S.; Wolfe, J.: A
physical map of the human PI and AACT genes. Genomics 7: 382-388,
1990.

16. Tsuda, M.; Sei, Y.; Matsumoto, M.; Kamiguchi, H.; Yamamoto, M.;
Shinohara, Y.; Igarashi, T.; Yamamura, M.: Alpha-1-antichymotrypsin
variant detected by PCR-single strand conformation polymorphism (PCR-SSCP)
and direct sequencing. Hum. Genet. 90: 467-468, 1992.

17. Tsuda, M.; Sei, Y.; Yamamura, M.; Yamamoto, M.; Shinohara, Y.
: Detection of a new mutant alpha-1-antichymotrypsin in patients with
occlusive-cerebrovascular disease. FEBS Lett. 304: 66-68, 1992.

*FIELD* CN
Victor A. McKusick - updated: 03/25/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/25/1997
terry: 3/10/1997
mark: 1/3/1997
terry: 12/26/1996
mark: 4/17/1996
terry: 4/10/1996
mark: 8/2/1995
pfoster: 3/25/1994
mimadm: 2/11/1994
carol: 10/14/1993
carol: 10/4/1993
carol: 9/21/1993

*RECORD*
*FIELD* NO
107285
*FIELD* TI
*107285 ANTILEUKOPROTEASE
SECRETORY LEUKOCYTE PROTEASE INHIBITOR; SLPI;;
HUMAN SEMINAL PROTEINASE INHIBITOR; HUSI
*FIELD* TX
Human mucous fluids such as seminal plasma, cervical mucus, bronchial
and nasal secretions, and tears contain acid-stable proteinase
inhibitors with strong affinity for trypsin and chymotrypsin as well as
for neutrophil lysosomal elastase and cathepsin G. The antileukoprotease
from human seminal plasma HUSI-I (human seminal plasma inhibitor-I) and
the inhibitor found in mucous secretions from the cervix, although
isolated from different tissues, seem to be identical proteins.
Therefore they are referred to as antileukoproteases.

Heinzel et al. (1986) isolated cDNA clones for the human
antileukoprotease HUSI-I from a library containing cDNA inserts made
from human cervix. By screening with a mixture of over 16 different
oligodeoxyribonucleotides which correspond to amino acids 79-84 and with
one 20mer oligodeoxyribonucleotide corresponding to amino acids 19-26,
they isolated 2 overlapping cDNA clones containing the entire coding
sequence and part of the 5-prime and 3-prime untranslated regions.
Seemuller et al. (1986) demonstrated structural homology to whey
proteins of rat and mouse.

Thompson and Ohlsson (1986) purified from human parotid secretions a
potent inhibitor of human leukocyte elastase and cathepsin G, as well as
of human trypsin, and reported the complete amino acid sequence. Stetler
et al. (1986) isolated the human gene encoding secretory leukocyte
protease inhibitor. The protein appears to contain 2 functional domains,
one having a trypsin inhibitory site and the other an elastase
inhibitory site. The 2-domain structure of the protein is reflected in
the organization of the gene, with each domain represented by a separate
exon. The intervening sequence separating the 2 exons is flanked by 11
bp direct repeats, suggesting that this intron may have been generated
by a transposition-type event. SLPI is a Mr 12,000 acid-stable
polypeptide found also in bronchial mucus, cervical mucus, and seminal
plasma.

*FIELD* RF
1. Heinzel, R.; Appelhans, H.; Gassen, G.; Seemuller, U.; Machleidt,
W.; Fritz, H.; Steffens, G.: Molecular cloning and expression of
cDNA for human antileukoprotease from cervix uterus. Europ. J. Biochem. 160:
61-67, 1986.

2. Seemuller, U.; Arnhold, M.; Fritz, H.; Wiedenmann, K.; Machleidt,
W.; Heinzel, R.; Appelhans, H.; Gassen, H.-G.; Lottspeich, F.: The
acid-stable proteinase inhibitor of human mucous secretions (HUSI-I,
antileukoprotease): complete amino acid sequence as revealed by protein
and cDNA sequencing and structural homology to whey proteins and Red
Sea turtle proteinase inhibitor. FEBS Lett. 199: 43-48, 1986.

3. Stetler, G.; Brewer, M. T.; Thompson, R. C.: Isolation and sequence
of a human gene encoding a potent inhibitor of leukocyte proteases.
Nucleic Acids Res. 14: 7883-7896, 1986.

4. Thompson, R. C.; Ohlsson, K.: Isolation, properties, and complete
amino acid sequence of human secretory leukocyte protease inhibitor,
a potent inhibitor of leukocyte elastase. Proc. Nat. Acad. Sci. 83:
6692-6696, 1986.

*FIELD* CD
Victor A. McKusick: 7/11/1990

*FIELD* ED
carol: 7/13/1992
supermim: 3/16/1992
carol: 7/11/1990

*RECORD*
*FIELD* NO
107290
*FIELD* TI
*107290 ANTIPYRINE METABOLISM
*FIELD* TX
In the rat, each of 3 urinary metabolites of antipyrine
(AP)--4-hydroxyantipyrine (4-OH-AP), 3-hydroxymethylantipyrine
(3-OHM-AP), and N-demethylantipyrine (NDM-AP)--appears to be formed by a
separate combination of hepatic cytochrome P-450-mediated
monooxygenases; variations in each separate monooxygenase appear to be
controlled by a separate genetic locus (Danhof et al., 1979; Inaba et
al., 1980). Penno et al. (1981) showed by means of twin study that
heritability for rate constants for formation of the above 3 metabolites
in man were 0.88, 0.85, and 0.70, respectively, and that in adult male
subjects whose environments were carefully controlled these rate
constants were highly reproducible. Penno and Vesell (1983) then studied
83 unrelated adults and 61 members of 13 families. Trimodal curves were
obtained for each of the 3 rate constants when the data from the 83
unrelated persons were plotted. The family studies supported monogenic
control of each phenotype. Nine phenotypes were under investigation.

*FIELD* RF
1. Danhof, M.; Krom, D. P.; Breimer, D. D.: Studies on the different
metabolic pathways of antipyrine in rats: influence of phenobarbital
and 3-methylcholanthrene treatment. Xenobiotica 9: 695-702, 1979.

2. Inaba, T.; Lucassen, M.; Kalow, W.: Antipyrine metabolism in the
rat by three hepatic monooxygenases. Life Sci. 26: 1977-1983, 1980.

3. Penno, M. B.; Dvorchik, B. H.; Vesell, E. S.: Genetic variation
in rates of antipyrine metabolite formation: a study in uninduced
twins. Proc. Nat. Acad. Sci. 78: 5193-5196, 1981.

4. Penno, M. B.; Vesell, E. S.: Monogenic control of variations in
antipyrine metabolite formation: new polymorphism of hepatic drug
oxidation. J. Clin. Invest. 71: 1698-1709, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
joanna: 02/05/1996
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107300
*FIELD* TI
*107300 ANTITHROMBIN III DEFICIENCY
THROMBOPHILIA, HEREDITARY, DUE TO DEFICIENCY OF AT-III
ANTITHROMBIN III; AT3, INCLUDED
*FIELD* TX
Rosenberg and Bauer (1987) gave an excellent review of defects in the
anticoagulant systems. They wrote as follows: 'The coagulation cascade
can be pictured as a series of reactions in which a zymogen, a cofactor,
and a converting enzyme interact to form a multimolecular complex on a
natural surface. In each case, the 4 reactants must be present if the
conversion of a zymogen to the corresponding serine protease is to take
place at any significant rate. The principal natural anticoagulant
systems that are able to exert damping effects on the various steps of
the cascade are the heparin-antithrombin and protein C-thrombomodulin
mechanisms that regulate the serine proteases and the cofactors or
activated cofactors, respectively.'

Egeberg (1965) described a pedigree in which persons in 3 generations
had florid thrombophlebitis and other thrombotic disease associated with
about half-normal levels of antithrombin III. He suggested that
antithrombin III may be the same as heparin cofactor. Antithrombin
deficiency in individual patients with severe venoocclusive disease and
an impressive family history was also reported by Penick (1969) and by
Nesje and Kordt (1970). Marciniak et al. (1974) described a large
kindred from eastern Kentucky, with an extensive history of recurrent
venous thrombosis and pulmonary embolism. Nine persons in 3 generations
showed low antithrombin III levels (26 to 49% of normal). Five others
were suspected of having the biochemical defect. Male-to-male
transmission was noted. They concluded that antithrombin III is the sole
blood component through which heparin exerts its anticoagulant effect.
Tullis and Watanabe (1978) described the seventh reported family and
suggested that familial hypercoagulability may be due, in some instances
at least, to platelet antithrombin deficiency (with the serum deficiency
representing a secondary defect). A CRM+ form of antithrombin III
deficiency was described by Sas et al. (1980). Not only does heparin
require AT-III for its anticoagulant effect, but it also increases the
turnover rate of AT-III. Both normal persons and persons with AT-III
deficiency show a decrease in plasma AT-III levels when given heparin
intravenously. In persons with AT-III deficiency the effect may lead to
recurrent thrombosis despite heparin therapy. Rosenberg (1975) placed
the prevalence of AT-III deficiency at 1 per 2,000 and the frequency
among hospitalized patients with recurrent or extensive thrombosis at 2
to 3%. The many special problems of pregnancy in women with AT-III
deficiency were discussed by Nelson et al. (1985). Wilson et al. (1987)
found that 16 of 123 patients with acute mesenteric infarction (13%) had
mesenteric venous thromboses. Of these, 6 patients could be studied for
antithrombin III deficiency; deficiency was found in 3. The family with
a 'new' variant of AT-III reported by Aiach et al. (1987) had apparently
no increased incidence of venous thrombosis. Johnson et al. (1990)
described 2 sisters who at ages 27 and 40 had serious peripheral and CNS
arterial thrombotic disease. Cigarette smoking was the only clear
additional risk factor. Rosendaal et al. (1991) found no evidence of
excess mortality in 171 individuals from 10 families with either proven
deficiency of AT-III or a 50% probability of being affected. They
suggested, therefore, that a policy of prophylactic anticoagulation for
patients with AT-III deficiency cannot be recommended. Mitchell et al.
(1991) proposed that the lower risk of thromboembolic complications in
AT-III-deficient children may be due in part to a protective effect of
elevated levels of alpha-2-macroglobulin (A2M; 103950) during childhood.

Heijboer et al. (1990) investigated the prevalence of isolated
deficiencies of antithrombin III, protein C, protein S, and plasminogen
in 277 consecutive outpatients with venographically proved acute
deep-vein thrombosis, as compared with 138 age-matched and sex-matched
controls without deep-vein thrombosis. They found deficiencies of 1 of
these proteins in 23 (8.3%) of the patients as compared with 2.2% of
controls. The positive predictive values for the presence of an isolated
protein deficiency in patients with recurrent, familial, or juvenile
deep-vein thrombosis, defined as the proportion of patients with the
clinical finding who had a deficiency of 1 or more of the proteins, were
9, 16, and 12%, respectively. They concluded that acute venous
thrombosis in most outpatients cannot be explained by abnormalities of
coagulation-inhibiting and fibrinolytic proteins and that information
from the medical history concerning recurrent or familial venous
thrombosis or the onset at an early age is not useful for identifying
patients with protein deficiencies. Pabinger et al. (1994) found that
the probability for thrombosis was significantly higher in AT3-deficient
females taking an oral contraceptive compared to AT3-deficient females
who were not. In patients with protein C and protein S deficiency, there
was no significant difference between the contraceptive and
noncontraceptive groups. Pabinger et al. (1994) suggested that all
contraceptives should be strictly avoided in these females and that AT3
measurement should be mandatory in female relatives of known
AT3-deficient patients before starting contraceptives.

Sas (1988) and De Stefano and Leone (1989) addressed the question of
classification of mutant forms of antithrombin III leading to
deficiency. Manson et al. (1989) reviewed the molecular defects. As with
many other deficiency states, they recognized CRM-negative (referred to
as 'classic' or type I) and CRM-positive (referred to as 'mutant' or
type II) cases; in type II immunologic methods demonstrate in the plasma
protein product from the mutant allele. Manson et al. (1989) further
classified the AT-III mutants into those involving 1 of the 2
heparin-binding sites toward the NH2-terminus (mutations at pro41 or
arg47) and those involving the thrombin-binding region toward the
COOH-terminus (mutations in ala382, arg393, ser394, or pro407). Sas
(1988) had commented on the confused state of the classification of
AT-III variants. He used the term 'toponym' for the geographical names
assigned to variants.

With Duffy blood group, Lovrien et al. (1978) found a lod score of 1.235
at a recombination fraction of 0.1 in males and 0.3 in females. Bishop
et al. (1978) presented corroborating data on linkage with Duffy. The
provisional assignment of antithrombin III deficiency to chromosome 1 by
linkage to the Duffy blood group locus was confirmed (Bishop et al.,
1982; Winter et al., 1982). For the linkage of AT3 and Fy, Winter et al.
(1982) found a combined maximum lod score of 4.2 at recombination
fractions around 0.1. Two patients with deletions of 1q had half-normal
levels of antithrombin III, suggesting that the AT3 locus lies in bands
1q22-q25. Using a purified cDNA probe of the AT3 gene and a series of
human/Chinese hamster cell hybrids, Kao et al. (1984) assigned the locus
to chromosome 1 by Southern blot analysis. Kao et al. (1984) assigned
the gene to 1p31.3-qter. By in situ hybridization and quantitative
analysis of DNA dosage in carriers of chromosome 1 deletions, Bock et
al. (1985) assigned AT3 to 1q23-q25. Pakstis et al. (1989) reported
linkage data between AT3 and the anonymous DNA fragment D1S75 (maximum
lod score = 4.67 at theta = 11.4). In a linkage map of chromosome 1
prepared by Rouleau et al. (1990), it was concluded that AT3 lies about
17 cM distal to Fy.

Prochownik et al. (1983) found deletion of the AT3 gene in affected
members of 1 family, whereas no deletion occurred in another family. A
common DNA polymorphism was found in the gene codons 304 and 305, which
code for leucine and glutamine, respectively, and are either CTGCAA or
CTGCAG. Although these are synonymous in amino acid code, they differ
with respect to Pst1 restriction, the former not being cleaved. In 1 of
16 kindreds with AT-III deficiency, Bock and Prochownik (1987) found
hemizygosity of the AT3 locus. In the remaining 15 kindreds, 2 copies of
the AT3 gene were present and appeared to be grossly normal at the level
of whole genome Southern blotting. This suggested to the authors that
small deletions, insertions or limited nucleotide substitutions in the
AT3 gene, or 'trans-acting' defects involving the processing,
modification, or secretion of biologically active AT3 were responsible
for the great majority of the abnormalities. Using DNA probes, Sacks et
al. (1988) found no evidence of gene deletion in 2 families with
inherited antithrombin III deficiency. However, linkage analysis showed
close linkage (no recombination) between the AT3 gene, as marked by a
common polymorphism, and the disorder. Borg et al. (1988) identified a
new AT-III variant that showed defective heparin binding. This and other
mutant forms of AT-III that showed a heparin-binding defect suggested
that arginine-47 is a prime heparin-binding site in antithrombin. Borg
et al. (1990) studied the basis of reduced heparin affinity. Leone et
al. (1988) used crossed immunoelectrofocusing (CIEF) to investigate
molecular heterogeneity in 16 families with congenital defects of
AT-III. Of these, 8 families had quantitative deficiency of AT-III and
showed a normal CIEF pattern. Out of the 8 AT-III molecular variants
studied, 6 had 1 of 2 abnormal patterns, depending on whether they were
variants with defective binding to heparin or variants with defective
binding to serine proteases. Two variants that were deficient in the
inactivation of serine proteases showed a normal CIEF pattern.

Wu et al. (1989) used PCR to demonstrate a DNA length polymorphism
5-prime to the AT3 gene due to the presence of 32- or 108-bp
nonhomologous DNA segments (Bock and Levitan, 1983). Mutations at
residues pro41 and arg47 lead to loss of heparin binding, whereas
mutation at residues arg393 and ser394 of the reactive site results in a
loss of thrombin inhibitory activity. Grundy et al. (1991) pointed out
that although AT-III deficiency usually follows an autosomal dominant
pattern of inheritance, a few patients with defective heparin binding
have been shown to be homozygous for a lesion in the arg47 residue (see
107300.0008, 107300.0015). Blajchman et al. (1992) provided a review of
molecular defects underlying inherited antithrombin deficiency.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988). Lane et al. (1994) described a database of
mutations in the AT3 gene. A recent update was said to list 184 entries:
68 reports of type I 'classical' and 116 reports of type II 'variant'
deficiencies. Perry and Carrell (1996) also provided a catalog of AT3
mutations responsible for types I and II deficiency. They estimated that
AT3 deficiency has a prevalence of 1:630 in the general population and
is found in 3% to 5% of patients with thrombotic disease. The gene
consists of 7 exons and 6 introns and spans 13,477 bp of genomic DNA.
Lane et al. (1996) gave an extensive review of the molecular genetics of
antithrombin deficiency.

*FIELD* AV
.0001
AT-III OSLO
AT3, ALA404THR
This variant was found in the family first described as an example of
thrombophilia due to deficiency of AT-III (Egeberg, 1965). Hultin et al.
(1988) provided further information. AT-III Oslo is a type I form of
deficiency. AT-III protein is decreased in both the immunologic and the
functional assay.

.0003
AT-III PADUA-2
AT3
This variant was described by Girolami et al. (1983).

.0004
AT-III ROMA
AT3
This variant was studied by Leone et al. (1983) and De Stefano et al.
(1987).

.0006
AT-III TRENTO
AT3
This variant was studied by Girolami et al. (1984).

.0007
AT-III CHARLEVILLE
AT-III CAMBRIDGE I AT-III SUDBURY AT-III VICENZA
AT3, ALA384PRO
AT-III Vicenza was described by Barbui et al. (1983). The same variant
was described by Aiach et al. (1985) as AT-III Charleville.
Molho-Sabatier et al. (1989) demonstrated that the AT-III Charleville
mutation represents a substitution of proline for alanine at residue
384. Molho-Sabatier et al. (1989) used genomic amplification by PCR for
the identification of this as well as 2 other mutant forms of AT-III,
namely, pro41-to-leu (107300.0024) and arg393-to-his (107300.0021).
Perry and Carrell (1989) and Caso et al. (1991) also demonstrated this
change, which resulted from a GCA-to-CCA transition in exon 6. This is a
reactive site mutation. Pewarchuk et al. (1990) used PCR to identify the
same abnormality in a family with an extensive history of deep venous
thrombosis.

.0008
AT-III TOYAMA
AT-III TOURS AT-III ALGER AT-III AMIENS
AT3, ARG47CYS
Koide et al. (1984) demonstrated substitution of cysteine for
arginine-47. The proband was homozygous and had recurrent
thrombophlebitis; heterozygous members of the family were asymptomatic.
The deficiency in AT-III(Tours) shows retention of normal activity in
the absence of heparin and diminished activity in the presence of
heparin, with a decrease or complete loss of heparin-binding ability.
Most type 3 deficiencies are silent in the heterozygous state and
associated with severe thrombotic disorders only in homozygotes (Boyer
et al., 1986; Sakuragawa et al., 1983; Duchange et al., 1987). The
abnormality was present in heterozygous state in 9 members of the French
family (Chasse et al., 1984), all without thrombotic complications.
Duchange et al. (1986) confirmed this by demonstrating in what they
called AT-III Tours a C-to-T change in codon 47 leading to the above
amino acid change. AT-III Toyama was described by Sakuragawa et al.
(1983). This variant, described in homozygous form by Fischer et al.
(1986), was shown by Brunel et al. (1987) also to have substitution of
cysteine for arginine-47. The same mutation, which interferes with
heparin binding, was demonstrated also by Perry and Carrell (1989).

.0009
AT-III FONTAINBLEAU
AT3
Boyer et al. (1986) described homozygosity for this variant.

.0010
AT-III PESCARA
AT3, ARG393PRO
This variant, described by Leone et al. (1987) in a family with a high
incidence of thrombosis, was shown by Lane et al. (1989) to have a
CGT-to-CCT change resulting in substitution of proline for arginine-393.
The defect concerned binding to serine proteases.

.0011
AT-III DENVER
AT-III MILANO-2
AT3, SER394LEU
This variant, described by Sambrano et al. (1986), was studied by
Stephens et al. (1987, 1988). In AT-III Milano-2, Olds et al. (1989)
found a TCG-to-TTG change in codon 394 predicting the same ser394-to-leu
substitution.

.0012
AT-III CLICHY
AT3
This variant was described by Aiach et al. (1987).

.0013
AT-III DUBLIN
AT3, VAL-3GLU
AT-III Dublin was described by Daly et al. (1987). The variant is
clinically silent (at the coagulation level) but may show an association
with acute lymphatic leukemia. Daly et al. (1990) demonstrated a
valine-to-glutamic acid substitution at position -3 by direct sequencing
of amplified exon 2. N-terminal sequencing of the antithrombin protein
from 2 heterozygotes showed a truncated antithrombin in which the
N-terminal dipeptide is absent. Daly et al. (1990) proposed that the
prepeptide mutation redirects signal peptidase cleavage to a site 2
amino acids downstream into the mature protein. Durr et al. (1992) found
this mutation in southwest Germans and Portuguese, with frequencies of
0.007 and 0.00024, respectively.

.0014
AT-III BARCELONA
AT3
Grau et al. (1988) described a quantitative and qualitative defect of
AT-III in 4 members of a Spanish family with a thrombotic tendency. The
authors referred to the variant as AT-III(Barcelona).

.0015
AT-III ROUEN-I
AT3, ARG47HIS
Owen et al. (1987) described this heparin-binding defect. Perry and
Carrell (1989) found the same substitution, caused by a CCG-to-CTG
change in exon 2.

.0016
AT-III ROUEN-II
AT3, ARG47SER
Borg et al. (1988) demonstrated substitution of serine for arginine-47.

.0017
AT-III BARCELONA-2
AT3
This variant was described by Fontcuberta et al. (1988).

.0018
AT-III AVRANCHES
AT3
This variant was described by Aiach et al. (1988).

.0019
AT-III UTAH
AT3, PRO407LEU
Bock et al. (1988) demonstrated substitution of leucine for proline-407.
AT-III Utah results in type I deficiency; antithrombin III shows a 50%
decrease in both the immunologic and the functional assay.

.0020
AT-III NORTHWICK PARK
AT-III MILANO-1
AT3, ARG393CYS
This variant, described by Lane et al. (1987), was shown by Erdjument et
al. (1988) to have substitution of cysteine for arginine-393. The same
mutation was found by Erdjument et al. (1988) in AT-III Milano.

.0021
AT-III GLASGOW
AT-III SHEFFIELD AT-III CHICAGO
AT3, ARG393HIS
This variant, described by Lane et al. (1987), was shown by Erdjument et
al. (1988) and by Owen et al. (1988) to have substitution of histidine
for arginine-393. Lane et al. (1989) showed that AT-III Sheffield has
the same substitution. Owen et al. (1988) also demonstrated replacement
of arginine by histidine at residue 393 in a 41-year-old male with a
history of thrombotic events. Arginine-393 is located in the site
involved in interaction with thrombin; the susceptibility to thrombosis
with this mutation is thus explained. Molho-Sabatier et al. (1989) found
the arg393-to-his mutation in a variant form of AT-III. Antithrombin
Chicago, a functionally inactive antithrombin III associated with
thrombotic disease, was found by Erdjument et al. (1989) to have the
same substitution.

.0022
AT-III HAMILTON
AT3, ALA382THR
In a French-Canadian family, Devraj-Kizuk et al. (1988) demonstrated a
structural mutant of AT-III with defective serine protease activity,
which they termed AT-III Hamilton. The propositus, a 54-year-old man
with a history of recurrent thromboembolic events, and his 2
asymptomatic adult children were heterozygous. Exon 6 showed a G-to-A
point mutation in the first base of codon 382, leading to the
substitution of threonine for alanine. Alanine-382, 12 residues from the
reactive center of the enzyme, is a highly conserved amino acid in the
family of serine protease inhibitors known as the serpins. In this
reactive site mutation, Perry and Carrell (1989) found substitution of
threonine for alanine-382 as a consequence of a GCA-to-ACA change in
exon 6.

.0023
AT-III ROUEN-III
AT3, ILE7ASN
Brennan et al. (1988) demonstrated a substitution of asparagine for
isoleucine at position 7 in a mutant antithrombin III isolated from the
plasma of a patient with pulmonary embolism. The mutation introduced a
new asn-cys-thr glycosylation sequence. The new oligosaccharide
attachment site occupied the base of the presumed heparin-binding site,
and the finding explained the consequent decrease in heparin affinity.
Perry and Carrell (1989) also found this substitution, which was due to
an ATC-to-AAC change, as the basis of a molecule defective in heparin
binding.

.0024
AT-III BASEL
AT-III FRANCONVILLE
AT3, PRO41LEU
Chang and Tran (1986) and Molho-Sabatier et al. (1989) found
substitution of leucine for proline-41. Perry and Carrell (1989)
described the same substitution in this heparin-binding mutation, which
was caused by a CGT-to-CAT change in exon 2. In a woman referred for
routine prepregnancy testing and in several members of her family, de
Roux et al. (1990) found heterozygosity for the pro41-to-leu mutation.
None had had thrombotic complications. Testing of the properties of the
mutant AT-III suggested that proline-41 is more involved in the
molecular changes induced by heparin than in the primary binding of the
activator.

.0025
AT-III PARIS
AT3
This variant was described by Wolf et al. (1982).

.0026
AT-III ROUEN-IV
AT3, ARG24CYS
In a heparin-binding mutation, Perry and Carrell (1989) found a
CGC-to-TGC change in exon 2 that resulted in substitution of cysteine
for arginine-24.

.0027
AT-III CAMBRIDGE II
AT3, ALA384SER
Harper et al. (1991) concluded that the frequency of antithrombin
deficiency is about 5% among patients who present with venous thrombosis
before the age of 40 years. About 2% of all such patients have a
dysfunctional variant of AT-III. A new dysfunctional antithrombin
variant, Cambridge II, showed substitution of serine for alanine-384.
This is a mutation at the same codon as is present in Cambridge I
(107300.0007). Perry et al. (1991) identified 4 unrelated persons with
an identical antithrombin variant, associated in one of them with
episodes of recurrent venous thromboses. In each case, the plasma
antithrombin concentration was normal and the only functional
abnormality was a minor but consistent decrease in the heparin-induced
thrombin inhibition, suggesting a mutation at or near the reactive
center of the molecule. Amplification and direct sequencing of exon 6
showed a G-to-T mutation at nucleotide 1246, which corresponded to a
substitution of serine for alanine at residue 384.

.0028
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, GLU245FS
Grundy et al. (1991) described 2 unrelated families with AT-III
deficiency with different frameshift mutations involving the same GAG
codon (glu 245) in exon 4 of the AT3 gene. One patient had a
heterozygous deletion of the A nucleotide whereas the second had a
heterozygous deletion of an A and a G. Grundy et al. (1991) pointed out
that the deletion-prone glu245 codon is located within a GAGAG motif
that is effectively a short overlapping direct repeat. In addition, a
short inverted repeat flanked the site of deletion. They pointed to
similar deletion hot spots in the F8, HPRT, HBA2, and HBB genes and
pointed out common characteristics of these hot spots.

.0029
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, GLU245FS
See 107300.0028.

.0030
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, LYS228FS
In a family with type I deficiency, Vidaud et al. (1991) observed
insertion of an adenine at position 780, according to the cDNA numbering
of Chandra et al. (1983). The mutation generated a frameshift that
modified the amino acid sequence and introduced a premature stop codon
at position 232 of the protein.

.0031
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, SER291PRO
In a family with thrombophilia and type I deficiency of AT-III, Vidaud
et al. (1991) observed a 2-bp deletion at positions 965 and 966 or at
967 and 968. (Because 2 AG dinucleotides were located next to each
other, it was impossible to tell which of the 2 was deleted.) The
deletion created a new reading frame from lysine-290 on, converting
ser291 to proline and introducing a stop codon at position 309 in the
protein sequence.

.0032
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, ASP309LYS
In a family with type I deficiency, Vidaud et al. (1991) found a
deletion of 4 bp resulting in a new reading frame beyond leu308,
changing aspartic acid-309 to lysine and resulting in a TGA stop codon
at amino acid position 313.

.0033
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, ARG129TER
In 2 apparently unrelated families with thrombophilia due to type Ia
deficiency of AT3, Gandrille et al. (1991) found a CGA-to-TGA mutation
in codon 129 resulting in change from arginine to stop. Olds et al.
(1991) reported 4 further kindreds in which the same mutation was
associated with type Ia AT deficiency and thrombotic disease. They
stated that this mutation was present in about 10% of their families
with type Ia. (Type Ia is characterized by the presence of only half the
normal AT concentration in plasma, with no detectable variant protein.)
It should be noted that the AT variant Geneva has a CGA-to-CAA mutation
in the same codon (arg129-to-gln).

.0034
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT-III GENEVA
AT3, ARG129GLN
In a case of type Ia deficiency of antithrombin 3, Gandrille et al.
(1990) found a CGA-to-CAA change in codon 129, resulting in substitution
of glutamine for arginine. The finding of mutations in arginine-129
indicates its importance to the heparin-binding site of AT3.

.0035
AT-III BUDAPEST
AT3, PRO429LEU
AT-III Budapest was the first type 2a AT-III variant described (Sas et
al., 1974, 1975, 1978). The propositus and several members of the
kindred had had thromboembolic episodes. The parents of the propositus
were consanguineous. Olds et al. (1992) showed that the AT-III Budapest
allele, for which the propositus was homozygous, contained a single
nucleotide substitution leading to the replacement of proline by leucine
at codon 429. Proline at this position is highly conserved across the
whole of the serpin family of proteins.

.0036
AT-III DEFICIENCY
AT3, SER349PRO
In an English family in which several members had recurrent venous
thrombosis, Grundy et al. (1992) found a point mutation in exon 4,
resulting in substitution of proline for serine-349.

.0037
AT-III STOCKHOLM
AT3, GLY392ASP
Antithrombin III Stockholm, found in a woman who developed a pulmonary
embolus while on oral contraceptives at age 19, was shown by Blajchman
et al. (1992) to have a substitution of aspartic acid for glycine-392,
resulting from a G-to-A change in the second base of codon 392.

.0038
AT-III BUDAPEST-3
AT3, LEU99PHE
Olds et al. (1992) described a CTC-to-TTC transition at codon 99,
altering the normal leucine to phenylalanine. The proband had a history
of venous thrombotic disease and was found to be homozygous for the
mutation. The variant protein showed reduced heparin affinity and
reduced antiproteinase activity in the presence of either unfractionated
heparin or the AT-binding heparin pentasaccharide, when compared to
normal AT. The substitution is located near the proposed heparin binding
site.

.0039
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, VAL48CYS
Using PCR and direct sequencing of amplified DNA, Daly et al. (1992)
identified a frameshift mutation due to insertion of a T converting
codon 48 from GTC (valine) to TGT (cysteine) and causing a frameshift
with a stop codon at position 72. A truncated AT3 could not be detected
in plasma, suggesting that it failed to be secreted or was rapidly
degraded.

.0040
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, ASN208LYS
Using PCR and direct sequencing of amplified DNA, Daly et al. (1992)
identified an insertion of an A changing codon 208 from AAT (asparagine)
to AAA (lysine) and creating a frameshift with a stop codon at position
209. No abnormal AT3 was detected in the plasma.

.0041
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, LYS370ARG
Using PCR and direct sequencing of amplified DNA, Daly et al. (1992)
identified a deletion of an A in codon 370 changing AAG (lysine) to AGG
(arginine) and resulting in frameshift with a stop codon at position
375. No abnormal antithrombin protein was detected in the plasma.

.0042
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
AT3, ALA387VAL
In a patient with recurrent venous thrombosis and an AT-III
activity/antigen level consistent with type I AT-III deficiency, White
et al. (1992) found a GCT-to-GTT transition in the AT3 gene, resulting
in an ala387-to-val substitution near the reactive site.

.0043
AT-III NAGASAKI
AT3, SER116PRO
In a 33-year-old man who had recurrent cerebral infarctions, Okajima et
al. (1993) found a T-to-C transition in exon 3a which resulted in the
substitution of proline for serine at codon 116. The patient was
heterozygous for the mutation, which lacked affinity for heparin.

*FIELD* SA
Bauer et al. (1985); Beukes and Heyns (1980); Blajchman et al. (1992);
Bock et al. (1985); Bock et al. (1982); Brenner et al. (1988); Carvalho
and Ellman (1976); Cosgriff et al. (1983); Egeberg  (1965); Erdjument
et al. (1988); Filip et al. (1976); Gallus  (1984); Griffith et al.
(1983); Gruenberg et al. (1975); Gyde et al. (1978); Halal et al.
(1983); Hofman et al. (1980); Kao et al. (1984); Knot et al. (1986);
Laharrague et al. (1980); Lane et al. (1989); Lane et al. (1987);
Leone et al. (1983); Leone et al. (1980); Magenis et al. (1978); Mannucci
et al. (1982); Manotti et al. (1982); Matsuo et al. (1979); Mohanty
et al. (1982); Odegard and Abildgaard (1977); Olds et al. (1992);
Peterson and Blackburn (1985); Pitney et al. (1980); Prochownik  (1985);
Scully et al. (1981); Shapiro et al. (1981); Stathakis et al. (1977);
Tengborn et al. (1985); Towne et al. (1981); Vomberg et al. (1987);
Williams and Murano (1981); Winter et al. (1982)
*FIELD* RF
1. Aiach, M.; Francois, D.; Priollet, P.; Capron, L.; Roncato, M.;
Alhenc-Gelas, M.; Fiessinger, J.-N.: An abnormal antithrombin III
(AT III) with low heparin affinity: AT III Clichy. Brit. J. Haemat. 66:
515-522, 1987.

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enhanced heparin binding. J. Biol. Chem. 260: 610-615, 1985.

107. Pewarchuk, W. J.; Fernandez-Rachubinski, F.; Rachubinski, R.
A.; Blajchman, M. A.: Antithrombin III Sudbury: an ala384-to-pro
mutation with abnormal thrombin-binding activity and thrombotic diathesis. Thromb.
Res. 59: 793-797, 1990.

108. Pitney, W. R.; Manoharan, A.; Dean, S.: Antithrombin III deficiency
in an Australian family. Brit. J. Haemat. 46: 147-149, 1980.

109. Prochownik, E. V.: Relationship between an enhancer element
in the human antithrombin III gene and an immunoglobulin light-chain
gene enhancer. Nature 316: 845-848, 1985.

110. Prochownik, E. V.; Antonarakis, S.; Bauer, K. A.; Rosenberg,
R. D.; Fearon, E. R.; Orkin, S. H.: Molecular heterogeneity of inherited
antithrombin III deficiency. New Eng. J. Med. 308: 1549-1552, 1983.

111. Rosenberg, R. D.: Actions and interactions of antithrombin and
heparin. New Eng. J. Med. 292: 146-151, 1975.

112. Rosenberg, R. D.; Bauer, K. A.: Thrombosis in inherited deficiencies
of antithrombin, protein C, and protein S. Hum. Path. 18: 253-262,
1987.

113. Rosendaal, F. R.; Heijboer, H.; Briet, E.; Buller, H. R.; Brandjes,
D. P. M.; de Bruin, K.; Hommes, D. W.; Vandenbroucke, J. P.: Mortality
in hereditary antithrombin-III deficiency--1830 to 1989. Lancet 337:
260-262, 1991.

114. Rouleau, G. A.; Bazanowski, A.; Gusella, J. F.; Haines, J. L.
: A genetic map of chromosome 1: comparison of different data sets
and linkage programs. Genomics 7: 313-318, 1990.

115. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

116. Sacks, S. H.; Old, J. M.; Reeders, S. T.; Weatherall, D. J.;
Douglas, A. S.; Winter, J. H.; Rizza, C. R.: Evidence linking familial
thrombosis with a defective antithrombin III gene in two British kindreds. J.
Med. Genet. 25: 20-24, 1988.

117. Sakuragawa, N.; Takahashi, K.; Kondo, S. I.; Koide, T.: Antithrombin
III Toyama: a hereditary abnormal antithrombin III of a patient with
recurrent thrombophlebitis. Thromb. Res. 31: 305-317, 1983.

118. Sambrano, J. E.; Jacobson, L. J.; Reeve, E. B.; Manco-Johnson,
M. J.; Hathaway, W. E.: Abnormal antithrombin III with defective
serine protease binding (antithrombin III 'Denver'). J. Clin. Invest. 77:
887-893, 1986.

119. Sas, G.: Classification of antithrombin III deficiencies: has
a new tower of Babel been built?. Thromb. Haemost. 60: 530-531,
1988.

120. Sas, G.; Blasko, G.; Banhegyi, D.; Jako, J.; Palos, L. A.: Abnormal
antithrombin III (antithrombin III 'Budapest') as a cause of a familial
thrombophilia. Thromb. Diath. Haemorrh. 32: 105-115, 1974.

121. Sas, G.; Koves, A.; Peto, I.; Domjan, G.: Thrombogenic effects
of some concentrates of coagulation factors: a possible role of contaminating
endotoxin. (Letter) Thromb. Haemost. 39: 530-532, 1978.

122. Sas, G.; Pepper, D. S.; Cash, J. D.: Further investigations
on antithrombin III in the plasmas of patients with the abnormality
of 'antithrombin III Budapest.'. Thromb. Diath. Haemorrh. 33: 564-572,
1975.

123. Sas, G.; Peto, I.; Banhegyi, D.; Blasko, G.; Domjan, G.: Heterogeneity
of the 'classical' antithrombin III deficiency. Thromb. Haemost. 43:
133-136, 1980.

124. Scully, M. F.; De Haas, H.; Chan, P.; Kakkar, V. V.: Hereditary
antithrombin III deficiency in an English family. Brit. J. Haemat. 47:
235-240, 1981.

125. Shapiro, M. E.; Rodvien, R.; Bauer, K. A.; Salzman, E. W.: Acute
aortic thrombosis in antithrombin III deficiency. J.A.M.A. 245:
1759-1761, 1981.

126. Stathakis, N. E.; Papayannis, A. G.; Antonopoulos, M.; Gardikas,
C.: Familial thrombosis due to antithrombin III deficiency in a Greek
family. Acta Haemat. 57: 47-54, 1977.

127. Stephens, A. W.; Siddiqui, A.; Hirs, C. H. W.: Site-directed
mutagenesis of the reactive center (serine 394) of antithrombin III. J.
Biol. Chem. 263: 15849-15852, 1988.

128. Stephens, A. W.; Thalley, B. S.; Hirs, C. H. W.: Antithrombin-III
Denver, a reactive site variant. J. Biol. Chem. 262: 1044-1048,
1987.

129. Tengborn, L.; Frohm, B.; Nilsson, L.-E.; Nilsson, I. M.: A Swedish
family with abnormal antithrombin III. Scand. J. Haemat. 34: 412-416,
1985.

130. Towne, J. B.; Bernhard, V. M.; Hussey, C.; Garancis, J. C.:
Antithrombin deficiency--a cause of unexplained thrombosis in vascular
surgery. Surgery 89: 735-742, 1981.

131. Tullis, J. L.; Watanabe, K.: Platelet antithrombin deficiency:
a new clinical entity. Am. J. Med. 65: 472-478, 1978.

132. Vidaud, D.; Emmerich, J.; Sirieix, M. E.; Sie, P.; Alhenc-Gelas,
M.; Aiach, M.: Molecular basis for antithrombin III type I deficiency:
three novel mutations located in exon IV. Blood 78: 2305-2309, 1991.

133. Vomberg, P. P.; Breederveld, C.; Fleury, P.; Arts, W. F. M.:
Cerebral thromboembolism due to antithrombin III deficiency in two
children. Neuropediatrics 18: 42-44, 1987.

134. White, D.; Abraham, G.; Carter, C.; Kakkar, V. V.; Cooper, D.
N.: A novel missense mutation in the antithrombin III gene (ala387-to-val)
causing recurrent venous thrombosis. Hum. Genet. 90: 472-473, 1992.

135. Williams, L.; Murano, G.: Human antithrombin III heterogeneity. Blood 57:
229-232, 1981.

136. Wilson, C.; Walker, I. D.; Davidson, J. F.; Imrie, C. W.: Mesenteric
venous thrombosis and antithrombin III deficiency. J. Clin. Path. 40:
906-908, 1987.

137. Winter, J. H.; Bennett, B.; Watt, J. L.; Brown, T.; San Roman,
C.; Schinzel, A.; King, J.; Cook, P. J. L.: Confirmation of linkage
between antithrombin III and Duffy blood group and assignment of AT3
to 1q22-1q25. Ann. Hum. Genet. 46: 29-34, 1982.

138. Winter, J. H.; Fenech, A.; Ridley, W.; Bennett, B.; Cumming,
A. M.; Mackie, M.; Douglas, A. S.: Familial antithrombin III deficiency. Quart.
J. Med. 51: 373-395, 1982.

139. Wolf, M.; Boyer, C.; Lavergne, J. M.; Larrieu, M. J.: A new
familial variant of antithrombin III: 'antithrombin III Paris.'. Brit.
J. Haemat. 51: 285-295, 1982.

140. Wu, S.; Seino, S.; Bell, G. I.: Human antithrombin II (AT3)
gene length polymorphism revealed by the polymerase chain reaction. Nucleic
Acids Res. 17: 6433, 1989.

*FIELD* CS

Heme:
   Hypercoagulability;
   Thrombosis

Vascular:
   Venoocclusive disease;
   Deep venous thrombosis (e.g. .0007 AT-III CHARLEVILLE);
   Recurrent thrombophlebitis (e.g. homozygous .0008 AT-III TOYAMA)

Pulmonary:
   Pulmonary embolism

GI:
   Mesenteric venous thrombosis;
   Acute mesenteric infarction

Oncology:
   Association with acute lymphatic leukemia (e.g. .0013 AT-III DUBLIN)

Lab:
   Antithrombin III deficiency;
   Type I, classic, CRM-negative;
   Type II, mutant, CRM-positive;
   Heparin-binding defect (e.g. .0015 AT-III ROUEN-I)

Inheritance:
   Autosomal dominant (1q23-q25)

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 12/26/1996
terry: 11/12/1996
mark: 1/30/1996
mark: 1/24/1996
terry: 12/22/1994
jason: 7/1/1994
mimadm: 3/28/1994
carol: 2/23/1994
carol: 7/9/1993
carol: 6/3/1993

*RECORD*
*FIELD* NO
107310
*FIELD* TI
*107310 SOLUTE CARRIER FAMILY 9, ISOFORM A1; SLC9A1
ANTIPORTER, SODIUM-HYDROGEN ION, AMILORIDE-SENSITIVE; APNH;;
SODIUM/HYDROGEN EXCHANGER 1; NHE1;;
Na+/H+ ANTIPORTER
*FIELD* TX
The Na+/H+ antiporter is a ubiquitous membrane-bound enzyme involved in
pH regulation of vertebrate cells. It is specifically inhibited by the
diuretic drug amiloride and activated by a variety of signals including
growth factors, mitogens, neurotransmitters, tumor promoters, and
others. Mattei et al. (1987) used reverse genetics to clone the gene.
The gene was first disrupted in mouse fibroblasts. The lost function was
then restored by transfection with human genomic DNA. Southern analysis
of secondary and tertiary mouse transfectants demonstrated that unique
EcoRI fragments containing 50 to 60 kb of human DNA were specifically
retained in transfectants expressing Na+/H+ exchange activity (Franchi
et al., 1986). Clones containing these specific human sequences were
isolated. One genomic fragment was identified as an exon-coding sequence
from the sodium-hydrogen ion antiporter gene by demonstration that it
could complement antiporter deficiency in mouse cells; that it
recognized an mRNA in cells expressing antiport activity but not in
deficient cells; and that it was amplified in variants overexpressing
antiport activity. The genomic probe was used to map the APNH gene to
1p36.1-p35 by in situ hybridization (Mattei et al., 1988). Mattei et al.
(1989) used in situ hybridization of the human cDNA probe to map the
antiporter gene to the distal portion of mouse chromosome 4 and to the
long arm of Chinese hamster chromosome 2, confirming the conserved
homology between the distal part of human chromosome 1p, the mouse
distal 4, and Chinese hamster distal 2q. By the analysis of fragment
length variations in recombinant inbred strains, Morahan and Rakar
(1993) likewise mapped the Nhe1 gene to mouse chromosome 4, between Lck
and Akp2. Sardet et al. (1989) presented the complete sequence of a cDNA
encoding SLC9A1. Lifton et al. (1990) used genomic clones of the SLC9A1
gene to identify 2 polymorphisms. Using these RFLPs in 59 reference
families, they found that the antiporter gene lies 3 cM proximal to the
RH locus. Dudley et al. (1990) PCR-amplified a 376-bp fragment
corresponding to the 5-prime end of SLC9A1 and detected a polymorphism
within this fragment by denaturing gradient gel electrophoresis. By
genetic linkage studies, they mapped SLC9A1 telomeric to D1S57 and close
to RH (111700) and ALPL (171760). They pointed out that SLC9A1 is a
plausible candidate gene for human essential hypertension.

*FIELD* SA
Mendoza  (1987)
*FIELD* RF
1. Dudley, C. R. K.; Giuffra, L. A.; Tippett, P.; Kidd, K. K.; Reeders,
S. T.: The Na+/H+ antiporter: a 'melt' polymorphism allows regional
mapping to the short arm of chromosome 1. Hum. Genet. 86: 79-83,
1990.

2. Franchi, A.; Perucca-Lostanlen, D.; Pouyssegur, J.: Functional
expression of a human Na+/H+ antiporter gene transfected into antiporter-deficient
mouse L cells. Proc. Nat. Acad. Sci. 83: 9388-9392, 1986.

3. Lifton, R. P.; Sardet, C.; Pouyssegur, J.; Lalouel, J.-M.: Cloning
of the human genomic amiloride-sensitive Na+/H+ antiporter gene, identification
of genetic polymorphisms, and localization on the genetic map of chromosome
1p. Genomics 7: 131-135, 1990.

4. Mattei, M.-G.; Galloni, M.; Sardet, C.; Franchi, A.; Counillon,
L.; Passage, E.; Pouyssegur, J.: Localization of the antiporter gene
(APNH) and chromosomal homology between human 1p, mouse 4 and Chinese
hamster 2q.  (Abstract) Cytogenet. Cell Genet. 51: 1041, 1989.

5. Mattei, M.-G.; Sardet, C.; Franchi, A.; Pouyssegur, J.: Chromosomal
mapping of the amiloride-sensitive Na+/H+ antiporter gene.  (Abstract) Cytogenet.
Cell Genet. 46: 658-659, 1987.

6. Mattei, M.-G.; Sardet, C.; Franchi, A.; Pouyssegur, J.: The human
amiloride-sensitive Na+/H+ antiporter: localization to chromosome
1 by in situ hybridization. Cytogenet. Cell Genet. 48: 6-8, 1988.

7. Mendoza, S. A.: The Na+/H+ antiport is a mediator of cell proliferation.
Acta Paediat. Scand. 76: 545-547, 1987.

8. Morahan, G.; Rakar, S.: Localization of the mouse Na+/H+ exchanger
gene on distal chromosome 4. Genomics 15: 231-232, 1993.

9. Sardet, C.; Franchi, A.; Pouyssegur, J.: Molecular cloning, primary
structure, and expression of the human growth factor-activatable Na(+)/H(+)
antiporter. Cell 56: 271-280, 1989.

*FIELD* CD
Victor A. McKusick: 9/22/1987

*FIELD* ED
terry: 05/16/1996
mark: 5/15/1995
terry: 11/18/1994
carol: 2/17/1993
carol: 8/25/1992
carol: 7/24/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
107320
*FIELD* TI
107320 ANTIPHOSPHOLIPID SYNDROME
*FIELD* TX
The designation 'antiphospholipid syndrome' was proposed for the
association of arterial and venous thrombosis, recurrent fetal loss, and
immune thrombocytopenia with a spectrum of autoantibodies directed
against cellular phospholipid components. Anticardiolipin antibodies may
react with cardiolipin and with other negatively charged phospholipids.
The term 'lupus anticoagulant' refers to a heterogeneous group of
antibodies, most commonly of the IgG type, that are detected by their
inhibitory effect on coagulant-active phospholipid components of in
vitro coagulation tests. Familial occurrence of lupus anticoagulant was
reported by Exner et al. (1980) and Mackie et al. (1987). In these
reports, the index cases had systemic lupus erythematosus (152700) or
related immune disorders, while many of their family members had a
variety of clinical serologic features suggestive of a lupus-like
syndrome. Matthey et al. (1989) described a family in which several
members had anticardiolipin antibodies and 2 had lupus anticoagulant,
but all were asymptomatic. Various autoimmune disorders that cluster in
families, including autoimmune thrombocytopenia (188030), are discussed
elsewhere (e.g., 109100, 269200).

From the offspring of a first-cousin marriage, Brenner et al. (1996)
observed a 23-year-old female and her 19-year-old sister who presented
with unusual recurrent severe thromboembolic phenomenon and were found
to have familial anti-phospholipid syndrome and to also be heterozygous
for the R506Q mutation of factor V (227400.0001). The coexistence of
hereditary and acquired APC-resistance was thought to explain the
severity of the thromboembolism. The older sib presented with deep vein
thrombosis of the proximal left leg and intrauterine fetal death at 20
weeks of gestation in her third pregnancy. During her fourth pregnancy
she received enoxaparine from the tenth week of gestation, but
intrauterine fetal death occurred at 20 weeks of gestation. Three weeks
later she developed right popliteal deep vein thrombosis. The younger
sister was admitted to hospital with infarction of lumbar vertebra L4
demonstrated by bone scan, first trimester abortion, and pancytopenia.

*FIELD* RF
1. Brenner, B.; Vulfsons, S. L.; Lanir, N.; Nahir, M.: Coexistence
of familial antiphospholipid syndrome and factor V Leiden: impact
on thrombotic diathesis. Brit. J. Haemat. 94: 166-167, 1996.

2. Exner, T.; Barber, S.; Kronenberg, H.; Rickard, K. A.: Familial
association of the lupus anticoagulant. Brit. J. Haemat. 45: 89-96,
1980.

3. Mackie, I. J.; Colaco, C. B.; Machin, S. J.: Familial lupus anticoagulants. Brit.
J. Haemat. 67: 359-363, 1987.

4. Matthey, F.; Walshe, K.; Mackie, I. J.; Machin, S. J.: Familial
occurrence of the antiphospholipid syndrome. J. Clin. Path. 42:
495-497, 1989.

*FIELD* CS

Vascular:
   Arterial thrombosis;
   Venous thrombosis

Misc:
   Recurrent fetal loss

Heme:
   Immune thrombocytopenia

Immunology:
   Autoantibodies against cellular phospholipid components;
   Anticardiolipin antibodies;
   Lupus anticoagulant antibodies

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 7/13/1989

*FIELD* ED
terry: 11/15/1996
terry: 11/5/1996
terry: 7/18/1994
mimadm: 3/11/1994
supermim: 3/16/1992
supermim: 1/26/1991
supermim: 3/20/1990
supermim: 2/2/1990

*RECORD*
*FIELD* NO
107323
*FIELD* TI
107323 ANTIQUITIN
*FIELD* TX
In screening a rat mucosa cDNA subtraction library, Lee et al. (1994)
found a clone that exhibited a remarkable degree of homology with a
previously described cDNA from the green garden pea, designated the 26g
pea turgor protein. They obtained a partial cDNA from rat and a complete
cDNA from human. The deduced human protein had a molecular weight of
55,285 and was designated antiquitin because of its remarkable level of
conservation through evolution. Human antiquitin was 60% homologous to
the green pea 26g. Analysis of mRNA indicated that the largest amounts
were found in rat kidney and liver and in cultured human hepatoma cells.
Only minimal amounts were detected in human peripheral blood leukocytes,
rat lung, or cultured human fibroblasts. Attempts to induce the mRNA by
heat-shock, dehydration, ionizing irradiation, or treatment with iron,
t-butylhydroperoxide, or glucocorticoids were unsuccessful. The function
of the protein remained unknown.

The evolutionary distance between higher organisms of the plant and the
animal kingdoms is so great that only a low level of homology is
expected between proteins performing the same functions in plants and
animals. Notable exceptions include the cytoskeletal proteins, such as
actin, tubulin, histone, and heat-shock proteins.

*FIELD* RF
1. Lee, P.; Kuhl, W.; Gelbart, T.; Kamimura, T.; West, C.; Beutler,
E.: Homology between a human protein and a protein of the green garden
pea. Genomics 21: 371-378, 1994.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
carol: 6/20/1994
jason: 6/17/1994

*RECORD*
*FIELD* NO
107325
*FIELD* TI
*107325 ANTISENSE ERCC1; ASE1
*FIELD* TX
In the course of characterizing ERCC1 (126380), a DNA repair gene,
Hoeijmakers et al. (1989) found that its 3-prime terminus overlapped
with the 3-prime end of another gene, which they designated ASE1 for
'antisense ERCC1.' This exceptional type of gene overlap was conserved
in the mouse and even in the yeast ERCC1 homolog, RAD10, suggesting an
important biologic function. ERCC1 was mapped to 19q13.2-q13.3 by a
combination of somatic hybrid and linkage studies.

*FIELD* RF
1. Hoeijmakers, J. H. J.; Weeda, G.; Troelstra, C.; van Duin, M.;
Wiegant, J.; van der Ploeg, M.; Geurts van Kessel, A. H. M.; Westerveld,
A.; Bootsma, D.: (Sub)chromosomal localization of the human excision
repair genes ERCC-3 and -6, and identification of a gene (ASE-1) overlapping
with ERCC-1.  (Abstract) Cytogenet. Cell Genet. 51: 1014 only, 1989.

*FIELD* CD
Victor A. McKusick: 2/25/1992

*FIELD* ED
supermim: 3/16/1992
carol: 2/25/1992

*RECORD*
*FIELD* NO
107400
*FIELD* TI
*107400 PROTEASE INHIBITOR 1 (ANTI-ELASTASE), ALPHA-1-ANTITRYPSIN; PI
ANTITRYPSIN;;
ALPHA-1-ANTITRYPSIN; AAT;;
PROTEASE INHIBITOR; PI
ALPHA-1-ANTITRYPSIN DEFICIENCY, AUTOSOMAL RECESSIVE, INCLUDED
*FIELD* MN

Alpha-1-antitrypsin (AAT) is a highly polymorphic glycoprotein,
synthesized primarily in hepatocytes and alveolar macrophages. It is a
member of the serine protease inhibitor superfamily and, in the lung,
protects elastic tissue from proteolytic attack by leukocyte elastase.
The gene for AAT, PI (for protease inhibitor), has been cloned and is
mapped to 14q 32.1 (Yamamoto et al., 1986). Mutations leading, in the
heterozygote, to AAT deficiency (less than about 35% of its normal
level) cause emphysema (because of the unopposed elastase) and, in some
types, liver disease. There are 3 macrophage-specific transcriptional
initiation sites and one hepatocyte-specific site (Hafeez et al., 1992).
More than 90 alleles are known (Faber et al., 1994). The normal allele
is Pi M.

Variants are classified by their electrophetic mobility. They can be
classified as null mutations, which (in the homozygote) cause lung
disease, and deficiency mutations, which cause lung disease, or both
lung and liver disease, or neither. Mutations may be deletions (null) or
base-pair substitutions that may be silent, or cause stop signals
(null), or decreased or abnormal protein. One intriguing base-pair
mutation changes the properties of the AAT molecule to that of the
related antithrombin molecule, leading to a fatal bleeding disorder
(Owen et al., 1983).

Homozygotes for Pi Z (with a frequency of about 0.03% in U. S. whites)
or for several much rarer variants (e.g ., .0015, .0016, .0020, .0021,
.0023, .0024, .0025) have a high risk of developing emphysema,
particularly if they smoke (Crystal, 1990). They account for about 1 %
of all emphysema patients. Compound heterozygotes with a Z or a null
allele may also have an increased risk of chronic obstructive lung
disease, increasing the frequency of potentially affected individuals to
about 5% (Lieberman, 1969). About 10% of ZZ homozygotes develop liver
disease that often leads to fatal childhood cirrhosis. There is an
abnormal polymerization of the Z antitrypsin, and the abnormal molecule
is poorly secreted; part of the remainder forms insoluble intracellular
inclusions that are presumably toxic (Lomas et al., 1992).

There is an oligonucleotide probe that reveals the presence of the Z
allele, and prenatal diagnosis is possible (Kidd et al., 1983; Abbott et
al., 1988).

Avoidance of smoking and of other lung irritants is an important part of
management. Antitrypsin is an acute phase protein and as such, undergoes
a manifold increase in association with temperature elevations during
bouts of inflammation. Control of inflammation and pyrexia in ZZ
homozygote infants is important. The effectiveness of intravenous enzyme
(Wewers et al., 1987) or estrogenic drugs (Holmes et al., 1990) have not
been established. The frequencies of the alleles vary between
populations (Crystal, 1989). Pi S and Z alleles are rare or absent in
blacks (DeCroo et al., 1991).

*FIELD* TX

DESCRIPTION

Alpha-1-antitrypsin is a protease inhibitor, deficiency of which is
associated with emphysema and liver disease. The protein is encoded by a
gene (PI) located on the distal long arm of chromosome 14.

CLINICAL FEATURES

Deficiency of protease inhibitor activity is associated with several of
the electrophoretic variants of serum alpha-1-antitrypsin; Axelsson and
Laurell (1965) first suggested that the genes for electrophoretic
variants are allelic with the deficiency gene. Laurell and Eriksson
(1963) described absence of alpha-1-antitrypsin from the plasma in
patients with degenerative lung disease leading to death in middle life.
(Eriksson (1989) gave an interesting historical account including the
pedigree of his first family (Eriksson, 1965).) Emphysematous changes
involve primarily the lower lung fields (Bell, 1970).

Many electrophoretic variants of serum alpha-1-antitrypsin have been
described, beginning with those reported by Axelsson and Laurell (1965).
Some of these variants are associated with reduced protease activity and
occasionally with clinical consequences. Kueppers and Bearn (1967)
studied an Italian family with multiple members heterozygous for an
electrophoretic variant that could not be distinguished from that which
Axelsson and Laurell (1965) found in a Swedish family. The polymorphism
of prealbumin described by Fagerhol and Braend (1965) was shown by
Fagerhol and Laurell (1967) to be the same as the alpha-1-antitrypsin
polymorphism. Fagerhol (1968) suggested that the system be called Pi for
protease inhibitor.

Gans et al. (1969) described familial infantile liver cirrhosis in
presumed homozygotes for alpha-1-antitrypsin deficiency. Udall et al.
(1982) speculated that a factor in the pathogenesis of infantile
cirrhosis may be lack of protease inhibitor to counteract the effects of
proteases that cross the intestinal barrier in the neonate. Lake-Bakaar
and Dooley (1982) found that alpha-1-antitrypsin is an important
proteolytic inhibitor in bile, thus providing support of the
pathogenetic theory of Udall et al. (1982). Aagenaes et al. (1972)
described the clinical picture in children with the ZZ genotype as
neonatal cholestasis. Five such cases were described.

Morin et al. (1975) concluded that heterozygotes are not at increased
risk of alcoholic cirrhosis. Eriksson et al. (1986) concluded that the
risk of cirrhosis and liver cancer is increased for males homozygous for
alpha-1-antitrypsin deficiency but not for females. The finding
suggested additive effects of exogenous factors. Geddes et al. (1977)
found that the frequency of non-M phenotypes was increased to a
significant extent in patients with sclerosing alveolitis with or
without rheumatoid arthritis. Fargion et al. (1981) found an increased
frequency of non-M phenotypes in patients with hepatocellular carcinoma.
Furthermore, patients with liver cancer and a non-M phenotype had a
lower average age than those with an M phenotype.

Phenotypic correlations indicate that there are 3 types of mutations:
those producing deficiency of enzyme action, null mutations, and
mutations causing altered function of the gene product. PI Z and PI
M(Malton) are deficiency mutations that are associated with both
emphysema and liver disease. PI S, M(Heerlen), M(Mineral Springs),
M(Procida), M(Nichinan), I, and P(Lowell) are deficiency mutations with
an increased risk of emphysema only. The null mutations are associated
with emphysema only. PI Pittsburgh is an example of a mutation leading
to altered function of the gene product with a bleeding disorder as the
clinical presentation. Crystal (1990) gave a comprehensive review of the
pathogenetic relationship between AAT deficiency and emphysema and liver
disease, including a detailed listing of the various mutations that have
been identified and a discussion of the possibilities for therapy.

An adult with antitrypsin deficiency and combined liver and lung disease
was reported by Gherardi (1971). See the study of 12 cases of combined
disease by Berg and Eriksson (1972). Contrary to the usual view that
liver disease, while a risk in children, is not a great risk to adults
with alpha-1-antitrypsin deficiency, Cox and Smyth (1983) found a
relatively high risk in men between 51 and 60 years. A low concentration
of serum prealbumin was a sensitive indicator of impaired liver
function.

Wiebicke et al. (1996) confirmed the absence of pulmonary function
abnormalities in the vast majority of children with homozygous
alpha-1-PI deficiency. Rodriguez-Cintron et al. (1995) suggested that
bronchiectasis should be considered part of the spectrum of pulmonary
pathology that may be encountered in individuals with AAT deficiency.
They described a 21-year-old man with massive hemoptysis and homozygous
ZZAAT deficiency. Neither panlobular emphysema nor cirrhosis of the
liver was present.

BIOCHEMICAL FEATURES

About 30 variants of alpha-1-antitrypsin had been described by 1981 (Hug
et al., 1981). The alleles have been given symbols according to the
relative electrophoretic mobility of the allele product. Cox (1978)
reported the recommendations of a workshop on Pi nomenclature. Several
reports (Bell and Carroll, 1973; Kuhlenschmidt et al., 1974; Eriksson
and Larsson, 1975) have suggested that the defect may be in a
sialyltransferase and that deficiency of antitrypsin in the blood is the
result of impaired secretion from hepatocytes, increased clearance of
the undersialated protein, or both. It is difficult to see how this
could cause codominant inheritance or account for the different types
that appear to be the products of at least 30 different alleles, unless
an amino acid substitution interferes with sialidation.

Yoshida et al. (1976) studied a variant protein from a ZZ homozygote and
showed 2 amino acid substitutions, glutamic acid to lysine and glutamic
acid to glutamine. The sialic acid content of the variant protein was
reduced, presumably as a result of change in configuration of the
protein since none of the carbohydrate-binding amino acids were
substituted.

The leukocytes of chronic granulomatous disease have a defect in
inactivation of antitrypsin. In their experiments, George et al. (1984)
found that addition of azide or catalase enhanced the effectiveness of
the mutant inhibitor. AT, like other serine protease inhibitors such as
antithrombin III, alpha-2-antiplasmin, and C1-inhibitor, has a single
inhibitor-specific reactive site peptide bond that is formed between
adjacent amino acid residues termed P(1) and P-prime(1). The reactivity
of these inhibitors with proteolytic enzymes depends heavily on the
nature of the residue at position P(1), the central position of the
reactive center.

Harrison et al. (1990) described an improved method for detecting what
they termed 'low Z expressor' phenotype in MZ heterozygotes. An obligate
carrier mother who was being typed as part of a family study appeared to
be a PI(M)/PI(null) heterozygote. By routine isoelectric focusing, she
was typed as M, her affected child as Z, and her husband as MZ.
Atypically low concentrations of circulating Z peptides were
demonstrated by the improved method.

Weitz et al. (1992) demonstrated a correlation between plasma levels of
elastase-specific fibrinopeptides and PI genotype. The levels of these
peptides were highest in ZZ homozygotes and intermediate in MZ
heterozygotes. This was interpreted as evidence that unopposed human
neutrophil elastase is responsible for emphysema in patients with
alpha-1-proteinase inhibitor deficiency.

INHERITANCE

Family studies indicate recessive inheritance of antitrypsin deficiency.
In early studies, heterozygotes, who can be detected chemically, were
unaffected clinically; later studies suggested that heterozygosity may
predispose to lung disease (Lieberman, 1969). For example, of 12
patients with obstructive lung disease present before age 40 years, 2
were judged by Tarkoff et al. (1968) to be homozygous for the deficiency
and 1 heterozygous. Among 103 patients, Kueppers et al. (1969) found 5
homozygotes and 25 heterozygotes for the deficiency gene. They suggested
that, especially in males, heterozygosity may predispose to chronic
obstructive lung disease. Stevens et al. (1971) concluded that
heterozygotes may develop emphysema qualitatively like that in
homozygotes, but at a later age. The importance of prompt treatment of
respiratory infections and avoidance of proteolytic aerosols, smoking
and employment entailing exposure to respiratory irritants are important
preventive measures in these families.

Lieberman et al. (1979) found an increased frequency of heterozygosity
for antitrypsin deficiency in twins and parents of twins. They concluded
that 'increased' fertility and twinning may be heterozygous advantages
for antitrypsin deficiency. Clark and Martin (1982) found that the
frequency of the S allele in mothers of dizygotic twins (0.088) was
double that in controls (0.044). The frequency of S in the parents of
monozygotic twins and in fathers of DZ twins was no higher than in
controls. Normal frequencies were observed for the Z allele. No
fertility indices other than twinning itself were available. To study
relationships between Pi types, fertility, and twinning, Boomsma et al.
(1992) studied 90 DZ and 70 MZ Dutch twin pairs and their parents. They
found that mothers of dizygotic twins had frequencies of the S and Z
alleles that were 3 times higher than those in a control sample. Mothers
of identical twins also had a higher frequency of S than controls. The S
allele may thus both increase ovulation rate and enhance the success of
multiple pregnancies.

MAPPING

A possible heterogeneity in recombination frequency between Pi variants
believed to be allelic was reported by Gedde-Dahl et al. (1972): Pi(Z)
had less recombination with Gm than Pi(non-Z). Gedde-Dahl et al. (1975)
gave further data on the Gm-Pi linkage. They considered heterogeneity of
recombination fraction among males of different Pi types to be likely.
The major difference seemed to be between the Pi(Z) and other alleles.
Possible explanations included a chromosomal deletion, inversion or
locus regulating recombination in linkage disequilibrium with the Pi
locus. Gedde-Dahl et al. (1981) showed that the allele-specific
heterogeneity of Gm-Pi linkage is attributable to 'reduced'
recombination in Z-allele heterozygotes. They found an equal sex ratio
for Pi 'non-Z' variants, as opposed to a 1:2 male-female ratio for 'Z'
families.

The location of Gm and Pi on 6p was excluded by Bender et al. (1979). By
studying hybrids of mouse or rat hepatoma cells with human lymphocytes,
Darlington et al. (1982) and Pearson et al. (1981) achieved direct
assignment of the Pi locus to chromosome 14. From study of 2 families
with abnormalities of the long arm of chromosome 14, Cox et al. (1982)
localized GM to 14q32.3 and PI to a more proximal position between
14q24.3 and 14q32.1. The immunoglobulin genes are in a chromosome region
noted for its high frequency of breaks associated with chromosome
rearrangement, occurring both spontaneously in cultured lymphocytes and
in certain malignancies.

By study of human-Chinese hamster somatic cell hybrids, both genes were
assigned to chromosome 14. By in situ hybridization, Schroeder et al.
(1985) narrowed the assignment of the PI locus to 14q31-q32. Turleau et
al. (1984) studied a patient with an interstitial deletion of 14q and
assigned the PI locus to 14q32.1 by exclusion mapping. In a similar
patient with an interstitial deletion of 14q, Yamamoto et al. (1986)
confirmed the assignment to 14q32.1. By the dosage principle, the level
of alpha-1-antitrypsin in the patient was only about half of that in his
parents and in controls.

MOLECULAR GENETICS

Lai et al. (1983) cloned the alpha-1-antitrypsin gene and showed that it
contains 3 introns in the peptide-coding region. All persons showed 2
distinct bands (9.6 kb and 8.5 kb long) when the cloned gene was used as
a hybridization probe to analyze EcoRI-digested genomic DNA. Analysis
using only intronic DNA as probe showed that the authentic gene resides
in the 9.6-kb fragment. The other gene may be a pseudogene. See 107410.

Long et al. (1984) provided the complete cDNA sequence of the PI gene.
The genomic length of the gene is 10.2 kb with a 1,434-bp coding region.
The gene has 4 introns; exon 1, the 5-prime portion of exon 2, and the
3-prime portion of exon 5 are noncoding regions. The first intron, 5.3
kb long, contains a 143-amino acid open reading frame (which does not
appear to be an actual protein coding region), an Alu family sequence,
and a pseudotranscription initiation region. Carrell (1986) cited
evidence for the existence of 2 genes coding for alpha-1-antitrypsin,
although the plasma findings are compatible with expression of the
alleles at a single locus. Sefton et al. (1989) used pulsed field gel
electrophoresis to demonstrate that the genes encoding
alpha-1-antitrypsin and alpha-1-antichymotrypsin (AACT) are
approximately 220 kb apart and oriented in opposite directions. By in
situ hybridization, Ledbetter et al. (1987) localized the AAT locus to
mouse chromosome 12.

Molecular studies of a ring chromosome 14 showed that the IGH and D14S1
loci were missing, whereas the PI locus was present (Keyeux et al.,
1989). Thus, PI is proximal to the other 2 loci, a conclusion that was
supported by much earlier data. A noncoding alpha-1-antitrypsin-like
gene (PIL) is located 12 kb 3-prime of the AAT gene. Billingsley et al.
(1989) found that this gene and the PI and AACT genes are carried by a
single 550-kb NarI fragment. Also see Billingsley et al. (1993).

Nukiwa et al. (1986) found in the Z gene a second substitution in
addition to that which is responsible for the change from glutamic acid
to lysine at amino acid 342. The latter mutation is located in exon 5;
the second mutation, GTG to GCG, was located in exon 3 and led to a
predicted substitution of alanine for valine as amino acid residue
number 213. The valine-to-alanine change at 213 was found in all of 40 Z
haplotypes, using synthetic oligonucleotide gene probes directed toward
the mutated exon 3 sequences in the Z gene. Furthermore, the exon 3
mutation eliminated a BstEII restriction endonuclease site, allowing
rapid identification of the change in genomic DNA. Surprisingly, only
23% of the M1 haplotypes were found to be BstEII site negative. The new
form of M1, i.e., M1(ala-213), is identical to M1 but has an isoelectric
focusing 'silent' amino acid substitution. M1 has a frequency of 68 to
76%; M2, 14 to 20%; and M3, 10 to 12%. The Z gene represents 1 to 2% of
all alpha-1-antitrypsin haplotypes.

Garver et al. (1986) investigated the molecular basis of the Pi
null-null alpha-1-antitrypsin phenotype. The gene appeared to be intact
without discernible deletion or other structural abnormality, yet there
was no detectable mRNA produced. The 5-prime promoter region also
appeared to be normal. No evidence of hypermethylation of cytosine
nucleotides in the promoter region was detected. The defect may be
comparable to that in some forms of thalassemia in which a change, at a
splicing site, for example, may lead to greatly reduced mRNA production.
The null-null phenotype is accompanied by emphysema as is the ZZ and SZ
phenotypes but an important difference is that cirrhosis and liver
cancer do not occur with the null-null phenotype; there is no abnormal
antitrypsin produced that is excreted with difficulty from the cells of
synthesis.

Nukiwa et al. (1987) identified a null form of alpha-1-antitrypsin
resulting from a frameshift causing a stop codon to be formed
approximately 44% from the N terminus of the precursor protein. Although
the molecular basis of antitrypsin deficiency was quite different from
that in the Z haplotype, the phenotypic consequences were similar:
severe deficiency associated with high risk of emphysema. Perlino et al.
(1987) found that the AAT gene in macrophages is transcribed from a
macrophage-specific promoter located about 2000 bp upstream of the
hepatocyte-specific promoter. Transcription from the 2 AAT promoters is
mutually exclusive; the macrophage promoter is silent in hepatocytes and
the hepatocyte promoter is silent in macrophages. In macrophages, 2
distinct mRNAs are generated by alternative splicing.

Cox et al. (1987) studied RFLPs associated with the AAT gene. They gave
information on extensive variability expressed by the polymorphic
information content (PIC) as proposed by Botstein et al. (1980). PI
types and M subtypes tended to be associated with specific RFLP
haplotypes. Bamforth and Kalsheker (1988) discussed a rare Pi null
allele that in homozygous state leads to pulmonary emphysema at an early
age. In 3 families, all the affected individuals presented in early
childhood with recurrent chest infections and wheezing, presumably
related to passive smoking. Even though there was no detectable AAT, no
partial or complete deletion of the gene could be identified.

By means of isoelectric focusing, Weber and Weidinger (1988) found a PI
variant that they called PI S (Cologne). A father and daughter were
heterozygous. Alpha-1-antitrypsin concentrations were within the normal
range.

Nukiwa et al. (1988) indicated that approximately 75 AAT alleles have
been identified at the protein and/or gene level. The most common
alleles are the 2 forms of M1, that with valine at position 213 and that
with alanine at position 213 (called here M1A and M1V).

Hafeez et al. (1992) demonstrated that the AAT gene has 3
macrophage-specific transcriptional initiation sites upstream from a
single hepatocyte-specific transcriptional initiation site. Macrophages
use these sites during basal and modulated expression. Hepatoma cells
use the hepatocyte-specific transcriptional initiation site during basal
and modulated expression but also switch on transcription from the
upstream macrophage transcriptional initiation sites during modulation
by the acute phase mediator interleukin-6 (IL6; 147620).

PATHOGENESIS

Lomas et al. (1992) presented an explanation for the accumulation of
insoluble intracellular inclusions in the ZZ homozygote. Only about 15%
of the AAT protein is secreted in the plasma in ZZ homozygotes. The 85%
that is not secreted accumulates in the endoplasmic reticulum (ER) of
the hepatocyte; much of it is degraded but the remainder aggregates to
form insoluble intracellular inclusions. About 10% of newborn ZZ
homozygotes develop liver disease that often leads to fatal childhood
cirrhosis. Lomas et al. (1992) demonstrated the molecular pathology
underlying this accumulation and described how the Z mutation in
antitrypsin results in a unique molecular interaction between the
reactive center loop of one molecule and the gap in the A-sheet of
another. This loop-sheet polymerization of Z antitrypsin occurs
spontaneously at 37 degrees C and is completely blocked by the insertion
of a specific peptide into the A-sheet of the antitrypsin molecule. The
loop-sheet polymerization is concentration- and temperature-dependent.
At times of stress, the formation of inclusions in the hepatocyte will
likely overwhelm the degradative mechanisms. Antitrypsin is an acute
phase protein and as such undergoes a manifold increase in association
with temperature elevations during bouts of inflammation. Control of
inflammation and pyrexia in ZZ homozygote infants is important. In the
longterm, more specific interventions may be possible, e.g., the
delivery to the hepatocyte of engineered loop peptides specific to
alpha-1-antitrypsin.

Liver injury in individuals with the ZZ genotype presumably results from
toxic effects of the abnormal AAT molecule accumulating within the
endoplasmic reticulum of liver cells; however, only 12 to 15% of
individuals with this genotype develop liver disease. Therefore, Wu et
al. (1994) predicted that other genetic factors determine susceptibility
to liver disease. To examine this hypothesis, they transduced skin
fibroblasts from ZZ individuals with liver disease and from ZZ
individuals without liver disease with amphotropic recombinant
retroviral particles designed to express the mutant AAT*Z gene under
direction of a constitutive viral promoter. Expression of the AAT gene
was conferred on each fibroblast cell line. Compared to the same cell
line transduced with the wildtype gene, there was selective
intracellular accumulation of the mutant protein in each case. However,
there was a marked delay in degradation of the mutant protein after it
accumulated in the fibroblasts from ZZ individuals with liver disease
('susceptible hosts') as compared to those without liver disease
('protected hosts'). Appropriate disease controls showed that the lag in
degradation in susceptible hosts is specific for the combination of the
ZZ genotype and liver disease. Biochemical characteristics of the ATT*Z
degradation in the protected hosts was found to be similar to those of a
common ER degradation pathway previously described for T-cell receptor
alpha subunits and asialoglycoprotein receptor subunits, therefore
raising the possibility that the lag in degradation in the susceptible
host is a defect in this common ER degradation pathway.

As reviewed by Lomas (1996), inclusions in the most frequent cause of
antitrypsin deficiency, the C mutation (glu342lys; 107400.0011), is
accompanied by accumulation of protein in the endoplasmic reticulum of
the liver. These hepatic inclusions in turn result from a
protein-protein interaction between the reactive center loop of 1
molecule and the beta-pleated sheet of a second. This loop-sheet
polymerization is the basis of deficiencies associated also with
mutations of C1-inhibitor (106100), antithrombin III (107300), and
alpha-1-antichymotrypsin (107280), all of which are serine proteinase
inhibitors (serpins).

Sigsgaard et al. (1992) showed that in cotton workers the airborne
concentration of respirable endotoxin was associated with byssinosis.
Endotoxin might induce byssinosis through the release of biochemical
mediators at the bronchoalveolar surface. Alpha-1-antitrypsin, which
neutralizes enzymes released by granulocytes, might have a counteracting
role. Sigsgaard et al. (1994) found that the MZ phenotype was associated
with an increased prevalence of byssinosis compared with the MM
phenotype: 3/8 (38%) and 25/187 (13%). An association between the MZ
phenotype and familial allergy was also found, although the association
was somewhat weaker.

DIAGNOSIS

Kidd et al. (1983) used a chemically synthesized specific
oligonucleotide probe (19-mer) as a sensitive and direct test for the
presence or absence of the Z gene (glu342 to lys; GAG to AAG). Kidd et
al. (1984) reported the use of such probes in the prenatal diagnosis of
the deficiency syndrome. George et al. (1984) showed that replacement of
this methionine-358 with valine in a genetically engineered mutant of
human alpha-1-antitrypsin resulted in an inhibitor of connective tissue
breakdown when tested in a model of inflammation. Degradation of
basement membrane collagen was efficiently inhibited by a concentration
of the mutant substance that was tenfold lower than that of the normal
antitrypsin.

CLINICAL MANAGEMENT

Wewers et al. (1987) reported on treatment of patients with
alpha-1-antitrypsin deficiency with intravenous plasma-derived enzyme
once a week. Although granting that a completely rigorous study was
impossible, the authors concluded that infusions of enzyme are safe and
can reverse the biochemical abnormalities in serum and lung fluid and,
further, that lifetime avoidance of cigarette smoking together with such
replacement may be a logical approach to long-term therapy.

The liver represents an excellent organ for gene therapy since many
genetic disorders result from deficiency of liver-specific gene
products. Kay et al. (1992) demonstrated the autologous transplantation
of canine hepatocytes transduced with a retroviral vector containing the
human alpha-1-antitrypsin cDNA under transcriptional control of the
cytomegalovirus promoter. At least 1 billion hepatocytes or 5% of the
liver mass could be transplanted by the portal vasculature. Human
alpha-1-antitrypsin was demonstrable in the serum of 2 dogs for 1 month.
Although the serum levels of the human enzyme eventually fell due to
inactivation of the cytomegalovirus promoter, PCR analysis demonstrated
that a significant fraction of the transduced hepatocytes migrated to
the liver and continued to survive in vivo.

As a model for gene therapy, Garver et al. (1987) used a retroviral
vector to insert human alpha-1-antitrypsin cDNA into the genome of mouse
fibroblasts. After demonstrating that the clone produced human
antitrypsin after more than 100 population doublings in the absence of
selection pressure, they transplanted the clone into the peritoneal
cavities of nude mice. When the animals were evaluated 4 weeks later,
human antitrypsin was detected in both sera and the epithelial surface
of the lungs. Lemarchand et al. (1992) reported experiments supporting
the feasibility of in vivo human gene transfer of recombinant human AAT
cDNA to endothelial cells by means of replication-deficiency adenovirus
vectors.

POPULATION GENETICS

Roychoudhury and Nei (1988) tabulated worldwide gene frequencies for
allelic variants M (M1, M2, M3, M4), S, Z, F, I, and V. Cox (1989) and
Crystal (1989) reviewed the variants, 'normal' and pathologic, of the PI
gene.

DeCroo et al. (1991) studied the frequency of alpha-1-antitrypsin
alleles in U.S. whites, U.S. blacks, and African blacks (living in
Nigeria). While the PI*S allele was present at a polymorphic level in
U.S. whites, it was present only sporadically in U.S. blacks and
completely absent in African blacks. The PI*Z allele was not detected in
the black populations tested. DeCroo et al. (1991) used the PI allele
frequency data to calculate white admixture in U.S. blacks. The average
white admixture estimate in U.S. blacks, based on all PI alleles, was
about 13%. This value was about 24% when only the S and Z alleles were
used.

ANIMAL MODEL

Kurachi et al. (1981) found more than 96% homology of cDNA and amino
acid sequences between the alpha-1-antitrypsin of man and baboon.
Comparison of baboon alpha-1-antitrypsin, human antithrombin III, and
chicken ovalbumin indicated about 30% homology of amino acid sequence.

The pallid (pa) mouse develops emphysema late in life. Martorana et al.
(1993) demonstrated that pallid mice have markedly reduced levels of
serum alpha-1-antitrypsin associated with severe deficiency in serum
elastase inhibitory capacity. However, they have normal
alpha-1-antitrypsin mRNA levels in the liver.

*FIELD* AV
.0001
PI M1-ALA213
PI, M1A
PI
M1A, a normal variant, is believed to be the 'oldest' human PI allele,
with the other common normal alleles M1V, M2, and M3 derived from M1A by
single base substitutions. M2 is derived from M3; it has the same amino
acid difference that distinguishes M3 from M1V but a second substitution
in addition. The 4 common normal alleles are considered the 'base' from
which all the other alleles are derived (see Fig. 4 in Crystal, 1989).
The M1A allele has a frequency of 0.20-0.23 in U.S. Caucasians.

.0002
PI M1-VAL213
PI, M1V
PI, ALA213VAL
This normal allele has a frequency of 0.44-0.49 in U.S. Caucasians.

.0003
PI M2
PI, ARG101HIS ON M3
M2, which has a frequency of 0.10-0.11 in U.S. Caucasians (Cox, 1989),
was studied by Nukiwa et al. (1988), who found that its coding exons are
identical to those of the more frequent form of M1 (val213) except for 2
bases: a change in codon 101 from CGT to CAT, leading to an amino acid
change of arginine to histidine; and a change in codon 376 from GAA to
GAC, resulting in an amino acid change from glutamic acid to aspartic
acid. Since 2 mutations separate these 2 common alleles, Nukiwa et al.
(1988) suggested that another AAT variant (presumably M3) was an
intermediate in their evolution. M2 has a frequency of 0.10-0.11 among
U.S. Caucasians.

.0004
PI M3
PI, GLU376ASP ON M1V
This normal variant allele has a frequency of 0.14-0.19 among U.S.
Caucasians. Graham et al. (1990) identified a single nucleotide
difference between M1 (val-213) and M3: a transversion in codon 376 from
GAA(glu) to GAC(asp).

.0005
PI M4
PI, ARG101HIS ON M1V
M4, an uncommon normal allele, is likely derived by single substitution
from M1V; however, it has the same mutation that changed M2 to M3, and
thus it is possible that M4 derived from M3 (or vice versa).

.0006
PI B(ALHAMBRA)
PI, ASP-LYS
Yoshida et al. (1979) found 2 amino acid substitutions in the rare
antitrypsin variant PiB Alhambra. One substitution was asp for lys at an
unknown location (Crystal, 1989).

.0007
PI F
PI, ARG223CYS ON M1V
This rare 'normal' allele has a CGT-to-TGT change in codon 223 (Crystal,
1989; Okayama et al., 1991).

.0008
PI P(ST. ALBANS)
PI, ASP341ASN ON M1V
In addition to a GAC-to-AAC change in codon 341, this rare 'normal'
allele has a 'silent' asp256GAT-to-asp256GAC change. The rare P-family
of AAT variants is defined by the position of migration of the protein
on isoelectric focusing (IEF) of serum between the common M and S
variants. The P(St. Albans) allele is associated with normal serum
levels of AAT, whereas the P(Lowell) allele (107400.0019) is associated
with reduced levels. Holmes et al. (1990) described the DNA change
underlying both of these variants.

.0009
PI X
PI, GLU204LYS ON M1V
This rare 'normal' allele has been sequenced only at the level of the
protein (Crystal, 1989).

.0010
PI CHRISTCHURCH
PI, GLU363LYS
Brennan and Carrell (1986) characterized antitrypsin Christchurch, which
shows a substitution of lysine for glutamic acid at position 363.
Although electrophoretic mobility of the mutant protein was abnormal, no
functional abnormality of the protein was detected. The base PI allele,
M1A or M1V, is unknown (Crystal, 1989).

.0011
PI Z
PI, GLU342LYS ON M1A
This is the most frequent allele leading to a high risk of emphysema
(and liver disease) in the homozygote; the allele frequency is 0.01-0.02
in U.S. Caucasians (Crystal, 1989). Nukiwa et al. (1986) demonstrated
the val213-to-ala substitution (here symbolized M1A) in PI*2 in addition
to the disease-producing glu342-to-lys mutation. Using 2 genomic probes
extending into the 5-prime and 3-prime flanking regions, respectively,
Cox et al. (1985) identified 8 polymorphic restriction sites for the PI
gene. Extensive linkage disequilibrium was found with the PI Z allele
throughout the probe region, but not with the normal PI M allele. The Z
allele occurred mainly with one haplotype, indicating a single,
relatively recent origin in Caucasians. This was an individual who lived
in northern Europe some 6000 years ago. Since then, the variant has
spread through Europe with a frequency gradient extending from north to
south: 5% of Scandinavians, 4% of Britains, 1 to 2% of southern
Europeans, and 3% of the heterogeneous white population in the United
States are MZ heterozygotes. Curiously, there is a reciprocal
distribution of the S variant form: 10% in southern Europe to 5% in the
north. As a general rule then, 1 in 10 persons of European origin will
be heterozygous for either the S or Z variant, i.e., MZ or MS (Carrell,
1986). Alpha-1-antitrypsin deficiency is said to be rare among Japanese.
Kawakami et al. (1981) cited 2 studies in which no Pi Z was found among
965 healthy Japanese and 183 Japanese with pulmonary diseases. This is
to be compared with a frequency of 1.6% for Pi Z among Norwegians.

From study of 60-year-old twins with ZZ alpha-1-antitrypsin deficiency,
one a heavy smoker who developed severe emphysema and the other a
lifelong nonsmoker who was asymptomatic with only mild evidence of
obstructive pulmonary disease, Kennedy and Brett (1985) demonstrated the
importance of the environmental factor. A brother died at age 40 years
of emphysema. To study the question of the role of alpha-1-antitrypsin
heterozygosity in the etiopathogenesis of chronic obstructive pulmonary
disease (COPD) and to obviate the difficulties of precise diagnosis,
Klasen et al. (1986) used a well-defined subgroup suffering from
so-called 'flaccid lung.' In these persons, there is a loss of
elasticity of the lung parenchyma with high compliance. Flaccid lung can
be found with a high vital capacity, with spontaneous pneumothorax, in
patients with giant bullae, and in all patients with lung emphysema.
Klasen et al. (1986) found a relative risk of 12.5 for PI ZZ persons and
1.8 for MZ persons. They concluded that the risk of MZ persons compared
to MM persons is almost negligible and that whether the MZ person
develops lung disease is probably highly influenced by environmental and
perhaps other genetic factors. Clark et al. (1982) reported the cases of
2 brothers with Weber-Christian panniculitis and the alpha-1-antitrypsin
Z phenotype. A younger brother had the Z phenotype without
Weber-Christian disease. Along with several earlier reported cases,
these observations establish a relationship. Hendrick et al. (1988)
described 3 patients in whom panniculitis was the presenting
manifestation of AAT deficiency. Two were young adults and 1 was a
child. The panniculitis in these cases is frequently, although not
always, precipitated by trauma. The panniculitis is chronic, relapsing,
and widely disseminated with new lesions appearing as old lesions
resolve.

Dycaico et al. (1988) established transgenic mouse lineages that carried
the normal (M) or mutant (Z) alleles of the human AAT gene. All
expressed the human protein in liver, cartilage, gut, kidneys, lymphoid
macrophages, and thymus. The human M-allele protein was secreted
normally into the serum. However, the human Z-allele protein accumulated
in several cell types, particularly in hepatocytes, and was found in
serum in concentrations 10 times lower than the M-allele protein. Mice
in one lineage carrying the Z allele displayed significant runting in
the neonatal period and had developed abnormalities in the liver with
accumulation of human Z protein in diastase-resistant cytoplasmic
globules that stained with periodic acid-Schiff reaction (PAS).

Crystallographic analysis of alpha-1-antitrypsin predicts that in the
normal protein a negatively charged glu342 is adjacent to a positively
charged lys290. Thus, the glu342-to-lys Z mutation causes the loss of a
normal salt bridge, resulting in intracellular aggregation of the Z
molecule. Brantly et al. (1988) predicted that a second mutation that
changed the positively charged lys290 to a negatively charged glu290
would correct the secretion defect. They demonstrated that such was the
case: when the second mutation was added to the Z-type cDNA, the
resulting gene directed the synthesis and secretion of AAT similar to
that directed by the normal AAT cDNA in an in vitro eukaryotic
expression system. In general it may be possible to correct human
hereditary disease by inserting an additional mutation in the gene.

Hejtmancik et al. (1986) compared prenatal diagnosis by RFLP analysis
with prenatal diagnosis by oligonucleotide probe analysis. They
concluded that although it seems reasonable to use oligonucleotide
analysis in families in which no sibs are available for comparison, in
all other situations RFLP analysis is preferable because it is as
accurate and reliable as oligonucleotide analysis and is technically
easier. Abbott et al. (1988) used the PCR for prenatal diagnosis of
alpha-1-antitrypsin deficiency associated with the ZZ genotype. To
identify accurately the SZ phenotype at the DNA level, Nukiwa et al.
(1986) prepared 19-mer synthetic oligonucleotide probes: 2 to show the
M/S difference in exon 3, and 2 to show the M/Z difference in exon 5.
Babron et al. (1990) confirmed a previous finding that the presence of
the Pi Z allele tends to decrease the recombination rate between the GM
(147100) and PI loci. This decrease appeared to be similar in both sexes
and not unique in males as previously noted. The results suggested a
possible linkage disequilibrium between the Pi Z allele and a large
inversion between the GM and PI loci. Fortin et al. (1991) reported a
third incidence of systemic vasculitis associated with the ZZ genotype,
which took the form of polyarteritis nodosa.

.0012
PI M(MALTON)
PI, PHE52DEL ON M2
Liver disease, as well as emphysema, has been described only with PI*Z
and PI*M(Malton). Fraizer et al. (1989) studied the molecular defect in
M(Malton), a deficiency allele which, like the Z allele, is associated
with hepatocyte inclusions and impairs secretion. They found that the
M(Malton) allele contains a deletion of the codon for 1 of the 2
adjacent phenylalanine residues (amino acid 51 or 52 of the mature
protein). Judging from the haplotype data, the M(Malton) mutation must
have derived from the normal M2 allele. Deletion of the 1 amino acid
would be expected to shorten 1 strand of the beta-sheet, B6, apparently
preventing normal processing and secretion. Like the common Z deficiency
mutation (glu342-to-lys), the M(Malton) allele is associated with both
alpha-1-antitrypsin deficiency and hepatic disease. Curiel et al. (1989)
also showed that the M(Malton) allele differs from the normal M2 allele
by deletion of the entire codon (TTC) for residue phe52. They
demonstrated abnormal intracellular accumulation of newly synthesized
AAT protein in a homozygote who also showed, on liver biopsy,
inflammation, mild fibrosis, and intrahepatocyte accumulation of the
protein. Furthermore, Curiel et al. (1989) showed by retroviral gene
transfer of AAT cDNA with the M(Malton) phe52 deletion into murine cells
that abnormal accumulation of the newly synthesized protein occurred.
This provides further evidence that abnormal intrahepatocyte AAT
accumulation is responsible for the liver injury. By means of gene
amplification and direct DNA sequencing, Graham et al. (1989) identified
the same mutation, pointing out that it could be either phenylalanine-51
or phenylalanine-52 that is deleted. Dry (1991) described a method for
detecting the single base substitution in PiZ useful for same-day
diagnosis of AAT deficiency in chorion villus samples.

.0013
PI S
PI, GLU264VAL ON M1V
Owen and Carrell (1976) and Yoshida et al. (1977) found substitution of
valine for glutamic acid at position 264 in the S variant of
alpha-1-antitrypsin. See Long et al. (1984). Curiel et al. (1989)
concluded that the S-type AAT protein is degraded intracellularly before
secretion. PI*S homozygotes are at no risk of emphysema, but compound
heterozygotes with Z or a null allele have a mildly increased risk.
Because of the high frequency of the PI*S allele (0.02-0.04 in U.S.
Caucasians), such compound heterozygotes are relatively frequent.

.0014
PI M(HEERLEN)
PI, PRO369LEU ON M1A
Hofker et al. (1989) demonstrated the molecular defect in the PI gene of
a patient with a serum level of only 5 mg/100 ml and a PI M-like
phenotype, designated PI M(Heerlen). They demonstrated a substitution of
leucine for proline at codon 369, which resulted from a C-to-T mutation
in exon 5. Otherwise the nucleotide sequence of the exons, intron/exon
junctions, and a part of the promoter region was similar to that of a PI
M1(ala213) gene. Kalsheker et al. (1992) described a family and
commented on the difficulties of diagnosis of rare PI (null) or QO
variants.

.0015
PI M(MINERAL SPRINGS)
PI, GLY67GLU ON M1A
This mutation, which causes AAT deficiency and emphysema, is unique
among antitrypsin mutations in that it was observed in a black family,
whereas most mutations causing AAT deficiency are confined to Caucasian
populations of European descent. The index case was homozygous. A
GGG-to-GAG change in codon 67 led to substitution of glutamic acid for
glycine (Curiel et al., 1990). Curiel et al. (1990) showed that this
mutation caused reduced AAT secretion on the basis of aberrant
posttranslational biosynthesis by a mechanism distinct from that
associated with the Z allele, whereby intracellular aggregation of the
mutant protein is responsible for the secretory defect. Furthermore, the
M(Mineral Springs) mutation markedly affected the ability of the protein
that did reach the circulation to inhibit neutrophil elastase.
Homozygotes have a high risk of emphysema (Crystal, 1989).

.0016
PI M(PROCIDA)
PI, LEU41PRO ON M1V
Takahashi et al. (1988) showed that M(Procida) has a substitution of
proline for leucine at position 41, resulting from a change of codon CTG
to CCG. The rare mutant protein shows somewhat reduced catalytic
activity; its concentration is low in plasma, apparently because of
instability and resulting intracellular degradation before secretion.
Homozygotes have a high risk of emphysema (Crystal, 1989).

.0017
PI M(NICHINAN)
PI, PHE52DEL AND GLY148ARG
Nakamura et al. (1980) found this variant in a 42-year-old Japanese
woman with neither pulmonary emphysema nor liver dysfunction. She was
the product of a consanguineous marriage. Radial immunodiffusion assay
showed a low level of AAT in serum (17.9 mg/dl as compared to the normal
range of 190-280 mg/dl). Aggregation of AAT molecules was demonstrated
histologically in hepatocytes, indicating profound reduction in the
secretion of the protein. Serum AAT levels in the members of the family
demonstrated that the proband was homozygous for the M(Nichinan) allele.
Matsunaga et al. (1990) demonstrated that the M(Nichinan) gene is
identical with the M1(val213) gene except for 2 changes: a TTC
trinucleotide deletion in the codon for phenylalanine-52 and a G-A
substitution by which the normal gly148(GGG) became arg148(AGG).
Matsunaga et al. (1990) suggested that the gly148-to-arg change is
unlikely to be the cause of the AAT deficiency because arg (not gly) is
located at the corresponding position of the protein C inhibitor which
belongs to the same family of serine protease. On the other hand,
Matsunaga et al. (1990) suggested that deletion of phenylalanine-52 may
cause the newly synthesized AAT protein to aggregate, resulting in serum
AAT deficiency. They suggested that the gly148-to-arg substitution
reflects the vulnerability of a CpG dinucleotide to mutation. They
pointed to a number of other variant forms of AAT that were probably
generated through a C-T transition. Indeed, the Z and M1(val213) genes
were generated from the M1(ala213) gene by the C-T transition at the CpG
dinucleotide on the antisense and the sense strands, respectively. The
M2 gene was generated from the M3 gene by the same mechanism.

.0018
PI I
PI, ARG39CYS ON M1V
By gene amplification and direct DNA sequencing, Graham et al. (1989)
identified this mutation, CGC to TGC, in a compound heterozygote.
Homozygotes are at no risk of emphysema, but compound heterozygotes with
Z or a null allele have a mildly increased risk (Crystal, 1989). In 1
individual and 3 independent families, Seri et al. (1992) confirmed that
the I variant resulted from a CGC (arg)-to-TGC (cys) transition at codon
39 within exon 2.

.0019
PI P(LOWELL)
PI NULL(CARDIFF) PI QO(CARDIFF)
PI, ASP256VAL ON M1V
Faber et al. (1989) demonstrated that the rare P allele, a cause of
deficiency of alpha-1-antitrypsin, results from an A-to-T transversion
in exon 3 of the gene. As a result, GAT (asparagine as residue 256) in
the M protein is converted to GTT (valine at that position) in the P
protein. The same change was found in a total of 4 families. By gene
amplification and direct DNA sequencing, Graham et al. (1989) identified
the same mutation in a variant they called Null(Cardiff). According to
the tabulation by Crystal (1989), homozygotes have no risk for
emphysema, but compound heterozygotes with a Z or null allele have a
mildly increased risk. By retroviral insertion of the P(Lowell) cDNA
into the genome of NIH-3T3 fibroblasts, Holmes et al. (1990)
demonstrated a pattern of biosynthesis of AAT consistent with the
intracellular degradation of newly synthesized protein. Because serum
AAT deficiency associated with other mutations resulting from
intracellular degradation of the protein can be overcome by
administration of estrogenlike drugs, Holmes et al. (1990) administered
tamoxifen to a subject with the P(Lowell)Z phenotype and demonstrated a
48% rise in AAT serum levels over a 5-month period, from below the
threshold for protection for emphysema to a value above that threshold.
Seri et al. (1992) confirmed the nature of the mutation in P(Lowell).
Hildesheim et al. (1993) demonstrated that P(Duarte) (107400.0037) has
the same mutation as that in P(Lowell) but that it is on a background of
the normal M4 allele (R101H; 107400.0005). Hildesheim et al. (1993)
pointed out that this is an example of genetic diversity resulting from
a limited repertoire of mutations on different common allelic
backgrounds--a combinatorial basis for genetic diversity. A similar
example is the occurrence of Creutzfeldt-Jakob disease and fatal
familial insomnia as a result of the same mutation, depending on the
nature of a nucleotide polymorphism at another site in the prion protein
gene (PRNP; 176640.0010).

.0020
PI NULL(GRANITE FALLS)
PI QO(GRANITE FALLS)
PI, TYR160TER ON M1A
The gene shows deletion of the third nucleotide in the tyr160 codon TAC,
causing a frameshift with new stop codon TAG at position 160 (Nukiwa et
al., 1987). Emphysema is associated with homozygosity.

.0021
PI NULL(BELLINGHAM)
PI QO(BELLINGHAM)
PI, LYS217TER ON M1V
By cloning and sequencing the Null(Bellingham) gene (which in homozygous
state is associated with early-onset emphysema), Satoh et al. (1988)
demonstrated that the promoter region, coding exons, and all exon-intron
junctions are normal except for a single base substitution in exon 3,
which causes the normal lys217 (AAG) to become a stop codon (TAG).

.0022
PI NULL(MATTAWA)
PI QO(MATTAWA)
PI, LEU353PHE
Curiel et al. (1989) studied a null AAT gene so-identified by the fact
that no trypsin in serum could be attributed to that gene. The specific
null allele studied was referred to as Null(Mattawa). The patient
studied was found to be a compound heterozygote for Null(Mattawa) and
Null(Bellingham). Sequencing of exons 1c-5 and all exon-intron junctions
of the Null(Mattawa) gene demonstrated that it was identical to the
common normal M1(val213) gene except for the insertion of a single
nucleotide within the coding region of exon 5, causing a 3-prime
frameshift with generation of a premature stop signal at position 376.
Monocytes were shown to have an mRNA transcript of normal size, and in
vitro translation showed that the mRNA was translated at a normal rate
but produced a truncated antitrypsin protein. Additionally, retroviral
transfer of the cDNA to murine fibroblasts demonstrated no detectable
intracellular or secreted protein despite the presence of Null(Mattawa)
mRNA. Thus, the molecular pathophysiology of Null(Mattawa) is probably
manifested at a posttranslational level. This allele is associated with
high risk of emphysema.

.0023
PI NULL(PROCIDA)
PI NULL(ISOLA DI PROCIDA) PI QO(PROCIDA)
PI, 17-KB DEL
Of the 5 previously known representatives of the 'null' group of
AAT-deficient alleles (i.e., genes incapable of producing AAT protein
detectable in serum) evaluated at the gene level, all had stop codons in
coding exons. Cloning and mapping of the Null(Isola di Procida) gene
demonstrated deletion of a 17-kb fragment that included exons 2-5 of the
AAT structural gene (Takahashi and Crystal, 1990). Sequence analysis
showed a 7-bp repeat sequence both 5-prime to the deletion and at the
3-prime end of the deletion, suggesting that the mechanism of the
deletion may have been a slipped mispairing. This mutation, which at
first was called Null(Procida), was found in heterozygous state with the
M(Procida) allele (107400.0016) reported by Takahashi et al. (1988). To
avoid confusion with M(Procida), Null(Procida) was renamed Null(Isola di
Procida). This mutation is associated with high risk of emphysema.

.0024
PI NULL(HONG KONG-1)
PI QO(HONG KONG-1)
PI, 2-BP DEL, FS334TER
Deletion of TC from CTC codon 318 for leucine causes frameshift with
stop codon TAA at position 334. Homozygosity for this allele, like other
null alleles, predisposes to early-onset emphysema. See Sifers et al.
(1988). This variant was initially called Null(Hong Kong) but later
Null(Hong Kong-1) because a second null allele called Null(Hong Kong-2)
(107400.0034) was identified in the same individual by haplotype
analysis (Fraizer et al., 1990).

.0025
PI NULL(BOLTON)
PI QO(BOLTON)
PI, 1-BP DEL
Fraizer et al. (1989) observed a unique PI null allele. By cloning and
sequencing the allele, they demonstrated deletion of a single cytosine
residue (the third C in the CCC codon 362 for proline) near the active
site of alpha-1-antitrypsin in exon 5 resulting in a frameshift which
caused an inframe stop codon downstream of the deletion. The stop codon
led to premature termination of protein translation at amino acid 373,
resulting in a truncated protein. PI QO(Bolton) was observed in
combination with PI*M(Malton) in 2 compound heterozygotes. The allele
carries a high risk of emphysema.

.0026
PI PITTSBURGH
'ANTITHROMBIN' PITTSBURGH
PI, MET358ARG
This structure mutation in the PI gene alters its function such that it
becomes an antithrombin and leads to a bleeding disorder.
Alpha-1-antitrypsin and antithrombin III (107300) have a similar
structure reflecting origin from a common ancestral protein some 500
million years ago. Both are inhibitors of proteolytic enzymes but have
different specificities. Alpha-1-antitrypsin protects the body against
released elastase, whereas AT III controls coagulation by inhibiting
thrombin and other activated coagulation factors. Owen et al. (1983)
described a mutation of alpha-1-antitrypsin that converts it to an
antithrombin. Whereas synthesis of alpha-1-antitrypsin increases in
response to trauma, AT III remains at a constant plasma concentration
and requires activation by heparin. The antithrombin activity of the
mutant alpha-1-antitrypsin was independent of heparin but its synthesis
was stimulated by trauma. The patient was a 14-year-old boy who died in
1981 with a huge hematoma of his leg and abdomen. This was the last of a
lifelong series of bleeding episodes occurring after trauma and
requiring hospitalization on more than 50 occasions. Lewis et al. (1978)
described the clinical picture and identified a variant 'antithrombin'
which they called antithrombin Pittsburgh. It had, however, the
electrophoretic and antigenic characteristics of a variant
alpha-1-antitrypsin. Owen et al. (1983) showed that the variant protein
has arginine at position 358, replacing the normal methionine. This
finding indicated that the reactive center of alpha-1-antitrypsin is
methionine 358, which acts as a 'bait' for elastase, just as the normal
reactive center of AT III is arginine-393, which acts as a bait for
thrombin. Neutrophils augment tissue proteolysis by the oxidative
inactivation of the methionine at the reactive center of
alpha-1-antitrypsin. Scott et al. (1986) and Schapira et al. (1986)
found that recombinant AAT-Pittsburgh (met358-to-arg) is a potent
inhibitor of plasma kallikrein and activated factor XII fragment,
although it has lost its anti-elastase activity. They suggested it might
have therapeutic potential in hereditary angioedema or septic shock.
Vidaud et al. (1992) demonstrated that a G-to-T transition at nucleotide
10038 is responsible for the substitution of arg for met, which converts
alpha-1-antitrypsin into an arg-ser protease inhibitor (serpin) that
inhibits thrombin and factor Xa more effectively than antithrombin III.
They observed a 15-year-old boy who surprisingly had no bleeding
history. They suggested that a large decrease in protein C concentration
may account for the mild or absent bleeding tendency. The deficiency of
protein C in turn was attributed to deleterious effect of the abnormal
inhibitor on both intracellular processing and catabolism of protein C.
In later studies, Emmerich et al. (1995) suggested that strong affinity
of the mutant AAT for protein C leads in the patient of Vidaud et al.
(1992) to an increased turnover and thus to a low circulating level of
protein C. They proposed that in the presence of the Pittsburgh mutant
protein C can be activated and is abnormally rapidly cleared. The
resultant relative lack of protein C anticoagulant function may
ameliorate the bleeding diathesis expected to be associated with the
Pittsburgh mutation.

Wilkie (1994) discussed the molecular basis of genetic dominance and
provided a useful table. He indicated altered substrate specificity as
one mechanism and antithrombin Pittsburgh as a specific example.

.0027
PI V(MUNICH)
PI, ASP2ALA ON M1V
In an alpha-1-antitrypsin variant called V(Munich) because the major
fraction focused in the 'V' region of the isoelectric focusing gel,
Holmes et al. (1990) found that the molecule differs from that of the
common M1V allele by a single nucleotide substitution of cytosine for
adenosine, with the resultant amino acid change asp2 to ala; the codon
change is GAT to GCT.

.0028
PI Z(AUGSBURG)
PI Z(TUN)
PI, GLU342LYS ON M2
Using isoelectric focusing with a narrow pH gradient, Weidinger et al.
(1985) recognized a rare deficient PI-variant, which they called PI
Z(Augsburg). To their surprise, Faber et al. (1990) found that the
sequence of the Z(Augsburg) gene showed the common PI*Z mutation (M1
glu342 GAG to Z lys342 AAG) which occurred, however, in an M2 ancestral
gene. Previous findings indicated that the Z mutation had always been
derived from an M1 ala213 background gene. Whitehouse et al. (1989)
studied 2 sibs with mild liver abnormality who were found to be compound
heterozygotes for the classical PI*Z allele and an allele that they
called PI*Z(Tun). The Z(Tun) protein appeared to be deficient in the
plasma to about the same degree as the Z protein. They found that the
mutation was precisely the same as that in the Z allele, namely, a
G-to-A transition at codon 342 resulting in the substitution of lysine
for glutamic acid; however, the Z(Tun) mutation had occurred on an
M2-like haplotype background rather than the M1A background. Because of
its association with a unique DNA haplotype and the gene frequency
estimates in populations of European origin, the Z mutation is thought
to have occurred only once, about 6000 years ago, in a North European
person. The Z gene is very rare among other ethnic groups.

.0029
PI W(BETHESDA)
PI, ALA336THR ON M1A
This variant allele, which is associated with increased risk of
emphysema and liver disease, has a mutation in exon 5 where codon 336 is
changed from GCT to ACT, resulting in substitution of threonine for
alanine (Crystal, 1990). Holmes et al. (1990) reported that the
W(Bethesda) form differs from the normal M1(ala-213) allele by a change
in codon 336 from GCT to ACT. Although W(Bethesda) mRNA was translated
normally in vitro, transfection of the W(Bethesda) cDNA into COS-I cells
was associated with AAT secretion only 50% that of cells transfected
with normal cDNA. There was no intracellular accumulation as observed
with the Z allele, but reduced intracellular AAT suggested degradation
of newly synthesized W(Bethesda) molecules.

.0030
PI NULL(DEVON)
PI QO(DEVON) PI NULL(NEWPORT) PI QO(NEWPORT)
PI, GLY115SER
This variant, which is associated with increased risk of emphysema and
liver disease, is due to a change in exon 2, resulting in substitution
of serine for glycine-115 (Crystal, 1990). In a compound heterozygote
carrying the common disease-producing mutation Pi Z (107400.0011),
Graham et al. (1990) found a substitution of glycine-115 by serine. The
mutation occurred on the background of M3. A change in codon 155 from
GGC to AGC was responsible.

.0031
PI NULL(LUDWIGSHAFEN)
PI QO(LUDWIGSHAFEN)
PI, ILE92ASN
In this variant, which is associated with increased risk of emphysema
and liver disease, a change in codon 92 from ATC to AAC in exon 2
results in substitution of asparagine for isoleucine (Crystal, 1990).
This substitution of a polar for a nonpolar amino acid occurs in 1 of
the alpha-helices and is predicted to disrupt the tertiary structure
(Fraizer et al., 1990). Fraizer et al. (1990) identified a T-to-A
substitution in a German patient.

.0032
PI Z(WREXHAM)
PI, SER-19LEU
In a compound heterozygote with the common disease-producing PI Z
mutation (107400.0011), Graham et al. (1990) found a change from TCG to
TTG in codon -19 which resulted in a change from serine to leucine in
the signal peptide.

.0034
PI NULL(HONG KONG-2)
PI QO(HONG KONG-2)
PI
See 107400.0024.

.0035
PI NULL(RIEDENBURG)
PI, DEL
Poller et al. (1991) found complete deletion of the AAT gene as the
basis for PI Q0(Riedenburg). The deletion extended into the 3-prime
flanking region of the gene but did not include the noncoding
AAT-related gene (PIL), which is located 12 kb downstream of AAT (Hofker
et al., 1988).

.0036
PI KALSHEKER-POLLER
PI, 3-PRIME ENHANCER DEFECT
Kalsheker et al. (1987) and Poller et al. (1990) reported a mutation in
the 3-prime flanking sequence of the AAT gene that occurs in about 17%
of patients with chronic respiratory disease. The mutation is a G-to-A
nucleotide substitution in an octamer (OCT)-like sequence. Because TCGA
is converted to TCAA, the mutation is detected as a restriction fragment
length polymorphism with the restriction enzyme TaqI. The mutation does
not appear to affect basal expression of the protein as the plasma
concentration of alpha-1-antitrypsin is normal in persons who carry the
mutation; however, binding and functional studies by Morgan et al.
(1993) suggested that it may reduce the rise in plasma AAT concentration
that occurs during inflammation. Stimulation by cytokines, such as
interleukin 6 (IL6; 147620), may be lacking. Morgan et al. (1993)
pointed out a precedent for such a mechanism in an unrelated gene: an
enhancer element in the 3-prime flanking sequence of the erythropoietin
gene increases gene expression nearly 15-fold during hypoxia.

.0037
PI P(DUARTE)
PI, ASP256VAL
Hildesheim et al. (1993) demonstrated that the deficiency-producing
change in the PI gene in P(Duarte) is the same as that in P(Lowell)
(107400.0019). The alleles differ with respect to polymorphic
nucleotides at other positions in the gene. They referred to this as
genetic diversity from a limited repertoire of mutations on different
common allelic backgrounds.

.0038
PI NULL(WEST)
PI QO(WEST)
PI, IVS2DS, G-T, +1
During routine screening of individuals applying for enrollment in the
USA alpha-1-AT Deficiency Registry, Laubach et al. (1993) identified a
patient with emphysema and a PI type heterozygous for a novel AAT null
allele. The novel allele, designated PI*QO(West), was characterized by a
single G-to-T transversion at position 1 of intron 2, a highly conserved
nucleotide position. This resulted in an inframe deletion of amino acids
gly164-to-lys191. This was the first splicing mutation observed in the
AAT gene.

.0039
PI S(IIYAMA)
PI, PHE53SER
In a 32-year-old Japanese male with pulmonary emphysema, Yuasa et al.
(1993) demonstrated homozygosity for a C-to-T transition at codon 53
resulting in substitution of serine for phenylalanine. They commented on
the fact that, in Japanese, deficiency in null alleles at the AAT locus
are extremely rare and PI*Z, which occurs at polymorphic frequencies in
Caucasians, has not been reported. The only other Japanese case of AAT
deficiency was that due to PI M(Nichinan) (107400.0017) reported by
Matsunaga et al. (1990).

*FIELD* SA
Arnaud et al. (1977); Arnaud et al. (1978); Carrell et al. (1982);
Chan et al. (1978); Chapuis-Cellier et al. (1981); Cox  (1975); Cox
(1980); Cox  (1981); Curiel et al. (1989); Curiel et al. (1989); Faber
et al. (1994); Faber et al. (1989); Fagerhol and Cox (1981); Fagerhol
and Gedde-Dahl (1969); Fagerhol and Hauge (1968); Fagerhol and Laurell
(1970); Fagerhol and Tenfjord (1968); Falk and Briscoe (1970); Falk
and Briscoe (1970); Fraizer et al. (1989); Frants and Eriksson (1980);
Freeman et al. (1976); Gedde-Dahl et al. (1975); Graham et al. (1990);
Guenter et al. (1971); Hall et al. (1976); Hepper et al. (1969); Hodges
et al. (1981); Holmes et al. (1990); Holmes et al. (1990); Hug et
al. (1980); Iammarino et al. (1979); Jeppsson et al. (1975); Kew et
al. (1978); Kramps et al. (1981); Kueppers et al. (1964); Kueppers
and Christopherson (1978); Langley et al. (1979); Lieberman et al.
(1971); Lopez et al. (1964); Meisen et al. (1988); Morse  (1978);
Neumann et al. (1976); Nukiwa et al. (1986); Owen et al. (1976); Perrault
et al. (1979); Pierce et al. (1969); Rodriguez-Soriano et al. (1978);
Rosenthal et al. (1979); Schmitt et al. (1975); Sharp et al. (1969);
Starzl et al. (1983); Stockley  (1979); Talamo et al. (1968); Talamo
and Feingold (1973); Townley et al. (1970); Weitkamp et al. (1978);
Welch et al. (1980); Yoshida et al. (1979)
*FIELD* RF
1. Aagenaes, O.; Matlary, A.; Elgjo, K.; Munthe, E.; Fagerhol, M.
: Neonatal cholestasis in alpha-1-antitrypsin deficient children:
clinical, genetic, histological and immunohistochemical findings. Acta
Paediat. Scand. 61: 632-642, 1972.

2. Abbott, C. M.; McMahon, C. J.; Whitehouse, D. B.; Povey, S.: Prenatal
diagnosis of alpha-1-antitrypsin deficiency using polymerase chain
reaction. (Letter) Lancet I: 763-764, 1988.

3. Arnaud, P.; Galbraith, R. M.; Faulk, W. P.: Increased frequency
of the MZ phenotype of alpha-1-protease inhibitor in juvenile chronic
polyarthritis. J. Clin. Invest. 60: 1442-1444, 1977.

4. Arnaud, P.; Galbraith, R. M.; Galbraith, G. M. P.; Allen, R. C.;
Fudenberg, H. H.: A new allele of human alpha-1-antitrypsin: Pi (N
Hampton). Am. J. Hum. Genet. 30: 653-659, 1978.

5. Axelsson, U.; Laurell, C. B.: Hereditary variants of serum alpha-1-antitrypsin. Am.
J. Hum. Genet. 17: 466-472, 1965.

6. Babron, M. C.; Constans, J.; Dugoujon, J. M.; Cambon-Thomsen, A.;
Bonaiti-Pellie, C.: The Gm-Pi linkage in 843 French families: effect
of the alleles Pi Z and Pi S. Ann. Hum. Genet. 54: 107-113, 1990.

7. Bamforth, F. J.; Kalsheker, N. A.: Alpha-1 antitrypsin deficiency
due to Pi null: clinical presentation and evidence for molecular heterogeneity. J.
Med. Genet. 25: 83-87, 1988.

8. Bell, O. F.; Carroll, R. W.: Basis of the defect in alpha-1-antitrypsin
deficiency. Nature 243: 410-411, 1973.

9. Bell, R. S.: The radiographic manifestations of alpha-1 antitrypsin
deficiency: an important recognizable pattern of chronic obstructive
pulmonary disease (COPD). Radiology 95: 19-24, 1970.

10. Bender, K.; Muller, C. R.; Schmidt, A.; Strohmaier, U.; Wienker,
T. F.: Linkage studies on the human Pi, Gm, GLO, and HLA genes. Hum.
Genet. 49: 159-166, 1979.

11. Berg, N. O.; Eriksson, S.: Liver disease in adults with alpha-1-antitrypsin
deficiency. New Eng. J. Med. 287: 1264-1267, 1972.

12. Billingsley, G. D.; Walter, M. A.; Cox, D. W.: Physical linkage
of alpha-1-antitrypsin and alpha-1-antichymotrypsin by pulsed field
gel electrophoresis. (Abstract) Am. J. Hum. Genet. 45 (suppl.):
A130, 1989.

13. Billingsley, G. D.; Walter, M. A.; Hammond, G. L.; Cox, D. W.
: Physical mapping of four serpin genes: alpha-1-antitrypsin, alpha-1-antichymotrypsin,
corticosteroid-binding globulin, and protein C inhibitor, within a
280-kb region on chromosome 14q32.1. Am. J. Hum. Genet. 52: 343-353,
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127. Lieberman, J.; Mittman, C.; Kent, J. R.: Screening for heterozygous
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128. Lomas, D. A.: New insights into the structural basis of alpha-1-antitrypsin
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130. Long, G. L.; Chandra, T.; Woo, S. L. C.; Davie, E. W.; Kurachi,
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131. Lopez, V.; Oetliker, O.; Colombo, J. P.; Butler, R.: Ein Fall
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132. Martorana, P. A.; Brand, T.; Gardi, C.; van Even, P.; de Santi,
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133. Matsunaga, E.; Shiokawa, S.; Nakamura, H.; Maruyama, T.; Tsuda,
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135. Morgan, K.; Scobie, G.; Kalsheker, N. A.: Point mutation in
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137. Morse, J. O.: Alpha-1-antitrypsin deficiency. New Eng. J. Med. 299:
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138. Nakamura, H.; Ogawa, A.; Hisano, S.; Fukuma, M.; Tachibana, N.;
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140. Nukiwa, T.; Brantly, M.; Garver, R.; Paul, L.; Courtney, M.;
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141. Nukiwa, T.; Brantly, M. L.; Ogushi, F.; Fells, G. A.; Crystal,
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143. Nukiwa, T.; Takahashi, H.; Brantly, M.; Courtney, M.; Crystal,
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146. Owen, M. C.; Carrell, R. W.: Alpha-1-antitrypsin: molecular
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148. Pearson, S.; Tetri, P.; George, D. L.; Francke, U.: Alpha-1-antitrypsin
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167. Sigsgaard, T.; Brandslund, I.; Rasmussen, J. B.; Lund, E. D.;
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169. Starzl, T. E.; Porter, K. A.; Francavilla, A.; Iwatsuki, S.:
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1979.

172. Takahashi, H.; Crystal, R. G.: Alpha-1-antitrypsin Null(isola
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403-413, 1990.

173. Takahashi, H.; Nukiwa, T.; Satoh, K.; Ogushi, F.; Brantly, M.;
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1973.

176. Tarkoff, M. P.; Kueppers, F.; Miller, W. F.: Pulmonary emphysema
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177. Townley, R. G.; Ryning, F.; Lynch, H. T.; Brody, A. W.: Obstructive
lung disease in hereditary alpha-1-antitrypsin deficiency. J.A.M.A. 214:
325-331, 1970.

178. Turleau, C.; de Grouchy, J.; Chavin-Colin, F.; Dore, F.; Seger,
J.; Dautzenberg, M.; Arthuis, M.; Jeanson, C.: Two patients with
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179. Udall, J. N.; Bloch, K. J.; Walker, W. A.: Transport of proteases
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180. Vidaud, D.; Emmerich, J.; Alhenc-Gelas, M.; Yvart, J.; Fiessinger,
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with protein C deficiency in a patient with mild bleeding tendency. J.
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181. Weber, W.; Weidinger, S.: PI Scologne: a new variant in the
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182. Weidinger, S.; Jahn, W.; Cujnik, F.; Schwarzfischer, F.: Alpha-1-antitrypsin:
evidence for a fifth PI M subtype and a new deficiency allele PI*Z(Augsburg). Hum.
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183. Weitkamp, L. R.; Cox, D.; Guttormsen, S.; Johnston, E.; Hempfling,
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184. Weitz, J. I.; Silverman, E. K.; Thong, B.; Campbell, E. J.:
Plasma levels of elastase-specific fibrinopeptides correlate with
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inhibitor. J. Clin. Invest. 89: 766-773, 1992.

185. Welch, S. G.; McGregor, I. A.; Williams, K.: Alpha-1-antitrypsin
(Pi) phenotypes in a village population from the Gambia, West Africa. Hum.
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186. Wewers, M. D.; Casolaro, A.; Sellers, S.; Swayze, S. C.; McPhaul,
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1987.

187. Whitehouse, D. B.; Abbott, C. M.; Lovegrove, J. U.; McIntosh,
I.; McMahon, C. J.; Mieli-Vergani, G.; Mowat, A. P.; Hopkinson, D.
A.: Genetic studies on a new deficiency gene (PI*Z-Tun) at the PI
locus. J. Med. Genet. 26: 744-749, 1989.

188. Wiebicke, W.; Niggemann, B.; Fischer, A.: Pulmonary function
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189. Wilkie, A. O. M.: The molecular basis of genetic dominance. J.
Med. Genet. 31: 89-98, 1994.

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Perlmutter, D. H.: A lag in intracellular degradation of mutant alpha-1-antitrypsin
correlates with the liver disease phenotype in homozygous PiZZ alpha-1-antitrypsin
deficiency. Proc. Nat. Acad. Sci. 91: 9014-9018, 1994.

191. Yamamoto, Y.; Sawa, R.; Okamoto, N.; Matsui, A.; Yanagisawa,
M.; Ikemoto, S.: Deletion 14q(q24.3 to q32.1) syndrome: significance
of peculiar facial appearance in its diagnosis, and deletion mapping
of Pi (alpha-1-antitrypsin). Hum. Genet. 74: 190-192, 1986.

192. Yoshida, A.; Chillar, R.; Taylor, J. C.: An alpha-1-antitrypsin
variant, PiB Alhambra (lys-to-asp, glu-to-asp), with rapid anodal
electrophoretic mobility. Am. J. Hum. Genet. 31: 555-563, 1979.

193. Yoshida, A.; Ewing, C.; Wessels, M.; Lieberman, J.; Gaidulis,
L.: Molecular abnormality of Pi S variant of human alpha-1-antitrypsin. Am.
J. Hum. Genet. 29: 233-239, 1977.

194. Yoshida, A.; Lieberman, J.; Gaidulis, L.; Ewing, C.: Molecular
abnormality of human alpha-1-antitrypsin variant (Pi-SZ) associated
with plasma activity deficiency. Proc. Nat. Acad. Sci. 73: 1324-1328,
1976.

195. Yoshida, A.; Taylor, J. C.; Van den Brock, W. G. M.: Structural
difference between the normal PiM(1) and the common PiM(2) variant
of human alpha-1-antitrypsin. Am. J. Hum. Genet. 31: 564-568, 1979.

196. Yuasa, I.; Sugimoto, Y.; Ichinose, M.; Matsumoto, Y.; Fukumaki,
Y.; Sasaki, T.; Okada, K.: PI*S(iiyama), a deficiency gene of alpha-1-antitrypsin:
evidence for the occurrence in western Japan. Jpn. J. Hum. Genet. 38:
185-191, 1993.

*FIELD* CS

Pulm:
   Homozygous and compound heterozygous deficiency causes severe degenerative
   lung disease (Z, S, null, M(Malton), M(Heerlen), M(Mineral Springs),
   M(Procida), M(Nichinan), I, and P(Lowell) alleles);
   Heterozygotes predisposed to chronic obstructive lung disease;
   Emphysema primarily in lower lung fields;
   Increased frequency of sclerosing alveolitis with or without rheumatoid
   arthritis

GI:
   Infantile liver cirrhosis in homozygote deficiency (Z, S, M(Malton)
   alleles);
   Juvenile esophageal varicies;
   Juvenile portal hypertension

Oncology:
   Increased hepatocellular carcinoma risk (ZZ, SZ)

GU:
   Increased ovulation rate and enhanced success of multiple pregnancies
   (S allele)

Heme:
   Bleeding disorder (Pittsburgh allele)

Misc:
   Important preventive measures are prompt treatment of respiratory
   infections;
   and avoidance of proteolytic aerosols, smoking and employment exposure
   to respiratory irritants

Radiology:
   Bibasilar emphysematous changes (loss of vascular markings)

Lab:
   Serum alpha-1-antitrypsin (Pi) deficiency;
   Accumulation of insoluble intracellular inclusions (ZZ homozygote;
   Abnormal liver function tests (SGOT, SGPT)

Inheritance:
   Autosomal dominant (14q32.1)

*FIELD* CN
Cynthia K. Ewing - updated: 10/23/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/10/1997
mark: 12/29/1996
jamie: 10/23/1996
jamie: 10/16/1996
jamie: 10/14/1996
mark: 3/25/1996
terry: 7/10/1995
mark: 6/13/1995
pfoster: 5/2/1995
davew: 8/18/1994
jason: 6/17/1994
warfield: 4/4/1994

*RECORD*
*FIELD* NO
107410
*FIELD* TI
107410 ANTITRYPSIN-RELATED PROTEIN; ATR
ALPHA-1-ANTITRYPSIN-RELATED GENE SEQUENCE; ARGS
*FIELD* TX
Kelsey et al. (1988) identified, 10 kb downstream of the authentic
alpha-1-antitrypsin gene (AAT; 107400), a genomic sequence with
considerable homology to the AAT gene. They designated this sequence,
which was approximately 5 kb long, the alpha-1-antitrypsin-related gene
(ATR). They introduced the AAT and ATR genes separately into L-cells by
transfection in order to establish a method for distinguishing between
expression of the 2 genes. RNA probes from the cloned ATR region were
then used in a ribonuclease protection assay against RNA from a range of
human adult and fetal tissues. No evidence of expression of ATR was
found, indicating that this region is probably a pseudogene. Bao et al.
(1988) cloned a 7.7-kb EcoRI genomic DNA fragment highly homologous to
the human AAT gene. Both were present in a single cosmid clone; the
newly found gene is located about 8 kb downstream of the AAT gene. The
nucleotide sequence of the antitrypsin-related gene (ATR) showed
extensive homology with the authentic AAT gene in the introns as well as
exons. The conservation of all RNA splice sites and lack of internal
termination codons in the exons suggested that it may not be a classic
pseudogene. If expressed, it would result in a protein of 420 amino acid
residues, exhibiting a 70% overall homology with AAT. The signal peptide
sequence was well conserved, but the active site of protease inhibition
(met-ser) in AAT had been changed to trp-ser. The findings suggested
that the putative protein is a secretory serine protease inhibitor with
an altered substrate specificity. Since even the introns showed 65%
nucleotide sequence homology with the authentic AAT gene, ATR appears to
have been derived from a recent duplication of the AAT gene. It
presumably represents a new member of the serine protease inhibitor
superfamily. Kalsheker and Watkins (1988) and others before them
demonstrated RFLPs in the antitrypsin-related gene sequence.

*FIELD* SA
Lai et al. (1983)
*FIELD* RF
1. Bao, J.; Reed-Fourquet, L.; Sifers, R. N.; Kidd, V. J.; Woo, S.
L. C.: Molecular structure and sequence homology of a gene related
to alpha-1-antitrypsin in the human genome. Genomics 2: 165-173,
1988.

2. Kalsheker, N. A.; Watkins, G. L.: Heterozygosity and localisation
of normal allelic fragments for an alpha-1-antitrypsin homologous
sequence. Hum. Genet. 80: 108-109, 1988.

3. Kelsey, G. D.; Parkar, M.; Povey, S.: The human alpha-1-antitrypsin-related
sequence gene: isolation and investigation of its expression. Ann.
Hum. Genet. 52: 151-160, 1988.

4. Lai, E. C.; Kao, F.-T.; Law, M. L.; Woo, S. L. C.: Assignment
of the alpha-1-antitrypsin gene and a sequence-related gene to human
chromosome 14 by molecular hybridization. Am. J. Hum. Genet. 35:
385-392, 1983.

*FIELD* CD
Victor A. McKusick: 11/25/1987

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 1/9/1989
root: 10/4/1988
root: 9/23/1988

*RECORD*
*FIELD* NO
107440
*FIELD* TI
107440 ANTIVIRAL STATE REPRESSOR, REGULATOR OF; AVRR
*FIELD* TX
Lin and Tan (1975) used the deletion method to assign an antiviral state
repressor regulator gene to 5p. There has been, it seems, no definitive
report of this observation nor has it been confirmed by others.

*FIELD* RF
1. Lin, C. C.; Tan, Y. H.: Allocation of a regulatory gene(s) for
the repressor of antiviral state in man on the short arm of chromosome
no. 5.  (Abstract) Canad. J. Genet. Cytol. 17: 462 only, 1975.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/23/1988
marie: 3/25/1988
reenie: 6/24/1986

*RECORD*
*FIELD* NO
107450
*FIELD* TI
*107450 INTERFERON (ALPHA, BETA AND OMEGA) RECEPTOR 1; IFNAR1
IFNAR;;
ANTIVIRAL PROTEIN, ALPHA TYPE; AVP;;
INTERFERON RECEPTOR ALPHA; IFRC
*FIELD* TX
Alpha-type antiviral protein is a factor, presumably protein in nature,
that mediates specific interferon inhibition of virus replication.
According to studies of mouse-man hybrid clones, the locus determining
this protein is carried on chromosome 21 (Tan et al., 1973). Tan et al.
(1974) made observations of dosage effect in monosomy-21 and trisomy-21
cells which supported assignment of the locus to chromosome 21. This
character was also called interferon sensitivity (IS). Chany et al.
(1975) showed that trisomy-21 cells have increased interferon
sensitivity. Trisomy-16 cells have reduced sensitivity. This might
suggest the presence on chromosome 16 of a regulator of mouse antiviral
protein.

Revel et al. (1976) showed that antibody to a cell-surface component
coded by human chromosome 21 inhibited the action of interferon. This
suggested that antiviral protein is an interferon receptor. See 147570,
147640, 147660 for a discussion of the gamma, beta, and alpha
interferons, respectively. De Clercq et al. (1976) concluded that it is
not a cell membrane receptor for interferon that is encoded by
chromosome 21.

In trisomy-21 fibroblasts, Epstein and Epstein (1976) demonstrated an
exaggerated response to both classic (virus-induced) and immune
(phytohemagglutinin-induced) forms of interferon. This suggested that
despite their physical and antigenic differences the antiviral
expression of the 2 interferons is mediated by the same genetic locus. A
line trisomic for the distal part of the long arm 21q21-qter also
demonstrated increased response, indicating that the AVP gene is located
on this part of chromosome 21. Lin et al. (1980) demonstrated that the
genes for soluble SOD (147450) and interferon sensitivity are syntenic
in the mouse and on chromosome 16.

Raziuddin et al. (1984) showed that the receptors for alpha- and
beta-interferons are specified by chromosome 21. Presumably, separate
genes code the alpha- and beta-interferon receptors. Sarkar and Gupta
(1984) showed that gamma-interferon binds to a separate receptor that is
carried by WISH cells (a human amnion cell line). The gene for the
receptor was designated also IFNAR. Langer et al. (1990) sublocalized
the IFNAR gene to 21q22.1-q22.2 by hybridization of (32)P-labeled
recombinant interferon-alpha/beta receptor with human-hamster somatic
cell hybrids containing various fragments of human chromosome 21. By in
situ hybridization, Lutfalla et al. (1990) refined the assignment to
21q22.1. Lutfalla et al. (1992) further refined the localization by
pulsed field gel electrophoresis and its linkage to adjacent markers.
They compared the exon structure of the IFNAR gene with that of the
genes for receptors of the cytokine/growth hormone/prolactin/interferon
receptor family and concluded that they have a common origin and have
diverged from the immunoglobulin superfamily with which they share a
common ancestor.

*FIELD* SA
Cox et al. (1980); Faltynek et al. (1983); Fournier et al. (1985);
Maroun  (1980); Slate and Ruddle (1978); Slate et al. (1978); Tan
(1976); Weil et al. (1983); Wiranowska-Stewart and Stewart (1977)
*FIELD* RF
1. Chany, C.; Vignal, M.; Couillin, P.; Van Cong, N.; Boue, J.; Boue,
A.: Chromosomal localization of human genes governing the interferon-induced
antiviral state. Proc. Nat. Acad. Sci. 72: 3129-3133, 1975.

2. Cox, D. R.; Epstein, L. B.; Epstein, C. J.: Genes coding for sensitivity
to interferon (IfRec) and soluble superoxide dismutase (SOD-1) are
linked in mouse and man and map to mouse chromosome 16. Proc. Nat.
Acad. Sci. 77: 2168-2172, 1980.

3. De Clercq, E.; Edy, V. G.; Cassiman, J.-J.: Chromosome 21 does
not code for an interferon receptor. Nature 264: 249-251, 1976.

4. Epstein, L. B.; Epstein, C. J.: Localization of the gene AVG for
the antiviral expression of immune and classical interferon to the
distal portion of the long arm of chromosome 21. J. Infect. Dis. 133
(suppl.): A56-A62, 1976.

5. Faltynek, C. R.; Branca, A. A.; McCandless, S.; Baglioni, C.:
Characterization of an interferon receptor on human lymphoblastoid
cells. Proc. Nat. Acad. Sci. 80: 3269-3273, 1983.

6. Fournier, A.; Zhang, Z. Q.; Tan, Y. H.: Human beta:alpha but not
gamma interferon binding site is a product of the chromosome 21 interferon
action gene. Somat. Cell Molec. Genet. 11: 291-295, 1985.

7. Langer, J. A.; Rashidbaigi, A.; Lai, L.-W.; Patterson, D.; Jones,
C.: Sublocalization on chromosome 21 of human interferon-alpha receptor
gene and the gene for an interferon-gamma response protein. Somat.
Cell Molec. Genet. 16: 231-240, 1990.

8. Lin, P.-F.; Slate, D. L.; Lawyer, F. C.; Ruddle, F. H.: Assignment
of the murine interferon sensitivity and cytoplasmic superoxide dismutase
genes to chromosome 16. Science 209: 285-287, 1980.

9. Lutfalla, G.; Gardiner, K.; Proudhon, D.; Vielh, E.; Uze, G.:
The structure of the human interferon alpha/beta receptor gene. J.
Biol. Chem. 267: 2802-2809, 1992.

10. Lutfalla, G.; Roeckel, N.; Mogensen, K. E.; Mattei, M. G.; Uze,
G.: Assignment of the human interferon-alpha receptor gene to chromosome
21q22.1 by in situ hybridization. J. Interferon Res. 10: 515-517,
1990.

11. Maroun, L. E.: Interferon action and chromosome 21 trisomy. (Letter) J.
Theor. Biol. 86: 603-606, 1980.

12. Raziuddin, A.; Sarkar, F. H.; Dutkowski, R.; Shulman, L.; Ruddle,
F. H.; Gupta, S. L.: Receptors for human alpha and beta interferon
but not for gamma interferon are specified by human chromosome 21. Proc.
Nat. Acad. Sci. 81: 5504-5508, 1984.

13. Revel, M.; Bash, D.; Ruddle, F. H.: Antibodies to a cell-surface
component coded by human chromosome 21 inhibit action of interferon. Nature 260:
139-141, 1976.

14. Sarkar, F. H.; Gupta, S. L.: Receptors for human gamma interferon:
binding and crosslinking of 125-I-labeled recombinant human gamma
interferon to receptors on WISH cells. Proc. Nat. Acad. Sci. 81:
5160-5164, 1984.

15. Slate, D. L.; Ruddle, F. H.: Antibodies to chromosome 21 coded
cell surface components can block response to human interferon. Cytogenet.
Cell Genet. 22: 265-269, 1978.

16. Slate, D. L.; Shulman, L.; Lawrence, J. B.; Revel, M.; Ruddle,
F. H.: Presence of human chromosome 21 alone is sufficient for hybrid
cell sensitivity to human interferon. J. Virol. 25: 319-325, 1978.

17. Tan, Y. H.: Chromosome 21 and the cell growth inhibitory effect
of human interferon preparations. Nature 260: 141-143, 1976.

18. Tan, Y. H.; Schneider, E. L.; Tischfield, J.; Epstein, C. J.;
Ruddle, F. H.: Human chromosome 21 dosage: effect on the expression
of the interferon induced antiviral state. Science 186: 61-63, 1974.

19. Tan, Y. H.; Tischfield, J.; Ruddle, F. H.: The linkage of genes
for the human interferon-induced antiviral protein and indophenoloxidase-B
traits to chromosome G-21. J. Exp. Med. 37: 317-330, 1973.

20. Weil, J.; Tucker, G.; Epstein, L. B.; Epstein, C. J.: Interferon
induction of (2-prime-5-prime) oligoisoadenylate synthetase in diploid
and trisomy 21 human fibroblasts: relation to dosage of the interferon
receptor gene (IFRC). Hum. Genet. 65: 108-111, 1983.

21. Wiranowska-Stewart, M.; Stewart, W. E., II: The role of human
chromosome 21 in sensitivity to interferons. J. Gen. Virol. 37:
629-633, 1977.

*FIELD* CN
Alan F. Scott - updated: 4/22/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 12/31/1996
mark: 4/22/1996
carol: 10/13/1992
carol: 9/3/1992
carol: 8/11/1992
supermim: 3/16/1992
carol: 11/8/1991
carol: 8/7/1991

*RECORD*
*FIELD* NO
107460
*FIELD* TI
*107460 ANTIVIRAL PROTEIN, BETA TYPE
INTERFERON, BETA, RECEPTOR FOR; IFNBR
*FIELD* TX
See 107450.

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986
*RECORD*
*FIELD* NO
107470
*FIELD* TI
*107470 INTERFERON, GAMMA, RECEPTOR-1; IFNGR1
AVP, TYPE II;;
ANTIVIRAL PROTEIN, TYPE II;;
IMMUNE INTERFERON RECEPTOR-1
*FIELD* TX
Interferons may be regarded as polypeptide hormones because of their
role in communicating from cell to cell a specific set of instructions
that lead to a wide variety of effects. Branca and Baglioni (1981)
concluded that types I and II interferons have different receptors.
(Viruses induce type I interferon, subdivided into alpha-interferon
(147660), produced by leukocytes or lymphoblastoid cells, and
beta-interferon (147640), produced by fibroblasts. Mitogens and
antigenic stimuli induce in lymphocytes type II, immune, or
gamma-interferon (107450, 147570).) The biologic effects of human
interferons, including increment of histocompatibility antigens, are
mediated through species-specific receptors. Human interferons are not
active, for example, in mouse cells. The genes for the separate
receptors of alpha- and beta-interferon are located on chromosome 21
(see 107450). Celada et al. (1985) demonstrated and partially
characterized the interferon-gamma receptor on macrophages.
Interferon-gamma has an important role in activating macrophages in host
defenses.

By studies in man-mouse somatic cell hybrids, Fellous et al. (1985)
suggested that chromosome 18 carries the gene for gamma-interferon
receptor. They examined the capacity of human interferons to induce
mouse H-2 antigens in these hybrid cells. Human 18 was required for
action of human gamma-interferon. On the other hand, Rashidbaigi et al.
(1986) concluded that the IFNG receptor or its binding subunit is coded
by a gene on 6q. They identified a complex with a molecular weight of
about 117,000 daltons when (32)P-labeled human recombinant DNA was
crosslinked to human cells with disuccinimidyl suberate. Formation of
the complex was inhibited when the binding was performed in the presence
of an excess of human IFNG. Mouse and Chinese hamster ovary cells did
not show complex formation. In studies of hamster-human and mouse-human
hybrid cells, they showed that human 6q is necessary and sufficient for
formation of complexes. Fellous (1986) reported that he had exchanged
somatic cell hybrids with Rashidbaigi and concluded that indeed
chromosome 6 is involved in the genetic control of human
gamma-interferon receptor, but that chromosome 18 was also necessary.
Jung et al. (1987) found that the presence of chromosome 6 in
hamster-human hybrids was by itself insufficient to confer sensitivity
to human immune interferon as measured by the induction of human HLA.
Human chromosome 21 was found to be the second chromosome essential for
HLA inducibility. Similar results were found with mouse-human somatic
cell hybrids. Thus, at least 2 steps are involved in the action of
gamma-interferon: the binding of gamma-interferon to its receptor coded
by chromosome 6 and the coupling of this binding event through a factor
coded by chromosome 21 to trigger biological action. Both of these steps
were shown to be species-specific. The finding of a receptor element on
chromosome 18 must be considered inconsistent (Fellous et al., 1985). Le
Coniat et al. (1989) confirmed the assignment to chromosome 6 and
regionalized the gene to 6q23-q24 by in situ hybridization. Mariano et
al. (1987) demonstrated that the mouse immune interferon receptor gene
(Ifgr) maps to chromosome 10. Mouse chromosome 10 also carries the gene
for gamma-interferon, which in man is coded by chromosome 12.

Novick et al. (1987) purified and characterized the gamma-interferon
receptor. They referred to their work (Orchansky et al., 1986)
suggesting that human cells of hematopoietic origin may have an IFNG
receptor that is structurally and functionally different from the
receptor in cells of nonhematopoietic origin. Rettig et al. (1988)
reported results with a panel of 22 monoclonal antibodies recognizing 21
distinct human cell surface antigens. The genes responsible for these
were mapped to multiple sites. According to the human gene mapping
nomenclature, the genes were designated by the name of the laboratory,
Sloan-Kettering. For example, MSK28 mapped to chromosome 6 in the same
vicinity as that of immune interferon receptor and may indeed be the
same antigen.

Levin et al. (1995) described a group of related children from a village
in Malta who appeared to have an autosomal recessive familial
immunologic defect predisposing them to infection with a range of
mycobacteria. Despite intensive treatment, 3 of the 4 affected patients
died and the survivor had persistent infection. Immunologic studies
showed that the affected children had defective production of tumor
necrosis factor alpha (191160) in response to endotoxin and a failure to
upregulate this cytokine in response to interferon-gamma. Newport et al.
(1996) performed a genome-wide search using microsatellite markers to
identify a region on 6q in which the affected children were all
homozygous for 8 markers. This finding led to focus on the gene for
interferon-gamma receptor 1 which maps to 6q23-q24. Sequence analysis of
cDNA for the gene revealed a point mutation at nucleotide 395 that
introduced a stop codon and resulted in a truncated protein that lacked
the transmembrane and cytoplasmic domains (107470.0001).

The attenuated strain of Mycobacterium bovis bacille Calmette-Guerin
(BCG) is the vaccine most widely used worldwide. Jouanguy et al. (1996)
noted that in most children, inoculation of live BCG vaccine is harmless
although it occasionally leads to a benign regional adenitis. In rare
cases, however, vaccination causes disseminated BCG infection, which may
be lethal. Most of these children have had severe combined
immunodeficiency and some have had chronic granulomatous disease. Rare
cases of BCG infection have also been reported in association with AIDS.
However, a specific immunodeficiency can be identified in only about
half the cases of disseminated BCG infection. Such idiopathic cases have
been reported from many countries with a prevalence in France of at
least 0.50 case per 1 million children vaccinated with BCG. Jouanguy et
al. (1996) stated that a high rate of consanguinity (30%) and familial
forms (17%) and the equal sex distribution support the hypothesis of a
new type of primary immune defect with an autosomal recessive pattern of
inheritance. Pathologic features and clinical outcome suggest 2 distinct
forms of idiopathic BCG infection. Well-circumscribed and
well-differentiated tuberculoid granulomas with few visible acid-fast
rods are associated with a good prognosis. In contrast, ill-defined and
poorly differentiated, leproma-like granulomas with many visible bacilli
are associated with a fatal outcome, despite antimycobacterial therapy.
The second form appears to represent a defect affecting an obligatory
and relatively specific step in the formation of a bactericidal BCG
granuloma. In mice in which the Ifngr1 gene or interferon-gamma
regulatory factor 1 (147475) has been deleted, there is failure to
control BCG growth (Dalton et al., 1993). Mice treated with antibodies
against tumor necrosis factor-alpha (191160) are susceptible to BCG
infection, with defective granuloma structure and a fatal outcome.
Jouanguy et al. (1996) examined these genes in an infant with fatal
idiopathic disseminated BCG infection and found a mutation in the IFNGR1
gene (107470.0002). The girl was born of Tunisian parents who were first
cousins (patient 16 of Casanova et al., 1995). The patient was
vaccinated with BCG at the age of 1 month and was healthy until age 2.5
months. She died at the age of 10 months from BCG infection with
multiorgan failure. Jouanguy et al. (1996) stated that intrafamilial
segregation of microsatellites which would be expected to show
homozygosity for genes closely linked to the affected locus pointed to
the IFNGR1 locus as a probable site of the mutation. Deletion of
nucleotide 131 in the coding region was found. Deletion of C at this
position caused a frameshift and led to a premature stop codon (TAA) at
nucleotides 187-189 of their sequence. Both the deletion and the stop
codon were located in the region that codes for the N-terminal portion
of the extracellular domain of the receptor.

*FIELD* AV
.0001
ATYPICAL MYCOBACTERIAL INFECTION, FAMILIAL DISSEMINATED
IFNGR1, 395C-A, SER-TER
In 4 children with familial disseminated atypical mycobacterial
infection in Malta, Newport et al. (1996) demonstrated homozygosity for
a C-to-A transversion of nucleotide 395 which resulted in a stop codon:
a change from TCA (ser) to TAA (stop).

.0002
BCG INFECTION, GENERALIZED FAMILIAL
IFNGR1, 1-BP DEL, FS, TER
Jouanguy et al. (1996) identified a mutation in the IFNGR1 gene in a
Tunisian patient with fatal BCG infection. A single nucleotide deletion,
designated 131delC by them, created a frameshift and led to a premature
stop codon (TAA) at nucleotides 187-189 of the coding region of the
IFNGR1 gene. The mutation was located in exon 2. The affected child was
homozygous; both parents and 2 healthy brothers were heterozygous.

*FIELD* SA
Alcaide-Loridan et al. (1989)
*FIELD* RF
1. Alcaide-Loridan, C.; Le Coniat, M.; Bono, R.; Benech, P.; Couillin,
P.; Van Cong, N.; Fisher, D. N.; Berger, R.; Fellous, M.: Mapping
of the human interferon gamma response. (Abstract) Cytogenet. Cell
Genet. 51: 949 only, 1989.

2. Branca, A. A.; Baglioni, C.: Evidence that types I and II interferons
have different receptors. Nature 294: 768-770, 1981.

3. Casanova, J.-L.; Jouanguy, E.; Lamhamedi, S.; Blanche, S.; Fischer,
A.: Immunological conditions of children with BCG disseminated infection.
(Letter) Lancet 346: 581 only, 1995.

4. Celada, A.; Allen, R.; Esparza, I.; Gray, P. W.; Schreiber, R.
D.: Demonstration and partial characterization of the interferon-gamma
receptor on human mononuclear phagocytes. J. Clin. Invest. 76: 2196-2205,
1985.

5. Dalton, D. K.; Pitts-Meek, S.; Keshav, S.; Figari, I. S.; Bradley,
A.; Stewart, T. A.: Multiple defects of immune cell function in mice
with disrupted interferon-gamma genes. Science 259: 1739-1742, 1993.

6. Fellous, M.: Personal Communication. Paris, France  10/24/1986.

7. Fellous, M.; Couillin, P.; Rosa, F.; Metezeau, P.; Foubert, C.;
Gross, M. S.; Frezal, J.; Van Cong, N.: Receptor for human gamma
interferon is specified by human chromosome 18. (Abstract) Cytogenet.
Cell Genet. 40: 627-628, 1985.

8. Jouanguy, E.; Altare, F.; Lamhamedi, S.; Revy, P.; Emile, J.-F.;
Newport, M.; Levin, M.; Blanche, S.; Seboun, E.; Fischer, A.; Casanova,
J.-L.: Interferon-gamma-receptor deficiency in an infant with fatal
bacille Calmette-Guerin infection. New Eng. J. Med. 335: 1956-1961,
1996.

9. Jung, V.; Rashidbaigi, A.; Jones, C.; Tischfield, J. A.; Shows,
T. B.; Pestka, S.: Human chromosomes 6 and 21 are required for sensitivity
to human interferon gamma. Proc. Nat. Acad. Sci. 84: 4151-4155,
1987.

10. Le Coniat, M.; Alcaide-Loridan, C.; Fellous, M.; Berger, R.:
Human interferon gamma receptor 1 (IFNGR1) gene maps to chromosome
region 6q23-6q24. Hum. Genet. 84: 92-94, 1989.

11. Levin, M.; Newport, M. J.; D'Souza, S.; Kalabalikis, P.; Brown,
I. N.; Lenicker, H. M.; Agius, P. V.; Davies, E. G.; Thrasher, A.;
Klein, N.; Blackwell, J. M.: Familial disseminated atypical mycobacterial
infection in childhood: a human mycobacterial susceptibility gene?. Lancet 345:
79-83, 1995.

12. Mariano, T. M.; Kozak, C. A.; Langer, J. A.; Pestka, S.: The
mouse immune interferon receptor gene is located on chromosome 10. J.
Biol. Chem. 262: 5812-5814, 1987.

13. Newport, M. J.; Huxley, C. M.; Huston, S.; Hawrylowicz, C. M.;
Oostra, B. A.; Williamson, R.; Levin, M.: A mutation in the interferon-gamma-receptor
gene and susceptibility to mycobacterial infection. New Eng. J. Med. 335:
1941-1949, 1996.

14. Novick, D.; Orchansky, P.; Revel, M.; Rubinstein, M.: The human
interferon-gamma receptor: purification, characterization, and preparation
of antibodies. J. Biol. Chem. 262: 8483-8487, 1987.

15. Orchansky, P.; Rubinstein, M.; Fischer, D. G.: The interferon-gamma
receptor in human monocytes is different from the one in nonhematopoietic
cells. J. Immun. 136: 169-173, 1986.

16. Rashidbaigi, A.; Langer, J. A.; Jung, V.; Jones, C.; Morse, H.
G.; Tischfield, J. A.; Trill, J. J.; Kung, H.-F.; Pestka, S.: The
gene for the human immune interferon receptor is located on chromosome
6. Proc. Nat. Acad. Sci. 83: 384-388, 1986.

17. Rettig, W. J.; Grzeschik, K.-H.; Yenamandra, A. K.; Garcia, E.;
Old, L. J.: Definition of selectable cell surface markers for human
chromosomes and chromosome segments in rodent-human hybrids. Somat.
Cell Molec. Genet. 14: 223-231, 1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 01/10/1997
jamie: 1/7/1997
terry: 1/6/1997
warfield: 4/7/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 11/8/1991
carol: 2/19/1991
supermim: 9/28/1990

*RECORD*
*FIELD* NO
107480
*FIELD* TI
*107480 ANUS, IMPERFORATE, WITH HAND, FOOT AND EAR ANOMALIES
TOWNES-BROCKS SYNDROME; TBS;;
DEAFNESS, SENSORINEURAL, WITH IMPERFORATE ANUS AND HYPOPLASTIC THUMBS
REAR SYNDROME, INCLUDED
*FIELD* TX
Townes and Brocks (1972) observed a father and 5 of his 7 children who
had imperforate anus, triphalangeal thumbs, other anomalies of the hands
and feet (fusion of metatarsals, absent bones, supernumerary thumbs),
mild sensorineural deafness, and lop ears. Reid and Turner (1976)
described the same syndrome. Kurnit et al. (1978) described autosomal
dominant inheritance of a syndrome of anal stenosis (or other anal
abnormalities), deformed external ears and perceptive deafness, renal
anomalies (mainly hypoplastic kidney), and radial dysplasia (REAR
syndrome). The features are those of the VATER syndrome (192350),
subsequently expanded into the VACTERL syndrome (acronym for vertebral
anomalies, anal atresia, congenital cardiac disease, tracheoesophageal
fistula, renal anomalies, radial dysplasia, and other limb defects).
Walpole and Hockey (1982) reported cases. Monteiro de Pina-Neto (1984)
reported a case in which congenital heart defect was also present and
proposed that the cases of Silver et al. (1972) were instances of this
syndrome rather than the Holt-Oram syndrome. Aylsworth (1985) observed
the Townes-Brocks syndrome in a mother and 2 children. De Vries-Van der
Weerd et al. (1988) described TBS in a father and son. The son, the
proband, showed the full spectrum of anomalies, including imperforate
anus, prominent perineal raphe, rectoperineal fistula, triphalangeal
thumb, preaxial hexadactyly, syndactyly, clinodactyly, preauricular
protuberances, hypoplastic satyr ears, sensorineural hearing loss, and
urorenal anomalies. In contrast, the father showed only limb anomalies,
sensorineural hearing loss, and renal anomalies. Anorectal
malformations, which are present in most patients with TBS, were absent
in the father. Ferraz et al. (1989) reported a sporadic case. The
patient's 'satyr ear' and CT scans of the deformities in the ossicles of
the ear were pictured. The cardiac lesion was ventricular septal defect.
At birth the girl had been noted to have type I imperforate anus with
rectovaginal fistula, bilateral supernumerary digits on the radial side
of the thumb base, and incomplete soft tissue syndactyly between fingers
2 and 3 on the right. Bilateral symmetrical mixed deafness was
discovered at age 6 years. The maternal grandfather may have been
affected, since he had deafness, polycystic kidneys, and a short
proximal phalanx of the left fifth finger. In a review of the
Townes-Brocks syndrome, O'Callaghan and Young (1990) pointed out that
the patients may have a prominent midline perineal raphe extending from
the site of the anal orifice to the scrotum. They pictured the feet of a
mother and son, both showing hypoplastic third toes overlapped by the
second and fourth toes, as well as a satyr form of lopped ear. Autosomal
dominant inheritance appears to be well established, male-to-male
transmission having been observed by Townes and Brocks (1972), Reid and
Turner (1976), Kurnit et al. (1978) and de Vries-Van der Weerd et al.
(1988). Cameron et al. (1991) suggested that there may be an increase of
mental retardation in persons with TBS. Ishikiriyama et al. (1996) also
saw a boy with both TBS and mental retardation.

Serville et al. (1993) described TBS in an infant with a 2-break
reciprocal translocation between chromosomes 5 and 16. They noted that
Friedman et al. (1987) described father and daughter with this syndrome
associated with a pericentric inversion of chromosome 16 with
breakpoints at p11.2 and q12.1. Since 16p12.1 was the location of 1 of
the breakpoints in the patient reported by Serville et al. (1993), they
suggested that this may be the location of the gene for TBS. Serville et
al. (1993) listed the main features as follows: abnormal placement of
the anus, anal atresia or stenosis; auricular pits, fistulas, or tags;
conductive and sensorineural deafness; dysplastic ears; hypoplastic or
bifid thumbs; deviation of distal phalanges of the thumbs; triphalangeal
thumbs; and cardiac and renal abnormalities. They noted that neither of
the patients reported by Friedman et al. (1987) had thumb anomalies, but
pointed to the fact that clinical variability is known in TBS.

Johnson et al. (1996) described a 3-generation family in which the
grandmother and mother were thought to have Goldenhar syndrome (164210)
but the birth of a grandson with typical features of TBS redirected the
diagnosis to that possibility. The mother was of short stature with
small ears, preauricular and tragal tags on the right and postauricular
tag on the left, facial asymmetry, epibulbar dermoids bilaterally,
micrognathia, and macrostomia with lateral extension more prominent on
the right. The thumbs were triphalangeal with a previously removed,
rudimentary, supernumerary digit that had been attached to the right
thumb. Midline clefting of the uterus was reported. The anus was normal.
The IQ at age 10 was 84; microcephaly was noted at the age of 24 years.

The grandmother in the family reported by Johnson et al. (1996) had
small ears with preauricular tags, epibulbar dermoid on the right, and
micrognathia without facial asymmetry. The thumbs were triphalangeal and
the great toe on the left was bifid representing syndactyly of toes 1
and 2 or absence of 2. Genitourinary abnormalities included
urethrostenosis and septate uterus. The anus showed redundant skin.
Height was 14 cm.

The grandson and propositus reported by Johnson et al. (1996) was born
with an imperforate anus covered by a thin membrane requiring a minor
surgical procedure. The left side of the face was smaller than the
right. The ears were small with overfolding of the helix more prominent
on the right which showed a small preauricular tag. Other findings were
epibulbar dermoid on the left, triphalangeal thumbs with ulnar
deviation.

Newman et al. (1997) reported a case of Townes-Brock syndrome in a male
who presented at the age of 23 years with end-stage renal failure. He
had severe hypertension and bilaterally small kidneys by ultrasound
scan. Surgery had been performed after birth to correct anal stenosis.
At that time the ears were noted to be low set with overfolded helices
and bilateral preauricular tags, bilateral preaxial hexadactyly of the
hands, and syndactyly of the third and fourth toes. Bilateral
sensorineural deafness was noted at 3 years of age.

*FIELD* SA
Hunter and MacMurray (1987); Pinsky  (1977); Reid and Turner (1977);
Townes  (1977)
*FIELD* RF
1. Aylsworth, A. S.: The Townes-Brocks syndrome: a member of the
anus-hand-ear family of syndromes. (Abstract) Am. J. Hum. Genet. 37:
A43, 1985.

2. Cameron, T. H.; Lachiewicz, A. M.; Aylsworth, A. S.: Townes-Brocks
syndrome in two mentally retarded youngsters. Am. J. Med. Genet. 41:
1-4, 1991.

3. de Vries-Van der Weerd, M.-A. C. S.; Willems, P. J.; Mandema, H.
M.; ten Kate, L. P.: A new family with the Townes-Brocks syndrome. Clin.
Genet. 34: 195-200, 1988.

4. Ferraz, F. G.; Nunes, L.; Ferraz, M. E.; Sousa, J. P.; Santos,
M.; Carvalho, C.; Maroteaux, P.: Townes-Brocks syndrome: report of
a case and review of the literature. Ann. Genet. 32: 120-123, 1989.

5. Friedman, P. A.; Rao, K. W.; Aylsworth, A. S.: Six patients with
the Townes-Brocks syndrome including five familial cases and an association
with a pericentric inversion of chromosome 16. (Abstract) Am. J.
Hum. Genet. 41 (suppl.): A60, 1987.

6. Hunter, A. G. W.; MacMurray, B.: Malformations of the VATER association
plus hydrocephalus in a male infant and his maternal uncle. Proc.
Greenwood Genet. Center 6: 146-147, 1987.

7. Ishikiriyama, S.; Kudoh, F.; Shimojo, N.; Iwai, J.; Inoue, T.:
Townes-Brocks syndrome associated with mental retardation. (Letter) Am.
J. Med. Genet. 61: 191-192, 1996.

8. Johnson, J. P.; Poskanzer, L. S.; Sherman, S.: Three-generation
family with resemblance to Townes-Brocks syndrome and Goldenhar/oculoauriculovertebral
spectrum. Am. J. Med. Genet. 61: 134-139, 1996.

9. Kurnit, D. M.; Steele, M. W.; Pinsky, L.; Dibbins, A.: Autosomal
dominant transmission of a syndrome of anal, ear, renal, and radial
congenital malformations. J. Pediat. 93: 270-273, 1978.

10. Monteiro de Pina-Neto, J.: Phenotypic variability in Townes-Brocks
syndrome. Am. J. Med. Genet. 18: 147-152, 1984.

11. Newman, W. G.; Brunet, M. D.; Donnai, D.: Townes-Brocks syndrome
presenting as end stage renal failure. Clin. Dysmorph. 6: 57-60,
1997.

12. O'Callaghan, M.; Young, I. D.: The Townes-Brocks syndrome. J.
Med. Genet. 27: 457-461, 1990.

13. Pinsky, L.: More on anal deformities. (Letter) J. Pediat. 90:
330, 1977.

14. Reid, I. S.; Turner, G.: Familial anal abnormality. J. Pediat. 88:
992-994, 1976.

15. Reid, I. S.; Turner, G.: More on anal deformities. (Letter) J.
Pediat. 90: 331, 1977.

16. Serville, F.; Lacombe, D.; Saura, R.; Billeaud, C.; Sergent, M.
P.: Townes-Brocks syndrome in an infant with translocation t(5;16). Genet.
Counseling 4: 109-112, 1993.

17. Silver, W.; Steier, M.; Schwartz, O.; Zeichner, M. B.: The Holt-Oram
syndrome with previously undescribed associated anomalies. Am. J.
Dis. Child. 124: 911-914, 1972.

18. Townes, P. L.: More on anal deformities. (Letter) J. Pediat. 90:
329-330, 1977.

19. Townes, P. L.; Brocks, E. R.: Hereditary syndrome of imperforate
anus with hand, foot, and ear anomalies. J. Pediat. 81: 321-326,
1972.

20. Walpole, I. R.; Hockey, A.: Syndrome of imperforate anus, abnormalities
of hands and feet, satyr ears, and sensorineural defects. J. Pediat. 100:
250-252, 1982.

*FIELD* CS

Ears:
   Sensorineural hearing loss;
   Auricular pits, fistulas, or tags;
   Lop ears;
   Dysplastic ears;
   Hypoplastic satyr ears

GI:
   Imperforate anus;
   Anal stenosis;
   Prominent perineal raphe;
   Rectovaginal fistula;
   Rectoperineal fistula

Limbs:
   Triphalangeal thumbs;
   Supernumerary thumbs;
   Hypoplastic or bifid thumbs;
   Thumb distal phalanx deviation;
   Radial dysplasia;
   Syndactyly;
   Clinodactyly;
   Fused metatarsals;
   Absent foot bones;
   Hypoplastic third toes overlapped by 2nd and 4th toes

GU:
   Hypoplastic kidney

Cardiac:
   Ventricular septal defect

Radiology:
   Deformed ear ossicles on CT scan

Inheritance:
   Autosomal dominant (?16p12.1)

*FIELD* CN
Victor A. McKusick - updated: 02/06/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/06/1997
terry: 2/3/1997
mark: 2/27/1996
terry: 2/20/1996
mimadm: 3/28/1994
carol: 2/4/1994
carol: 10/15/1993
supermim: 3/16/1992
carol: 2/29/1992
carol: 10/28/1991

*RECORD*
*FIELD* NO
107500
*FIELD* TI
107500 AORTIC ARCH ANOMALY WITH PECULIAR FACIES AND MENTAL RETARDATION
*FIELD* TX
In a mother and 3 of her children, Strong (1968) found right aortic
arch, mental subnormality, and facial peculiarity difficult to describe.
Three of the patients had esophageal indentation demonstrated by barium
swallow, suggesting left ligamentum arteriosum or anomalous left
subclavian artery. Two of the patients had microcephaly. A stillborn
child had anencephaly and another died at 10 months with congenital
heart disease and microcephaly.

*FIELD* RF
1. Strong, W. B.: Familial syndrome of right-sided aortic arch, mental
deficiency, and facial dysmorphism. J. Pediat. 73: 882-888, 1968.

*FIELD* CS

Cardiac:
   Right aortic arch

Neuro:
   Mental retardation

Facies:
   Peculiar facies

Radiology:
   Esophageal indentation on barium swallow

Head:
   Microcephaly

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107550
*FIELD* TI
107550 AORTIC ARCH INTERRUPTION, FACIAL PALSY, AND RETINAL COLOBOMA
*FIELD* TX
Levin et al. (1973) described monozygotic female twins with a syndrome
of hypoplasia or interruption of the transverse aortic arch, facial
weakness involving particularly the depressor anguli oris, and bilateral
retinal coloboma. Marden and Venters (1966) described macular coloboma
and coarctation of the aorta in a single patient who also had the linear
nevus sebaceous syndrome. Whether this is a genuine syndrome and, if so,
whether it is mendelian is not clear.

*FIELD* RF
1. Levin, D. L.; Muster, A. J.; Newfeld, E. A.; Paul, M. H.: Concordant
aortic arch anomalies in monozygotic twins. J. Pediat. 83: 459-461,
1973.

2. Marden, P. M.; Venters, P. M.: A new neurocutaneous syndrome.
Am. J. Dis. Child. 112: 79-81, 1966.

*FIELD* CS

Cardiac:
   Hypoplastic/atretic transverse aortic arch;
   Coarctation of aorta

Neuro:
   Facial weakness, esp. depressor anguli oris

Eyes:
   Bilateral retinal coloboma;
   Macular coloboma

Skin:
   Linear nevus sebaceous syndrome

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107580
*FIELD* TI
*107580 TRANSCRIPTION FACTOR AP-2 ALPHA; TFAP2A
AP2;;
ACTIVATING ENHANCER-BINDING PROTEIN 2 ALPHA;;
AP-2 TRANSCRIPTION FACTOR; AP2TF;;
TFAP2
*FIELD* TX
AP-2 alpha is a 52-kD transcription factor that binds to a consensus
DNA-binding sequence CCCCAGGC in the SV40 and metallothionein (156350)
promoters. By analysis of somatic cell hybrids and in situ hybridization
to chromosomes, Gaynor et al. (1991) mapped the gene encoding AP-2 to
6p24-p22.3. Williamson et al. (1996) identified 2 other members of this
gene family, AP-2-beta (601601) and AP-2-gamma (601602). Using
fluorescence in situ hybridization (FISH), Warren et al. (1996) mapped
the homologous gene, Tcfap2, to mouse chromosome 13A5-B1. Williamson et
al. (1996) obtained human and mouse genomic clones for AP-2-alpha and
used FISH to confirm the location of the gene to human chromosome 6p24
and to mouse 13A5-B1.

Bauer et al. (1994) described the genomic organization of the TFAP2A
gene, including the promoter. The mature AP-2 mRNA is spliced from 7
exons distributed over 18 kb of genomic DNA. They demonstrated that the
promoter of the AP2TF gene is subject to positive autoregulation by its
own gene product. A consensus AP-2 binding site was located at position
-622 with respect to the ATG initiation codon.

Homozygous knockout mice for AP-2-alpha were shown by Zhang et al.
(1996) to have observable neural tube defects at day 9.5 which were
followed by craniofacial and body wall abnormalities later in
embryogenesis. This is consistent with the developmental expression of
AP-2-alpha in tissues of ectodermal origin.

*FIELD* RF
1. Bauer, R.; Imhof, A.; Pscherer, A.; Kopp, H.; Moser, M.; Seegers,
S.; Kerscher, M.; Tainsky, M. A.; Hofstaedter, F.; Buettner, R.:
The genomic structure of the human AP-2 transcription factor. Nucleic
Acids Res. 22: 1413-1420, 1994.

2. Gaynor, R. B.; Muchardt, C.; Xia, Y.; Klisak, I.; Mohandas, T.;
Sparkes, R. S.; Lusis, A. J.: Localization of the gene for the DNA-binding
protein AP-2 to human chromosome 6p22.3-pter. Genomics 10: 1100-1102,
1991.

3. Warren, G.; Gordon, M.; Siracusa, L. D.; Buchberg, A. M.; Williams,
T.: Physical and genetic localization of the gene encoding the AP-2
transcription factor to mouse chromosome 13. Genomics 31: 234-237,
1996.

4. Williamson, J. A.; Bosher, J. M.; Skinner, A.; Sheer, D.; Williams,
T.; Hurst, H. C.: Chromosomal mapping of the human and mouse homologues
of two new members of the AP-2 family of transcription factors. Genomics 35:
262-264, 1996.

5. Zhang, J.; Hagopian-Donaldson, S.; Serbedzija, G.; Elsemore, J.;
Plehn-Dujowich, D.; McMahon, A. P.; Flavell, R. A.; Williams, T.:
Neural tube, skeletal and body wall defects in mice lacking transcription
factor AP-2. Nature 381: 238-241, 1996.

*FIELD* CN
Alan F. Scott - updated: 1/3/1997

*FIELD* CD
Victor A. McKusick: 2/28/1992

*FIELD* ED
jenny: 01/07/1997
mark: 1/3/1997
terry: 1/2/1997
mark: 3/29/1996
mark: 3/18/1996
terry: 3/6/1996
jason: 6/28/1994
supermim: 3/16/1992
carol: 2/28/1992

*RECORD*
*FIELD* NO
107600
*FIELD* TI
*107600 APLASIA CUTIS CONGENITA; ACC
CONGENITAL DEFECT OF SKULL AND SCALP;;
SCALP DEFECT, CONGENITAL
*FIELD* TX
A defect in the scalp and underlying calvaria characterizes this
condition. The skin appears as a thin, transparent membrane through
which the skull may be seen to have a disturbance of development. Only
the skin was involved in the affected persons in 3 generations of the
family reported by Tisserand-Perrier (1953). Parent and child were
affected in at least 3 families and sibs and cousins in others (Hodgman
et al., 1965). Cutlip et al. (1967) reported mother and child. Pap
(1970) described 4 persons in 3 generations. Deeken and Caplan (1970)
described a father and 2 sons, who had 2 reportedly affected collateral
relatives. Their series also contained 2 pairs of affected sibs.
Dubosson and Schneider (1978) stated that although the disorder is
usually inherited as a dominant, some cases, including their own of a
girl with unaffected and probably consanguineous parents, appear to be
recessive (see 207700). Circumscript cutaneous aplasia of the vertex
also occurs in the Johanson-Blizzard syndrome (243800). Anderson et al.
(1979) reported a family with aplasia cutis congenita in 3 and possibly
4 generations, to a total of 7 or 8 affected persons. In 4 of these
there was also unilateral facial palsy and in 6 there was ear
abnormality, usually lop ear. No male-to-male transmission was noted.
(It is not certain that I am justified in including 2 asterisked
entries--this and 168500.) David et al. (1991) reported congenital heart
disease in association with the features of Adams-Oliver syndrome. This
brought to 6 the number of cases of such an association. Ishikiriyama et
al. (1992) added to the description of the association. They suggested
that ventricular septal defect, including tetralogy of Fallot, may be
the predominant type of congenital heart defect in the Adams-Oliver
syndrome. Dunn (1992) pointed out that litigation may be brought against
obstetricians because parents believe their child's scalp was injured
during surgical induction of labor or by a fetal scalp electrode.

Fryns et al. (1992) reported a 6-month-old, developmentally retarded
male with a congenital scalp defect associated with valvular pulmonary
stenosis. They pictured the craniofacial appearance with macrocephaly
and large, high forehead. They pointed to a previous report of the
association by Paltzik and Aiello (1985).

Evers et al. (1995) provided a list of disorders associated with aplasia
cutis congenita, classified according to etiology. They also tabulated
points of particular significance in history taking in examination of
patients with ACC.

*FIELD* SA
Johnsonbaugh et al. (1965); Lynch and Kahn (1970); McMurray et al.
(1977); Rauschkolb and Enriquez (1962); Weippl and Ader (1975)
*FIELD* RF
1. Anderson, C. E.; Hollister, D.; Szalay, G. C.: Autosomal dominantly
inherited cutis aplasia congenita, ear malformations, right-sided
facial paresis, and dermal sinuses. Birth Defects Orig. Art. Ser. XV(5B):
265-270, 1979.

2. Cutlip, B. D., Jr.; Cryan, D. M.; Vineyard, W. R.: Congenital
scalp defects in mother and child. Am. J. Dis. Child. 113: 597-599,
1967.

3. David, A.; Roze, J.-C.; Melon-David, V.: Adams-Oliver syndrome
associated with congenital heart defect: not a coincidence.  (Letter) Am.
J. Med. Genet. 40: 126-127, 1991.

4. Deeken, J. H.; Caplan, R. M.: Aplasia cutis congenita. Arch.
Derm. 102: 386-389, 1970.

5. Dubosson, J.-D.; Schneider, P.: Manifestation familiale d'une
aplasie cutanee circonscrite du vertex (ACCV), associee dans un cas
a une malformation cardiaque. J. Genet. Hum. 26: 351-365, 1978.

6. Dunn, P. M.: Litigation over congenital scalp defects.  (Letter) Lancet 339:
440 only, 1992.

7. Evers, M. E. J. W.; Steijlen, P. M.; Hamel, B. C. J.: Aplasia
cutis congenita and associated disorders: an update. Clin. Genet. 47:
295-301, 1995.

8. Fryns, J. P.; de Cock, P.; van den Berghe, H.: Occipital scalp
defect associated with valvular pulmonary stenosis: a new entity?.
Clin. Genet. 42: 97-99, 1992.

9. Hodgman, J. E.; Mathies, A. W., Jr.; Levan, N. E.: Congenital
scalp defects in twin sisters. Am. J. Dis. Child. 110: 293-295,
1965.

10. Ishikiriyama, S.; Kaou, B.; Udagawa, A.; Niwa, K.: Congenital
heart defect in a Japanese girl with Adams-Oliver syndrome: one of
the most important complications.  (Letter) Am. J. Med. Genet. 43:
900-901, 1992.

11. Johnsonbaugh, R. E.; Light, I. J.; Sutherland, J. M.: Congenital
scalp defects in father and son. Am. J. Dis. Child. 110: 297-298,
1965.

12. Lynch, P. J.; Kahn, E. A.: Congenital defects of the scalp. A
surgical approach to aplasia cutis congenita. J. Neurosurg. 33:
198-202, 1970.

13. McMurray, B. R.; Martin, L. W.; Dignan, P. S. J.; Fogelson, M.
H.: Hereditary aplasia cutis congenita and associated defects: three
instances in one family and a survey of reported cases. Clin. Pediat. 16:
610-614, 1977.

14. Paltzik, R. L.; Aiello, A. M.: Aplasia cutis congenita associated
with valvular heart disease. Cutis 36: 57-58, 1985.

15. Pap, G. S.: Congenital defect of scalp and skull in three generations
of one family: case report. Plast. Reconst. Surg. 46: 194-196,
1970.

16. Rauschkolb, R. R.; Enriquez, S. I.: Aplasia cutis congenita.
Arch. Derm. 86: 54-57, 1962.

17. Tisserand-Perrier, M.: Transmission pendant plusieurs generations
d'une aplasie cutanee circonscrite du vertex. Bull. Soc. Franc.
Derm. Syph. 60: 77-78, 1953.

18. Weippl, G.; Ader, H.: Kongenitaler Skalp-defekt in vier Generationen.
Klin. Paediat. 187: 84-86, 1975.

*FIELD* CS

Skin:
   Congenital scalp defect

Head:
   Skull defect;
   Abnormal calvaria;
   Macrocephaly;
   Large, high forehead

Neuro:
   Unilateral facial palsy;
   Mental retardation

Ears:
   Lop ear

Cardiac:
   Congenital heart defect;
   Ventricular septal defect;
   Tetralogy of Fallot;
   Valvular pulmonary stenosis

Inheritance:
   Autosomal dominant;
   also a recessive form

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 9/18/1995
mimadm: 4/9/1994
carol: 10/1/1992
carol: 9/24/1992
carol: 8/24/1992
carol: 6/24/1992

*RECORD*
*FIELD* NO
107601
*FIELD* TI
107601 APLASIA CUTIS CONGENITA AND COARCTATION OF AORTA; ACCCA
*FIELD* TX
Dallapiccola et al. (1992) observed aplasia cutis congenita and
coarctation of the aorta in mother and son. Both had coarctectomy, at
age 14 years and 5 months, respectively. The aortic valve was bicuspid
in the son.

*FIELD* RF
1. Dallapiccola, B.; Giannotti, A.; Marino, B.; Digilio, C.; Obregon,
G.: Familial aplasia cutis congenita and coarctation of the aorta.
Am. J. Med. Genet. 43: 762-763, 1992.

*FIELD* CS

Skin:
   Congenital scalp defect

Head:
   Skull defect

Cardiac:
   Congenital heart defect;
   Coarctation of the aorta;
   Bicuspid aortic valve

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 7/7/1992

*FIELD* ED
mimadm: 4/9/1994
carol: 7/7/1992

*RECORD*
*FIELD* NO
107640
*FIELD* TI
107640 APNEA, CENTRAL SLEEP
*FIELD* TX
Sequeiros and Martins da Silva (1988) studied a large family with 6
cases of sudden infant death syndrome (SIDS; 272120) and at least 4
cases of infantile sleep apnea ('near-miss SIDS') that occurred in 2
successive generations. They postulated that a structural CNS defect or
a delay in maturation inherited in an autosomal dominant manner
predisposes to SIDS in this family, with peak risk at about age 3
months. Survivors may suffer from recurrent episodes of infantile apnea
or be completely asymptomatic. Somnograms remained abnormal as late as
age 5 years.

*FIELD* RF
1. Sequeiros, J.; Martins da Silva, A.: Autosomal dominant central
sleep apnea: the sudden infant death syndrome (SIDS), infantile sleep
apnea ('near-miss SIDS'), and asymptomatic carriers, in two generations
of a large family.  (Abstract) Am. J. Hum. Genet. 43: A70 only,
1988.

*FIELD* CS

Neuro:
   Infantile sleep apnea

Misc:
   Frequent sudden infant death syndrome

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/20/1988

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/20/1988

*RECORD*
*FIELD* NO
107650
*FIELD* TI
*107650 APNEA, OBSTRUCTIVE SLEEP
SLEEP APNEA/HYPOPNEA SYNDROME; SAHS
*FIELD* TX
Strohl et al. (1978) described 2 males and their father with severe
hypersomnolence and obstructive sleep apnea. A third son, although
asymptomatic, was shown to have upper-airway obstruction during sleep.
Electromyographic recordings of genioglossal muscle activity showed loss
of tonic activity in early stages of sleep when sleep apnea occurred.
(The bilateral genioglossus muscles play a crucial role in the normal
mechanism for maintaining a patent oropharyngeal lumen, especially
during sleep in the supine position, for they are the muscles that force
the tongue forward during inspiration.) The asymptomatic son showed loss
of tonic activity during rapid-eye-movement sleep, the period when
upper-airway obstruction occurred. A fourth son died in his sleep at age
30 years and a daughter of the asymptomatic brother (member of the third
generation) died at age 4 months from presumed sudden-infant-death
syndrome. The tongue may be responsible for airway obstruction in this
seemingly hereditary syndrome. Daytime somnolence was striking in these
persons and narcolepsy (161400) had been diagnosed in some. When the
subjects slept, observers described restless movements, loud snorts and
snoring, and long periods of apnea. Rostand (1978) observed an affected
man with an affected son and brother. Manon-Espaillat et al. (1988)
described a family in which sleep apnea was associated with partial
complex seizures and anosmia and segregated in an autosomal dominant
pattern. Both the proband and his affected father had seizure disorder;
in addition, the proband and his brother were colorblind. The authors
designated this 'familial sleep apnea plus' syndrome.

Douglas et al. (1993) did a prospective study of first-degree relatives
of 20 consecutive nonobese patients with the sleep apnea/hypopnea
syndrome. They concluded that there is an increased frequency of
abnormal breathing during sleep in relatives. Teculescu et al. (1994)
found evidence for a 'familial factor' in habitual snoring.
Guilleminault et al. (1995) conducted a mail survey of first-degree
relatives of 157 subjects with obstructive sleep apnea syndrome and
friends who were approximately the same age who were not relatives of
the index case. A more extensive investigation was performed on
first-degree relatives of the index group living in the San Francisco
Bay area or vicinity. The latter investigation indicated that, when
first first-degree relatives were compared with friends, the complaint
of daytime tiredness, sleepiness, or both with the presence of a high
and narrow (ogival) hard palate sharply differentiated between friends
and relatives. Disproportinate craniofacial anatomy, as indicated by
cephalometric x-ray films, was common in familial groups with OSAS. They
concluded that craniofacial familial features can be a strong indicator
of risk for the development of OSAS.

*FIELD* SA
Bartall et al. (1980); Block et al. (1979); Cozzi  (1979); Elliott
(1978); Guilleminault  (1979); Guilleminault et al. (1976); Redline
et al. (1992); Strohl et al. (1979); Turino and Goldring (1978)
*FIELD* RF
1. Bartall, H. Z.; Tye, K.-H.; Rober, P.; Desser, K. B.; Benchimol,
A.: Atrial flutter associated with obstructive sleep apnea syndrome:
a case report. Arch. Intern. Med. 140: 121-122, 1980.

2. Block, A. J.; Rostand, R. A.; Boysen, P. G.; Wynne, J. W.: Familial
obstructive sleep apnea.  (Letter) New Eng. J. Med. 300: 506 only,
1979.

3. Cozzi, F.: Familial obstructive sleep apnea.  (Letter) New Eng.
J. Med. 300: 507 only, 1979.

4. Douglas, N. J.; Luke, M.; Mathur, R.: Is the sleep apnoea/hypopnoea
syndrome inherited?. Thorax 48: 719-721, 1993.

5. Elliott, J.: Obstructive sleep apnea in Georgia family: is it
hereditary?. J.A.M.A. 240: 2611 only, 1978.

6. Guilleminault, C.: Familial obstructive sleep apnea.  (Letter) New
Eng. J. Med. 300: 506 only, 1979.

7. Guilleminault, C.; Partinen, M.; Hollman, K.; Powell, N.; Stoohs,
R.: Familial aggregates in obstructive sleep apnea syndrome. Chest 107:
1545-1551, 1995.

8. Guilleminault, C.; Tilkian, A.; Dement, W. C.: The sleep apnea
syndromes. Ann. Rev. Med. 27: 465-484, 1976.

9. Manon-Espaillat, R.; Gothe, B.; Adams, N.; Newman, C.; Ruff, R.
: Familial 'sleep apnea plus' syndrome: report of a family. Neurology 38:
190-193, 1988.

10. Redline, S.; Tosteson, T.; Tishler, P. V.; Carskadon, M. A.; Milliman,
R. P.: Studies in the genetics of obstructive sleep apnea: familial
aggregation of symptoms associated with sleep-related breathing disturbances.
Am. Rev. Resp. Dis. 145: 440-444, 1992.

11. Rostand, R. A.: Gainesville, Fla.: Unpublished observations reported
in Medical News. J.A.M.A. 240: 2611 only, 1978.

12. Strohl, K. P.; Saunders, N. A.; Feldman, N. T.; Hallett, M.:
Obstructive sleep apnea in family members. New Eng. J. Med. 299:
969-973, 1978.

13. Strohl, K. P.; Saunders, N. A.; Feldman, N. T.; Hallett, M.:
Familial obstructive sleep apnea.  (Letter) New Eng. J. Med. 300:
507 only, 1979.

14. Teculescu, D. B.; Mauffret-Stephan, E.; Gaultier, C.: Familial
predisposition to snoring.  (Letter) Thorax 49: 95 only, 1994.

15. Turino, G. M.; Goldring, R. M.: Sleeping and breathing.  (Editorial) New
Eng. J. Med. 299: 1009-1011, 1978.

*FIELD* CS

Resp:
   Obstructive sleep apnea;
   Snoring

Misc:
   Hypersomnolence;
   Restless movements during sleep

Neuro:
   Partial complex seizures;
   Anosmia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 9/18/1995
mimadm: 4/13/1994
carol: 3/23/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
107670
*FIELD* TI
*107670 APOLIPOPROTEIN A-II; APOA2
*FIELD* TX
Like apolipoprotein A-I, this is a major apolipoprotein in high density
lipoprotein (HDL). In the mouse, the genes for apoA-I and apoA-II are on
separate chromosomes (Lusis et al., 1983)--mouse chromosomes 9 and 1,
respectively. Thus, in man, apoA-II was presumably not coded by 11q, the
site of the APOA1 gene. Sakaguchi et al. (1984) and Lackner et al.
(1984) isolated the gene for apolipoprotein A-II from a human cDNA
library using synthetic oligonucleotides as probes. A restriction
fragment of 300 bp was isolated from the apoA-II cDNA clone and used as
a probe in filter hybridization assay of DNA from human-mouse somatic
cell hybrids. Restriction digestion was performed with HindIII. They
found that apoA-II segregates with chromosome 1. The gene was
regionalized to 1p21-qter and may reside in a conserved linkage group
with renin and peptidase C. Moore et al. (1984) confirmed the assignment
of the APOA2 locus to chromosome 1. By in situ hybridization,
Middleton-Price et al. (1988) mapped the APOA2 gene to 1q21-q23.
Southern hybridization to the DNA from somatic cell hybrids made from
cells carrying a balanced translocation between X and 1 confirmed the
localization as proximal to 1q23. In the course of creating a physical
map of human 1q21-q23, Oakey et al. (1992) confirmed this assignment.
Using a cDNA probe, Rogne et al. (1989) found tight linkage with Duffy
blood group (110700). No recombination was found in 19 meioses examined,
giving a maximal lod score of 4.2 at theta = 0.0. This information,
combined with other data, made the most likely distance between FY and
APOA2 about 10% recombination, with a combined lod score of 5.6 for both
sexes. Kessling et al. (1988) studied the
high-density-lipoprotein-cholesterol concentrations along with
restriction fragment length polymorphisms in the APOA2 and
APOA1-APOC3-APOA4 gene cluster in 109 men selected from a random sample
of 1,910 men aged 45-59 years. They found no significant difference in
allelic frequencies at either locus between the groups of individuals
with high and low HDL-cholesterol levels. They did find an association
between a PstI RFLP associated with apoA-I and genetic variation
determining the plasma concentration of apoA-I. No significant
association was found between alleles for the apoA-II MspI RFLP and
apoA-II or HDL concentrations.

Although apolipoprotein A-II is the second most abundant protein of high
density lipoprotein particles, its function remains largely unknown.
Warden et al. (1993) showed that in both mice and humans, the APOA2 gene
is linked to a gene that controls plasma levels of apolipoprotein A-II
and that the APOA2 gene or its product influences, by an unknown
mechanism, plasma levels of free fatty acids (FFA).

*FIELD* AV
.0001
APOLIPOPROTEIN A-II DEFICIENCY, FAMILIAL, DUE TO APOA-II (HIROSHIMA)
APOA2, IVS3, G-A, +1
In the first known case of familial apolipoprotein A-II deficiency,
discovered in Hiroshima, Japan, and designated apoA-II(Hiroshima), Deeb
et al. (1990) found that the proband and her sister were homozygous for
a G-to-A transition at position 1 of intron 3 of the APOA2 gene. The
proband had no immunologically detectable apolipoprotein A-II in her
plasma but the deficiency had little influence either on lipid and
lipoprotein profiles or, so it seemed, on the occurrence of coronary
artery disease.

*FIELD* SA
Knott et al. (1984); Knott et al. (1985); Lackner et al. (1985); Scott
et al. (1985); Tsao et al. (1985)
*FIELD* RF
1. Deeb, S. S.; Takata, K.; Peng, R.; Kajiyama, G.; Albers, J. J.
: A splice-junction mutation responsible for familial apolipoprotein
A-II deficiency. Am. J. Hum. Genet. 46: 822-827, 1990.

2. Kessling, A. M.; Rajput-Wiliams, J.; Bainton, D.; Scott, J.; Miller,
N. E.; Baker, I.; Humphries, S. E.: DNA polymorphisms of the apolipoprotein
AII and AI-CIII-AIV genes: a study in men selected for differences
in high-density-lipoprotein cholesterol concentration. Am. J. Hum.
Genet. 42: 458-467, 1988.

3. Knott, T. J.; Eddy, R. L.; Robertson, M. E.; Priestley, L. M.;
Scott, J.; Shows, T. B.: Chromosomal localization of the human apoprotein
CI gene and of a polymorphic apoprotein AII gene. Biochem. Biophys.
Res. Commun. 125: 299-306, 1984.

4. Knott, T. J.; Wallis, S. C.; Robertson, M. E.; Priestley, L. M.;
Urdea, M.; Rall, L. B.; Scott, J.: The human apolipoprotein AII gene:
structural organization and sites of expression. Nucleic Acids Res. 13:
6387-6398, 1985.

5. Lackner, K. J.; Law, S. W.; Brewer, H. B., Jr.: The human apolipoprotein
A-II gene: complete nucleic acid sequence and genomic organization.
Nucleic Acids Res. 13: 4597-4608, 1985.

6. Lackner, K. J.; Law, S. W.; Brewer, H. B., Jr.; Sakaguchi, A. Y.;
Naylor, S. L.: The human apolipoprotein A-II gene is located on chromosome
1. Biochem. Biophys. Res. Commun. 122: 877-883, 1984.

7. Lusis, A. J.; Taylor, B. A.; Wangenstein, R. W.; LeBoeuf, R. C.
: Genetic control of lipid transport in mice. II. Genes controlling
structure of high density lipoproteins. J. Biol. Chem. 258: 5071-5078,
1983.

8. Middleton-Price, H. R.; vandenBerghe, J. A.; Scott, T.; Knott,
T. J.; Malcolm, S.: Regional chromosomal localisation of APOA2 to
1q21-1q23. Hum. Genet. 79: 283-285, 1988.

9. Moore, M. N.; Kao, F.-T.; Tsao, Y.-K.; Chan, L.: Human apolipoprotein
A-II: nucleotide sequence of a cloned cDNA, and localization of its
structural gene on human chromosome 1. Biochem. Biophys. Res. Commun. 123:
1-7, 1984.

10. Oakey, R. J.; Watson, M. L.; Seldin, M. F.: Construction of a
physical map on mouse and human chromosome 1: comparison of 13 Mb
of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620,
1992.

11. Rogne, S.; Myklebost, O.; Hoyheim, B.; Olaisen, B.; Gedde-Dahl,
T., Jr.: The genes for apolipoprotein AII (APOA2) and the Duffy blood
group (FY) are linked on chromosome 1 in man. Genomics 4: 169-173,
1989.

12. Sakaguchi, A. Y.; Naylor, S. L.; Fojo, S.; Lackner, K. J.; Law,
S.; Brewer, H. B., Jr.: Chromosomal array of apolipoprotein genes
in man.  (Abstract) Am. J. Hum. Genet. 36: 207S only, 1984.

13. Scott, J.; Knott, T. J.; Priestley, L. M.; Robertson, M. E.; Mann,
D. V.; Kostner, G.; Miller, G. J.; Miller, N. E.: High-density lipoprotein
composition is altered by a common DNA polymorphism adjacent to apoprotein
AII gene in man. Lancet I: 771-773, 1985.

14. Tsao, Y.-K.; Wei, C.-F.; Robberson, D. L.; Gotto, A. M., Jr.;
Chan, L.: Isolation and characterization of the human apolipoprotein
A-II gene: electron microscopic analysis of RNA:DNA hybrids, nucleotide
sequence, identification of a polymorphic MspI site, and general structural
organization of apolipoprotein genes. J. Biol. Chem. 260: 15222-15231,
1985.

15. Warden, C. H.; Daluiski, A.; Bu, X.; Purcell-Huynh, D. A.; De
Meester, C.; Shieh, B.-H.; Puppione, D. L.; Gray, R. M.; Reaven, G.
M.; Chen, Y.-D. I.; Rotter, J. I.; Lusis, A. J.: Evidence for linkage
of the apolipoprotein A-II locus to plasma apolipoprotein A-II and
free fatty acid levels in mice and humans. Proc. Nat. Acad. Sci. 90:
10886-10890, 1993.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 7/5/1994
carol: 12/9/1993
carol: 2/9/1993
carol: 3/23/1992
supermim: 3/16/1992
carol: 1/29/1992

*RECORD*
*FIELD* NO
107680
*FIELD* TI
*107680 APOLIPOPROTEIN A-I OF HIGH DENSITY LIPOPROTEIN; APOA1
APOA1/APOC3 FUSION GENE
HYPOALPHALIPOPROTEINEMIA, PRIMARY, INCLUDED
*FIELD* TX
Apolipoprotein A-I is the major apoprotein of HDL and is a relatively
abundant plasma protein with a concentration of 1.0-1.5 mg/ml. It is a
single polypeptide chain with 243 amino acid residues of known primary
amino acid sequence (Brewer et al., 1978). ApoA-I is a cofactor for LCAT
(245900), which is responsible for the formation of most cholesteryl
esters in plasma. ApoA-I also promotes efflux of cholesterol from cells.
The liver and small intestine are the sites of synthesis of apoA-I. The
primary translation product of the APOA1 gene contains both a pre and a
pro segment and posttranslational processing of apoA-I may be involved
in the formation of the functional plasma apoA-I isoproteins. Defective
processing may be the underlying problem in Tangier disease, with which
patients have low plasma HDL and apoA-I levels despite normal apoA-I
synthesis. Dayhoff (1976) pointed to sequence homologies of A-I, A-II,
C-I, and C-III.

Yui et al. (1988) found that apoA-I is identical to serum PGI(2)
stabilizing factor (PSF). PGI(2), or prostacyclin, is synthesized by the
vascular endothelium and smooth muscle, and functions as a potent
vasodilator and inhibitor of platelet aggregation. The stabilization of
PGI(2) by HDL and apoA-I may be an important protective action against
the accumulation of platelet thrombi at sites of vascular damage. The
beneficial effects of HDL in the prevention of coronary artery disease
may be partly explained by this effect. A-I(Milano) and A-I(Marburg)
give rise to HDL deficiency. Other HDL deficiency states are Tangier
disease (205400), LCAT deficiency (245900), and 'fish-eye' disease
(136120). Tangier disease may be caused by a defect in posttranslational
conversion, due to deficiency of an unidentified enzyme or to a
structural apoA-I mutation that renders it resistant to
posttranslational modification.

Breslow et al. (1982) isolated and characterized cDNA clones for human
apoA-I. Rees et al. (1983) studied the cloned APOA1 gene and a DNA
polymorphism 3-prime to it. In a healthy control population, the
frequency of heterozygotes was about 5%. Among hypertriglyceridemic
subjects, 34% were heterozygotes and about 6% were homozygotes for the
variant. The primary gene transcript encodes a preproapoA-I containing
24 amino acids on the amino terminus of the mature plasma apoA-I (Law et
al., 1983). Law et al. (1984) assigned the APOA1 gene to 11p11-q13 by
filter hybridization analysis of human-mouse cell hybrid DNAs. The genes
for apoA-I and apoC-III are on chromosome 9 in the mouse. Mouse homologs
of other genes on human 11p (insulin, beta-globin, LDHA, HRAS) are
situated on mouse chromosome 7. Using a cDNA probe to detect apoA-I
structural gene sequences in human-Chinese hamster cell hybrids, Cheung
et al. (1984) assigned the gene to the region 11q13-qter. Since other
information had suggested 11p11-q13 as the location, the SRO becomes
11q13. It is noteworthy that in the mouse and in man, APOA1 and PGBD
(called Ups in the mouse) are syntenic. Both are on chromosome 11 in man
and chromosome 9 in the mouse. Bruns et al. (1984) localized the genes
for apoA-I and apoC-III (previously shown to be in a 3-kb segment of the
genome; Breslow et al., 1982; Shoulders et al., 1983) to chromosome 11
by Southern blot analysis of DNA from human-rodent cell hybrids. Because
in the mouse apoA-I is on chromosome 9 and apoA-II is on chromosome 1
(Lusis et al., 1983), the gene for human apoA-II is probably not on
chromosome 11. Indeed, APOA2 (107670) is on human chromosome 1. Because
the XmnI genotype at the APOA1 locus was heterozygous in a boy with
partial deletion of the long arm of chromosome 11, del(11)(q23.3-qter),
Arinami et al. (1990) localized the gene to 11q23 by excluding the
region 11q24-qter.

Haddad et al. (1986) found that in the rat, as in man, the APOA1, APOC3
and APOA4 genes are closely linked. Indeed, their direction of
transcription, size, relative location and intron-exon organization were
found to be remarkably similar to those of the corresponding human
genes.

There are 8 well-characterized apolipoproteins: apoA-I, apoA-II,
apoA-IV, apoB, apoC-I, apoC-II, apoC-III, and apoE. The APOA1 and APOC3
genes are oriented 'foot-to-foot,' i.e., the 3-prime end of APOA1 is
followed after an interval of about 2.5 kb by the 3-prime end of APOC3
(Karathanasis et al., 1983).

Utermann et al. (1982) described methods for rapid screening and
characterization of variant group A apolipoproteins.

In 4 generations of a Norwegian kindred, Schamaun et al. (1983) found,
by 2-D electrophoresis, a variant of apolipoprotein A-I. Codominant
inheritance was displayed. One homozygote was identified. There was no
obvious cardiovascular disease, even in the homozygote. Karathanasis et
al. (1983) found that a group of severely hypertriglyceridemic patients
with types IV and V hyperlipoproteinemia had an increased frequency of
an RFLP associated with the apoA-I gene. Rees et al. (1985) found a
strong correlation between hypertriglyceridemia and a DNA sequence
polymorphism located in or near the 3-prime noncoding region of APOC3
and revealed by digestion of human DNA with the restriction enzyme Sst-1
and hybridization with an APOA1 cDNA probe. In 74 hypertriglyceridemic
Caucasians, 3 were homozygous and 23 were heterozygous for the
polymorphism, giving a gene frequency of 0.19; none of 52
normotriglyceridemics had the polymorphism, although it was frequent in
Africans, Chinese, Japanese and Asian Indians. No differences in high
density lipoprotein or in apolipoproteins A-I and C-III phenotypes were
found in persons with or without the polymorphism. Ferns et al. (1985)
found an uncommon allelic variant (called S2) of the apoA-I/C-III gene
cluster in 10 of 48 postmyocardial infarction patients (21%). In 47
control subjects it was present in only 2 and in none of those who were
normotriglyceridemic. (The S2 allele, a DNA polymorphism, is
characterized by SstI restriction fragments of 5.7 and 3.2 kb length,
whereas the common S1 allele produces fragments of 5.7 and 4.2 kb
length.) Ferns et al. (1985) found no difference in the distribution of
alleles in the highly polymorphic region of 11p near the insulin gene.
Kessling et al. (1985) failed to find an association between any allele
of several RFLPs studied and hypertriglyceridemia. Buraczynska et al.
(1985) found association between an EcoRI polymorphism of the APOA1 gene
and noninsulin-dependent diabetes mellitus.

Familial hypoalphalipoproteinemia, by far the most common of the forms
of primary depression of HDL-cholesterol, has been thought to be an
autosomal dominant. It is associated with premature coronary artery
disease and stroke (Vergani and Bettale, 1981; Third et al., 1984;
Daniels et al., 1982). Using a PstI polymorphism at the 3-prime end of
the APOA1 gene, Ordovas et al. (1986) found the rarer allele ('3.3-kb
band') in 4.1% of 123 randomly selected control subjects and 3.3% of 30
subjects with no angiographic evidence of coronary artery disease. In
contrast, among 88 patients who had severe coronary artery disease
before age 60, as documented by angiography, the frequency was 32%. It
was also found in 8 of 12 index cases of kindreds with familial
hypoalphalipoproteinemia. Among all patients with coronary artery
disease, 58% had HDL cholesterol levels below the 10th percentile;
however, this frequency increased to 73% when patients with the 3.3-kb
band were considered. Borecki et al. (1986) studied 16 kindreds
ascertained through probands clinically determined to have primary
hypoalphalipoproteinemia characterized by low HDL cholesterol but
otherwise normal blood lipids. They concluded that 'these families
provided clear evidence for a major gene.' Moll et al. (1986) measured
apoA-I levels in families ascertained through cases of hypertension or
early coronary artery disease. They concluded that the findings
supported 'a major effect of a single genetic locus on the quantitative
variation of plasma apoA-I in a sample of pedigrees enriched for
individuals at risk for coronary artery disease.' Using a
radioimmunoassay, Moll et al. (1989) measured plasma apoA-I levels in
1,880 individuals from 283 pedigrees. Complex segregation analysis
suggested heterogeneous etiologies for the individual differences in
adjusted apoA-I levels observed. The authors concluded that
environmental factors and polygenic loci account for 32 and 65%,
respectively, of the adjusted variation in a subset of 126 families. In
the other 157 pedigrees, segregation analysis strongly supported the
presence of a single locus accounting for 27% of the adjusted variation.
In Japanese, Rees et al. (1986) found association of triglyceridemia
with a different haplotype of the A-I/C-III region than that found in
Caucasians.

Ferns et al. (1986) found a common allele of the APOA2 locus which
showed a weak association with hypertriglyceridemia; in contrast, an
uncommon allele of the APOA1-APOC3-APOA4 gene cluster demonstrated a
stronger relationship with hypertriglyceridemia. Ferns et al. (1986)
found higher levels of serum triglycerides with possession of both
disease-related alleles than with either singly. Fager et al. (1981)
found an inverse relationship between serum apoA-II and a risk of
myocardial infarction. Hayden et al. (1987) found an association between
certain RFLPs and familial combined hyperlipidemia (144250). APOA1 is
linked to THY1 (188230) at a distance of about 1 cM (Gatti, 1987); thus,
the more distal location of this apolipoprotein cluster as suggested by
other evidence may be true. In certain patients with premature
atherosclerosis, Karathanasis et al. (1987) demonstrated a DNA inversion
containing portions of the 3-prime ends of the APOA1 and APOC3 genes,
including the DNA region between these genes. The breakpoints of this
DNA inversion were found to be located between the fourth exon of the
APOA1 gene and the first intron of the APOC3 gene; thus, the inversion
results in reciprocal fusion of the 2 gene transcriptional units. The
absence of transcripts with correct mRNA sequences causes deficiency of
both apolipoproteins in the plasma of these patients, leading to
atherosclerosis. Bojanovski et al. (1987) found that both
proapolipoprotein A-I and the mature protein are metabolized abnormally
rapidly in Tangier disease. Thompson et al. (1988) investigated the
seeming paradox that 2 RFLPs at the A-I/C-III cluster were in strong
linkage disequilibrium while a third variant, located between the 2
other markers, appeared to be in linkage equilibrium with these 2
'outside' markers. Thompson et al. (1988) showed that, for the gene
frequencies encountered, very large sample sizes would be required to
demonstrate negative (i.e., repulsion-phase) linkage disequilibrium.
Such numbers are usually difficult to attain in human studies.
Therefore, failure to demonstrate linkage disequilibrium by conventional
methods does not necessarily imply its absence. On the basis of data
provided by Pearson (1987), the APOA1 locus was assigned to 11q23-qter
by HGM9. This would place APOC3 and APOA4 in the same region.

Kessling et al. (1988) studied the high-density-lipoprotein-cholesterol
concentrations along with restriction fragment length polymorphisms in
the APOA2 and APOA1-APOC3-APOA4 gene cluster in 109 men selected from a
random sample of 1,910 men aged 45-59 years. They found no significant
difference in allelic frequencies at either locus between the groups of
individuals with high and low HDL-cholesterol levels. They did find an
association between a PstI RFLP associated with apoA-I and genetic
variation determining the plasma concentration of apoA-I. No significant
association was found between alleles for the apoA-II MspI RFLP and
apoA-II or HDL concentrations. ApoA-I has 243 amino acids of known
sequence. It is secreted into the bloodstream by the liver and intestine
as a protein that is rapidly converted to mature apoA-I. Two major
isoforms of mature, normal A-I, which arise by deamidation, can be
separated in human serum. Antonarakis et al. (1988) studied DNA
polymorphism of a 61-kb segment of 11q that contains the APOA1, APOC3,
and APOA4 genes within a 15-kb stretch. Eleven RFLPs located within the
61-kb segment were used by haplotype analysis. Considerable linkage
disequilibrium was found. Several haplotypes had arisen by recombination
and the rate of recombination within the gene cluster was estimated to
be at least 4 times greater than that expected based on uniform
recombination. Taken individually, the polymorphism information content
(PIC) of each of the 11 polymorphisms ranged from 0.053 to 0.375, while
that of their haplotypes ranged between 0.858 and 0.862. (The PIC value,
which was introduced by Botstein et al. (1980) in their classic paper on
the use of RFLPs as linkage markers, represents the sum of the frequency
of each possible mating multiplied by the probability that an offspring
will be informative.) By genetic linkage analysis using RFLPs in the
APOA1/C3/C4 gene cluster, Kastelein et al. (1990) showed that the
mutation causing familial hypoalphalipoproteinemia (familial HDL
deficiency) in a family of Spanish descent was not located in this
cluster.

Smith et al. (1992) investigated the common G/A polymorphism in the
APOA1 gene promoter at a position 76 bp upstream of the transcriptional
start site (-76). Of 54 subjects whose apoA-I production rates had been
determined by turnover studies, 35 were homozygous for a guanosine at
this locus and 19 were heterozygous for a guanosine and adenosine (G/A).
The apoA-I production rates were significantly lower (by 11%) in the G/A
heterozygotes than in the G homozygotes (P = 0.025). However, no effect
on HDL cholesterol or apoA-I levels were noted. Differential gene
expression of the 2 alleles was tested by linking each of the alleles to
the reporter gene chloramphenicol acetyltransferase and determining
relative promoter efficiencies after transfection into the human HepG2
hepatoma cell line. The A allele, as well as the G allele, expressed
only 68%.

In addition to its ability to remove cholesterol from cells, HDL also
delivers cholesterol to cells through a poorly defined process in which
cholesteryl esters are selectively transferred from HDL particles into
the cell without the uptake and degradation of the lipoprotein particle.
In steroidogenic cells of rodents, the selective uptake pathway accounts
for 90% or more of the cholesterol destined for steroid production or
cholesteryl ester accumulation. To test the importance of the 3 major
HDL proteins in determining cholesteryl ester accumulation in
steroidogenic cells of the adrenal gland, ovary, and testis, Plump et
al. (1996) used mice which had been rendered deficient in apoA-I,
apoA-II, or apoE by gene targeting in embryonic stem cells. ApoE and
apoA-II deficiencies were found to have only modest effects on
cholesteryl ester accumulation. In contrast, apoA-I deficiency caused an
almost complete failure to accumulate cholesteryl ester in steroidogenic
cells. Plump et al. (1996) interpreted these results as indicating that
apoA-I is essential for the selective uptake of HDL-cholesteryl esters.
They stated that the lack of apoA-I has a major impact on adrenal gland
physiology, causing diminished basal corticosteroid production, a
blunted steroidogenic response to stress, and increased expression of
compensatory pathways to provide cholesterol substrate for steroid
production.

*FIELD* AV
.0001
APOLIPOPROTEIN A-I (MILANO)
APOA1, ARG173CYS
Franceschini et al. (1980) found hypertriglyceridemia with marked
decrease of high density lipoprotein (HDL) levels in father, son and
daughter of an Italian family. The affected persons showed no clinical
signs of atherosclerosis and the family had no unusual occurrence of
atherosclerotic disease. Analytical isoelectric focusing of HDL
apoproteins and 2-dimensional immunoelectrophoresis against apoA
antiserum showed quantitative and qualitative changes in apolipoprotein
A-I. In the anomalous protein, Weisgraber et al. (1980) found a cysteine
residue which is not present in the normal apoprotein. The anomalous
protein was designated A-I (Milano) and denoted A-I (cys) by them. This
was the first discovered example of variation in the amino acid sequence
of a plasma lipoprotein. Serum cholesterol was normal. Weisgraber et al.
(1983) showed that cysteine is substituted for arginine at position 173.
This change in the protein probably reflects a change of CGC to TGC,
since this is the only possibility requiring change of a single
nucleotide. Gualandri et al. (1985) traced the origin of the gene for
A-I (Milano) to Limone sul Garda, a small community of about 1,000
persons in Northern Italy. In a study of the entire population, 33
living carriers were found, ranging in age from 2 to 81 years. The
genealogy showed origin of all cases from a single couple living in the
18th century. Despite low HDL-cholesterol levels and increased (though
not significantly so) mean level of triglycerides, no evidence of
increased atherosclerosis was found.

.0002
APOLIPOPROTEIN A-I (MARBURG)
APOA1
Utermann et al. (1982) described a variant apolipoprotein they named
apo-A-I-Marburg. See also apo-A-I-Giessen (107680.0006). Utermann et al.
(1982) found a frequency of about 1 per 750 persons for apoA-I(Marburg)
in West Germany (3 heterozygotes in 2,282 unrelated persons). All 3 had
hypertriglyceridemia and subnormal HDL-cholesterol. Family data from 2
kindreds were consistent with autosomal codominant inheritance.

.0003
APOLIPOPROTEIN A-I
APOA1, GLU198LYS
Strobl et al. (1988) described the third case of mutation of glutamic
acid 198 to lysine and the first instance in which a family study was
performed, with identification of 5 other persons with the variant in
heterozygous form. The mutation appeared to bear no relationship to
premature atherosclerosis. Despite the fact that the mutation occurred
in a part of the molecule thought to be involved in lipid binding, it
bound almost exclusively to HDL as does normal apoA-I.

.0004
APOLIPOPROTEIN A-I
APOA1, GLU136LYS
An apoA-I mutant with electrophoretic mobility similar to that of
glu198-to-lys was found to have a glu136-to-lys substitution (Schamaun
et al., 1983; Rall et al., 1986).

.0005
APOLIPOPROTEIN A-I
APOA1, LYS107DEL
Rall et al. (1984) demonstrated reduced activation of LCAT (245900) but
no reduction in HDL cholesterol or clinical consequences in association
with deletion of lysine-107. The same was found with apoA-I (Giessen)
(107680.0006).

.0006
APOLIPOPROTEIN A-I (GIESSEN)
APOA1, PRO143ARG
Utermann et al. (1982) described the apoA-I variant they designated
apo-A-I-Giessen. See also apo-A-I-Marburg (107680.0002). Utermann et al.
(1984) observed defective activation of LCAT by the Giessen variant of
apoA-I.

.0007
APOLIPOPROTEIN A-I
APOA1, PRO3ARG
Using a simple and rapid method for the structural analysis of mutant
apolipoproteins, von Eckardstein et al. (1989) demonstrated 3 variants
in the mature apolipoprotein A-I polypeptide of 243 amino acids:
pro3-to-arg, pro4-to-arg, and pro165-to-arg. All the variant carriers
were heterozygous for the mutant. In the case of the pro3-to-arg mutant,
the variant proapoA-I was present in increased concentrations as
compared to the normal proapoA-I, suggesting that the
interspecies-conserved proline residue in position 3 of mature apoA-I is
functionally important for the enzymatic conversion of the proprotein to
the mature protein. The pro165-to-arg variant was associated with lower
levels of apoA-I and HDL cholesterol. The variant protein accounted for
only 30% of the total apoA-I in plasma instead of the expected 50%.

.0008
APOLIPOPROTEIN A-I
APOA1, PRO4ARG
See von Eckardstein et al. (1989) in 107680.0007.

.0009
APOLIPOPROTEIN A-I
APOA1, PRO165ARG
See von Eckardstein et al. (1989) in 107680.0007.

.0010
AMYLOIDOSIS, IOWA TYPE
AMYLOIDOSIS, VAN ALLEN TYPE
AMYLOIDOSIS IV, FORMERLY
AMYLOID POLYNEUROPATHY-NEPHROPATHY
APOA1, GLY26ARG
In a family of English-Scottish-Irish extraction, Van Allen et al.
(1968) studied a form of amyloidosis in which neuropathy dominated the
clinical picture early in the course and nephropathy late in the course.
The average age of onset was about 35 years and the average survival
after onset was about 12 years, with death ascribable in most cases to
renal amyloidosis. Severe peptic ulcer disease occurred in some and
hearing loss was frequent. Cataracts were present in several, but
vitreous opacities were not observed. The pedigree was typical of
autosomal dominant inheritance. In the Iowa or Van Allen type of
amyloidosis, Nichols et al. (1987, 1988) found that apolipoprotein A-I
is a major constituent of the amyloid. In this condition, the
apolipoprotein A-I protein was found to contain a substitution of
glycine by arginine at position 26. The mutation of arg for gly26
predicted a guanine-to-cytosine substitution as the nucleotide
corresponding to the first base of codon 26 (GGC-to-CGC) of the APOA1
gene. Using PCR and direct sequencing, Nichols et al. (1989, 1990)
confirmed the prediction on DNA extracted from paraffin-embedded tissues
from 3 members of the kindred who died in the 1960s with amyloid
neuropathy. Since the mutation does not alter the restriction pattern of
the APOA1 gene, they used PCR with an arg26 allele-specific primer for
detection of asymptomatic gene carriers. They demonstrated inheritance
of the APOA1 variant through 3 generations of the Iowa kindred and
confirmed its association with the development of systemic amyloidosis.
Zalin et al. (1991) referred to other families with nonneuropathic
familial amyloidosis characterized by renal and hepatic infiltration and
with the same gly26-to-arg mutation of the APOA1 gene. Furthermore, they
described a family with nephropathic nonneuropathic amyloidosis of the
Ostertag type (105200) in which the amyloid was shown by
immunohistochemistry to be derived from apolipoprotein A-I, but
allele-specific DNA amplification indicated that the arg26 variant was
not present.

.0011
HDL DEFICIENCY, DETROIT TYPE
HIGH DENSITY LIPOPROTEIN DEFICIENCY, DETROIT TYPE
APOLIPOPROTEINS A-I AND C-III, COMBINED DEFICIENCY OF
APOA1/APOC3, INV, EX4/IVS1
Norum et al. (1980, 1982) studied 2 sisters, aged 30 and 25, with very
low HDL and heart failure from coronary artery disease. Both had arcus
cornealis, xanthelasmata and extensive infiltrative xanthoma of the neck
and antecubital fossa, resembling somewhat the changes of pseudoxanthoma
elasticum. The skin histology showed collections of lipid-laden
histiocytes. Plasma cholesterol was 177 and 135 mg/dl; HDL cholesterol
was 4 and 7 mg/dl. Only traces of apoprotein A-I were detected in whole
plasma; in addition, apoprotein C-III was not detectable. The parents
and children of the 2 women had low HDL cholesterol and apoA-I levels
consistent with heterozygosity. Low levels of HDL cholesterol
concentration have been associated with an increased frequency of
coronary artery disease even when HDL is no less than 50% of normal
(Miller and Miller, 1975). Heart failure without myocardial infarction
is unusual in coronary atherosclerosis, especially in young women,
suggesting small vessel disease. Why precocious coronary atherosclerosis
occurs in this condition and is absent or relatively inconspicuous in
Tangier disease (205400) and in A-I Milano is unknown. The patient of
Gustafson et al. (1979), although clinically similar, differed by having
high apoC-III rather than absent apoC-III. Karathanasis et al. (1983)
showed that the probands in the family of Norum et al. (1982) were both
homozygous for a defect in the apoA-I locus, namely, an insertion in an
intron. This was done by use of a cDNA clone. They could identify
heterozygotes unequivocally. The parents had the same gene defect; they
were not known to be related but both had ancestors of Scottish
extraction who lived in the Appalachian mountain region of southeastern
Kentucky. When I saw the 2 sisters in 1983, I was impressed that the
xanthomatosis of the neck and antecubital fossae simulated the changes
of PXE (177850, 264800). The obligatory heterozygotes may be at
increased risk of atherosclerosis. Norum and Alaupovic (1984) pointed
out that although the only lesion demonstrated is the insertion in the
apoA-I gene, the finding of reduced concentrations of both A-I and C-III
in heterozygotes suggests that the apoC-III deficiency in the
homozygotes is not secondary but due either to mutation also in the
apoC-III gene or to an effect of the apoA-I gene on the cis apoC-III
gene. Either hypothesis suggests linkage of the two loci. Norum (1983)
suggested that the gene for apolipoprotein C-II may be in the same
cluster on chromosome 11 because it, like C-III, was severely deficient
in the 2 sisters. Karathanasis et al. (1983) studied the genomic
sequences flanking the APOA1 gene and found that the APOC3 gene (see
107720) lies about 2.6 kb downstream of the 3-prime end of the APOA1
gene. They also showed that the 2 genes are 'convergently transcribed'
and that the polymorphism reported by Rees et al. (1983) to be
associated with hypertriglyceridemia may be due to a single basepair
substitution in the 3-prime-noncoding region of apoC-III mRNA. Forte et
al. (1984) cited evidence that the 6.5-kb insert in the APOA1 gene is
deleted from its normal position in the promoter region for the closely
linked APOC3 gene. Protter et al. (1984) isolated and characterized the
APOC3 gene. The coding sequence was found to be interrupted by 3
introns. The authors compared it with the APOA1 gene and sequenced the
DNA lying between the 2 genes. Karathanasis et al. (1986) studied the
restriction pattern of the APOA4 gene the sisters with combined apoA-I
and apoC-III deficiency. Although apoA-IV had not been demonstrated in
the plasma of these patients, the relatively high levels of plasma LCAT
activity (40% of normal) and the possible involvement of apoA-IV in LCAT
activation suggested that the APOA4 gene of these patients is
functionally normal. Karathanasis et al. (1987) demonstrated that these
patients had a rearrangement in the form of an inversion containing
portions of the 3-prime ends of the APOA1 and APOC3 genes, including the
DNA between these genes. The breakpoints were located within the fourth
exon of the APOA1 gene and the first intron of the APOC3 gene. The
fusion gene was expressed as a fusion mRNA.

.0012
APOLIPOPROTEIN A-I, ABSENCE OF, DUE TO DELETION OF APOA1/APOC3/APOA4
GENE COMPLEX
APOA1, DEFICIENCY
Schaefer et al. (1982) studied the plasma lipids of a middle-aged woman
who died following coronary artery bypass grafting for atherosclerotic
narrowing of multiple arteries. She had markedly reduced high density
lipoprotein, no detectable apolipoprotein A-I, normal A-II, and
moderately reduced apolipoproteins B and C. Both of her children, all 6
of her living sibs, and both parents had reduced apolipoprotein A-I and
HDL levels and normal apolipoprotein A-II. Three of the sibs and their
mother had coronary disease. The proband had corneal clouding due to
diffuse lipid deposits in the epithelial cells; none of the
heterozygotes had this finding. The condition in this family differs
from Tangier disease (205400; analphalipoproteinemia) in the complete
absence of apolipoprotein A-I and normal levels of A-II in the
homozygote. Heterozygotes in this condition have reduced A-I only,
whereas Tangier heterozygotes have reduced A-I and A-II. Consanguinity
in this family, while likely on the basis of geographic isolation, was
not proved. In the family reported by Schaefer et al. (1982), Ordovas et
al. (1989) demonstrated that all of the APOA1/APOC3/APOA4 gene complex
was deleted from a point about 3.1 kb 5-prime to the APOA1 gene to a
point 3-prime to the APOA4 gene.

.0013
APOLIPOPROTEIN A-I (BALTIMORE)
APOA1, ARG10LEU
Ladias et al. (1990) detected this variant in a man with
hypoalphalipoproteinemia who was under study for coronary artery
disease. A G-to-T substitution in codon 34 of the third exon of the
APOA1 gene resulted in an arg-to-leu amino acid substitution at the
tenth residue of mature apoA-I. (ApoA-I is synthesized in the liver and
small intestine as a 267-residue preproapolipoprotein. The presegment,
18 amino acid residues long, is cleaved at the time of translation by a
signal peptidase. The resulting proapoA-I contains a hexapeptide
prosegment covalently linked to the NH(2) terminus of mature apoA-I; it
is secreted into plasma and lymph and undergoes extracellular
posttranslational cleavage to the mature 243-residue apoA-I.) The
mutation changed a CG dinucleotide to CT and therefore was an exception
to the CG-to-TG mutation rule, in which methylation/deamination of the C
in the CpG dinucleotide results in a C-to-T substitution. Ladias et al.
(1990) were unable to demonstrate linkage between apoA-I Baltimore and
hypoalphalipoproteinemia.

.0014
CORNEAL CLOUDING DUE TO APOLIPOPROTEIN A-I DEFICIENCY
APOA1, 1BP DEL, FS229TER
Funke et al. (1991) studied an otherwise healthy 42-year-old man for
massive corneal clouding that resembled that described in patients with
fish-eye disease. There was no history in the patient or in his family
of precocious coronary artery disease and no evidence of inbreeding; the
parents came from different parts of Germany. Funke et al. (1991)
identified a homozygous base deletion in the fourth exon of the APOA1
gene as the basic defect responsible for complete absence of HDL from
the plasma and corneal opacities. Heterozygous carriers of the base
deletion showed approximately half-normal HDL cholesterol
concentrations. A guanine residue from codon 202 was deleted, leading to
frameshift and premature termination at amino acid 229. The proband's
mother and all 3 of his children were heterozygous.

.0015
APOLIPOPROTEIN A-I DEFICIENCY
APOA1, GLN84TER
In a Japanese female patient with deficiency of APOA1 and premature
atherosclerosis, Matsunaga et al. (1991) demonstrated homozygosity for a
nonsense mutation of codon 84 in exon 4: CAG-to-TAG, gln-to-stop. The
patient was also homozygous for another mutation, ala37-to-thr
(GCC-to-ACC) in exon 3; this mutation represented a polymorphism because
it was found in other persons with normal levels of APOA1 and high
density lipoprotein cholesterol. The patient's parents were first
cousins.

.0016
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
APOA1, LEU60ARG
In an English family with autosomal dominant nonneuropathic systemic
amyloidosis, Soutar et al. (1992) identified a CTG (leu)-to-CGG (arg)
transversion at codon 60. The affected individuals were heterozygotes.
The Iowa variant of amyloidosis is another form due to mutation in the
APOA1 gene (107680.0010). They suggested that the systemic
nonneuropathic form is the same as the Iowa form, which in turn is the
same as the Ostertag type. Indeed, the phenotype appears to be different
from that originally described by Van Allen et al. (1968); in the Iowan
family, neuropathy dominated the clinical picture early in the course
and nephropathy late in the course.

.0017
ANALPHALIPOPROTEINEMIA
APOA1, GLN(-2)TER
Ng et al. (1994) discovered a novel mutation causing
analphalipoproteinemia in a Canadian kindred. The 34-year-old Caucasian
proposita, the product of a consanguineous marriage, initially presented
at the age of 30 years because of xanthelasmata. In the same year, the
patient was diagnosed to have bilateral cataracts requiring cataract
extraction in the right eye. She also had bilateral subretinal lipid
deposition with exudative proliferative retinopathy complicated by
bilateral retinal detachments, which were treated surgically. She had a
longstanding history of mild imbalance, i.e., unsteadiness. Examination
showed mildly thickened Achilles tendons and mild midline cerebellar
ataxia. One sister had had a mild myocardial infarction at age 34.
Another sister with angina had cerebellar ataxia. High density
lipoprotein cholesterol was very low and apo-I was undetectable. Genomic
DNA sequencing of the APOA1 gene identified homozygosity for a nonsense
mutation at codon -2, which Ng et al. (1994) designated as Q(-2)X. The
mutation was a C-to-T transition in exon 3, which transformed a codon at
position -2 relative to the first amino acid of circulating mature
apoA-I. The normal sequence at this position encodes glutamine, but the
mutated codon encoded premature termination.

.0018
HYPOALPHALIPOPROTEINEMIA, PRIMARY
APOA1, 1BP INS, C, GLN5PRO, FS, GLU34TER
In a Japanese family with primary hypoalphalipoproteinemia and an
anomalous apolipoprotein A-I, designated APOA1-Tsukuba, Nakata et al.
(1993) found insertion of a single C in the run of 7 cytosines in codons
325 of the mature sequence. This resulted in a frameshift, with change
of codon 5 from gln to pro and the creation of a stop at codon 34. The
proband and her mother and aunt showed low high-density lipoprotein
cholesterol and low apoA-I levels.

.0019
XANTHELASMAS, PERIORBITAL
APOA1, GLN32TER
Romling et al. (1994) found homozygosity for a Q32X mutation in the
APOA1 gene in a 31-year-old woman who presented with no signs of
coronary artery or other atherosclerosis. She came from a large Sicilian
family with no apparent increased prevalence of myocardial infarction.
Among 8 sibs of the proband's heterozygous parents, 7 persons, aged 57
to 73, were alive and had no symptoms of atherosclerotic disease. The
parents were first cousins. During her first pregnancy at age 22, the
homozygous proband developed bilateral periorbital xanthelasmas, which
did not progress after delivery. She had smoked 10 to 12 cigarettes per
day since the age of 18 years. Heterozygotes showed half-normal plasma
concentrations of HDL cholesterol and apoA-I.

.0020
AMYLOIDOSIS HEPATIC AND SYSTEMIC TYPE
APOA1, 12-BP DEL AND 2-BP INS
Booth et al. (1996) described a Spanish family with autosomal dominant
nonneuropathic hereditary amyloidosis with a unique hepatic presentation
and death from liver failure, usually by the 6th decade. The disorder
was caused by a previously unreported deletion/insertion mutation in
exon 4 of the APOA1 gene encoding loss of residues 60-71 of the normal
mature APOA1 and insertion at that position of 2 new residues, Val and
Thr. Affected individuals were heterozygous for the mutation and had
both normal APOA1 and variant molecules bearing 1 extra positive charge,
as predicted from the DNA sequence. The amyloid fibrils were composed
exclusively of N-terminal fragments of the variant, ending mainly at
positions corresponding to residues 83 and 92 in the mature wildtype
sequence. Amyloid fibrils derived from the other 3 known amyloidogenic
APOA1 variants (107680.0010, 107680.0016, and 107680.0021) are composed
of similar N-terminal fragments. All known amyloidogenic APOA1 variants
carry 1 extra positive charge in this region, suggesting that it may be
responsible for their enhanced amyloidogenicity. In addition to causing
a new phenotype, this was the first deletion mutation to be described in
association with hereditary amyloidosis.

.0021
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
APOA1, TRP50ARG
Booth et al. (1996) described a trp50-to-arg variant of APOA1 causing
hereditary amyloidosis.

*FIELD* SA
Breslow et al. (1983); Cohen et al. (1986); Frossard et al. (1986);
Ginsberg et al. (1986); Glueck et al. (1982); Karathanasis et al.
(1983); Karathanasis et al. (1983); Law and Brewer (1984); Law et
al. (1984); Law et al. (1983); O'Donnell and Lusis (1983); Schroeder
and Saunders (1987); Stocks et al. (1987)
*FIELD* RF
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62. Pearson, P. L.: Personal Communication. Leiden, The Netherlands
9/1987.

63. Plump, A. S.; Erickson, S. K.; Weng, W.; Partin, J. S.; Breslow,
J. L.; Williams, D. L.: Apolipoprotein A-I is required for cholesteryl
ester accumulation in steroidogenic cells and for normal adrenal steroid
production. J. Clin. Invest. 97: 2660-2671, 1996.

64. Protter, A. A.; Levy-Wilson, B.; Miller, J.; Bencen, G.; White,
T.; Seilhamer, J. J.: Isolation and sequence analysis of the human
apolipoprotein CIII gene and the intergenic region between the Apo
AI and Apo CIII genes. DNA 3: 449-456, 1984.

65. Rall, S. C.; Weisgraber, K. H.; Mahley, R. W.; Ehnholm, C.; Schamaun,
O.; Olaisen, B.; Blomhoff, J. P.; Teisberg, P.: Identification of
homozygosity for a human apolipoprotein A-I variant. J. Lipid Res. 27:
436-441, 1986.

66. Rall, S. C., Jr.; Weisgraber, K. H.; Mahley, R. W.; Ogawa, Y.;
Fielding, C. J.; Utermann, G.; Haas, J.; Steinmetz, A.; Menzel, H.
J.; Assmann, G.: Abnormal lecithin:cholesterol acyltransferase activation
by a human apolipoprotein A-I variant in which a single lysine residue
is deleted. J. Biol. Chem. 259: 10063-10070, 1984.

67. Rees, A.; Shoulders, C. C.; Stocks, J.; Galton, D. J.; Baralle,
F. E.: DNA polymorphism adjacent to human apoprotein A-1 gene: relation
to hypertriglyceridaemia. Lancet I: 444-446, 1983.

68. Rees, A.; Stocks, J.; Paul, H.; Ohuchi, Y.; Galton, D.: Haplotypes
identified by DNA polymorphisms at the apolipoprotein A-I and C-III
loci and hypertriglyceridaemia: a study in a Japanese population. Hum.
Genet. 72: 168-171, 1986.

69. Rees, A.; Stocks, J.; Sharpe, C. R.; Vella, M. A.; Shoulders,
C. C.; Katz, J.; Jowett, N. I.; Baralle, F. E.; Galton, D. J.: Deoxyribonucleic
acid polymorphism in the apolipoprotein A-I-C-III gene cluster: association
with hypertriglyceridemia. J. Clin. Invest. 76: 1090-1095, 1985.

70. Romling, R.; von Eckardstein, A.; Funke, H.; Motti, C.; Fragiacomo,
G. C.; Noseda, G.; Assmann, G.: A nonsense mutation in the apolipoprotein
A-I gene is associated with high-density lipoprotein deficiency and
periorbital xanthelasmas. Arteriosclerosis Thromb. 14: 1915-1922,
1994.

71. Schaefer, E. J.; Heaton, W. H.; Wetzel, M. G.; Brewer, H. B.,
Jr.: Plasma apolipoprotein A-I, absence associated with a marked
reduction of high density lipoproteins and premature coronary artery
disease. Arteriosclerosis 2: 16-26, 1982.

72. Schamaun, O.; Olaisen, B.; Gedde-Dahl, T., Jr.; Teisberg, P.:
Genetic studies of an apoA-I lipoprotein variant. Hum. Genet. 64:
380-383, 1983.

73. Schroeder, W. T.; Saunders, G. F.: Localization of the human
catalase and apolipoprotein A-I genes to chromosome 11. Cytogenet.
Cell Genet. 44: 231-233, 1987.

74. Shoulders, C. C.; Kornblihtt, A. R.; Munro, B. S.; Baralle, F.
E.: Gene structure of human apolipoprotein A-I. Nucleic Acids Res. 11:
2827-2837, 1983.

75. Smith, J. D.; Brinton, E. A.; Breslow, J. L.: Polymorphism in
the human apolipoprotein A-I gene promoter region: association of
the minor allele with decreased production rate in vivo and promoter
activity in vitro. J. Clin. Invest. 89: 1796-1800, 1992.

76. Soutar, A. K.; Hawkins, P. N.; Vigushin, D. M.; Tennent, G. A.;
Booth, S. E.; Hutton, T.; Nguyen, O.; Totty, N. F.; Feest, T. G.;
Hsuan, J. J.; Pepys, M. B.: Apolipoprotein AI mutation arg-60 causes
autosomal dominant amyloidosis. Proc. Nat. Acad. Sci. 89: 7389-7393,
1992.

77. Stocks, J.; Paul, H.; Galton, D.: Haplotypes identified by DNA
restriction-fragment-length polymorphisms in the A-I C-III A-IV gene
region and hypertriglyceridemia. Am. J. Hum. Genet. 41: 106-118,
1987.

78. Strobl, W.; Jabs, H.-U.; Hayde, M.; Holzinger, T.; Assmann, G.;
Widhalm, K.: Apolipoprotein A-I (glu198-to-lys): a mutant of the
major apolipoprotein of high-density lipoproteins occurring in a family
with dyslipoproteinemia. Pediat. Res. 24: 222-228, 1988.

79. Third, J. L. H. C.; Montag, J.; Flynn, M.; Freidel, J.; Laskarzewski,
P.; Glueck, C. J.: Primary and familial hypoalphalipoproteinemia. Metabolism 33:
136-146, 1984.

80. Thompson, E. A.; Deeb, S.; Walker, D.; Motulsky, A. G.: The detection
of linkage disequilibrium between closely linked markers: RFLPs at
the AI-CIII apolipoprotein genes. Am. J. Hum. Genet. 42: 113-124,
1988.

81. Utermann, G.; Feussner, G.; Franceschini, G.; Haas, J.; Steinmetz,
A.: Genetic variants of group A apolipoproteins: rapid methods for
screening and characterization without ultracentrifugation. J. Biol.
Chem. 257: 501-507, 1982.

82. Utermann, G.; Haas, J.; Steinmetz, A.; Paetzold, R.; Rall, S.
C., Jr.; Weisgraber, K. H.; Mahley, R. W.: Apolipoprotein A-I(Giessen)
(pro143-to-arg): a mutant that is defective in activating lecithin:cholesterol
acyltransferase. Europ. J. Biochem. 144: 325-331, 1984.

83. Utermann, G.; Steinmetz, A.; Paetzold, R.; Wilk, J.; Feussner,
G.; Kaffarnik, H.; Mueller-Eckhardt, C.; Seidel, D.; Vogelberg, K.-H.;
Zimmer, F.: Apolipoprotein AI(Marburg): studies of two kindreds with
a mutant of human apolipoprotein AI. Hum. Genet. 61: 329-337, 1982.

84. Van Allen, M. W.; Frohlich, J. A.; Davis, J. R.: Inherited predisposition
to generalized amyloidosis: clinical and pathological studies of a
family with neuropathy, nephropathy and peptic ulcer. Neurology 19:
10-25, 1968.

85. Vergani, C.; Bettale, G.: Familial hypo-alpha-lipoproteinemia. Clin.
Chim. Acta 114: 45-52, 1981.

86. von Eckardstein, A.; Funke, H.; Henke, A.; Altland, K.; Benninghoven,
A.; Assmann, G.; Welp, S.; Roetrige, A.; Kock, R.: Apolipoprotein
A-I variants: naturally occurring substitutions of proline residues
affect plasma concentration of apolipoprotein A-I. J. Clin. Invest. 84:
1722-1730, 1989.

87. Weisgraber, K. H.; Bersot, T. P.; Mahley, R. W.; Franceschini,
G.; Sirtori, C. R.: A-I (Milano) apoprotein: isolation and characterization
of a cysteine-containing variant of the A-I apoprotein from human
high density lipoproteins. J. Clin. Invest. 66: 901-907, 1980.

88. Weisgraber, K. H.; Rall, S. C., Jr.; Bersot, T. P.; Mahley, R.
W.; Franceschini, G.; Sirtori, C. R.: Apolipoprotein A-I (Milano):
detection of normal A-I in affected subjects and evidence for a cysteine
for arginine substitution in the variant A-I. J. Biol. Chem. 258:
2508-2513, 1983.

89. Yui, Y.; Aoyama, T.; Morishita, H.; Takahashi, M.; Takatsu, Y.;
Kawai, C.: Serum prostacyclin stabilizing factor is identical to
apolipoprotein A-I (Apo A-I): a novel function of Apo A-I. J. Clin.
Invest. 82: 803-807, 1988.

90. Zalin, A. M.; Jones, S.; Fitch, N. J. S.; Ramsden, D. B.: Familial
nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry
and chemistry. Quart. J. Med. 81: 945-956, 1991.

*FIELD* CS

Eye:
   Cataracts but no vitreous opacities (Iowa Type .0010);
   Corneal arcus (Detroit type .0011);
   Corneal clouding (Absent APOA1 .0012, APOA1 .0014)

GI:
   Peptic ulcer (Iowa Type .0010);
   Hepatic amyloid infiltration (Iowa Type .0010)

GU:
   Renal failure (most common cause of death) (Iowa Type .0010)

Neuro:
   Sensorimotor polyneuropathy affecting legs more than arms (Iowa Type
   .0010);
   Autonomic dysfunction early (Iowa Type .0010)

Cardiac:
   Coronary atherosclerosis (Detroit type .0011, Absent APOA1 .0012,
   Baltimore type .0013, APOA1 .0015);
   Congestive heart failure (Detroit type .0011)

Skin:
   Xanthelasmata (Detroit type .0011);
   Xanthoma of neck and antecubital fossa (Detroit type .0011)

Misc:
   Onset third to fourth decade (Iowa Type .0010);
   Fatal after seven to twelve years (Iowa Type .0010)

Lab:
   Generalized amyloid deposition (Iowa Type .0010) Amyloidosis, systemic
   (Nonneuropathic .0016);
   Hypertriglyceridemia with low high density lipoprotein (HDL) but no
   atherosclerosis (APOA1 (MILANO) .0001, APOAI (MARBURG) .0002);
   High density lipoprotein deficiency

Inheritance:
   Autosomal dominant (11q13)

*FIELD* CN
Mark H. Paalman - updated: 10/01/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/01/1996
mark: 9/5/1996
terry: 8/27/1996
marlene: 8/15/1996
terry: 7/16/1996
terry: 7/15/1996
mark: 1/27/1996
terry: 1/19/1996
carol: 2/13/1995
terry: 11/18/1994
jason: 7/5/1994
warfield: 4/7/1994
pfoster: 3/31/1994
mimadm: 2/21/1994

*RECORD*
*FIELD* NO
107690
*FIELD* TI
*107690 APOLIPOPROTEIN A-IV; APOA4
UNIDENTIFIED SERUM PEPTIDE-1; USP1, INCLUDED
*FIELD* TX
Apolipoprotein A-IV is a component of chylomicrons and high-density
lipoproteins. By isoelectric focusing, 2 isoforms, designated A-IV-1 and
A-IV-2, can be identified. Menzel et al. (1982) demonstrated another
variant form. Anderson and Anderson (1977) and Tracy et al. (1982)
described genetic polymorphism of an unidentified serum peptide (USP1)
with a molecular weight of about 45,000. Schamaun et al. (1984)
immunologically identified this serum protein as apoA-IV. Karathanasis
et al. (1986) isolated and characterized the APOA4 gene. In contrast to
APOA1 and APOA3 genes, which contain 3 introns, the APOA4 gene contains
only 2. The similarities suggest, however, that the 3 closely linked
genes were derived from a common evolutionary ancestor, and that during
evolution, the APOA4 gene lost one of its introns. A polymorphic site in
the second intron and a polymorphic site 9 kb 3-prime to the APOA4 gene
were found to be polymorphic in Mediterranean and other European
populations. Elshourbagy et al. (1987) determined the complete
nucleotide sequence of the APOA4 gene and, contrary to the findings
described above, reported that the gene contains 3 exons of 162, 127,
and 1180 nucleotides separated by 2 introns of 357 and 777 nucleotides.
They stated that the human APOA4 gene lacks an intron in the area
encoding the 5-prime untranslated region of its mRNA, which
distinguishes it from all the other human apolipoprotein genes whose
sequences are known. Kamboh and Ferrell (1987) determined the frequency
of polymorphism at the APOA4 locus by a simple and rapid one-dimensional
isoelectric-focusing technique followed by immunoblotting. In an
Icelandic population, Menzel et al. (1990) found a higher frequency of
the APOA4*2 allele (0.117 vs 0.077) than in Tyroleans (Menzel et al.,
1988). In both populations the alleles at the APOA4 locus had
significant effects on plasma high density lipoprotein cholesterol and
triglyceride levels. In the Icelandic population, the average effect of
the APO4*2 allele was to raise cholesterol by 4.9 mg/dl and to lower
triglyceride levels by 19.4 mg/dl. Menzel et al. (1990) estimated that
the genetic variability at the APOA4 locus accounted for 3.1% of the
total variability of HDL cholesterol and for 2.8% of the total
variability of triglycerides in the Icelandic population. Genetically
determined polymorphism of apoA-IV has been reported in dogs, horses,
and baboons, in addition to humans. Data on gene frequencies of allelic
variants were tabulated by Roychoudhury and Nei (1988).

In a Norwegian family with a mutant APOA1 gene and polymorphism of
APOA4, Schamaun et al. (1984) found close linkage of the APOA1 and APOA4
loci; for the sexes combined, the peak lod score was 3.01 at a
recombination fraction of 0.00. Rogne et al. (1986) raised the lod score
to 6.32 by using 2 DNA polymorphisms of an APOA1 probe to study families
informative for apoA-IV protein variants. Karathanasis (1985) showed
that the APOA4 gene is located 12 kb 3-prime to the APOA1 gene.

*FIELD* AV
.0001
APOLIPOPROTEIN A-IV POLYMORPHISM, APOA4*1/APOA4*2
APOA4, GLN360HIS
Lohse et al. (1990) demonstrated that the genetic polymorphism of plasma
apolipoprotein A-IV, detected by isoelectric focusing followed by
immunoblotting, results from a single nucleotide change. Specifically,
the difference between APOA4*1 and APOA4*2 is a G-to-T substitution
leading to a conversion of glutamine-360 to histidine in the mature
protein. The allelic change is predicted to cause the loss of 2
restriction enzyme sites in the formation of a new restriction site for
a third enzyme. In Caucasian populations, the APOA4*1 and APOA4*2
alleles have a frequency of about 0.9 and 0.08, respectively; 3 rare
alleles, APOA4*0, APOA4*3, and APOA4*4, have been described. In a study
of various polymorphisms of APOA4, von Eckardstein et al. (1992) could
not confirm the previously reported association of elevated
HDL-cholesterol concentrations with the 360-his allele and from other
associations concluded that the APOA4 gene locus has an important role
in the metabolism of apolipoprotein B and, to a lesser extent,
apolipoprotein A-I containing lipoproteins.

.0002
APOLIPOPROTEIN A-IV RARE VARIANT, APOA4*0
APOA4, 12BP INS, GLU-GLN-GLN-GLN INS, CODONS 361-362
Lohse et al. (1990) described the molecular basis of the rare variant
APOA4*0: an insertion of 12 nucleotides in the carboxyl-terminal region,
which is highly conserved among human, rat, and mouse A-IV
apolipoproteins. This inframe insertion of 4 amino acids,
glu-gln-gln-gln, between residues 361 and 362 of the mature protein
produces the 1-charge unit, more acidic APOA4*0 isoprotein (pI = 4.92).

.0003
APOLIPOPROTEIN A-IV RARE VARIANT, APOA4*3
APOA4, GLU230LYS
Lohse et al. (1990) identified a single G-to-A substitution that
converted the glutamic acid (GAG) at position 230 of the mature apoA-IV
protein to lysine (AAG). The change added 2 positive charge units to the
apoA-IV-1 isoprotein (pI = 4.97) to give the more basic APOA4*3
isoprotein (pI, 5.08).

.0003
APOLIPOPROTEIN A-IV RARE VARIANT, APOA4*5
APOA4, 12BP INS, GLU-GLN-GLN-GLN INS
Kamboh et al. (1992) described the same inframe insertion of 12
nucleotides (coding for the 4 amino acids glu-gln-gln-gln) near the
carboxyl-terminal region of the mature protein as Lohse et al. (1990)
(see 107690.0002). This study also revealed a polymorphism (G to T,
codon 316, third position) that did not result in an amino acid
substitution. Kamboh et al. (1992) noted that finding the exact position
of the 12 inserted bases was difficult because the sequence of 2 of the
5 repeat units in the APOA4*5 allele are identical. One possible site of
insertion is between codons 357 or 358 and it could also be between
codons 361 and 362. They estimated the frequency of the APOA4*5 allele
in African Americans (N = 308) to be 3.2%.

*FIELD* SA
Elshourbagy et al. (1986); Green et al. (1980); Lohse et al. (1990)
*FIELD* RF
1. Anderson, L.; Anderson, N. G.: High resolution two-dimensional
electrophoresis of human plasma proteins. Proc. Nat. Acad. Sci. 12:
5421-5425, 1977.

2. Elshourbagy, N. A.; Walker, D. W.; Boguski, M. S.; Gordon, J. I.;
Taylor, J. M.: The nucleotide and derived amino acid sequence of
human apolipoprotein A-IV mRNA and the close linkage of its gene to
the genes of apolipoproteins A-I and C-III. J. Biol. Chem. 261:
1998-2002, 1986.

3. Elshourbagy, N. A.; Walker, D. W.; Paik, Y.-K.; Boguski, M. S.;
Freeman, M.; Gordon, J. I.; Taylor, J. M.: Structure and expression
of the human apolipoprotein A-IV gene. J. Biol. Chem. 262: 7973-7981,
1987.

4. Green, P. H. R.; Glickman, R. M.; Riley, J. W.; Quinet, E.: Human
apolipoprotein A-IV: intestinal origin and distribution in plasma.
J. Clin. Invest. 65: 911-919, 1980.

5. Kamboh, M. I.; Ferrell, R. E.: Genetic studies of human apolipoproteins.
I. Polymorphism of apolipoprotein A-IV. Am. J. Hum. Genet. 41:
119-127, 1987.

6. Kamboh, M. I.; Williams, E. R.; Law, J. C.; Aston, C. E.; Bunker,
C. H.; Ferrell. R. E.; Pollitzer, W. S.: Molecular basis of a unique
African variant (A-IV 5) of human apolipoprotein A-IV and its significance
in lipid metabolism. Genet. Epidemiol. 9: 379-388, 1992.

7. Karathanasis, S. K.: Apolipoprotein multigene family: tandem organization
of human apolipoprotein AI, CIII, and AIV genes. Proc. Nat. Acad.
Sci. 82: 6374-6378, 1985.

8. Karathanasis, S. K.; Oettgen, P.; Haddad, I. A.; Antonarakis, S.
E.: Structure, evolution, and polymorphisms of the human apolipoprotein
A4 gene (APOA4). Proc. Nat. Acad. Sci. 83: 8457-8461, 1986.

9. Lohse, P.; Kindt, M. R.; Rader, D. J.; Brewer, H. B., Jr.: Genetic
polymorphism of human plasma apolipoprotein A-IV is due to nucleotide
substitutions in the apolipoprotein A-IV gene. J. Biol. Chem. 265:
10061-10064, 1990.

10. Lohse, P.; Kindt, M. R.; Rader, D. J.; Brewer, H. B., Jr.: Human
plasma apolipoproteins A-IV-0 and A-IV-3: molecular basis for two
rare variants of apolipoprotein A-IV-1. J. Biol. Chem. 265: 12734-12739,
1990.

11. Menzel, H.-J.; Boerwinkel, E.; Schrangl-Will, S.; Utermann, G.
: Human apolipoprotein A-IV polymorphism: frequency and effect on
lipid and lipoprotein levels. Hum. Genet. 79: 368-372, 1988.

12. Menzel, H.-J.; Kovary, P. M.; Assmann, G.: Apolipoprotein A-IV
polymorphism in man. Hum. Genet. 62: 349-352, 1982.

13. Menzel, H.-J.; Sigurdsson, G.; Boerwinkle, E.; Schrangl-Will,
S.; Dieplinger, H.; Utermann, G.: Frequency and effect of human apolipoprotein
A-IV polymorphism on lipid and lipoprotein levels in an Icelandic
population. Hum. Genet. 84: 344-346, 1990.

14. Rogne, S.; Myklebost, O.; Olaisen, B.; Gedde-Dahl, T., Jr.; Prydz,
H.: Confirmation of the close linkage between the loci for human
apolipoproteins AI and AIV by the use of a cloned cDNA probe and two
restriction site polymorphisms. Hum. Genet. 72: 68-71, 1986.

15. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

16. Schamaun, O.; Olaisen, B.; Mevag, B.; Gedde-Dahl, T., Jr.; Ehnholm,
C.; Teisberg, P.: The two apolipoprotein loci apoA-I and apoA-IV
are closely linked in man. Hum. Genet. 68: 181-184, 1984.

17. Tracy, R. P.; Currie, R. M.; Young, D. S.: Two-dimensional gel
electrophoresis of serum specimens from a normal population. Clin.
Chem. 28: 890-899, 1982.

18. von Eckardstein, A.; Funke, H.; Schulte, M.; Erren, M.; Schulte,
H.; Assmann, G.: Nonsynonymous polymorphic sites in the apolipoprotein
(apo) A-IV gene are associated with changes in the concentration of
apo B- and apo A-I-containing lipoproteins in a normal population.
Am. J. Hum. Genet. 50: 1115-1128, 1992.

*FIELD* CS

Misc:
   Influences apolipoprotein B metablism and apolipoprotein A-I containing
   lipoproteins;
   Affects plasma high density lipoprotein cholesterol and triglyceride
   levels

Inheritance:
   Autosomal dominant

*FIELD* CN
Stylianos E. Antonarakis - updated: 07/08/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 07/08/1996
mimadm: 4/9/1994
carol: 7/6/1992
supermim: 3/19/1992
supermim: 3/16/1992
carol: 1/27/1992
carol: 2/8/1991

*RECORD*
*FIELD* NO
107700
*FIELD* TI
107700 APPENDICITIS, PRONENESS TO
*FIELD* TX
Baker (1937) and others have reported families with numerous persons
with appendicitis in a pattern consistent with dominant inheritance with
irregular penetrance. Barker and Morris (1988) and Barker et al. (1988)
reported results of epidemiologic studies in the U.K. demonstrating a
relationship between housing conditions and the consumption of green
vegetables in the frequency of acute appendicitis. These results remind
us that familial aggregation may have a nongenetic basis. Basta et al.
(1990) found that a positive family history for appendectomy was
significantly more frequent in families of 80 consecutive patients with
histopathologically proven acute appendicitis than in families of
surgical controls matched for sex, age, and number of sibs. The relative
risk was 10.0. Analysis of a collection of pedigrees supported a
polygenic or multifactorial model with a total heritability of 56%.
There is no evidence to support a major gene, although a rare gene could
not be ruled out as the cause of a small proportion of cases.

Shamis et al. (1994) studied 2-generation families containing a total of
2,331 persons. Aggregation of acute appendicitis in 782 families
indicated a familial factor in predisposition.

*FIELD* RF
1. Baker, E. G. S.: A family pedigree for appendicitis. J. Hered. 28:
187-191, 1937.

2. Barker, D. J. P.; Morris, J.: Acute appendicitis, bathrooms, and
diet in Britain and Ireland. Brit. Med. J. 296: 953-955, 1988.

3. Barker, D. J. P.; Osmond, C.; Golding, J.; Wadsworth, M. E. J.
: Acute appendicitis and bathrooms in three samples of British children.
Brit. Med. J. 296: 956-958, 1988.

4. Basta, M.; Morton, N. E.; Mulvihill, J. J.; Radovanovic, Z.; Radojicic,
C.; Marinkovic, D.: Inheritance of acute appendicitis: familial aggregation
and evidence of polygenic transmission. Am. J. Hum. Genet. 46:
377-382, 1990.

5. Shamis, I.; Livshits, G.; Feldman, U.: Ethnicity and familial
factors in the etiology of acute appendicitis. Am. J. Hum. Biol. 6:
351-358, 1994.

*FIELD* CS

GI:
   Appendicitis proneness

Inheritance:
   Polygenic or multifactorial with heritability of 56%

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 11/18/1994
terry: 8/26/1994
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/27/1990

*RECORD*
*FIELD* NO
107710
*FIELD* TI
*107710 APOLIPOPROTEIN C-I; APOC1
*FIELD* TX
Tata et al. (1985) synthesized a mixed oligonucleotide 17 bases long and
used it to isolate cDNA clones for apoC-I from an adult liver cDNA
library. They then used the probe and Southern blot techniques to
identify the human APOC1 gene in the DNA of various human-rodent cell
hybrids. Their results assigned the gene to chromosome 19. By the study
of somatic cell hybrids containing rearranged chromosome 19, Scott et
al. (1985) concluded that the chromosome 19 cluster of apolipoprotein
genes probably lies in the 19p13-19cen region. (HGM8 placed the cluster
in the 19cen-19q13 region.) Davison et al. (1986) showed that there are
two APOC1 sequences on chromosome 19 and that one of them is 4 kb
3-prime to APOE and oriented in the same way as APOE. One APOC1 gene may
be a pseudogene (Lauer et al., 1987). There are two APOC1 mRNA
transcripts, but these may be the consequence of differential processing
of a single primary transcript. Lusis et al. (1986) used a reciprocal
whole arm translocation between the long arm of chromosome 19 and the
short arm of chromosome 1 to determine that the APOC1, APOC2, APOE and
GPI loci are on the long arm and the LDLR, C3 and PEPD loci on the short
arm. They isolated a single lambda phage carrying APOC1 and part of
APOE. These genes are 6 kb apart and arranged tandemly. APOC2 and APOE
were previously shown to be tightly linked. Studying a cDNA APOC1 clone
and a genomic APOE clone, Myklebost and Rogne (1986) concluded that the
loci are 4.3 kb apart. By comparison, on chromosome 11, APOA1 (107680)
is 2.6 kb from APOC3 (107720). Using separate probes for each locus,
Bailey and Miller (1987) mapped APOC2 and APOE to 19q13.1 at the border
of q12 by in situ hybridization. Smit et al. (1988) presented a map of
the apolipoprotein E-C1-C2 gene cluster on chromosome 19:
5-prime--APOE--4.3 kb--APOC1--6 kb--APOC1 pseudogene--about 22
kb--APOC2--3-prime. Thus, the cluster spans approximately 48 kb. This
gene order and the size of the cluster were confirmed by Myklebost and
Rogne (1988) by pulsed-field gel electrophoresis mapping methods. A HpaI
RFLP in the APOE-C1-C2 gene cluster on chromosome 19 is strongly
associated with familial dysbetalipoproteinemia. Smit et al. (1988)
showed that this RFLP site is between APOE and APOC1 and specifically
that it is located 317 bp upstream of the transcription initiation site
of the APOC1 gene. They constructed a detailed restriction map of the
gene cluster, showing that the APOC2 gene is located 15 kb downstream of
the APOC1 pseudogene. Two copies of the APOC1 gene were identified by
molecular genetic studies, but one appeared to be a pseudogene because
no mRNA product could be detected in any tissue (Lauer et al., 1988).
Although Trask et al. (1993) did not map the APOC1 gene directly, the
mapping of the APOE and APOC2 genes to 19q13.2 by fluorescence in situ
hybridization established that the APOC1 gene is also in this band.

*FIELD* SA
Smit et al. (1988)
*FIELD* RF
1. Bailey, R.; Miller, D. A.: Mapping the human apolipoprotein genes
CII and E to band 19q13.1 by in situ hybridization.  (Abstract) Am.
J. Hum. Genet. 41: A156 only, 1987.

2. Davison, P. J.; Norton, P.; Wallis, S. C.; Gill, L.; Cook, M.;
Williamson, R.; Humphries, S. E.: There are two gene sequences for
human apolipoprotein CI (APO CI) on chromosome 19, one of which is
4 kb from the gene for APO E. Biochem. Biophys. Res. Commun. 136:
876-884, 1986.

3. Lauer, S.; Walker, D.; Levy-Wilson, B.; Taylor, J. M.: There are
two copies of the human apolipoprotein C-I gene linked closely downstream
from the apolipoprotein E gene.  (Abstract) Fed. Proc. 46: 1948
only, 1987.

4. Lauer, S. J.; Walker, D.; Elshourbagy, N. A.; Reardon, C. A.; Levy-Wilson,
B.; Taylor, J. M.: Two copies of the human apolipoprotein C-I gene
are linked closely to the apolipoprotein E gene. J. Biol. Chem. 263:
7277-7286, 1988.

5. Lusis, A. J.; Heinzmann, C.; Sparkes, R. S.; Scott, J.; Knott,
T. J.; Geller, R.; Sparkes, M. C.; Mohandas, T.: Regional mapping
of human chromosome 19: organization of genes for plasma lipid transport
(APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI. Proc.
Nat. Acad. Sci. 83: 3929-3933, 1986.

6. Myklebost, O.; Rogne, S.: The gene for human apolipoprotein CI
is located 4.3 kilobases away from the apolipoprotein E gene on chromosome
19. Hum. Genet. 73: 286-289, 1986.

7. Myklebost, O.; Rogne, S.: A physical map of the apolipoprotein
gene cluster on human chromosome 19. Hum. Genet. 78: 244-247, 1988.

8. Scott, J.; Knott, T. J.; Shaw, D. J.; Brook, J. D.: Localization
of genes encoding apolipoproteins CI, CII, and E to the p13-cen region
of human chromosome 19. Hum. Genet. 71: 144-146, 1985.

9. Smit, M.; van der Kooij-Meijs, E.; Frants, R. R.; Havekes, L.;
Klasen, E. C.: Apolipoprotein gene cluster on chromosome 19: definite
localization of the APOC2 gene and the polymorphic HpaI site associated
with type III hyperlipoproteinemia. Hum. Genet. 78: 90-93, 1988.

10. Smit, M.; van der Kooij-Meijs, E.; Woudt, L. P.; Havekes, L. M.;
Frants, R. R.: Exact localization of the familial dysbetalipoproteinemia
associated HpaI restriction site in the promoter region of the APOC1
gene. Biochem. Biophys. Res. Commun. 152: 1282-1288, 1988.

11. Tata, F.; Henry, I.; Markham, A. F.; Wallis, S. C.; Weil, D.;
Grzeschik, K. H.; Junien, C.; Williamson, R.; Humphries, S. E.: Isolation
and characterisation of a cDNA clone for human apolipoprotein CI and
assignment of the gene to chromosome 19. Hum. Genet. 69: 345-349,
1985.

12. Trask, B.; Fertitta, A.; Christensen, M.; Youngblom, J.; Bergmann,
A.; Copeland, A.; de Jong, P.; Mohrenweiser, H.; Olsen, A.; Carrano,
A.; Tynan, K.: Fluorescence in situ hybridization mapping of human
chromosome 19: cytogenetic band location of 540 cosmids and 70 genes
or DNA markers. Genomics 15: 133-145, 1993.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/11/1993
supermim: 3/16/1992
carol: 8/23/1990
supermim: 4/28/1990
supermim: 3/20/1990
supermim: 3/9/1990

*RECORD*
*FIELD* NO
107720
*FIELD* TI
*107720 APOLIPOPROTEIN C-III; APOC3
*FIELD* TX
See 107680. Ferns et al. (1985) found an uncommon allelic variant
(called S2) of the apoA-I/C-III gene cluster in 10 of 48 postmyocardial
infarction patients (21%). In 47 control subjects it was present in only
2 and in none of those who were normotriglyceridemic. (The S2 allele, a
DNA polymorphism, is characterized by SstI restriction fragments of 5.7
and 3.2 kb length, whereas the common S1 allele produces fragments of
5.7 and 4.2 kb length.) In the same group of patients, Ferns et al.
(1985) found no difference in the distribution of alleles in the highly
polymorphic region of 11p near the insulin gene. Henderson et al. (1987)
found an increased prevalence of an SstI RFLP, localized to the
apolipoprotein C-III gene, in lipid clinic patients with a variety of
hyperlipidemic phenotypes. Dammerman et al. (1993) detected 5 DNA
polymorphisms in the promoter of the APOC3 gene in a subject with type
III hyperlipidemia and severe hypertriglyceridemia. The sites were in
strong linkage disequilibrium with each other and with the polymorphic
SstI site in the APOC3 3-prime untranslated region whose presence (S2
allele) had been shown to be associated with hypertriglyceridemia.
Carriers of the haplotype designated 211 were at decreased risk and
carriers of the so-called 222 haplotype were at increased risk for
hypertriglyceridemia.

The promoter of the APOC3 gene contains 5 sites of single BP sequence
variation between -641 and -455. Li et al. (1995) stated that one
possible explanation for the association of the variant promoter with
elevated triglycerides is that one or more these changes increases the
transcriptional activity of the APOC3 gene, thereby causing an increase
in apoCIII levels and inducing the development of hypertriglyceridemia.
Overexpression of plasma apolipoprotein CIII causes hypertriglyceridemia
in transgenic mice. In animals and in cultured cells, the APOC3 gene is
transcriptionally downregulated by insulin. Li et al. (1995) found that,
unlike the wildtype promoter, the variant promoter is defective in its
response to insulin treatment, remaining constitutively active in all
concentrations of insulin. The loss of insulin regulation was mapped to
polymorphic sites at -482 and -455, which fall within a previously
identified insulin response element. The authors stated that loss of
insulin regulation could result in overexpression of the APOC3 gene and
contribute to the development of hypertriglyceridemia. The variant
promoter is common in the general population and may represent a major
contributing factor to the development of hypertriglyceridemia.

*FIELD* AV
.0001
APOLIPOPROTEIN C-III, NONGLYCOSYLATED
APOC3, THR74ALA
In a subject whose serum contained unusually high amounts of apoC-III
lacking the carbohydrate moiety, Maeda et al. (1987) found that the
cloned APOC3 gene contained a single nucleotide substitution (A-to-G)
that encodes an alanine at position 74 instead of the normal threonine.
As a result of this amino acid replacement, the mutant apoC-III
polypeptide was not glycosylated. The mutation also created a novel AluI
site which permitted diagnosis of the change by Southern blotting of
genomic DNA. The family, first described by Maeda et al. (1981), showed
the unusual apolipoprotein (called apolipoprotein C-III-0) in an
autosomal dominant pedigree pattern. Three polymorphic forms of
apo-C-III, designated apolipoprotein C-III-0, apolipoprotein C-III-1,
and apolipoprotein C-III-2, depend on sialic acid content. The proband
of Maeda et al. (1981) was a mildly hypertensive 63-year-old woman whose
very low density lipoprotein and high density lipoprotein contained
unusually high amounts of apolipoprotein C-III-0. This lipoprotein was
inherited by 2 of her 4 children without clinical symptoms. Blood lipid
levels were normal.

.0002
HYPERALPHALIPOPROTEINEMIA
APOC3, LYS58GLU
In a family with hyperalphalipoproteinemia, von Eckardstein et al.
(1991) identified a heterozygous carrier of an apolipoprotein C-III
variant by the presence of additional bands after isoelectric focusing
(IEF) of very low density lipoprotein (VLDL). Structural analysis of the
variant protein revealed a lysine-to-glutamic acid change in position
58. The underlying A-to-G exchange was verified by direct sequencing
subsequent to amplification by polymerase chain reaction (PCR) of exon 4
of the APOC3 gene. Two variant carriers exhibited plasma concentrations
of HDL cholesterol and APOA1 above the 95th percentile for sex-matched
controls. A causal relationship between the APOC3 variant and
hyperalphalipoproteinemia is not certain.

*FIELD* SA
Karathanasis et al. (1984); Oettgen et al. (1986)
*FIELD* RF
1. Dammerman, M.; Sandkuijl, L. A.; Halaas, J. L.; Chung, W.; Breslow,
J. L.: An apolipoprotein CIII haplotype protective against hypertriglyceridemia
is specified by promoter and 3-prime untranslated region polymorphisms.
Proc. Nat. Acad. Sci. 90: 4562-4566, 1993.

2. Ferns, G. A. A.; Stocks, J.; Ritchie, C.; Galton, D. J.: Genetic
polymorphisms of apolipoprotein C-III and insulin in survivors of
myocardial infarction. Lancet II: 300-303, 1985.

3. Henderson, H. E.; Landon, S. V.; Michie, J.; Berger, G. M. B.:
Association of a DNA polymorphism in the apolipoprotein C-III gene
with diverse hyperlipidaemic phenotypes. Hum. Genet. 75: 62-65,
1987.

4. Karathanasis, S. K.; McPherson, J.; Zannis, V. I.; Breslow, J.
L.: Linkage of human apolipoproteins A-I and C-III genes. Nature 304:
371-373, 1984.

5. Li, W. W.; Dammerman, M. M.; Smith, J. D.; Metzger, S.; Breslow,
J. L.; Leff, T.: Common genetic variation in the promoter of the
human apo CIII gene abolishes regulation by insulin and may contribute
to hypertriglyceridemia. J. Clin. Invest. 96: 2601-2605, 1995.

6. Maeda, H.; Hashimoto, R. K.; Oguro, T.; Hiraga, S.; Uzawa, H.:
Molecular cloning of a human apoC-III variant: thr 74-to-ala 74 mutation
prevents O-glycosylation. J. Lipid Res. 28: 1405-1409, 1987.

7. Maeda, H.; Uzawa, H.; Kamei, R.: Unusual familial lipoprotein
C-III associated with apolipoprotein C-III-0 preponderance. Biochim.
Biophys. Acta 665: 578-585, 1981.

8. Oettgen, P.; Antonarakis, S. E.; Karathanasis, S. K.: PvuII polymorphic
site upstream to the human apoCIII gene. Nucleic Acids Res. 14:
5571, 1986.

9. von Eckardstein, A.; Holz, H.; Sandkamp, M.; Weng, W.; Funke, H.;
Assmann, G.: Apolipoprotein C-III(lys58-to-glu): identification of
an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia.
J. Clin. Invest. 87: 1724-1731, 1991.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 01/27/1996
carol: 6/17/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/27/1992
carol: 5/21/1991
carol: 12/6/1990

*RECORD*
*FIELD* NO
107730
*FIELD* TI
*107730 APOLIPOPROTEIN B; APOB
APOB-100, INCLUDED;;
APOB-48, INCLUDED;;
ABETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC, STEINBERG TYPE, INCLUDED;;
APOLIPOPROTEIN B ALLOTYPES, INCLUDED;;
Ag LIPOPROTEIN TYPES, INCLUDED;;
HYPOBETALIPOPROTEINEMIA, FAMILIAL, INCLUDED;;
ACANTHOCYTOSIS WITH HYPOBETALIPOPROTEINEMIA, INCLUDED;;
DEFECTIVE APOLIPOPROTEIN B-100, INCLUDED
*FIELD* TX
Apolipoprotein B is the main apolipoprotein of chylomicrons and low
density lipoproteins (LDL). It occurs in the plasma in 2 main forms,
apoB-48 and apoB-100. The first is synthesized exclusively by the gut,
the second by the liver. Lusis et al. (1985) identified cDNA clones for
human apoB; examination of a somatic cell panel indicated that the APOB
gene resides on chromosome 2, unlinked to the 3 other apolipoprotein
clusters. Law et al. (1985) cloned the gene and assigned it to
chromosome 2 by filter hybridization with DNA from human/mouse somatic
cell hybrids. By somatic cell hybrid studies and by in situ
hybridization, Knott et al. (1985) assigned the gene to the tip of 2p in
band p24. Deeb et al. (1986) used a hybridization probe to detect
homologous sequences in both flow-sorted and in situ metaphase
chromosomes. The gene was assigned to 2p24-p23. They found, furthermore,
that RNA isolated from monkey small intestine contained sequences
homologous to the cDNA of apolipoprotein B-100. These results were
interpreted as indicating that intestinal (B-48) and hepatic (B-100)
forms of apoB are coded by a single gene. Glickman et al. (1986) found a
single mRNA transcript for apoB regardless of the form of apoB (apoB-100
or apoB-48) synthesized in the liver or intestine. From study of
chromosomal aberrations in somatic cell hybrids, Huang et al. (1986)
concluded that the APOB locus is located in either the 2p21-p23 or the
2p24-pter segment. Mehrabian et al. (1986) localized APOB to 2p24-p23 by
somatic cell hybridization and in situ hybridization. Filter
hybridization studies with genomic DNA and with hepatic and intestinal
mRNA suggested that hepatic and intestinal apoB are derived from the
same gene. Hospattankar et al. (1986) presented some immunologic data
suggesting that the 2 proteins share a common carboxyl region sequence.
Chen et al. (1986) determined the complete cDNA and amino acid sequence
of apoB-100. Knott et al. (1986) reported the primary structure of
apolipoprotein B. The precursor has 4,563 amino acids; the mature
apoB-100 has 4,536 amino acid residues. This represents a very large
mRNA of more than 16 kb. Law et al. (1986) also provided the complete
nucleotide acid and derived amino acid sequence of apoB-100 from a study
of cDNA. Strong evidence that apoB-100 and apoB-48 are products of the
same gene was provided by Young et al. (1986). They used a specific
mouse monoclonal antibody, MB19, to characterize a common form of
genetic polymorphism of APOB. They found that the polymorphism was
expressed in a parallel manner in apoB-100 and apoB-48.

Cladaras et al. (1986) concluded from the sequence of apolipoprotein
B-100 that apoB-48 may result from differential splicing of the same
primary apoB mRNA transcript. Hardman et al. (1987) found that mature,
circulating B-48 is homologous over its entire length (estimated to be
between 2,130 and 2,144 amino acid residues) with the amino-terminal
portion of B-100 and contains no sequence from the carboxyl end of
B-100. From structural studies, Innerarity et al. (1987) concluded that
apoB-48 represents the amino-terminal 47% of apoB-100 and that the
carboxyl terminus of apoB-48 is in the vicinity of residue 2151 of
apoB-100. Chen et al. (1987) deduced that human apolipoprotein B-48 is
the product of an intestinal mRNA with an inframe UAA stop codon
resulting from a C-to-U change in the codon CAA encoding Gln(2153) in
apoB-100 mRNA. The carboxyl-terminal ile-2152 of apoB-48 purified from
chylous ascites fluid has apparently been cleaved from the initial
translation product, leaving met-2151 as the new carboxyl-terminus. The
organ-specific introduction of a stop codon to an mRNA is an
unprecedented finding. Only the sequence that codes B-100 is present in
genomic DNA. The change from CAA to UAA as codon 2153 of the message is
a unique RNA editing process. Higuchi et al. (1988) reported similar
findings. ApoB-48 contains 2,152 residues compared to 4,535 residues in
apoB-100. Using a cloned rat cDNA as a probe, Lau et al. (1994) cloned
cDNA and genomic sequences of the gene for the human APOB mRNA editing
protein (BEDP; 600130). Expression of the cDNA in HepG2 cells resulted
in editing of the intracellular apoB mRNA. By fluorescence in situ
hybridization, they localized the BEDP gene to 12p13.2-p13.1. By
Northern blot analysis, they showed that the human BEDP mRNA is
expressed exclusively in the small intestine. The cDNA sequence
predicted a translation product of 236-amino acid residues. They found
that the editing protein undergoes spontaneous polymerization and exists
as a dimer. The editing protein is a cytidine deaminase showing
structural homology to other known mammalian and bacteriophage
deoxycytidylate deaminases.

Steinberg et al. (1979) described a kindred with a new form of
hypobetalipoproteinemia characterized by unusually low LDL cholesterol,
normal triglyceride levels, low levels of HDL, mild fat malabsorption,
and a defect in chylomicron clearance. On a high-carbohydrate diet, the
triglyceride levels of the 67-year-old proband fell rather than rising.
The proband, a retired Naval chaplain, was asymptomatic. He came to
attention because of total serum cholesterol of 47 mg/dl. The proband's
mother, aged 92, 1 brother, 1 sister, and 2 daughters also had
hypobetalipoproteinemia. Young et al. (1987) found an abnormality of
apoB, called apolipoprotein B-37, in the plasma lipoproteins of multiple
members of this kindred. Young et al. (1987) reported an intensive study
of 41 members in 3 generations of this kindred. They documented the
presence, in addition to the abnormal, truncated apoB species B-37, of
another apoB allele that was associated with reduced plasma
concentrations of the normal apoB-100. The proband (H.J.B.) and 2 of his
sibs had both abnormal apoB alleles and were therefore compound
heterozygotes for familial hypobetalipoproteinemia. All of the offspring
of the 3 compound heterozygotes had hypobetalipoproteinemia, and each
had evidence of only 1 of the abnormal apoB alleles. The average
LDL-cholesterol levels were: in the compound heterozygotes, 6 mg/dl; in
the 6 heterozygotes who had only the abnormal apoB-37 allele, 31 mg/dl;
in the 10 heterozygotes who had only the allele for reduced plasma
concentrations of apoB-100, 31 mg/dl; and in 22 unaffected family
members, 110 mg/dl.

Law et al. (1986) found that 60 of 83 middle-aged white men had an XbaI
restriction site polymorphism within the coding sequence of the apoB
gene. Persons homozygous or heterozygous for the XbaI restriction site
had mean serum triglyceride levels 36% higher than homozygotes without
the site. Mean serum cholesterol was less strikingly elevated in those
with the restriction site. The Ag system of lipoprotein antigens (see
later) is known to represent polymorphism of the APOB locus. It is in
strong linkage disequilibrium with the XbaI RFLP; the 2 probably reveal
the same association with plasma lipids. Mehrabian et al. (1986) also
identified 2 common RFLPs which should be useful in family studies.
Antonarakis (1987) and his colleagues identified a missense point
mutation in the APOB gene associated with hyperbetalipoproteinemia. The
mutation occurred at a potential site of binding of APOB to LDLR and
apparently resulted in interference with the metabolism of
apolipoprotein B. The finding of no recombination between the
hypobetalipoproteinemia phenotype and a particular DNA haplotype of the
APOB gene (Leppert et al., 1988) indicated that, at least in the family
studied, hypobetalipoproteinemia was the result of a molecular defect in
apolipoprotein B.

The nature of the mutation underlying abetalipoproteinemia (200100)
remains unknown. Since the heterozygote cannot be identified, linkage
requires study of pairs of affected sibs; the findings to 1986 were
consistent with linkage but the total lod score was not yet at the level
of formal proof. Keidar et al. (1990) described apparent compound
heterozygosity for abetalipoproteinemia and familial
hypobetalipoproteinemia. The findings may indicate that
abetalipoproteinemia is, like hypobetalipoproteinemia, due to a mutation
in the APOB gene. The proband, a 10-year-old boy with
abetalipoproteinemia, had a father with a normal apolipoprotein profile;
however, his mother and maternal grandfather suffered from familial
hypobetalipoproteinemia. Talmud et al. (1988) presented evidence that
the defect in abetalipoproteinemia (at least in the 2 families studied)
does not involve the APOB gene: in each of these 2 families, 2 affected
children inherited different APOB RFLP alleles from at least 1 parent,
whereas the sibs would be anticipated to share common alleles if this
disorder were due to an APOB mutation. Demant et al. (1988) found a
significant association between a particular RFLP of the APOB gene and
the total fractional clearance rate of LDL. Presumably, this effect acts
through variable binding to the LDLR and is a significant factor in the
rate of catabolism of LDL. Corsini et al. (1989) described familial
hypercholesterolemia (FH) due, not to a defect in the LDLR as in
conventional FH (143890), but to binding-defective LDL, presumably
familial defective apoB-100. Rajput-Williams et al. (1988) demonstrated
association of specific alleles for the apoB gene with obesity, high
blood cholesterol levels, and increased risk of coronary artery disease.
Several of the RFLPs used as markers do not change the amino acid
sequence. The authors concluded that these RFLPs are in linkage
disequilibrium with nearby functional variation predisposing to obesity
or increased risk of coronary artery disease. Variations in serum
cholesterol level were associated with 3 functional alleles
corresponding to amino acid variants at positions 3611 and 4154, both of
which lie near the LDLR binding region of apoB. Products of the APOB
gene with high or low affinity for the MB-19 monoclonal antibody can be
distinguished. Gavish et al. (1989) used this antibody to identify
heterozygotes and detect allele-specific differences in the amount of
APOB in the plasma. A family study confirmed that the unequal expression
phenotype was inherited in an autosomal dominant manner and was linked
to the APOB locus.

As a clinical entity, familial hypobetalipoproteinemia is ill defined.
The consistent laboratory findings of reduced serum cholesterol and
beta-lipoprotein define it as a distinct syndrome. Brown et al. (1974)
found 4 reported kindreds and added a fifth. Only 2 of the patients in
the reported families had symptoms. Mars et al. (1969) observed a family
in which 1 of the 14 hypobetalipoproteinemic persons (in 3 generations),
a 37-year-old woman, had signs and symptoms of progressive demyelination
of the central nervous system, lack of responsiveness to local
anesthesia, and dislike for animal fats and milk. The family reported by
Brown et al. (1974) contained a child with psychomotor retardation.
Although the peripheral blood smear showed no acanthocytes, the red
cells on symptomatic and asymptomatic persons became acanthocytotic when
placed in tissue culture medium with 10% autologous serum. Biemer and
McCammon (1975) described a family and reviewed others in the literature
in which a person with 'homozygous hypobetalipoproteinemia' had
occurred. They pointed out that although some of these cases were milder
than cases of abetalipoproteinemia, homozygous hypobetalipoproteinemia
could often be distinguished from abetalipoproteinemia only by the
demonstration of presumably heterozygous hypobetalipoproteinemic
first-degree relatives of the homozygote. This may not indicate that
these are determined by different loci; it may be a situation like the 3
probably allelic forms of cystinuria (220100) which are distinguishable
only by whether aminoaciduria is demonstrable in heterozygotes.

Kahn and Glueck (1978) reported remarkable freedom from atheroma in a
76-year-old woman who died from hepatic failure due apparently to
hemochromatosis. The woman had been found to have
hypobetalipoproteinemia in a study done previously (Glueck et al.,
1976). This and hyperalphalipoproteinemia (143470) are accompanied by
increased life expectancy. Berger et al. (1983) studied a kindred in
which the proband manifested the clinical and biochemical features of
the homozygous state. Unlike the apparent absence of apolipoprotein B in
the plasma in 5 previous cases of homozygous hypobetalipoproteinemia,
they found a minute amount of apoB (about 0.025% of normal) in the
plasma and suggested that the disorder might result not from a
structural gene defect but from a failure of secretion. (I would
interpret this finding as supporting rather than refuting the structural
mutation idea.) Since LDLs are a main source of cholesterol for steroid
hormone formation, Parker et al. (1986) were interested in studying the
endocrine changes during pregnancy in homozygous familial
hypobetalipoproteinemia. They found it surprising that the woman, with
phenotypic abetalipoproteinemia, could become 'pregnant, let alone carry
the pregnancy to term without hormonal therapy.' They noted successful
pregnancy in 3 other abetalipoproteinemic women. Harano et al. (1989)
identified homozygous hypobetalipoproteinemia in 3 sibs. Both parents
and 2 children of 1 of the sibs were heterozygous. The 75-year-old
proband, the father of the 3 sibs, died of fever of unknown cause,
thrombocytopenia, and anemia. He had ataxic movements of the hands and
gait disturbance in later life. The 3 homozygotes showed marked
deficiency of apoB-100, although trace amounts were noted in LDL. In
contrast, apoB-48 was present in chylomicrons obtained after a fatty
meal in 2 of the patients with homozygous hypobetalipoproteinemia,
indicating a selective deficiency of apoB-100. In 2 patients with
homozygous hypobetalipoproteinemia, Ross et al. (1988) found that
Southern blot analysis with 10 different cDNA probes revealed a normal
gene without major insertions, deletions, or rearrangements. Northern
and slot blot analyses of total liver mRNA showed a normal-sized apoB
mRNA that was present in greatly reduced quantities. ApoB protein was
detected in liver cells immunohistochemically but was markedly reduced
in quantity, and no apoB was detectable in the plasma with an ELISA
assay. Ross et al. (1988) interpreted the findings as indicating a
mutation in the coding portion of the apoB gene, leading to an abnormal
apoB protein and apoB mRNA instability. These findings were quite
distinct from those previously noted in abetalipoproteinemia (200100),
which is characterized by an elevated level of hepatic apoB mRNA and
accumulation of intracellular hepatic apoB protein. The blood-lipid
changes that accompany heterozygous hypobetalipoproteinemia are reduced
plasma concentrations of LDL cholesterol, total triglycerides, and APOB
to less than 50% of normal values. Leppert et al. (1988) found that a
DNA haplotype of the APOB gene cosegregated with the phenotype in an
Idaho pedigree, with a maximum lod score of 7.56 at theta = 0.0. This
finding strongly suggests that a mutation in the APOB gene underlies
hypobetalipoproteinemia and indicates the usefulness of the candidate
gene approach. As indicated in the listing of allelic variants, a number
of mutations resulting in a truncated apolipoprotein B have been found
as the basis of hypobetalipoproteinemia. On the other hand, other
patients with this disorder have been found to have reduced
concentrations of a full-length apoB-100 (Young et al., 1987; Berger et
al., 1983; Gavish et al., 1989). This type of gene defect may prove to
be analogous to beta(+)-thalassemia, which has been shown to be caused
by promoter mutations, intron-exon splicing errors, or mutation in the
polyadenylation signal. Araki et al. (1991) described a 55-year-old man
with cerebellar ataxia due apparently to hypobetalipoproteinemia. A
brother also had hypobetalipoproteinemia with neurologic symptoms. The 2
children of the proband, aged 31 and 29 years, and a sister of the
proband had only hypobetalipoproteinemia. The proband and his
neurologically affected brother as well as members of the 2 previous
generations had steatocystoma multiplex (184500). The latter condition
may have been coincidental.

Allison and Blumberg (1961) and Blumberg et al. (1963) described a
polymorphic system including serum beta lipoprotein distinct from that
discovered by Berg and Mohr and designated Lp(a) (see 152200). They
detected this by the study of patients who had received multiple
transfusions. The first type was called Ag-a; the second was called
Ag-b. Blumberg et al. (1964) proposed the symbol LP for lipoprotein.
Lower case letters are used for designating different loci (i.e., LPa,
LPb, LPc, etc.) and superscript numbers for alleles at the locus (i.e.,
LPa-1, LPa-2, etc.). Retention of the Ag designation may be advisable to
avoid confusion with the Berg type. Jackson et al. (1974) observed a
family in which variation of a chromosome 21 appeared to be linked with
Ag type. The peak lod score was 2.1 at a recombination fraction of 0.0.
Berg et al. (1975), on the other hand, found considerable recombination
with IPO-A (147450), in family studies. IPO-A is known to be on
chromosome 21 from hybrid cell studies. Berg et al. (1976) showed that
serum cholesterol and triglyceride levels were higher in Ag(x-) than in
Ag(x+) persons. Thus, a small but significant effect of a single
autosomal locus in atherogenesis may have been demonstrated. Morganti et
al. (1975) indicated that there are at least 5 closely linked loci. This
serum protein polymorphism was discovered by Blumberg on the basis of
his hypothesis that multitransfused patients should have antibodies
against polymorphic serum proteins. The Australia antigen was found in
the process of the same studies, applying the additional principle that
the wider the anthropologic spread of sera tested (e.g., Australian
aborigines), the greater the likelihood of finding a polymorphism. Of
course, the Australia antigen proved to be not a polymorphism but a
viremia--an even more important discovery, as recognized by the Nobel
Prize. By this approach, Blumberg (1978) found other apparent
polymorphisms that he has not yet fully studied. Allotypic variation in
LDL comparable to Ag has been found in most species studied. Berg et al.
(1986) demonstrated close linkage of the Ag allotypes of LDL and DNA
polymorphisms at the APOB locus. Linkage disequilibrium (allelic
association) was found between the Ag polymorphism and 2 of the 3 DNA
polymorphisms studied. Xu et al. (1989) demonstrated that a particular
Ag epitope (h/i) is determined by an arginine-to-glutamine substitution
at residue 3611 of the mature protein. The amino acid difference results
from a CGG-to-CAG change and causes loss of an MspI restriction site.
Breguet et al. (1990) found that, with the exception of the Amerindians,
the Ag system is highly polymorphic in populations worldwide. They
suggested that the system has evolved as a neutral or nearly-neutral
polymorphism and is therefore highly informative for 'modern human
peopling history' studies. Following the cloning of the human APOB gene,
nucleotide substitutions were reported as candidates for the molecular
basis of all the Ag epitopes (reviewed by Dunning et al., 1992). Dunning
et al. (1992) found complete linkage disequilibrium between the
immunochemical polymorphism of LDL that is designated antigen group
Ag(x/y) and the alleles at 2 sites in the mature apoB-100 molecule:
pro2712-to-leu and asn4311-to-ser. It appeared that the Ag(y) epitope
was associated with asparagine-4311 plus proline-2712, whereas the
allele encoding serine-4311 plus leucine-2712 represented the Ag(x)
epitope. In 4 different population groups, they found complete
association between the sites encoding residues 2712 and 4311, although
there were large allele frequency differences between these populations.
In addition, there was strong linkage disequilibrium with allelic
association between the alleles of these sites and those of the XbaI
RFLP in all populations examined. Taken together, these data suggest
that there has been little or no recombination in the 3-prime end of the
human APOB gene since the divergence of the major ethnic groups.

Ludwig et al. (1989) described a hypervariable region 3-prime to the
human APOB gene. By PCR amplification of the region followed by
electrophoresis in a denaturing acrylamide gel, they found 14 different
alleles containing 25 to 52 repeats of a 15-basepair unit in 318
unrelated individuals. Boerwinkle et al. (1989) also made observations
on this VNTR polymorphism. Boehnke (1991) used the VNTR polymorphism
near the APOB locus as a test case for his method of estimating allele
frequency from data on relatives. He stated that there are 15 known APOB
VNTR alleles and that 12 were observed in the families he studied. By
use of both pedigree linkage analysis and sib-pair linkage analysis in
23 informative families, Coresh et al. (1992) found no evidence of
common APOB alleles that had a major influence on plasma levels of
apoB-100.

Familial hypocholesterolemia can be caused not only by defects in the
LDL receptor (LDLR; 143890) but also by mutations in apolipoprotein B
causing decreased LDLR binding affinity, so-called familial
ligand-defective apolipoprotein B. The first mutation of this sort was
described by Soria et al. (1989); see 107730.0009. A second was
described by Pullinger et al. (1995); see 107730.0017.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988). Linton et al. (1993) tabulated 25 apoB gene
mutations associated with familial hypobetalipoproteinemia.

ANIMAL MODEL

Rapacz et al. (1986) described a strain of pigs bearing 3
immunogenetically defined lipoprotein-associated markers (allotypes)
associated with marked hypercholesterolemia despite a low-fat,
cholesterol-free diet. LDL receptor activity was normal. By 7 months of
age the animals had extensive atherosclerotic lesions in all 3 coronary
arteries. One of the 3 variant apolipoproteins was apolipoprotein B. The
identity of the other 2 apolipoproteins was not clear, although one was
a component of low density lipoprotein and was genetically linked to the
variant identified with apolipoprotein B.

Homanics et al. (1993) used gene targeting to generate a mouse model of
hypobetalipoproteinemia. Mice carrying the disrupted Apob gene
synthesized apoB48 and a truncated apoB (apoB-70) but no apoB-100. In
addition to having a lipoprotein phenotype remarkably similar to
familial hypobetalipoproteinemia in humans, these mice also exhibited
exencephalus and hydrocephalus. Huang et al. (1995) likewise generated
APOB gene knockout mice by targeting the gene in embryonic stem cells.
Homozygous deficiency led to embryonic lethality, with resorption of all
embryos by gestational day 9. Heterozygotes showed an increased tendency
to intrauterine death with some fetuses having incomplete neural tube
closure and some liveborn heterozygotes developing hydrocephalus. Most
heterozygous males were sterile, although the GU system and sperm were
grossly normal. Viable heterozygotes had normal triglycerides, but total
LDL and HDL cholesterol levels were decreased by 37, 37, and 39%,
respectively. Hepatic and intestinal APOB mRNA levels were decreased in
heterozygotes.

Callow et al. (1995) noted that the engineering of mice that express a
human APOB transgene results in animals with high levels of human-like
LDL particles. Additionally, through crosses with transgenics for the
human LPA gene, high levels of human-like lipoprotein(a) particles are
seen. Callow et al. (1995) found that such mice demonstrated marked
increases in apoB and LDL, resulting in atherosclerotic lesions
extending down the aorta that resembled human lesions immunochemically.
The findings suggested to the authors that APO(a) associated with apo(B)
and lipid may result in a more pro-atherogenic state than when APO(a) is
free in plasma.

Huang et al. (1996) found that male mice heterozygous for targeted
mutation of the ApoB gene exhibit severely compromised fertility. Sperm
from these mice fail to fertilize eggs both in vitro and in vivo.
However, these sperm were able to fertilize eggs once the zona pellucida
was removed but displayed persistent abnormal binding to the egg after
fertilization. In vitro fertilization-related and other experiments
revealed reduced sperm motility, survival time, and sperm count also
contributed to the infertility phenotype. Recognition of the infertility
phenotype led to the identification of ApoB mRNA in the testes and
epididymides of normal mice, and these transcripts were substantially
reduced in the mutant animal. Moreover, when the genomic sequence
encoding human ApoB was introduced into these animals, normal fertility
was restored. The findings of Huang et al. (1996) suggested that the
APOB locus may have an important impact on male fertility and identified
a previously unrecognized function of ApoB.

To provide models for understanding the physiologic purpose for the 2
forms of apo-B (B100 and B48), Farese et al. (1996) used targeted
mutagenesis of the APOB gene to generate mice that synthesized
exclusively apo-B48 and mice that synthesized exclusively apo-B100. The
B48-only and B100-only mice were produced by introducing into mouse ES
cells stop and nonstop mutations, respectively, in the apo-B48 editing
codon (codon 2153) of the mouse Apob gene. Both types of mice developed
normally, were healthy, and were fertile. Thus, apo-B48 synthesis
sufficed for normal embryonic development, and the synthesis of apo-B100
in the intestine adult mice caused no readily apparent adverse effects
on intestinal function or nutrition. Compared with wildtype mice fed the
same diet, the levels of LDL cholesterol and VLDL and LPL
triacylglycerols were lower in the B48-only mice and higher in the
B100-only mice. Farese et al. (1996) stated that in the setting of apo-E
deficiency, the B100-only mutation lowered cholesterol levels,
consistent with the fact that B100-lipoproteins can be cleared from the
plasma via the LDL receptor, whereas B48-lipoproteins lacking apo-E
cannot.

*FIELD* AV
.0001
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, ASN1728THR AND SER1729TER
In a patient with hypobetalipoproteinemia and small amounts of truncated
protein (B-37) in VLDL, LDL, and HDL fractions of the plasma, Young et
al. (1987, 1988) found deletion of nucleotides 5391-5394 resulting in a
frameshift causing change of asn1728 to thr and ser1729 to stop. The
truncated apoB protein contained 1,728 amino acids. This was one of the
mutant alleles in the family with hypobetalipoproteinemia first reported
by Steinberg et al. (1979). Linton et al. (1992) investigated the reason
for the curious finding that low levels of apoB-100 were produced by the
mutant allele carrying this mutation. The clue that led to the
understanding of what was going on with this allele was the recognition
that the proband in the family, H.J.B., as well as the other 2 compound
heterozygotes, actually had 4 bona fide apoB species within their plasma
lipoproteins: apoB-37, apoB-48, apoB-100, and apoB-86. Linton et al.
(1992) demonstrated that the apoB-86 and apoB-100 were products of a
single mutant apoB allele, which they designated the apoB-86 allele.
They showed that this allele has a 1-bp deletion in exon 26 of the APOB
gene and that this frameshift is responsible for the synthesis of
apoB-86. Nevertheless, as shown by cell culture expression studies, the
apoB-86 allele, which contains a premature stop codon, results in the
synthesis of a full-length apoB protein. The 1-bp deletion creates a
stretch of 8 consecutive adenines. Addition of a single adenine within
the 8 consecutive adenines appears to take place during transcription,
restoring the correct reading frame and accounting for the formation of
apoB-100 by the apoB-86 allele. Eleven percent of the cDNA clones had an
additional adenine within the stretch of 8 adenines.

.0002
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-39
APOB39
APOB, 1-PB DEL, FS1799TER
Collins et al. (1988) described a truncated apoB protein due to deletion
of a single guanine nucleotide from leucine codon 1794, resulting in a
frameshift and a stop codon after codon 1799. The truncated protein was
referred to as apoB-39. The mutation occurred in a CpG dinucleotide.

.0003
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, ARG1306TER
A second truncated variant of apoB found in hypobetalipoproteinemia by
Collins et al. (1988) had a change of arginine codon 1306, converting it
to a stop codon and resulting in a protein of 1,305 residues which,
however, could not be detected in the circulation. This mutation was a
C-to-T transition in a CpG dinucleotide.

.0004
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-40
APOB40
APOB, VAL1829CYS
Krul et al. (1989) found 2 distinct truncated apoB proteins, apoB-40 and
apoB-90, in a kindred with hypobetalipoproteinemia. Talmud et al. (1989)
showed that the molecular basis was deletion of 2 nucleotides converting
val1829 to cys and codon 1830 to stop.

.0005
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-90 OR APOB-89
APOB90 APOB89
APOB, GLU4034ARG
See Krul et al. (1989). The molecular basis was deletion of 1 nucleotide
in glutamic acid codon 4034 converting that codon to arginine and
causing a frameshift with a stop codon at position 4040 (Talmud et al.,
1989). Parhofer et al. (1992) showed that enhanced catabolism of VLDL,
IDL, and LDL particles containing the truncated apolipoprotein is
responsible for the relatively low levels of apoB-89 seen in these
subjects.

.0006
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-46
APOB46
APOB, ARG2058TER
Young et al. (1989) characterized an apoB gene mutation in a kindred
with familial hypobetalipoproteinemia. Six members of the family had low
plasma apoB and LDL cholesterol levels, and each was shown to be
heterozygous for a mutant apoB allele that yielded a unique truncated
species of apoB, namely apoB-46, with only 2,037 amino acids. They
further showed that apoB-46 is caused by the substitution of T for C at
apoB cDNA nucleotide 6381, resulting in a nonsense mutation. The change
occurred in a CG dinucleotide. A C-to-T transition in the APOB gene was
responsible for hypobetalipoproteinemia in one of the families studied
by Collins et al. (1988). Like CETP deficiency (118470), this appears to
be an antiatherogenic mutation.

.0007
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-87
APOB87
APOB
Young et al. (1990) referred to a truncated apoB species, apoB-87, on
the basis of their unpublished work.

.0008
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-31
APOB31
APOB, 1-BP DEL, FS1425TER
Young et al. (1990) identified a mutation of the APOB gene that resulted
in formation of a truncated apoB species, apoB-31. The mutation
consisted of deletion of a single guanine residue which caused a
frameshift and a premature termination with formation of a protein
predicted to contain 1,425 amino acids. This is the shortest of the
mutant apoB species identified in the plasma of subjects with
hypobetalipoproteinemia. In contrast to the longer truncated proteins,
apoB-31 was undetectable in VLDL and LDL but was present in the HDL
fraction and in the lipoprotein-deficient fraction of the plasma. This
mutation was found in the course of studying the apoB-46 mutant (Young
et al., 1989).

.0009
HYPERCHOLESTEROLEMIA DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B-100
APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE
APOB, ARG3500GLN
Vega and Grundy (1986) showed that some patients have reduced clearance
of LDL not because of decreased activity of LDL receptors but because of
a defect in the structure (or composition) of LDL that reduces its
affinity for receptors. In 5 of 15 patients, turnover rates indicated
that clearance of autologous LDL was significantly lower than for
homologous normal LDL. In these 5 patients, autologous LDL appeared to
be a poor ligand for LDL receptors. The authors did not carry the
investigations far enough to determine whether abnormality in the
primary structure of apoB-100 accounted for the poor binding to
receptors. Innerarity et al. (1987) found that moderate
hypercholesterolemia could be attributed to defective receptor binding
of a genetically altered apoB-100 to the LDL receptor. A finding of the
same abnormality in several of the proband's first-degree relatives
indicated the inherited nature of the defect. The proband of the family
studied by Innerarity et al. (1987) was described earlier by Vega and
Grundy (1986). This disorder was referred to as familial defective
apolipoprotein B-100. Weisgraber et al. (1988) found an antibody, whose
isotope is between residues 3350 and 3506 of apoB, that distinguishes
abnormal LDL from normal LDL in this disorder; the antibody MB47 bound
with a higher affinity to abnormal LDL. Thus, an assay was provided for
screening large populations for this disorder. Illingworth et al. (1992)
found that LDL cholesterol was reduced after administration of
lovastatin in 12 hypercholesterolemic patients from 10 unrelated
families with familial defective apoB-100.

By extensive sequence analysis of the 2 alleles of the APOB gene of a
subject heterozygous for familial defective apolipoprotein, Soria et al.
(1989) demonstrated a mutation in the codon for amino acid 3500 that
results in the substitution of glutamine for arginine. This same mutant
allele was found in 6 other, unrelated subjects and in 8 affected
relatives in 2 of these families. A partial haplotype of this mutant
apoB-100 allele was constructed by sequence analysis and restriction
enzyme digestion at positions where variations in the apoB-100 are known
to occur. This haplotype was found to be the same in 3 probands and 4
affected members of 1 family and lacks a polymorphic XbaI site whose
presence has been correlated with high cholesterol levels. Thus, it
appears that the mutation in the codon for amino acid 3500 (CGG-to-CAG),
a CG mutational 'hot spot,' defines a minor apoB-100 allele associated
with defective low density lipoproteins and hypercholesterolemia. Ludwig
and McCarthy (1990) used 10 markers for haplotyping at the APOB locus in
cases of familial defective apolipoprotein B-100: 8 diallelic markers
within the structural gene and 2 hypervariable markers flanking the
gene. In 14 unrelated subjects heterozygous for the mutation, 7 of 8
unequivocally deduced haplotypes were identical, and 1 revealed only a
minor difference at one of the hypervariable loci. The genotypes of the
other 6 affected subjects was consistent with the same haplotype.
Familial defective apolipoprotein B-100 (FDB) results from a G-to-A
transition at nucleotide 10708 in exon 26 of the APOB gene. Ludwig and
McCarthy (1990) interpreted the data as consistent with the existence of
a common ancestral chromosome. In a screening for the APOB-3500 mutation
by PCR amplification and hybridization with an allele-specific
oligonucleotide, Loux et al. (1993) found only 1 case among 101 French
subjects with familial hypercholesterolemia. The son of this individual,
a 45-year-old man, was found also to have the mutation. Haplotype
analysis revealed strict identity to that previously reported by Ludwig
and McCarthy (1990), thus supporting a unique European ancestry. The
family lived in the southwest of France and had no knowledge of Germanic
origin.

Rauh et al. (1992) stated that the frequency of the arg3500-to-gln
mutation has been found to be approximately 1/500 to 1/700 in several
Caucasian populations in North America and Europe. On the other hand,
Friedlander et al. (1993) found no instance of this mutation in a large
screening program in Israel. They pointed out that the mutation has also
not been found in Finland (Hamalainen et al., 1990) and is said to be
absent in Japan. Tybjaerg-Hansen and Humphries (1992) gave a review
suggesting that the risk of premature coronary artery disease in the
carriers of the mutation is increased to levels as high as those seen in
patients with familial hypercholesterolemia; at age 50, about 40% of
males and 20% of females heterozygous for the mutation have developed
coronary artery disease.

To their surprise, Marz et al. (1992) found only moderate
hypercholesterolemia in a 54-year-old man who was homozygous for the
arg3500-to-gln mutation and on a normal diet without lipid-lowering
medication. There was no evidence of atherosclerosis and no history of
cardiovascular complaints. The levels of apoE-containing lipoproteins
were normal. Marz et al. (1992) suggested that the intact metabolism of
apoE-containing particles decreases LDL production in this disorder,
explaining the difference from familial hypercholesterolemia due to a
receptor defect in which apoE levels are raised. Marz et al. (1993)
investigated possible compensatory mechanisms that may have alleviated
the consequences of the familial defective apoB-100 (FDB). They showed
that the receptor interaction of buoyant LDL is normal due to the
presence of apoE in these particles. In addition, they provided evidence
that the arg3500-to-gln substitution profoundly alters the conformation
of the apoB receptor binding domain when apolipoprotein B resides on
particles at the lower and upper limits of the LDL density range. They
concluded that these mechanisms distinguish FDB from FH and account for
the mild hypercholesterolemia in homozygous FDB. Among 43 patients with
clinically and biochemically defined type III hyperlipoproteinemia
(107741), Feussner and Schuster (1992) found no instance of the
arg3500-to-gln mutation.

In the course of investigating the reason that 2 unrelated French
patients heterozygous for mutations in the LDLR gene (143890) had
aggravated hypercholesterolemia, Benlian et al. (1996) found that each
carried the identical arg3500-to-gln mutation in the APOB gene, i.e.,
were double heterozygotes. One of the patients was a 10-year-old boy
when he was referred for hypercholesterolemia discovered at the time of
a cardiac arrest. He had no planar xanthomata, although he exhibited
bilateral xanthomas of the Achilles and metacarpal phalangeal tendons.
Peripheral arterial disease was demonstrated by the presence of arterial
murmurs and by arterial wall irregularity on ultrasound analysis.
Stenoses of coronary arteries necessitated surgical angioplasty. The
second patient was a 39-year-old man with myocardial infarction and
acute ischemia of the legs. Both families came from the Perche region
from which many French Canadians originated. The LDLR mutations
trp66-to-gly (143890.0003) and glu207-to-lys (143890.0007) had been
previously described in French Canadians. Rubinsztein et al. (1993)
described an Afrikaner family with 6 FH/FDB double heterozygotes
carrying another LDLR mutation, asp206-to-glu (143890.0006). (Benlian et
al. (1996), in the title of their article, correctly referred to these
patients as double heterozygotes; in the paper itself they incorrectly
referred to them as FH/FDB compound heterozygotes. The latter term is
used for heterozygosity for alleles at the same locus.)

.0010
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, EX21DEL
In an Arab patient with hypobetalipoproteinemia and absent plasma
apolipoprotein B, Huang et al. (1989) demonstrated deletion of the
entire exon 21 (211 basepairs coding for amino acids 1014 to 1084).

.0011
APOB POLYMORPHISM IN SIGNAL PEPTIDE
APOB, INS AND DEL
Visvikis et al. (1990) described an insertion/deletion polymorphism in
the signal peptide. One allele, coding a peptide 27 amino acids long,
had a frequency of 0.655; the second allele, coding a peptide 24 amino
acids long, had a frequency of 0.345.

.0012
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, LEU3041TER
In a man with hypobetalipoproteinemia and 6 of his 12 children, Welty et
al. (1991) found that the plasma lipoproteins contained a unique species
of apolipoprotein B, apoB-67, in addition to the normal species,
apoB-100 and apoB-48. Further study indicated that the apoB-67 was a
truncated species that contained approximately the amino-terminal 3,000
to 3,100 amino acids of apoB-100. Heterozygosity was identified for a
mutant APOB allele containing a single nucleotide deletion in exon 26
(cDNA nucleotide 9327). The change in codon 3041 from ATA (leu) to TAG
(stop) led to truncation after amino acid 3040. Mean total and LDL
cholesterol levels were 120 and 42 mg/dl, respectively. All affected
members of the kindred had high HDL cholesterol levels.

.0013
ABETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC
APOB50; APOB, GLN2252TER
Malloy et al. (1981) described a patient (A.F.) with a metabolic
disorder they termed normotriglyceridemic abetalipoproteinemia. Similar
cases were reported by Takashima et al. (1985), Herbert et al. (1985),
and Harano et al. (1989). The disorder was characterized by the absence
of LDLs and apoB-100 in plasma with apparently normal secretion of
triglyceride-rich lipoproteins containing apoB-48. Subsequent studies in
A.F. suggested that the patient's plasma might be a truncated form of
apoB-100, slightly longer than the normal apoB-48 chain. Hardman et al.
(1991) demonstrated that the patient was homozygous for a single C-to-T
substitution at nucleotide 6963 of apoB cDNA. This substitution resulted
in a change from CAG (glutamine) to TAG (stop) at position 2252. Thus,
this was a rare example of homozygous hypobetalipoproteinemia. Because
LDL particles that contained apoB-50 lacked the putative ligand domain
of the LDL receptor, the very low level of LDL was presumably due to the
rapid removal of the abnormal VLDL particles before their conversion to
LDL could take place. As reviewed by Hardman et al. (1991), a
considerable number of mutations resulting in truncated versions of apoB
have been described, the smallest variant being apoB-31, and the
longest, apoB-90. Using 3 genetic markers of the APOB gene in a study of
the family reported by Takashima et al. (1985), Naganawa et al. (1992)
found that the proband and her affected brother showed completely
different APOB alleles, indicating that in this family the defect was
not in the APOB gene.

.0014
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB-32
APOB32
APOB, GLN1450TER
In a person with heterozygous hypobetalipoproteinemia, McCormick et al.
(1992) identified a nonsense mutation, gln1450-to-ter that prevented
full-length translation. The new apolipoprotein B, apoB-32, is predicted
to contain the 1,449 amino-terminal amino acids of apoB-100. It was
associated with a markedly decreased level of low density lipoprotein
(LDL cholesterol). Unique among the truncated apoB species, apoB-32 was
found in the high density lipoprotein and lipoprotein-depleted
fractions, suggesting that it was mainly assembled into abnormally dense
lipoprotein particles.

.0015
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, ARG2495TER
Talmud et al. (1992) identified a C-to-T transition at nucleotide 7692
of the APOB gene which changed the CGA arginine codon to a stop codon
resulting in a premature termination of apoB-100. The truncated protein
was predicted to be 2,494 amino acids long with the predicted size of
apoB-55. The patient had low total cholesterol and LDL-cholesterol as
did also other relatives in an autosomal dominant pattern. In addition,
the propositus, his mother, and both of his sibs had atypical retinitis
pigmentosa. Since the RP-affected brother did not have the APOB
mutation, Talmud et al. (1992) concluded that the eye disease was
independent of the hypobetalipoproteinemia. They speculated, however,
that a reduction in apoB-containing lipoproteins might alter the balance
of the fatty acid supply to the retina and thus affect the evolution of
retinitis pigmentosa in this family. The retinitis pigmentosa was late
in onset.

.0016
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, 1-BP DEL
In H.J.B. and 2 sibs with asymptomatic familial hypobetalipoproteinemia
reported by Steinberg et al. (1979), Linton et al. (1992) demonstrated
that one of the alleles, which yielded very low levels of apoB-100, had
a deletion of a single cytosine in exon 26 (nucleotide 11840 of the apoB
cDNA). This frameshift mutation was predicted to yield a 20-amino acid
sequence (KKQIMLKQSWIPHAAQPYSS) not found in the wildtype, followed by a
premature stop codon. Indeed, they found an antiserum to a synthetic
peptide containing this 20-amino acid sequence (frameshift peptide
3877-3896) bound specifically to apoB-86 but not to apoB-100. Thus the
compound heterozygotes had 2 mutant apoB alleles, one primarily
responsible for apoB-37 (107730.0001) and the other responsible for
apoB-86, both of which contained frameshift mutations in exon 26. Linton
et al. (1992) further demonstrated that the 1-bp deletion in the apoB-86
allele created a stretch of 8 consecutive adenines. Addition of a single
adenine within the 8 consecutive adenines would be predicted to correct
the altered reading frame, thereby resulting in the production of a
full-length protein. They presented evidence that a significant
percentage (about 11%) of the apoB cDNA clones from rat hepatoma cells
transformed with an apoB construct containing the 1-bp deletion indeed
had 9 consecutive adenines. It appeared that the addition of an extra
adenine during transcription restored the correct reading frame and
accounted for the formation of some apoB-100 from the apoB-86 allele.
Other experiments were thought to exclude an alternative explanation,
the activation of a cryptic splice site within exon 26 upstream from the
deletion.

.0017
HYPERCHOLESTEROLEMIA DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B
APOLIPOPROTEIN B, FAMILIAL LIGAND-DEFECTIVE
APOB, ARG531CYS
Suspecting that mutations in the APOB gene other than the arg3500-to-gln
mutation (107730.0009) may cause familial hypercholesterolemia,
Pullinger et al. (1995) used single-strand conformation polymorphism
analysis to screen genomic DNA from patients attending a lipid clinic
and looked for mutations in the putative LDL receptor-binding domain of
apoB-100. They found a novel arg3531-to-cys mutation, caused by a C-to-T
transition at nucleotide 10800, in a 46-year-old woman of Celtic and
Native American ancestry with primary hypercholesterolemia and
pronounced peripheral vascular disease. After screening 1,560
individuals, one unrelated 59-year-old man of Italian ancestry was found
to have the same mutation. He had coronary heart disease, a triglyceride
cholesterol of 310 mg/dl, and an LDL cholesterol of 212 mg/dl. A total
of 8 individuals were found with the same defect in the families of
these 2 patients. The age- and sex-adjusted TC and LDL-C were 240 and
169, respectively, for the 8 affected individuals, as compared with 185
and 124, respectively, for 8 unaffected family members. In a
dual-labeled fibroblast binding assay, LDL from the 8 subjects with the
mutation had an affinity for the LDL receptor that was 63% that of
control LDL. LDL from 8 unaffected family members had an affinity of
91%. By way of comparison, LDL from 6 patients heterozygous for the
arg3500-to-gln mutation had an affinity of 36%. Deduced haplotypes using
10 APOB gene markers showed the arg3531-to-cys alleles to be different
in the 2 kindreds and indicated that the mutations arose independently.
This was the second reported cause of familial ligand-defective apoB.

*FIELD* SA
Aggerbeck et al. (1974); Allison and Blumberg (1965); Barni et al.
(1986); Butler and Brunner (1969); Butler et al. (1970); Carlsson
et al. (1985); Chan et al. (1985); Cottrill et al. (1974); Frossard
et al. (1986); Hegele et al. (1986); Illingworth et al. (1979); Innerarity
et al. (1987); Knott et al. (1986); Law et al. (1986); Morganti et
al. (1970); Protter et al. (1986); Protter et al. (1986); Shoulders
et al. (1985); Tamir et al. (1976); Yang et al. (1986); Young et al.
(1987); Young et al. (1986)
*FIELD* RF
1. Aggerbeck, L. P.; McMahon, J. P.; Scanu, A. M.: Hypobetalipoproteinemia:
clinical and biochemical description of a new kindred with Friedreich's
ataxia. Neurology 24: 1051-1063, 1974.

2. Allison, A. C.; Blumberg, B. S.: An isoprecipitation reaction
distinguishing human serum-protein types. Lancet I: 634-637, 1961.

3. Allison, A. C.; Blumberg, B. S.: Serum lipoprotein allotypes in
man. Prog. Med. Genet. 4: 176-201, 1965.

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familial defective apo B-100. Arteriosclerosis Thromb. 13: 1076-1081,
1993.

97. Shoulders, C. C.; Myant, N. B.; Sidoli, A.; Rodriguez, J. C.;
Cortese, C.; Baralle, F. E.; Cortese, R.: Molecular cloning of human
LDL apolipoprotein B cDNA: evidence for more than one gene per haploid
genome. Atherosclerosis 58: 277-289, 1985.

98. Soria, L. F.; Ludwig, E. H.; Clarke, H. R. G.; Vega, G. L.; Grundy,
S. M.; McCarthy, B. J.: Association between a specific apolipoprotein
B mutation and familial defective apolipoprotein B-100. Proc. Nat.
Acad. Sci. 86: 587-591, 1989.

99. Steinberg, D.; Grundy, S. M.; Mok, H. Y. I.; Turner, J. D.; Weinstein,
D. B.; Brown, W. V.; Albers, J. J.: Metabolic studies in an unusual
case of asymptomatic familial hypobetalipoproteinemia with hypoalphalipoproteinemia
and fasting chylomicronemia. J. Clin. Invest. 64: 292-301, 1979.

100. Takashima, Y.; Kodama, T.; Iida, H.; Kawamura, M.; Aburatani,
H.; Itakura, H.; Akanuma, Y.; Takaku, F.; Kawade, M.: Normotriglyceridemic
abetalipoproteinemia in infancy: an isolated apolipoprotein B-100
deficiency. Pediatrics 75: 541-546, 1985.

101. Talmud, P.; King-Underwood, L.; Krul, E.; Schonfeld, G.; Humphries,
S.: The molecular basis of truncated forms of apolipoprotein B in
a kindred with compound heterozygous hypobetalipoproteinemia. J.
Lipid Res. 30: 1773-1779, 1989.

102. Talmud, P. J.; Converse, C.; Krul, E.; Huq, L.; McIlwaine, G.
G.; Series, J. J.; Boyd, P.; Schonfeld, G.; Dunning, A.; Humphries,
S.: A novel truncated apolipoprotein B (apo B55) in a patient with
familial hypobetalipoproteinemia and atypical retinitis pigmentosa. Clin.
Genet. 42: 62-70, 1992.

103. Talmud, P. J.; Lloyd, J. K.; Muller, D. P. R.; Collins, D. R.;
Scott, J.; Humphries, S.: Genetic evidence from two families that
the apolipoprotein B gene is not involved in abetalipoproteinemia. J.
Clin. Invest. 82: 1803-1806, 1988.

104. Tamir, I.; Levtow, O.; Lotan, D.; Legum, C.; Heldenberg, D.;
Werbin, B.: Further observations on familial hypobetalipoproteinemia. Clin.
Genet. 9: 149-155, 1976.

105. Tybjaerg-Hansen, A.; Humphries, S. E.: Familial defective apolipoprotein
B-100: a single mutation that causes hypercholesterolemia and premature
coronary artery disease. Atherosclerosis 96: 91-107, 1992.

106. Vega, G. L.; Grundy, S. M.: In vivo evidence for reduced binding
of low density lipoproteins to receptors as a cause of primary moderate
hypercholesterolemia. J. Clin. Invest. 78: 1410-1414, 1986.

107. Visvikis, S.; Chan, L.; Siest, G.; Drouin, P.; Boerwinkle, E.
: An insertion deletion polymorphism in the signal peptide of the
human apolipoprotein B gene. Hum. Genet. 84: 373-375, 1990.

108. Weisgraber, K. H.; Innerarity, T. L.; Newhouse, Y. M.; Young,
S. G.; Arnold, K. S.; Krauss, R. M.; Vega, G. L.; Grundy, S. M.; Mahley,
R. W.: Familial defective apolipoprotein B-100: enhanced binding
of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc.
Nat. Acad. Sci. 85: 9758-9762, 1988.

109. Welty, F. K.; Hubl, S. T.; Pierotti, V. R.; Young, S. G.: A
truncated species of apolipoprotein B (B67) in a kindred with familial
hypobetalipoproteinemia. J. Clin. Invest. 87: 1748-1754, 1991.

110. Xu, C.; Nanjee, N.; Tikkanen, M. J.; Huttunen, J. K.; Pietinen,
P.; Butler, R.; Angelico, F.; Del Ben, M.; Mazzarella, B.; Antonio,
R.; Miller, N. G.; Humphries, S.; Talmud, P. J.: Apolipoprotein B
amino acid 3611 substitution from arginine to glutamine creates the
Ag (h/i) epitope: the polymorphism is not associated with differences
in serum cholesterol and apolipoprotein B levels. Hum. Genet. 82:
322-326, 1989.

111. Yang, C.-Y.; Chen, S.-H.; Gianturco, S. H.; Bradley, W. A.; Sparrow,
J. T.; Tanimura, M.; Li, W.-H.; Sparrow, D. A.; DeLoof, H.; Rosseneu,
M.; Lee, F.-S.; Gu, Z.-W.; Gotto, A. M., Jr.; Chan, L.: Sequence,
structure, receptor-binding domains and internal repeats of human
apolipoprotein B-100. Nature 323: 738-742, 1986.

112. Young, S. G.; Bertics, S. J.; Curtiss, L. K.; Casal, D. C.; Witztum,
J. L.: Monoclonal antibody MB19 detects genetic polymorphism in human
apolipoprotein B. Proc. Nat. Acad. Sci. 83: 1101-1105, 1986.

113. Young, S. G.; Bertics, S. J.; Curtiss, L. K.; Dubois, B. W.;
Witztum, J. L.: Genetic analysis of a kindred with familial hypobetalipoproteinemia:
evidence for two separate gene defects: one associated with an abnormal
apolipoprotein B species, apolipoprotein B-37; and a second associated
with low plasma concentrations of apolipoprotein B-100. J. Clin.
Invest. 79: 1842-1851, 1987.

114. Young, S. G.; Bertics, S. J.; Curtiss, L. K.; Witztum, J. L.
: Characterization of an abnormal species of apolipoprotein B, apolipoprotein
B-37, associated with familial hypobetalipoproteinemia. J. Clin.
Invest. 79: 1831-1841, 1987.

115. Young, S. G.; Bertics, S. J.; Scott, T. M.; Dubois, B. W.; Curtiss,
L. K.; Witztum, J. L.: Parallel expression of the MB19 genetic polymorphism
in apoprotein B-100 and apoprotein B-48: evidence that both apoproteins
are products of the same gene. J. Biol. Chem. 261: 2995-2998, 1986.

116. Young, S. G.; Hubl, S. T.; Chappell, D. A.; Smith, R. S.; Claiborne,
F.; Snyder, S. M.; Terdiman, J. F.: Familial hypobetalipoproteinemia
associated with a mutant species of apolipoprotein B (B-46). New
Eng. J. Med. 320: 1604-1610, 1989.

117. Young, S. G.; Hubl, S. T.; Smith, R. S.; Snyder, S. M.; Terdiman,
J. F.: Familial hypobetalipoproteinemia caused by a mutation in the
apolipoprotein B gene that results in a truncated species of apolipoprotein
B (B-31): a unique mutation that helps to define the portion of the
apolipoprotein B molecule required for the formation of buoyant, triglyceride-rich
lipoproteins. J. Clin. Invest. 85: 933-942, 1990.

118. Young, S. G.; Northey, S. T.; McCarthy, B. J.: Low plasma cholesterol
levels caused by a short deletion in the apolipoprotein B gene. Science 241:
591-593, 1988.

*FIELD* CS

Neuro:
   Progressive CNS demyelination;
   Ataxic hand movements;
   Late gait diturbance

Heme:
   Red cell acanthocytosis in tissue culture medium with 10% autologous
   serum

Cardiac:
   Antiatherogenic (APOB46 .0006);
   Coronary artery disease (APOB defect .0009)

GI:
   Mild fat malabsorption;
   Defect in chylomicron clearance

Lab:
   Hypobetalipoproteinemia;
   Decreased serum cholesterol;
   Normal/low triglyceride levels;
   Hypercholesterolemia (APOB defect .0009);
   High HDL cholesterol levels (APOB .0012)

Inheritance:
   Autosomal dominant (2p24-p23)

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
terry: 02/06/1997
jamie: 12/6/1996
terry: 12/4/1996
mark: 11/22/1996
terry: 11/7/1996
mark: 7/22/1996
terry: 6/11/1996
terry: 6/7/1996
terry: 5/30/1996
mark: 2/2/1996
terry: 1/26/1996
mark: 10/12/1995
terry: 7/18/1994
jason: 7/5/1994
davew: 6/8/1994
warfield: 4/7/1994
pfoster: 3/25/1994

*RECORD*
*FIELD* NO
107740
*FIELD* TI
*107740 APOLIPOPROTEIN D; APOD
*FIELD* TX
Apolipoprotein D is a member of the alpha (2 mu)-microglobulin
superfamily of carrier proteins also known as lipocalins (e.g.,
lipocalin 1; 151675). It is a protein component of high-density
lipoprotein in human plasma, comprising about 5% of total high-density
lipoprotein (Fielding and Fielding, 1980). It is a glycoprotein of
estimated molecular weight 33,000 Da. Apo-D is closely associated with
the enzyme lecithin:cholesterol acyltransferase (LCAT, 245900). Drayna
et al. (1986) reported the amino acid sequence of apo-D based on the
nucleotide sequence of the coding portion of the APOD gene and on the
cloned cDNA sequence. The 169-amino acid protein bore little similarity
to other lipoprotein sequences but had a high degree of homology to
plasma retinol-binding protein (180250, 180260, 180280, 180290), a
member of the alpha-2mu-globulin superfamily. This structural similarity
may indicate some functional homology of these proteins. Apo-D mRNA has
been detected in many tissues. Drayna et al. (1987) described multiple
RFLPs at the APOD locus. Kamboh et al. (1989) demonstrated for the first
time polymorphism of apolipoprotein D by an isoelectric
focusing-immunoblotting technique.

Drayna et al. (1987) assigned the gene for APOD to 3p14.2-qter by dot
blot hybridization to DNA from sorted human chromosomes and by in situ
hybridization. Cellular retinol-binding proteins (180260, 180280) are
coded by chromosome 3; interstitial RBP (180290) is coded by a gene on
chromosome 10. Warden et al. (1992) demonstrated that the ApoD gene is
located on mouse chromosome 16.

Zeng et al. (1996) noted several studies in humans suggesting that
axillary odors and secretions from both males and females are a source
of chemical signals containing physiologically active components capable
of altering the female menstrual cycle. These alterations include the
menstrual synchrony affect first documented by McClintock (1971) in an
all-female living group and later replicated by others in coeducational
facilities (Graham and McGrew, 1980; Quadagno et al., 1981). In nonhuman
mammals such as rodents, estrus synchrony has been shown to be mediated
by airborne chemical signals (McClintock, 1978). Certain axillary
components currently function as chemical signals involved in the
regulation of reproductive function via alteration of the
hypothalamic-pituitary-gonadal axis; chemical signals for this mode of
action are termed primer pheromones. Characterization of the source of
the odor in the human axillary region is not only of commercial interest
but is also important biologically because axillary extracts can alter
the length and timing of the female menstrual cycle. In males, the most
abundant odor component is known to be E-3-methyl-2-hexenoic acid
(E-3M2H), which is liberated from nonodorous apocrine secretions by
axillary microorganisms. In the apocrine gland secretions, 3M2H is
carried on the skin surface bound to 2 proteins, apocrine secretion
odor-binding proteins 1 and 2 (ASOB1 and ASOB2) with apparent molecular
masses of 45 kD and 26 kD, respectively. To understand better the
formation of axillary odors and the structural relationship between 3M2H
and its carrier protein, Zeng et al. (1996) determined the amino acid
sequence and glycosylation pattern of ASOB2 by mass spectrometry. The
ASOB2 protein was identified as apolipoprotein D. The pattern of
glycosylation for axillary apoD differs from that reported for plasma
apoD, suggesting to Zeng et al. (1996) that there are different sites of
expression for the 2 glycoproteins. In situ hybridization of an
oligonucleotide probe against apoD mRNA with axillary tissue
demonstrated that the message for synthesis of this protein is specific
to the apocrine glands. These results suggested a remarkable similarity
between human axillary secretions and nonhuman mammalian odor sources,
where lipocalins have been shown to carry the odoriferous signals used
in pheromonal communication.

*FIELD* SA
Drayna et al. (1987)
*FIELD* RF
1. Drayna, D.; Fielding, C.; McLean, J.; Baer, B.; Castro, G.; Chen,
E.; Comstock, L.; Henzel, W.; Kohr, W.; Rhee, L.; Wion, K.; Lawn,
R.: Cloning and expression of human apolipoprotein D cDNA. J. Biol.
Chem. 261: 16535-16539, 1986.

2. Drayna, D.; Scott, J. D.; Lawn, R.: Multiple RFLPs at the human
apolipoprotein D (APOD) locus. Nucleic Acids Res. 15: 9617 only,
1987.

3. Drayna, D. T.; McLean, J. W.; Wion, K. L.; Trent, J. M.; Drabkin,
H. A.; Lawn, R. M.: Human apolipoprotein D gene: gene sequence, chromosome
localization, and homology to the alpha-2mu-globulin superfamily. DNA 6:
199-204, 1987.

4. Fielding, P. E.; Fielding, C. J.: A cholesteryl ester transfer
complex in human plasma. Proc. Nat. Acad. Sci. 77: 3327-3330, 1980.

5. Graham, C. A.; McGrew, W. C.: Menstrual synchrony in female undergaduates
living on a coeducational campus. Psychoneuroendocrinology 5: 245-252,
1980.

6. Kamboh, M. I.; Albers, J. J.; Majumder, P. P.; Ferrell, R. E.:
Genetic studies of human apolipoproteins. IX. Apolipoprotein D polymorphism
and its relation to serum lipoprotein lipid levels. Am. J. Hum. Genet. 45:
147-154, 1989.

7. McClintock, M. K.: Menstrual synchrony and suppression. Nature 229:
244-245, 1971.

8. McClintock, M. K.: Estrous synchrony and its mediation by airborn
chemical communication (Rattus norvegicus). Horm. Behav. 10: 264-276,
1978.

9. Quadagno, D. M.; Shubeita, H. E.; Deck, J.; Francoeur, D.: Influence
of male social contacts, exercise and all-female living conditions
on the menstrual cycle. Psychoneuroendocrinology 6: 239-244, 1981.

10. Warden, C. H.; Diep, A.; Taylor, B. A.; Lusis, A. J.: Localization
of the gene for apolipoprotein D on mouse chromosome 16. Genomics 12:
851-852, 1992.

11. Zeng, C.; Spielman, A. I.; Vowels, B. R.; Leyden, J. J.; Biemann,
K.; Preti, G.: A human axillary odorant is carried by apolipoprotein
D. Proc. Nat. Acad. Sci. 93: 6626-6630, 1996.

*FIELD* CD
Victor A. McKusick: 2/9/1987

*FIELD* ED
jamie: 10/23/1996
jamie: 10/16/1996
mark: 10/11/1996
terry: 9/20/1996
carol: 4/1/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/16/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
107741
*FIELD* TI
*107741 APOLIPOPROTEIN E; APOE
APOLIPOPROTEIN E, DEFICIENCY OR DEFECT OF, INCLUDED;;
HYPERLIPOPROTEINEMIA, TYPE III, INCLUDED;;
DYSBETALIPOPROTEINEMIA DUE TO DEFECT IN APOLIPOPROTEIN E-d, INCLUDED;;
FAMILIAL HYPERBETA- AND PREBETALIPOPROTEINEMIA, INCLUDED;;
FAMILIAL HYPERCHOLESTEROLEMIA WITH HYPERLIPEMIA, INCLUDED;;
HYPERLIPEMIA WITH FAMILIAL HYPERCHOLESTEROLEMIC XANTHOMATOSIS, INCLUDED;;
BROAD-BETALIPOPROTEINEMIA, INCLUDED;;
FLOATING-BETALIPOPROTEINEMIA, INCLUDED
*FIELD* TX

DESCRIPTION

- Early Delineation

Utermann et al. (1979) described 2 phenotypes, apoE(IV+) and apoE(IV-),
differentiated by analytical isoelectric focusing. They concluded that
this polymorphism of apolipoprotein E in human serum is determined by 2
autosomal codominant alleles, apoE(n) and apoE(d). Homozygosity for the
latter results in primary dysbetalipoproteinemia but only some persons
develop gross hyperlipidemia (hyperlipoproteinemia type III). Vertical
transmission is pseudodominance due to high frequency of the apoE(d)
gene (Utermann et al., 1979). Dysbetalipoproteinemia is already
expressed in childhood. They concluded that primary
dysbetalipoproteinemia is a frequent monogenic variant of lipoprotein
metabolism, but not a disease. Coincidence of the genes for this
dyslipoproteinemia with any of the genes for monogenic or polygenic
forms of familial hyperlipemia results in hyperlipoproteinemia type III.
Further complexities of the genetics of the apolipoprotein E system were
discussed by Utermann et al. (1980). Apolipoprotein E (apoE) of very low
density lipoprotein (VLDL) from different persons shows 1 of 2 complex
patterns, termed alpha and beta (Zannis et al., 1981). Three subclasses
of each pattern were found and designated alpha-II, alpha-III and
alpha-IV and beta-II, beta-III and beta-IV. From family studies, Zannis
et al. (1981) concluded that a single locus with 3 common alleles is
responsible for these patterns. The alleles were designated epsilon-II,
-III, and-IV. The authors further concluded that beta class phenotypes
represent homozygosity for one of the epsilon alleles, e.g., beta-II
results from homozygosity for the epsilon-II allele. In contrast, the
alpha phenotypes are thought to represent compound heterozygosity, i.e.,
heterozygosity for 2 different epsilon alleles: alpha II from epsilon II
and III; alpha III from epsilon III and IV. The frequency of the epsilon
II, III, and IV alleles was estimated at 0.11, 0.72, and 0.17,
respectively. ApoE subclass beta-IV was found to be associated with type
III hyperlipoproteinemia. Rall et al. (1982) published the full amino
acid sequence. Mature apoE is a 299-amino acid polypeptide.

- Molecular Basis of Polymorphism

The 3 major isoforms of human apolipoprotein E (apoE2, -E3, and -E4), as
identified by isoelectric focusing, are coded for by 3 alleles (epsilon
2, 3, and 4). The E2 (107741.0001), E3 (107741.0015), and E4
(107741.0016) isoforms differ in amino acid sequence at 2 sites, residue
112 (called site A) and residue 158 (called site B). At sites A/B,
apoE2, -E3, and -E4 contain cysteine/cysteine, cysteine/arginine, and
arginine/arginine, respectively (Weisgraber et al., 1981; Rall et al.,
1982). The 3 forms have 0, 1+, and 2+ charges to account for
electrophoretic differences (Margolis, 1982). (The nomenclature of the
apolipoprotein E isoforms, defined by isoelectric focusing, has gone
through an evolution.) E3 is the most frequent ('wildtype') isoform. As
reviewed by Smit et al. (1990), E4 differs from E3 by a cys-to-arg
change at position 112 and is designated E4(cys112-to-arg). Four
different mutations giving a band at the E2 position with isoelectric
focusing have been described: E2(arg158-to-cys), E2(lys146-to-gln),
E2(arg145-to-cys) and E2-Christchurch(arg136-to-ser). E2(arg158-to-cys)
is the most common of the 4.

In a comprehensive review of APOE variants, de Knijff et al. (1994)
found that 30 variants had been characterized, including the most common
variant, APOE3. To that time, 14 APOE variants had been found to be
associated with familial dysbetalipoproteinemia, characterized by
elevated plasma cholesterol and triglyceride levels and an increased
risk for atherosclerosis.

Data on gene frequencies of APOE allelic variants were tabulated by
Roychoudhury and Nei (1988).

- Role of APOE in Abnormalities of Blood Lipids and in Cardiovascular
Disease

In normal individuals, chylomicron remnants and very low density
lipoprotein (VLDL) remnants are rapidly removed from the circulation by
receptor-mediated endocytosis in the liver. In familial
dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III),
increased plasma cholesterol and triglycerides are the consequence of
impaired clearance of chylomicron and VLDL remnants because of a defect
in apolipoprotein E. Accumulation of the remnants can result in
xanthomatosis and premature coronary and/or peripheral vascular disease.
Hyperlipoproteinemia III can be either due to primary heritable defects
in apolipoprotein metabolism or secondary to other conditions such as
hypothyroidism, systemic lupus erythematosus, or diabetic acidosis. Most
patients with familial dysbetalipoproteinemia (HLP III) are homozygous
for the E2 isoform (Breslow et al., 1982). Only rarely does the disorder
occur with the heterozygous phenotypes E3E2 or E4E2. The E2 isoform
shows defective binding of remnants to hepatic lipoprotein receptors
(Schneider et al., 1981; Rall et al., 1982) and delayed clearance from
plasma (Gregg et al., 1981). Additional genetic and/or environmental
factors must be required for development of the disorder, however,
because only 1-4% of E2E2 homozygotes develop familial
dysbetalipoproteinemia. Since the defect in this disorder involves the
exogenous cholesterol transport system, the degree of
hypercholesterolemia is sensitive to the level of cholesterol in the
diet (Brown et al., 1981). Even on a normal diet, the patient may show
increased plasma cholesterol and the presence of an abnormal lipoprotein
called beta-VLDL. VLDL in general is markedly increased while LDL is
reduced. Carbohydrate induces or exacerbates the hyperlipidemia,
resulting in marked variability in plasma levels and ready therapy
through dietary means. Often tuberous and planar and sometimes tendon
xanthomas occur as well as precocious atherosclerosis and abnormal
glucose tolerance. Tuberous and tuberoeruptive xanthomas are
particularly characteristic. Hazzard (1978) demonstrated the eliciting
effects of electric shock in a man revived from accidental electrocution
and later showing striking xanthomas of the palms. Development of the
phenotype is age dependent, being rarely evident before the third
decade. The nosography of the type III hyperlipoproteinemia phenotype up
to 1977 was reviewed by Levy and Morganroth (1977). Subsequent
description of specific biochemical alterations in apolipoprotein
structure and metabolism has proven this phenotype to be genetically
heterogeneous. In the first application of apoprotein immunoassay to
this group of disorders, Kushwaha et al. (1977) found that
apolipoprotein E (arginine-rich lipoprotein) is high in the VLD
lipoproteins of type III. They also found that exogenous estrogen, which
stimulates triglyceride production in normal women and those with
endogenous hypertriglyceridemia, exerted a paradoxical
hypotriglyceridemic effect in this disorder (Kushwaha et al., 1977). The
abnormal pattern of apoE by isoelectric focusing (IEF), specifically,
the absence of apoE3, is the most characteristic biochemical feature of
HLP III. Gregg et al. (1981) showed that apoE isolated from subjects
with type III HLP had a decreased fractional catabolic rate in vivo in
both type III HLP patients and normal persons.

Hazzard et al. (1981) reported on the large O'Donnell kindred, studied
because of a proband with type III HLP. They studied specifically the
VLDL isoapolipoprotein E distributions. The findings confirmed earlier
work indicating that the ratio of E3 to E2 is determined by two apoE3
alleles, designated d and n, which produce three phenotypes, apoE3-d,
apoE3-nd, and apoE3-n, corresponding to the low, intermediate, and high
ratios.

Ghiselli et al. (1981) studied a black kindred with type III HLP due to
deficiency of apolipoprotein E. No plasma apolipoprotein E could be
detected. Other families with type III HLP have had increased amounts of
an abnormal apoE. In addition, the patients of Ghiselli et al. (1981)
had only mild hypertriglyceridemia, increased LDL cholesterol, and a
much higher ratio of VLDL cholesterol to plasma triglyceride than
reported in other type III HLP families. The proband was a 60-year-old
woman with a 10-year history of tuberoeruptive xanthomas of the elbows
and knees, a 3-year history of angina pectoris, and 80% narrowing of the
first diagonal coronary artery by arteriography. Her father had
xanthomas and died at age 62 of myocardial infarction. Her mother was
alive and well at age 86. Three of 7 sibs also had xanthomas; her 2
offspring had no xanthomas. The evidence suggests that apoE is important
for the catabolism of chylomicron fragments. The affected persons in the
family studied by Ghiselli et al. (1981) had plasma levels of apoE less
than 0.05 mg/dl by radioimmunoassay, and no structural variants of apoE
were detected by immunoblot of plasma or VLDL separated by 2-dimensional
gel electrophoresis. Anchors et al. (1986) reported that the apoE gene
was present in the apoE-deficient patient and that there were no major
insertions or deletions in the gene by Southern blot analysis. Blood
monocyte-macrophages isolated from a patient contained levels of apoE
mRNA 1 to 3% of that present in monocyte-macrophages isolated from
normal subjects. The mRNA from the patient appeared to be of normal
size. Anchors et al. (1986) suggested that the decreased apoE mRNA might
be due to a defect in transcription or processing of the primary
transcript or to instability of the apoE mRNA. The decreased plasma
level of apoE resulted in delayed clearance of remnants of
triglyceride-rich lipoproteins, hyperlipidemia, and the phenotype of
type III HLP. In the kindred with apolipoprotein E deficiency studied by
Ghiselli et al. (1981), the defect was shown by Cladaras et al. (1987)
to involve an acceptor splice site mutation in intron 3 of the APOE gene
(107741.0005).

ApoE, a main apoprotein of the chylomicron, binds to a specific receptor
on liver cells and peripheral cells. The E2 variant binds less readily.
A defect in the receptor for apoE on liver and peripheral cells might
also lead to dysbetalipoproteinemia, but such has not been observed.
Weisgraber et al. (1982) showed that human E apoprotein of the E2 form,
which contains cysteine (rather than arginine) at both of the 2 variable
sites, binds poorly with cell surface receptors, whereas E3 and E4 bind
well. They postulated that a positively charged residue at variable site
B is important for normal binding. To test the hypothesis, they treated
E2 apoE with cysteamine to convert cysteine to a positively charged
lysine analog. This resulted in a marked increase in the binding
activity of the E2 apoE. Although nearly every type III
hyperlipoproteinemic person has the E2/E2 phenotype, 95 to 99% of
persons with this phenotype do not have type III HLP nor do they have
elevated plasma cholesterol levels. Rall et al. (1983) showed that apoE2
of hypo-, normo-, and hypercholesterolemic subjects showed the same
severe functional abnormalities. Thus, factors in addition to the
defective receptor binding activity of the apoE2 are necessary for
manifestation of type III HLP. A variety of factors exacerbate or
modulate type III. In women, it most often occurs after the menopause
and in such patients is particularly sensitive to estrogen therapy.
Hypothyroidism exacerbates type III and thyroid hormone is known to
enhance receptor-mediated lipoprotein metabolism. Obesity, diabetes and
age are associated with increased hepatic synthesis of VLDL and/or
cholesterol; occurrence of type III in E2/E2 persons with these factors
may be explained thereby. Furthermore, the defect in familial combined
HLP (144250), which is, it seems, combined with E2/E2 in the production
of type III (Utermann et al., 1979; Hazzard et al., 1981), may be
hepatic overproduction of cholesterol and VLDL. As pointed out by Brown
and Goldstein (1983), familial hypercholesterolemia (FH) is a genetic
defect of the LDL receptor (LDLR; 143890), whereas familial
dysbetalipoproteinemia is a genetic defect in a ligand. The puzzle that
all apoE2/2 homozygotes do not have extremely high plasma levels of IDL
and chylomicron remnants (apoE-containing lipoproteins) may be solved by
the observation that the lipoprotein levels in these patients are
exquisitely sensitive to factors that reduce hepatic LDL receptors,
e.g., age, decreased levels of thyroid hormone and estrogen, and the
genetic defect of FH. Presumably, high levels of hepatic LDL receptors
can compensate for the genetic binding defect of E2 homozygotes.

Gregg et al. (1983) suggested that apoE4 is associated with severe type
V hyperlipoproteinemia in a manner comparable to the association of
apoE2 with type III. Vogel et al. (1985) showed that large amounts of
apoE can be produced by E. coli transformed with a plasmid containing a
human apoE cDNA. The use in studies of structure-function relationships
through production of site-specific mutants was noted. Wardell et al.
(1989) demonstrated that the defect is a 7-amino acid insertion that
represents a tandem repeat of amino acid residues 121-127 resulting in
the normal protein having 306 amino acids rather than the normal 299.
Schaefer et al. (1986) described a unique American black kindred with
premature cardiovascular disease, tuberoeruptive xanthomas, and type III
HLP associated with familial apolipoprotein E deficiency. Four
homozygotes had marked increases in cholesterol-rich, very low density
lipoproteins and intermediate density lipoproteins (IDL). Homozygotes
had only trace amounts of plasma apoE, and accumulations of apoB-48
(107730) and apoA-4 (107690) in VLDL, IDL, and low density lipoproteins.
Obligate heterozygotes generally had normal plasma lipids and mean
plasma apoE concentrations that were 42% of normal. The findings
indicated that apoE is essential for the normal catabolism of
triglyceride-rich lipoprotein constituents. It had been shown that
cultured peripheral blood monocytes synthesized low amounts of 2
aberrant forms of apoE mRNA but produced no immunoprecipitable forms of
apoE. The expression studies were done comparing the normal and abnormal
APOE genes transfected into mouse cells in combination with the mouse
metallothionein I promoter. Bersot et al. (1983) studied atypical
dysbetalipoproteinemia characterized by severe hypercholesterolemia and
hypertriglyceridemia, xanthomatosis, premature vascular disease, the
apoE3/3 phenotype (rather than the classic E2/2 phenotype), and a
preponderance of beta-VLDL. They showed that the beta-VLDL from these
subjects stimulated cholesteryl ester accumulation in mouse peritoneal
macrophages. They suggested that the accelerated vascular disease
results from this uptake by macrophages which are converted into the
foam cells of atherosclerotic lesions. Smit et al. (1987) described 3
out of 41 Dutch dysbetalipoproteinemic patients who were apparent E3/E2
heterozygotes rather than the usual E2/E2 homozygotes. All 3 genetically
unrelated patients showed an uncommon E2 allele that contained only 1
cysteine residue. The uncommon allele cosegregated with familial
dysbetalipoproteinemia which in these families seemed to behave as a
dominant. Smit et al. (1990) showed that these 3 unrelated patients had
E2(lys146-to-gln). Eto et al. (1989) presented data from Japan
indicating that both the E2 allele and the E4 allele are associated with
an increased risk of ischemic heart disease as compared with the E3
allele. Boerwinkle and Utermann (1988) studied the simultaneous effect
of apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B,
and cholesterol metabolism. Since both apoB and apoE bind to the LDL
receptor and since the different isoforms show different binding
affinity, these effects are not unexpected.

Subjects with typical dysbetalipoproteinemia are homozygous for an amino
acid substitution in apoE at residue 158 (107741.0001). Chappell (1989)
studied the binding properties of lipoproteins in 9 subjects with
dysbetalipoproteinemia who were either homozygous or heterozygous for
substitutions at atypical sites: at residue 142 in 6, at 145 in 2, and
at 146 in 1.

In 5 of 19 Australian men, aged 30 to 50, who were referred for coronary
angioplasty (26%), van Bockxmeer and Mamotte (1992) observed
homozygosity for E4. This represented a 16-fold increase compared with
controls. Payne et al. (1992), O'Malley and Illingworth (1992), and de
Knijff et al. (1992) expressed doubts concerning a relationship between
E4 and atherosclerosis.

Feussner et al. (1996) reported a 20-year-old man with a combination of
type III hyperlipoproteinemia and heterozygous familial
hypercholesterolemia (FH; 143890). Multiple xanthomas were evident on
the elbows, interphalangeal joints and interdigital webs of the hands.
Lipid-lowering therapy caused significant decrease of cholesterol and
triglycerides as well as regression of the xanthomas. Flat xanthomas of
the interdigital webs were also described in 3 out of 4 previously
reported patients with combination of these disorders of lipoprotein
metabolism. Feussner et al. (1996) stated that these xanthomas may
indicate compound heterozygosity for type III hyperlipoproteinemia and
FH.

- Role in Alzheimer Disease

Saunders et al. (1993) reported an increased frequency of the E4 allele
in a small prospective series of possible-probable AD patients
presenting to the memory disorders clinic at Duke University, in
comparison with spouse controls. Corder et al. (1993) found that the
APOE*E4 allele is associated with the late-onset familial and sporadic
forms of Alzheimer disease. In 42 families with the late-onset form of
Alzheimer disease (AD2; 104310), the gene had been mapped to the same
region of chromosome 19 as the APOE gene. Corder et al. (1993) found
that the risk for AD increased from 20 to 90% and mean age of onset
decreased from 84 to 68 years with increasing number of APOE*E4 alleles.
Homozygosity for APOE*E4 was virtually sufficient to cause AD by age 80.

Lannfelt et al. (1995) compared allelic frequency of apolipoprotein E4
in 13 dizygotic twin pairs discordant for Alzheimer disease and found
the expected increased frequency of the epsilon-4 allele in Alzheimer
compared to healthy cotwins. In a well-known American kindred with
late-onset Alzheimer disease, descended from a couple who immigrated to
the United States from France in the 18th century, Borgaonkar et al.
(1993) found evidence confirming a dosage effect of the E4 allele of 6
affected individuals; 4 E4/E4 homozygotes had onset in their 60s,
whereas 2 E4/E3 heterozygotes had onset at ages 77 and 78, respectively.
Apolipoprotein E is found in senile plaques, congophilic angiopathy, and
neurofibrillary tangles of Alzheimer disease. Strittmatter et al. (1993)
compared the binding of synthetic amyloid beta peptide to purified APOE4
and APOE3, the most common isoforms. Both isoforms in oxidized form
bound the amyloid beta peptide; however, binding to APOE4 was observed
in minutes, whereas binding to APOE3 required hours. Strittmatter et al.
(1993) concluded that binding of amyloid beta peptide by oxidized apoE
may determine their sequestration and that isoform-specific differences
in apoE binding or oxidation may be involved in the pathogenesis of the
lesions of Alzheimer disease.

In a study of 91 patients with sporadic Alzheimer disease and 74
controls, Poirier et al. (1993) found a significant association between
E4 and sporadic AD. The association was more pronounced in women. Scott
(1993) pointed to the need for caution in the application of knowledge
gained through screening of E4 in relation to this very common disorder.

In a case-control study of 338 centenarians compared with adults aged 20
to 70 years of age, Schachter et al. (1994) found that the E4 allele of
apoE, which promotes premature atherosclerosis, was significantly less
frequent in centenarians than in controls (p = less than 0.001), while
the frequency of the E2 allele, associated previously with types III and
IV hyperlipidemia, was significantly increased (p = less than 0.01).

Talbot et al. (1994) presented data suggesting that the E2 allele may
confer protection against Alzheimer disease and that its effect is not
simply the absence of an E4 allele. Corder et al. (1994) presented data
demonstrating a protective effect of the E2 allele, in addition to the
dosage effect of the E4 allele in sporadic AD. Although a substantial
proportion (65%) of AD is attributable to the presence of E4 alleles,
risk of AD is lowest in subjects with the E2/E3 genotype, with an
additional 23% of AD attributable to the absence of an E2 allele. The
opposite actions of the E2 and E4 alleles were interpreted by Corder et
al. (1994) to provide further support for the direct involvement of APOE
in the pathogenesis of AD.

Sanan et al. (1994) demonstrated that the E4 isoform binds to the beta
amyloid (A-beta) peptide more rapidly than the E3 isoform. Soluble
SDS-stable complexes of E3 or E4, formed by coincubation with the A-beta
peptide, precipitated after several days of incubation at 37 degrees C,
with E4 complexes precipitating more rapidly than E3 complexes.

Hyman et al. (1996) demonstrated homozygosity for the E4 genotype in an
86-year-old man with no history of neurological disease and whose
autopsy did not reveal any neurofibrillary tangles and only rare mature
senile plaques. This suggested to the authors that inheritance of apoE4
does not necessarily result in the development of dementia or Alzheimer
disease.

Myers et al. (1996) examined the association of apolipoprotein E4 with
Alzheimer disease and other dementias in 1,030 elderly individuals in
the Framingham Study cohort. They found an increased risk for Alzheimer
disease as well as other dementias in patients who were homozygous or
heterozygous for E4. However they pointed out that most apoE4 carriers
do not develop dementia and about one-half of Alzheimer disease is not
associated with apoE4.

Kawamata et al. (1994) examined the E4 frequency in 40 patients with
late-onset sporadic Alzheimer disease, 13 patients with early-onset
sporadic Alzheimer disease, 19 patients with vascular dementia, and 49
nondemented control subjects. In the late-onset sporadic Alzheimer
group, the allele frequency was 0.25, considerably higher than the
frequency in controls, 0.09. In contrast, there was no increased
frequency in early-onset sporadic Alzheimer disease or in patients with
vascular dementia. Olichney et al. (1996) found that the Apo protein E
epsilon-4 allele is strongly associated with increased neuritic plaques
but not neocortical or fibrillary tangles in both Alzheimer disease and
the Lewy body variant.

Greenberg et al. (1995) found that the presence of apolipoprotein E
epsilon-4 increased the odds ratio for moderate or severe cerebral
amyloid angiopathy significantly, even after controlling for the
presence of Alzheimer disease.

Kawamata et al. (1994) speculated that the lower magnitude of the raised
frequency of E4 in the Japanese group compared to that of North American
families may be due to a lower E4 frequency in the normal Japanese
population and lower morbidity from Alzheimer disease in Japan.
Nalbantoglu et al. (1994) performed apolipoprotein analysis on 113
postmortem cases of sporadic Alzheimer disease and 77 control brains in
Montreal. In this population, the odds ratio associating E4 with
Alzheimer disease was 15.5 and the population attributable risk was
0.53. Yoshizawa et al. (1994) examined the apolipoprotein genotypes in
83 Japanese patients with Alzheimer disease. They found a significant
increase in apoE4 frequency in late-onset sporadic Alzheimer disease and
a mild increase of apoE4 frequency in late- and early-onset familial
Alzheimer disease. In contrast, they found no association between apoE4
and early-onset sporadic Alzheimer disease.

Lucotte et al. (1994) examined the apoE4 frequency in 132 French
patients with onset of Alzheimer disease after 60 years of age. They
found that homozygosity for the E4 allele was associated with a younger
age of disease occurrence than was heterozygosity or absence of the E4
allele. Osuntokun et al. (1995) found no association between E4 and
Alzheimer disease in elderly Nigerians, in contrast to the strong
association reported in their previous study of African Americans in
Indianapolis. Levy-Lahad et al. (1995) found that the epsilon 4 allele
did not affect the age of onset in either Alzheimer disease type 4
present in Volga Germans (600753) or Alzheimer disease type 3 (104311).
This suggested to them that some forms of early onset familial Alzheimer
disease are not influenced by the apolipoprotein E system.

Bennett et al. (1995) examined the APOE genotype in family
history-positive and family history-negative cases of Alzheimer disease
and found a distortion of the APOE allele frequencies similar to those
with previous studies. However, they also examined the allele
distribution of at-risk sibs and found an excess of the E4 allele which
did not differ from that of affected sibs. In these families, they found
no evidence for linkage between the APOE4 locus and Alzheimer disease.
They concluded that the APOE locus is neither necessary nor sufficient
to cause Alzheimer disease and speculated that it may modify the
preclinical progression, and therefore the age of onset, in people
otherwise predisposed to develop Alzheimer disease.

Head injury is an epidemiologic risk factor for Alzheimer disease and
deposition of A-beta occurs in approximately one-third of individuals
dying after severe head injury. Nicoll et al. (1995) found that the
frequency of APOE4 in individuals with A-beta deposition following head
injury (0.52) was higher than in most studies of Alzheimer disease,
while in those head-injured individuals without A-beta deposition, the
APOE4 frequency (0.16) was similar to controls without Alzheimer disease
(P = less than 0.00001). Thus, environmental and genetic risk factors
for Alzheimer disease may act additively.

In a review of apolipoprotein E and Alzheimer disease, Strittmatter and
Roses (1995) pointed out that isoform-specific differences have been
identified in the binding of apoE to the microtubule-associated protein
tau (157140), which forms the paired helical filament and
neurofibrillary tangles, and to amyloid beta peptide (104760), a major
component of the neuritic plaque. Identification of apoE in the
cytoplasm of human neurons and isoform-specific binding of apoE to the
microtubule-associated protein tau and MAP-2 (157130) make it possible
that apoE may affect microtubule function in the Alzheimer brain.
Blennow et al. (1994) demonstrated a significant reduction of CSF
apolipoprotein E in Alzheimer disease compared to that of controls. They
suggested that the increased reutilization of apolipoprotein E lipid
complexes in the brain in Alzheimer disease may explain the low CFS
concentration.

The observation that the APOE4 allele is neither necessary nor
sufficient for the expression of AD emphasizes the significance of other
environmental or genetic factors that, either in conjunction with APOE4
or alone, increase the risk of AD. Kamboh et al. (1995) noted that among
the candidate genes that might affect the risk for Alzheimer disease is
alpha-1-antichymotrypsin (AACT; 107280) because, like APOE protein, AACT
binds to beta-amyloid peptide with high affinity in the filamentous
deposits found in the AD brain. Additionally, it serves as a strong
stimulatory factor in the polymerization of beta-amyloid peptide into
amyloid filaments. Kamboh et al. (1995) demonstrated that a common
polymorphism in the signal peptide of AACT (107280.0005) confers a
significant risk for AD and that the APOE4 gene dosage effect associated
with AD risk is significantly modified by the AACT polymorphism. They
identified the combination of the AACT 'AA' genotype with the APOE4/4
genotype as a potential susceptibility marker for AD, as its frequency
was 1/17 in the AD group compared to 1/313 in the general population
controls. It is noteworthy that one form of Alzheimer disease
(designated Alzheimer type 3, 104311), like AACT, maps to 14q; however,
AACT and AD3 are located at somewhat different sites on 14q.

Tang et al. (1996) compared relative risks by APOE genotypes in a
collection of cases and controls from 3 ethnic groups in a New York
community. The relative risk for Alzheimer disease associated with APOE4
homozygosity was increased in all ethnic groups: African American RR =
3.0; Caucasian RR = 7.3; and Hispanic RR = 2.5 (compared with the RR
with APOE3 homozygosity). The risk was also increased for APOE4
heterozygous Caucasians and Hispanics, but not for African Americans.
The age distribution of the proportion of Caucasian and Hispanics
without AD was consistently lower for APOE4 homozygous and APOE4
heterozygous individuals than for those with other APOE genotypes. In
African Americans this relationship was observed only in APOE4
homozygotes. Differences in risk among APOE4 heterozygous African
Americans suggested to the authors that other genetic or environmental
factors may modify the effect of APOE4 in some populations.

In a study of 85 Scottish persons with early onset Alzheimer disease, St
Clair et al. (1995) found highly significant enrichment for both
homozygous and heterozygous APOE epsilon-4 allele carriers in both
familial and sporadic cases with a pattern closely resembling that in
late onset AD.

As reviewed earlier, the APOE4 allele is associated with sporadic and
late-onset familial Alzheimer disease. Gene dose has an effect on risk
of developing AD, age of onset, accumulation of senile plaques in the
brain, and reduction of choline acetyltransferase (118490) in the
hippocampus of AD patients. Poirier et al. (1995) examined the effect of
APOE4 allele copy number on pre- and postsynaptic markers of cholinergic
activity. APOE4 allele copy number showed an inverse relationship with
residual brain CHAT activity and nicotinic receptor binding sites in
both the hippocampal formation and the temporal cortex of AD subjects.
AD subjects lacking the APOE4 allele showed CHAT activities close to or
within the age-matched normal control range. Poirier et al. (1995) then
assessed the effect of the APOE4 allele on cholinomimetic drug
responsiveness in 40 AD patients who completed a double-blind, 30-week
clinical trial of the cholinesterase inhibitor tacrine. Results showed
that more than 80% of APOE4-negative AD patients showed marked
improvement after 30 weeks, whereas 60% of APOE4 carriers had poor
responses.

Polvikoski et al. (1995) reported on an autopsy study involving
neuropathologic analysis and DNA analysis of frozen blood specimens
performed in 92 of 271 persons who were at least 85 years of age, who
had been living in Vantaa, Finland, on April 1, 1991, and who had died
between that time and the end of 1993. All subjects had been tested for
dementia. Apolipoprotein E genotyping was done with a solid-phase
minisequencing technique. The percentage of cortex occupied by
methenamine silver-stained plaques was used as an estimate of the extent
of beta-amyloid protein deposition. They found that the APOE4 allele was
significantly associated with Alzheimer disease. Even in elderly
subjects without dementia, the apolipoprotein E4 genotype was related to
the degree of deposition of beta-amyloid protein in the cerebral cortex.

Reiman et al. (1996) found that in late middle age, cognitively normal
subjects who are homozygous for the APOE4 allele had reduced glucose
metabolism in the same regions of the brain as in patients with probable
Alzheimer disease. These findings provided preclinical evidence that the
presence of the APOE4 allele is a risk factor for Alzheimer disease.
Positron-emission tomography (PET) was used in these studies; Reiman et
al. (1996) suggested that PET may offer a relatively rapid way of
testing treatments to prevent Alzheimer disease in the future.

In late-onset familial AD, women have a significantly higher risk of
developing the disease than do men. Studying 58 late-onset familial AD
kindreds, Payami et al. (1996) detected a significant gender difference
for the APOE4 heterozygous genotype. In women, APOE4 heterozygotes had
higher risk than those without APOE4; there was no significant
difference between APOE4 heterozygotes and APOE4 homozygotes. In men,
APOE4 heterozygotes had lower risk than APOE4 homozygotes; there was no
significant difference between APOE4 heterozygotes and those without
APOE4. A direct comparison of APOE4 heterozygous men and women revealed
a significant 2-fold increased risk in women. These results were
corroborated in studies of 15 autopsy-confirmed AD kindreds from the
National Cell Repository at Indiana University Alzheimer Disease Center.

Mahley (1988) provided a review documenting the expanding role of apoE
as a cholesterol transport protein in cell biology. The pronounced
production and accumulation of apoE in response to peripheral nerve
injury and during the regenerative process indicates, for example, that
apoE plays a prominent role in the redistribution of cholesterol to the
neurites for membrane biosynthesis during axon elongation and to the
Schwann cells for myelin formation. Poirier (1994) reviewed the
coordinated expression of apoE and its receptor, the apoE/apoB LDL
receptor (143890), in the regulation of transport of cholesterol and
phospholipids during the early and intermediate phases of reinnervation,
both in the peripheral and in the central nervous system. He proposed
that the linkage of the E4 allele to Alzheimer disease (104300) may
represent dysfunction of the lipid transport system associated with
compensatory sprouting and synaptic remodeling central to the Alzheimer
disease process.

Tomimoto et al. (1995) found only 3 cases with focal accumulation of
apolipoprotein E in dystrophic axons and accompanying macrophages in 9
cases of cerebral vascular disease and 4 control subjects. The results
suggested to the authors that apolipoprotein E may have a role in
recycling cholesterol in other membrane components in the brain, but
that this phenomenon is restricted to the periphery of infarctions and
may be less prominent than in the peripheral nervous system.

Egensperger et al. (1996) determined the apoE allele frequencies in 35
subjects with neuropathologically confirmed Lewy body parkinsonism with
and without concomitant Alzheimer lesions, 27 patients with AD, and 54
controls. They concluded that the apoE4 allele does not function as a
risk factor which influences the development of AD lesions in PD.

In aggregate, the association studies on ApoE in Alzheimer disease
suggest epsilon-4 accelerates the neurodegenerative process in Alzheimer
disease. However, in 3 independent studies, Kurz et al. (1996), Growdon
et al. (1996), and Asada et al. (1996) found no differences in the
clinical rate of decline of newly diagnosed Alzheimer disease patients
with or without the epsilon-4 allele.

Bickeboller et al. (1997) confirmed the increased risk for AD associated
with the APOE4 allele in 417 patients compared with 1,030 control
subjects. When compared to the APOE3 allele, the authors demonstrated an
increased risk associated with the APOE4 allele (odds ratio = 2.7) and a
protective effect of the APOE2 allele (odds ratio = 0.5). An effect of
E4 allele dosage on susceptibility was confirmed: the odds ratio of
E4/E4 versus E3/E3 = 11.2; odds ratio of E3/E4 versus E3/E3 = 2.2. In
E3/E4 individuals, sex-specific lifetime risk estimates by age 85 years
(i.e., sex-specific penetrances by age 85 years) were 0.14 for men and
0.17 for women.

- Role in Other Progressive Neurologic Disorders

Saunders et al. (1993) found no association of E4 with other
amyloid-forming diseases, i.e., Creutzfeldt-Jakob disease (CJD; 123400),
familial amyloidotic polyneuropathy, and Down syndrome (190685). On the
other hand, Amouyel et al. (1994) concluded that E4 is a major
susceptibility factor for CJD. They found a relative risk of CJD between
subjects with at least one E4 allele and subjects with none to range
between 1.8 and 4.2, depending on the control group used. A variation in
disease duration was also noted, depending on apoE genotype, with an
increase in duration of illness in E2 allele carriers.

Frisoni et al. (1994) assessed the apoE allele frequency in 51 elderly
control subjects, 23 subjects with vascular dementia, and 93 patients
with Alzheimer disease. There was increased frequency of the E4 allele
both in Alzheimer disease and in vascular dementia with respect to both
elderly and young control subjects. There was no difference in the
proportion of E2, E3, and E4 frequency in Alzheimer disease and vascular
dementia patients. In contrast, Mahieux et al. (1994) found an increase
of E4 in Alzheimer disease, but not in vascular dementia. They
speculated that the difference between their results and those of
Frisoni et al. (1994) may be attributable to the small size of the
groups or to the different mean ages of the populations that they
studied.

Myers et al. (1996) examined the association of apolipoprotein E4 with
Alzheimer disease and other dementias in 1,030 elderly individuals in
the Framingham Study cohort. They found an increased risk for Alzheimer
disease as well as other dementias in patients who were homozygous or
heterozygous for E4. However they pointed out that most apoE4 carriers
do not develop dementia and about one-half of Alzheimer disease is not
associated with apoE4.

Blesa et al. (1996) found an apoE epsilon-4 frequency of 0.315 in
patients with age-related memory decline without dementia, similar to
the 0.293 allele frequency found in an Alzheimer disease group. This
contrasted to the frequency of 0.057 found in their control group.

In a study of 79 patients with Parkinson disease, 22 of whom were
demented, Marder et al. (1994) found that the E4 allele frequency was
0.13 in patients without dementia and 0.068 in those with dementia as
opposed to a control value of 0.102. The authors concluded that the
biologic basis for dementia in Parkinson disease differs from that of
Alzheimer disease.

Tabaton et al. (1995) found that, although apolipoprotein E
immunoreactivity was found to be associated with neurofibrillary tangles
in an autopsy study of 12 patients with progressive supranuclear palsy
(601104), the apolipoprotein E allele frequency was similar to that of
age-matched controls. Farrer et al. (1995) demonstrated that the number
of epsilon-4 alleles was inversely related to the age at onset of Pick
disease (172700). Their results suggested that epsilon-4 may be a
susceptibility factor for dementia and not specifically for AD.

Mui et al. (1995) found no association between apolipoprotein E4 and the
incidence or the age of onset of sporadic of autosomal dominant
amyotrophic lateral sclerosis (105400). Garlepp et al. (1995) found an
increased frequency of the epsilon 4 allele in patients with inclusion
body myositis (147421) compared with that in patients with other
inflammatory muscle diseases or that in the general population.

In a study of ApoE genotypes in schizophrenic patients coming to
autopsy, Harrington et al. (1995) found that schizophrenia is associated
with an increased E4 allele frequency. The E4 allele frequency in
schizophrenia was indistinguishable from that found in either Alzheimer
disease or Lewy body dementia (127750). From the age range at autopsy
(from 19 to 95 years), they determined that the epsilon 4 frequency was
not associated with increased age.

Betard et al. (1994) analyzed allele frequencies of apoE in 166
autopsied French-Canadian patients with dementia. The E4 frequency was
highest in Lewy body dementia (0.472); presenile Alzheimer disease
(0.405); senile Alzheimer disease (0.364); and Alzheimer disease with
cerebrovascular disease (0.513). In contrast, the E4 allele frequency
was 0.079 in autopsied cases of individuals with vascular dementia but
no changes of Alzheimer disease. Subjects with vascular dementia
demonstrated an increased relative E2 allele frequency of 0.211 compared
to 0.144 in elderly controls. In contradistinction to the findings of
Betard et al. (1994), Lippa et al. (1995) found much lower frequency of
E4, 0.22, when they were careful to exclude Lewy body patients that had
concurrent Alzheimer disease by the Cerat criterion. They did, however,
find that a neuritic degeneration in CA2-3 was slightly greater in those
Lewy body disease patients with the apoE4 allele than those with the
E3/3 genotype. Hyman et al. (1995) found that senile plaques in the
Alzheimer disease of Down syndrome were abnormally large, whereas those
of APOE4-related Alzheimer disease were unusually numerous. The findings
suggested that the pathology in Down syndrome is due to increased
amyloid production and deposition, whereas that in APOE4, disease is
related to an increased probability of senile plaque initiation. Royston
et al. (1994) assessed the ApoE genotype in elderly Down syndrome
patients and found that the epsilon-2 variant was associated both with
increased longevity and a significantly decreased frequency of
Alzheimer-type dementia. They noted that none of their elderly Down
patients was homozygous for the epsilon-4 allele.

In a case-control study of apoE genotypes in Alzheimer disease
associated with Down syndrome, van Gool et al. (1995) showed that the
frequencies of ApoE type 2, 3, or 4 were not significantly different in
Down syndrome cases with Alzheimer disease compared with aged-matched
Down syndrome controls. The ApoE 4 frequency in Down syndrome cases with
Alzheimer disease was significantly lower than in any other Alzheimer
disease populations studied thus far, suggesting that ApoE 4 does not
significantly affect the pathogenesis of Alzheimer disease in Down
syndrome patients.

MAPPING

Olaisen et al. (1982) found linkage of C3 (120700) and apoE with a lod
score of 3.00 in males at a recombination fraction of 13%. Since the C3
locus is on chromosome 19, apoE can be assigned to that chromosome also.
The authors stated that preliminary evidence suggested that the apoE
locus is close to the secretor locus (182100). Berg et al. (1984)
studied apoE-C3 linkage with a C3 restriction fragment length
polymorphism. Low positive lod scores were found when segregation was
from a male (highest score at recombination fraction 0.17). Using DNA
probes, Das et al. (1985) mapped the apoE gene to chromosome 19 by
Southern blot analysis of DNA from human-rodent somatic cell hybrids.
Humphries et al. (1984) used a common TaqI RFLP near the APOC2 gene to
demonstrate close linkage to APOE in 7 families segregating for APOE
protein variants. No recombination was observed in 20 opportunities.
Apparent linkage disequilibrium was observed. On the other hand,
Houlston et al. (1989), using a robust PCR-based method for apoE
genotyping, found no strong linkage disequilibrium between the APOE and
APOC2 loci. Gedde-Dahl et al. (1984) found linkage between Se and APOE
with a peak lod score of 3.3 at recombination fraction of 0.08 in males
and 1.36 at 0.22 in females, and linkage between APOE and Lu with a lod
score 4.52 at zero recombination (sexes combined). The C3-APOE linkage
gave lod score 4.00 at theta 0.18 in males and 0.04 at theta 0.45 in
females. Triply heterozygous families confirmed that APOE is on the Se
side and on the Lu side of C3. Lusis et al. (1986) used a reciprocal
whole arm translocation between the long arm of 19 and the short arm of
chromosome 1 to map APOC1, APOC2, APOE and GPI to the long arm and LDLR,
C3 and PEPD to the short arm. Furthermore, they isolated a single lambda
phage that carried both APOC1 and APOE separated by about 6 kb of
genomic DNA. Since family studies indicate close linkage of APOE and
APOC2, the 3 must be in a cluster on 19q.

ANIMAL MODEL

Because apolipoprotein E is a ligand for receptors that clear remnants
of chylomicrons and very low density lipoproteins, lack of apoE would be
expected to cause accumulation in plasma of cholesterol-rich remnants
whose prolonged circulation should be atherogenic. Zhang et al. (1992)
demonstrated that this was indeed the case: apoE-deficient mice
generated by gene targeting (Piedrahita et al., 1992) had 5 times normal
plasma cholesterol and developed foam cell-rich depositions in their
proximal aortas by age 3 months. These spontaneous lesions progressed
and caused severe occlusion of the coronary artery ostium by 8 months.
Plump et al. (1992) independently found the same in apoE-deficient mice
created by homologous recombination in ES cells. The findings in the
mouse model are comparable to those in 3 human kindreds with inherited
apoE deficiency (Ghiselli et al., 1981; Mabuchi et al., 1989; Kurosaka
et al., 1991). Commenting on the articles of Plump et al. (1992) and
Zhang et al. (1992), Brown and Goldstein (1992) pointed out that
molecular genetics has given us the opportunity to satisfy Koch's
postulates for multifactorial metabolic diseases. Further use of the
apoE gene-targeted mice was made by Linton et al. (1995), who showed
that the severe hyperlipidemia and atherosclerosis in these mice could
be prevented by bone marrow transplantation. Although the majority of
apoE in plasma is of hepatic origin, the protein is synthesized by a
variety of cell types, including macrophages. Because macrophages derive
from hematopoietic cells, bone marrow transplantation seemed a possible
therapeutic approach. ApoE-deficient mice given transplants of normal
bone marrow showed apoE in the serum and a normalization of serum
cholesterol levels. Furthermore, they showed virtually complete
protection from diet-induced atherosclerosis.

To unravel the metabolic relationship between apoE and apoC1 in vivo,
van Ree et al. (1995) generated mice deficient in both apolipoproteins.
This enabled subsequent production of transgenic mice with variable
ratios of normal and mutant apoE and apoC1 on a null background. They
found that double inactivation of the ApoE and ApoC1 (107710) loci in
mice, as well as single inactivations at either one of these loci, also
affected the levels of RNA expression of other members of the Apoe-c1-c2
cluster. Homozygous Apoe-c1 knockout mice were hypercholesterolemic and,
with serum cholesterol levels more than 4 times the control value,
resembled mice solely deficient in apoE.

Kashyap et al. (1995) noted that apolipoprotein E-deficient mice,
generated using homologous recombination for targeted gene disruption in
embryonic stem cells, developed marked hyperlipidemia as well as
atherosclerosis. Kashyap et al. (1995) found that intravenous infusion
of a recombinant adenovirus containing the human APOE gene resulted in
normalization of the lipid and lipoprotein profile with markedly
decreased total cholesterol, VLDL, IDL, and LDL, as well as increased
HDL. A marked reduction in the extent of aortic atherosclerosis was
observed after one month.

Plump et al. (1992) and Zhang et al. (1992) created apoE-deficient mice
by gene targeting in embryonic stem cells. These mice displayed severe
hypercholesterolemia even on a low-fat, low cholesterol diet. A key
regulator of cholesterol-rich lipoprotein metabolism, apoE, is
synthesized by numerous extra hepatic tissues. It is synthesized, for
example, in macrophages. To assess the contribution of
macrophage-derived apoE to hepatic clearance of serum cholesterol,
Boisvert et al. (1995) performed bone marrow transplantation on
hypercholesterolemic apoE-deficient 'knockout' mice. Serum cholesterol
levels dropped dramatically in the bone marrow-treated mice largely due
to a reduction in VLDL cholesterol. The extent of atherosclerosis in the
treated mice was also greatly reduced. Wildtype apoE mRNA was detected
in the liver, spleen, and brain of the treated mice indicating that gene
transfer was successfully achieved through bone marrow transplantation.
Masliah et al. (1995) observed an age-dependent loss of
synaptophysin-immunoreactive nerve terminals and microtubule-associated
protein 2-immunoreactive dendrites in the neocortex and hippocampus of
apoE-deficient (knockout) mice. They suggested that apoE may play a role
in maintaining the stability of the synapto-dendritic apparatus.

*FIELD* AV
.0001
APOE2 ISOFORMS
HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL RECESSIVE
APOE, ARG158CYS
Apolipoprotein E2 exists in 2 main isoforms, arg158 and cys158 (Rall et
al., 1982; Gill et al., 1985). The second isoform (arg158-to-cys) was
found in 98 of 100 E2 alleles by Emi et al. (1988). The other isoforms
that give a band at the E2 position with isoelectric focusing include
E2(lys146-to-gln) and E2(arg145-to-cys). Type III hyperlipoproteinemia
is typically associated with homozygosity for a change in apolipoprotein
E2 from arg158 to cys.

.0002
HYPERLIPOPROTEINEMIA AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5
APOE, GLU3LYS
This change was identified in Japanese by Tajima et al. (1988). Using
isoelectric focusing with immunoblotting in the study of blood specimens
from 1,269 Japanese subjects, Matsunaga et al. (1995) found that the
epsilon-5 allele had a frequency of 0.001.

.0003
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-CHRISTCHURCH
APOE, ARG136SER
This variant was described by Wardell et al. (1987) and Emi et al.
(1988). Wardell et al. (1987) studied the primary structure of apoE in 7
type III hyperlipoproteinemic patients with the apoE2/E2 phenotype. Six
of the patients had identical 2-dimensional tryptic peptide maps; these
differed from the normal by the altered mobility of a single peptide.
Amino acid analysis and sequencing showed that these patients had the
most common form of apoE2 (158 arg-to-cys). The seventh patient had a
unique peptide map with the new peptide resulting from a substitution of
136 arginine-to-serine. He was heterozygous for this and for the common
158 arg mutation; thus, he was a genetic compound.

.0004
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2
FAMILIAL DYSBETALIPOPROTEINEMIA
APOE, ARG145CYS
This variant was described by Rall et al. (1982) and Emi et al. (1988).
Rall et al. (1982) demonstrated heterogeneity in type III
hyperlipoproteinemia. They studied 3 subjects who were phenotypically
homozygous for apoE2 but showed considerable differences in the binding
activity to the fibroblast receptor. The subject with the poorest
binding apoE2 was genotypically homozygous for an apoE allele (epsilon
2); cysteine was found at sites A and B. The subject with the most
actively binding apoE2 was genotypically homozygous for an apoE allele
(epsilon 2*); cysteine was found at site A and at a new site, site C,
residue 145, which in apoE2 has arginine. Epsilon 2*, furthermore,
specifies a protein with arginine at site B (residue 158). The third
subject, whose apoE2 displayed binding activity intermediate between the
activities of the other 2, was genotypically heterozygous, having 1
epsilon 2 allele and 1 epsilon 2* allele.

.0005
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY
APOE, IVS3AS, A-G, -1
Cladaras et al. (1987) showed that one form of familial apoE deficiency
results from a point mutation in the 3-prime splice junction of the
third intron of the APOE gene. The change, an A-to-G substitution in the
penultimate 3-prime nucleotide of the third intron, abolished the
correct 3-prime splice site, thus creating 2 abnormally spliced mRNA
forms. Both mRNAs contain chain termination codons within the intronic
sequence. The clinical features of the patient were described by
Ghiselli et al. (1981) and Schaefer et al. (1986).

.0006
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE LEIDEN
APOE, 21-BP INS, DUP CODONS 121-127
Havekes et al. (1986) found type III hyperlipoproteinemia (HLP) in a
dominant pedigree pattern in a family with a variant of E3 they called
E3(Leiden). By isoelectric focusing, the affected persons appeared to be
homozygous for normal apoE3, but the variant E3 showed defective binding
to LDL receptor, and on sodium dodecyl sulfate polyacrylamide gel
electrophoresis showed mobility intermediate to those of normal E3 and
normal E2. The mother and 5 of 8 sibs had type III HLP; 4 of the 5 had
xanthomatosis. The affected persons were heterozygotes E3/E3(Leiden).
Wardell et al. (1989) demonstrated a 7-amino acid inversion that is a
tandem repeat of residues 121-127. In a screening of patients with
familial dysbetalipoproteinemia, de Knijff et al. (1991) found 5
probands showing heterozygosity for the APOE*3-Leiden allele.
Genealogical studies revealed that these probands shared common ancestry
in the 17th century. In 1 large kindred spanning 3 generations, 37
additional heterozygotes were detected. Although severity varied, all
carriers showed characteristics of dysbetalipoproteinemia such as: (a)
elevated levels of cholesterol in VLDL and IDL fractions; (b) elevated
ratios of cholesterol levels in these density fractions over total
plasma levels of triglycerides; and (c) strongly increased plasma levels
of apoE. Multiple linear regression analysis showed that most of the
variability in expression of familial dysbetalipoproteinemia in
APOE*3-Leiden allele carriers can be explained by age.

In a discussion of mouse models of atherosclerosis, Breslow (1996)
referred to the development of a transgenic mouse carrying the
APOE-Leiden mutation. When fed a very high cholesterol diet containing
cholic acid, these mice had cholesterol levels of 1,600 to 2,000 mg/dl
and developed fatty streak and fibrous plaque lesions.

.0007
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE7
APOE-SUITA
APOE, GLU244LYS AND GLU245LYS
Maeda et al. (1989) and Tajima et al. (1989) found that 2 contiguous
glutamic acid residues, glu244 and glu245, are changed to lysine
residues, lys244 and lys245. This involved a change from GAC-GAG to
AAC-AAG. Using isoelectric focusing with immunoblotting in the study of
blood specimens from 1,269 Japanese subjects, Matsunaga et al. (1995)
found that the epsilon-7 allele had a frequency of 0.007.

.0008
HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT
FAMILIAL DYSBETALIPOPROTEINEMIA
APOE, CYS112ARG AND ARG142CYS
In a family reported by Havel et al. (1983), Rall et al. (1989) found
that the members with type III hyperlipoproteinemia (HLP) were compound
heterozygotes for 2 different APOE alleles, one coding for the normal
APOE3 and one for a previously undescribed variant APOE3 with 2 changes:
arginine replacing cysteine at residue 112 and cysteine replacing
arginine at residue 142. The variant APOE3 was defective in its ability
to bind to lipoprotein receptors, a functional defect probably
contributing to expression of type III HLP in this kindred. Type III HLP
typically is associated with homozygosity for apolipoprotein E2
(arg158-to-cys); see 107741.0001. Dominant expression of type III HLP
associated with apoE phenotype E3/3 is caused by heterozygosity for a
common apoE variant, apoE3 (cys112-to-arg; arg142-to-cys). To determine
the functional characteristics of the variant protein, Horie et al.
(1992) used recombinant DNA techniques to produce the variant in
bacteria. They also produced a non-naturally occurring variant,
apoE(arg142cys), that had only the cysteine substituted at residue 142.
They demonstrated that the cys142 variant was responsible for the
defective binding to lipoprotein receptors because both showed the same
defect. The arg112,cys142 variant predominates 3:1 over normal apoE3 in
the very low density lipoproteins of plasma from an affected subject.
Horie et al. (1992) concluded that unique properties of the
arg112,cys142 variant provided an explanation for its association with
dominant expression of type III HLP.

.0009
APOLIPOPROTEINEMIA E1
APOE, GLY127ASP AND ARG148CYS
Weisgraber et al. (1984) found an electrophoretic variant of apoE in a
Finnish hypertriglyceridemic subject. The variant was designated E1
(gly127-to-asp, arg148-to-cys). Family studies showed 'vertical
transmission.' The relation of E1 to hypertriglyceridemia was unclear.

.0010
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG
APOE, LYS146GLU
Mann et al. (1989) described this mutation as the basis of familial
dysbetalipoproteinemia.

The mutation led to the dominant expression of type III
hyperlipoproteinemia in all 5 affected patients heterozygous for the
mutant allele in this family. A second family with type III
hyperlipoproteinemia due to the identical mutation was reported by
Moriyama et al. (1992). Mann et al. (1995) determined the structural
defect in the ApoE-1 molecule resulting from this mutation and studied
its functional implications using in vivo kinetic studies in the
original proband and in normal subjects, and using in vitro binding
assays with human fibroblasts and the proteoglycan heparin. They
concluded that the functional dominance of the mutation resulted from
the abnormal in vitro binding characteristics and the altered in vivo
metabolism of the mutant protein.

.0011
DYSBETALIPOPROTEINEMIA DUE TO APOE2
APOE, LYS146GLN
As in APOE1-Harrisburg, a mutation at position 146 leads to
dysbetalipoproteinemia, suggesting that this residue plays a crucial
role in removal of chylomicrons and VLDL in vivo. In the Netherlands,
Smit et al. (1990) found that all 40 patients with familial
dyslipoproteinemia and the E2E2 phenotype were homozygous for the
E2(arg158-to-cys) mutation. On the other hand, all 3 unrelated patients
with the E3E2 phenotype showed the rare E2(lys146-to-gln) mutation due
to an A-to-C substitution at nucleotide 3847 of the APOE gene. This
mutation was not found in normolipidemic persons with the E2E2 (N = 13)
or E3E2 (N = 120) phenotype selected from a random population sample.
Family studies showed predisposition to type III hyperlipoproteinemia
with high penetrance. Thus, this is a highly penetrant dominant form of
the disease; E2(arg158-to-cys) is a low penetrant, recessive form.
Dominant inheritance has been observed also with E1(Harrisburg),
E3(Leiden), and E3(cys112-to-arg; arg142-to-cys). Some of the reduced
penetrance of the E2 allele in causing familial dysbetalipoproteinemia
is based on the fact that all E2 as phenotyped by isoelectric focusing
is not genetically a single entity.

.0012
APOE2-DUNEDIN
APOE, ARG228CYS
In identical twin brothers with the E2/2 phenotype but with type IV/V
hyperlipoproteinemia, Wardell et al. (1990) found compound
heterozygosity for the arg158-to-cys mutation and a second unusual
mutation representing a substitution of cysteine for arginine at
position 228.

.0013
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA
APOE, GLU13LYS AND ARG145CYS
In a 24-year-old white female with severe type III hyperlipoproteinemia
(HLP), Lohse et al. (1991) found 2 rare point mutations. One was a
C-to-T mutation which converted arginine (CGT) at position 145 of the
mature protein to cysteine (TGT), thus creating the APOE-2* variant
(107741.0004). A second G-to-A substitution at amino acid 13 led to the
exchange of lysine (AAG) for glutamic acid (GAG), thereby adding 2
positive charge units to the protein and producing the APOE-5 variant.
Both mutations resulted in loss of restriction enzyme cleavage sites.
The proband was homozygous for both mutations. Lohse et al. (1992)
extended their analyses to include 9 additional family members of the
Philadelphia kindred spanning 4 generations. DNA and protein analysis
demonstrated that the originally described proposita, called by them
propositus, was a true homozygote for the apolipoprotein
E4(Philadelphia) allele and that 6 of the 9 family members were
heterozygous for the mutant allele and the normal E3 allele or, in 1
case, the E4 allele. Heterozygosity led to the expression of a moderate
form of type III HLP without clinical manifestations. The simultaneous
presence of unaffected persons, heterozygotes, and a homozygote makes it
possible to conclude that the mutation shows incomplete dominance.

.0014
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY
APOE3-WASHINGTON
APOE, TRP210TER
Lohse et al. (1992) studied a kindred with apolipoprotein E deficiency
and a truncated low molecular weight apoE mutant, designated
apoE-3(Washington). Gel electrophoresis demonstrated complete absence of
the normal apoE isoproteins and the presence of a small quantity of a
lower molecular weight apoE. Plasma apoE levels in the proband were
approximately 4% of normal. This marked deficiency of apoE resulted in
delayed uptake of chylomicron and very low density lipoprotein (VLDL)
remnants by the liver, elevated plasma cholesterol levels, mild
hypertriglyceridemia, and the development of type III
hyperlipoproteinemia. Sequence analysis demonstrated a G-to-A transition
which converted amino acid 210 of the mature protein, tryptophan (TGG),
to a premature chain termination codon (TAG), thus leading to the
synthesis of a truncated E apolipoprotein of 209 amino acids with a
molecular mass of 23.88 kD. The nucleotide substitution also resulted in
the formation of a new restriction site for MaeI. Using this enzyme,
they were able to establish that the proband was a homozygote and that
her 2 offspring were heterozygotes. They stated that only a single
kindred with apoE deficiency had been reported previously. This was the
kindred reported by Ghiselli et al. (1981) and elucidated at the
molecular level by Cladaras et al. (1987); see 107741.0005.

.0015
APOE3 ISOFORM
APOE, CYS112 AND ARG158
Weisgraber et al. (1981) and Rall et al. (1982) identified one of the 3
major apolipoprotein E isoforms, apolipoprotein E3. The variant has
cys112 and arg158. This is the most common variant, with frequencies of
40% to 90% in various populations.

.0016
APOE4 ISOFORM
APOE, CYS112ARG
Weisgraber et al. (1981), Das et al. (1985) and Paik et al. (1985)
identified the apolipoprotein E4 isoform in which there is a
cys112-to-arg substitution. This variant is found in 6% to 37% of
individuals from different populations. Individuals carrying the
apolipoprotein E4 allele display low levels of apolipoprotein E and high
levels of plasma cholesterol, low density lipoprotein-cholesterol,
apolipoprotein B, lipoprotein (a), and are at higher risk for coronary
artery disease than other individuals.

.0017
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY, AUTOSOMAL
RECESSIVE
APOE, 1-BP DEL, 2919G DEL, FS60TER
Feussner et al. (1992) identified in German subjects with autosomal
recessive familial dysbetalipoproteinemia a 1-bp deletion (G) at the
last nucleotide of codon 30 at position 2919 of exon 3 (or the first 2
nucleotides of codon 31 at nucleotide positions 2920 or 2921). This
frameshift mutation (called APOE0) creates a termination at codon 60
resulting in a truncated protein. Individuals heterozygous for this
mutation display reduced plasma apolipoprotein E levels. Subjects
homozygous for this allele have undetectable plasma apolipoprotein E
levels concomitant with severe forms of familial dysbetalipoproteinemia.

.0018
HYPERLIPOPROTEINEMIA, TYPE III
APOE3(-)-KOCHI
APOE, ARG145HIS
This arg145-to-his amino acid change was identified in a Japanese
subject with familial dysbetalipoproteinemia by Suehiro et al. (1990).
The variant was designated E3(-) because it is slightly more acidic than
apolipoprotein E3 (107741.0015).

.0019
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2-FUKUOKA
APOE2-FUKUOKA
APOE, ARG158CYS AND ARG224GLN
In Japanese subjects with familial dysbetalipoproteinemia, Moriyama et
al. (1992) identified compound heterozygosity for the arg158-to-cys
(ApoE2; 107741.0001) mutation and a G-to-A transition at exon 4 leading
to a change from arginine-224 to glutamine.

.0020
HYPERCHOLESTEROLEMIA AND HYPERTRIGLYCERIDEMIA, TYPE III
APOE, GLU3LYS AND GLU13LYS
In French-Canadian subjects with hypercholesterolemia and
hypertriglyceridemia, Mailly et al. (1991) identified an apolipoprotein
E5 (107741.0002) with a glu13-to-lys substitution.

.0021
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2
APOE, ARG158CYS AND VAL236GLU
Van den Maagdenberg et al. (1993) identified in Dutch subjects with
hypertriglyceridemia T-to-A transition leading to a substitution of
glutamic acid for valine-236 in an APOE2 allele.

.0022
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE4
APOE, CYS112ARG AND ARG251GLY
Van den Maagdenberg et al. (1993) identified in Dutch subjects with
hypertriglyceridemia 2 substitutions in an APOE3 allele: cys112arg and
arg251gly.

.0023
APOE4(-)-FREIBURG
APOE, LEU28PRO AND CYS112ARG
Wieland et al. (1991) identified an apolipoprotein E4 variant in
German-Caucasian subjects not associated with hyperlipidemia. The
variant was designated E4(-) because it is slightly more acidic than E4
(107741.0016). This variant has a leu28-to-pro substitution
(CTG-to-CCG).

.0024
APOE3(-)-FREIBURG
APOE, THR42ALA
In German-Caucasian subjects, Wieland et al. (1991) identified an
apolipoprotein E3 variant designated E3(-) that is slightly more acidic
than E3. This variant has a thr42-to-ala substitution (ACA-to-GCA) and
was not associated with hyperlipidemia.

.0025
APOE4 VARIANT
APOE, PRO84ARG AND CYS112ARG
In American-white subjects, Ordovas et al. (1987) and Wardell et al.
(1991) identified an apolipoprotein E4 variant not associated with
hyperlipidemia. This variant has a pro84-to-arg substitution
(CCG-to-CGG).

.0026
APOE3 VARIANT
APOE, ALA99THR AND ALA152PRO
In American subjects, McLean et al. (1984) identified an apolipoprotein
E3 variant not associated with hyperlipidemia. This variant has
ala99-to-thr and ala152-to-pro substitutions (GCG-to-ACG and GCC-to-CCC,
respectively).

.0027
APOE2 VARIANT
APOE, ARG134GLN
De Knijff et al. (1994) cited unpublished data identifying an
apolipoprotein E2 variant in Dutch subjects with no hyperlipidemia. This
variant has an arg134-to-gln substitution (CGG-to-CAG). The mutation is
located in the receptor-binding domain.

.0028
APOE4 VARIANT
APOE, ARG274HIS
In Dutch subjects, Van den Maagdenberg et al. (1993) identified an
apolipoprotein E4 variant not associated with hyperlipidemia. This
variant has an arg274-to-his substitution (TGC-to-CGC).

.0029
APOE4(+)
APOE, SER296ARG
In Dutch subjects, Van den Maagdenberg et al. (1993) identified an
apolipoprotein E4 variant not associated with hyperlipidemia. The
variant was designated E4(+) because it is slightly more basic than E4.
This variant has a ser296-to-arg substitution (AGC-to-CGC).

*FIELD* SA
Amatruda et al. (1974); Blum et al. (1982); Borresen and Berg (1981);
Chait et al. (1977); Cumming and Robertson (1984); Eto et al. (1986);
Fredrickson et al. (1967); Ghiselli et al. (1982); Gofman et al. (1954);
Havel et al. (1980); Hazzard et al. (1975); Kamboh et al. (1991);
Kushwaha et al. (1977); Lohse et al. (1992); Morganroth et al. (1975);
Rall et al. (1983); Stalenhoef et al. (1986); Strittmatter et al.
(1993); Utermann et al. (1977); Utermann et al. (1984); Utermann et
al. (1984); Utermann et al. (1982); Utermann et al. (1979); Utermann
et al. (1984); Vessby et al. (1977); Wallis et al. (1983); Yamamura
et al. (1984); Yamamura et al. (1984)
*FIELD* RF
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isoform apoE4 associates more efficiently than apoE3. J. Clin. Invest. 94:
860-869, 1994.

123. Saunders, A. M.; Schmader, K.; Breitner, J. C. S.; Benson, M.
D.; Brown, W. T.; Goldfarb, L.; Goldgaber, D.; Manwaring, M. G.; Szymanski,
M. H.; McCown, N.; Dole, K. C.; Schmechel, D. E.; Strittmatter, W.
J.; Pericak-Vance, M. A.; Roses, A. D.: Apolipoprotein E epsilon-4
allele distributions in late-onset Alzheimer's disease and in other
amyloid-forming diseases. Lancet 342: 710-711, 1993.

124. Saunders, A. M.; Strittmatter, W. J.; Schmechel, D.; St. George-Hyslop,
P. H.; Pericak-Vance, M. A.; Joo, S. H.; Rosi, B. L.; Gusella, J.
F.; Crapper-MacLachlan, D. R.; Alberts, M. J.; Hulette, C.; Crain,
B.; Goldgaber, D.; Roses, A. D.: Association of apolipoprotein E
allele E4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:
1467-1472, 1993.

125. Schachter, F.; Faure-Delanef, L.; Guenot, F.; Rouger, H.; Froguel,
P.; Lesueur-Ginot, L.; Cohen, D.: Genetic associations with human
longevity at the APOE and ACE loci. Nature Genet. 6: 29-32, 1994.

126. Schaefer, E. J.; Gregg, R. E.; Ghiselli, G.; Forte, T. M.; Ordovas,
J. M.; Zech, L. A.; Brewer, H. B., Jr.: Familial apolipoprotein E
deficiency. J. Clin. Invest. 78: 1206-1219, 1986.

127. Schneider, W. J.; Kovanen, P. T.; Brown, M. S.; Goldstein, J.
L.; Utermann, G.; Weber, W.; Havel, R. J.; Kotite, L.; Kane, J. P.;
Innerarity, T. L.; Mahley, R. W.: Familial dysbetalipoproteinemia:
abnormal binding of mutant apoprotein E to low density lipoprotein
receptors of human fibroblasts and membranes from liver and adrenal
of rats, rabbits, and cows. J. Clin. Invest. 68: 1075-1085, 1981.

128. Scott, J.: Apolipoprotein E and Alzheimer's disease. Lancet 342:
696, 1993.

129. Smit, M.; de Knijff, P.; Frants, R. R.; Klasen, E. C.; Havekes,
L. M.: Familial dysbetalipoproteinemic subjects with the E3/E2 phenotype
exhibit an E2 isoform with only one cysteine residue. Clin. Genet. 32:
335-341, 1987.

130. Smit, M.; de Knijff, P.; van der Kooij-Meijs, E.; Groenendijk,
C.; van den Maagdenberg, A. M. J. M.; Gevers Leuven, J. A.; Stalenhoef,
A. F. H.; Stuyt, P. M. J.; Frants, R. R.; Havekes, L. M.: Genetic
heterogeneity in familial dysbetalipoproteinemia: the E2(lys146-to-gln)
variant results in a dominant mode of inheritance. J. Lipid Res. 31:
45-53, 1990.

131. Stalenhoef, A. F. H.; Malloy, M. J.; Kane, J. P.; Havel, R. J.
: Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich
lipoproteins in patients with familial dysbetalipoproteinemia. J.
Clin. Invest. 78: 722-728, 1986.

132. St Clair, D.; Rennie, M.; Slorach, E.; Norrman, J.; Yates, C.;
Carothers, A.: Apolipoprotein E epsilon-4 allele is a risk factor
for familial and sporadic presenile Alzheimer's disease in both homozygote
and heterozygote carriers. J. Med. Genet. 32: 642-644, 1995.

133. Strittmatter, W. J.; Roses, A. D.: Apolipoprotein E and Alzheimer
disease. Proc. Nat. Acad. Sci. 92: 4725-4727, 1995.

134. Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance,
M.; Enghild, J.; Salvesen, G. S.; Roses, A. D.: Apolipoprotein E:
high-avidity binding to beta-amyloid and increased frequency of type
4 allele in late-onset familial Alzheimer disease. Proc. Nat. Acad.
Sci. 90: 1977-1981, 1993.

135. Strittmatter, W. J.; Weisgraber, K. H.; Huang, D. Y.; Dong, L.-M.;
Salvesen, G. S.; Pericak-Vance, M.; Schmechel, D.; Saunders, A. M.;
Goldgaber, D.; Roses, A. D.: Binding of human apolipoprotein E to
synthetic amyloid beta peptide: isoform-specific effects and implications
for late-onset Alzheimer disease. Proc. Nat. Acad. Sci. 90: 8098-8102,
1993.

136. Suehiro, T.; Yoshida, K.; Yamano, T.; Ohno, F.: Identification
and characterization of a new variant of apolipoprotein E (apo E-Kochi). Jpn.
J. Med. 29: 587-594, 1990.

137. Tabaton, M.; Rolleri, M.; Masturzo, P.; Cammarata, S.; Angelini,
G.; Hansen, L. A.; Saitoh, T.; Petersen, R. B.; Perry, G.; Richey,
P.; Gambetti, P.; Bertolini, S.: Apolipoprotein E epsilon-4 allele
frequency is not increased in progressive supranuclear palsy. Neurology 45:
1764-1765, 1995.

138. Tajima, S.; Yamamura, T.; Menju, M.; Yamamoto, A.: Analysis
of apolipoprotein E7 (apolipoprotein E-Suita) gene from a patient
with hyperlipoproteinemia. J. Biochem. 105: 249-253, 1989.

139. Tajima, S.; Yamamura, T.; Yamamoto, A.: Analysis of apolipoprotein
E5 gene from a patient with hyperlipoproteinemia. J. Biochem. 104:
48-52, 1988.

140. Talbot, C.; Lendon, C.; Craddock, N.; Shears, S.; Morris, J.
C.; Goate, A.: Protection against Alzheimer's disease with apoE epsilon-2.
(Letter) Lancet 343: 1432-1433, 1994.

141. Tang, M.-X.; Maestre, G.; Tsai, W.-Y.; Liu, X.-H.; Feng, L.;
Chung, W.-Y.; Chun, M.; Schofield, P.; Stern, Y.; Tycko, B.; Mayeux,
R.: Relative risk of Alzheimer disease and age-at-onset distributions,
based on APOE genotypes among elderly African Americans, Caucasians,
and Hispanics in New York City. Am. J. Hum. Genet. 58: 574-584,
1996.

142. Tomimoto, H.; Akiguchi, I.; Suenaga, T.; Wakita, H.; Nakamura,
S.; Kimura, J.; Budka, H.: Immunohistochemical study of apolipoprotein
E in human cerebrovascular white matter lesions. Acta Neuropath. 90:
608-614, 1995.

143. Utermann, G.; Canzler, H.; Hess, M.; Jaeschke, M.; Muhleffner,
G.; Schoenborn, W.; Vogelberg, K. H.: Studies on the metabolic defect
in broad-B disease (hyperlipoproteinaemia type III). Clin. Genet. 12:
139-154, 1977.

144. Utermann, G.; Hardewig, A.; Zimmer, F.: Apolipoprotein E phenotypes
in patients with myocardial infarction. Hum. Genet. 65: 237-241,
1984.

145. Utermann, G.; Kindermann, I.; Kaffarnik, H.; Steinmetz, A.:
Apolipoprotein E phenotypes and hyperlipidemia. Hum. Genet. 65:
232-236, 1984.

146. Utermann, G.; Langenbeck, U.; Beisiegel, U.; Weber, W.: Genetics
of the apolipoprotein E system in man. Am. J. Hum. Genet. 32: 339-347,
1980.

147. Utermann, G.; Pruin, N.; Steinmetz, A.: Polymorphism of apolipoprotein
E. III. Effect of a single polymorphic gene locus on plasma lipid
levels in man. Clin. Genet. 15: 63-72, 1979.

148. Utermann, G.; Steinmetz, A.; Weber, W.: Genetic control of human
apoprotein E polymorphism: comparison of one- and two-dimensional
techniques of isoprotein analysis. Hum. Genet. 60: 344-351, 1982.

149. Utermann, G.; Vogelberg, K. H.; Steinmetz, A.; Schoenborn, W.;
Pruin, N.; Saeschke, M.; Hess, M.; Canzler, H.: Polymorphism of apolipoprotein
E. II. Genetics of hyperlipoproteinemia type III. Clin. Genet. 15:
37-62, 1979.

150. Utermann, G.; Weisgraber, K. H.; Weber, W.; Mahley, R. W.: Genetic
polymorphism of apolipoprotein E: a variant form of apolipoprotein
E2 distinguished by sodium dodecyl sulfate--polyacrylamide gel electrophoresis. J.
Lipid Res. 25: 378-382, 1984.

151. van Bockxmeer, F. M.; Mamotte, C. D. S.: Apolipoprotein epsilon-4
homozygosity in young men with coronary heart disease. Lancet 340:
879-880, 1992.

152. van den Maagdenberg, A. M.; Weng, W.; de Bruijn, I. H.; de Knijff,
P.; Funke, H.; Smelt, A. H.; Gevers Leuven, J. A.; van`t Hooft, F.
M.; Assmann, G.; Hofker, M. H.; Havekes, L. M.; Frants, R. R.: Characterizaiton
of five new mutants in the carboxyl-terminal domain of human apolipoprotein
E: no cosegregation with severe hyperlipidemia. Am. J. Hum. Genet. 52:
937-946, 1993.

153. van Gool, W. A.; Evenhuis, H. M.; van Duijn, C. M.: A case-control
study of apolipoprotein E genotypes in Alzheimer's disease associated
with Down's syndrome. Ann. Neurol. 38: 225-230, 1995.

154. van Ree, J. H.; van den Broek, W. J. J. A.; van der Zee, A.;
Dahlmans, V. E. H.; Wieringa, B.; Frants, R. R.; Havekes, L. M.; Hofker,
M. H.: Inactivation of Apoe and Apoc1 by two consecutive rounds of
gene targeting: effects on mRNA expression levels of gene cluster
members. Hum. Molec. Genet. 4: 1403-1409, 1995.

155. Vessby, B.; Hedstrand, H.; Lundin, L.-G.; Olsson, U.: Inheritance
of type III hyperlipoproteinemia: lipoprotein patterns in first-degree
relatives. Metabolism 26: 225-254, 1977.

156. Vogel, T.; Weisgraber, K. H.; Zeevi, M. I.; Ben-Artzi, H.; Levanon,
A. Z.; Rall, S. C., Jr.; Innerarity, T. L.; Hui, D. Y.; Taylor, J.
M.; Kanner, D.; Yavin, Z.; Amit, B.; Aviv, H.; Gorecki, M.; Mahley,
R. W.: Human apolipoprotein E expression in Escherichia coli: structural
and functional identity of the bacterially produced protein with plasma
apolipoprotein E. Proc. Nat. Acad. Sci. 82: 8696-8700, 1985.

157. Wallis, S. C.; Rogne, S.; Gill, L.; Markham, A.; Edge, M.; Woods,
D.; Williamson, R.; Humphries, S.: The isolation of cDNA clones for
human apolipoprotein E and the detection of apoE RNA in hepatic and
extra-hepatic tissues. EMBO J. 2: 2369-2373, 1983.

158. Wardell, M. R.; Brennan, S. O.; Janus, E. D.; Fraser, R.; Carrell,
R. W.: Apolipoprotein E2-Christchurch (136 arg-to-ser): new variant
of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J.
Clin. Invest. 80: 483-490, 1987.

159. Wardell, M. R.; Rall, S. C.; Schaefer, E. J.; Kane, J. P.; Weisgraber,
K. H.: Two apolipoprotein E5 variants illustrate the importance of
the position of additional positive charge on receptor-binding activity. J.
Lipid Res. 32: 521-528, 1991.

160. Wardell, M. R.; Rall, S. C., Jr.; Brennan, S. O.; Nye, E. R.;
George, P. M.; Janus, E. D.; Weisgraber, K. H.: Apolipoprotein E2-Dunedin
(228arg-to-cys): an apolipoprotein E2 variant with normal receptor-binding
activity. J. Lipid Res. 31: 535-543, 1990.

161. Wardell, M. R.; Weisgraber, K. H.; Havekes, L. M.; Rall, S. C.,
Jr.: Apolipoprotein E3-Leiden contains a seven-amino acid insertion
that is a tandem repeat of residues 121-127. J. Biol. Chem. 264:
21205-21210, 1989.

162. Weisgraber, K. H.; Innerarity, T. L.; Mahley, R. W.: Abnormal
lipoprotein receptor-binding activity of the human E apoprotein due
to cysteine-arginine interchange at a single site. J. Biol. Chem. 257:
2518-2521, 1982.

163. Weisgraber, K. H.; Rall, S. C., Jr.; Innerarity, T. L.; Mahley,
R. W.; Kuusi, T.; Ehnholm, C.: A novel electrophoretic variant of
human apolipoprotein E: identification and characterization of apolipoprotein
E1. J. Clin. Invest. 73: 1024-1033, 1984.

164. Weisgraber, K. H.; Rall, S. C., Jr.; Mahley, R. W.: Human E
apoprotein heterogeneity: cysteine-arginine interchanges in the amino
acid sequence of the apo-E isoforms. J. Biol. Chem. 256: 9077-9083,
1981.

165. Wieland, H.; Funke, H.; Krieg, J.; Luley, C.: ApoE3-Freiburg
and apoE4Freiburg are two genetic apoE variants which are caused by
exchanges of uncharged amino acids and do not appear to be associated
with lipid disorders or heart disease.In: Abstract Book of the Ninth
International Symposium on Atherosclerosis Rosemont, Illinois
1991. Pp. 164.

166. Yamamura, T.; Yamamoto, A.; Hiramori, K.; Nambu, S.: A new isoform
of apolipoprotein E--apo E-5--associated with hyperlipidemia and atherosclerosis. Atherosclerosis 50:
159-172, 1984.

167. Yamamura, T.; Yamamoto, A.; Sumiyoshi, T.; Hiramori, K.; Nishioeda,
Y.; Nambu, S.: New mutants of apolipoprotein E associated with atherosclerotic
diseases but not to type III hyperlipoproteinemia. J. Clin. Invest. 74:
1229-1237, 1984.

168. Yoshizawa, T.; Yamakawa-Kobayashi, K.; Komatsuzaki, Y.; Arinami,
T.; Oguni, E.; Mizusawa, H.; Shoji, S.; Hamaguchi, H.: Dose-dependent
association of apolipoprotein E allele epsilon-4 with late-onset,
sporadic Alzheimer's disease. Ann. Neurol. 36: 656-659, 1994.

169. Zannis, V. I.; Just, P. W.; Breslow, J. L.: Human apolipoprotein
E isoprotein subclasses are genetically determined. Am. J. Hum. Genet. 33:
11-24, 1981.

170. Zhang, S. H.; Reddick, R. L.; Piedrahita, J. A.; Maeda, N.:
Spontaneous hypercholesterolemia and arterial lesions in mice lacking
apolipoprotein E. Science 258: 468-471, 1992.

*FIELD* CS

Skin:
   Xanthomatosis (tuberous, tuberoeruptive, planar and/or tendon)

Cardiac:
   Premature coronary disease;
   Angina pectoris

Vascular:
   Premature peripheral vascular disease

Metabolic:
   Abnormal glucose tolerance

Neuro:
   APOE*E4 allele associated with late-onset familial and sporadic forms
   of Alzheimer disease

Misc:
   Primary dysbetalipoproteinemia a monogenic variant (APOE1-HARRISBURG
   .0010, APOE3 LEIDEN .0006, APOE2 .0011);
   Incompletely dominant type III hyperlipoproteinemia without clinical
   manifestations (APOE4-PHILADELPHIA .0013);
   Age dependent, rarely evident before the third decade;
   Hyperlipidemia exacerbated by carbohydrate, hypothyroidism and obesity

Lab:
   Apolipoprotein E;
   Increased plasma cholesterol;
   Increased triglycerides;
   Impaired clearance of chylomicron and VLDL remnants;
   Type III hyperlipoproteinemia with some alleles;
   Defective apoE3 binding to LDL receptor (APOE LEIDEN .0006, APOE .0008);
   Mild hypertriglyceridemia (APOE3-WASHINGTON .0014)

Inheritance:
   Autosomal recessive with pseudodominance due to high gene frequency
   (e.g. APOE .0009)

*FIELD* CN
Victor A. McKusick - updated: 4/8/1997
Stylianos E. Antonarakis - updated: 3/20/1997
Iosif W. Lurie - updated: 1/8/1997
Orest Hurko - edited: 12/19/1996
Orest Hurko - updated: 12/16/1996
Lori M. Kelman - updated: 11/15/1996
Orest Hurko - updated: 5/14/1996
Orest Hurko - updated: 5/8/1996
Orest Hurko - updated: 4/3/1996
Orest Hurko - updated: 3/6/1996
Orest Hurko - updated: 2/22/1996
Orest Hurko - updated: 2/7/1996
Orest Hurko - updated: 1/25/1996
Orest Hurko - updated: 11/13/1995

*FIELD* CD
Victor A. McKusick: 1/26/1990

*FIELD* ED
terry: 04/10/1997
jenny: 4/8/1997
terry: 4/4/1997
jenny: 3/31/1997
jenny: 3/25/1997
jenny: 3/21/1997
jenny: 3/20/1997
jenny: 3/18/1997
mark: 3/10/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 2/24/1997
jenny: 1/21/1997
jenny: 1/8/1997
mark: 12/19/1996
mark: 12/16/1996
terry: 12/9/1996
jamie: 11/15/1996
jamie: 11/6/1996
jamie: 11/1/1996
terry: 10/22/1996
mark: 7/22/1996
mark: 6/21/1996
mark: 6/20/1996
terry: 5/17/1996
terry: 5/14/1996
mark: 5/10/1996
terry: 5/10/1996
mark: 5/8/1996
terry: 5/2/1996
mark: 4/25/1996
terry: 4/19/1996
mark: 4/12/1996
terry: 4/5/1996
mark: 4/3/1996
terry: 3/23/1996
mark: 3/6/1996
terry: 2/23/1996
mark: 2/22/1996
terry: 2/9/1996
mark: 2/7/1996
mark: 2/2/1996
terry: 1/27/1996
mark: 1/25/1996
terry: 1/19/1996
mark: 10/12/1995
jason: 6/14/1994
warfield: 4/7/1994
pfoster: 4/1/1994
mimadm: 2/21/1994

*RECORD*
*FIELD* NO
107748
*FIELD* TI
*107748 APURINIC ENDONUCLEASE; APE; APE1
HUMAN APURINIC ENDONUCLEASE 1; HAP1
*FIELD* TX
The continuous loss of bases is a prominent insult to cellular DNA. The
resulting abasic sites can block the progress of the DNA replication
apparatus and cause mutations. These abasic sites must be corrected to
restore genetic integrity. Demple et al. (1991) cloned and analyzed cDNA
encoding major human apurinic endonuclease (APE). The predicted APE
protein, which contained probable nuclear transport signals, was
identified as a member of a family of DNA repair enzymes found in lower
organisms. See also Robson and Hickson (1991) and Cheng et al. (1992).
With a primer pair based on the published sequence of the bovine cDNA
used in PCR, Zhao et al. (1992) amplified a 437-bp segment from human
DNA without amplifying mouse or hamster DNA in somatic cell hybrids. By
this method, they assigned the APE gene to chromosome 14. Using 2
contiguous APE genomic clones as probes and in situ hybridization, they
regionalized the assignment to 14q12, very near to the junction of bands
q11.2 and q12. Using in situ hybridization, Robson et al. (1992) mapped
the APE gene to 14q11.2-q12.

Harrison et al. (1992) determined the sequence of the APE gene, which
contains 4 small introns (ranging from 130-566 bp) and 5 exons, the
first of which is untranslated. Consistent with the constitutive
expression of AP endonuclease activity observed in other studies, the
0.5 kb of DNA sequence upstream of APE revealed only a possible CCAAT
box and no other regulatory sites or a TATA box.

*FIELD* RF
1. Cheng, X.; Bunville, J.; Patterson, T. A.: Nucleotide sequence
of a cDNA for an apurinic/apyrimidinic endonuclease from HeLa cells.
Nucleic Acids Res. 20: 370 only, 1992.

2. Demple, B.; Herman, T.; Chen, D. S.: Cloning and expression of
APE, the cDNA encoding the major human apurinic endonuclease: definition
of a family of DNA repair enzymes. Proc. Nat. Acad. Sci. 88: 11450-11454,
1991.

3. Harrison, L.; Ascione, G.; Menninger, J. C.; Ward, D. C.; Demple,
B.: Human apurinic endonuclease gene (APE): structure and genomic
mapping (chromosome 14q11.2-12). Hum. Molec. Genet. 1: 677-680,
1992.

4. Robson, C. N.; Hickson, I. D.: Isolation of cDNA clones encoding
a human apurinic/apyrimidinic endonuclease that corrects DNA repair
and mutagenesis defects in E. coli xth (exonuclease III) mutants.
Nucleic Acids Res. 19: 5519-5523, 1991.

5. Robson, C. N.; Hochhauser, D.; Craig, R.; Rack, K.; Buckle, V.
J.; Hickson, I. D.: Structure of the human DNA repair gene HAP1 and
its localisation to chromosome 14q11.2-12. Nucleic Acids Res. 20:
4417-4421, 1992.

6. Zhao, B.; Grandy, D. K.; Hagerup, J. M.; Magenis, R. E.; Smith,
L.; Chauhan, B. C.; Henner, W. D.: The human gene for apurinic/apyrimidinic
endonuclease (HAP1): sequence and localization to chromosome 14 band
q12. Nucleic Acids Res. 20: 4097-4098, 1992.

*FIELD* CD
Victor A. McKusick: 1/3/1992

*FIELD* ED
davew: 6/8/1994
carol: 9/13/1993
carol: 2/2/1993
carol: 10/22/1992
carol: 10/9/1992
carol: 10/8/1992

*RECORD*
*FIELD* NO
107750
*FIELD* TI
#107750 ARBITRARY RESTRICTION POLYMORPHISM-1
ANONYMOUS RESTRICTION POLYMORPHISM-1; ARP-1;;
RESTRICTION FRAGMENT LENGTH POLYMORPHISM-14A;;
RFLP-14A;;
ARP-14A; D14S1
*FIELD* TX
A number sign (#) is used with this entry because it does not represent
an expressed gene. It is included here mainly for historical purposes,
since D14S1 was the first RFLP to be identified (after the DNA
polymorphism discovered by Kan and Dozy (1978).

Botstein et al. (1980) suggested that variation in nucleotide sequences
resulting in variation in cleavage by site-specific endonucleases
('restriction enzymes') are sufficiently frequent in the human genome as
to be highly useful as markers in chromosome mapping. They suggested the
designation restriction fragment length polymorphism (acronym, RFLP,
pronounced 'rif-lip'). To be useful, the polymorphism should be in a
single-copy sequence. A collection of 150-200 such polymorphisms
distributed over the genome would have the potential for greatly
enhancing the power of family linkage studies. Disorders of reduced
penetrance and multifactorial causation might be amenable to genetic
analysis. The HpaI polymorphism (143020) in a noncoding segment on the
3-prime flank of the beta-globin gene was the first to be found, by Kan
and Dozy (1978). Polymorphism was then defined in the noncoding part of
the gamma-globin genes (142200). Before the paper of Botstein et al.
(1980), Solomon and Bodmer (1979) had suggested the usefulness of
restriction polymorphisms as markers in linkage studies.

Wyman and White (1980) found a human DNA segment (which they referred to
as 'a locus') that was the site of restriction fragment length
polymorphism. The polymorphism was found by hybridizing a
16-kilobase-pair segment of single-copy human DNA, selected from the
human genome library cloned by Maniatis's group (Lawn et al., 1978) in
lambda phage Charon 4A, to a Southern transfer of total human DNA
digested with EcoRI. The 'locus' was found to be highly variable with a
potential usefulness in linkage studies exceeded only by HLA (White,
1981). Family studies supported mendelian inheritance. Studies by
somatic cell hybridization assigned the 'locus' to chromosome 14 (White,
1981). Terminology tentatively suggested was 'arbitrary restriction
polymorphism' (ARP), with numbers in sequence of discovery. 'Anonymous'
might be substituted for 'arbitrary.' It seemed desirable for the
designation to include the chromosomal site (and such should be
determined as early as possible). When more than one such polymorphism
was assigned to one chromosome, a letter can be used following the
chromosome number. According to this convention, the polymorphism
described by Wyman and White (1980) was designated ARP-14A, or simply
ARP-14, until another on that chromosome was found. The symbol adopted
at HGM6 (Oslo) called for D (for DNA), then the chromosome number, then
S for segment, and 1 for the first such identified on chromosome 14:
D14S1. De Martinville et al. (1982) assigned the polymorphism to
chromosome 14 in the q21-qter region. At least 8 alleles were
demonstrated. Balazs et al. (1982) concluded that D14S1 maps to the
subtelomeric region of 14q, 14q32, in close proximity to the IGH-CG1
locus (Kirsch et al., 1982). The conclusion was based on 3 independent
lines of evidence: gene dosage, somatic cell hybrid studies, and
pedigree analysis. It is probably significant that the highly
polymorphic D14S1 'locus' is in the same region where much somatic
rearrangement goes on during differentiation of immunoglobulin-producing
B lymphocytes, specifically in 'class switch', and where the break
occurs in the generation of de novo translocations in lymphatic
malignancies. GM73 and GM74 (otherwise known as KOP) were used in the
gene dosage studies and in cell hybrid studies. (KOP cell lines,
carrying an X;14 translocation, were used by Ricciuti and Ruddle (1973)
in the mapping of X-chromosome loci.) They studied 13 pedigrees
segregating for Gm variants at the gamma-1 locus. A recombination
fraction of 3.1%, with a 90% fiducial limit for the upper recombination
value of 11.5%, was found. The data were consistent with the generally
held estimate that one unit of meiotic recombination corresponds to
about 1 million basepairs. By in situ hybridization, Donlon et al.
(1983) assigned D14S1 to 14q32.1-q32.2.

*FIELD* RF
1. Balazs, I.; Purrello, M.; Rubinstein, P.; Alhadeff, B.; Siniscalco,
M.: Highly polymorphic DNA site D14S1 maps to the region of Burkitt
lymphoma translocation and is closely linked to the heavy chain gamma-1
locus. Proc. Nat. Acad. Sci. 79: 7395-7399, 1982.

2. Botstein, D.; White, R. L.; Skolnick, M.; Davis, R. M.: Construction
of a genetic linkage map in man using restriction fragment length
polymorphisms. Am. J. Hum. Genet. 32: 314-331, 1980.

3. de Martinville, B.; Wyman, A. R.; White, R.; Francke, U.: Assignment
of the first random restriction fragment length polymorphism (RFLP)
locus (D14S1) to a region of human chromosome 14. Am. J. Hum. Genet. 34:
216-226, 1982.

4. Donlon, T. A.; Litt, M.; Newcom, S. R.; Magenis, R. E.: Localization
of the restriction fragment length polymorphism D14S1 (pAW-101) to
chromosome 14q32.1-32.2 by in situ hybridization. Am. J. Hum. Genet. 35:
1097-1106, 1983.

5. Kan, Y. W.; Dozy, A. M.: Polymorphism of DNA sequence adjacent
to human beta-globin structural gene: relationship to sickle mutation.
Proc. Nat. Acad. Sci. 75: 5631-5635, 1978.

6. Kirsch, I. R.; Morton, C. C.; Nakahara, K.; Leder, P.: Human immunoglobulin
heavy chain genes map to a region of translocations in malignant B
lymphocytes. Science 216: 301-303, 1982.

7. Lawn, R. W.; Fritsch, E. F.; Parker, R. C.; Blake, G.; Maniatis,
T.: The isolation and characterization of linked alpha- and beta-globin
genes from a cloned library of human DNA. Cell 15: 1157-1174, 1978.

8. Ricciuti, F. C.; Ruddle, F. H.: Assignment of three gene loci
(PGK, HGPRT, G6PD) to the long arm of the human X chromosome by somatic
cell genetics. Genetics 74: 661-678, 1973.

9. Solomon, E.; Bodmer, W. F.: Evolution of sickle variant gene.
(Letter) Lancet I: 923 only, 1979.

10. White, R. L.: Personal Communication. Salt Lake City, Utah
3/30/1981.

11. Wyman, A. R.; White, R.: A highly polymorphic locus in human
DNA. Proc. Nat. Acad. Sci. 77: 6754-6758, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 7/5/1994
warfield: 4/7/1994
mimadm: 2/11/1994
carol: 10/19/1993
supermim: 3/16/1992
carol: 2/6/1992

*RECORD*
*FIELD* NO
107760
*FIELD* TI
107760 APOLIPOPROTEIN F; APOF
*FIELD* TX
Apolipoprotein F, one of the minor apolipoproteins in human plasma, was
isolated and partially characterized by Olofsson et al. (1978). Koren et
al. (1982) studied the interaction of apoF with other apolipoproteins
and lipids in human plasma. They suggested that apoF-containing
lipoproteins may be involved in transport and/or esterification of
cholesterol.

*FIELD* RF
1. Koren, E.; McConathy, W. J.; Alaupovic, P.: Isolation and characterization
of simple and complex lipoproteins containing apolipoprotein F from
human plasma. Biochemistry 21: 5347-5351, 1982.

2. Olofsson, S.-O.; McConathy, W. J.; Alaupovic, P.: Isolation and
partial characterization of a new acidic apolipoprotein (apolipoprotein
F) from high density lipoproteins of human plasma. Biochemistry 17:
1032-1036, 1978.

*FIELD* CD
Victor A. McKusick: 2/9/1988

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 2/10/1988
root: 2/9/1988

*RECORD*
*FIELD* NO
107770
*FIELD* TI
*107770 APOLIPOPROTEIN RECEPTOR; APR
LIPOPROTEIN RECEPTOR RELATED PROTEIN; LRP;;
LOW DENSITY LIPOPROTEIN-RELATED PROTEIN 1; LRP1;;
ALPHA-2-MACROGLOBULIN RECEPTOR; A2MR;;
APOLIPOPROTEIN E RECEPTOR; APOER
*FIELD* TX
Herz et al. (1988) cloned a cDNA for the low density lipoprotein
receptor related protein (LRP) by virtue of its close homology to the
LDL receptor (143890). Kristensen et al. (1990) and Strickland et al.
(1990) demonstrated that LRP is identical to the alpha-2-macroglobulin
receptor (A2MR). Like the mannose-6-phosphate receptor (147280), the
A2MR/LRP molecule is probably bifunctional. Myklebost et al. (1989)
mapped the gene for the LRP-related protein to 12q13-q14 by study of DNA
from rodent-human cell hybrids and by in situ hybridization; the symbol
APOER was used initially because of the putative APOE receptor function.
Forus et al. (1991) found that the APR and GLI (165220) genes are
coamplified in a rhabdomyosarcoma cell line. Furthermore, by pulsed
field gel analysis, they found that the genes are closely situated;
probes for either gene hybridized to DNA fragments of molecular weight
300-400 kb. More detailed restriction analysis showed that the
intergenic region was between 200 and 300 kb (Forus and Myklebost,
1992). Hilliker et al. (1992) confirmed the assignment to 12q13-q14
using both nonisotopic and isotopic in situ hybridization. Also by in
situ hybridization, they assigned the corresponding locus to mouse
chromosome 15. In the free-living nematode Caenorhabditis elegans,
Yochem and Greenwald (1993) isolated and sequenced a gene more than 23
kb long that encodes a large integral membrane protein with a predicted
structure similar to that of LRP of mammals. The 4,753-amino acid
product predicted for the C. elegans gene shared a nearly identical
number and arrangement of amino acid sequence motifs with human LRP, and
several exons of the C. elegans LRP gene corresponded to exons of
related parts of the human LRP gene.

*FIELD* SA
Beisiegel et al. (1989)
*FIELD* RF
1. Beisiegel, U.; Weber, W.; Ihrke, G.; Herz, J.; Stanley, K. K.:
The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding
protein. Nature 341: 162-164, 1989.

2. Forus, A.; Maelandsmo, G. M.; Fodstad, Y.; Myklebost, O.: The
genes for the alpha-2-macroglobulin receptor/LDL receptor-related
protein and GLI are located within a chromosomal segment of about
300 kilobases and are coamplified in a rhabdomyosarcoma cell line.
(Abstract) Cytogenet. Cell Genet. 58: 1977 only, 1991.

3. Forus, A.; Myklebost, O.: A physical map of a 1.3-Mb region on
the long arm of chromosome 12, spanning the GLI and LRP loci. Genomics 14:
117-120, 1992.

4. Herz, J.; Hamann, U.; Rogne, S.; Myklebost, O.; Gausepohl, H.;
Stanley, K. K.: Surface location and high affinity for calcium of
a 500 kd liver membrane protein closely related to the LDL-receptor
suggest a physiological role as lipoprotein receptor. EMBO J. 7:
4119-4127, 1988.

5. Hilliker, C.; Van Leuven, F.; Van Den Berghe, H.: Assignment of
the gene coding for the alpha(2)-macroglobulin receptor to mouse chromosome
15 and to human chromosome 12q13-q14 by isotopic and nonisotopic in
situ hybridization. Genomics 13: 472-474, 1992.

6. Kristensen, T.; Moestrup, S. K.; Gliemann, J.; Bendtsen, L.; Sand,
O.; Sottrup-Jensen, L.: Evidence that the newly cloned low-density-lipoprotein
receptor related protein (LRP) is the alpha-2-macroglobulin receptor.
FEBS Lett. 276: 151-155, 1990.

7. Myklebost, O.; Arheden, K.; Rogne, S.; Geurts van Kessel, A.; Mandahl,
N.; Herz, J.; Stanley, K.; Heim, S.; Mitelman, F.: The gene for the
human putative apoE receptor is on chromosome 12 in the segment q13-14.
Genomics 5: 65-69, 1989.

8. Strickland, D. K.; Ashcom, J. D.; Williams, S.; Burgess, W. H.;
Migliorini, M.; Argraves, W. S.: Sequence identity between the alpha-2-macroglobulin
receptor and low density lipoprotein receptor-related protein suggests
that this molecule is a multifunctional receptor. J. Biol. Chem. 265:
17401-17404, 1990.

9. Yochem, J.; Greenwald, I.: A gene for a low density lipoprotein
receptor-related protein in the nematode Caenorhabditis elegans. Proc.
Nat. Acad. Sci. 90: 4572-4576, 1993.

*FIELD* CD
Victor A. McKusick: 11/23/1988

*FIELD* ED
carol: 8/3/1994
warfield: 3/11/1994
carol: 6/17/1993
carol: 9/22/1992
carol: 6/1/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
107773
*FIELD* TI
*107773 TRANSCRIPTION FACTOR COUP 2; TFCOUP2
CHICKEN OVALBUMIN UPSTREAM PROMOTER TRANSCRIPTION FACTOR 2;;
APOLIPOPROTEIN REGULATORY PROTEIN I; ARP1
*FIELD* TX
Hepatocyte-specific expression of the human apolipoprotein A-I gene
(107680) is dependent on synergistic actions between nuclear proteins
bound to distinct sites within a liver-specific enhancer located
upstream of the APOA1 transcription start site (Widom et al., 1991).
From analysis of the cDNA derived amino acid sequence, Ladias and
Karathanasis (1991) found that one of these proteins, apolipoprotein
regulatory protein I, is a novel member of the steroid/thyroid nuclear
receptor of ligand-dependent transcription factors. Using a 3.9-kb
fragment, Modi et al. (1991) assigned the ARP1 gene to 15q26.1-q26.2 by
Southern analysis of human-rodent somatic cell hybrid DNAs and in situ
chromosomal hybridization.

Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are
members of the steroid/thyroid hormone receptor superfamily. They are
often called orphan receptors, since their ligands have not been
identified. COUP-TF homologs have been cloned in many species, from
Drosophila to human. The protein sequences are highly homologous across
species, suggesting functional conservation. ARP1, also called COUP-TF
II, and COUP-TF I (132890), were cloned from the human and their genomic
organization characterized. Qiu et al. (1995) isolated the mouse genes
for encoding COUP-TFs I and II and characterized their genomic
structures. Both have relatively simple structures similar to those of
their human counterparts. Qiu et al. (1995) used interspecific backcross
analysis to map Tcfcoup1 to mouse chromosome 13 and Tcfcoup2 to mouse
chromosome 7. By isotopic in situ hybridization, they mapped the human
counterparts to 5q14 and 15q26, in regions that show homology of synteny
between mouse and human. The previous assignment of the so-called ARP1
gene was confirmed.

*FIELD* RF
1. Ladias, J. A. A.; Karathanasis, S. K.: Regulation of the apolipoprotein
AI gene by ARP-1, a novel member of the steroid receptor superfamily.
Science 251: 561-565, 1991.

2. Modi, W. S.; Seuanez, H.; Mietus-Snyder, M.; O'Brien, S. J.; Karathanasis,
S. K.: Chromosomal localization of the ARP-1 gene to 15q26.   (Abstract) Cytogenet.
Cell Genet. 58: 1995 only, 1991.

3. Qiu, Y.; Krishnan, V.; Zeng, Z.; Gilbert, D. J.; Copeland, N. G.;
Gibson, L.; Yang-Feng, T.; Jenkins, N. A.; Tsai, M.-J.; Tsai, S. Y.
: Isolation, characterization, and chromosomal localization of mouse
and human COUP-TF I and II genes. Genomics 29: 240-246, 1995.

4. Widom, R. L.; Ladias, J. A. A.; Kouidou, S.; Karathanasis, S. K.
: Synergistic interactions between transcription factors control expression
of the apolipoprotein AI gene in liver cells. Molec. Cell. Biol. 11:
677-687, 1991.

*FIELD* CD
Victor A. McKusick: 8/19/1991

*FIELD* ED
mark: 12/13/1995
mark: 10/2/1995
supermim: 3/16/1992
carol: 2/21/1992
carol: 10/15/1991
carol: 10/8/1991
carol: 8/19/1991

*RECORD*
*FIELD* NO
107776
*FIELD* TI
*107776 AQUAPORIN-1; AQP1
AQUAPORIN-CHIP;;
AQP-CHIP;;
CHANNEL-LIKE INTEGRAL MEMBRANE PROTEIN, 28-KILODALTON; CHIP28
*FIELD* TX
During isolation of the 32-kD Rh polypeptides from human erythrocytes, a
28-kD integral membrane protein was isolated The protein was thought at
first to be a breakdown product of the Rh polypeptide but was later
shown to be a unique molecule that is abundant in erythrocytes and renal
tubules. A subpopulation is N-glycosylated. Preston and Agre (1991)
isolated a cDNA for this protein, called CHIP28, from human fetal liver.
Analysis of the deduced amino acid sequence suggested that CHIP28
protein contains 6 bilayer-spanning domains, 2 exofacial potential
N-glycosylation sites, and intracellular N and C termini. The sequence
showed strong homology with the major intrinsic protein of bovine lens
(MIP26; 154050), which is the prototype of an ancient family of membrane
channels. These proteins are believed to form channels permeable to
water and possibly other small molecules.

Aquaporin-CHIP is a 28-kD integral protein purified from the plasma
membranes of red cells and renal tubules by Denker et al. (1988) and
Preston and Agre (1991) who referred to it as CHIP28 ('channel forming
integral protein of 28 kD'). The protein exists as a homotetramer which
physically resembles channel proteins and was the first molecular water
channel identified. The AQP-CHIP cDNA isolated from a human bone marrow
cDNA library was found to be related to the major intrinsic protein of
lens (154050). Two other related proteins were found to be water
transporters (Fushimi et al., 1993; Maurel et al., 1993) and these 3
proteins were referred to as the aquaporins. AQP-CHIP is also expressed
in diverse epithelia with distinct developmental patterns. By
immunochemical and functional means, Smith et al. (1993) showed that
AQP-CHIP is essentially absent in neonatal red cells of the rat. After
birth, AQP-CHIP appears in the red cells and increases within several
weeks to the adult level of expression. The neonatal kidney, while
displaying low levels of AQP-CHIP expression, has a parallel increase in
the amount and distribution of AQP-CHIP in the proximal tubules and the
descending thin limbs of the loops of Henle, commensurate with the
kidney's ability to form concentrated urine. Smith et al. (1993)
suggested that the water channels act to promote the rehydration of red
cells after their shrinkage in the hypertonic environment of the renal
medulla. Rapid rehydration would return the cells to their normal
volume, optimizing their deformability for transit in the
microcirculation. See Hoffman (1993).

Moon et al. (1993) isolated the AQP1 structural gene and partially
sequenced it. Genomic Southern analysis indicated the existence of a
single AQP1 gene which was localized to 7p14 by in situ hybridization.
Sequence comparisons with similar proteins from diverse species
suggested a common evolutionary origin. Deen et al. (1994) showed that
the gene is on chromosome 7 by Southern blot hybridization to
human/rodent hybrid cell lines and regionalized it to 7p15-p14 by in
situ hybridization.

Moon et al. (1995) showed that the 13-kb Aqp1 gene in the mouse contains
4 exons with intronic boundaries corresponding to other known aquaporin
genes. By interspecific mouse backcross mapping they showed that the
gene is located on chromosome 6 in a region with homology of synteny
with human 7p14.

The location of the AQP1 gene is the same as that of the Colton blood
group (110450) on 7p. Smith et al. (1994) demonstrated that the
CHIP-glycan is the molecular site of the Colton polymorphism. They also
showed that Colton blood group antigen differences result from an
ala-val polymorphism at residue 45, located on the first extracellular
loop of CHIP. CHIP was selectively immunoprecipitated with anti-Co(a) or
anti-Co(b). Approximately 92% of Caucasians are Co(a+b-), approximately
8% are Co(a+b+), and only 0.2% are Co+(a-b+).

Worldwide blood group referencing had led to the identification of 5
kindreds in which red cells expressed no Colton antigens; these
individuals were said to be Co(a-b-). Preston et al. (1994) obtained
blood samples and urine sediment from 3 of these individuals, 1 member
from each of 3 kindreds. They were unrelated women of northern European
ancestry, and none had hematologic, renal, ocular, respiratory,
gastrointestinal, reproductive, or neurologic dysfunction. Cells in
these Co(a-b-) individuals appeared morphologically normal, but their
red cells exhibited low osmotic water permeability. Genomic DNA analyses
demonstrated that 2 individuals were homozygous for different nonsense
mutations (exon deletion or frameshift), and the third had a missense
mutation encoding a nonfunctioning CHIP molecule. Surprisingly, none of
the 3 suffered any apparent clinical consequence, which raised questions
about the physiologic importance of CHIP and implied that other
mechanisms may compensate for its absence.

Colton antigens cause clinical difficulties infrequently, although
maternal-fetal incompatibility and transfusion reactions are known. The
power of worldwide blood group referencing makes the rarest of
phenotypes accessible, and the single Co+(a-b-) red cell membrane sample
in the reference collection was found to lack CHIP by immunoblot. Lack
of Colton antigens in association with monosomy 7 has been reported in
some cases of leukemia (de la Chapelle et al., 1975; Pasquali et al.,
1982).

Wickramasinghe et al. (1991) described a Danish girl with a novel form
of congenital dyserythropoietic anemia (CDA) associated with persistent
embryonic and fetal hemoglobin (Tang et al., 1993) and absent red cell
CD44 (107269) protein (Parsons et al., 1994). The patient had a unique
blood group phenotype: In(a-b-), Co(a-b-). Agre et al. (1994) showed
that the red cells from this patient contained less than 10% of the
normal level of CHIP and had remarkably low osmotic water permeability,
but no mutation was identified in the AQP1 gene. The characteristics of
CDA in this patient were different from those of the 3 types of CDA that
had already been defined (224120; 224100; 105600). The CD44 and CHIP
deficiencies were not thought to represent primary defects in this
patient. Agre et al. (1994) also found that, compared with the adult,
second and third trimester human fetal red cells had lower CHIP/spectrin
ratios and reduced osmotic water permeability; CHIP was already present
in human renal tubules by the second trimester.

Keen et al. (1995) localized the AQP1 gene on chromosome 7 within a YAC
contig containing 2 polymorphic markers, D7S632 and D7S526. Since
aquaporin is known to be expressed in a diverse range of secretory and
absorptive epithelia, including many in the eye, it had been proposed as
a possible candidate for disorders involving an imbalance in ocular
fluid movement. Keen et al. (1995) raised a question of possible
involvement in 2 eye diseases that map to that region, retinitis
pigmentosa-9 (180104) and dominant cystoid macular dystrophy (153880).

Knepper (1994) provided a review of the aquaporin family of molecular
water channels.

*FIELD* AV
.0001
COLTON BLOOD GROUP POLYMORPHISM
AQP1, ALA45VAL
Smith et al. (1994) found that the DNA sequence of the AQP1 gene from
Colton-typed individuals predicted that residue 45 is alanine in the
Co(a+b-) phenotype and valine in the Co(a-b+) phenotype. The nucleotide
polymorphism corresponds to a PflMI endonuclease digestion site in the
DNA from Co(a-b+) individuals.

*FIELD* SA
Parsons et al. (1994)
*FIELD* RF
1. Agre, P.; Smith, B. L.; Baumgarten, R.; Preston, G. M.; Pressman,
E.; Wilson, P.; Illum, N.; Anstee, D. J.; Lande, M. B.; Zeidel, M.
L.: Human red cell aquaporin CHIP. II. Expression during normal fetal
development and in a novel form of congenital dyserythropoietic anemia. J.
Clin. Invest. 94: 1050-1058, 1994.

2. Deen, P. M. T.; Weghuis, D. O.; Geurts van Kessel, A.; Wieringa,
B.; van Os, C. H.: The human gene for water channel aquaporin 1 (AQP1)
is localized on chromosome 7p15-p14. Cytogenet. Cell Genet. 65:
243-246, 1994.

3. de la Chapelle, A.; Vuopio, P.; Sanger, R.; Teesdale, P.: Monosomy-7
and the Colton blood-groups. (Letter) Lancet II: 817 only, 1975.

4. Denker, B. M.; Smith, B. L.; Kuhajda, F. P.; Agre, P.: Identification,
purification, and partial characterization of a novel M(r) 28,000
integral membrane protein from erythrocytes and renal tubules. J.
Biol. Chem. 263: 15634-15642, 1988.

5. Fushimi, K.; Uchida, S.; Hara, Y.; Hirata, Y.; Marumo, F.; Sasaki,
S.: Cloning and expression of apical membrane water channel of rat
kidney collecting tubule. Nature 361: 549-552, 1993.

6. Hoffman, J. F.: Aquaporin: a wee burn runs through it. (Editorial) J.
Clin. Invest. 92: 1604-1605, 1993.

7. Keen, T. J.; Inglehearn, C. F.; Patel, R. J.; Green, E. D.; Peluso,
D. C.; Bhattacharya, S. S.: Localization of the aquaporin 1 (AQP1)
gene within a YAC contig containing the polymorphic markers D7S632
and D7S526. Genomics 25: 599-600, 1995.

8. Knepper, M. A.: The aquaporin family of molecular water channels. Proc.
Nat. Acad. Sci. 91: 6255-6258, 1994.

9. Maurel, C.; Reizer, J.; Schroeder, J. I.; Chrispeels, M.: The
vacuolar membrane protein gamma-TIP creates water specific channels
in Xenopus oocytes. EMBO J. 12: 2241-2247, 1993.

10. Moon, C.; Preston, G. M.; Griffin, C. A.; Jabs, E. W.; Agre, P.
: The human aquaporin-CHIP gene: structure, organization, and chromosomal
localization. J. Biol. Chem. 268: 15772-15778, 1993.

11. Moon, C.; Williams, J. B.; Preston, G. M.; Copeland, N. G.; Gilbert,
D. J.; Nathans, D.; Jenkins, N. A.; Agre, P.: The mouse Aquaporin-1
gene. Genomics 30: 354-357, 1995.

12. Parsons, S. F.; Jones, J.; Anstee, D. J.; Judson, P. A.; Gardner,
B.; Wiener, E.; Poole, J.; Illum, N.; Wickramasinghe, S. N.: A novel
form of congenital dyserythropoietic anemia associated with deficiency
of erythroid CD44 and a unique blood group phenotype [In(a-b-), Co(a-b-)]. Blood 83:
860-868, 1994.

13. Pasquali, F.; Bernasconi, P.; Casalone, R.; Fraccaro, M.; Bernasconi,
C.; Lazzarino, M.; Morra, E.; Alessandrino, E. P.; Marchi, M. A.;
Sanger, R.: Pathogenic significance of 'pure' monosomy 7 in myeloproliferative
disorders: analysis of 14 cases.. Hum. Genet. 62: 40-51, 1982.

14. Preston, G. M.; Agre, P.: Isolation of the cDNA for erythrocyte
integral membrane protein of 28 kilodaltons: member of an ancient
channel family. Proc. Nat. Acad. Sci. 88: 11110-11114, 1991.

15. Preston, G. M.; Agre, P.: Isolation of the cDNA for erythrocyte
integral membrane protein of 28 kilodaltons: member of an ancient
channel family. Proc. Nat. Acad. Sci. 88: 11110-11114, 1991.

16. Preston, G. M.; Smith, B. L.; Zeidel, M. L.; Moulds, J. J.; Agre,
P.: Mutations in aquaporin-1 in phenotypically normal humans without
functional CHIP water channels. Science 265: 1585-1587, 1994.

17. Smith, B. L.; Baumgarten, R.; Nielsen, S.; Raben, D.; Zeidel,
M. L.; Agre, P.: Concurrent expression of erythroid and renal aquaporin
CHIP and appearance of water channel activity in perinatal rats. J.
Clin. Invest. 92: 2035-2041, 1993.

18. Smith, B. L.; Preston, G. M.; Spring, F.; Anstee, D. J.; Agre,
P.: Human red blood cell aquaporin CHIP: I. Molecular characterization
of ABH and Colton blood group antigens. J. Clin. Invest. 94: 1043-1049,
1994.

19. Tang, W.; Cai, S.-P.; Eng, B.; Poon, M.-C.; Waye, J. S.; Illum,
N.; Chui, D. H. K.: Expression of embryonic zeta-globin and epsilon-globin
chains in a 10-year-old girl with congenital anemia. Blood 81: 1636-1640,
1993.

20. Wickramasinghe, S. N.; Illum, N.; Wimberley. P. D.: Congenital
dyserythropoietic anaemia with novel intra-erythroblastic and intra-erythrocytic
inclusions. Brit. J. Haemat. 79: 322-330, 1991.

*FIELD* CN
Alan F. Scott - edited: 12/27/1996

*FIELD* CD
Victor A. McKusick: 9/14/1993

*FIELD* ED
mark: 12/27/1996
mark: 1/15/1996
terry: 3/7/1995
carol: 10/5/1994
carol: 10/29/1993
carol: 9/14/1993

*RECORD*
*FIELD* NO
107777
*FIELD* TI
*107777 AQUAPORIN-2; AQP2
AQUAPORIN-CD
*FIELD* TX
Whereas aquaporin-CHIP (AQP1; 107776) is located in the proximal renal
tubule, aquaporin-CD (AQP2) is located in the collecting tubule. Fushimi
et al. (1993) cloned the cDNA for the water channel of the apical
membrane of the kidney collecting tubule in the rat. It showed 42%
identity in amino acid sequence to AQP1. Expression in Xenopus oocytes
markedly increased osmotic water permeability. The functional expression
and the limited localization suggested that AQP2 is the
vasopressin-regulated water channel. Fushimi et al. (1993) referred to
AQP2 as WCH-CD, for 'water channel-collecting duct.' Sasaki et al.
(1993, 1994) cloned a cDNA for the human homolog, which was found to
have 91% amino acid identity to the rat protein. By in situ
hybridization, the gene was assigned to 12q13, very close to the site of
major intrinsic protein (MIP; 154050) which shows 59% homology to AQP2.
A defect in this gene as the basis of the autosomal dominant form of
nephrogenic diabetes insipidus (NDI; 125800) was suggested. Indeed,
mutations were discovered by Deen et al. (1994) in a male patient with a
variant, autosomal recessive form of diabetes insipidus (222000). The
X-linked form (304800) is also characterized by a failure of the
endothelium to release coagulation and fibrinolysis factors in response
to the specific V2 agonist desamino-8-D-arginine vasopressin (dDAVP). In
the patient with the variant form of diabetes insipidus, the abnormal
dDAVP response was restricted to the kidney and the coding region of the
vasopressin V2 receptor did not harbor any potentially harmful mutation.
By screening kidney cDNA in cosmid libraries with a rat aquaporin-2 cDNA
probe, Deen et al. (1994) isolated the human AQP2 gene, showed by
fluorescence in situ hybridization that the gene maps to chromosome 12,
and demonstrated that the cDNA had a sequence with 89.7% identity in
terms of amino acid sequence with the rat protein. The patient was found
to be a compound heterozygote for 2 mutations in the AQP2 gene, an R187C
mutation inherited from the father and an S216P mutation from the
mother. Functional expression studies in Xenopus oocytes revealed that
each mutation resulted in nonfunctional water channel proteins. Findings
demonstrated that aquaporin-2 is the vasopressin-regulated water channel
in man. Thus, mutations have been identified at the first and last
stages of the pathway for vasopressin-induced antidiuresis.
Identification of patients with vasopressin-resistant diabetes who do
not have mutations in either of these 2 genes may help identify further
elements essential for vasopressin-regulated water transport in the
kidney.

Missense mutations and a single nucleotide deletion in the AQP2 gene
were found by van Lieburg et al. (1994) in 3 NDI patients from
consanguineous matings; see 107777.0003, 107777.0004, and 107777.0005.
Expression studies in Xenopus oocytes showed that the missense AQP2
proteins were nonfunctional.

Nielsen et al. (1995) showed that vasopressin (192340) increases
cellular water permeability by inducing exocytosis of AQP2-laden
vesicles, transferring water channels from intracellular vesicles to
apical plasma membrane.

Kanno et al. (1995) reported that aquaporin-2 is detectable in the urine
in both soluble and membrane-bound forms. In normal subjects, an
infusion of desmopressin increased the urinary excretion of aquaporin-2.
In 5 patients with central diabetes insipidus, administration of
vasopressin in the same form likewise increased urinary excretion of
aquaporin-2, but such did not occur in 4 patients with X-linked or
autosomal nephrogenic diabetes insipidus.

Deen et al. (1995) found that expression of 3 mutant AQP2 proteins,
gly64-to-arg (107777.0004), arg187-to-cys (107777.0001), and
ser216-to-pro (107777.0002), in Xenopus oocytes resulted in
nonfunctional water channels. The transcripts encoding the missense AQPs
were translated as efficiently as was wildtype transcript and were
equally stable. Immunocytochemistry demonstrated that the mutant AQP2
did not label in the plasma membrane. Thus, the authors proposed that
the inability of the AQP2 proteins to facilitate water transport was
caused by an impaired routing to the plasma membrane. Mulders et al.
(1997) reported 3 additional NDI patients who were homozygous for
mutations in the AQP2 gene (107777.0006, 107777.0007, 107777.0008). They
performed functional analyses of the mutant AQP2 proteins in Xenopus
oocytes and concluded that 2 of the mutations (107777.0006 and
107777.0007) result in functional proteins that were apparently retained
in the endoplasmic reticulum and thus were impaired in their routing to
the plasma membrane.

*FIELD* AV
.0001
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, ARG187CYS
Deen et al. (1994) found a C-to-T transition at nucleotide 559 in exon 3
of the AQP2 gene, resulting in substitution of cys for arg187 in a
patient with diabetes insipidus. The other chromosome carried a T-to-C
transition at nucleotide 646 in exon 4, resulting in substitution of
proline for serine-216. The former mutation was inherited from the
father and the latter from the mother. By injection into Xenopus
oocytes, Deen et al. (1994) demonstrated that both mutations result in a
nonfunctional protein.

.0002
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, SER216PRO
See 107777.0001.

.0003
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, ARG187CYS
In a Dutch family, van Lieburg et al. (1994) found a C-to-T transition
at nucleotide 559 in exon 3 of the AQP2 gene, resulting in an
arg187-to-cys change.

.0004
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, GLY64ARG
In a family of Italian origin, van Lieburg et al. (1994) found that NDI
was caused by a G-to-A transition at nucleotide 190 in exon 1 of the
AQP2 gene, leading to substitution of an arginine for a glycine
(gly64-to-arg).

.0005
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, 1BP DEL, C369, FS131TER
In a consanguineous Palestinian family, van Lieburg et al. (1994) found
that NDI was due to a 1-bp deletion in the AQP2 gene; deletion of
cytosine-369 (codon 123) resulted in frameshift and generation of a
sequence of 8 missense amino acids followed by premature termination
after amino acid position 131.

.0006
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, ALA147THR
In a consanguineous Austrian family, Mulders et al. (1997) found that
NDI was due to a G-to-A transition at nucleotide 533 in exon 2 of the
AQP2 gene, resulting in an alanine-to-threonine substitution at amino
acid 147 (A147T). The mutant AQP2 protein was functional when expressed
in Xenopus oocytes but was apparently impaired in its routing to the
plasma membrane.

.0007
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, THR126MET
In a consanguineous family from Sri Lanka, Mulders et al. (1997) found
that NDI was due to a C-to-T transition at nucleotide 471 in exon 2 of
the AQP2 gene, resulting in a threonine-to-methionine substitution at
amino acid 126 (T126M). The mutant AQP2 protein was functional when
expressed in Xenopus oocytes but was apparently impaired in its routing
to the plasma membrane.

.0008
DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL RECESSIVE
AQP2, ASN68SER
In a consanguineous Turkish family, Mulders et al. (1997) found that NDI
was due to an A-to-G transition at nucleotide 297 in exon 1 of the AQP2
gene, resulting in an asparagine-to-serine substitution at amino acid 68
(N68S). When expressed in oocytes, this mutant AQP2 was not functional
because the substituted amino acid is part of the NPA box in loop B,
which forms, together with a second NPA box in loop E, the most
conserved amino acid sequence of the MIP-family.

*FIELD* RF
1. Deen, P. M. T.; Croes, H.; van Aubel, R. A. M. H.; Ginsel, L. A.;
van Os, C. H.: Water channels encoded by mutant aquaporin-2 genes
in nephrogenic diabetes insipidus are impaired in their cellular routing. J.
Clin. Invest. 95: 2291-2296, 1995.

2. Deen, P. M. T.; Verdijk, M. A. J.; Knoers, N. V. A. M.; Wieringa,
B.; Monnens, L. A. H.; van Os, C. H.; van Oost, B. A.: Requirement
of human renal water channel aquaporin-2 for vasopressin-dependent
concentration of urine. Science 264: 92-94, 1994.

3. Deen, P. M. T.; Weghuis, D. O.; Sinke, R. J.; Geurts van Kessel,
A.; Wieringa, B.; van Os, C. H.: Assignment of the human gene for
the water channel of renal collecting duct aquaporin 2 (AQP2) to chromosome
12 region q12-q13. Cytogenet. Cell Genet. 66: 260-262, 1994.

4. Fushimi, K.; Uchida, S.; Hara, Y.; Hirata, Y.; Marumo, F.; Sasaki,
S.: Cloning and expression of apical membrane water channel of rat
kidney collecting tubule. Nature 361: 549-552, 1993.

5. Kanno, K.; Sasaki, S.; Hirata, Y.; Ishikawa, S.; Fushimi, K.; Nakanishi,
S.; Bichet, D. G.; Marumo, F.: Urinary excretion of aquaporin-2 in
patients with diabetes insipidus. New Eng. J. Med. 332: 1540-1545,
1995.

6. Mulders, S. M.; Knoers, N. V. A. M.; van Lieburg, A. F.; Monnens,
L. A. H.; Leumann, E.; Wuhl, E.; Schober, E.; Rijss, J. P. L.; van
Os, C. H.; Deen, P. M. T.: New mutations in the AQP2 gene in nephrogenic
diabetes insipidus resulting in functional but misrouted water channels. J.
Am. Soc. Nephrol. 8: 242-248, 1997.

7. Nielsen, S.; Chou, C.-L.; Marples, D.; Christensen, E. I.; Kishore,
B. K.; Knepper, M. A.: Vasopressin increases water permeability of
kidney collecting duct by inducing translocation of aquaporin-CD water
channels to plasma membrane. Proc. Nat. Acad. Sci. 92: 1013-1017,
1995.

8. Sasaki, S.; Fushimi, K.; Saito, H.; Saito, F.; Uchida, S.; Ishibashi,
K.; Kuwahara, M.; Ikeuchi, T.; Inui, K.; Nakajima, K.; Watanabe, T.
X.; Marumo, F.: Cloning, characterization, and chromosomal mapping
of human aquaporin of collecting duct. J. Clin. Invest. 93: 1250-1256,
1994.

9. Sasaki, S.; Saito, H.; Saito, F.; Fushimi, K.; Uchida, S.; Rai,
Y.; Ikeuchi, T.; Inui, K.; Marumo, F.: Cloning, expression and chromosomal
mapping of human collecting duct water channel (hWCH-CD). (Abstract) J.
Am. Soc. Nephrol. 4: 858 only, 1993.

10. van Lieburg, A. F.; Verdijk, M. A. J.; Knoers, V. V. A. M.; van
Essen, A. J.; Proesmans, W.; Mallmann, R.; Monnens, L. A. H.; van
Oost, B. A.; van Os, C. H.; Deen, P. M. T.: Patients with autosomal
nephrogenic diabetes insipidus homozygous for mutations in the aquaporin
2 water-channel gene. Am. J. Hum. Genet. 55: 648-652, 1994.

*FIELD* CN
Beat Steinmann - updated: 4/28/1997

*FIELD* CD
Victor A. McKusick: 11/5/1993

*FIELD* ED
joanna: 04/28/1997
joanna: 4/28/1997
terry: 10/25/1995
mark: 8/21/1995
carol: 3/3/1995
jason: 6/28/1994
carol: 11/5/1993

*RECORD*
*FIELD* NO
107800
*FIELD* TI
107800 ARCUS CORNEAE
ARCUS SENILIS
*FIELD* TX
Although arcus may be a manifestation of a disorder of lipid metabolism,
it is likely that this is by no means always the case. MacAraeg et al.
(1968) showed that arcus corneae occurs in higher frequency and develops
at an earlier age in blacks than in whites. They could not relate it to
diastolic hypertension, myocardial infarction or cerebrovascular
accidents. Arcus corneae develops precociously in Tangier disease, Norum
disease and in homozygotes for type II hyperlipoproteinemia. In
osteogenesis imperfecta a ring resembling arcus is seen. The
Kayser-Fleischer ring of Wilson disease (277900) bears some similarity.

*FIELD* SA
Ahuja  (1959)
*FIELD* RF
1. Ahuja, Y. R.: L'heredite de l'arcus corneae. J. Genet. Hum. 8:
95-107, 1959.

2. MacAraeg, P. V. J., Jr.; Lasagna, L.; Snyder, B.: Arcus not so
senilis. Ann. Intern. Med. 68: 345-354, 1968.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107820
*FIELD* TI
*107820 ARGINYL-tRNA SYNTHETASE; RARS
*FIELD* TX
Arfin et al. (1985) assigned the gene for arginyl-tRNA synthetase to
chromosome 5 by study of somatic cell hybrids. Of the 7 aminoacyl-tRNA
synthetase genes mapped to that time, 4 were on chromosome 5, which
represents only about 7% of the total human genome.

Girjes et al. (1995) isolated a full-length cDNA corresponding to the
RARS gene and identified an open reading frame of 1983 nucleotides with
87% homology to other mammalian RARS. Northern blot analysis revealed
the presence of a single mRNA species of approximately 2.2 kb.

*FIELD* SA
Carlock et al. (1985)
*FIELD* RF
1. Arfin, S.; Carlock, L.; Gerken, S.; Wasmuth, J.: Clustering of
genes encoding aminoacyl-tRNA synthetases on human chromosome 5.
(Abstract) Am. J. Hum. Genet. 37: A228, 1985.

2. Carlock, L. R.; Skarecky, D.; Dana, S. L.; Wasmuth, J. J.: Deletion
mapping of human chromosome 5 using chromosome-specific DNA probes.
Am. J. Hum. Genet. 37: 839-852, 1985.

3. Girjes, A. A.; Hobson, K.; Chen, P.; Lavin, M. F.: Cloning and
characterization of cDNA encoding a human arginyl-tRNA synthetase. Gene 164:
347-350, 1995.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/11/1996
terry: 2/28/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107830
*FIELD* TI
*107830 ARGINASE II; ARG2
*FIELD* TX
Spector et al. (1980) presented evidence for the existence of 2
arginases. The one found in liver and red cells (ARG1) is severely
deficient in argininemia (207800). In patients with this disorder, some
urea is produced, presumably because the arginase of kidney, brain and
gastrointestinal tract is less affected; 'liver-type' enzyme constitutes
only about half the enzyme in these tissues. In argininemia, kidney
enzyme is about 3 times normal. Spector et al. (1980, 1983) demonstrated
immunologic differences between liver and kidney enzymes by means of
rabbit anti-human liver arginase. In addition to the immunologic
differences and differences in tissue location, the second enzyme
differs in electrophoretic mobility in polyacrylamide gels, in its
quantitatively different requirement for divalent manganese activation,
and in its differential inhibition by proline and isoleucine; it is
localized to the mitochondrial matrix, whereas arginase I is
cytoplasmic.

*FIELD* RF
1. Spector, E. B.; Rice, S. C. H.; Cederbaum, S. D.: Evidence for
two genes encoding human arginase.  (Abstract) Am. J. Hum. Genet. 32:
55A only, 1980.

2. Spector, E. B.; Rice, S. C. H.; Cederbaum, S. D.: Immunologic
studies of arginase in tissues of normal human adult and arginase-deficient
patients. Pediat. Res. 17: 941-944, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
carol: 3/1/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
^107840
*FIELD* TI
^107840 MOVED TO 215700
*FIELD* TX
This entry was incorporated into 215700 on 18 January 1997.

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
mark: 01/18/1997
carol: 1/28/1993
carol: 1/5/1993
supermim: 3/16/1992
carol: 3/3/1992
supermim: 3/20/1990
supermim: 3/2/1990
*RECORD*
*FIELD* NO
107850
*FIELD* TI
107850 ARM FOLDING PREFERENCE
*FIELD* TX
If in folding his arms the right arm is on top, the person is classed R.
Hand clasping (139800) is a comparable trait. Falk and Ayala (1971)
concluded that, although both traits are heritable to a significant
extent, a simple mendelian hypothesis is not tenable. Ferronato et al.
(1974) found no significant correlation between parents and children for
arm folding preference, i.e., right arm or left arm on top.

*FIELD* RF
1. Falk, C. T.; Ayala, F. J.: Genetic aspects of arm folding and
hand clasping. Jpn. J. Hum. Genet. 15: 241-247, 1971.

2. Ferronato, S.; Thomas, D.; Sadava, D.: Preferences for handedness,
arm folding, and hand clasping in families. Hum. Hered. 24: 345-351,
1974.

*FIELD* CS

Misc:
   Arm folding preference

Inheritance:
   Non-Mendelian, ? heritability

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/12/1988

*RECORD*
*FIELD* NO
107900
*FIELD* TI
107900 ARMS, MALFORMATION OF
*FIELD* TX
Twelve cases of short, absent or partially fused radius and ulna and
abnormalities of the digits were found in 3 generations by Stiles and
Dougan (1940).

*FIELD* RF
1. Stiles, K. A.; Dougan, P.: A pedigree of malformed upper extremities
showing variable dominance. J. Hered. 31: 65-72, 1940.

*FIELD* CS

Limbs:
   Short, absent or partially fused radius and ulna;
   Abnormal digits

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
107910
*FIELD* TI
*107910 CYTOCHROME P450, SUBFAMILY XIX; CYP19
AROMATASE; ARO;;
GYNECOMASTIA, FAMILIAL, DUE TO INCREASED AROMATASE ACTIVITY, INCLUDED;;
AROMATASE ACTIVITY, INCREASED, INCLUDED;;
AROMATASE DEFICIENCY, INCLUDED
*FIELD* TX
Aromatase (EC 1.14.14.1), also called estrogen synthetase, is a
cytochrome P450 enzyme which catalyzes the formation of aromatic C18
estrogens from C19 androgens; it is symbolized CYP19. Using the amino
acid sequence from the amino terminal end of the molecule as described
by Chen et al. (1986), Sparkes et al. (1987) synthesized oligonucleotide
probes and used them to screen a human placental lambda gt11 cDNA
expression library. The cDNA thus identified was used in the study of
human/mouse somatic cell hybrids for assignment of the gene to human
chromosome 15. By in situ hybridization, Chen et al. (1988) mapped the
ARO gene to 15q21.1. Evans et al. (1986) cloned and sequenced cDNA
corresponding to this gene. Harada (1988) isolated a complete cDNA clone
encoding a human aromatase from a human placental cDNA library in
lambda-gt11. A study of the deduced 503-amino acid sequence and a
comparison with other forms of cytochrome P450 indicated that this
enzyme is a unique member of the cytochrome P450 superfamily. In
reviewing the regulation of expression of P450 genes, Whitlock (1986)
discussed P450-aromatase, which is induced by follicle-stimulating
hormone (FSH) via formation of cyclic AMP. Presumably the increased
activity reflects increased transcription of the P450-aromatase gene.
Aromatase is present in many tissues including skin, muscle, fat and
nerve, where it may contribute to sex-specific differences in cellular
metabolism. Corbin et al. (1988) cloned a full-length cDNA for CYP19.
The insert contained an open reading frame encoding a protein of 503
amino acids. The sequence contains regions of striking similarity to
those of other members of the cytochrome P450 gene superfamily. The
expressed protein is similar in size to human placental aromatase as
detected by immunoblot analysis, and catalyzed the aromatization of all
3 major physiologic substrates: androstenedione, testosterone, and
16-alpha-hydroxyandrostenedione. Toda et al. (1990) found that the CYP19
gene spans at least 70 kb of genomic DNA and comprises 10 exons. The
translational initiation site and the termination site are located in
exon 2 and exon 10, respectively.

Hemsell et al. (1977) reported a case of gynecomastia due apparently to
excessive peripheral conversion of androgen to estrogen as a result of
50 times normal aromatase activity. The patient was an adopted boy, aged
11 years 7 months. Effects of excessive estrogen became evident at age
8, the time when plasma androstenedione begins to increase.
Extraglandular aromatization, as well as sulfurylation, is extensively
involved in C19-steroid metabolism in the fetus, but the activity of the
enzymes falls rapidly after birth. In the patient of Hemsell et al.
(1977), the fetal situation appeared to persist. Berkovitz et al. (1985)
investigated a black family in which marked gynecomastia with normal
male genitalia occurred in 5 men in 3 sibships of 2 generations
connected through females. In each, gynecomastia and male sexual
differentiation began at an early age (10-11 years). The ratio of the
concentration of plasma estradiol-17 beta to that of plasma testosterone
was elevated in each. In 3 affected sibs, the transfer constant of
conversion of androstenedione to estrone (i.e., the fraction of plasma
androstenedione that was converted to estrone as measured in the urine)
was 10 times the normal. Despite elevated extraglandular aromatase
activity, the hypothalamic-pituitary axis responded normally to
provocative stimuli. None of the 5 males had children but 4 were still
in their teens; the fifth was 29 years of age. The pattern of
inheritance of familial gynecomastia with increased aromatase activity
is consistent with either X-linked recessive or autosomal dominant,
male-limited inheritance. Mapping of the aromatase locus to an autosome
makes the latter possibility highly likely. Proof will come with
demonstration of a lesion at the CYP19 gene (or its promoter). Autosomal
dominant inheritance appeared to obtain in a family in which increased
steroid aromatization seemed to be responsible for 'familial adrenal
feminization.' The father and 2 male and 2 female sibs had gynecomastia,
early growth, and short final stature. The 8-year-old propositus had
advanced bone age, facial acne, gynecomastia, pubic hair, and
prepubertal testicular volume. ACTH-dependent adrenal feminization was
confirmed by a transient reduction of breast tissue following
dexamethasone or cypropterone acetate treatment. Testolactone, which is
an inhibitor of peripheral aromatase activity in vivo, temporarily
reduced the breast tissue. This was the first example of male-to-male
and male-to-female transmission reported.

Leshin et al. (1981) showed that a similar lesion exists in the henny
feathering trait of Sebright bantam and concluded that it results from a
regulatory mutation affecting aromatase activity. George et al. (1990)
showed that the henny feathering trait in the Golden Campine chicken is
identical to that in the Sebright Bantam; indeed, it may be the same
gene, the trait in the Campine having been derived from the Sebright. In
the chicken the trait behaves as an incomplete dominant; heterozygotes
express half the levels of extraglandular aromatase as do homozygotes on
average.

Zhou et al. (1991) studied structure-function relationships in human
aromatase using site-directed mutagenesis and a stable expression system
that involved a plasmid containing human placenta aromatase cDNA in
Chinese hamster ovary (CHO) cells. A phe406-to-arg mutant was completely
inactive. Only small changes in enzyme kinetics occurred with mutants
tyr361-to-phe and tyr361-to-leu, leading to the conclusion that tyr361
is not directly involved in substrate binding. The mutant pro308-to-phe
had altered catalytic properties, suggesting that pro308 is situated in
the active site of the enzyme.

Aromatase, or estrogen synthetase, is located in the ovary and placenta
and participates in the regulation of reproductive functions. The enzyme
is also widely distributed in extragonadal tissues such as muscle,
liver, hair follicles, adipose tissue, and brain. This finding suggests
that estrogen produced by this enzyme has physiologic functions not only
as a sex steroid hormone but also in growth or differentiation. It also
suggests that few, if any, cases of deficiency of aromatase will be
found. In fact, there are very few reports of cases of deficiency of
either aromatase or estrogen receptor, although lack of androgen
receptor is well known (see 300068 and 313700). Mango et al. (1978)
reported the case of a primigravida who showed low urinary estrogen
excretion and demonstrated lack of placental aromatase activity by in
vitro assays. Shozu et al. (1991) reported a case of placental aromatase
deficiency in which there was maternal and fetal virilization and female
pseudohermaphroditism in the infant. Harada et al. (1992) demonstrated
that placental aromatase was expressed only in parts of fetal origin and
that the placental aromatase deficiency in the case reported by Shozu et
al. (1991) was caused by the expression of an abnormal aromatase protein
molecule resulting from a genetic defect in the fetus. Specifically, the
CYP19 gene was found to have an insert of 87 bp, encoding 29 amino acids
inframe with no termination codon. The insert was located at the splice
point between exon 6 and intron 6 of the normal gene, and the extra DNA
fragment was the first part of intron 6 except that its initial GT was
altered to GC. By transient expression in COS-7 cells, the aromatase
cDNA of the patient was found to contain a protein with a trace of
activity. Harada et al. (1992) suggested that the defect in the
placental aromatase gene, a feature of the infant's genotype, might be
inherited since the parents were consanguineous in the 'fifth degree.'
They showed that the offspring was homozygous for a defect that was
present in heterozygous state in both parents (107910.0003). Ito et al.
(1993) described the molecular defects in the CYP19 gene in what they
claimed was the first example of fully documented aromatase deficiency
in an adult.

*FIELD* AV
.0001
AROMATASE DEFICIENCY
CYP19, ARG435CYS
Ito et al. (1993) described compound heterozygosity for 2 mutations in
the CYP19 gene in a case of aromatase deficiency suspected on the basis
of clinical and biochemical evidence. The patient was an 18-year-old
46,XX female with sexual infantilism, primary amenorrhea, ambiguous
external genitalia at birth, and polycystic ovaries. They indicated that
this was the first definitive case of an adult with aromatase deficiency
to be reported. Coding exons 2-10 of the CYP19 gene were amplified by
PCR from genomic DNA and sequenced directly. Two single-base changes
were found in exon 10: a C-to-T transition at bp 1303 and a G-to-A
transition at bp 1310. These resulted in a change of arginine-435 to
cysteine and of cysteine-437 to tyrosine, respectively. The results of
RFLP analysis and direct sequencing of the amplified exon 10 DNA from
the patient's mother indicated maternal inheritance of the R435C
mutation. Transient expression experiments showed that the R435C mutant
protein had approximately 1.1% of the activity of the wildtype, whereas
C437Y was totally inactive.

.0002
AROMATASE DEFICIENCY
CYP19, CYS437TYR
See 107910.0001.

.0003
AROMATASE DEFICIENCY, PLACENTAL
CYP19, IVS6DS, T-C, +2
Shozu et al. (1991) observed progressive virilization of a primigravida
during pregnancy, as well as female pseudohermaphroditism of her baby,
and showed that they were caused by deficiency of placental aromatase
activity. Harada et al. (1992) showed that the aromatase gene from the
placenta was transcribed as an abnormally large mRNA with an 87-bp
insertion and was translated as an abnormally large protein molecule
with 29 extra amino acids, resulting in an almost inactive enzyme.
Harada et al. (1992) showed that the splice donor sequence (GT) of
intron 6 in controls was mutated to GC in the patient, whereas the
parents showed both GT and GC, indicating their heterozygous state.

.0004
AROMATASE DEFICIENCY
CYP19, ARG375CYS
Morishima et al. (1995) described a C-to-T transition at nucleotide 1123
in exon IX of the CYP19 gene in a 28-year-old XX proband and her
24-year-old XY sib. During both pregnancies the mother exhibited signs
of progressive virilization that regressed postpartum. The XX proband,
followed since infancy, exhibited the cardinal features of the aromatase
deficiency syndrome. She had nonadrenal female pseudohermaphrodism at
birth and underwent repair of the external genitalia, including a
clitorectomy. At the age of puberty, she developed progressive signs of
virilization, pubertal failure with no signs of estrogen action,
hypergonadotropic hypogonadism, polycystic ovaries on pelvic sonography,
and tall stature. The basal concentrations of plasma testosterone,
androstenedione, and 17-hydroxyprogesterone were elevated, whereas
plasma estradiol was low. Hormone replacement therapy led to breast
development, menses, resolution of ovarian cysts, and suppression of the
elevated FSH and LH values. Her adult height was 177.6 cm. Her brother
was 204 cm tall with eunuchoid skeletal proportions. He was sexually
fully mature and had macroorchidism. The bone age was 14 years at a
chronologic age of 24 years. Striking osteopenia was noted at the wrist
and at other sites. The observations in these sibs was considered
consistent with the following interpretations by Morishima et al.
(1995): (1) estrogens are essential for normal skeletal maturation and
proportions (but not linear growth) in men as well as in women, the
accretion and maintenance of bone mineral density and mass, and the
control of the rate of bone turnover; (2) estrogens have a significant
role in the sex steroid-gonadotropin feedback mechanism in the male,
even in the face of high circulating testosterone; (3) deficient
estrogens in the adult male are associated with hyperinsulinemia and
abnormal plasma lipids; and (4) placental aromatase has a critical role
in protecting the female fetus from fetal masculinization and the
pregnant woman from virilization.

*FIELD* SA
George and Wilson (1980); Harada et al. (1992); Leiberman and Zachmann
(1992); Leshin et al. (1981)
*FIELD* RF
1. Berkovitz, G. D.; Guerami, A.; Brown, T. R.; MacDonald, P. C.;
Migeon, C. J.: Familial gynecomastia with increased extraglandular
aromatization of plasma carbon(19)-steroids. J. Clin. Invest. 75:
1763-1769, 1985.

2. Chen, S.; Besman, M. J.; Sparkes, R. S.; Zollman, S.; Klisak, I.;
Mohandas, T.; Hall, P. F.; Shively, J. E.: Human aromatase: cDNA
cloning, Southern blot analysis, and assignment of the gene to chromosome
15. DNA 7: 27-38, 1988.

3. Chen, S.; Shively, J. E.; Nakajin, S.; Shinoda, M.; Hall, P. F.
: Amino terminal sequence analysis of human placenta aromatase. Biochem.
Biophys. Res. Commun. 135: 713-719, 1986.

4. Corbin, C. J.; Graham-Lorence, S.; McPhaul, M.; Mason, J. I.; Mendelson,
C. R.; Simpson, E. R.: Isolation of a full-length cDNA insert encoding
human aromatase system cytochrome P-450 and its expression in nonsteroidogenic
cells. Proc. Nat. Acad. Sci. 85: 8948-8952, 1988.

5. Evans, C. T.; Ledesma, D. B.; Schulz, T. Z.; Simpson, E. R.; Mendelson,
C. R.: Isolation and characterization of a complementary DNA specific
for human aromatase-system cytochrome P-450 mRNA. Proc. Nat. Acad.
Sci. 83: 6387-6391, 1986.

6. George, F. W.; Matsumine, H.; McPhaul, M. J.; Somes, R. G., Jr.;
Wilson, J. D.: Inheritance of the henny feathering trait in the Golden
Campine chicken: evidence for allelism with the gene that causes henny
feathering in the Sebright Bantam. J. Hered. 81: 107-110, 1990.

7. George, F. W.; Wilson, J. D.: Pathogenesis of the henny feathering
trait in the Sebright Bantam chicken. J. Clin. Invest. 66: 57-65,
1980.

8. Harada, N.: Cloning of a complete cDNA encoding human aromatase:
immunochemical identification and sequence analysis. Biochem. Biophys.
Res. Commun. 156: 725-732, 1988.

9. Harada, N.; Ogawa, H.; Shozu, M.; Yamada, K.: Genetic studies
to characterize the origin of the mutation in placental aromatase
deficiency. Am. J. Hum. Genet. 51: 666-672, 1992.

10. Harada, N.; Ogawa, H.; Shozu, M.; Yamada, K.; Suhara, K.; Nishida,
E.; Takagi, Y.: Biochemical and molecular genetic analyses on placental
aromatase (P-450-AROM) deficiency. J. Biol. Chem. 267: 4781-4785,
1992.

11. Hemsell, D. L.; Edman, C. D.; Marks, J. F.; Siiteri, P. K.; MacDonald,
P. C.: Massive extraglandular aromatization of plasma androstenedione
resulting in feminization of a prepubertal boy. J. Clin. Invest. 60:
455-464, 1977.

12. Ito, Y.; Fisher, C. R.; Conte, F. A.; Grumbach, M. M.; Simpson,
E. R.: Molecular basis of aromatase deficiency in an adult female
with sexual infantilism and polycystic ovaries. Proc. Nat. Acad.
Sci. 90: 11673-11677, 1993.

13. Leiberman, E.; Zachmann, M.: Familial adrenal feminization probably
due to increased steroid aromatization. Hormone Res. 37: 96-102,
1992.

14. Leshin, M.; Baron, J.; George, F. W.; Wilson, J. D.: Increased
estrogen formation and aromatase activity in fibroblasts cultured
from the skin of chickens with the Henny feathering trait. J. Biol.
Chem. 256: 4341-4344, 1981.

15. Leshin, M.; George, F. W.; Wilson, J. D.: Increased estrogen
synthesis in the Sebright bantam is due to a mutation that causes
increased aromatase activity. Trans. Assoc. Am. Phys. 94: 97-105,
1981.

16. Mango, D.; Montemurro, A.; Scirpa, P.; Bompiani, A.; Menini, E.
: Four cases of pregnancy with low estrogen production due to placental
enzymatic deficiency. Europ. J. Obstet. Gynec. Reprod. Biol. 8:
65-71, 1978.

17. Morishima, A.; Grumbach, M. M.; Simpson, E. R.; Fisher, C.; Qin,
K.: Aromatase deficiency in male and female siblings caused by a
novel mutation and the physiological role of estrogens. J. Clin.
Endocr. Metab. 80: 3689-3698, 1995.

18. Shozu, M.; Akasofu, K.; Harada, T.; Kubota, Y.: A new cause of
female pseudohermaphroditism: placental aromatase deficiency. J.
Clin. Endocr. Metab. 72: 560-566, 1991.

19. Sparkes, R. S.; Mohandas, T.; Chen, S.; Besman, M. J.; Zollman,
S.; Shively, J. E.: Assignment of the aromatase gene to human chromosome
15q21. (Abstract) Cytogenet. Cell Genet. 46: 696-697, 1987.

20. Toda, K.; Merashima, M.; Kawamoto, T.; Sumimoto, H.; Yokoyama,
Y.; Kuribayashi, I.; Mitsuuchi, Y.; Maeda, T.; Yamamoto, Y.; Sagara,
Y.; Ikeda, H.; Shizuta, Y.: Structural and functional characterization
of human aromatase P-450 gene. Europ. J. Biochem. 193: 559-565,
1990.

21. Whitlock, J. P., Jr.: The regulation of cytochrome P-450 gene
expression. Annu. Rev. Pharm. Toxicol. 26: 333-369, 1986.

22. Zhou, D.; Pompon, D.; Chen, S.: Structure-function studies of
human aromatase by site-directed mutagenesis: kinetic properties of
mutants pro308-to-phe, tyr361-to-phe, tyr361-to-leu, and phe406-to-arg. Proc.
Nat. Acad. Sci. 88: 410-414, 1991.

*FIELD* CS

Thorax:
   Gynecomastia

GU:
   Normal male genitalia;
   Early male sexual differentiation;
   Normal hypothalamic-pituitary axis response

Growth:
   Short final stature

Skel:
   Advanced bone age

Misc:
   Induced by follicle-stimulating hormone (FSH)

Lab:
   Increased aromatase (estrogen synthetase) activity

Inheritance:
   Autosomal dominant, male-limited (15q21.1);
   AROMATASE DEFICIENCY

GU:
   Female sexual infantilism;
   Primary amenorrhea;
   Ambiguous external genitalia at birth;
   Polycystic ovaries

Lab:
   Aromatase deficiency

Inheritance:
   Autosomal recessive with compound heterozygosity

*FIELD* CD
Victor A. McKusick: 8/31/1987

*FIELD* ED
mark: 03/27/1997
mark: 3/6/1997
mark: 2/2/1996
terry: 1/25/1996
mimadm: 4/18/1994
carol: 3/28/1994
carol: 12/22/1992
carol: 12/14/1992
carol: 6/11/1992
carol: 5/5/1992

*RECORD*
*FIELD* NO
107920
*FIELD* TI
107920 AROMATIC ALPHA-KETO ACID REDUCTASE
ALPHA-KETO ACID REDUCTASE; KAR
*FIELD* TX
Aromatic alpha-keto acid reductase catalyzes the reduction of
phenylpyruvic and p-OH-phenylpyruvic acids to their corresponding
lactate derivatives in the presence of NADH2. By study of human-Chinese
hamster somatic cell hybrids, Donald (1982) concluded that the gene for
KAR is on chromosome 12. Interestingly, KAR's substrate specificity
overlaps that of lactate dehydrogenase which, in one of its isozymic
forms, is also determined by a gene on chromosome 12. However, the
enzymes are distinctly different in electrophoretic mobility and subunit
composition. In a single person, Donald (1982) found an unusual
phenotype of KAR following electrophoresis in starch gel and interpreted
this to represent a genetic variant. Friedrich and Ferrell (1985) found
no variants in a starch gel electrophoresis of 509 persons from many
different racial groups and none in a survey by thin layer isoelectric
focusing in polyacrylamide gel involving 232 persons. Friedrich et al.
(1987, 1988) presented evidence from several nonhuman species and from
humans that alpha-ketoacid reductase and cytoplasmic malate
dehydrogenase (MDH1; 154200) are identical. In starch-gel
electrophoresis the 2 enzyme functions comigrated in all species studied
except some marine species. Inhibition with malate, the end-product of
the MDH reaction, substantially reduced or totally eliminated KAR
activity. Genetically determined electrophoretic variants of MDH1 seen
in fresh water bony fish and in the amphibian Rana pipiens exhibited
identical variation of KAR, and the 2 traits cosegregated in the
offspring from 1 R. pipiens heterozygote studied. Both enzymes
comigrated with no electrophoretic variation among several inbred
strains of mice. Antisera raised against purified chicken MDH1 totally
inhibited both MDH1 and KAR activity in chicken liver homogenates. In
all species examined, KAR activity was associated only with cytoplasmic
MDH, not with mitochondrial MDH (MDH2; 154100). MDH1 in man maps to
2p23. Friedrich et al. (1988) called into question the assignment of KAR
to chromosome 12 in somatic cell hybrids because interspecific hybrid
bands of both MDH1 and LDH appeared with slightly different mobility
approximately midway between the human and hamster controls in somatic
cell hybrid studies. Friedrich et al. (1988) concluded that the bulk of
KAR activity in human blood is due to MDH1, with a minor fraction
catalyzed by LDH, as is the case in most other species studied.

*FIELD* SA
Donald  (1982)
*FIELD* RF
1. Donald, L. J.: Assignment of the gene for aromatic alpha-keto
acid reductase.  (Abstract) Cytogenet. Cell Genet. 32: 267 only,
1982.

2. Donald, L. J.: A description of human aromatic alpha-keto acid
reductase. Ann. Hum. Genet. 46: 299-306, 1982.

3. Friedrich, C. A.; Ferrell, R. E.: A population study of alpha-keto
acid reductase. Ann. Hum. Genet. 49: 111-114, 1985.

4. Friedrich, C. A.; Ferrell, R. E.; Siciliano, M. J.; Kitto, G. B.
: Biochemical and genetic identity of alpha-keto acid reductase and
cytoplasmic malate dehydrogenase from human erythrocytes. Ann. Hum.
Genet. 198: 25-37, 1988.

5. Friedrich, C. A.; Morizot, D. C.; Siciliano, M. J.; Ferrell, R.
E.: The reduction of aromatic alpha-keto acids by cytoplasmic malate
dehydrogenase and lactate dehydrogenase. Biochem. Genet. 25: 657-669,
1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 3/8/1988
root: 1/28/1988

*RECORD*
*FIELD* NO
107930
*FIELD* TI
*107930 AROMATIC L-AMINO ACID DECARBOXYLASE; AADC
DOPA DECARBOXYLASE; DDC
*FIELD* TX
DOPA decarboxylase (EC 4.1.1.28) is an enzyme implicated in 2 metabolic
pathways, synthesizing 2 important neurotransmitters, dopamine and
serotonin (Christenson et al., 1972). Following the hydroxylation of
tyrosine to form L-dihydroxyphenylalanine (L-DOPA), catalyzed by
tyrosine hydroxylase (TH; 191290), DDC decarboxylates L-DOPA to form
dopamine. This neurotransmitter is found in different areas of the brain
and is particularly abundant in basal ganglia. Dopamine is also produced
by DDC in the sympathetic nervous system and is the precursor of the
catecholaminergic hormones, noradrenaline and adrenaline in the adrenal
medulla. In the nervous system, tryptophan hydroxylase (191060) produces
5-OH tryptophan, which is decarboxylated by DDC, giving rise to
serotonin. DDC is a homodimeric, pyridoxal phosphate-dependent enzyme.
Ichinose et al. (1989) prepared a cDNA clone for the coding region of
human aromatic L-amino acid decarboxylase by screening a human
pheochromocytoma cDNA library with an oligonucleotide probe that
corresponded to a partial amino acid sequence of the enzyme purified
from the tumor. The cDNA clone encoded a protein of 480 amino acids,
with a calculated molecular mass of 53.9 kD. The amino acid sequence
asn-phe-asn-pro-his-lys-trp around a possible pyridoxal phosphate
cofactor binding site was shown to be identical in human, Drosophila,
and pig enzymes. The protein encoded by hepatoma cells is the same as
that encoded by adrenal chromaffin-derived pheochromocytoma cells.
Sumi-Ichinose et al. (1992) showed that the DDC gene consists of 15
exons spanning more than 85 kb and exists as a single copy in the
haploid genome. The boundaries between exons and introns followed the
AG/GT rule. The sizes of exons and introns ranged from 20 to 400 bp and
from 1.0 to 17.7 kb, respectively. Untranslated regions located in the
5-prime region of mRNA were encoded by exons 1 and 2.

By hybridization of a cDNA probe to somatic cell hybrid DNAs, Bruneau et
al. (1990) concluded that the DDC gene is located on chromosome 7.
Scherer et al. (1992) confirmed the localization of the DDC gene to
chromosome 7 using a new panel of somatic cell hybrids. They localized
the gene to 7p11 by fluorescence in situ hybridization (FISH).
Sumi-Ichinose et al. (1992) mapped the gene to 7p12.3-p12.1 by
fluorescence in situ hybridization. By isotopic in situ hybridization,
Craig et al. (1992) localized the DDC gene to 7p13-p11, with the largest
concentration of grains in 7p12.

*FIELD* RF
1. Bruneau, G.; Gross, M.-S.; Krieger, M.; Bernheim, A.; Thibault,
J.; Nguyen, V. C.: Preparation of a human DOPA decarboxylase cDNA
probe by PCR and its assignment to chromosome 7. Ann. Genet. 33:
208-213, 1990.

2. Christenson, J. G.; Dairman, W.; Udenfriend, S.: On the identity
of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase (immunological
titration-aromatic L-amino acid decarboxylase-serotonin-dopamine-norepinephrine).
Proc. Nat. Acad. Sci. 69: 343-347, 1972.

3. Craig, S. P.; Le Van Thai, A.; Weber, M.; Craig, I. W.: Localisation
of the gene for human aromatic L-amino acid decarboxylase (DDC) to
chromosome 7p13-p11 by in situ hybridisation. Cytogenet. Cell Genet. 61:
114-116, 1992.

4. Ichinose, H.; Kurosawa, Y.; Titani, K.; Fujita, K.; Nagatsu, T.
: Isolation and characterization of a cDNA clone encoding human aromatic
L-amino acid decarboxylase. Biochem. Biophys. Res. Commun. 164:
1024-1030, 1989.

5. Scherer, L. J.; McPherson, J. D.; Wasmuth, J. J.; Marsh, J. L.
: Human dopa decarboxylase: localization to human chromosome 7p11
and characterization of hepatic cDNAs. Genomics 13: 469-471, 1992.

6. Sumi-Ichinose, C.; Ichinose, H.; Takahashi, E.; Hori, T.; Nagatsu,
T.: Molecular cloning of genomic DNA and chromosomal assignment of
the gene for human aromatic L-amino acid decarboxylase, the enzyme
for catecholamine and serotonin biosynthesis. Biochemistry 31:
2229-2238, 1992.

*FIELD* CD
Victor A. McKusick: 8/24/1990

*FIELD* ED
carol: 1/19/1993
carol: 12/21/1992
carol: 6/22/1992
carol: 6/3/1992
supermim: 3/16/1992
supermim: 6/4/1991

*RECORD*
*FIELD* NO
107940
*FIELD* TI
*107940 ARRESTIN, BETA, 1
BETA-ARRESTIN-1; ARB1; ARRB1
*FIELD* TX
Homologous or agonist-specific desensitization is a widespread process
that causes specific dampening of cellular responses to stimuli such as
hormones, neurotransmitters, or sensory signals. It is defined by a loss
of responsiveness of receptors that have been continuously or repeatedly
stimulated, while the responses of other receptors remain intact.
Homologous desensitization of beta-adrenergic receptors is thought to be
mediated by a specific kinase, called beta-adrenergic receptor kinase
(BARK, or ADRBK1; 109635). A cofactor is required for this kinase to
inhibit receptor function. Lohse et al. (1990) cloned the cDNA for this
cofactor and found that it encodes a 418-amino acid protein homologous
to the retinal protein arrestin. The purified protein, beta-arrestin,
inhibited the signaling function of BARK-phosphorylated beta-adrenergic
receptors by more than 75%, but not that of rhodopsin.

By fluorescence in situ hybridization, Calabrese et al. (1994)
demonstrated that the ARRB1 gene maps to 11q13, the region where the
gene for the functionally related BARK gene is located. By 2-color FISH,
Calabrese et al. (1994) directly confirmed the close localization of
these 2 genes, showing ARRB1 to be distal to BARK1. Based on the
presence of distinguishable yellow and red signals in a number of
metaphases analyzed, it was argued that the 2 loci should be about 1 to
2 Mb apart.

*FIELD* RF
1. Calabrese, G.; Sallese, M.; Stornaiuolo, A.; Morizio, E.; Palka,
G.; De Blasi, A.: Assignment of the beta-arrestin 1 gene (ARRB1)
to human chromosome 11q13. Genomics 24: 169-171, 1994.

2. Lohse, M. J.; Benovic, J. L.; Codina, J.; Caron, M. G.; Lefkowitz,
R. J.: Beta-arrestin: a protein that regulates beta-adrenergic receptor
function. Science 248: 1547-1550, 1990.

*FIELD* CD
Victor A. McKusick: 7/9/1990

*FIELD* ED
carol: 12/5/1994
carol: 2/4/1993
carol: 10/22/1992
supermim: 3/16/1992
carol: 7/9/1990

*RECORD*
*FIELD* NO
107941
*FIELD* TI
*107941 ARRESTIN, BETA, 2
BETA-ARRESTIN-2; ARB2; ARRB2
*FIELD* TX
Using a low stringency hybridization technique to screen a rat brain
cDNA library, Attramadal et al. (1992) isolated cDNA clones representing
2 distinct beta-arrestin-like genes. One of the cDNAs is the rat homolog
of bovine beta-arrestin (beta-arrestin-1; ARB1; 107940). In addition,
Attramadal et al. (1992) isolated a cDNA clone encoding a novel
beta-arrestin-related protein, which they termed beta-arrestin-2. ARB2
exhibited 78% amino acid identity with ARB1. The primary structure of
these proteins delineated a family of proteins that regulate receptor
coupling to G proteins. ARB1 and ARB2 are predominantly localized in
neuronal tissues and in the spleen.

By fluorescence in situ hybridization, Calabrese et al. (1994) mapped
the ARRB2 gene to 17p13.

*FIELD* RF
1. Attramadal, H.; Arriza, J. L.; Aoki, C.; Dawson, T. M.; Codina,
J.; Kwatra, M. M.; Snyder, S. H.; Caron, M. G.; Lefkowitz, R. J.:
Beta-arrestin-2, a novel member of the arrestin/beta-arrestin gene
family. J. Biol. Chem. 267: 17882-17890, 1992.

2. Calabrese, G.; Sallese, M.; Stornaiuolo, A.; Stuppia, L.; Palka,
G.; De Blasi, A.: Chromosome mapping of the human arrestin (SAG),
beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2)
genes. Genomics 23: 286-288, 1994.

*FIELD* CD
Victor A. McKusick: 10/22/1992

*FIELD* ED
terry: 11/7/1994
carol: 3/19/1994
carol: 10/22/1992

*RECORD*
*FIELD* NO
107950
*FIELD* TI
*107950 ARRHENOBLASTOMA--THYROID ADENOMA
*FIELD* TX
Jensen et al. (1974) described ovarian tumors in a mother and 2
daughters. The tumor proved to be arrhenoblastoma in the 2 daughters.
Thyroid adenomas occurred in several members of the family and were
found to be associated frequently with ovarian arrhenoblastoma in young
women surveyed separately. See 166970 and 167000. O'Brien and Wilansky
(1981) described a family in which the 16-year-old proband had a nodular
thyroid and a functioning ovarian arrhenoblastoma. Males and females to
a total of 6 in 4 generations were known to have nodular thyroids. The
disorder was apparently transmitted through an unaffected male. The
authors raised the question of testicular tumors in males with the gene.

*FIELD* RF
1. Jensen, R. D.; Norris, H. J.; Fraumeni, J. F., Jr.: Familial arrhenoblastoma
and thyroid adenoma. Cancer 33: 218-223, 1974.

2. O'Brien, P. K.; Wilansky, D. L.: Familial thyroid nodulation and
arrhenoblastoma. Am. J. Clin. Path. 75: 578-581, 1981.

*FIELD* CS

GU:
   Arrhenoblastoma;
   ? increased testicular tumors

Endo:
   Thyroid adenoma

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
107970
*FIELD* TI
*107970 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 1; ARVD1
ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY-1
UHL ANOMALY, INCLUDED;;
RIGHT VENTRICULAR DILATED CARDIOMYOPATHY, INCLUDED
*FIELD* TX
Arrhythmogenic right ventricular dysplasia is a clinical and pathologic
entity whose diagnosis rests on electrocardiographic and angiographic
criteria; pathologic findings, replacement of ventricular myocardium
with fatty and fibrous elements, preferentially involve the right
ventricular free wall. When the dysplasia is extensive, it may represent
the Uhl anomaly ('parchment right ventricle'). The presenting finding is
usually recurrent, sustained ventricular tachycardia with left
bundle-branch block configuration. Laurent et al. (1987) described a
family with 4 proven cases and 7 strongly suggestive cases. Laurent et
al. (1987) referred to earlier reports of probable (Marcus et al., 1982)
or documented (Ruder et al., 1985) instances of familial ARVD. They also
pointed to the occurrence of familial right ventricular dilated
cardiomyopathy (Ibsen et al., 1985), which may represent the same
disorder. Ibsen et al. (1985) reported the cases of 3 (out of 6) sibs
who suffered from cardiomyopathy characterized by life-threatening
supraventricular and ventricular arrhythmias, sinoatrial block,
atrioventricular block, and, in 1 patient, embolism. Dilatation of the
right ventricle predominated. Death occurred at ages 32 and 48 years in
2 of the sibs. Investigation of 33 other family members in 3 generations
uncovered no further cases. This disorder is unusually frequent in
northern Italy; 14 families were diagnosed in the cardiology department
of Padua University (Rampazzo, 1993). Four families descended from a
common ancestor were grouped together into a large 4-generation kindred
in which special studies permitted the diagnosis of ARVD in 13 persons.
Negative lod scores using markers on chromosome 14 indicated that the
mutation is not in the myosin gene involved in one form of hypertrophic
cardiomyopathy (see MYH1; 160760).

The major clinical features of ARVD are different types of arrhythmias
with a left branch block pattern. The natural history is rarely
characterized by cardiac failure, which is only present in those few
patients with the cardiomegalic form. Syncopal attacks and sudden death
due to ventricular fibrillation are possible, but normally the
arrhythmias are well tolerated. The affected patients usually have good
exercise tolerance and do not have a history of previous myocarditis
(Nava et al., 1992). The most important electrocardiographic
abnormalities are T wave inversion in the right precordial leads and the
presence of late potentials in signal averaging ECG. The diagnosis of
right ventricular cardiomyopathy is based on echocardiographic and
angiographic documentation of localized or widespread structural and
dynamic abnormalities involving mainly or exclusively the right
ventricle, in the absence of valve disease, shunts, active myocarditis,
and coronary disease (McKenna et al., 1994). Endomyocardial biopsy
(Angelini et al., 1993) is useful in the differential diagnosis.

Rampazzo et al. (1994) performed linkage studies in 2 large Italian
families, 1 of which had 19 affected members in 4 generations. A maximum
lod score of 6.04 was obtained at theta = 0.0 for linkage with the
polymorphic marker D14S42, located at 14q23-q24. Severini et al. (1996)
studied linkage in 3 ARVD families of various descent: Italian,
Slovenian, and Belgium. They found linkage to markers thought to be in a
more proximal portion of 14q, namely 14q12-q22. There was a cumulative
2-point lod score of 3.26 for D14S252 with no recombination. With
multipoint linkage analysis, a maximal cumulative lod score of 4.7 was
obtained in a region between D14S252 and D14S257. They interpreted this
to indicate that there are 2 distinct loci on chromosome 14 at either of
which mutation can give rise to ARVD. They proposed to designate the
proximal form as ARVD2. This designation had been preempted for the form
of ARVD.

Pinamonti et al. (1996) described a father and daughter with right
ventricular dysplasia. Both presented with ventricular arrhythmias for
which they were evaluated at 28 and 12 years of age, respectively. The
father subsequently had a 'flu-like' syndrome, heart failure, and
biventricular dysfunction; 'active' myocarditis was found at
endomyocardial biopsy. He died suddenly at the age of 35 years. The
daughter died at the age of 18 years after a slowly progressive increase
in dyspnea and peripheral edema. In both patients, necropsy showed
severe right ventricular atrophy and fibro-adipose substitution
associated with biventricular fibrosis. In the father, inflammatory
infiltration was also present.

In an analysis of specimens obtained at autopsy from a right ventricular
myocardium of 8 patients with arrhythmogenic right ventricular
dysplasia, Mallat et al. (1996) found that evidence of apoptosis was
detectable in 6 and was absent in all of 4 age-matched normal controls.
High levels of expression of apopain (CCP32; 600636) were associated
with positive in situ end-labeling of fragmented DNA. They concluded
that apoptotic myocardial cell death may be contribute to loss of
myocardial cells in this disorder.

Kearney et al. (1995) described 3 sibs with right ventricular dysplasia.
A brother died at age 13. Both twin sisters underwent cardiac
transplantation at age 11. Histologic sections showed striking fatty
infiltration of the right ventricle with focal complete transmural
lipomatosis. Extensive fatty infiltration of the right ventricular
myocardium was also found in a post-transplantation biopsy from one of
the sisters 4.5 years after cardiac transplantation. Echocardiography on
both parents of the 3 sibs reported by Kearney et al. (1995) were
normal, suggesting autosomal recessive inheritance in this family.

*FIELD* SA
Child et al. (1984)
*FIELD* RF
1. Angelini, A.; Thiene, G.; Boffa, G. M.; Calliaris, I.; Daliento,
L.; Valente, M.; Chioin, R.; Nava, A.; Dalla Volta, S.: Endomyocardial
biopsy in right ventricular cardiomyopathy. Int. J. Cardiol. 40:
273-282, 1993.

2. Child, J. S.; Perloff, J. K.; Francoz, R.; Yeatman, L. A.; Henze,
E.; Schelbert, H. R.; Laks, H.: Uhl's anomaly (parchment right ventricle):
clinical, echocardiographic, radionuclear, hemodynamic and angiocardiographic
features in 2 patients. Am. J. Cardiol. 53: 635-637, 1984.

3. Ibsen, H. H. W.; Baandrup, U.; Simonsen, E. E.: Familial right
ventricular dilated cardiomyopathy. Brit. Heart J. 54: 156-159,
1985.

4. Kearney, D. L.; Towbin, J. A.; Bricker, J. T.; Radovancevic, B.;
Frazier, O. H.: Familial right ventricular dysplasia (cardiomyopathy). Pediat.
Path. Lab. Med. 15: 181-189, 1995.

5. Laurent, M.; Descaves, C.; Biron, Y.; Deplace, C.; Almange, C.;
Daubert, J.-C.: Familial form of arrhythmogenic right ventricular
dysplasia. Am. Heart J. 113: 827-829, 1987.

6. Mallat, Z.; Tedgui, A.; Fontaliran, F.; Frank, R.; Durigon, M.;
Fontaine, G.: Evidence of apoptosis in arrhythmogenic right ventricular
dysplasia. New Eng. J. Med. 335: 1190-1196, 1996.

7. Marcus, F. I.; Fontaine, G. H.; Guiraudon, G.; Frank, R.; Laurenceau,
J. L.; Malergue, C.; Grosgogeat, Y.: Right ventricular dysplasia:
a report of 24 adult cases. Circulation 65: 384-398, 1982.

8. McKenna, W. J.; Thiene, G.; Nava, A.; Fontaliran, F.; Blomstrom-Lundqvist,
C.; Fontaine, G.; Camerini, F.; members of the ARVD task force: Diagnosis
of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Brit.
Heart J. 71: 215-218, 1994.

9. Nava, A.; Thiene, G.; Canciani, B.; Martini, B.; Daliento, L.;
Buja, G.; Fasoli, G.: Clinical profile of concealed form of arrhythmogenic
right ventricular cardiomyopathy presenting with apparently idiopathic
ventricular arrhythmias. Int. J. Cardiol. 35: 195-206, 1992.

10. Pinamonti, B.; Miani, D.; Sinagra, G.; Bussani, R.; Silvestri,
F.; Camerini, F.; Heart Muscle Disease Study Group: Familial right
ventricular dysplasia with biventricular involvement and inflammatory
infiltration. Heart 76: 66-69, 1996.

11. Rampazzo, A.: Personal Communication. Padua, Italy  5/30/1993.

12. Rampazzo, A.; Nava, A.; Danieli, G. A.; Buja, G.; Daliento, L.;
Fasoli, G.; Scognamiglio, R.; Corrado, D.; Thiene, G.: The gene for
arrhythmogenic right ventricular cardiomyopathy maps to chromosome
14q23-q24. Hum. Molec. Genet. 3: 959-962, 1994.

13. Ruder, M. A.; Winston, S. A.; David, J. C.; Abbott, J. A.; Eldar,
M.; Scheinman, M. M.: Arrhythmogenic right ventricular dysplasia
in a family. Am. J. Cardiol. 56: 799-800, 1985.

14. Severini, G. M.; Krajinovic, M.; Pinamonti, B.; Sinagra, G.; Fioretti,
P.; Brunazzi, M. C.; Falaschi, A.; Camerini, F.; Giacca, M.; Mestroni,
L.; Heart Muscle Disease Study Group: A new locus for the arrhythmogenic
right ventricular dysplasia on the long arm of chromosome 14. Genomics 31:
193-200, 1996.

*FIELD* CS

Cardiac:
   Arrhythmogenic right ventricular dysplasia;
   Recurrent, sustained ventricular tachycardia;
   Right ventricular dilated cardiomyopathy;
   Supraventricular and ventricular arrhythmias;
   Sinoatrial block;
   Atrioventricular block

Vascular:
   Embolism

Lab:
   Ventricular myocardium replacement by fat and fibrosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 4/22/1987

*FIELD* ED
jamie: 01/07/1997
jamie: 1/6/1997
terry: 11/15/1996
terry: 11/12/1996
terry: 11/6/1996
mark: 3/18/1996
terry: 3/6/1996
mark: 1/19/1996
mark: 1/18/1996
terry: 1/17/1996
mark: 12/12/1995
jason: 7/27/1994
mimadm: 4/9/1994
warfield: 4/7/1994
carol: 6/3/1993
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
108000
*FIELD* TI
108000 ARTERIES, ANOMALIES OF
*FIELD* TX
Gates (1946) cited a family in which the grandfather showed bilaterally
a radial artery that passed over the supinator longus muscle 3 to 4 cm
above the wrist and ran over the radial extensors above the styloid
process. All his children were said to have the same anomaly on the left
side. Among his grandchildren the anomaly was found on both sides in 4,
on one side in 4, and on neither side in 7. Barbosa Sueiro (1933-34)
described the case of a man in whom the ulnar artery on the left arm ran
along the medial border of the biceps, arising by precocious bifurcation
of the branchial artery. There was also a superficial right interosseous
artery. The latter condition was present also in the father and a
brother and the former condition in the 2 brothers.

Schneck (1879) described the Brown family in which 15 of 22 members of 3
generations showed an abnormal course of 1 or both radial arteries. Out
of 44 arteries, the same abnormal course was taken 19 times. Both
arteries were abnormal in 4 individuals; both were normal in 7. The
right only was abnormal twice and the left only was abnormal 9 times.
The artery took the usual course until within 3 to 4 cm of the wrist,
according to the length of the arm, when suddenly it turned backwards
over the supinator longus muscle, passing on the outside of the extensor
tendons of the thumb and above the styloid process of the radius, thence
behind the thumb into the palm, to form the palmar arch. Persons
marrying into the family all showed radial arteries. This was clearly
the family cited by Gates (1946).

*FIELD* RF
1. Barbosa Sueiro, M. B.: Observation de quelques arteres avec son
trajet superficiel anormal chez quelques membres d'une famille. Arq.
Anat. Anthrop. 16: 163-164, 1933.

2. Gates, R. R.: Human Genetics.  New York: Macmillan (pub.)
1946. Pp. 1304 only.

3. Schneck, J.: Hereditary variation in the radial arteries. Chicago
Med. J. Exam. 39: 475-476, 1879.

*FIELD* CS

Vascular:
   Abnormal radial, ulnar, or interosseous artery

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/12/1996
terry: 12/5/1996
mimadm: 5/2/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
108010
*FIELD* TI
108010 ARTERIOVENOUS MALFORMATIONS OF THE BRAIN
CEREBRAL ARTERIOVENOUS MALFORMATIONS
*FIELD* TX
Snead et al. (1979) reported cerebral arteriovenous malformations in 3
sibs with the same mother. Two were by one father and the third by
another. Hereditary hemorrhagic telangiectasia and von Hippel-Lindau
disease were excluded. They found reports of 4 instances of familial
aggregation. Aberfeld and Rao (1981) reported affected brother and
sister. Yokoyama et al. (1991) described 6 cases in 3 families. These
included a father-son pair, a mother-son pair, and male and female first
cousins. They commented on the report by Boyd et al. (1985) of affected
father and 3 sons and another father and daughter combination.

*FIELD* SA
Barre et al. (1978); Kidd and Cumings (1947); Laing and Smith (1974)
*FIELD* RF
1. Aberfeld, D. C.; Rao, K. R.: Familial arteriovenous malformation
of the brain. Neurology 31: 184-186, 1981.

2. Barre, R. G.; Suter, C. G.; Rosenblum, W. I.: Familial vascular
malformation or chance occurrence?. Neurology 28: 98-100, 1978.

3. Boyd, M. C.; Steinbok, P.; Paty, D. W.: Familial arteriovenous
malformations: report of four cases in one family. J. Neurosurg. 62:
597-599, 1985.

4. Kidd, H. A.; Cumings, J. N.: Cerebral angiomata in an Icelandic
family. Lancet I: 747-748, 1947.

5. Laing, J. W.; Smith, R. R.: Intracranial arteriovenous malformation
in sisters: a case report. J. Miss. State Med. Assoc. 15: 203-206,
1974.

6. Snead, O. C., III; Acker, J. D.; Morawetz, R.: Familial arteriovenous
malformation. Ann. Neurol. 5: 585-587, 1979.

7. Yokoyama, K.; Asano, Y.; Murakawa, T.; Takada, M.; Ando, T.; Sakai,
N.; Yamada, H.; Iwata, H.: Familial occurrence of arteriovenous malformation
of the brain. J. Neurosurg. 74: 585-589, 1991.

*FIELD* CS

Vascular:
   Cerebral arteriovenous malformation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 8/5/1991

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 8/5/1991

*RECORD*
*FIELD* NO
108050
*FIELD* TI
108050 ARTERITIS, FAMILIAL GRANULOMATOUS, WITH JUVENILE POLYARTHRITIS
*FIELD* TX
Rotenstein et al. (1982) described a family in which 4 females in 3
successive generations shared the clinical triad of fever, hypertension,
and juvenile polyarthritis, along with the pathologic feature of
noncaseating granulomas in vascular and extravascular distribution. The
proband was a 5-year-old white girl who at age 8 months developed fever
and a persistent macular erythematous rash. At 10 months nodules were
noted on her wrists. At 18 months she had fever and symmetrical
swelling, warmth and redness of hands, knees, and ankles, and
pericardial effusion was noted. At age 4.5 years she had spiking fever,
headache, and a seizure, with blood pressure of 200-140 mm Hg, bilateral
iritis, papilledema, and pericardial friction rub. Abdominal aortograms
showed beading of the splenic, renal and iliac arteries, proximal
stenosis and poststenotic dilatation, and intrarenal arterial stenoses.
Skin biopsy showed noncaseating granulomatous inflammation. After 1 year
of therapy with prednisone and cyclophosphamide, aortograms showed
dramatic improvement. In her mother, the diagnosis of rheumatoid
arthritis with features of Still disease was made at age 8 years; in her
twenties, she had 5 episodes of unexplained fever. At age 28, she
developed fever, jaundice, and elevated alkaline phosphatase; liver
biopsy showed noncaseating granulomas. At age 35 she had a pleural
effusion. The proband's maternal grandmother, aged 62, had
juvenile-onset polyarthritis, unexplained fever only during childhood,
recent chronic iritis and noncaseating granulomas on conjunctival
biopsy. The proband's maternal aunt, who died at age 24, had rheumatoid
arthritis with features of Still disease beginning at age 8 years.
Throughout her life, she had recurrent episodes of unexplained fever. In
a final hospitalization she had seizures and severe hypertension.
Autopsy showed systemic noncaseating granulomas.

Di Liberti (1982) suggested that the patients reported by Rotenstein et
al. (1982) had the same disorder as that in a family he and his
associates presented at the 1974 Birth Defects Conference in Newport
Beach, California. Five persons in 2 generations had arthritis beginning
in early childhood and initially affecting the hands, wrists and ankles.
The dorsal tendon sheaths of the hands and feet were particularly
involved. By late childhood the swelling had diminished, but flexion
contractures of the fingers and elbows were evident. Periarticular
osteoporosis was also present. One child had iritis with prominent
synechiae. He died suddenly at play, and at autopsy had granulomatous
arteritis of the aorta, coronary arteries, kidneys, liver and other
organs. The coronary arteries were almost totally occluded. Although
some features suggested childhood sarcoidosis, the conspicuous arteritis
is probably a differentiating feature. Malleson et al. (1981) reported
on a Mexican-American family in which the mother and a daughter and 3
sons had camptodactyly and arthritis. Another son had arthritis but no
camptodactyly. One of the affected sons died at age 4.5 years and was
shown to have granulomatous arteritis which affected the aorta,
pericardium, myocardium, and coronary arteries. He had also had chronic
bilateral iridocyclitis. Some of these features suggest Jabs syndrome
(186580).

*FIELD* SA
Di Liberti et al. (1975)
*FIELD* RF
1. Di Liberti, J. H.: Granulomatous vasculitis.   (Letter) New Eng.
J. Med. 306: 1365, 1982.

2. Di Liberti, J. H.; McKean, R.; Hecht, F.: Progressive tenosynovitis
with contractures and possible systemic involvement--a new heritable
disorder of connective tissue?. Birth Defects Orig. Art. Ser. XI(6):
81-82, 1975.

3. Malleson, P.; Schaller, J. G.; Dega, F.; Cassidy, S. B.; Pagon,
R. A.: Familial arthritis and camptodactyly. Arthritis Rheum. 24:
1199-1204, 1981.

4. Rotenstein, D.; Gibbas, D. L.; Majmudar, B.; Chastain, E. A.:
Familial granulomatous arteritis with polyarthritis of juvenile onset.
New Eng. J. Med. 306: 86-90, 1982.

*FIELD* CS

Endo:
   Hypertension

Joints:
   Juvenile polyarthritis;
   Rheumatoid arthritis

Skin:
   Macular erythematous rash;
   Subcutaneous nodules;
   Jaundice

Cardiac:
   Pericardial effusion;
   Granulomatous coronary arteritis

Neuro:
   Headache;
   Seizures

Eyes:
   Iritis;
   Papilledema

Pulmonary:
   Pleural effusion

Misc:
   Fever

Radiology:
   Abdominal aortograms show beading of the splenic, renal and iliac
   arteries, proximal stenosis and poststenotic dilatation, and intrarenal
   arterial stenoses

Lab:
   Noncaseating granulomas, vascular and extravascular esp;
   hepatic;
   Elevated alkaline phosphatase

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/15/1996
terry: 4/9/1996
terry: 5/13/1994
mimadm: 4/9/1994
carol: 4/7/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
108100
*FIELD* TI
108100 ARTHRITIS, SACROILIAC
*FIELD* TX
There is inadequate information provided in the report of Stauffer and
Merrihew (1944) to be certain about the nature of the ailment referred
to by this designation. Twenty-two persons in 4 generations were said to
be affected.

*FIELD* RF
1. Stauffer, J.; Merrihew, N. H.: A pedigree of sacro-iliac arthritis.
J. Hered. 35: 112-118, 1944.

*FIELD* CS

Joints:
   ? Sacroiliac arthritis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
108110
*FIELD* TI
108110 ARTHROGRYPOSIS MULTIPLEX CONGENITA; AMC
*FIELD* TX
Lacassie et al. (1977) and Sack (1978) reported a man who was born with
limited flexion of all joints of the upper limbs and neck and with
absent flexion creases of the fingers. Talipes equinovarus was corrected
by bilateral triple arthrodeses and later Achilles tendon extensions. As
an adult he was short with scoliosis and 4 symmetric dimples over the
posterior ilia. Gaze, especially upward, was generally limited, and the
muscles below the knees were atrophic. Intelligence was normal. His
2-year-old daughter showed the same findings. Muscle biopsy was normal.
Hall et al. (1983) recognized a specific congenital contracture
(arthrogryposis) syndrome in 135 of 350 patients with various kinds of
congenital contractures. Always sporadic, this is the disorder which is
usually meant when the term arthrogryposis multiplex congenita is used.
Amyoplasia is the designation chosen by Hall et al. (1983) because
absence of limb muscles which are replaced by fibrous and fatty tissue
is the finding. At birth, characteristic positioning includes internal
rotation at the shoulders, extension at the elbows, and flexion at the
wrists. Severe equinovarus deformity of the feet is usually present. The
face is typically round with a frontal midline capillary hemangioma and
slightly small jaw. Intelligence is normal. About 63% had involvement of
4 limbs (usually symmetrically), 24% mainly of the lower limbs, and 13%
mainly of the upper limbs. All cases are sporadic. Identical twins are
always discordantly affected. Hall et al. (1983) found among 135
patients 11 who were the discordantly affected member of a pair of
identical twins. As 8% of the total, this incidence seems to be a
remarkable and probably biologically significant excess.

*FIELD* RF
1. Hall, J. G.; Reed, S. D.; Driscoll, E. P.: Part 1. Amyoplasia:
a common, sporadic condition with congenital contractures. Am. J.
Med. Genet. 15: 571-590, 1983.

2. Lacassie, Y.; Sack, G. H., Jr.; McKusick, V. A.: An autosomal
dominant form of arthrogryposis multiplex congenita (AMC) with unusual
dermatoglyphics.  (Abstract) Birth Defects Orig. Art. Ser. XIII(3B):
246-247, 1977.

3. Sack, G. H., Jr.: A dominantly inherited form of arthrogryposis
multiplex congenita with unusual dermatoglyphics. Clin. Genet. 14:
317-323, 1978.

*FIELD* CS

Joints:
   Limited joint flexion of upper limbs and neck

Limbs:
   Absent finger flexion creases;
   Internal shoulder rotation;
   Elbow extension;
   Wrist flexion;
   Talipes equinovarus

Growth:
   Short stature

Spine:
   Scoliosis

Skin:
   Symmetric dimples over posterior ilia

Facies:
   Round face;
   Frontal midline capillary hemangioma;
   Slightly small jaw

Eyes:
   Limited gaze, esp. upward

Muscle:
   Lower leg muscle atrophy

Neuro:
   Normal intelligence

Inheritance:
   All cases sporadic;
   other inherited forms

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
108120
*FIELD* TI
*108120 ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE 1; AMCD1
DISTAL ARTHROGRYPOSIS, TYPE I; DA1
*FIELD* TX
Arthrogryposis is a highly heterogeneous category (Hall et al., 1977).
The classic form of peripheral AMC, called amyoplasia by Hall et al.
(1977), is always sporadic. An overall recurrence risk of about 5%
results from admixture of cases of mendelian types (see 208100, 301830,
etc.). They concluded that there is at least one autosomal dominant form
of distal AMC. The involvement in some persons can be very mild. Lin et
al. (1977) and Hall et al. (1982) delineated the distal form of AMC by
its autosomal dominant inheritance, intrafamilial variability,
involvement primarily of the distal part of the limbs (especially hands
and feet), a characteristic position of the hands (medially overlapping
fingers, clenched fists, ulnar deviation of fingers, and camptodactyly),
positional foot deformities, and relatively good response to physical
therapy. Contractures at other joints are variable. There are no
associated visceral anomalies; intelligence is normal. Daentl et al.
(1974) described a father and his 2 daughters who had congenital
contracture and deformity of the fingers, inguinal hernia, clubfoot, hip
dislocation, small mandible, limitation of motion in the shoulders,
elbows, wrist, knees and ankles, short neck, and elevated serum creatine
phosphokinase. The authors reviewed familial forms of arthrogryposis and
arthrogryposis-like disorders. McCormack et al. (1980) reported affected
father, son and daughter. See digitotalar dysmorphism (126050). Baty et
al. (1988) reported the prenatal diagnosis of distal arthrogryposis type
I by ultrasound at 18 weeks' gestation in a family with 2 other affected
members (mother and sister). The abnormality in the female infant was
confirmed at birth. The diagnosis was based on the fact that the wrist
remained extended and the fingers 'fisted' throughout a period of
ultrasonic observation. Prenatal diagnosis in other forms of multiple
joint contractures was reviewed.

Klemp and Hall (1995) described a Maori family in which dominant distal
arthrogryposis showed marked variability of expression. The index case
was a Maori bushman who presented with severe congenital spinal stenosis
and manifestations of distal arthrogryposis. One son and 2 sisters, as
well as 2 sons of one sister and 2 daughters of the second, were
definitely affected. Two affected members had severe hand and foot
involvement as well as craniofacial changes compatible with a diagnosis
of Freeman-Sheldon syndrome (193700).

Distal arthrogryposis type I is a frequent cause of dominantly inherited
clubfoot. Using short tandem repeat (STR) polymorphisms in a genome-wide
search, Bamshad et al. (1994) mapped the DA1 gene to the pericentromeric
region of chromosome 9 in a large kindred. Linkage analysis generated a
lod score of 5.90 at theta = 0.0 with the marker GS-4. Analysis of an
additional family demonstrated no linkage to the same locus, indicating
probable locus heterogeneity.

Krakowiak et al. (1997) provided a useful classification of the distal
arthrogryposes; see also 601680.

*FIELD* RF
1. Bamshad, M.; Watkins, W. S.; Zenger, R. K.; Bohnsack, J. F.; Carey,
J. C.; Otterud, B.; Krakowiak, P. A.; Robertson, M.; Jorde, L. B.
: A gene for distal arthrogryposis type I maps to the pericentromeric
region of chromosome 9. Am. J. Hum. Genet. 55: 1153-1158, 1994.

2. Baty, B. J.; Cubberley, D.; Morris, C.; Carey, J.: Prenatal diagnosis
of distal arthrogryposis. Am. J. Med. Genet. 29: 501-510, 1988.

3. Daentl, D. L.; Berg, B. O.; Layzer, R. B.; Epstein, C. J.: A new
familial arthrogryposis without weakness. Neurology 24: 55-60, 1974.

4. Hall, J. G.; Greene, G.; Powers, E.: Arthrogryposis--clinical
and genetic heterogeneity. (Abstract) Vth Int. Conf. on Birth Defects,
Montreal , 8/1977.

5. Hall, J. G.; Reed, S. D.; Greene, G.: The distal arthrogryposes:
delineation of new entities--review and nosologic discussion. Am.
J. Med. Genet. 11: 185-239, 1982.

6. Klemp, P.; Hall, J. G.: Dominant distal arthrogryposis in a Maori
family with marked variability of expression. Am. J. Med. Genet. 55:
414-419, 1995.

7. Krakowiak, P. A.; O'Quinn, J. R.; Bohnsack, J. F.; Watkins, W.
S.; Carey, J. C.; Jorde, L. B.; Bamshad, M.: A variant of Freeman-Sheldon
syndrome maps to 11p15.5-pter. Am. J. Hum. Genet. 60: 426-432, 1997.

8. Lin, P.; Hall, J.; Giever, R.; Powers, E.: A new familial arthrogryposis
with autosomal dominant type of inheritance. (Abstract) West. Pediat.
Clin. Res. Meeting, Carmel, Calif. , 1977.

9. McCormack, M. K.; Coppola-McCormack, P. J.; Lee, M.-L.: Autosomal-dominant
inheritance of distal arthrogryposis. Am. J. Med. Genet. 6: 163-169,
1980.

*FIELD* CS

Joints:
   Distal limb involvement (esp. hands and feet)

Limbs:
   Medially overlapping fingers;
   Clenched fists;
   Ulnar deviation of fingers;
   Camptodactyly;
   Positional foot deformities;
   Clubfoot

Neuro:
   Normal intelligence

Misc:
   Intrafamilial variability;
   Relatively good response to physical therapy;
   No associated visceral anomalies

Inheritance:
   Autosomal dominant form

*FIELD* CN
Victor A. McKusick - updated: 02/17/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/17/1997
terry: 2/10/1997
carol: 3/19/1995
mimadm: 4/15/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 4/25/1988

*RECORD*
*FIELD* NO
108130
*FIELD* TI
108130 ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE II
*FIELD* TX
Hall et al. (1982) called distal arthrogryposis the condition of
congenital contractures with major involvement of the hands and feet.
They further defined 2 types: type I with only distal limb involvement
(e.g., 108120) and type II with other defects. In a mother and her
dizygotic twin fetuses, Kawira and Bender (1985) described what they
considered to be a new type of dominant distal arthrogryposis type II.
The mother, height 143 cm, had, in addition to hand and foot
contractures, fused cervical vertebrae, anterior and lateral cervical
pterygia, scoliosis, and congenital hip dislocation. Her mother had felt
no fetal movements during her pregnancy and she felt essentially none
during the pregnancy which resulted in the birth of affected male and
female twins at about 20 weeks. The twins showed short webbed neck,
retrognathia, contractures of the elbows, knees and hips, scoliosis, and
deformities of the hands and feet apparently similar to the mother's at
birth. Reiss and Sheffield (1986) described a family in which 3 sisters
and a son and daughter of 1 of the sisters had various features of type
II arthrogryposis: cleft lip and palate, micrognathia, ptosis, webbed
neck, kyphoscoliosis, and short stature. All of those with distal
arthrogryposis had trismus.

*FIELD* RF
1. Hall, J. G.; Reed, S. D.; Greene, G.: The distal arthrogryposes:
delineation of new entities--review and nosologic discussion. Am.
J. Med. Genet. 11: 185-239, 1982.

2. Kawira, E. L.; Bender, H. A.: An unusual distal arthrogryposis. Am.
J. Med. Genet. 20: 425-429, 1985.

3. Reiss, J. A.; Sheffield, L. J.: Distal arthrogryposis type II:
a family with varying congenital abnormalities. Am. J. Med. Genet. 24:
255-267, 1986.

*FIELD* CS

Joints:
   Distal limb involvement (esp. hands and feet);
   Contractures of elbows, knees and hips

Limbs:
   Medially overlapping fingers;
   Clenched fists;
   Ulnar deviation of fingers;
   Camptodactyly;
   Positional foot deformities;
   Clubfoot;
   Hip dislocation

Neuro:
   Normal intelligence

Abdomen:
   Inguinal hernia

Facies:
   Retrognathia;
   Micrognathia;
   Cleft lip and palate;
   Ptosis;
   Trismus

Spine:
   Fused cervical vertebrae;
   Scoliosis;
   Kyphoscoliosis

Neck:
   Anterior and lateral cervical pterygia

Growth:
   Short stature

Misc:
   Intrafamilial variability;
   Relatively good response to physical therapy

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/13/1997
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 11/16/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
108140
*FIELD* TI
108140 ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE II, WITH CRANIOFACIAL
ABNORMALITIES
*FIELD* TX
In 3 and possibly 4 generations of a family, Moore and Weaver (1989)
observed an apparently 'new' form of type II distal arthrogryposis (see
108130). Associated craniofacial anomalies included facial asymmetry,
hypertelorism, downslanting palpebral fissures, high nasal bridge, malar
hypoplasia, micrognathia, highly arched palate, notched chin, and
posteriorly angulated ears. No male-to-male transmission was observed
(see also 601680).

*FIELD* RF
1. Moore, C. A.; Weaver, D. D.: Familial distal arthrogryposis with
craniofacial abnormalities: a new subtype of type II?. Am. J. Med.
Genet. 33: 231-237, 1989.

*FIELD* CS

Joints:
   Distal limb involvement (esp. hands and feet);
   Contractures of elbows, knees and hips

Limbs:
   Medially overlapping fingers;
   Clenched fists;
   Ulnar deviation of fingers;
   Camptodactyly;
   Positional foot deformities;
   Clubfoot;
   Hip dislocation

Neuro:
   Normal intelligence

Abdomen:
   Inguinal hernia

Facies:
   Facial asymmetry;
   Hypertelorism;
   Downslanting palpebral fissures;
   High nasal bridge;
   Malar hypoplasia;
   Highly arched palate;
   Notched chin;
   Posteriorly angulated ears;
   Trismus

Spine:
   Fused cervical vertebrae;
   Scoliosis;
   Kyphoscoliosis

Neck:
   Anterior and lateral cervical pterygia

Growth:
   Short stature

Misc:
   Intrafamilial variability;
   Relatively good response to physical therapy

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 8/16/1989

*FIELD* ED
terry: 02/13/1997
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/18/1989
root: 8/17/1989

*RECORD*
*FIELD* NO
108145
*FIELD* TI
108145 ARTHROGRYPOSIS WITH OCULOMOTOR LIMITATION AND ELECTRORETINAL ABNORMALITIES
OCULOMELIC AMYOPLASIA
*FIELD* TX
Lai et al. (1991) described a father and son with congenital limb
contractures, limitation of ocular movements, and, in the father,
abnormal electroretinogram. In the father there was internal rotation of
the arms with flexion at the wrists, bilateral talipes, and aplasia of
limb muscles with their replacement by fibrous bands and fatty tissue.
Lai et al. (1991) thought that this could be distinguished from
arthrogryposis type II (108130) of Hall et al. (1982) because the
subjects were not short of stature and did not have short neck or
epicanthic folds. (See also 108140.) Oculomelic amyoplasia may be a
useful designation for this condition. Schrander-Stumpel et al. (1993)
described an isolated case in a Dutch family. The ages of the father and
mother were 35 and 27, respectively, at his birth. Rigid fingers and
bilateral club feet were noted at birth, and in the neonatal period
hypertrophic pylorus stenosis was surgically treated. Deep set eyes were
evident from an early age. At age 17 he was unable to move his eyes
laterally or to look upward. The fingers were long and phalangeal
creases were totally absent. Flexion was limited to about 30 degrees.
Abnormal pigmentation was present in both retinal maculas. He showed a
rigid trunk with hunched and anteverted shoulders.

Altman and Davidson (1939) reported the case of a boy they considered to
have amyoplasia congenita or arthrogryposis multiplex congenita which
they appear to have considered a synonymous designation. The boy had
contractures of the fingers, toes, wrist, ankles, knees, and elbows with
a lack of interphalangeal creases. Bilateral ptosis was described, but
ophthalmoplegia was not reported. He subsequently had 3 children, one of
whom a son likewise had distal contractures and ptosis. Friedman and
Heidenreich (1995) provided follow-up information on the father at age
63 years and the affected son at 30 years of age. He was identically
affected to his father. On recent examination, limitation of extraocular
movements were noted in both the father and the son. In the son, a
number of teeth, especially the lateral incisors, were cornical in
shape; dentition could not be evaluated in the father because all
secondary teeth had been extracted. Both the father and the son had an
unusual pattern of hair loss with thinning over the parietotemporal
areas.

*FIELD* RF
1. Altman, H. S.; Davidson, L. T.: Amyoplasia congenita (arthrogryposis
multiplex congenita). J. Pediat. 15: 551-557, 1939.

2. Friedman, B. D.; Heidenreich, R. A.: Distal arthrogryposis type
IIB: further clinical delineation and 54-year follow-up of an index
case. Am. J. Med. Genet. 58: 125-127, 1995.

3. Hall, J. G.; Reed, S. D.; Greene, G.: The distal arthrogryposes:
delineation of new entities--review and nosologic discussion. Am.
J. Med. Genet. 11: 185-239, 1982.

4. Lai, M. M. R.; Tettenborn, M. A.; Hall, J. G.; Smith, L. J.; Berry,
A. C.: A new form of autosomal dominant arthrogryposis. J. Med.
Genet. 28: 701-703, 1991.

5. Schrander-Stumpel, C. T. R. M.; Howeler, C. J.; Reekers, A. B.
A.; De Smet, N. M. A. F. A.; Hall, J. G.; Fryns, J.-P.: Arthrogryposis,
ophthalmoplegia, and retinopathy: confirmation of a new type of arthrogryposis.
J. Med. Genet. 30: 78-80, 1993.

*FIELD* CS

Joints:
   Congenital limb contractures;
   Rigid trunk;
   Hunched and anteverted shoulders

Eyes:
   Limitation of ocular movements;
   Deep set eyes;
   Abnormal macular pigmentation

Limbs:
   Internal arm rotation with wrist flexion;
   Bilateral talipes;
   Long fngers;
   Partially absent phalangeal creases

Muscle:
   Limb muscle aplasia

GI:
   Hypertrophic pyloric stenosis

Lab:
   Abnormal electroretinogram

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 11/7/1991

*FIELD* ED
mark: 9/13/1995
carol: 1/30/1995
mimadm: 4/9/1994
carol: 3/10/1993
supermim: 3/16/1992
carol: 12/13/1991

*RECORD*
*FIELD* NO
108200
*FIELD* TI
108200 ARTHROGRYPOSIS-LIKE HAND ANOMALY AND SENSORINEURAL DEAFNESS
*FIELD* TX
Stewart and Bergstrom (1971) described a 'new' syndrome of
arthrogryposis-like hand anomaly and sensorineural deafness. Both
features of the syndrome varied widely in severity. Two members of the
most recent generation had only the hand anomaly. Male-to-male
transmission was observed.

*FIELD* RF
1. Stewart, J. M.; Bergstrom, L.: Familial hand abnormality and sensori-neural
deafness: a new syndrome. J. Pediat. 78: 102-110, 1971.

*FIELD* CS

Ears:
   Sensorineural hearing loss

Limbs:
   Arthrogryposis-like hand anomaly

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
108300
*FIELD* TI
#108300 STICKLER SYNDROME, TYPE I; STL1
ARTHROOPHTHALMOPATHY, HEREDITARY PROGRESSIVE; AOM
*FIELD* TX
A number sign (#) is used with this entry because some cases of Stickler
syndrome result from mutation in the COL2A1 gene (120140). A second form
of Stickler syndrome is caused by mutation in the COL11A2 gene
(120290.0001). A third form of Stickler syndrome appears to be caused by
mutation in the COL11A1 gene (120280).

Stickler et al. (1965), from a long experience at the Mayo Clinic with
multiple members of a kindred, described a new dominant entity
consisting of progressive myopia beginning in the first decade of life
and resulting in retinal detachment and blindness. Affected persons also
exhibited premature degenerative changes in various joints with abnormal
epiphyseal development and slight hypermobility in some. In a second
paper, Stickler and Pugh (1967) pointed out that the family reported by
David (1953) probably had the same condition. Changes in vertebrae and
hearing deficit were also noted. Opitz et al. (1972) suggested that the
patients reported by Smith (1969), Walker (1971) and others may have had
this syndrome. Wagner syndrome (143200) seems more likely in these
cases. Both Stickler's patients and David's patient had dish-face. A
combination of retinal detachment, unusual facies and skeletal
abnormalities occurs also in the Wagner syndrome. Opitz (1972) pointed
out that patients with Stickler syndrome have the features of Pierre
Robin syndrome. Hall (1974) described a family in which 1 infant had
died of Pierre Robin anomaly. The mother had spent the first 18 months
of her life hospitalized for Pierre Robin syndrome. Later she developed
progressive myopia, cataract and bilateral retinal detachments leading
to bilateral enucleation in her teens. Young affected members had
midface hypoplasia. None had joint hyperextensibility or marfanoid
habitus. Any deafness in the family was apparently explained by otitis
media. Although neither examination nor history gave any reason to
suspect a skeletal abnormality, skeletal x-rays showed mild flattening
of epiphyses and mild irregularity of the margins of the vertebral
bodies (all changes suggesting a mild spondyloepiphyseal dysplasia).
Herrmann et al. (1975) suggested that this is 'the most common autosomal
dominant connective tissue dysplasia in the North American Midwest.'
Furthermore, they thought that 'the Stickler syndrome may have been the
condition affecting Abraham Lincoln and his son, Tad.' Others have
thought Lincoln had the Marfan syndrome (154700).

Among 57 patients with Stickler syndrome, Liberfarb and Goldblatt (1986)
found that 50% of females and 43% of males had mitral valve prolapse.
They suggested that Stickler syndrome should be considered in cases of
dominantly inherited mitral valve prolapse with or without joint laxity
and slender bones, just as it must be considered in all cases of Pierre
Robin syndrome, dominantly inherited myopia with or without retinal
detachment and deafness, and dominantly inherited cleft palate. The
Stickler syndrome is one of the conditions in which a familial
'Legg-Perthes disease' is a finding (WRB, JHH2235443). Spallone (1987)
studied 10 families with multiple cases and 2 isolated cases. The
validity of the diagnosis might be questioned in some of these cases
inasmuch as ectopia lentis was present in 5. All 12 probands had retinal
detachment. The diagnosis of Stickler syndrome was made on the basis of
ocular lesions (mainly retinal detachment in high congenital myopia and
vitreoretinal degeneration) and nonocular lesions. Seery et al. (1990)
found cataracts of various types or aphakia in 115 of 231 eyes of
patients with Stickler syndrome. The most frequent and distinctive
lesions, described as wedge and fleck cataracts, accounted for 40 of the
93 cataracts observed. Zlotogora et al. (1992) concluded from a study of
3 families and a review of the literature that variability in Stickler
syndrome is mainly interfamilial; within families less variability is
found. In one of their families all the affected members had high-grade
myopia and most developed retinal detachment at a young age. In the
second family the major symptoms were cleft palate and characteristic
facial changes associated with mild ocular changes. In the third family,
all patients had a marfanoid habitus, high myopia, and mental
retardation. This variability may reflect the heterogeneity that is
demonstrated by linkage to COL2A1.

Francomano et al. (1986) obtained preliminary evidence suggesting that
the type II collagen gene may be the site of the mutation in Stickler
syndrome; no recombination was found with polymorphisms of the COL2A1
locus. Francomano et al. (1987) found no recombinants and a total lod
score of 3.59 at theta = 0 for linkage of the Stickler syndrome and
COL2A1. Weaver et al. (1989) found evidence of recombination between
COL2A1 and the Stickler syndrome locus (which they symbolized AOM) in
some families. As they suggested, the findings in these 2 reports are
consistent with genetic heterogeneity and tight linkage between COL2A1
and one AOM locus. Knowlton et al. (1989) demonstrated no recombination
between COL2A1 and Stickler syndrome in 2 families; the maximum lod
score was 3.52 in the first and 1.20 in the second at a recombination
distance of 0. However, in a third family, at least 1 crossover was
observed. Priestley et al. (1990) presented evidence supporting linkage;
by amplification of a variable region 3-prime to the COL2A1 gene, they
found 5 distinguishable alleles, of which 3 were segregating in a
3-generation Stickler syndrome pedigree. The lod score in favor of
linkage was 2.86 at zero recombination. Temple (1989) gave a review.

See 277610 for a discussion of the nosology of the
Weissenbacher-Zweymuller syndrome and Marshall syndrome in relation to
Stickler syndrome. Schwartz et al. (1989) used the Wagner eponym for
vitreoretinal degeneration without extraocular manifestations and the
Stickler eponym for the form with extraocular manifestations in the
skeleton and craniofacial system. In a family that answered the
description for the Wagner type, they found segregation discordant with
COL2A1 RFLPs. In 4 families with a phenotype consistent with Stickler
syndrome, 2 showed recombinants with COL2A1 RFLPs. Vintiner et al.
(1991) studied 6 multigeneration families. In 2 of them, they found
crossovers between the disease locus and COL2A1. In 1 family, with
typical findings, a translocation t(5;17)(q15;q23) was found to
segregate with the disease in 4 affected relatives. They suggested that
one or the other of the breakpoints could be the position of a second
gene responsible for Stickler syndrome. Bonaventure et al. (1992)
described a 3-generation family with Stickler syndrome in which linkage
to COL2A1 was excluded. Affected patients showed myopia with frequent
retinal detachment or glaucoma. Most of them had characteristic facial
dysmorphism, the Pierre Robin sequence being observed in 4. Neonatal
radiologic signs of the Weissenbacher-Zweymuller syndrome were also
noticed.

Ritvaniemi et al. (1993) described a fourth mutation in the COL2A1 gene
as the cause of the Stickler syndrome. Like the 3 previously described
mutations causing the disease, it also introduced a premature
termination signal, the mutation being a single base deletion in exon 43
resulting in a frameshift and a stop codon in exon 44. Since only one
mutation introducing a premature termination codon was found in the
course of defining 120 or more mutations in types I and III procollagen,
the results suggested that stop mutations may have a special
relationship to the Stickler syndrome.

Williams et al. (1996) confirmed that the disorder in the kindred on the
basis of which Stickler et al. (1965) first described Stickler syndrome
had a mutation in the COL2A1 gene (120140.0024). The family was a large
Minnesota kindred which had been examined at the Mayo Clinic as early as
1897 by Dr. C. H. Mayo.

*FIELD* SA
Beals  (1977); Blair et al. (1979); Daniel et al. (1974); Gellis and
Feingold (1976); Popkin and Polomeno (1974); Regenbogen and Godel
(1980); Say et al. (1977); Spranger  (1968); Turner  (1974); Weingeist
et al. (1982); Weissenbacher and Zweymuller (1964); Winter et al.
(1983)
*FIELD* RF
1. Beals, R. K.: Hereditary arthro-ophthalmopathy (the Stickler syndrome):
report of a kindred with protrusio acetabuli. Clin. Orthop. 125:
32-35, 1977.

2. Blair, N. P.; Albert, D. M.; Liberfarb, R. M.; Hirose, T.: Hereditary
progressive arthro-ophthalmopathy of Stickler. Am. J. Ophthal. 88:
876-888, 1979.

3. Bonaventure, J.; Philippe, C.; Plessis, G.; Vigneron, J.; Lasselin,
C.; Maroteaux, P.; Gilgenkrantz, S.: Linkage study in a large pedigree
with Stickler syndrome: exclusion of COL2A1 as the mutant gene. Hum.
Genet. 90: 164-168, 1992.

4. Daniel, R.; Kanski, J. J.; Glasspool, M. G.: Hyalo-retinopathy
in the clefting syndrome. Brit. J. Ophthal. 58: 96-102, 1974.

5. David, B.: Ueber einen dominanten Erbgang bei einer polytopen
enchondralen Dysostose Typ Pfaundler-Hurler. Z. Orthop. 84: 657-660,
1953.

6. Francomano, C. A.; Le, P.-L.; Liberfarb, R.; Streeten, E.; Pyeritz,
R. E.: Collagen gene linkage analysis in the Marfan and Stickler
syndromes.(Abstract) Am. J. Hum. Genet. 39: A92 only, 1986.

7. Francomano, C. A.; Liberfarb, R. M.; Hirose, T.; Maumenee, I. H.;
Streeten, E. A.; Meyers, D. A.; Pyeritz, R. E.: The Stickler syndrome:
evidence for close linkage to the structural gene for type II collagen. Genomics 1:
293-296, 1987.

8. Gellis, S. S.; Feingold, M.: Stickler syndrome (hereditary arthro-ophthalmopathy). Am.
J. Dis. Child. 130: 65-66, 1976.

9. Hall, J.: Stickler syndrome presenting as a syndrome of cleft
palate, myopia and blindness inherited as a dominant trait. Birth
Defects Orig. Art. Ser. X(8): 157-171, 1974.

10. Herrmann, J.; France, T. D.; Spranger, J. W.; Opitz, J. M.; Wiffler,
C.: The Stickler syndrome (hereditary arthroophthalmopathy). Birth
Defects Orig. Art. Ser. XI(2): 76-103, 1975.

11. Knowlton, R. G.; Weaver, E. J.; Struyk, A. F.; Knobloch, W. H.;
King, R. A.; Norris, K.; Shamban, A.; Uitto, J.; Jimenez, S. A.; Prockop,
D. J.: Genetic linkage analysis of hereditary arthro-ophthalmopathy
(Stickler syndrome) and the type II procollagen gene. Am. J. Hum.
Genet. 45: 681-688, 1989.

12. Liberfarb, R. M.; Goldblatt, A.: Prevalence of mitral-valve prolapse
in the Stickler syndrome. Am. J. Med. Genet. 24: 387-392, 1986.

13. Opitz, J. M.: Ocular anomalies in malformation syndromes. Trans.
Am. Acad. Ophthal. Otolaryng. 76: 1193-1202, 1972.

14. Opitz, J. M.; France, T.; Herrmann, J.; Spranger, J. W.: The
Stickler syndrome.(Letter) New Eng. J. Med. 286: 546-547, 1972.

15. Popkin, J. S.; Polomeno, R. C.: Stickler's syndrome (hereditary
progressive arthro-ophthalmopathy). Canad. Med. Assoc. J. 111: 1071-1076,
1974.

16. Priestley, L.; Kumar, D.; Sykes, B.: Amplification of the COL2A1
3-prime variable region used for segregation analysis in a family
with the Stickler syndrome. Hum. Genet. 85: 525-526, 1990.

17. Regenbogen, L.; Godel, V.: Hereditary degeneration, cleft lip
and palate, deafness, and skeletal dysplasia. Am. J. Ophthal. 89:
414-418, 1980.

18. Ritvaniemi, P.; Hyland, J.; Ignatius, J.; Kivirikko, K. I.; Prockop,
D. J.; Ala-Kokko, L.: A fourth example suggests premature termination
codons in the COL2A1 gene are a common cause of the Stickler syndrome.(Abstract) Am.
J. Hum. Genet. 53 (suppl.): A1115 only, 1993.

19. Say, B.; Berry, J.; Barber, N.: The Stickler syndrome (hereditary
arthro-ophthalmopathy). Clin. Genet. 12: 179-182, 1977.

20. Schwartz, R. C.; Watkins, D.; Fryer, A. E.; Goldberg, R.; Marion,
R.; Polomeno, R. C.; Spallone, A.; Upadhyaya, M.; Harper, P.; Tsipouras,
P.: Non-allelic genetic heterogeneity in the vitreoretinal degenerations
of the Stickler and Wagner types and evidence for intragenic recombination
at the COL2A1 locus.(Abstract) Am. J. Hum. Genet. 45 (suppl.): A218
only, 1989.

21. Seery, C. M.; Pruett, R. C.; Liberfarb, R. M.; Cohen, B. Z.:
Distinctive cataract in the Stickler syndrome. Am. J. Ophthal. 110:
143-148, 1990.

22. Smith, W. K.: Pierre Robin syndrome in brothers. Birth Defects
Orig. Art. Ser. V(2): 220-221, 1969.

23. Spallone, A.: Stickler's syndrome: a study of 12 families. Brit.
J. Ophthal. 71: 504-509, 1987.

24. Spranger, J. W.: Hereditary arthro-ophthalmopathy. Ann. Radiol. 11:
359-364, 1968.

25. Stickler, G. B.; Belau, P. G.; Farrell, F. J.; Jones, J. D.; Pugh,
D. G.; Steinberg, A. G.; Ward, L. E.: Hereditary progressive arthro-ophthalmopathy. Mayo
Clin. Proc. 40: 433-455, 1965.

26. Stickler, G. B.; Pugh, D. G.: Hereditary progressive arthro-ophthalmopathy.
II. Additional observations on vertebral abnormalities, a hearing
defect, and a report of a similar case. Mayo Clin. Proc. 42: 495-500,
1967.

27. Temple, I. K.: Stickler's syndrome. J. Med. Genet. 26: 119-126,
1989.

28. Turner, G.: The Stickler syndrome in a family with the Pierre
Robin syndrome and severe myopia. Aust. Paediat. J. 10: 103-108,
1974.

29. Vintiner, G. M.; Temple, I. K.; Middleton-Price, H. R.; Baraitser,
M.; Malcolm, S.: Genetic and clinical heterogeneity of Stickler syndrome. Am.
J. Med. Genet. 41: 44-48, 1991.

30. Walker, B. A.: A syndrome of nerve deafness, eye anomalies and
marfanoid habitus with autosomal dominant inheritance. Birth Defects
Orig. Art. Ser. VII(4): 137-139, 1971.

31. Weaver, E. J.; King, R. A.; Norris, K.; Knobloch, W. H.; Shamban,
A.; Jimenez, S. A.; Prockop, D. J.; Knowlton, R. G.: Linkage analysis
of the type II collagen gene (COL2A1) and hereditary arthro-ophthalmopathy
(AOM) in three large families.(Abstract) Cytogenet. Cell Genet. 51:
1103 only, 1989.

32. Weingeist, T. A.; Hermsen, V.; Hanson, J. W.; Bumsted, R. M.;
Weinstein, S. L.; Olin, W. H.: Ocular and systemic manifestations
of Stickler's syndrome: a preliminary report. Birth Defects Orig.
Art. Ser. XVIII(6): 539-560, 1982.

33. Weissenbacher, G.; Zweymuller, E.: Gleichzeitiges Vorkommen eines
Syndroms von Pierre Robin und einer fetalen Chondrodysplasie. Mschr.
Kinderheilk. 112: 315-317, 1964.

34. Williams, C. J.; Ganguly, A.; Considine, E.; McCarron, S.; Prockop,
D. J.; Walsh-Vockley, C.; Michels, V. V.: A(-2)-to-G transition at
the 3-prime acceptor splice site of IVS17 characterizes the COL2A1
gene mutation in the original Stickler syndrome kindred. Am. J. Med.
Genet. 63: 461-467, 1996.

35. Winter, R. M.; Baraitser, M.; Laurence, K. M.; Donnai, D.; Hall,
C. M.: The Weissenbacher-Zweymuller, Stickler, and Marshall syndromes:
further evidence for their identity. Am. J. Med. Genet. 16: 189-199,
1983.

36. Zlotogora, J.; Sagi, M.; Schuper, A.; Leiba, H.; Merin, S.: Variability
of Stickler syndrome. Am. J. Med. Genet. 42: 337-339, 1992.

*FIELD* CS

Skel:
   Osteochondrodysplasia

Head:
   Normocephaly

Facies:
   Flat facies;
   Dish facies

Eyes:
   Myopia;
   Retinal detachment;
   Blindness;
   Occasional cataracts

Ears:
   Hearing loss

Mouth:
   Cleft palate;
   Glossoptosis

Spine:
   Spondyloepiphyseal dysplasia

Limbs:
   Epiphyseal dysplasia;
   Relative arachnodactyly

Joints:
   Arthropathy;
   Degenerative arthritis;
   Hyperextensible joints

Cardiac:
   Mitral valve prolapse

Neuro:
   Normal intelligence

Inheritance:
   Autosomal dominant COL2A1-linked, and other

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/13/1997
mark: 11/24/1996
terry: 11/21/1996
mark: 6/25/1996
terry: 6/14/1996
terry: 6/27/1995
carol: 2/3/1995
mimadm: 4/9/1994
carol: 9/29/1993
carol: 9/15/1993
carol: 12/4/1992

*RECORD*
*FIELD* NO
108320
*FIELD* TI
108320 ARTICHOKE, MODIFICATION OF TASTE BY
*FIELD* TX
Eating an artichoke (Cynara scolymus) makes water taste sweet in some
subjects. Bartoshuk et al. (1972) encountered 6 males who failed to show
the effect. They commented that whether the insensitivity to the effect
has a genetic basis is unknown. The effect is induced by a temporary
alteration in the tongue. Blakeslee (1935) reported that at the AAAS
biologists' dinner in 1934, water tasted sweet to 60% of the nearly 250
persons present after eating artichokes as the salad course.

*FIELD* RF
1. Bartoshuk, L. M.; Lee, C.-H.; Scarpellino, R.: Sweet taste induced
by artichoke (Cynara scolymus). Science 178: 988-989, 1972.

2. Blakeslee, A. F.: A dinner demonstration of threshold differences
in taste and smell. Science 81: 504-507, 1935.

*FIELD* CS

Neuro:
   Artichoke modification of taste;
   Water tastes sweet

Inheritance:
   ? Mendelian

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
warfield: 4/6/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
108330
*FIELD* TI
*108330 CYTOCHROME P450, SUBFAMILY I, POLYPEPTIDE 1; CYP1A1
ARYL HYDROCARBON HYDROXYLASE; AHH;;
FLAVOPROTEIN-LINKED MONOOXYGENASE
CYTOCHROME P1-450, DIOXIN-INDUCIBLE, INCLUDED;;
CYTOCHROME P1-450 INDUCIBLE BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN;;
TCDD-INDUCIBLE CYTOCHROME P1-450; P450DX; CYP1;;
POLYCYCLIC AROMATIC COMPOUND-INDUCIBLE P450;;
P(1)450; CYP1A1
*FIELD* TX
From study of mouse-human hybrid cells, Brown et al. (1976) concluded
that a structural gene for AHH is on chromosome 2 and that possibly a
regulatory gene is there also. Ocraft et al. (1985) localized the gene
to 2q31-2pter. According to McBride (1985), the gene mapped to
chromosome 2 by expression assays is almost certainly not the structural
locus; the structural locus is that assigned to chromosome 15:
dioxin-inducible P1-450. (Possibly the locus on chromosome 2 is
concerned with AHH inducibility; see 108340.) Nebert (1988) recommended
that the AHH locus held to be on chromosome 2 be removed from that
listing. The assignment was based on measurements of AHH inducibility in
tissue culture, and effects of dibutyryl cAMP or other factor on the
enzyme activity might have been observed. Neither the Ah receptor nor
the P(1)450 or P(3)450 genes that it regulates map to chromosome 2 or to
its mouse or hamster homolog.

Cytochrome P1-450 is the form of P-450 most closely associated with
polycyclic-hydrocarbon-induced AHH activity. Chen et al. (1983) cloned a
portion of the genomic gene. The compound
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of many
proteins including drug-metabolizing enzymes such as the cytochrome
P-450 proteins. The P1-450 that is induced by TCDD is the same as AHH.
Jaiswal et al. (1985) used a human cell line in which TCDD resulted in
high levels of AHH (P1-450) activity and of human P1-450. Jaiswal et al.
(1985) estimated that the TCDD-inducible P-450 gene family diverged from
the phenobarbital-inducible P-450 gene family (123960) more than 200
million years ago. Nebert and Gonzalez (1987) estimated that this
divergence occurred more than 750 million years ago. Jaiswal et al.
(1985) expressed hope that finding RFLPs representing high and low
inducibility may make it possible to predict risk for persons exposed to
various environmental pollutants. Kouri et al. (1982) reported that
individuals with the high-inducibility phenotype (present in
approximately 10% of the human population) might be at greater risk than
low-inducibility individuals for cigarette smoke-induced bronchogenic
carcinoma. In a 3-generation family of 15 individuals, Petersen et al.
(1991) showed that the high-CYP1A1-inducibility phenotype segregated
concordantly with an infrequent polymorphic site located 450 bases
downstream from the CYP1A1 gene. These findings were consistent with
those of Kawajiri et al. (1986, 1990), who demonstrated an association
between this polymorphism and an increased incidence of squamous-cell
lung cancer. Quattrochi et al. (1985) cloned human P450DX genes and
concluded that there are at least 2 in humans. Hildebrand et al. (1985)
used a full-length cDNA for human 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD)-inducible cytochrome P1-450 to study DNA from somatic hybrid
cells. They assigned the gene to chromosome 15. Jaiswal and Nebert
(1986) indicated that this locus is in the 15q22-qter segment, near MPI
(154550). The P3-450 gene (CYP1A2) has also been located on chromosome
15; see 124060. See also CYP1B1 (601771).

The nomenclature and symbolization of the P450 enzymes and their genes
have gone through many changes. The currently preferred system (Nebert,
1988) uses the symbol CYP followed by a number for family and a letter
for subfamily. CYP1 is the designation of the family of P450 genes
located on human chromosome 15 and mouse chromosome 9. (CYP1 was
previously used for a P450 gene on chromosome 19 (123960), which is now
called CYP2.) The number assigned to the family is sometimes arbitrary
or selected for reasons of historical priority; in other cases it has
specific significance, e.g., in the case of CYP21 on 6p and CYP17 on 10,
which are genes for the enzymes of classes designated P450XXI (steroid
21-hydroxylase) and P450XVII (steroid 17-alpha-hydroxylase),
respectively. Hildebrand et al. (1985) showed that in the mouse, which
has 2 dioxin-inducible P-450 genes, P1-450 and P3-450, the 2 genes are
situated in the middle portion of chromosome 9 near the Mpi-1 locus,
between Thy-1 and Pk-3. Treatment of mice with polycyclic aromatic
hydrocarbons results in induction of P1-450 and P3-450. Their genes have
been cloned and shown to be coordinately regulated by the cytosolic
receptor which is coded by the Ah locus and specifically binds the
inducing chemicals. By Southern blot analysis of DNA from hamster-mouse
somatic cell hybrids, Tukey et al. (1984) demonstrated that the genes
for P1-450 and P3-450 map to chromosome 9 in the mouse. The major
regulatory gene controlling P1-450 induction in the mouse is located in
the centromeric region of chromosome 12. Mouse chromosome 9 shows other
homology of synteny with human 15. Jaiswal et al. (1985) and Kawajiri et
al. (1986) isolated and analyzed the complete nucleotide sequence of a
human genomic clone highly homologous to the rat cytochrome P-450 that
is induced by methylcholanthrene and TCDD. A fusion gene, which was
constructed by ligating the 5-prime flanking region of the gene to the
structural gene for prokaryotic chloramphenicol acetyltransferase (CAT),
expressed the CAT activity in mouse cells in response to administered
methylcholanthrene. Thus, the isolated human gene was indeed one for
methylcholanthrene inducibility. Jones et al. (1991) coupled a DNA
fragment containing the murine Cyp1a-1 enhancer elements and promoter
region to the chloramphenicol acetyltransferase (CAT) reporter gene and
used it to create transgenic mice. Treatment with 3-methylcholanthrene
increased hepatic expression levels by as much as 10,000-fold.
Differences in the response to induction between male and female mice
suggested that Cyp1a-1 expression may be governed in a gender-related
manner.

(The chloramphenicol acetyltransferase (CAT) assay system for monitoring
gene expression was reported by Gorman et al. (1983). Gorman (1993)
described the circumstances surrounding the development of the method.
The initial report was turned down by the journal Nature, whose
editorial staff charged that the work was not of wide enough interest
for publication there.)

*FIELD* SA
Hildebrand et al. (1985); Jaiswal et al. (1985); Jaiswal et al. (1987);
Jaiswal et al. (1986); Jaiswal et al. (1987); Wiebel et al. (1981)
*FIELD* RF
1. Brown, S.; Wiebel, F. J.; Gelboin, H. V.; Minna, J. D.: Assignment
of a locus required for flavoprotein-linked monooxygenase expression
to human chromosome 2. Proc. Nat. Acad. Sci. 73: 4628-4632, 1976.

2. Chen, Y. T.; Tukey, R. H.; Swan, D. C.; Negishi, N.; Nebert, D.
W.: Characterization of the human P1-450 genomic gene. (Abstract) Clin.
Res. 31: 456A, 1983.

3. Gorman, C.; Padmanabhan, R.; Howard, B. H.: High efficiency DNA-mediated
transformation of primate cells. Science 221: 551-553, 1983.

4. Gorman, C. M.: CAT: an easy assay for gene expression (citation
classic). Current Contents (Life Sciences) 36(22): 8, 1993.

5. Hildebrand, C. E.; Gonzalez, F. J.; Kozak, C. A.; Nebert, D. W.
: Regional linkage analysis of the dioxin-inducible P-450 gene family
on mouse chromosome 9. Biochem. Biophys. Res. Commun. 130: 396-406,
1985.

6. Hildebrand, C. E.; Gonzalez, F. J.; McBride, O. W.; Nebert, D.
W.: Assignment of the human 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible
cytochrome P1-450 gene to chromosome 15. Nucleic Acids Res. 13:
2009-2016, 1985.

7. Jaiswal, A. K.; Gonzalez, F. J.; Nebert, D. W.: Human dioxin-inducible
cytochrome P1-450: complementary DNA and amino acid sequence. Science 228:
80-83, 1985.

8. Jaiswal, A. K.; Gonzalez, F. J.; Nebert, D. W.: Human P(1)-450
gene sequence and correlation of mRNA with genetic differences in
benzo(a)pyrene metabolism. Nucleic Acids Res. 13: 4503-4520, 1985.

9. Jaiswal, A. K.; Gonzalez, F. J.; Nebert, D. W.: Comparison of
human mouse P(1)450 upstream regulatory sequences in liver- and nonliver-derived
cell lines. Molec. Endocr. 1: 312-320, 1987.

10. Jaiswal, A. K.; Nebert, D. W.: Two RFLPs associated with the
human P(1)450 gene linked to the MPI locus on chromosome 15 (HGM8
D15S8). Nucleic Acids Res. 14: 4376, 1986.

11. Jaiswal, A. K.; Nebert, D. W.; Gonzalez, F. J.: Human P(3)450:
cDNA and complete amino acid sequence. Nucleic Acids Res. 14: 6773-6774,
1986.

12. Jaiswal, A. K.; Nebert, D. W.; McBride, O. W.; Gonzalez, F. J.
: Human P(3)450: cDNA and complete protein sequence, repetitive Alu
sequences in the 3-prime nontranslated region, and localization of
gene to chromosome 15. J. Exp. Path. 3: 1-17, 1987.

13. Jones, S. N.; Jones, P. G.; Ibarguen, H.; Caskey, C. T.; Craigen,
W. J.: Induction of the Cyp1a-1 dioxin-responsive enhancer in transgenic
mice. Nucleic Acids Res. 19: 6547-6551, 1991.

14. Kawajiri, K.; Nakachi, K.; Imai, K.; Yoshii, A.; Shinoda, N.;
Watanabe, J.: Identification of genetically high risk individuals
to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene. FEBS
Lett. 263: 131-133, 1990.

15. Kawajiri, K.; Watanabe, J.; Gotoh, O.; Tagashira, Y.; Sogawa,
K.; Fujii-Kuriyama, Y.: Structure and drug inducibility of the human
cytochrome P-450c gene. Europ. J. Biochem. 159: 219-225, 1986.

16. Kouri, R. E.; McKinney, C. E.; Slomiany, D. J.; Snodgrass, D.
R.; Wray, N. P.; McLemore, T. L.: Positive correlation between high
aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed
in cryopreserved lymphocytes. Cancer Res. 42: 5030-5037, 1982.

17. McBride, O. W.: Personal Communication. Bethesda, Md.  9/16/1985.

18. Nebert, D. W.: Personal Communication. Bethesda, Md.  2/1/1988.

19. Nebert, D. W.; Gonzalez, F. J.: P450 genes: structure, evolution,
and regulation. Annu. Rev. Biochem. 56: 945-993, 1987.

20. Ocraft, K. P.; Muskett, J. M.; Brown, S.: Localization of the
human arylhydrocarbon hydroxylase gene to the 2q31-2pter region of
chromosome 2. Ann. Hum. Genet. 49: 237-239, 1985.

21. Petersen, D. D.; McKinney, C. E.; Ikeya, K.; Smith, H. H.; Bale,
A. E.; McBride, O. W.; Nebert, D. W.: Human CYP1A1 gene: cosegregation
of the enzyme inducibility phenotype and an RFLP. Am. J. Hum. Genet. 48:
720-725, 1991.

22. Quattrochi, L. C.; Okino, S. T.; Pendurthi, U. R.; Tukey, R. H.
: Cloning and isolation of human cytochrome P-450 cDNAs homologous
to dioxin-inducible rabbit mRNAs encoding P-450 4 and P-450 6. DNA 4:
395-400, 1985.

23. Tukey, R. H.; Lalley, P. A.; Nebert, D. W.: Localization of cytochrome
P1-450 and P3-450 genes to mouse chromosome 9. Proc. Nat. Acad. Sci. 81:
3163-3166, 1984.

24. Wiebel, F. J.; Hlavica, P.; Grzeschik, K. H.: Expression of aromatic
polycyclic hydrocarbon-induced monooxygenase (aryl hydrocarbon hydroxylase)
in man-mouse hybrids is associated with human chromosome 2. Hum.
Genet. 59: 277-280, 1981.

*FIELD* CS

Oncology:
   ? High-inducibility phenotype at greater risk for bronchogenic carcinoma

Inheritance:
   Autosomal dominant (15q22-qter)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 04/29/1997
terry: 5/24/1996
terry: 5/12/1994
mimadm: 4/9/1994
warfield: 4/7/1994
pfoster: 3/31/1994
carol: 10/19/1993
carol: 6/11/1993

*RECORD*
*FIELD* NO
108340
*FIELD* TI
108340 ARYL HYDROCARBON HYDROXYLASE INDUCIBILITY
AHH INDUCIBILITY; AHHI
*FIELD* TX
AHH is one of the mixed function oxidases in the microsomal fraction.
Busbee et al. (1972) found three distinct groups--low, intermediate, and
high--in regard to inducibility of AHH measured in cultured lymphocytes
24 hours after introduction of 3-methylcholanthrene. Family studies
indicated diallelic determination at a single locus. Using the same
inducer, Kellermann et al. (1973) found polymorphic inducibility of
lymphocyte AHH. Since AHH is an enzyme involved in metabolism of
carcinogens, the genetic difference might be relevant to the occurrence
of cancer. In a normal white U.S. population, Kellermann et al. (1973)
found low, intermediate and high inducibility in the following
proportions: 44.7%, 45.9%, 9.4%, respectively. Among 50 patients with
bronchogenic cancer, they found the following proportions: 4.0%, 66.0%,
and 30.0%, respectively. Genetically determined high inducibility of AHH
may be associated with enhanced risk of cancer in cigarette smokers
(Kouri et al., 1982). In the mouse it was shown by Shichi et al. (1978)
that homozygotes and heterozygotes for the Ah(b) allele (which renders
the mouse susceptible to AHH induction by 3-methylcholanthrene)
developed an irreversible opacity of the anterior portion of the lens,
resembling a senile cataract, within 6 hours after a large
intraperitoneal dose of acetaminophen. Whether the same occurs in man is
not known. Fletcher et al. (1978) emphasized the poor reproducibility of
AHH inducibility in lymphocytes. From studies of AHH in twins, Paigen et
al. (1978) concluded that AHH inducibility may be determined by a single
or a few polymorphic genes. From a twin study, Borresen et al. (1981)
concluded that inducibility (but not basal level) is heritable
(heritability = 0.7). Major control of inducibility by one locus was
considered possible.

*FIELD* SA
Bickers and Kappas (1978); Emery et al. (1978); Kellermann et al.
(1973); Paigen et al. (1977); Trell et al. (1976)
*FIELD* RF
1. Bickers, D. R.; Kappas, A.: Human skin aryl hydrocarbon hydroxylase:
induction by coal tar. J. Clin. Invest. 62: 1061-1068, 1978.

2. Borresen, A.-L.; Berg, K.; Magnus, P.: A twin study of aryl hydrocarbon
hydroxylase (AHH) inducibility in cultured lymphocytes. Clin. Genet. 19:
281-289, 1981.

3. Busbee, D. L.; Shaw, C. R.; Cautrell, E. T.: Aryl hydrocarbon
hydroxylase induction in human leucocytes. Science 178: 315-316,
1972.

4. Emery, A. E. H.; Danford, N.; Anand, R.; Duncan, W.; Paton, L.
: Aryl-hydrocarbon-hydroxylase inducibility in patients with cancer.
Lancet I: 470-472, 1978.

5. Fletcher, K. A.; Evans, D. A. P.; Canning, M. V.: Inducibility
of aryl hydrocarbon hydroxylase in cultured human lymphocytes: a study
of repeatability. J. Med. Genet. 15: 182-188, 1978.

6. Kellermann, G.; Luyter-Kellermann, M.; Shaw, C. R.: Genetic variation
of aryl hydrocarbon hydroxylase in human lymphocytes. Am. J. Hum.
Genet. 25: 327-331, 1973.

7. Kellermann, G.; Shaw, C. R.; Luyter-Kellermann, M.: Aryl hydrocarbon
hydroxylase inducibility and bronchogenic carcinoma. New Eng. J.
Med. 289: 934-937, 1973.

8. Kouri, R. E.; McKinney, C. E.; Slomiany, D. J.; Snodgrass, D. R.;
Wray, N. P.; McLemore, T. L.: Positive correlation between high aryl
hydrocarbon hydroxylase activity and primary lung cancer as analyzed
in cryopreserved lymphocytes. Cancer Res. 42: 5030-5037, 1982.

9. Paigen, B.; Gurtoo, H. L.; Minowada, J.; Houten, L.; Vincent, R.
A., Jr.; Paigen, K.; Parker, N. B.; Ward, E.; Hayner, N. T.: Questionable
relation of aryl hydrocarbon hydroxylase to lung-cancer risk. New
Eng. J. Med. 297: 346-350, 1977.

10. Paigen, B.; Ward, E.; Steenland, K.; Houten, L.; Gurtoo, H. L.;
Minowada, J.: Aryl-hydrocarbon hydroxylase in cultured lymphocytes
of twins. Am. J. Hum. Genet. 30: 561-571, 1978.

11. Shichi, H.; Gaasterland, D. E.; Jensen, N. M.; Nebert, D. W.:
Ah locus: genetic differences in susceptibility to cataracts induced
by acetaminophen. Science 200: 539-541, 1978.

12. Trell, E.; Korsgaard, R.; Hood, B.; Kitzing, P.; Norden, G.; Simonsson,
B. G.: Aryl hydrocarbon hydroxylase inducibility and laryngeal carcinomas.
(Letter) Lancet II: 140 only, 1976.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 5/12/1994
pfoster: 4/1/1994
warfield: 3/31/1994
mimadm: 2/11/1994
supermim: 3/16/1992
supermim: 4/28/1990

*RECORD*
*FIELD* NO
108345
*FIELD* TI
*108345 ARYLAMIDE ACETYLASE 1; AAC1
ARYLAMINE N-ACETYLTRANSFERASE-1;;
N-ACETYLTRANSFERASE-1; NAT1;;
ACETYL-CoA:ARYLAMINE N-ACETYLTRANSFERASE
*FIELD* TX
Using a rabbit cDNA for arylamine N-acetyltransferase (NAT; EC 2.3.1.5),
Blum et al. (1990) cloned 3 NAT genes from human leukocyte DNA. Two of
them, NAT1 and NAT2 (243400), were shown to be functional; the third
appeared to be a pseudogene (NATP). Both NAT1 and NAT2 mapped to
8pter-q11 by probing of somatic cell hybrid DNA. Blum et al. (1990)
presented evidence that the NAT2 gene is the site of the polymorphism
that was first identified through 'isoniazid inactivation' and is also
known as 'acetylator phenotype.' The other gene, NAT1, is responsible
for the N-acetylation of certain arylamine drugs such as
p-aminosalicylic acid and shows no variability, i.e., is monomorphic.
The rates of elimination in vivo and assimilation in vitro of
p-aminosalicylic acid do not differ among rapid and slow acetylators.
Vatsis et al. (1991), who confirmed that isoniazid acetylation is
produced by the NAT2 locus, also demonstrated a NAT pseudogene.

Hickman et al. (1994) mapped both the NAT1 and NAT2 genes to
8p23.1-p21.3 by fluorescence in situ hybridization. The 2 loci were
mapped to mouse chromosome 8 by Mattano et al. (1988).

Nomenclature: The gene symbol has been designated AAC1. Vatsis et al.
(1995) described a consolidated classification system and nomenclature
for prokaryotic and eukaryotic N-acetyltransferases. The root symbol,
NAT, was used throughout.

*FIELD* RF
1. Blum, M.; Grant, D. M.; McBride, W.; Heim, M.; Meyer, U. A.: Human
arylamine N-acetyltransferase genes: isolation, chromosomal localization,
and functional expression. DNA Cell Biol. 9: 193-203, 1990.

2. Hickman, D.; Risch, A.; Buckle, V.; Spurr, N. K.; Jeremiah, S.
J.; McCarthy, A.; Sim, E.: Chromosomal localization of human genes
for arylamine N-acetyltransferase. Biochem. J. 297: 441-445, 1994.

3. Mattano, S. S.; Erickson, R. P.; Nesbitt, M. N.; Weber, W. W.:
Linkage of Nat and Es-1 in the mouse and development of strains congenic
for N-acetyltransferase. J. Hered. 79: 430-433, 1988.

4. Vatsis, K. P.; Martell, K. J.; Weber, W. W.: Diverse point mutations
in the human gene for polymorphic N-acetyltransferase. Proc. Nat.
Acad. Sci. 88: 6333-6337, 1991.

5. Vatsis, K. P.; Weber, W. W.; Bell, D. A.; Dupret, J.-M.; Price
Evans, D. A.; Grant, D. M.; Hein, D. W.; Lin, H. J.; Meyer, U. A.;
Relling, M. V.; Sim, E.; Suzuki, T.; Yamazoe, Y.: Nomenclature for
N-acetyltransferases. Pharmacogenetics 5: 1-17, 1995.

*FIELD* CS

Misc:
   No variability, i.e., a monomorphic trait

Lab:
   Arylamine N-acetyltransferase-1;
   N-acetylation of certain arylamine drugs, e.g;
   p-aminosalicylic acid

Inheritance:
   Autosomal dominant (8pter-q11)

*FIELD* CD
Victor A. McKusick: 8/24/1990

*FIELD* ED
mark: 12/31/1996
randy: 8/31/1996
terry: 10/27/1995
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/17/1992
carol: 8/20/1991
carol: 9/6/1990

*RECORD*
*FIELD* NO
108355
*FIELD* TI
*108355 ASH PROTEIN
ABUNDANT SRC HOMOLOGY
*FIELD* TX
The SRC homology regions (SH) 2 and 3, sequences conserved among
noncatalytic regions of nonreceptor tyrosine kinases, are found in a
variety of oncogenic, signaling, and cellular substructure-associated
proteins. Both the SH2 and SH3 domains are considered to be involved in
intermolecular interactions. To elucidate the roles of SH2 domains in
cell regulation, Matuoka et al. (1992) investigated the multiplicity and
diversity of the SH2-containing molecules. They found 1 gene product,
referred to as ASH (for 'abundant SRC homology'), composed of one SH2
domain and two SH3 domains. The amino acid sequence of ASH suggested
that it is a mammalian homolog of Sem-5, the product of a nematode gene
responsible for communication between a receptor protein tyrosine kinase
and a Ras protein. ASH was thought to function as a similar ubiquitous
signal transducer. Induced expression of an antisense ASH cDNA led to a
reduction in cell growth.

*FIELD* RF
1. Matuoka, K.; Shibata, M.; Yamakawa, A.; Takenawa, T.: Cloning
of ASH, a ubiquitous protein composed of one Src homology region (SH)
2 and two SH3 domains, from human and rat cDNA libraries. Proc.
Nat. Acad. Sci. 89: 9015-9019, 1992.

*FIELD* CD
Victor A. McKusick: 10/16/1992

*FIELD* ED
carol: 10/16/1992

*RECORD*
*FIELD* NO
108360
*FIELD* TI
*108360 ASIALOGLYCOPROTEIN RECEPTOR-1; ASGR1
*FIELD* TX
Partially deglycosylated plasma glycoproteins are efficiently and
specifically removed from the circulation by a receptor-mediated
process. In mammals, the asialoglycoprotein receptor, specific for
desialylated (galactosyl-terminal) glycoproteins, is expressed
exclusively in hepatic parenchymal cells. Following binding of the
ligand to this cell surface receptor, the receptor-ligand complex is
internalized and transported by a series of membrane vesicles and
tubules to an acidic-sorting organelle where receptor and ligand
dissociate. The receptor returns to the cell surface, while the ligand
is transported to lysosomes where it is degraded. Many of the functional
studies describing the kinetics of ligand-binding, internalization, and
recycling of the receptor, as well as its biosynthesis, have been
performed on the human hepatoma cell line Hep G2. Spiess et al. (1985)
prepared a cDNA library from this cell line in the expression vector
lambda-gt11. Using specific antibodies, a cDNA clone containing the
entire coding sequence of the human asialoglycoprotein receptor was
isolated and sequenced. The deduced amino acid sequence of 291 residues
was found to be highly homologous to the sequence of the major
asialoglycoprotein receptor protein in the rat. There is no significant
posttranslational processing and no leader sequence, cleaved or
uncleaved, at the amino terminus. An internal signal sequence, probably
the membrane-spanning segment (residues 41-59), is assumed to direct
insertion of the carboxyl-terminal ligand-binding portion of the
receptor across the endoplasmic reticulum membrane. The ASGR1 gene is
probably situated on chromosome 17p; Hsieh et al. (1990) demonstrated
that the Asgr-1 and Asgr-2 genes are located on mouse chromosome 11 near
Zpf-3 (194480) and Amog (182331) in a region of mouse chromosome 11 that
is homologous to human 17p. Sanford et al. (1991) demonstrated that this
is indeed the case; they mapped the ASGR1 gene to 17p13-p11 by analysis
of somatic cell hybrids.

*FIELD* SA
Sanford et al. (1988)
*FIELD* RF
1. Hsieh, C.-L.; Cheng-Deutsch, A.; Gloor, S.; Schachner, M.; Francke,
U.: Assignment of Amog (adhesion molecule on glia) gene to mouse
chromosome 11 near Zfp-3 and Asgr-1,2 and to human chromosome 17.
Somat. Cell Molec. Genet. 16: 401-405, 1990.

2. Sanford, J. P.; Eddy, R. L.; Doyle, D.; Shows, T. B.: Assignment
of human asialoglycoprotein receptor gene (ASGR1) to chromosome 17p11-13.
Genomics 11: 779-781, 1991.

3. Sanford, J. P.; Elliott, R. W.; Doyle, D.: Asialoglycoprotein
receptor genes are linked on chromosome 11 in the mouse. DNA 7:
721-728, 1988.

4. Spiess, M.; Schwartz, A. L.; Lodish, H. F.: Sequence of human
asialoglycoprotein receptor cDNA: an internal signal sequence for
membrane insertion. J. Biol. Chem. 260: 1979-1982, 1985.

*FIELD* CD
Victor A. McKusick: 7/10/1990

*FIELD* ED
supermim: 3/16/1992
carol: 10/23/1991
carol: 1/14/1991
carol: 1/8/1991
carol: 8/15/1990
carol: 7/12/1990

*RECORD*
*FIELD* NO
108361
*FIELD* TI
*108361 ASIALOGLYCOPROTEIN RECEPTOR-2; ASGR2
*FIELD* TX
From the same cDNA library that was made from the human hepatoma cell
line HepG2 and was used to isolate an asialoglycoprotein receptor
(ASGR1; H1; 108360), Spiess and Lodish (1985) isolated and sequenced a
clone encoding a second asialoglycoprotein receptor, which they referred
to as H2 and which had protein sequence homology of 58% to H1. The rat
similarly has 2 ASG receptors, R1 and R2. Spiess and Lodish (1985) found
that H1 is more homologous to R1 than to H2, and H2 is more homologous
to R2 than to H1. Thus, the 2 receptor genes evolved before the
separation of rat and man. Spiess and Lodish (1985) identified 2
versions of H2 cDNA, differing only by the presence or absence of a
segment of 15 bp within the coding region. They interpreted this as
reflecting differential splicing of an intron.

*FIELD* RF
1. Spiess, M.; Lodish, H. F.: Sequence of a second human asialoglycoprotein
receptor: conservation of two receptor genes during evolution. Proc.
Nat. Acad. Sci. 82: 6465-6469, 1985.

*FIELD* CD
Victor A. McKusick: 7/12/1990

*FIELD* ED
supermim: 3/16/1992
carol: 8/20/1990
carol: 7/13/1990
carol: 7/12/1990

*RECORD*
*FIELD* NO
108370
*FIELD* TI
*108370 ASPARAGINE SYNTHETASE; ASNS; AS
HUMAN COMPLEMENT FOR HAMSTER TEMPERATURE-SENSITIVE MUTANT ts11
*FIELD* TX
Asparagine synthetase is involved in the synthesis of asparagine, a
nonessential amino acid for mammalian cells. The gene for ASNS has been
assigned to chromosome 7 by enzymatic analyses of human/hamster hybrids
(Arfin et al., 1983). Lambert et al. (1986) confirmed this assignment
with molecular probes. The asparagine synthetase gene has been
identified as the gene that is mutant in the temperature-sensitive
hamster mutant ts11, which blocks progression through the G(1) phase of
the cell cycle at nonpermissive temperature. The ts11 gene is
transcribed into an mRNA of 2 kb that was expressed in all human,
hamster, and mouse cell lines tested (Greco et al., 1987) and encodes a
protein of about 550 amino acids. It is the sequence homology that
identifies the protein as asparagine synthetase. Presence of the enzyme
confers the ability of exogenous asparagine to bypass the ts11 block.
Using a genomic probe, Greco et al. (1989) found that the ts11 locus is
derived from the long arm of human chromosome 7, proximal to the TCRB
locus (186930). In situ hybridization mapped the locus more precisely to
7q21-q31. Two other members of the gene family detected by the ts11
probe were mapped to 8pter-q24 and 21pter-q22. Zhang et al. (1989)
demonstrated that the ASNS gene spans 35 kb and contains 13 exons. The
5-prime upstream region of this gene, like other housekeeping genes,
lacks conventional TATA and CAAT boxes. Both the human and the hamster
genes have a high 5-prime G + C content which may play a role in
expression through DNA methylation. Heng et al. (1994) refined the
localization of the ASNS gene to 7q21.3 by fluorescence in situ
hybridization.

*FIELD* RF
1. Arfin, S. M.; Cirullo, R. E.; Arredondo-Vega, F. X.; Smith, M.
: Assignment of the structural gene for asparagine synthetase to human
chromosome 7. Somat. Cell Genet. 9: 517-531, 1983.

2. Greco, A.; Ittmann, M.; Barletta, C.; Basilico, C.; Croce, C. M.;
Cannizzaro, L. A.; Huebner, K.: Chromosomal localization of human
genes required for G(1) progression in mammalian cells. Genomics 4:
240-245, 1989.

3. Greco, A.; Ittmann, M.; Basilico, C.: Molecular cloning of a gene
that is necessary for G(1) progression in mammalian cells. Proc.
Nat. Acad. Sci. 84: 1565-1569, 1987.

4. Heng, H. H. Q.; Shi, X.-M.; Scherer, S. W.; Andrulis, I. L.; Tsui,
L.-C.: Refined localization of the asparagine synthetase gene (ASNS)
to chromosome 7, region q21.3, and characterization of the somatic
cell hybrid line 4AF/106/KO15. Cytogenet. Cell Genet. 66: 135-138,
1994.

5. Lambert, M. A.; Cairney, A. E. L.; Ray, P. N.; Weksberg, R.; Andrulis,
I. L.: Genomic characterization of the human asparagine synthetase
gene.  (Abstract) Am. J. Hum. Genet. 39: A207 only, 1986.

6. Zhang, Y. P.; Lambert, M. A.; Cairney, A. E. L.; Wills, D.; Ray,
P. N.; Andrulis, I. L.: Molecular structure of the human asparagine
synthetase gene. Genomics 4: 259-265, 1989.

*FIELD* CS

Misc:
   Housekeeping gene

Lab:
   Asparagine synthetase

Inheritance:
   Autosomal dominant (7q21-q31)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 7/12/1994
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/17/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
108390
*FIELD* TI
108390 ASPARAGUS, SPECIFIC SMELL HYPERSENSITIVITY
*FIELD* TX
Lison et al. (1980) concluded that the urinary excretion of an odorous
substance after eating asparagus is not an inborn error of metabolism as
had been supposed (see 108400). Instead they suggested that the
detection of the odor constitutes a specific smell hypersensitivity.
Their observations on a large number of individuals indicated that those
who could smell the odor in their own urine could also smell it in the
urine of anyone who had eaten asparagus, whether or not that person was
able to smell it himself. Thresholds for detecting the odor appeared to
be bimodal in distribution, with 10% of 307 subjects tested able to
smell it at high dilutions. No family studies were reported. There were
no differences in the distribution of smellers and nonsmellers for this
specific odor in the 3 ethnic groups of Israeli Jews studied.

*FIELD* RF
1. Lison, M.; Blondheim, S. H.; Melmed, R. N.: A polymorphism of
the ability to smell urinary metabolites of asparagus. Brit. Med.
J. 281: 1676-1678, 1980.

*FIELD* CS

Neuro:
   Detection of urine asparagus odor

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/17/1987

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 8/10/1987

*RECORD*
*FIELD* NO
108400
*FIELD* TI
108400 ASPARAGUS, URINARY EXCRETION OF ODORIFEROUS COMPONENT OF
*FIELD* TX
The odoriferous component seems to be methanethiol. Forty-six of 115
persons were excreters in the experience of Allison and McWhirter
(1956). They suggested, furthermore, that 'excreter' is dominant to
'nonexcreter.' I am told (Maas, 1972) that a nonexcreter may become an
excreter during pregnancy, the unborn child presumably being an
excreter. This is yet to be tested. Lison et al. (1980) concluded that
the urinary excretion of an odorous substance after eating asparagus is
not an inborn error of metabolism, but rather that the detection of the
odor constitutes a specific smell hypersensitivity; see 108390.

*FIELD* RF
1. Allison, A. C.; McWhirter, K. G.: Two unifactorial characters
for which man is polymorphic. Nature 178: 748-749, 1956.

2. Lison, M.; Blondheim, S. H.; Melmed, R. N.: A polymorphism of
the ability to smell urinary metabolites of asparagus. Brit. Med.
J. 281: 1676-1678, 1980.

3. Maas, W. K.: Personal Communication. New York, N. Y.  1972.

*FIELD* CS

Misc:
   Odorous substance excretion after eating asparagus

Lab:
   Methanethiol urinary excretion

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
pfoster: 4/25/1994
mimadm: 4/9/1994
warfield: 4/7/1994
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
108410
*FIELD* TI
*108410 ASPARAGINYL-tRNA SYNTHETASE; NARS; ASNRS
*FIELD* TX
Using a DNA probe in human-rodent hybrid cells, Shows (1983) found that
asparaginyl-tRNA synthetase segregated with peptidase A, a chromosome 18
marker. Cirullo et al. (1983) used the abbreviation-symbol 'asnS.' They
isolated hybrids between human peripheral leukocytes and a
temperature-sensitive CHO cell line with a thermolabile asparaginyl-tRNA
synthetase. Hybrids selected at 39 degrees C required the presence of
human chromosome 18. Temperature-resistant hybrid cells contained 2
forms of ASNRS: 1 highly thermal resistant like the human enzyme and 1
highly thermolabile like the CHO mutant enzyme.

*FIELD* RF
1. Cirullo, R. E.; Arredondo-Vega, F. X.; Smith, M.; Wasmuth, J. J.
: Isolation and characterization of interspecific heat-resistant hybrids
between a temperature-sensitive Chinese hamster cell asparaginyl-tRNA
synthetase mutant and normal human leukocytes: assignment of human
asnS gene to chromosome 18. Somat. Cell Genet. 9: 215-233, 1983.

2. Shows, T. B.: Personal Communication. Buffalo, N. Y.  1/11/1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
supermim: 3/16/1992
carol: 11/12/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
108420
*FIELD* TI
108420 ASPERMIOGENESIS FACTOR; ASG
*FIELD* TX
Giraldo et al. (1981) described 3 phenotypically normal brothers, 2 with
azoospermia and 1 with severe oligozoospermia, who had a pericentric
inversion of chromosome 1 with breakpoints at p13 and q25. The authors
suggested that the mother, then deceased, may have had the same
inversion which had no effect on reproduction in the female.

*FIELD* RF
1. Giraldo, A.; Silva, E.; Martinez, I.; Campos, C.; Guzman, J.:
Pericentric inversion of chromosome 1 in three sterile brothers. Hum.
Genet. 58: 226-227, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
108450
*FIELD* TI
108450 ASYMMETRIC SHORT STATURE SYNDROME
*FIELD* TX
Jung and Smith (1980) described mother and daughter with asymmetric
short stature associated with craniofacial, ocular, and skeletal
anomalies. The mother was 132 cm tall; the daughter was 82 cm tall at
3.5 years of age (-4 SD). Both showed mild frontal bossing, small almost
beaked nose, mandibular hypoplasia with dental crowding, esotropia, and
hyperopia. The right leg was shorter than the left with pelvic tilt and
lumbar scoliosis. Fusion and atypicality of cervical vertebrae, carpal
bones and ribs were shown in the mother by radiographs. Intelligence was
normal. This was the mother's only pregnancy; there was no increased
incidence of abortion to suggest X-linked dominance with lethality in
the hemizygous male. The disorder could be confused with Russell-Silver
syndrome (180860) or Hallermann-Streiff syndrome (234100). Asymmetric
short stature and facial anomalies including small nose occur also with
chondrodysplasia punctata (118650).

*FIELD* RF
1. Jung, H. H.; Smith, D. W.: Dominantly inherited asymmetric short
stature with associated anomalies: a new syndrome.  (Abstract) Am.
J. Hum. Genet. 32: 114A only, 1980.

*FIELD* CS

Growth:
   Asymmetric short stature

Head:
   Mild frontal bossing;
   Small almost beaked nose;
   Mandibular hypoplasia

Eyes:
   Esotropia;
   Hyperopia

Teeth:
   Dental crowding

Limbs:
   Asymmetric leg shortening

Spine:
   Pelvic tilt;
   Lumbar scoliosis

Radiology:
   Fused atypical cervical vertebrae, carpal bones and ribs

Neuro:
   Normal intelligence

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 4/29/1994
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
108500
*FIELD* TI
#108500 ATAXIA, PERIODIC VESTIBULOCEREBELLAR
CEREBELLOPATHY, HEREDITARY PAROXYSMAL;;
ATAXIA, FAMILIAL PAROXYSMAL;;
ACETAZOLAMIDE-RESPONSIVE HEREDITARY PAROXYSMAL CEREBELLAR ATAXIA;;;
APCA;;
EPISODIC ATAXIA, TYPE 2; EA2;;
EPISODIC ATAXIA, NYSTAGMUS-ASSOCIATED;;
CEREBELLAR ATAXIA, PAROXYSMAL, ACETOZOLAMIDE-RESPONSIVE; CAPA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by mutations in the calcium ion channel CACNL1A4
(601011).

Parker (1946) may have been the first to describe this disorder. In 16
members of a white, rural North Carolina family, Farmer and Mustian
(1963) described recurrent attacks of vertigo, diplopia and ataxia
beginning in early adulthood. Slowly progressive cerebellar ataxia
occurred in some. Hill and Sherman (1968) described episodic cerebellar
ataxia occurring particularly in children in a large kindred with an
autosomal dominant pattern of inheritance. Unlike the disorder in Farmer
and Mustian's cases, the symptoms ameliorated in later life with no
permanent or progressive cerebellar abnormalities. The cases presented
by White (1969) showed gradual abatement of symptoms. Donat and Auger
(1979) reported ataxia in a 16-year-old boy and his 41-year-old mother,
both of whom had 'downbeating nystagmus' of the eyes when in the primary
position of gaze. The attacks of dizziness, which began at the age of 9
in the boy, were relieved with acetazolamide. Vance et al. (1984)
identified a second extensively affected kindred which, like the family
of Farmer and Mustian (1963), lived in North Carolina. Although no
relationship between the 2 kindreds could be established, such was
suspected. Koller and Bahamon-Dussan (1987) reported a family with
affected individuals in 3 generations, including 1 instance of
male-to-male transmission. Stress or emotion precipitated attacks.
Examination between attacks showed nystagmus, but no other neurologic
signs. After adolescence, there was no progression of symptoms. The
authors found, as have others (e.g., Zasorin et al., 1983), that
acetazolamide therapy successfully abolished the attacks. This disorder
may have first been recognized by Parker (1946). Vighetto et al. (1988)
indicated that 15 kindreds had been reported. They were the first to
report selective atrophy of the cerebellar vermis in all 3 members of 2
affected families that were studied by magnetic resonance imaging. In
the family reported by Boel and Casaer (1988), all affected members had
their first attacks before the age of 10 and the symptoms usually
disappeared during the second decade of life. Ataxia was precipitated by
stressful classroom situations or exciting football or tennis contests.
Ataxia usually lasted 3 to 8 minutes with no loss of consciousness but
was followed by a period of fatigue which often lasted for more than an
hour. Bain et al. (1992) reported that in 6 affected members of 2
unrelated families with familial periodic cerebellar ataxia, symptoms
were relieved with oral acetazolamide. When untreated, all subjects
showed abnormal intracellular pH levels in the cerebellum by (31)P
nuclear magnetic resonance (NMR) spectroscopy. These levels returned to
normal with treatment. In 1 family studied, cerebral pH values were
normal before and after treatment. In 3 additional patients with similar
attacks, but without a family history, normal pH values were found in
both cerebellum and cerebrum.

In a large family with this form of episodic ataxia, Litt et al. (1994)
excluded linkage to 12p where the locus for the episodic ataxia/myokymia
syndrome (EA1; 160120) had been mapped. In 2 large kindreds with
paroxysmal ataxia, von Brederlow et al. (1995) found linkage to 19p. The
microsatellite marker UT705 was found to be linked to the ataxia locus
with a 2-point analysis yielding a maximum lod score of 8.20 at theta =
0.00 in a 5-generation pedigree. Linkage to this region was confirmed in
the second kindred. They referred to the disorder as
acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (APCA).
Vahedi et al. (1995) reported linkage in a large family with this type
of episodic ataxia to a 30-cM region on 19p flanked by D19S216 and
D19S215.

In the 2 families reported by von Brederlow et al. (1995), physical and
emotional stress was the most consistent precipitating factor, although
attacks were also triggered occasionally by carbohydrate-rich meals.
Attacks lasted between one-half hour and 6 hours. Typical attacks were
observed in children as young as age 2 to 5 years, although onset was
more common in the second decade. Frequency of the episodes ranged from
3 to 4 times per week to 1 to 2 times per year. Symptoms were fully
controlled with acetazolamide. Attacks recurred promptly within 48 to 72
hours upon cessation of medication.

Kramer et al. (1994) suggested that there are 2 autosomal dominant forms
of episodic ataxia. In EA1, attacks last minutes and interictal myokymia
may be present. This form maps to chromosome 12 and by the candidate
gene approach was shown to be due to mutations in a specific potassium
voltage-gated channel gene (KCNA1; 176260). The second form, EA-2, is
often associated with nystagmus or trunkal instability and shows
beneficial response to acetazolamide. Kramer et al. (1994) and Kramer et
al. (1995) demonstrated that the nystagmus-associated form was mapped to
19p. They studied 3 families in which detailed clinical descriptions had
been given by Zasorin et al. (1983), Gancher and Nutt (1986), and Baloh
and Winder (1991). The strongest evidence for linkage occurred at
D19S221; total lod score = 5.07 at theta = 0.01 with no obligate
crossovers in any of the 3 kindreds.

Hemiplegic migraine, type 1 (MHP1; 141500) has also been mapped to
19p13. The possibility should be considered that one form of hemiplegic
migraine and episodic ataxia type 2 are allelic disorders. Since a
potassium channel gene is the site of the mutations in type 1 episodic
ataxia, 1 of the potassium channel genes such as KCNA7 (176268), which
maps to chromosome 19, is a possible site of the mutations in EA2. In
fact, Ophoff et al. (1996) found mutations in the calcium ion channel
gene CACNL1A4 in both familial hemiplegic migraine (e.g., 601011.0001)
and episodic ataxia type 2 (see 601011.0005 and 601011.0006). The
CACNL1A4 gene had been previously mapped to 19p13.

*FIELD* SA
Kramer et al. (1994)
*FIELD* RF
1. Bain, P. G.; O'Brien, M. D.; Keevil, S. F.; Porter, D. A.: Familial
periodic cerebellar ataxia: a problem of cerebellar intracellular
pH homeostasis. Ann. Neurol. 31: 147-154, 1992.

2. Baloh, R. W.; Winder, A.: Acetazolamide-responsive vestibulocerebellar
syndrome: clinical and oculographic features. Neurology 41: 429-433,
1991.

3. Boel, M.; Casaer, P.: Familial periodic ataxia responsive to flunarizine. Neuropediatrics 19:
218-220, 1988.

4. Donat, J. R.; Auger, R.: Familial periodic ataxia. Arch. Neurol. 36:
568-569, 1979.

5. Farmer, T. W.; Mustian, V. M.: Vestibulo-cerebellar ataxia: a
newly defined hereditary syndrome with periodic manifestations. Arch.
Neurol. 8: 471-480, 1963.

6. Gancher, S. T.; Nutt, J. G.: Autosomal dominant episodic ataxia:
a heterogeneous syndrome. Mov. Disord. 1: 239-253, 1986.

7. Hill, W.; Sherman, H.: Acute intermittent familial cerebellar
ataxia. Arch. Neurol. 18: 350-357, 1968.

8. Koller, W.; Bahamon-Dussan, J.: Hereditary paroxysmal cerebellopathy:
responsiveness to acetazolamide. Clin. Neuropharm. 10: 65-68, 1987.

9. Kramer, P.; Litt, M.; Browne, D.; Promchotikul, T.; Brunt, E. R.
P.; Dubay, C.; Gancher, S.; Nutt, J.: Autosomal dominant episodic
ataxia represents at least two genetic disorders. (Abstract) Ann.
Neurol. 36: 279, 1994.

10. Kramer, P. L.; Smith, E.; Carrero-Valenzuela, R.; Root, D.; Browne,
D.; Lovrien, E.; Gancher, S.; Nutt, J.; Litt, M.: A gene for nystagmus-associated
episodic ataxia maps to chromosome 19p. (Abstract) Am. J. Hum. Genet. 55
(Suppl.): A191, 1994.

11. Kramer, P. L.; Yue, Q.; Gancher, S. T.; Nutt, J. G.; Baloh, R.;
Smith, E.; Browne, D.; Bussey, K.; Lovrien, E.; Nelson, S.; Litt,
M.: A locus for the nystagmus-associated form of episodic ataxia
maps to an 11-cM region on chromosome 19p. (Letter) Am. J. Hum. Genet. 57:
182-185, 1995.

12. Litt, M.; Kramer, P.; Browne, D.; Gancher, S.; Brunt, E. R .P.;
Root, D.; Phromchotikul, T.; Dubay, C. J.; Nutt, J.: A gene for episodic
ataxia/myokymia maps to chromosome 12p13. Am. J. Hum. Genet. 55:
702-709, 1994.

13. Ophoff, R. A.; Terwindt, G. M.; Vergouwe, M. N.; van Eijk, R.;
Oefner, P. J.; Hoffman, S. M. G.; Lamerdin, J. E.; Mohrenweiser, H.
W.; Bulman, D. E.; Ferrari, M.; Haan, J.; Lindhout, D.; van Ommen,
G.-J. B.; Hofker, M. H.; Ferrari, M. D.; Frants, R. R.: Familial
hemiplegic migraine and episodic ataxia type-2 are caused by mutations
in the Ca(2+) channel gene CACNL1A4. Cell 87: 543-552, 1996.

14. Parker, H. L.: Periodic ataxia.In: Hewlett, R. M.; Nevling, A.
B.; Minor, J. R.: Collected Papers of the Mayo Clinic.  Philadelphia:
W. B. Saunders (pub.)  1946. Pp. 642-645.

15. Vahedi, K.; Joutel, A.; Van Bogaert, P.; Ducros, A.; Maciazeck,
J.; Bach, J. F.; Bousser, M. G.; Tournier-Lasserve, E.: A gene for
hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann.
Neurol. 37: 289-293, 1995.

16. Vance, J. M.; Pericak-Vance, M. A.; Payne, C. S.; Coin, J. T.;
Olanow, C. W.: Linkage and genetic analysis in adult onset periodic
vestibulo-cerebellar ataxia: report of a new family. (Abstract) Am.
J. Hum. Genet. 36: 78S, 1984.

17. Vighetto, A.; Froment, J. C.; Trillet, M.; Aimard, G.: Magnetic
resonance imaging in familial paroxysmal ataxia. Arch. Neurol. 45:
547-549, 1988.

18. von Brederlow, B.; Hahn, A. F.; Koopman, W. J.; Ebers, G. C.;
Bulman, D. E.: Mapping the gene for acetazolamide responsive hereditary
paryoxysmal (sic) cerebellar ataxia to chromosome 19p. Hum. Molec.
Genet. 4: 279-284, 1995.

19. White, J. C.: Familial periodic nystagmus, vertigo and ataxia. Arch.
Neurol. 20: 276-280, 1969.

20. Zasorin, N. L.; Baloh, R. W.; Myers, L. B.: Acetazolamide-responsive
episodic ataxia syndrome. Neurology 33: 1212-1214, 1983.

*FIELD* CS

Neuro:
   Episodic ataxia;
   Cerebellar ataxia;
   Vertigo

Eyes:
   Diplopia;
   Downbeat nystagmus

Misc:
   Ataxia precipitated by stress or excitement;
   Response to oral acetazolamide

Radiology:
   Cerebellar vermis atrophy on MRI

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/18/1996
terry: 11/15/1996
mark: 2/7/1996
terry: 2/1/1996
terry: 7/28/1995
mark: 7/12/1995
carol: 11/16/1994
mimadm: 4/18/1994
carol: 5/12/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
108600
*FIELD* TI
*108600 ATAXIA, SPASTIC
*FIELD* TX
Mahloudji (1963) described a rare hereditary syndrome of spastic ataxia,
closely resembling disseminated sclerosis (126200), in 18 persons in an
Iranian family. The pedigree, covering 5 generations, strongly suggests
transmission as an autosomal dominant. It appears to be the same
disorder as was reported by Ferguson and Critchley (1929). Gayle and
Williams (1933) described 17 cases in 4 generations of a disorder
beginning in the sixth decade with stiffness in the leg muscles,
followed by stumbling, dysarthria, and loss of memory. Although
progression to severe spastic paraplegia occurred, the disorder did not
shorten life. These patients lived in Accomac and Northampton counties
on the eastern shore of Virginia. In their classic study into the
genetic nosology of spinocerebellar 'degenerations,' Bell and Carmichael
(1939) classified the conditions as Friedreich ataxia, familial spastic
ataxia, and hereditary spastic paraplegia. They recognized two forms of
familial spastic ataxia, a dominant form with relatively late onset and
a recessive form with onset at ages 10 to 12 years (see 270500). It is
difficult to know whether these dominant and recessive forms are
entities separate from some of the other cerebelloparenchymal,
olivopontocerebellar and spinocerebellar disorders listed here.

*FIELD* RF
1. Bell, J. M.; Carmichael, E. A.: On hereditary ataxia and spastic
paraplegia. . In: Treasury of Human Inheritance.  London: Cambridge
Univ. Press (pub.)  4: 1939. Pp. 141-281.

2. Ferguson, F. R.; Critchley, M.: A clinical study of an heredo-familial
disease resembling disseminated sclerosis. Brain 52: 203-225, 1929.

3. Gayle, R. F., Jr.; Williams, J. P.: A familial disease of the
central nervous system resembling multiple sclerosis. Sth. Med.
J. 26: 242-246, 1933.

4. Mahloudji, M.: Hereditary spastic ataxia simulating disseminated
sclerosis. J. Neurol. Neurosurg. Psychiat. 26: 511-513, 1963.

*FIELD* CS

Neuro:
   Spastic ataxia;
   Spastic paraplegia;
   Stumbling;
   Dysarthria;
   Memory loss

Muscle:
   Leg muscle stiffness

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/17/1994
pfoster: 3/31/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
108650
*FIELD* TI
*108650 ATAXIA, SPASTIC, WITH CONGENITAL MIOSIS
MIOSIS, CONGENITAL, WITH SPASTIC ATAXIA
*FIELD* TX
Sanger Brown (1892) described a kindred with 21 persons in 4 generations
who showed symmetric ataxia of gait and limb movement, dysarthria and
pyramidal signs in the limbs. Three had impaired pupillary reaction to
light; at least 1 developed a disorder of conjugate eye movement. Dick
et al. (1983) described a mother and 3 of her 5 children (2 males, 1
female) with hereditary spastic ataxia combined with congenital miosis.
The affected persons were late in walking unaided and had slurred
speech, small nonreacting pupils, and nystagmus. Deep tendon reflexes
were increased and the plantar reflexes were often extensor.

*FIELD* RF
1. Brown, S.: On hereditary ataxia with a series of twenty-one cases.
Brain 15: 250-268, 1892.

2. Dick, D. J.; Newman, P. K.; Cleland, P. G.: Hereditary spastic
ataxia with congenital miosis: four cases in one family. Brit. J.
Ophthal. 67: 97-101, 1983.

*FIELD* CS

Neuro:
   Spastic ataxia;
   Increased deep tendon reflexes;
   Extensor plantar reflexes;
   Dysarthria

Eyes:
   Congenital miosis;
   Nystagmus;
   Abnormal conjugate eye movement

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
108700
*FIELD* TI
108700 ATAXIA WITH FASCICULATIONS
*FIELD* TX
Singh and Sham (1964) described autosomal dominant inheritance of
progressive ataxia associated with persistent fasciculations of the
muscles of the limbs. Members of 4 sibships in 3 generations were
affected.

*FIELD* RF
1. Singh, H.; Sham, R.: Heredofamilial ataxia with muscle fasciculations
(a report of two cases in brothers). Brit. J. Clin. Pract. 18:
91-92, 1964.

*FIELD* CS

Neuro:
   Ataxia;
   Fasciculation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
108720
*FIELD* TI
108720 ATELOSTEOGENESIS TYPE I; AO I
GIANT CELL CHONDRODYSPLASIA;;
SPONDYLOHUMEROFEMORAL HYPOPLASIA
*FIELD* TX
Atelosteogenesis is the name given by Maroteaux et al. (1982) to a
lethal chondrodysplasia characterized by distal hypoplasia of the humeri
and femurs, hypoplasia of the mid-thoracic spine, occasionally complete
lack of ossification of single hand bones, and the finding in cartilage
of multiple degenerated chondrocytes which are encapsulated in fibrous
tissue. Rimoin et al. (1980) termed it 'giant cell chondrodysplasia.'
Sillence et al. (1982) reported 2 sporadic cases. The fibulae were
absent. Only the distal phalanges of the hands were ossified. They
termed the disorder 'spondylohumerofemoral hypoplasia.' Hypocellular
areas of growth plate cartilage contained occasional multinuclear giant
cells. The genetics is unclear. Maroteaux et al. (1982) pointed to a
case reported by Kozlowski et al. (1981). Clubfoot and elbow or knee
subluxation may be present. Cleft palate has been observed. The patients
are stillborn or die very early of respiratory distress. Yang et al.
(1983) reported an infant in whom the findings were consistent with
atelosteogenesis. A second case also with giant chondrocytes on
histologic examination of bone, severe laryngeal stenosis and lethal
outcome appeared to have some other skeletal dysplasia, an as yet
unclassified form of spondyloepiphyseal dysplasia. Yang et al. (1983)
concluded, and Sillence and Kozlowski (1983) agreed on the basis of
further observations, that giant chondrocytes are not specific to one
lethal skeletal dysplasia. Temple et al. (1990) reviewed 10 reported
cases, all of which had been sporadic, and reported an eleventh case,
that in an infant with first-cousin Bengali parents. Polyhydramnios had
been a complication of pregnancy. Multiple joint dislocations and
radiological features, of which the most characteristic were short,
distally tapering humeri, absent or hypoplastic fibulae, deficient
vertebral ossification with coronal clefting, and anarchic ossification
of phalanges, were described. The disorder that has been called
atelosteogenesis type II (Sillence et al., 1987) may be the same as de
la Chapelle dysplasia (256050). Stern et al. (1990) recommended
discarding the term atelosteogenesis type II, but proposed the term
atelosteogenesis III for a distinct condition (see 108721). Hunter and
Carpenter (1991) reported a case of atelosteogenesis type I. They
concluded that boomerang dysplasia (112310) and AO I are 'part of a
spectrum, probably reflecting a common etiology.' In a male fetus with a
lethal chondrodysplasia, Greally et al. (1993) documented clinical and
radiologic overlap between AO I and boomerang dysplasia. From histologic
examination, they suggested a defect of cartilage and bone formation as
the basic abnormality.

*FIELD* SA
Maroteaux et al. (1982); Stevenson and Wilkes (1983)
*FIELD* RF
1. Greally, M. T.; Jewett, T.; Smith, W. L., Jr.; Penick, G. D.; Williamson,
R. A.: Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis
I and boomerang dysplasia. Am. J. Med. Genet. 47: 1086-1091, 1993.

2. Hunter, A. G. W.; Carpenter, B. F.: Atelosteogenesis I and boomerang
dysplasia: a question of nosology. Clin. Genet. 39: 471-480, 1991.

3. Kozlowski, K.; Tsuruta, T.; Kameda, Y.; Kan, A.; Leslie, G.: New
forms of neonatal death dwarfism: report of 3 cases. Pediat. Radiol. 10:
155-160, 1981.

4. Maroteaux, P.; Spranger, J.; Stanescu, V.; Le Marec, B.; Pfeiffer,
R. A.; Beighton, P.; Mattei, J. F.: Atelosteogenesis. Am. J. Med.
Genet. 13: 15-25, 1982.

5. Maroteaux, P.; Stanescu, V.; Stanescu, R.: Four recently described
osteochondrodysplasias. In: Papadatos, C. J.; Bartsocas, C. S.: Skeletal
Dysplasias.  New York: Alan R. Liss (pub.)  1982. Pp. 345-350.

6. Rimoin, D. L.; Sillence, D. O.; Lachman, R. S.; Jenkins, T.; Riccardi,
V.: Giant cell chondrodysplasia: a second case of a rare lethal newborn
skeletal dysplasia.  (Abstract) Am. J. Hum. Genet. 32: 125A only,
1980.

7. Sillence, D.; Kozlowski, K.: 'Giant cell' chondrodysplasia.  (Letter) Am.
J. Med. Genet. 15: 627 only, 1983.

8. Sillence, D.; Kozlowski, K.; Rogers, J.; Sprague, P.; Cullity,
G.; Osborn, R.: Atelosteogenesis: evidence for heterogeneity. Pediat.
Radiol. 17: 112-118, 1987.

9. Sillence, D. O.; Lachman, R. S.; Jenkins, T.; Riccardi, V. M.;
Rimoin, D. L.: Spondylohumerofemoral hypoplasia (giant cell chondrodysplasia):
a neonatally lethal short-limb skeletal dysplasia. Am. J. Med. Genet. 13:
7-14, 1982.

10. Stern, H. J.; Graham, J. M., Jr.; Lachman, R. S.; Horton, W.;
Bernini, P. M.; Spiegel, P. K.; Bodurtha, J.; Ives, E. J.; Bocian,
M.; Rimoin, D. L.: Atelosteogenesis type III: a distinct skeletal
dysplasia with features overlapping atelosteogenesis and oto-palato-digital
syndrome type II. Am. J. Med. Genet. 36: 183-195, 1990.

11. Stevenson, R. E.; Wilkes, G.: Atelosteogenesis with survival
beyond the neonatal period. Proc. Greenwood Genet. Center 2: 32-38,
1983.

12. Temple, K.; Hall, C. A.; Chitty, L.; Baraitser, M.: A case of
atelosteogenesis. J. Med. Genet. 27: 194-197, 1990.

13. Yang, S. S.; Roskamp, J.; Liu, C. T.; Frates, R.; Singer, D. B.
: Two lethal chondrodysplasias with giant chondrocytes. Am. J. Med.
Genet. 15: 615-625, 1983.

*FIELD* CS

Skel:
   Lethal chondrodysplasia

Limbs:
   Distal humeral and femoral hypoplasia;
   Clubfoot;
   Occasional unossified single hand bone

Spine:
   Mid-thoracic spine hypoplasia

Joints:
   Elbow or knee subluxation

Mouth:
   Cleft palate

Misc:
   Stillborn or early death from respiratory distress

Lab:
   Degenerated fibrous tissue encapsulated chondrocytes;
   Absent fibulae;
   Occasional multinuclear giant cells in hypocellular areas of growth
   plate cartilage;
   Giant chondrocytes

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
carol: 11/22/1993
supermim: 3/16/1992
carol: 7/9/1991
carol: 2/21/1991
carol: 7/9/1990

*RECORD*
*FIELD* NO
108721
*FIELD* TI
108721 ATELOSTEOGENESIS TYPE III; AO III
*FIELD* TX
Stern et al. (1990) described 5 examples of a short-limb dwarfism
syndrome with manifestations overlapping those of atelosteogenesis
(108720) and otopalatodigital syndrome type II (304120). They presented
clinical, radiographic, genetic, and histologic data that demonstrated
differences between these patients and previously reported cases of the
other conditions. Like AO I, this new disorder, designated AO III, has
been observed only in isolated cases, suggesting fresh dominant
mutation. In 1 of the 5 patients with AO III, there was advanced
paternal age consistent with this possibility. On the other hand,
Pyeritz (1993) informed me of a case of affected sibs.

*FIELD* RF
1. Pyeritz, R. E.: Personal Communication. Baltimore, Md.  5/5/1993.

2. Stern, H. J.; Graham, J. M., Jr.; Lachman, R. S.; Horton, W.; Bernini,
P. M.; Spiegel, P. K.; Bodurtha, J.; Ives, E. J.; Bocian, M.; Rimoin,
D. L.: Atelosteogenesis type III: a distinct skeletal dysplasia with
features overlapping atelosteogenesis and oto-palato-digital syndrome
type II. Am. J. Med. Genet. 36: 183-195, 1990.

*FIELD* CS

Growth:
   Short-limb dwarfism

Skel:
   Chondrodysplasia

Limbs:
   Abnormal fibula;
   Foot anomalies

Misc:
   Advanced paternal age;
   All observed cases isolated

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 7/9/1990

*FIELD* ED
mimadm: 4/9/1994
warfield: 4/7/1994
carol: 5/6/1993
supermim: 3/16/1992
carol: 7/9/1990

*RECORD*
*FIELD* NO
108725
*FIELD* TI
108725 ATHEROGENIC LIPOPROTEIN PHENOTYPE; ALP
ATHEROSCLEROSIS SUSCEPTIBILITY; ATHS
*FIELD* TX
The atherogenic lipoprotein phenotype (ALP) is a common heritable trait
characterized by a preponderance of small, dense low density lipoprotein
(LDL) particles (subclass pattern B), increased levels of
triglyceride-rich lipoproteins, reduction in high density lipoprotein,
and a 3-fold increased risk of myocardial infarction. Nishina et al.
(1992) found close linkage between the atherogenic lipoprotein phenotype
and the LDL receptor locus; maximum lod = 4.07 at theta = 0.04, assuming
100% penetrance of the ALP pattern B, and 4.27 at a recombination
fraction of 0.0, assuming 90% penetrance of pattern B. The gene, which
may be the same as the LDLR gene (143890), was symbolized ATHS (for
atherosclerosis susceptibility). It appeared to be located distal to
D19S76 near or at the LDL receptor locus. (Because of the uncertainty as
to whether ATHS represents a gene separate from LDLR, no asterisk is
used with this entry.)

Small dense LDL particles carry a 3-fold increased risk for coronary
artery disease. By utilizing nonparametric quantitative sib-pair and
relative-pair-analysis methods in coronary artery disease families,
Rotter et al. (1996) confirmed linkage to the LDLR locus (P = 0.008). No
evidence of linkage could be found to 6 candidate gene loci: APOB,
APOA2, Lp(a), APOE, lipoprotein lipase, and high-density
lipoprotein-binding protein (142695). Significant evidence for linkage
was found with the CETP locus on chromosome 16 (118470) and the SOD1
locus on chromosome 6 (147450). A suggestion of linkage was found with
the APOA1/APOC3/APOA4 cluster on chromosome 11.

*FIELD* RF
1. Nishina, P. M.; Johnson, J. P.; Naggert, J. K.; Krauss, R. M.:
Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein
receptor locus on the short arm of chromosome 19. Proc. Nat. Acad.
Sci. 89: 708-712, 1992.

2. Rotter, J. I.; Bu, X.; Cantor, R. M.; Warden, C. H.; Brown, J.;
Gray, R. J.; Blanche, P. J.; Krauss, R. M.; Lusis, A. J.: Multilocus
genetic determinants of LDL particle size in coronary artery disease
families. Am. J. Hum. Genet. 58: 585-594, 1996.

*FIELD* CS

Cardiac:
   Increased myocardial infarction risk

Lab:
   Preponderance of small, dense low density lipoprotein (LDL) particles
   (subclass pattern B);
   Increased triglyceride-rich lipoproteins;
   Reduced high density lipoprotein

Inheritance:
   Autosomal dominant;
   ? same as LDLR

*FIELD* CD
Victor A. McKusick: 2/17/1992

*FIELD* ED
mark: 03/10/1996
terry: 3/5/1996
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/17/1992

*RECORD*
*FIELD* NO
108728
*FIELD* TI
*108728 ATP CITRATE LYASE; ACLY
CLATP;;
ATPCL
*FIELD* TX
ATP citrate lyase is the primary enzyme responsible for the synthesis of
cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative
molecular weight approximately 440,000) of apparently identical
subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from
citrate and CoA with a concomitant hydrolysis of ATP to ADP and
phosphate. The product, acetyl-CoA, serves several important
biosynthetic pathways, including lipogenesis and cholesterogenesis. In
nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of
acetylcholine. Cloning of cDNAs has been reported for murine (Sul et
al., 1984), rat (Elshourbagy et al., 1990), and human (Elshourbagy et
al., 1992) ATP citrate lyase. Elshourbagy et al. (1992) found that the
subunits of the enzyme have 1,105 amino acids and a calculated molecular
mass of 121,419 Da. The human and rat ATPCL cDNAs showed 96.3% amino
acid identity.

Remmers et al. (1992) found that the genes for growth hormone (139250),
pancreatic polypeptide (167780), ERBB2 (164870), sex hormone binding
globulin (182205), embryonic skeletal myosin heavy chain (160720), and
asialoglycoprotein receptor (108360) map to human chromosome 17 and rat
chromosome 10. Many of the same genes are known to be located on mouse
chromosome 11. Furthermore, Remmers et al. (1992) showed that in the rat
the gene for ATP citrate lyase is closely linked to the gene for PPY,
which in turn is close to the GH gene, on chromosome 10. They predicted,
therefore, that the homologous gene in the human would be located on
chromosome 17, probably close to PPY which is situated at 17q22-q24.
Couch et al. (1994) mapped the ACLY gene to 17q12-q21 by PCR analysis of
a panel of human/rodent somatic cell hybrids and localized it to 17q21.1
by PCR on a panel of radiation hybrids. The radiation hybrid panel
indicated that the most likely position of ACLY on 17q21.1 is between
gastrin (137250) and D17S856 at a distance of 170 to 290 kb from the GAS
locus.

*FIELD* RF
1. Couch, F. J.; Abel, K. J.; Brody, L. C.; Boehnke, M.; Collins,
F. S.; Weber, B. L.: Localization of the gene for ATP citrate lyase
(ACLY) distal to gastrin (GAS) and proximal to D17S856 on chromosome
17q12-q21. Genomics 21: 444-446, 1994.

2. Elshourbagy, N. A.; Near, J. C.; Kmetz, P. J.; Sathe, G. M.; Southan,
C.; Strickler, J. E.; Gross, M.; Young, J. F.; Wells, T. N. C.; Groot,
P. H. E.: Rat ATP citrate-lyase: molecular cloning and sequence analysis
of a full-length cDNA and mRNA abundance as a function of diet, organ,
and age. J. Biol. Chem. 265: 1430-1435, 1990.

3. Elshourbagy, N. A.; Near, J. C.; Kmetz, P. J.; Wells, T. N. C.;
Groot, P. H. E.; Saxty, B. A.; Hughes, S. A.; Franklin, M.; Gloger,
I. S.: Cloning and expression of a human ATP-citrate lyase cDNA.
Europ. J. Biochem. 204: 491-499, 1992.

4. Remmers, E. F.; Goldmuntz, E. A.; Cash, J. M.; Crofford, L. J.;
Misiewicz-Poltorak, B.; Zha, H.; Wilder, R. L.: Genetic map of nine
polymorphic loci comprising a single linkage group on rat chromosome
10: evidence for linkage conservation with human chromosome 17 and
mouse chromosome 11. Genomics 14: 618-623, 1992.

5. Sul, H. S.; Wise, L. S.; Brown, M. L.; Rubin, C. S.: Cloning of
cDNA sequences for murine ATP-citrate lyase: construction of recombinant
plasmids using an immunopurified mRNA template and evidence for the
nutritional regulation of ATP-citrate lyase mRNA content in mouse
liver. J. Biol. Chem. 259: 1201-1205, 1984.

*FIELD* CD
Victor A. McKusick: 11/4/1992

*FIELD* ED
mark: 05/20/1996
jason: 6/9/1994
carol: 4/9/1994
carol: 12/31/1992
carol: 12/16/1992
carol: 11/12/1992
carol: 11/4/1992

*RECORD*
*FIELD* NO
108729
*FIELD* TI
*108729 ATP SYNTHASE, MITOCHONDRIAL, GAMMA SUBUNIT; ATP5C
ATP SYNTHASE, H+ TRANSPORTING, MITOCHONDRIAL F1 COMPLEX, GAMMA POLYPEPTIDE;;
1; ATP5C1
*FIELD* TX
Mitochondria provide most of ATP for eukaryotic cells by oxidative
phosphorylation. Mitochondrial ATP synthase catalyzes ATP synthesis,
utilizing an electrochemical gradient of protons across the inner
membrane during oxidative phosphorylation. The catalytic portion of
mitochondrial ATP synthase consists of 5 different subunits (alpha,
beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3
alpha, 3 beta, and a single representative of the other 3. The gamma
subunit is encoded by the nuclear genome. Matsuda et al. (1993) reported
the complete sequence of the gene for the human ATP synthase gamma
subunit and described tissue-specific isoforms of the subunit generated
by alternative splicing of exon 9. The liver (L) isoform differed from
the heart (H) isoform by the addition of a single amino acid (asp273) at
the C terminus.

By somatic cell hybrid analysis, Jabs et al. (1994) mapped human
homologs of the rat liver gamma subunit of the ATP synthase gene (ATP5C)
to 2 different chromosomes, 10 and 14. It was not known if 1 of the 2
subunits is a pseudogene or if there are 2 isoforms of the subunit in
the human.

*FIELD* RF
1. Jabs, E. W.; Thomas, P. J.; Bernstein, M.; Coss, C.; Ferreira,
G. C.; Pedersen, P. L.: Chromosomal localization of genes required
for the terminal steps of oxidative metabolism: alpha and gamma subunits
of ATP synthase and the phosphate carrier. Hum. Genet. 93: 600-602,
1994.

2. Matsuda, C.; Endo, H.; Ohta, S.; Kagawa, Y.: Gene structure of
human mitochondrial ATP synthase gamma-subunit: tissue specificity
produced by alternative RNA splicing. J. Biol. Chem. 268: 24950-24958,
1993.

*FIELD* CD
Victor A. McKusick: 2/3/1995

*FIELD* ED
carol: 2/3/1995

*RECORD*
*FIELD* NO
108730
*FIELD* TI
*108730 ATPase, Ca(2+)-TRANSPORTING, FAST-TWITCH; ATP2A1
SARCOPLASMIC RETICULUM Ca(2+)-ATPase; SERCA1
*FIELD* TX
MacLennan et al. (1987) found that a rabbit cDNA for the fast-twitch
ATPase hybridizes to a prominent single fragment in human genomic DNA
digested with the restriction enzyme BamHI. By correlating the presence
of this fragment in somatic cell hybrid DNA with the human chromosome
content of the hybrids, they assigned the fast-twitch ATPase gene to
human chromosome 16. The function of calcium-transporting ATPase found
in different membranes is to lower cytoplasmic Ca(2+) concentration by
pumping Ca(2+) to luminal or extracellular spaces. Although there has
long been evidence of differences between the Ca(2+) ATPase found in
fast-twitch skeletal muscle fibers and those of slow-twitch/cardiac
fibers, the differences were not clarified until cDNAs encoding the 2
forms were cloned and sequenced (Brandl et al., 1986). The proteins bear
84% amino acid sequence identity and 76% nucleic acid sequence homology.
Coding for these 2 proteins is clearly carried out by different genes
which are presumably related to one another by an ancient gene
duplication event.

MacLennan et al. (1987) suggested that this gene, located on chromosome
16, may be the site of the mutation in Brody disease, an unusual,
apparently familial disorder characterized by increasing impairment of
muscular relaxation during exercise (Brody, 1969). Parental
consanguinity in the family of Karpati et al. (1986) suggests autosomal
recessive inheritance in at least some of the patients with Brody
disease. A deficiency of Ca(2+) transport ATPase activity in the
sarcoplasmic reticulum of fast-twitch but not slow-twitch skeletal
muscle has been demonstrated (Karpati et al., 1986). Probable autosomal
dominant inheritance was found in the family reported by Danon et al.
(1988): the mother, her son, and 2 daughters suffered from impaired
muscle relaxation aggravated by exercise. Muscle biopsies from the 2
sisters showed a moderate degree of atrophy of type 2 fibers and an
excess of internal nuclei. Microscopic immunocytochemistry, using a
monoclonal antibody raised against purified chicken sarcoplasmic
reticulum adenosine triphosphatase, showed severe reduction of
immunoreactive protein limited to type 2 fibers. Immunoreactive
Ca(2+)-ATPase of sarcoplasmic reticulum was markedly decreased on
Western blots of muscle proteins. Although clinically,
electromyographically, and biochemically similar to the other cases, the
mode of inheritance was apparently different. Benders et al. (1994)
found 12 reported cases. They concluded that the clinical signs and
symptoms are not specific. Exercise-induced impairment of muscle
relaxation, stiffening and cramps, and muscle pain had been described.
These symptoms were sometimes exacerbated in the cold and were referred
to as pseudo-myotonia. Benders et al. (1994) detected 10 patients with
Brody disease in 7 different families. Two were brother and sister, 2
others were brothers, and yet 2 others were mother and son. One of the
patients had previously been reported by Wevers et al. (1992) and Poels
et al. (1993). For all patients, myotonia was excluded by
electromyography. Glycolytic, mitochondrial, and lipid storage
myopathies were also excluded by appropriate investigations. Impaired
muscle relaxation was absent in 4 patients and in a patient reported by
Taylor et al. (1988). A disturbance in ion transport could lead to this
disorder. In muscle, an action potential is associated with an influx of
Na(+) and an efflux of K(+). This depolarization of the sarcolemma
induces a Ca(2+) release from the sarcoplasmic reticulum (SR) into the
cytosol, causing muscle contraction. After excitation of skeletal
muscle, ATP-dependent ion pumps restore the disturbed ion homeostasis.
SR Ca(2+)-ATPase transports Ca(2+) from the cytosol into the lumen of
the SR, and Na(+)/K(+)-dependent ATPase re-uptakes K(+) from the
interstitial fluid into the muscle and releases Na(+). Referring to the
fast-twitch muscle cytoplasmic reticulum Ca(2+)-ATPase isoform as
SERCA1, Benders et al. (1994) studied its activity in both quadriceps
muscle and cultured muscle cells. The enzyme activity was decreased by
approximately 50% in patients with Brody myopathy. The concentration of
the protein was normal, however, implying reduction in the molecular
activity of SERCA1 in Brody disease. Studies in cultured cells suggested
a beneficial clinical effect from dantrolene or verapamil.

Zhang et al. (1995) appeared to have excluded the ATP2A1 gene as the
site of the mutation causing Brody disease. They isolated and
characterized genomic DNA and cDNA encoding human SERCA1, i.e., the
ATP2A1 gene. The cDNA encoded 994 amino acids. The genomic DNA is 26 kb
long and contains 23 exons, 1 of which can be alternatively spliced. The
locations of each of the exon/intron boundaries are the same as those
previously identified in the rabbit ATP2A1 gene. Zhang et al. (1995)
sequenced the exons of the ATP2A1 gene in the patient shown by Karpati
et al. (1986) to be deficient in SERCA1 protein and Ca(2+)-ATPase
activity in type 2 muscle fibers and found no mutation. They also
sequenced full-length cDNAs for SERCA1 in 2 other, unrelated Brody
patients; again, no sequence abnormality was discovered. In all 3 cases,
the coding and splice junction sequences were normal.

During the course of mapping the gene for Batten disease (204200) to
16p12.1-p11.2, Callen et al. (1991) mapped ATP2A to the same region just
distal to the fragile site FRA16E. This was accomplished by physical
mapping of markers linked to CLN3 and ATP2A using somatic cell hybrid
analysis and in situ hybridization. Schleef et al. (1996) mapped the
Atp2a1 gene to mouse chromosome 7 by analysis of an interspecific
backcross.

Odermatt et al. (1996) demonstrated mutations in the ATP2A1 gene in 2
families with autosomal recessive inheritance of Brody myopathy. One
mutation occurred in the splice donor site of intron 3 (108730.0003),
while the other 2 mutations (108730.0001, 108730.0002) led to premature
stop codons, truncating a CRCA1 and deleting essential functional
domains. This raised the question of how patients with Brody myopathy
partially compensate for functional knockout of a gene product believed
to be essential for fast-twitch skeletal muscle relaxation.

*FIELD* AV
.0001
BRODY MYOPATHY
ATP2A1, ARG198TER
In a family with 3 individuals affected with autosomal recessive Brody
myopathy, Odermatt et al. (1996) found that although no consanguinity
was known in the family the parents contained the same haplotype for the
6.6-cM interval between markers D16S288 and D16S304. The affected
patients inherited this common haplotype from each parent. A C-to-T
transition of nucleotide 592 was found, resulting in a change of codon
198 from CGA (arg) to TGA (stop). The authors stated that the truncated
product would be devoid of phosphorylation, nucleotide binding, and
Ca(2+) binding domains.

.0002
BRODY MYOPATHY
ATP2A1, CYS675TER
In a family with 2 sibs affected by Brody myopathy, Odermatt et al.
(1996) demonstrated that the affected brothers were compound
heterozygotes for a cys675-to-ter (C675X) mutation and a mutation of the
invariant GT dinucleotide to CT at the splice donor site of intron 3 of
the maternally inherited chromosome (108730.0003). The paternally
inherited C675X mutation was predicted to lead to a truncated protein of
674 amino acids. The truncated gene product was predicted to contain
phosphorylation and nucleotide binding domains, but the Ca(2+) binding
domain would be disrupted. The maternally inherited splice mutation was
predicted to lead to the preferential skipping of exon 3 and less
frequently to partial retention of intron 3. If exon 2 were spliced to
exon 4 and transcribed, the product would be truncated; if intron 3 were
partially retained and transcribed, the product would also be truncated.
Both gene products would be missing phosphorylation, nucleotide binding,
and Ca(2+) binding domains.

.0003
BRODY MYOPATHY
ATP2A1, IVS3DS G-C, -2
See 108730.0002 and Odermatt et al. (1996).

*FIELD* RF
1. Benders, A. A. G. M.; Veerkamp, J. H.; Oosterhof, A.; Jongen, P.
J. H.; Bindels, R. J. M.; Smit, L. M. E.; Busch, H. F. M.; Wevers,
R. A.: Ca(2+) homeostasis in Brody's disease: a study in skeletal
muscle and cultured muscle cells and the effects of dantrolene and
verapamil. J. Clin. Invest. 94: 741-748, 1994.

2. Brandl, C. J.; Green, N. M.; Korczak, B.; MacLennan, D. H.: Two
Ca(2+) ATPase genes: homologies and mechanistic implications of deduced
amino acid sequences. Cell 44: 597-607, 1986.

3. Brody, I. A.: Muscle contracture induced by exercise: a syndrome
attributable to decreased relaxing factor. New Eng. J. Med. 281:
187-192, 1969.

4. Callen, D. F.; Baker, E.; Lane, S.; Nancarrow, J.; Thompson, A.;
Whitmore, S. A.; MacLennan, D. H.; Berger, R.; Cherif, D.; Jarvela,
I.; Peltonen, L.; Sutherland, G. R.; Gardiner, R. M.: Regional mapping
of the Batten disease locus (CLN3) to human chromosome 16p12. Am.
J. Hum. Genet. 49: 1372-1377, 1991.

5. Danon, M. J.; Karpati, G.; Charuk, J.; Holland, P.: Sarcoplasmic
reticulum adenosine triphosphatase deficiency with probable autosomal
dominant inheritance. Neurology 38: 812-815, 1988.

6. Karpati, G.; Charuk, J.; Carpenter, S.; Jablecki, C.; Holland,
P.: Myopathy caused by a deficiency of Ca(2+)-adenosine triphosphatase
in sarcoplasmic reticulum (Brody's disease). Ann. Neurol. 20: 38-49,
1986.

7. MacLennan, D. H.; Brandl, C. J.; Champaneria, S.; Holland, P. C.;
Powers, V. E.; Willard, H. F.: Fast-twitch and slow-twitch/cardiac
Ca(2+) ATPase genes map to human chromosomes 16 and 12. Somat. Cell
Molec. Genet. 13: 341-346, 1987.

8. Odermatt, A.; Taschner, P. E. M.; Khanna, V. K.; Busch, H. F. M.;
Karpati, G.; Jablecki, C. K.; Breuning, M. H.; MacLennan, D. H.:
Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle
sarcoplasmic reticulum Ca(2+) ATPase, are associated with Brody disease. Nature
Genet. 14: 191-194, 1996.

9. Poels, P. J. E.; Wevers, R. A.; Braakhekke, J. P.; Benders, A.
A. G. M.; Veerkamp, J. H.; Joosten, E. M. G.: Exertional rhabdomyolysis
in a patient with calcium adenosine triphosphatase deficiency. J.
Neurol. Neurosurg. Psychiat. 56: 823-826, 1993.

10. Schleef, M.; Simon-Chazottes, D.; Lengeling, A.; Klocke, R.; Jockusch,
H.; Yarden, Y.; Guenet, J.-L.: The gene encoding sarcoplasmic reticulum
calcium ATPase-1 (Atp2a1) maps to distal mouse chromosome 7. Mammalian
Genome 7: 788 only, 1996.

11. Taylor, D. J.; Brosnan, M. J.; Arnold, D. L.; Bore, P. J.; Styles,
P.; Walton, J.; Radda, G. K.: Ca(2+)-ATPase deficiency in a patient
with an exertional muscle pain syndrome. J. Neurol. Neurosurg. Psychiat. 51:
1425-1433, 1988.

12. Wevers, R. A.; Poels, P. J. E.; Joosten, E. M. G.; Steenbergen,
G. G. H.; Benders, A. A. G. M.; Veerkamp, J. H.: Ischaemic forearm
testing in a patient with Ca(2+)-ATPase deficiency. J. Inherit. Metab.
Dis. 15: 423-425, 1992.

13. Zhang, Y.; Fujii, J.; Phillips, M. S.; Chen, H.-S.; Karpati, G.;
Yee, W.-C.; Schrank, B.; Cornblath, D. R.; Boyland, K. B.; MacLennan,
D. H.: Characterization of cDNA and genomic DNA encoding SERCA1,
the Ca(2+)-ATPase of human fast-twitch skeletal muscle sarcoplasmic
reticulum, and its elimination as a candidate gene for Brody disease. Gemomics 30:
415-424, 1995.

*FIELD* CD
Victor A. McKusick: 11/13/1987

*FIELD* ED
terry: 12/10/1996
mark: 9/30/1996
terry: 9/30/1996
mark: 2/19/1996
terry: 2/15/1996
mark: 1/21/1996
terry: 1/18/1996
carol: 10/10/1994
carol: 10/15/1992
supermim: 3/16/1992
carol: 7/10/1991
carol: 1/10/1991
carol: 9/9/1990

*RECORD*
*FIELD* NO
108731
*FIELD* TI
*108731 ATPase, Ca(2+)-TRANSPORTING, PLASMA MEMBRANE, 1; ATP2B1
PLASMA MEMBRANE Ca(2+)-ATPase, TYPE 1; PMCA1
*FIELD* TX
The human plasma membrane Ca(2+)-ATPase (PMCA) isoforms are encoded by
at least 4 separate genes and the diversity of these enzymes is further
increased by alternative splicing of transcripts. These enzymes are
members of the P class of ion-motive ATPases; they form an acylphosphate
intermediate as part of the reaction mechanism. PMCA removes bivalent
calcium ions from eukaryotic cells and plays a critical role in
intracellular calcium homeostasis by its capacity for removing calcium
ions from cells against very large concentration gradients. Olson et al.
(1991) used cloned cDNAs for the PMCA1 isoform to map its gene,
symbolized ATP2B1, to 12q21-q23 by 3 independent methods: Southern
analysis of human-rodent somatic cell hybrids, in situ hybridization of
human metaphase spreads, and genetic linkage analysis in the CEPH
pedigrees. Three other PMCAs have been mapped: ATP2A1 (108730) to
chromosome 16, ATP2A2 (108740) to chromosome 12, and ATP2B2 (108732) to
chromosome 1.

*FIELD* RF
1. Olson, S.; Wang, M. G.; Carafoli, E.; Strehler, E. E.; McBride,
O. W.: Localization of two genes encoding plasma membrane Ca(2+)-transporting
ATPases to human chromosomes 1q25-32 and 12q21-23. Genomics 9:
629-641, 1991.

*FIELD* CD
Victor A. McKusick: 2/1/1991

*FIELD* ED
carol: 10/15/1992
supermim: 3/16/1992
carol: 2/27/1992
carol: 7/2/1991
carol: 3/22/1991
carol: 2/4/1991

*RECORD*
*FIELD* NO
108732
*FIELD* TI
*108732 ATPase, Ca(2+)-TRANSPORTING, PLASMA MEMBRANE, 4; ATP2B4
ATP2B2, FORMERLY;;
PLASMA MEMBRANE Ca(2+)-ATPase, TYPE 4; PMCA4
*FIELD* TX
The plasma membrane Ca(2+)-transporting ATPase designated as PMCA4 was
mapped to 1q25-q32 by Olson et al. (1991) by 3 independent methods:
Southern analysis of human-rodent somatic cell hybrids, in situ
hybridization of human metaphase spreads, and genetic linkage analysis
in the CEPH pedigrees. No evidence was obtained for multiple copies of
the gene at this locus; however, a cross-hybridizing sequence was
detected on Xq13-qter at low stringency. Further studies were required
to determine whether the X-chromosomal sequence represented another
member of the PMCA gene family.

*FIELD* RF
1. Olson, S.; Wang, M. G.; Carafoli, E.; Strehler, E. E.; McBride,
O. W.: Localization of two genes encoding plasma membrane Ca(2+)-transporting
ATPases to human chromosomes 1q25-32 and 12q21-23. Genomics 9:
629-641, 1991.

*FIELD* CD
Victor A. McKusick: 2/1/1991

*FIELD* ED
carol: 10/15/1992
carol: 8/28/1992
supermim: 3/16/1992
carol: 2/27/1992
carol: 7/2/1991
carol: 3/22/1991

*RECORD*
*FIELD* NO
108733
*FIELD* TI
*108733 ATPase, Ca(2+)-TRANSPORTING, PLASMA MEMBRANE, 2; ATP2B2
PLASMA MEMBRANE Ca(2+)-ATPase, TYPE 2; PMCA2
*FIELD* TX
The Ca(2+)-ATPases are a family of plasma membrane pumps that are
encoded by at least 4 genes. Brandt et al. (1992) isolated and
characterized a cDNA for the human version of the PMCA2 isoform. The
human and rat cDNA sequences showed 95% identity in the coding domain
and this homology was reflected in the deduced protein sequence which
showed greater than 98% identity. Using the PMCA2 cDNA to probe Southern
blots of human-rodent somatic cell hybrid DNAs, Brandt et al. (1992)
found that the PMCA2 gene is located on human chromosome 3. Richards et
al. (1993) reported that the PMCA2 gene, which is located on 3p, is
situated centromeric to the gene for von Hippel-Lindau disease (VHL;
193300). They reported other results that excluded PMCA2 as the site of
the mutation in VHL.

By a combination of fluorescence in situ hybridization, analysis of
somatic cell hybrids, and genetic linkage analysis in CEPH families,
Wang et al. (1994) confirmed assignment of the ATP2B2 gene to 3p26-p25.

*FIELD* RF
1. Brandt, P.; Ibrahim, E.; Bruns, G. A. P.; Neve, R. L.: Determination
of the nucleotide sequence and chromosomal localization of the ATP2B2
gene encoding human Ca(2+)-pumping ATPase isoform PMCA2. Genomics 14:
484-487, 1992.

2. Richards, F. M.; Phipps, M. E.; Latif, F.; Yao, M.; Crossey, P.
A.; Foster, K.; Linehan, W. M.; Affara, N. A.; Lerman, M. I.; Zbar,
B.; Ferguson-Smith, M. A.; Maher, E. R.: Mapping the von Hippel-Lindau
disease tumour suppressor gene: identification of germline deletions
by pulsed field gel electrophoresis. Hum. Molec. Genet. 2: 879-882,
1993.

3. Wang, M. G.; Yi, H.; Hilfiker, H.; Carafoli, E.; Strehler, E. E.;
McBride, O. W.: Localization of two genes encoding plasma membrane
Ca(2+)-ATPases isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes
3p26-p25 and Xq28, respectively. Cytogenet. Cell Genet. 67: 41-45,
1994.

*FIELD* CD
Victor A. McKusick: 10/15/1992

*FIELD* ED
terry: 10/10/1994
jason: 7/5/1994
carol: 8/17/1993
carol: 10/15/1992

*RECORD*
*FIELD* NO
108740
*FIELD* TI
*108740 ATPase, Ca(2+)-DEPENDENT, SLOW-TWITCH/CARDIAC MUSCLE; ATP2A2; ATP2B
*FIELD* TX
Lytton and MacLennan (1988) cloned, from human kidney, cDNAs coding for
2 alternatively spliced products of the cardiac Ca(2+)-ATPase gene. The
difference between the 2 proteins is the replacement of the
carboxyl-terminal 4 amino acids in one by an extended sequence of 49
amino acids in the other. See 108730. MacLennan et al. (1987) mapped the
slow-twitch ATPase gene to chromosome 12. By fluorescence in situ
hybridization, Otsu et al. (1993) demonstrated that the ATP2A2 gene,
which encodes the SERCA2 isoform of the Ca(2+) pump, maps to
12q23-q24.1.

*FIELD* RF
1. Lytton, J.; MacLennan, D. H.: Molecular cloning of cDNAs from
human kidney coding for two alternatively spliced products of the
cardiac Ca(2+)-ATPase gene. J. Biol. Chem. 263: 15024-15031, 1988.

2. MacLennan, D. H.; Brandl, C. J.; Champaneria, S.; Holland, P. C.;
Powers, V. E.; Willard, H. F.: Fast-twitch and slow-twitch/cardiac
Ca(2+) ATPase genes map to human chromosomes 16 and 12. Somat. Cell
Molec. Genet. 13: 341-346, 1987.

3. Otsu, K.; Fujii, J.; Periasamy, M.; Difilippantonio, M.; Uppender,
M.; Ward, D. C.; MacLennan, D. H.: Chromosome mapping of five human
cardiac and skeletal muscle sarcoplasmic reticulum protein genes.
Genomics 17: 507-509, 1993.

*FIELD* CD
Victor A. McKusick: 11/13/1987

*FIELD* ED
carol: 8/23/1993
carol: 10/16/1992
supermim: 3/16/1992
carol: 7/10/1991
carol: 9/9/1990
carol: 6/11/1990

*RECORD*
*FIELD* NO
108745
*FIELD* TI
*108745 ATPase, H+ TRANSPORTING, LYSOSOMAL; ATP6C
VACUOLAR PROTON PUMP
*FIELD* TX
In an attempt to isolate candidate genes for autosomal dominant
polycystic kidney disease (PKD1; 173900), Gillespie et al. (1991)
identified a number of CpG-rich islands from a region defined
genetically as the site of the PKD1 mutation. Genomic fragments adjacent
to one of these islands were used to isolate cDNAs from both HeLa cells
and cultured cystic epithelium that encode a 155-amino acid peptide
having 4 putative transmembrane domains. The corresponding transcript
was found in all tissues tested but was most abundant in brain and
kidney. The deduced amino acid sequence had 93% similarity to the 16-kD
proteolipid component that is believed to be part of the proton channel
of the vacuolar H(+)-ATPase. A mutated proton channel might be
implicated in the pathogenesis of cystic disease. However, sequencing of
cDNAs corresponding to both alleles of an affected person revealed no
differences in the deduced amino acid sequence. Moreover, transcript
size and abundance were not altered in cystic kidney.

*FIELD* RF
1. Gillespie, G. A. J.; Somlo, S.; Germino, G. G.; Weinstat-Saslow,
D.; Reeders, S. T.: CpG island in the region of an autosomal dominant
polycystic kidney disease locus defines the 5-prime end of a gene
encoding a putative proton channel. Proc. Nat. Acad. Sci. 88: 4289-4293,
1991.

*FIELD* CD
Victor A. McKusick: 12/22/1993

*FIELD* ED
carol: 12/22/1993

*RECORD*
*FIELD* NO
108746
*FIELD* TI
*108746 ATPase, H+ TRANSPORTING, VACUOLAR, E SUBUNIT; ATP6E
*FIELD* TX
Baud et al. (1994) isolated heterogeneous nuclear RNA from somatic cell
hybrids selected for their chromosome 22 content. Inter-Alu PCR
amplification yielded a series of human DNA fragments that detected
evolutionarily conserved sequences. The gene fragment closest to the
centromere, designated XEN61, was found to be present in 4 copies in 6
patients with the cat eye syndrome (115470), a disorder of known partial
trisomy of 22pter-q11.2. A fetal brain cDNA clone was identified with
XEN61 and completely sequenced. The deduced protein was the E subunit of
vacuolar H(+)-ATPase. This 31-kD component of a proton pump is essential
in eukaryotic cells because it both controls acidification of the
vacuolar system and provides it with its main protonmotive force. RT-PCR
experiments indicated that the corresponding mRNA is widely transcribed.

*FIELD* RF
1. Baud, V.; Mears, A. J.; Lamour, V.; Scamps, C.; Duncan, A. M. V.;
McDermid, H. E.; Lipinski, M.: The E subunit of vacuolar H(+)-ATPase
localizes close to the centromere on human chromosome 22. Hum. Molec.
Genet. 3: 335-339, 1994.

*FIELD* CD
Victor A. McKusick: 5/2/1994

*FIELD* ED
carol: 5/2/1994

*RECORD*
*FIELD* NO
108760
*FIELD* TI
*108760 ATRESIA OF EXTERNAL AUDITORY CANAL AND CONDUCTION DEAFNESS
*FIELD* TX
Hefter and Ganz (1969) described this combination in a woman and 3 of
her 4 children. The bony stenosis of the external meatus was so marked
that the eardrums were not visible. The mastoid processes were found to
be poorly pneumatized on radiography. At surgery the middle ear
structures were found to be in various stages of hypoplasia or aplasia.
Robinow and Jahrsdoerfer (1979) observed an extensively affected kindred
with several instances of male-to-male transmission. Stenosis rather
than atresia of the auditory canal was present in some.

*FIELD* RF
1. Hefter, E.; Ganz, H.: Bericht ueber vererbte Gehoergangsmissbildungen.
HNO 17: 76-78, 1969.

2. Robinow, M.; Jahrsdoerfer, R. A.: Autosomal dominant atresia of
the auditory canal and conductive deafness. Am. J. Med. Genet. 4:
89-94, 1979.

*FIELD* CS

Ears:
   Conductive hearing loss;
   External auditory canal stenosis/atresia;
   Hypoplastic/aplastic middle ear structures

Radiology:
   Mastoid processes poorly pneumatized

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
108770
*FIELD* TI
108770 ATRIAL CARDIOMYOPATHY WITH HEART BLOCK
CARDIOMYOPATHY, FAMILIAL, WITH CONDUCTION DISTURBANCE
*FIELD* TX
In 3 of 5 sibs and in the son of 1 of the 3 sibs (a male), Williams et
al. (1972) found first-degree heart block and ectopic supraventricular
rhythms progressing to persistent standstill with complete loss of
response to direct atrial stimulation. The extensively affected kindred
reported by Amat-y-Leon et al. (1974) may have had the same condition.
Familial atrial standstill is characteristic of amyloidosis type III
(176300.0007), also known as the Danish or cardiac form. Ward et al.
(1984) described a brother and sister, aged 15 months and 3.5 years,
respectively, with atrial standstill and inexcitability. Autopsy in the
boy showed endocardial fibroelastosis of atria and ventricles. See also
entries 115080 and 163800. Shah et al. (1992) reported the cases of
adult sisters with total atrial standstill.

Kass et al. (1994) found linkage to markers near the centromere of
chromosome 1 in affected members of a family with conduction system
disease beginning in the second and third decades and later development
of dilated cardiomyopathy; see 115200.

*FIELD* RF
1. Amat-y-Leon, F.; Racki, A. J.; Denes, P.; Ten Eick, R. E.; Singer,
D. H.; Baharati, S.; Lev, M.; Rosen, K. M.: Familial atrial dysrhythmia
with A-V block: intracellular microelectrode, clinical electrophysiologic,
and morphologic observations. Circulation 50: 1097-1104, 1974.

2. Kass, S.; MacRae, C.; Graber, H. L.; Sparks, E. A.; McNamara, D.;
Boudoulas, H.; Basson, C. T.; Baker, P. B., III; Cody, R. J.; Fishman,
M. C.; Cox, N.; Kong, A.; Wooley, C. F.; Seidman, J. G.; Seidman,
C. E.: A gene defect that causes conduction system disease and dilated
cardiomyopathy maps to chromosome 1p1-1q1. Nature Genet. 7: 546-551,
1994.

3. Shah, M. K.; Subramanyan, R.; Tharakan, J.; Venkitachalam, C. G.;
Balakrishnan, K. G.: Familial total atrial standstill. Am. Heart
J. 123: 1379-1382, 1992.

4. Ward, D. E.; Ho, S. Y.; Shinebourne, E. A.: Familial atrial standstill
and inexcitability in childhood. Am. J. Cardiol. 53: 965-967, 1984.

5. Williams, D. O.; Jones, E. L.; Nagle, B.; Smith, S.: Familial
atrial cardiomyopathy with heart block. Quart. J. Med. 41: 491-508,
1972.

*FIELD* CS

Cardiac:
   First-degree heart block;
   Ectopic supraventricular rhythms;
   Atrial standstill;
   Atrial inexcitability;
   Atrial cardiomyopathy

Lab:
   Endocardial fibroelastosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 11/8/1994
mimadm: 4/9/1994
carol: 6/19/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/20/1990

*RECORD*
*FIELD* NO
108780
*FIELD* TI
*108780 NATRIURETIC PEPTIDE PRECURSOR A; NPPA
ATRIAL NATRIURETIC POLYPEPTIDES; ANP;;
CARDIONATRIN;;
ATRIONATRIURETIC FACTOR;;
ATRIAL NATRIURETIC FACTOR; ANF;;
PRONATRIODILATIN; PND;;
ATRIOPEPTIN
*FIELD* TX
From human as well as rat atrial tissue, peptides of
natriuretic-diuretic activity have been identified and implicated in the
control of extracellular fluid volume and electrolyte homeostasis. There
are multiple forms of these so-called atrial natriuretic polypeptides
(ANP), ranging in molecular weight from 3,000 to 13,000, and it has been
suggested that all may derive from the same precursor. Working from
established amino acid sequence of human alpha-ANP, a 28-residue peptide
with potent natriuretic action, Oikawa et al. (1984) elucidated the
structure of its precursor and the gene encoding it. The cDNA encodes
gamma-ANP, a polypeptide of 13,000 MW, whose C-terminal 28 amino acids
are processed as alpha-ANP. From the work of Zivin et al. (1984), atrial
natriuretic factor (ANF) appears to be synthesized as a large precursor,
atrial pronatriodilatin. The cDNA has an open reading frame potentially
encoding a protein of 152 amino acids, of which the first 24 amino acids
strongly resemble a signal sequence. This is followed by a sequence with
80% homology to a second vasoactive protein, porcine cardiodilatin. The
ANF peptide is contained in the COOH-terminal portion of the protein.
The diagram of silver grains from the in situ hybridization studies of
Yang-Feng et al. (1985) suggested localization in 1p36.2; 1p36.3 carried
the next most grains, with 1p36.1 in third place. Quirion et al. (1986)
found high density of ANP binding sites in various regions of the brain
and suggested the existence of a family of heart-brain peptides, in
analogy to the well-known brain-gut peptides. Furthermore, the wide
distribution of ANP binding sites suggested that the role of ANP may not
be limited to central regulation of cardiovascular functions. Johansson
et al. (1987) showed that the amyloid that is commonly deposited in the
atria in older persons has the immunologic properties of ANP and is
presumably derived from that peptide. Sachse et al. (1988) reported on
the construction of synthetic ANF genes for both the human and rat
molecules. The synthetic genes were cloned into the beta-galactosidase
gene of plasmid pUR289 and used in an expression system to form fusion
proteins which were immunoreactive with anti-ANF antiserum.

To determine if defects in the ANP system can cause hypertension, John
et al. (1995) generated mice with a disruption of the ANP gene.
Homozygous mutants had no circulating or atrial ANP, and their blood
pressures were elevated when they were fed standard and intermediate
salt diets. On standard salt diets, heterozygotes had normal amounts of
circulating ANP and normal blood pressures. However, on high salt diets,
they were hypertensive. These results demonstrate that genetically
reduced production of ANP can lead to salt-sensitive hypertension. The
findings encourage the search for human genetic variants that affect the
function of the ANP system. Detecting such variants may identify
hypertensive patients likely to benefit from reduced salt intake.

*FIELD* SA
Ackermann  (1986); de Bold  (1985); Flynn and Davies (1985); Greenberg
et al. (1984); Kennedy et al. (1984); Lang et al. (1985); Laragh
(1985); Maki et al. (1984); Napier et al. (1984); Needleman and Greenwald
(1986); Nemer et al. (1984); Seidman et al. (1984); Yamaji et al.
(1985)
*FIELD* RF
1. Ackermann, U.: Structure and function of atrial natriuretic peptides.
Clin. Chem. 32: 241-247, 1986.

2. de Bold, A. J.: Atrial natriuretic factor: a hormone produced
by the heart. Science 230: 767-770, 1985.

3. Flynn, T. G.; Davies, P. L.: The biochemistry and molecular biology
of atrial natriuretic factor. Biochem. J. 232: 313-321, 1985.

4. Greenberg, B. D.; Bencen, G. H.; Seilhamer, J. J.; Lewicki, J.
A.; Fiddes, J. C.: Nucleotide sequence of the gene encoding human
atrial natriuretic factor precursor. Nature 312: 656-658, 1984.

5. Johansson, B.; Wernstedt, C.; Westermark, P.: Atrial natriuretic
peptide deposited as atrial amyloid fibrils. Biochem. Biophys. Res.
Commun. 148: 1087-1092, 1987.

6. John, S. W. M.; Krege, J. H.; Oliver, P. M.; Hagaman, J. R.; Hodgin,
J. B.; Pang, S. C.; Flynn, T. G.; Smithies, O.: Genetic decreases
in atrial natriuretic peptide and salt-sensitive hypertension. Science 267:
679-681, 1995.

7. Kennedy, B. P.; Marsden, J. J.; Flynn, T. G.; de Bold, A. J.; Davies,
P. L.: Isolation and nucleotide sequence of a cloned cardionatrin
cDNA. Biochem. Biophys. Res. Commun. 122: 1076-1082, 1984.

8. Lang, R. E.; Tholken, H.; Ganten, D.; Luft, F. C.; Ruskoaho, H.;
Unger, T.: Atrial natriuretic factor--a circulating hormone simulated
by volume loading. Nature 314: 264-266, 1985.

9. Laragh, J. H.: Atrial natriuretic hormone, the renin-aldosterone
axis, and blood pressure-electrolyte homeostasis. New Eng. J. Med. 313:
1330-1340, 1985.

10. Maki, M.; Parmentier, M.; Inagami, T.: Cloning of genomic DNA
for human atrial natriuretic factor. Biochem. Biophys. Res. Commun. 125:
797-802, 1984.

11. Napier, M. A.; Vandlen, R. L.; Albers-Schonberg, G.; Nutt, R.
F.; Brady, S.; Lyle, T.; Winquist, R.; Faison, E. P.; Heinel, L. A.;
Blaine, E. H.: Specific membrane receptors for atrial natriuretic
factor in renal and vascular tissues. Proc. Nat. Acad. Sci. 81:
5946-5950, 1984.

12. Needleman, P.; Greenwald, J. E.: Atriopeptin: a cardiac hormone
intimately involved in fluid, electrolyte, and blood-pressure homeostasis.
New Eng. J. Med. 314: 828-834, 1986.

13. Nemer, M.; Chamberland, M.; Sirois, D.; Argentin, S.; Drouin,
J.; Dixon, R. A. F.; Zivin, R. A.; Condra, J. H.: Gene structure
of human cardiac hormone precursor, pronatriodilatin. Nature 312:
654-656, 1984.

14. Oikawa, S.; Imai, M.; Ueno, A.; Tanaka, S.; Noguchi, T.; Nakazato,
H.; Kangawa, K.; Fukuda, A.; Matsuo, H.: Cloning and sequence analysis
of cDNA encoding a precursor for human atrial natriuretic polypeptide.
Nature 309: 724-726, 1984.

15. Quirion, R.; Dalpe, M.; Dam, T.-V.: Characterization and distribution
of receptors for the atrial natriuretic peptides in mammalian brain.
Proc. Nat. Acad. Sci. 83: 174-178, 1986.

16. Sachse, H.; Hagendorff, G.; Preuss, K. D.; Sharma, H. S.; Scheit,
K. H.: Synthesis, molecular cloning and expression of genes coding
for atrial natriuretic factors from rat and human. Nucleosides Nucleotides 7:
61-73, 1988.

17. Seidman, C. E.; Bloch, K. D.; Klein, K. A.; Smith, J. A.; Seidman,
J. G.: Nucleotide sequences of the human and mouse atrial natriuretic
factor genes. Science 226: 1206-1209, 1984.

18. Yamaji, T.; Ishibashi, M.; Takaku, F.: Atrial natriuretic factor
in human blood. J. Clin. Invest. 76: 1705-1709, 1985.

19. Yang-Feng, T. L.; Floyd-Smith, G.; Nemer, M.; Drouin, J.; Francke,
U.: The pronatriodilatin gene is located on the distal short arm
of human chromosome 1 and on mouse chromosome 4. Am. J. Hum. Genet. 37:
1117-1128, 1985.

20. Zivin, R. A.; Condra, J. H.; Dixon, R. A. F.; Seidah, N. G.; Chretien,
M.; Nemer, M.; Chamberland, M.; Drouin, J.: Molecular cloning and
characterization of DNA sequences encoding rat and human atrial natriuretic
factors. Proc. Nat. Acad. Sci. 81: 6325-6329, 1984.

*FIELD* CS

Endocrine:
   Extracellular fluid volume control;
   Electrolyte homeostatic control

Lab:
   Multiple atrial natriuretic polypeptides (ANP), with m.w;
   3,000 to 13,000

Inheritance:
   Autosomal dominant (1p36.1-p36.3)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 05/21/1996
carol: 2/20/1995
jason: 7/29/1994
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 11/7/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
108800
*FIELD* TI
*108800 ATRIAL SEPTAL DEFECT; ASD
ASD, HLA-LINKED, INCLUDED;;
ASD2, INCLUDED
*FIELD* TX
This congenital heart defect is almost always sporadic, but occasional
families in which multiple persons have isolated ASD suggest that a
single 'major' gene may sometimes be responsible. The family reported by
Zuckerman et al. (1962) suggests dominant inheritance. Zetterqvist
(1960) reported a family with 8 proved cases and 5 probable cases of ASD
of secundum type in 3 generations. Johansson and Sievers (1967) found 6
proved and 1 probable case of ASD in 3 generations. Furthermore, they
were able to show that Zetterqvist's and their cases traced their
ancestry to a common couple who lived in the 18th century. Zetterqvist
et al. (1971) gave a full report on the family which they felt provided
strong evidence for the existence of a single major gene as a
determining factor. Sanchez-Cascos (1972) examined 109 cases of ASD, 84
of the ostium secundum type and 25 of the ostium primum type; of these,
92 presented ASD as an isolated defect and 17 were associated with other
malformations. He concluded, from the incidence of familial aggregation
among first-degree relatives of affected cases, from the fact that the
sex ratio deviated from 1 for his cases (0.64 males per 1 female), and
from other findings, that multifactorial inheritance is consistent with
the demonstrated pattern of transmission. He also reported significant
dermatoglyphic findings in these ASD cases--a high proportion of whorls
and a parallel diminution in the number of ulnar loops. Mohl and Mayr
(1977) studied 3 multigeneration families with secundum type ASD and
found no recombination with HLA (which is at 6p21.3). The data yielded a
lod score of +3.612 at a recombination fraction of 0.000, but the
confidence limits were wide. The gene for the HLA-linked form has been
symbolized ASD2 at Human Gene Mapping Workshops. Insufficient
information was given to know whether this was the Holt-Oram syndrome
(142900) or ASD with conduction defect (108900) rather than this entity.
Lynch et al. (1978) restudied a large kindred reported by Zuckerman et
al. (1962) and concluded that two autosomal dominant forms of ASD occur:
one with (108900) and one without prolongation of the PR interval. Li
Volti et al. (1991) observed 3 Sicilian families in which 17 persons (10
females and 7 males) had atrial septal defect of the ostium secundum
type without conduction defects. There were several instances of
male-to-male transmission.

*FIELD* RF
1. Johansson, B. W.; Sievers, J.: Inheritance of atrial septal defect.
(Letter) Lancet I: 1224-1225, 1967.

2. Li Volti, S.; Distefano, G.; Garozzo, R.; Romeo, M. G.; Sciacca,
P.; Mollica, F.: Autosomal dominant atrial septal defect of ostium
secundum type: report of three families. Ann. Genet. 34: 14-18,
1991.

3. Lynch, H. T.; Bachenberg, K.; Harris, R. E.; Becker, W.: Hereditary
atrial septal defect: update of a large kindred. Am. J. Dis. Child. 132:
600-604, 1978.

4. Mohl, W.; Mayr, W. R.: Atrial septal defect of the secundum type
and HLA. Tissue Antigens 10: 121-122, 1977.

5. Sanchez-Cascos, A.: Genetics of atrial septal defect. Arch.
Dis. Child. 47: 581-588, 1972.

6. Zetterqvist, P.: Multiple occurrence of atrial septal defect in
a family. Acta Paediat. 49: 741-747, 1960.

7. Zetterqvist, P.; Turesson, I.; Johansson, B. W.; Laurell, S.; Ohlsson,
N. M.: Dominant mode of inheritance in atrial septal defect. Clin.
Genet. 2: 78-86, 1971.

8. Zuckerman, H. S.; Zuckerman, G. H.; Mammen, R. E.; Wassermil, M.
: Atrial septal defect: familial occurrence in four generations of
one family. Am. J. Cardiol. 9: 515-520, 1962.

*FIELD* CS

Cardiac:
   Atrial septal defect

Inheritance:
   Autosomal dominant in occasional families

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 9/16/1991
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
108900
*FIELD* TI
*108900 ATRIAL SEPTAL DEFECT WITH ATRIOVENTRICULAR CONDUCTION DEFECTS
ASD WITH ATRIOVENTRICULAR CONDUCTION DEFECTS
*FIELD* TX
Amarasingham and Fleming (1967) and Kahler et al. (1966) reported a
total of 3 families with this combination. Because of the rarity of
conduction defects with atrial septal defects of the secundum type, this
may be a specific mendelizing form of atrial septal defect. Bizarro et
al. (1970) referred to the form of atrial septal defect as fossa ovalis
type (a synonym for secundum type). They demonstrated male-to-male
transmission. The family of Weil and Allenstein (1961) probably
represented an example of this syndrome. The occurrence of other forms
of congenital heart disease in this syndrome was suggested by the family
reported by Pease et al. (1976). Bosi et al. (1992) suggested that a
prolonged PR interval can be the only manifestation of the gene in this
condition. The finding of a prolonged PR interval in healthy
first-degree relatives of patients with ASD secundum can be useful in
genetic counseling.

*FIELD* RF
1. Amarasingham, R.; Fleming, H. A.: Congenital heart disease with
arrhythmia in a family. Brit. Heart J. 29: 78-82, 1967.

2. Bizarro, R. O.; Callahan, J. A.; Feldt, R. H.; Kurland, L. T.;
Gordon, H.; Brandenburg, R. O.: Familial atrial septal defect with
prolonged atrioventricular conduction: a syndrome showing the autosomal
dominant pattern of inheritance. Circulation 41: 677-684, 1970.

3. Bosi, G.; Sensi, A.; Calzolari, E.; Scorrano, M.: Familial atrial
septal defect with prolonged atrioventricular conduction.  (Letter) Am.
J. Med. Genet. 43: 641 only, 1992.

4. Kahler, R. L.; Braunwald, E.; Plauth, W. H., Jr.; Morrow, A. G.
: Familial congenital heart disease: familial occurrence of atrial
septal defect with A-V conduction abnormalities, supravalvular aortic
and pulmonic stenosis, and ventricular septal defect. Am. J. Med. 40:
384-399, 1966.

5. Pease, W. E.; Nordenberg, A.; Ladda, R. L.: Genetic counselling
in familial atrial septal defect with prolonged atrio-ventricular
conduction. Circulation 53: 759-762, 1976.

6. Weil, M. H.; Allenstein, B. J.: A report of congenital heart disease
in five members of one family. New Eng. J. Med. 265: 661-667, 1961.

*FIELD* CS

Cardiac:
   Atrial septal defect, secundum type;
   Atrioventricular conduction defects

Lab:
   Electrocardiographic prolonged PR interval

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
carol: 7/6/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
108950
*FIELD* TI
108950 ATRIAL TACHYARRHYTHMIA WITH SHORT PR INTERVAL
*FIELD* TX
Brodsky et al. (1977) described a family in which a short PR interval in
the electrocardiogram occurred in members in 3 generations with
male-to-male transmission. Several members of the family with short PR
had paroxysmal or chronic atrial fibrillation or paroxysmal atrial
tachycardia from an early age. Five members of the family had short PR
intervals but had not yet shown tachyarrhythmia. The proband, aged 18,
had left ventricular dysfunction during paroxysmal atrial tachycardia.
Both were reversed with administration of digoxin and propranolol. This
condition may represent a variant of the Lown-Ganong-Levine syndrome;
several affected relatives were described but not studied extensively in
the original report (Lown et al., 1952). Noting the evidence for genetic
factors in atrioventricular conduction time (108980), one wonders
whether the affected persons in the family of Brodsky et al. (1977)
represented a 'tail' of the distribution for a multifactorial trait. Two
families with multiple generations affected by late-onset, chronic
atrial fibrillation in the absence of organic heart disease may
represent a related disorder (Gould, 1957; Phair, 1963). The
Wolff-Parkinson-White syndrome (194200) is another syndrome of short PR
interval with proneness to supraventricular tachycardia.

*FIELD* RF
1. Brodsky, M.; Wu, D.; Denes, P.; Rosen, K. M.: Familial atrial
tachyarrhythmia with short PR interval. Arch. Intern. Med. 137:
165-169, 1977.

2. Gould, W. L.: Auricular fibrillations: report on a study of a
familial tendency, 1920-1956. Arch. Intern. Med. 100: 916-926,
1957.

3. Lown, B.; Ganong, W. F.; Levine, S. A.: The syndrome of short
P-R interval, normal QRS complex and paroxysmal rapid heart action.
Circulation 5: 693-706, 1952.

4. Phair, W. B.: Familial atrial fibrillation. Canad. Med. Assoc.
J. 89: 1274-1276, 1963.

*FIELD* CS

Lab:
   Electrocardiographic short PR interval

Cardiac:
   Paroxysmal or chronic atrial fibrillation;
   Paroxysmal atrial tachycardia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/29/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
108960
*FIELD* TI
*108960 NATRIURETIC PEPTIDE RECEPTOR A/GUANYLATE CYCLASE A; NPR1
ATRIAL NATRIURETIC PEPTIDE RECEPTOR, TYPE A; ANPRA;;
ATRIONATRIURETIC PEPTIDE RECEPTOR, TYPE A
*FIELD* TX
Lowe et al. (1990) assigned the ANPRA gene to 1q12-qter by PCR analysis
of genomic DNA from somatic cell hybrids. By in situ hybridization, the
gene was further localized to 1q21-q22.

*FIELD* RF
1. Lowe, D. G.; Klisak, I.; Sparkes, R. S.; Mohandas, T.; Goeddel,
D. V.: Chromosomal distribution of three members of the human natriuretic
peptide receptor/guanylyl cyclase gene family. Genomics 8: 304-312,
1990.

*FIELD* CD
Victor A. McKusick: 9/7/1990

*FIELD* ED
mark: 12/29/1996
terry: 5/17/1996
carol: 4/21/1994
supermim: 3/16/1992
carol: 11/7/1990
carol: 10/9/1990
supermim: 9/28/1990
carol: 9/7/1990

*RECORD*
*FIELD* NO
108961
*FIELD* TI
*108961 NATRIURETIC PEPTIDE RECEPTOR B/GUANYLATE CYCLASE B; NPR2
ATRIAL NATRIURETIC PEPTIDE RECEPTOR, TYPE B; ANPRB;;
ATRIONATRIURETIC PEPTIDE RECEPTOR, TYPE B
*FIELD* TX
By PCR analysis of genomic DNA from somatic cell hybrids, Lowe et al.
(1990) assigned the ANPRB gene to 9p22-p11. The localization was further
narrowed to 9p21-p12 by in situ hybridization.

*FIELD* RF
1. Lowe, D. G.; Klisak, I.; Sparkes, R. S.; Mohandas, T.; Goeddel,
D. V.: Chromosomal distribution of three members of the human natriuretic
peptide receptor/guanylyl cyclase gene family. Genomics 8: 304-312,
1990.

*FIELD* CD
Victor A. McKusick: 9/7/1990

*FIELD* ED
mark: 12/29/1996
terry: 5/17/1996
carol: 4/19/1994
supermim: 3/16/1992
carol: 11/7/1990
carol: 10/9/1990
supermim: 9/28/1990
carol: 9/7/1990

*RECORD*
*FIELD* NO
108962
*FIELD* TI
*108962 NATRIURETIC PEPTIDE RECEPTOR C; NPR3
ATRIAL NATRIURETIC PEPTIDE CLEARANCE RECEPTOR; ANPRC;;
ATRIONATRIURETIC PEPTIDE RECEPTOR, TYPE C
*FIELD* TX
The family of natriuretic peptides (108780) elicit a number of vascular,
renal, and endocrine effects that are important in the maintenance of
blood pressure and extracellular fluid volume. These effects are
mediated by specific binding of the peptides to cell surface receptors
in the vasculature, kidney, adrenal, and brain. Using a bovine ANP
C-type receptor cDNA as a hybridization probe, Porter et al. (1990)
cloned cDNA encoding the human atrial natriuretic peptide clearance
receptor (ANPRC; gene symbol = NPR3) from human placental and kidney
cDNA libraries. The ANPC receptor mediates the internalization and
metabolic clearance of ANP. The human sequence was shown to be highly
homologous to the bovine sequence. Corresponding mRNA was expressed in
human placenta, adult and fetal kidney, and fetal heart. Lowe et al.
(1990) assigned the ANPRC gene to chromosome 5 by use of human-specific
PCR primers identified by screening a human primer panel on parental DNA
samples (shotgun primer screening). The gene was regionalized to
5p14-p13 by in situ hybridization. Lowe et al. (1990) reported the
sequence of the cDNA.

It is thought that atrial natriuretic peptide released from the heart in
response to atrial stretch binds to a guanylyl cyclase-coupled receptor
(which they symbolized GC-A) in the kidney to mediate natriuresis and
diuresis, and to the same receptor in the vasculature to mediate
relaxation. Lopez et al. (1995) reported that disruption of the GC-A
gene by transfection of mouse embryonic stem cells resulted in mice with
chronic elevations of blood pressure on a normal salt diet. Pressure was
elevated by 27.4 mm Hg in homozygotes and 10.5 mm Hg in heterozygotes.
Unexpectedly, the blood pressure remained elevated and unchanged in
response to either minimal salt diet or high salt diet. Aldosterone and
ANP concentrations were not affected by the genotype. Thus, the authors
speculated that mutations in the receptor gene could explain some
salt-resistant forms of essential hypertension in humans. Coupled with
other work, this also suggested that the GC-A signaling pathway
dominates at the level of peripheral resistance, where it can operate
independently of ANP.

*FIELD* SA
Lowe et al. (1990)
*FIELD* RF
1. Lopez, M. J.; Wong, S. K.-F.; Kishimoto, I.; Dubois, S.; Mach,
V.; Friesen, J.; Garbers, D. L.; Beuve, A.: Salt-resistant hypertension
in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic
peptide. Nature 378: 65-68, 1995.

2. Lowe, D. G.; Camerato, T. R.; Goeddel, D. V.: cDNA sequence of
the human atrial natriuretic peptide clearance receptor. Nucleic
Acids Res. 18: 3412 only, 1990.

3. Lowe, D. G.; Klisak, I.; Sparkes, R. S.; Mohandas, T.; Goeddel,
D. V.: Chromosomal distribution of three members of the human natriuretic
peptide receptor/guanylyl cyclase gene family. Genomics 8: 304-312,
1990.

4. Porter, J. G.; Arfsten, A.; Fuller, F.; Miller, J. A.; Gregory,
L. C.; Lewicki, J. A.: Isolation and functional expression of the
human atrial natriuretic peptide clearance receptor cDNA. Biochem.
Biophys. Res. Commun. 171: 796-803, 1990.

*FIELD* CD
Victor A. McKusick: 9/7/1990

*FIELD* ED
mark: 12/08/1995
carol: 4/21/1994
supermim: 3/16/1992
carol: 7/12/1991
carol: 1/10/1991
carol: 11/7/1990
carol: 10/9/1990

*RECORD*
*FIELD* NO
108970
*FIELD* TI
108970 ATRIOPEPTIDASE
*FIELD* TX
The kidney contains an endopeptidase, called atriopeptidase (EC
3.4.24.11), that specifically degrades atrial natriuretic factor (ANF;
108780) (Stephenson and Kenny, 1987; Koehn et al., 1987). Northridge et
al. (1989) developed a specific enzyme inhibitor and reported that it
had effects similar to those of low-dose ANF infusion. These effects
include diuresis, natriuresis, vasodilatation, and suppression of the
renin-angiotensin-aldosterone system.

*FIELD* RF
1. Koehn, J. A.; Norman, J. A.; Jones, B. N.; LeSoeur, L.; Sakane,
Y.; Ghai, R. D.: Degradation of atrial natriuretic factor by kidney
cortex membranes. J. Biol. Chem. 262: 11623-11627, 1987.

2. Northridge, D. B.; Jardine, A. G.; Alabaster, C. T.; Barclay, P.
L.; Connell, J. M. C.; Dargie, H. J.; Dilly, S. G.; Findlay, I. N.;
Lever, A. F.; Samuels, G. M. R.: Effects of UK 69 578: a novel atriopeptidase
inhibitor. Lancet II: 591-593, 1989.

3. Stephenson, S. L.; Kenny, A. J.: The hydrolysis of human atrial
natriuretic peptide by pig kidney microvillar membranes is initiated
by endopeptidase-24.11. Biochem. J. 243: 183-187, 1987.

*FIELD* CD
Victor A. McKusick: 11/10/1989

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
carol: 11/10/1989

*RECORD*
*FIELD* NO
108980
*FIELD* TI
108980 ATRIOVENTRICULAR CONDUCTION TIME
PR INTERVAL
*FIELD* TX
Moller and Heiberg (1980) suggested the existence of major genes
influencing atrioventricular conduction time. They studied the PR
interval in the adult first-degree relatives of 6 and 9 probands with
short and long PR intervals, respectively. The distributions differed
significantly, relatives of probands with short PR intervals having
shorter PR intervals than did relatives of probands with long PR
intervals. Twin studies (Hawlik et al., 1980; Moller et al., 1982)
supported the genetic hypothesis. Griggs et al. (1986) found
heritability of 0.46 for PR interval in Tokelau Islanders. Segregation
analysis provided evidence for a polygenic influence on A-V conduction
but no support for a single major gene.

*FIELD* RF
1. Griggs, L. H.; Chapman, C. J.; McHaffie, D. J.: Inheritance of
atrioventricular conduction time in Tokelau islanders. Clin. Genet. 29:
56-61, 1986.

2. Hawlik, R. J.; Garrison, R. J.; Fabsitz, R.; Feinleib, M.: Variability
of heart rate, P-R, QRS and QT durations in twins. J. Electrocardiol. 13:
45-48, 1980.

3. Moller, P.; Heiberg, A.: Atrioventricular conduction time--a heritable
trait? II. Family studies. Clin. Genet. 18: 454-455, 1980.

4. Moller, P.; Heiberg, A.; Berg, K.: The atrioventricular conduction
time--a heritable trait? III. Twin studies. Clin. Genet. 21: 181-183,
1982.

*FIELD* CS

Lab:
   Electrocardiographic atrioventricular conduction time

Inheritance:
   ? polygenic influence

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
108985
*FIELD* TI
*108985 ATROPHIA AREATA; AA
PERIPAPILLARY CHORIORETINAL DEGENERATION, ICELANDIC TYPE;;
HELICOIDAL PERIPAPILLARY CHORIORETINAL DEGENERATION
*FIELD* TX
Sveinsson (1939) first described this disorder in an Icelandic mother
and son. The fundus showed peripapillary chorioretinal atrophy with wide
tongue-shaped extensions to the periphery having no connection with the
retinal vessels. He referred to the condition as 'chorioiditis areata'
but later recognized the inappropriateness of this designation since
there was no inflammation. In a follow-up of this family, Sveinsson
(1979) found a total of 13 affected persons (6 male and 7 female) in 4
generations with at least 3 instances of male-to-male transmission.
Sveinsson saw his patients in Reykjavik. Magnusson (1981), who used the
designation atrophia areata, observed 38 patients in the northern part
of Iceland. One pedigree contained 26 of these patients; the other 12
came from the same district. The pedigree with 26 affected showed no
instance of male-to-male transmission. Magnusson (1981) stated that the
atrophy is slowly progressive, most likely beginning in the retinal
pigment epithelium, and that usually there is combined myopia and
astigmatism. Franceschetti (1962) reviewed comprehensively the
peripapillary atrophies and classified the Icelandic form in a category
he called helicoid peripapillar chorioretinal degeneration. The question
of autosomal dominant versus X-linked dominant inheritance was settled
by the demonstration of linkage to 11p15 by Fossdal et al. (1995). In
the course of a genome linkage search with 112 microsatellite DNA
markers, Fossdal et al. (1995) found that D11S1323 and D11S902 on 11p15
flanked the region encompassing the AA gene.

Since there was no instance of male-to-male transmission (indeed, there
was only 1 affected male with children) and there were 16 females to 9
males (2 males were in a set of triplets), X-linked dominant inheritance
is a possibility. No comment was made about the relative severity of the
disorder in males and females. Some similarities to choroideremia
(303100) could be noted.

*FIELD* RF
1. Fossdal, R.; Magnusson, L.; Weber, J. L.; Jensson, O.: Mapping
the locus of atrophia areata, a helicoid peripapillary chorioretinal
degeneration with autosomal dominant inheritance, to chromosome 11p15.
Hum. Molec. Genet. 4: 479-483, 1995.

2. Franceschetti, A.: A curious affection of the fundus oculi: helicoid
peripapillar chorioretinal degeneration. Its relation to pigmentary
paravenous chorioretinal degeneration. Docum. Ophthal. 16: 81-110,
1962.

3. Magnusson, L.: Atrophia areata: a variant of peripapillary chorioretinal
degeneration. Acta Ophthal. 59: 659-664, 1981.

4. Sveinsson, K.: Chorioiditis areata. Acta Ophthal. 17: 73-80,
1939.

5. Sveinsson, K.: Helicoidal peripapillary chorioretinal degeneration.
Acta Ophthal. 57: 69-75, 1979.

*FIELD* CS

Eyes:
   Peripapillary chorioretinal atrophy;
   Combined myopia and astigmatism

Misc:
   Slowly progressive

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/8/1990

*FIELD* ED
terry: 4/24/1995
carol: 5/16/1994
mimadm: 4/9/1994
carol: 4/7/1992
supermim: 3/16/1992
carol: 10/8/1990

*RECORD*
*FIELD* NO
108990
*FIELD* TI
*108990 ATTACHED CELL ANTIGEN 28.3.7; MIC7
*FIELD* TX
Human cells growing in vitro attached to the substratum express a cell
antigen called 28.3.7 identified by a species-specific monoclonal
antibody. This antigen is not expressed on cells growing in suspension.
The antigen has a molecular weight of 95,000 and is encoded by human
chromosome 15, according to the results of somatic cell hybrid studies
(Blaineau et al., 1983). The gene is symbolized MIC7 (for monoclonal and
Imperial Cancer, the laboratory where it was identified, plus 7 for the
sequential monoclonal in that laboratory). The antigen is a marker for
macrophage differentiation.

*FIELD* RF
1. Blaineau, C.; Avner, P.; Tunnacliffe, A.; Goodfellow, P.: 'Attached
cell' antigen 28.3.7 mapping to human chromosome 15 characterises
TPA-induced differentiation of the promyelocytic HL-60 cell line to
give macrophage/monocyte populations. EMBO J. 2: 2007-2012, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
109000
*FIELD* TI
*109000 AURICULOOSTEODYSPLASIA
*FIELD* TX
Beals (1967) gave this designation to a syndrome that he observed in
many members of 2 families. Multiple osseous dysplasia, characteristic
ear shape, and somewhat short stature were features. Dysplasia of the
radiocapitellar joint, with or without radial-head dislocation, was a
constant finding. Inheritance was unequivocally autosomal dominant. Hip
dysplasia was present in 4 of 13 affected females and in none of the
males. Roentgenographic abnormalities at the wrist were pictured.
Although the severity of the auricular anomaly varied, this feature
alone distinguished the affected members in both families and was
present at birth in the single newborn examined. Affected members were
always identified on this basis by other family members. The
distinguishing feature was elongation of the lobe which was attached and
accompanied by a small, slightly posterior lobule. Radial heads,
posterior dislocation of (179200), may be an independent mendelian
trait, although it occurs also as a component of several syndromes,
e.g., nail-patella syndrome (161200), OPD syndrome (311300), Noonan
syndrome (163950), tarsal-carpal coalition syndrome (186570), and
ophthalmomandibulomelic dysplasia (164900). Kimberling (1972) reported
possible linkage of auriculoosteodysplasia to Rh and Duffy (which are
now known to be on chromosome 1). Further studies of the original family
and of another did not support linkage with chromosome 1 markers (Human
Gene Mapping Workshop-4). Beals (1982) had heard of no other cases. He
suggested that looking for the combination of radial head dislocations
and hip dysplasia might be the best way to locate further cases.
Identification of more families might be useful for pursuing the
question of linkage.

*FIELD* RF
1. Beals, R. K.: Auriculo-osteodysplasia: a syndrome of multiple
osseous dysplasia, ear anomaly, and short stature. J. Bone Joint
Surg. 49A: 1541-1550, 1967.

2. Beals, R. K.: Personal Communication. Portland, Ore.  5/27/1982.

3. Kimberling, W. J.: Computers and gene localization. In: Wright,
S. W.; Crandall, D. I.; Boyer, P. D.: Perspectives in Cytology.
Springfield, Ill.: Charles C Thomas (pub.)  1972. Pp. 131 only.

*FIELD* CS

Ears:
   Characteristic ear shape;
   Elongated attached ear lobe;
   Extra small, slightly posterior ear lobule

Skel:
   Multiple osseous dysplasia

Growth:
   Short stature

Joints:
   Radiocapitellar joint dysplasia;
   Radial-head dislocation;
   Hip dysplasia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/3/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
109050
*FIELD* TI
109050 AUROCEPHALOSYNDACTYLY
AURALCEPHALOSYNDACTYLY
*FIELD* TX
Kurczynski and Casperson (1988) described a new craniosynostosis
syndrome inherited apparently as an autosomal dominant. Associated with
the craniosynostosis were characteristic pinnae, a short columella, and
symmetric syndactyly of toes 4 and 5. Three males and a female in 1
generation and the daughter of the female in the next generation were
affected. Two of the brothers had craniectomies and developed mild
mental retardation and hearing loss. The third affected brother died of
congenital heart disease in infancy. The father of these 4 affected sibs
and some of his sibs were said to have similar head shapes but none ever
sought medical evaluation.

*FIELD* RF
1. Kurczynski, T. W.; Casperson, S. M.: Auralcephalosyndactyly: a
new hereditary craniosynostosis syndrome. J. Med. Genet. 25: 491-493,
1988.

*FIELD* CS

Head:
   Craniosynostosis

Ears:
   Characteristic pinnae;
   Hearing loss

Facies:
   Short columella

Limbs:
   Symmetric syndactyly, toes 4 and 5

Neuro:
   Mild mental retardation

Cardiac:
   Congenital heart disease

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 8/15/1988

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 8/25/1988
root: 8/15/1988

*RECORD*
*FIELD* NO
109090
*FIELD* TI
*109090 AUTOANTIGEN La
SJOGREN SYNDROME ANTIGEN B; SSB
*FIELD* TX
La is an autoimmune RNA-binding protein that plays a role in the
transcription of RNA polymerase III. La protein was originally defined
by its reactivity with autoantibodies from patients with Sjogren
syndrome (270150) and systemic lupus erythematosus (SLE; 152700).
Chambers et al. (1988) determined the amino acid sequence and genomic
structure of the La protein. The gene comprises 11 exons. The cDNA
sequence encodes a protein of 408 amino acids. By immunoprecipitation
and immunoblotting, it appears to be a single phosphoprotein of 46 to 50
kD. Chambers et al. (1988) also identified at least 3 antigenic epitopes
on the La protein and predicted regions of the protein involved in RNA
binding based on structural similarities with other RNA-binding
proteins. See Bini et al. (1990).

*FIELD* RF
1. Bini, P.; Chu, J.-L.; Okolo, C.; Elkon, K.: Analysis of autoantibodies
to recombinant La (SS-B) peptides in systemic lupus erythematosus
and primary Sjogren's syndrome. J. Clin. Invest. 85: 325-333, 1990.

2. Chambers, J. C.; Kenan, D.; Martin, B. J.; Keene, J. D.: Genomic
structure and amino acid sequence domains of the human La autoantigen.
J. Biol. Chem. 263: 18043-18051, 1988.

*FIELD* CD
Victor A. McKusick: 12/12/1989

*FIELD* ED
supermim: 3/16/1992
carol: 1/30/1991
carol: 9/7/1990
carol: 5/1/1990
supermim: 3/20/1990
supermim: 3/1/1990

*RECORD*
*FIELD* NO
109091
*FIELD* TI
*109091 CALRETICULIN; CALR
AUTOANTIGEN Ro; RO
*FIELD* TX
Calreticulin is a multifunctional protein that acts as a major
Ca(2+)-binding (storage) protein in the lumen of the endoplasmic
reticulum. It is also found in the nucleus, suggesting that it may have
a role in transcription regulation. Calreticulin binds to the synthetic
peptide KLGFFKR, which is almost identical to an amino acid sequence in
the DNA-binding domain of the superfamily of nuclear receptors.
McCauliffe et al. (1990) showed that calreticulin binds to antibodies in
certain sera of systemic lupus and Sjogren patients which contain
anti-Ro/SSA antibodies, that it is highly conserved among species, and
that it is located in the endoplasmic and sarcoplasmic reticulum where
it may bind calcium. With synthetic oligonucleotides corresponding to
the amino acid sequence, McCauliffe et al. (1990) isolated a full-length
cDNA clone that encodes a human Ro ribonucleoprotein autoantigen.
Southern filter hybridization analysis showed that the gene is not
highly polymorphic and exists in single copy in the human genome. By
analysis of somatic cell hybrids, they assigned the gene to 19p. There
was perfect concordance with LDLR (143890) but discordance with C3
(120700). Thus, the calreticulin, or RO, locus may be located in the
region 19pter-p13.2, distal to C3 and near LDLR. Frank (1994) pointed
out that the gene mapped to 19p encodes the 48-kD calreticulin, a
protein with Ro/SSA properties. Itoh et al. (1991) showed that the 52-kD
and the 60-kD forms of Ro/SSA ribonucleoproteins are encoded by separate
genes. The gene for the 52-kD form (109092) maps to chromosome 11,
whereas the gene for the 60-kD form (600063) maps to chromosome 1.

Burns et al. (1994) reported that the amino terminus of calreticulin
interacts with the DNA-binding domain of the glucocorticoid receptor and
prevents the receptor from binding to its specific glucocorticoid
response element. Dedhar et al. (1994) showed that calreticulin can
inhibit the binding of androgen receptor to its hormone-responsive DNA
element and can inhibit androgen receptor and retinoic acid receptor
transcriptional activities in vivo, as well as retinoic acid-induced
neuronal differentiation. Thus, calreticulin can act as an important
modulator of the regulation of gene transcription by nuclear hormone
receptors.

Boehm et al. (1994) showed that SLE is associated with increased
autoantibody titers against calreticulin but that calreticulin is not a
Ro/SS-A antigen. Orth et al. (1996) found increased autoantibody titers
against human calreticulin in infants with complete congenital heart
block (234700) of both the IgG and IgM classes.

*FIELD* SA
McCauliffe et al. (1990)
*FIELD* RF
1. Boehm, J.; Orth, T.; Van Nguyen, P.; Soling, H. D.: Systemic lupus
erythematosus is associated with increased auto-antibody titers against
calreticulin and grp94, but calreticulin is not the Ro/SS-A antigen. Europ.
J. Clin. Invest. 24: 248-257, 1994.

2. Burns, K.; Duggan, B.; Atkinson, E. A.; Famulski, K. S.; Nemer,
M.; Bleackley, R. C.; Michalak, M.: Modulation of gene expression
by calreticulin binding to the glucocorticoid receptor. Nature 367:
476-480, 1994.

3. Dedhar, S.; Rennie, P. S.; Shago, M.; Hagesteijn, C.-Y. L.; Yang,
H.; Filmus, J.; Hawley, R. G.; Bruchovsky, N.; Cheng, H.; Matusik,
R. J.; Giguere, V.: Inhibition of nuclear hormone receptor activity
by calreticulin. Nature 367: 480-483, 1994.

4. Frank, M. B.: Personal Communication. Oklahoma City, Oklahoma
6/3/1994.

5. Itoh, K.; Itoh, Y.; Frank, M. B.: Protein heterogeneity in the
human Ro/SSA ribonucleoproteins: the 52- and 60-kD Ro/SSA autoantigens
are encoded by separate genes. J. Clin. Invest. 87: 177-186, 1991.

6. McCauliffe, D. P.; Lux, F. A.; Lieu, T.-S.; Sanz, I.; Hanke, J.;
Newkirk, M. M.; Bachinski, L. L.; Itoh, Y.; Siciliano, M. J.; Reichlin,
M.; Sontheimer, R. D.; Capra, J. D.: Molecular cloning, expression,
and chromosome 19 localization of a human Ro/SS-A autoantigen. J.
Clin. Invest. 85: 1379-1391, 1990.

7. McCauliffe, D. P.; Zappi, E.; Lieu, T.-S.; Michalak, M.; Sontheimer,
R. D.; Capra, J. D.: A human Ro/SS-A autoantigen is the homologue
of calreticulin and is highly homologous with onchocercal RAL-1 antigen
and an aplysia 'memory molecule.'. J. Clin. Invest. 86: 332-335,
1990.

8. Orth, T.; Dorner, T.; Meyer Zum Buschenfelde, K.-H.; Mayet, W.-J.
: Complete congenital heart block is associated with increased autoantibody
titers against calreticulin. Europ. J. Clin. Invest. 26: 205-215,
1996.

*FIELD* CD
Victor A. McKusick: 8/15/1990

*FIELD* ED
terry: 05/02/1996
mark: 4/27/1996
terry: 4/22/1996
carol: 11/30/1994
jason: 7/28/1994
mimadm: 4/21/1994
pfoster: 3/25/1994
carol: 3/1/1993
carol: 5/22/1992

*RECORD*
*FIELD* NO
109092
*FIELD* TI
*109092 AUTOANTIGEN Ro/SSA, 52-KD; RO52
SJOGREN SYNDROME ANTIGEN A1; SSA1;;
SICCA SYNDROME ANTIGEN A; SSA
*FIELD* TX
Ro/SSA is a ribonucleoprotein that binds to autoantibodies in 35 to 50%
of patients with systemic lupus erythematosus (SLE; 152700) and in up to
97% of patients with Sjogren syndrome (270150). The Ro/SSA particle
consists of a single 60-kD immunoreactive protein noncovalently bound
with 1 of 4 small RNA molecules. Most anti-Ro/SSA-positive sera have
antibodies not only against the 60-kD protein (600063), but also against
a 52-kD Ro/SSA protein. Itoh et al. (1991) demonstrated that the 52-kD
and 60-kD autoantigens are encoded by separate genes. By radioisotopic
in situ hybridization, Frank et al. (1993) mapped the RO52 gene to
11p15.5. Hybridization of portions of the cDNA probe to restriction
enzyme-digested DNA indicated that the gene is composed of at least 3
exons. The exon encoding the putative zinc fingers of this protein was
found to be distinct from that which encodes the leucine zipper. Frank
et al. (1993) identified a RFLP of the RO52 gene and demonstrated that
it is associated with SLE, primarily in black Americans. The RO60 gene
maps to chromosome 1 (Frank and Mattei, 1994). A third molecule with the
properties of a Ro/SSA autoantigen is calreticulin (109091), a 48,000-Da
protein encoded by a gene on chromosome 19.

Schoenlebe et al. (1993) reported an experience indicating that neonatal
hemochromatosis, also known as perinatal hemochromatosis or neonatal
iron storage disease, can occur as part of the neonatal lupus
erythematosus syndrome, associated with maternal anti-Ro/SS-A and
anti-La/SS-B (109090) autoantibodies. They reported a 6-week-old girl
with neonatal hemochromatosis whose mother had these autoantibodies
associated with Sjogren syndrome; an older child had congenital heart
block.

*FIELD* RF
1. Frank, M. B.; Itoh, K.; Fujisaku, A.; Pontarotti, P.; Mattei, M.-G.;
Neas, B. R.: The mapping of the human 52-kD Ro/SSA autoantigen gene
to human chromosome 11, and its polymorphisms. Am. J. Hum. Genet. 52:
183-191, 1993.

2. Frank, M. B.; Mattei, M.-G.: Mapping of the human 60000 M(r) Ro/SSA
locus: the genes for three Ro/SSA autoantigens are located on separate
chromosomes. Immunogenetics 39: 428-431, 1994.

3. Itoh, K.; Itoh, Y.; Frank, M. B.: Protein heterogeneity in the
human Ro/SSA ribonucleoproteins: the 52- and 60-kD Ro/SSA autoantigens
are encoded by separate genes. J. Clin. Invest. 87: 177-186, 1991.

4. Schoenlebe, J.; Buyon, J. P.; Zitelli, B. J.; Friedman, D.; Greco,
M. A.; Knisely, A. S.: Neonatal hemochromatosis associated with maternal
autoantibodies against Ro/SS-A and La/SS-B ribonucleoproteins. Am.
J. Dis. Child. 147: 1072-1075, 1993.

*FIELD* CD
Victor A. McKusick: 3/1/1993

*FIELD* ED
jason: 7/28/1994
carol: 12/22/1993
carol: 3/20/1993
carol: 3/1/1993

*RECORD*
*FIELD* NO
109100
*FIELD* TI
#109100 AUTOIMMUNE DISEASES
*FIELD* TX
A number sign (#) is used with this entry because it relates to a
category of disorders.

In many of the disorders in which autoimmunity has been incriminated, or
at least accused, as a leading etiologic factor, familial aggregation is
observed. For example, see thyroid autoantibodies (140300), alopecia
areata (104000), pernicious anemia (170900), hypoadrenocorticism with
hypoparathyroidism and superficial moniliasis (240300), Schmidt syndrome
(269200), systemic lupus erythematosus (152700), Sjogren syndrome
(270150), and anemia, autoimmune hemolytic (205700). The genetic
significance of this is unclear. It is possible that if maternal
antithyroid antibodies are responsible for athyreotic cretinism, then
multiple sibs might be affected by this congenital anomaly without any
genetic basis. Reports on the aggregation of possible autoimmune
disorders include the following: Greenberg (1964) described 2 sisters
with myasthenia gravis and thyrotoxicosis and a third sister with
Hashimoto struma. Pirofsky (1968) found that 20% of 44 patients with
idiopathic autoimmune hemolytic anemia had close relatives with
clinically detectable autoimmune disease. Karpatkin et al. (1981)
described a family in which the mother and 3 of her 4 children (a son
and 2 daughters) had autoimmune thrombocytopenia purpura with bound
platelet antibody. The 4 affected persons shared an HLA haplotype: A1,
C-, B8, DR3 and Dw3. Lippman et al. (1982) found a high frequency of
autoimmune manifestations, both clinical and laboratory, in relatives of
a proband with autoimmune hemolytic anemia, 1 with immune
thrombocytopenic purpura and 8 with systemic lupus erythematosus (SLE;
152700). Segregation analysis was most compatible with an autosomal
dominant pattern. The odds against linkage to HLA were 100:1.

Bias et al. (1983) suggested that autoimmunity is an autosomal dominant
trait. They studied 2 large kindreds in which serologic abnormalities as
well as overt autoimmune disease were used in the definition of the
autoimmune phenotype. Linkage studies in a second series of 23 families
excluded linkage with HLA, Gm, and Km. The only positive score was with
MNS (0.78 at theta = 0.30). Cales et al. (1983) studied the family of 2
brothers with primary biliary cirrhosis. Granulomatous hepatitis
associated with autoimmune thyroiditis was found in a sister.
Immunologic abnormalities were found in 6 members of the family:
antinuclear antimitochondrial and antithyroid autoantibodies and
rheumatoid factor. In a study of 6 families of probands with primary
Sjogren syndrome (270150), Reveille et al. (1984) found various other
autoimmune diseases and autoantibodies. Maclaren and Riley (1986) found
that autoimmune Addison disease was strongly associated with HLA-DR3 and
DR4; relative risks were 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/DR4,
respectively. This is similar to the findings for insulin-dependent
diabetes. Patients with type I autoimmune polyglandular syndrome did not
show the association. Bias et al. (1986) suggested that although
autoimmune diseases show a distribution in families consistent with
multifactorial etiology, the autoimmune trait is defined by the presence
of autoimmune disease and/or high titer autoantibody as a familial
occurrence consistent with autosomal dominant inheritance. They analyzed
18 autoimmune kindreds, concluding that the population frequency of the
postulated autoimmune gene is approximately 0.10 with penetrance
estimates of 92% in females and 49% in males. They proposed the
existence of a primary autoimmune disease gene that is epistatic to
other secondary genes that influence the autoimmune phenotype, including
those of the major histocompatibility complex (MHC). The secondary
genes, according to their hypothesis, confer specificity to the
phenotype. (See comments of Grundbacher (1988) and of Bias (1988).)

Adams and Knight (1980) suggested that autoimmunity results from somatic
mutations permitting the emergence of 'forbidden clones' of immunocytes.
Reveille et al. (1989) described a father and son with polyarteritis
nodosa (PAN) following hepatitis B infection. Further study of the
family showed that the spouse of the father had long-standing SLE, a
38-year-old maternal uncle had had seropositive nodular rheumatoid
arthritis since age 10, a 30-year-old maternal aunt had had seropositive
rheumatoid arthritis since age 13, and a 68-year-old maternal aunt had
rheumatoid factor-negative rheumatoid-like polyarthritis associated with
xerophthalmia. The 75-year-old paternal grandmother had had idiopathic
thrombocytopenic purpura, and a 69-year-old paternal great aunt had a
10-year history of seropositive nodular rheumatoid arthritis.
Transmission of hepatitis in this family was thought to be due to the
sharing of a razor. No correlation with a specific HLA haplotype could
be demonstrated.

Epplen (1992) discussed autoimmunity from the perspective of evolution.
The immune system furnished the organism with the utmost effective
defense mechanisms against 'foreign' or 'nonself' as well as against
changes in 'self' without doing self-harm. Optimized efficacy in the
defense against the immense variety of foreign antigens generates a
higher risk for inadvertent self challenge--what in the military would
be referred to as the consequences of 'friendly fire.'

Mason et al. (1994) described polyarteritis nodosa in an Asian boy who
presented at 13 years of age with livedo reticularis, Raynaud
phenomenon, arthralgia, and hypertension. At the age of 17, he was shown
by arteriography to have multiple small aneurysms of the renal, hepatic,
and celiac axis vessels, consistent with a diagnosis of polyarteritis
nodosa. He was treated successfully with prednisolone and
immunosuppressive agents but pursued a relapsing, intermittent course,
the relapses being associated with recurrence of a positive perinuclear
antinucleophil cytoplasmic antibody test. His sister was admitted to the
hospital at age 17 with fever and epigastric pain and showed palpable
nodules over both temporal arteries, marked livedo reticularis, and
hypertension. The parents were first cousins. A sib had died at the age
of 9 within 24 hours of collapsing suddenly. Autopsy demonstrated a
ruptured superficial vessel in the posterior part of the left frontal
lobe. The father, having recently been diagnosed as hypertensive,
collapsed and died suddenly at the age of 44 years while traveling
abroad. Despite their consanguinity, the parents shared no HLA
haplotypes. The 2 sibs with proven PAN shared 1 HLA haplotype derived
from the mother.

*FIELD* SA
Rose et al. (1980)
*FIELD* RF
1. Adams, D. D.; Knight, J. G.: H gene theory of inherited autoimmune
disease. Lancet I: 396-398, 1980.

2. Bias, W. B.: Evidence that autoimmunity in man is a mendelian
dominant trait.  (Letter) Am. J. Hum. Genet. 42: 178-179, 1988.

3. Bias, W. B.; Meyers, D. A.; Conley, C. L.; Reveille, J. D.; Wilson,
R. W.; Arnett, F. C.: Evidence that autoimmunity is a mendelian dominant
trait.  (Abstract) Am. J. Hum. Genet. 35: 77A only, 1983.

4. Bias, W. B.; Reveille, J. D.; Beaty, T. H.; Meyers, D. A.; Arnett,
F. C.: Evidence that autoimmunity in man is a mendelian dominant
trait. Am. J. Hum. Genet. 39: 584-602, 1986.

5. Cales, P.; Calot, M.; Voigt, J.-J.; Oksman, F.; Cassigneul, J.;
Vinel, J.-P.; Pascal, J.-P.: Pathologie auto-immune familiale comportant
deux cas de cirrhose biliaire primitive. Gastroenterol. Clin. Biol. 7:
777-784, 1983.

6. Epplen, J. T.: On genetic components in autoimmunity: a critical
review based on evolutionarily oriented rationality. Hum. Genet. 90:
331-341, 1992.

7. Greenberg, J.: Myasthenia gravis and hyperthyroidism in two sisters.
Arch. Neurol. 11: 219-222, 1964.

8. Grundbacher, F. G.: Classification of experimental data for genetic
analysis in autoimmune disease.  (Letter) Am. J. Hum. Genet. 42:
178 only, 1988.

9. Karpatkin, S.; Fotino, M.; Winchester, R.: Hereditary autoimmune
thrombocytopenic purpura: an immunologic and genetic study. Ann.
Intern. Med. 94: 781-782, 1981.

10. Lippman, S. M.; Arnett, F. C.; Conley, C. L.; Ness, P. M.; Meyers,
D. A.; Bias, W. B.: Genetic factors predisposing to autoimmune diseases:
autoimmune hemolytic anemia, chronic thrombocytopenic purpura, and
systemic lupus erythematosus. Am. J. Med. 73: 827-840, 1982.

11. Maclaren, N. K.; Riley, W. J.: Inherited susceptibility to autoimmune
Addison's disease is linked to human leukocyte antigens-DR3 and/or
DR4, except when associated with type I autoimmune polyglandular syndrome.
J. Clin. Endocr. Metab. 62: 455-459, 1986.

12. Mason, J. C.; Cowie, M. R.; Davies, K. A.; Schofield, J. B.; Cambridge,
J.; Jackson, J.; So, A.; Allard, S. A.; Walport, M. J.: Familial
polyarteritis nodosa. Arthritis Rheum. 37: 1249-1253, 1994.

13. Pirofsky, B.: Hereditary aspects of autoimmune hemolytic anemia:
a retrospective analysis. Vox Sang. 14: 334-347, 1968.

14. Reveille, J. D.; Goodman, R. E.; Barger, B. O.; Acton, R. T.:
Familial polyarteritis nodosa: a serologic and immunogenetic analysis.
J. Rheum. 16: 181-185, 1989.

15. Reveille, J. D.; Wilson, R. W.; Provost, T. T.; Bias, W. B.; Arnett,
F. C.: Primary Sjogren's syndrome and other autoimmune diseases in
families: prevalence and immunogenetic studies in six kindreds. Ann.
Intern. Med. 101: 748-756, 1984.

16. Rose, N. R.; Kong, Y.-C. M.; Sundick, R. S.: The genetic lesions
of autoimmunity. Clin. Exp. Immun. 39: 545-550, 1980.

*FIELD* CS

Immunology:
   Autoimmune disease

Lab:
   High titer autoantibody

Inheritance:
   Autosomal dominant gene epistatic to other secondary genes conferring
   specificity to the autoimmune phenotype

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 12/30/1994
terry: 12/22/1994
mimadm: 4/14/1994
carol: 4/2/1993
carol: 3/31/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
109110
*FIELD* TI
*109110 AUTONOMOUSLY REPLICATING SEQUENCE-1; ARS1
*FIELD* TX
ARS1 is a sequence of human DNA that allows replication of Saccharomyces
cerevisiae integrative plasmids as autonomously replicating elements in
S. cerevisiae cells (Montiel et al., 1984). Montiel et al. (1984) found
several conserved sequences, 1 of which is strikingly similar to the
yeast ARS consensus sequence.

*FIELD* RF
1. Montiel, J. F.; Norbury, C. J.; Tuite, M. F.; Dobson, M. J.; Mills,
J. S.; Kingsman, A. J.; Kingsman, S. M.: Characterization of human
chromosomal DNA sequences which replicate autonomously in Saccharomyces
cerevisiae. Nucleic Acids Res. 12: 1049-1068, 1984.

*FIELD* CD
Victor A. McKusick: 11/23/1988

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 11/23/1988

*RECORD*
*FIELD* NO
109120
*FIELD* TI
109120 AXENFELD-RIEGER ANOMALY WITH PARTIALLY ABSENT EYE MUSCLES, DISTINCTIVE
FACE, HYDROCEPHALY, AND SKELETAL ABNORMALITIES
*FIELD* TX
The Axenfeld-Rieger group of anomalies includes Axenfeld anomaly
(defects limited to the peripheral anterior segment of the eye), Rieger
anomaly (peripheral abnormalities of the anterior segment with
additional changes in the iris), and Rieger syndrome (eye abnormalities
plus nonocular developmental defects; see 180500). Chitty et al. (1991)
described a mother and her 2 children, a daughter and son, who, in
addition to having Axenfeld-Rieger eye anomalies (prominent Schwalbe
ring, hypoplasia of the anterior iris stroma, and iris processes), had
absence of some of the eye muscles, proptosis and hypertelorism,
communicating hydrocephalus, prominent forehead with flat midface, and
skeletal changes such as flat femoral epiphyses. The mother and her
children were apparently of normal intelligence. De Hauwere et al.
(1973) described Rieger anomaly with orbital hypertelorism and
psychomotor retardation in a mother and 3 children. Dilatation of the
cerebral ventricles and mild sensory neural deafness were also present.
Absent eye muscles also is observed with the Moebius syndrome (157900)
and the Poland-Moebius syndrome (173750).

*FIELD* RF
1. Chitty, L. S.; McCrimmon, R.; Temple, I. K.; Russell-Eggitt, I.
M.; Baraitser, M.: Dominantly inherited syndrome comprising partially
absent eye muscles, hydrocephaly, skeletal abnormalities, and a distinctive
facial phenotype. Am. J. Med. Genet. 40: 417-420, 1991.

2. De Hauwere, R. C.; Leroy, J. G.; Adriaenssens, K.: Iris dysplasia,
orbital hypertelorism, and psychomotor retardation: a dominantly inherited
developmental syndrome. J. Pediat. 82: 679-681, 1973.

*FIELD* CS

Eyes:
   Abnormal anterior segment;
   Abnormal iris;
   Schwalbe ring;
   Hypoplastic anterior iris stroma;
   Absent eye muscles;
   Proptosis;
   Hypertelorism

Facies:
   Prominent forehead;
   Flat midface

Ears:
   Mild sensorineural deafness

Neuro:
   Communicating hydrocephalus;
   Psychomotor retardation

Skel:
   Flat femoral epiphyses

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 9/27/1991

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 9/27/1991

*RECORD*
*FIELD* NO
109130
*FIELD* TI
109130 AXIAL OSTEOMALACIA
*FIELD* TX
Axial osteomalacia is a rare osteosclerotic disorder first described by
Frame et al. (1961). Characteristically, trabecular bone has 'a unique
coarsening and spongelike appearance in the x-rays of the axial
skeleton.' Radiographically, the skull and appendicular skeleton are
normal. Vague chronic axial skeletal pain is the presenting symptom in
most patients. Despite osteosclerosis and normal circulating levels of
calcium, inorganic phosphate and alkaline phosphatase, bone biopsy
specimens show osteomalacia. Until the report of Whyte et al. (1981), 10
cases had been described, all in middle-aged or elderly white men. Whyte
et al. (1981) showed that it can occur in blacks, in females, in family
clusters, and in association with polycystic kidney and liver disease.
They reported affected mother and son. The son, who showed x-ray changes
as early as age 22, had an unexplained myopathy characterized by
proximal weakness, persistently elevated circulating creatine
phosphokinase levels, and myopathic changes on muscle biopsy. The
authors suggested that this is a disorder of vitamin D action. (Muscular
weakness is conspicuous also in vitamin D deficiency.) It may be a
pleiotropic disorder with polycystic kidney as a feature. This may be
the same disorder as that described elsewhere under the designation
osteomesopyknosis (166450).

*FIELD* RF
1. Frame, B.; Frost, H. M.; Ormond, R. S.; Hunter, R. B.: Atypical
osteomalacia involving the axial skeleton. Ann. Intern. Med. 55:
632-639, 1961.

2. Whyte, M. P.; Fallon, M. D.; Murphy, W. A.; Teitelbaum, S. L.:
Axial osteomalacia: clinical, laboratory and genetic investigation
of an affected mother and son. Am. J. Med. 71: 1041-1049, 1981.

*FIELD* CS

Skel:
   Osteosclerosis;
   Vague chronic axial skeletal pain

Muscle:
   Myopathy;
   Proximal muscle weakness

Misc:
   Associated polycystic kidney and liver disease

Radiology:
   Unique coarsening and spongelike appearance of trabecular bone of
   axial skeleton;
   Normal skull and appendicular skeleton

Lab:
   Normal blood calcium, inorganic phosphate and alkaline phosphatase;
   Osteomalacia on bone biopsy;
   Elevated circulating creatine phosphokinase;
   Myopathic changes on muscle biopsy

Inheritance:
   Autosomal dominant;
   ? same as osteomesopyknosis (166450)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
carol: 12/1/1989
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
109135
*FIELD* TI
*109135 AXL RECEPTOR TYROSINE KINASE; AXL
ONCOGENE AXL;;
AXL TRANSFORMING GENE
*FIELD* TX
In an effort to determine genes involved in the progression of chronic
myelogenous leukemia (CML) to acute-phase leukemia, Liu et al. (1988)
identified a transforming gene in the DNAs of 2 patients with this
disorder. O'Bryan et al. (1991) found by molecular cloning and
characterization of this gene, which they termed AXL (from the Greek
word 'anexelekto,' or uncontrolled), that it is a receptor tyrosine
kinase with a structure novel among tyrosine kinases. They showed that
the AXL protein is capable of transforming NIH 3T3 cells. Furthermore,
its transforming capacity results from overexpression of AXL mRNA rather
than from structural mutation. By fluorescence in situ hybridization,
O'Bryan et al. (1991) localized the gene to 19q13.2. Janssen et al.
(1991) independently found transforming activity by a tumorigenicity
assay using NIH 3T3 cells transfected with DNA from a patient with a
chronic myeloproliferative disorder. They reported the cDNA cloning of
the corresponding oncogene, which they designated UFO, in allusion to
the unidentified function of the protein. Nucleotide sequence analysis
revealed a 2,682-bp open reading frame capable of directing the
synthesis of an 894-amino acid polypeptide. It was evolutionarily
conserved among vertebrate species. The predicted protein showed
features characteristic of a transmembrane receptor with tyrosine kinase
activity. By nonisotopic in situ hybridization, they mapped the gene to
19q13.1. The gene was transcribed into two 5.0-kb and 3.2-kb mRNAs in
human bone marrow and human tumor cell lines.

The transforming activity of AXL demonstrates that the receptor can
drive cellular proliferation. Although the function of AXL in
nontransformed cells and tissues was unknown, Varnum et al. (1995)
suspected that it may involve the stimulation of cell proliferation in
response to an appropriate signal, i.e., a ligand that activates the
receptor. Varnum et al. (1995) purified an AXL stimulatory factor and
identified it as the product of the growth arrest-specific gene-6
(600441) (Manfioletti et al., 1993).

*FIELD* RF
1. Janssen, J. W. G.; Schulz, A. S.; Steenvoorden, A. C. M.; Schmidberger,
M.; Strehl, S.; Ambros, P. F.; Bartram, C. R.: A novel putative tyrosine
kinase receptor with oncogenic potential. Oncogene 6: 2113-2120,
1991.

2. Liu, E.; Hjelle, B.; Bishop, J. M.: Transforming genes in chronic
myelogenous leukemia. Proc. Nat. Acad. Sci. 85: 1952-1956, 1988.

3. Manfioletti, G.; Brancolini, C.; Avanzi, G.; Schneider, C.: The
protein encoded by a growth arrest-specific gene (gas6) is a new member
of the vitamin K-dependent proteins related to protein S, a negative
coregulator in the blood coagulation cascade. Molec. Cell. Biol. 13:
4976-4985, 1993.

4. O'Bryan, J. P.; Frye, R. A.; Cogswell, P. C.; Neubauer, A.; Kitch,
B.; Prokop, C.; Espinosa, R., III; Le Beau, M. M.; Earp, H. S.; Liu,
E. T.: Axl, a transforming gene isolated from primary human myeloid
leukemia cells, encodes a novel receptor tyrosine kinase. Molec.
Cell. Biol. 11: 5016-5031, 1991.

5. Varnum, B. C.; Young, C.; Elliott, G.; Garcia, A.; Bartley, T.
D.; Fridell, Y.-W.; Hunt, R. W.; Trail, G.; Clogston, C.; Toso, R.
J.; Yanagihara, D.; Bennett, L.; Sylber, M.; Merewether, L. A.; Tseng,
A.; Escobar, E.; Liu, E. T.; Yamane, H. K.: Axl receptor tyrosine
kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific
gene 6. Nature 373: 623-626, 1995.

*FIELD* CD
Victor A. McKusick: 8/18/1993

*FIELD* ED
mark: 06/10/1996
terry: 3/7/1995
carol: 3/6/1995
carol: 8/30/1993
carol: 8/18/1993

*RECORD*
*FIELD* NO
109150
*FIELD* TI
*109150 MACHADO-JOSEPH DISEASE; MJD
AZOREAN NEUROLOGIC DISEASE;;
JOSEPH DISEASE
SPINOPONTINE ATROPHY, INCLUDED;;
NIGROSPINODENTATAL DEGENERATION, INCLUDED
*FIELD* TX
Among Portuguese immigrants living in New England, Nakano et al. (1972)
described a form of dominantly inherited ataxia occurring in descendants
of William Machado, a native of an island in the Portuguese Azores. The
disorder began as ataxic gait after age 40. Six patients studied in
detail showed abnormally large amounts of air in the posterior fossa on
pneumoencephalogram, denervation atrophy of muscle, and diabetes
mellitus. Other families of Azorean origin living in Massachusetts
(Romanul et al., 1977; Woods and Schaumburg, 1972) and in California
(Rosenberg et al., 1976) were reported. Romanul et al. (1977) suggested
that all 4 reported kindreds had the same mutant gene despite
differences in expression. The progressive neurologic disorder was
characterized by gait ataxia, features similar to those in Parkinson
disease in some patients, limitation of eye movements, widespread
fasciculations of muscles, loss of reflexes in the lower limbs, followed
by nystagmus, mild cerebellar tremors and extensor plantar responses.
Postmortem examinations showed loss of neurons and gliosis in the
substantia nigra, nuclei pontis (and in the putamen in one case) as well
as the nuclei of the vestibular and cranial nerves, columns of Clarke
and anterior horns. Rosenberg (1977) referred to the disorder he and his
colleagues described as Joseph disease (Rosenberg et al., 1976) and
questioned that one can be certain of its identity to the disorder in
other families of Azorean origin.

Machado-Joseph disease has been described in several families not known
to be of Portuguese ancestry, e.g., an American black family originating
from North Carolina (Healton et al., 1980), a family in Japan (Sakai et
al., 1983; Ishino et al., 1971, probably dealt with the same family),
and an Italian-American family (Livingstone and Sequeiros, 1984).
Sequeiros et al. (1984) referred to 7 families without known Portuguese
ancestry. Because of the early influence of the Portuguese in Japan, the
Japanese family may suffer from the same mutation as that in the Azorean
cases. This possibility is supported by the fact that the Portuguese
type of familial amyloid polyneuropathy (see 176300.0001) has been
identified in at least 46 families in Japan (Araki et al., 1980).
Livingstone and Sequeiros (1984) noted that 28 families with
Machado-Joseph disease had been described in the Azorean Islands, mainly
Flores and Sao Miguel, and 3 non-Azorean families in northeast Portugal.
Burt et al. (1993) described a dominantly inherited form of ataxia
resembling Machado-Joseph disease in members of 4 families of the Arnhem
Land Aboriginal people of northern Australia. Portuguese ancestry was
possible, although not proven. Goldberg-Stern et al. (1994) reported a
family of Machado-Joseph disease in a Yemenite Jewish kindred that
originated from a remote village named Ta'izz. This family, incidentally
named Yoseph, had no documentation of Portuguese ancestry. Portuguese
trade connections with the Yemenites most likely did not reach Ta'izz
which is far from the coast and is almost inaccessible because of a wall
of high mountains.

Under the designation 'spinopontine degeneration,' Boller and Segarra
(1969) reported 24 persons with late-onset ataxia in 4 generations of an
Anglo-Saxon family. Taniguchi and Konigsmark (1971) described 16
affected persons in 3 generations of a black family. The pathologic
findings were similar in the 2 families. The cerebellum was relatively
spared and the inferior olives were normal. The spinal cord showed loss
of myelinated fibers in the spinocerebellar tracts and posterior
funiculi. There was also marked loss of nuclei basis ponti. Pogacar et
al. (1978) followed up on the Boller-Segarra family (members of which
had lived in northern Rhode Island for over 300 years). In 2 clinical
cases and 1 autopsy, they questioned the separation from
olivopontocerebellar ataxia, because they found abolished tendon
reflexes and flexion contractures of the legs in 1 patient, and onset at
18 years of age, palatal myoclonus and optic atrophy in the second.
Dementia developed in both. Pathologic findings, in contrast to earlier
reports, showed involvement of the cerebellum and inferior olivary
nuclei. Eto et al. (1990) described a family of German extraction with
progressive ataxia, eye movement abnormalities, peripheral sensory loss,
and spinal muscular atrophy of adult onset. The pedigree pattern in 4
generations was consistent with autosomal dominant inheritance. Eto et
al. (1990) suggested that the form of spinopontine atrophy might be
different from Machado-Joseph disease: the eyes were not protuberant,
extraocular movements were abnormal to a minor degree, and
neuropathologically the substantia nigra and dentate nucleus were
spared. Eto et al. (1990) considered their family to resemble most that
reported by Boller and Segarra (1969). Sequeiros (1985) pointed out that
the diagnosis of Machado-Joseph disease had been made (Healton et al.,
1980) in an American black family originating from North Carolina; that
on further check this proved to be the family reported by Taniguchi and
Konigsmark (1971); that Coutinho et al. (1982), in commenting on the
neuropathology of Machado-Joseph disease, noted the similarity to the
spinopontine atrophy reported by Boller and Segarra (1969), Taniguchi
and Konigsmark (1971), and Ishino et al. (1971); and, finally, that the
disorder reported in the last family, Japanese, had been proved to be
Machado-Joseph disease. See Sequeiros and Suite (1986). Lazzarini et al.
(1992) expanded on the pedigree of the family first reported by Boller
and Segarra (1969) and concluded that the disorder represented a
spinocerebellar ataxia phenotypically similar to that of spinocerebellar
ataxia type 1 (SCA1; 164400) which shows linkage to HLA. However,
linkage to HLA was excluded in this kindred, leading to the designation
SCA2 (183090) for this and other HLA-unlinked SCA kindreds. Silveira et
al. (1993) demonstrated that the disorder designated Holguin ataxia, or
SCA2, that is frequent in Cubans is genetically distinct from MJD; MJD
was excluded from a location on 12q where linkage studies showed the
SCA2 locus to be situated.

Myers et al. (1986) found no clear evidence of linkage of Machado-Joseph
disease with 18 protein markers. Forse et al. (1989) showed that
Machado-Joseph disease is not caused by an allele at the Huntington
disease locus, inasmuch as linkage with the D4S10 marker within a
distance of 10 cM was excluded.

In Japanese kindreds with this disorder, Takiyama et al. (1993) assigned
the gene to 14q24.3-q32 by genetic linkage to microsatellite loci D14S55
and D14S48; multipoint maximum lod score = 9.719. They commented on the
fact that although MJD was first described in families of
Portuguese-Azorean ancestry, the disorder had been reported in
non-Azorean families in many countries and had come to be regarded as
one of the most common autosomal dominant spinocerebellar degenerations.
Using 4 microsatellite DNA polymorphisms (STRPs), Sequeiros et al.
(1994) likewise mapped the MJD gene to 14q. Using HOMOG, Sequeiros et
al. (1994) could find no evidence for heterogeneity with the 5 Japanese
families in whom linkage had been reported. St. George-Hyslop et al.
(1994) provided evidence that MJD in 5 pedigrees of Azorean descent was
also linked to 14q in an 18-cM region between the markers D14S67 and
AACT (107280); multipoint lod score = 7.00 near D14S81. They also
reported molecular evidence for homozygosity at the MJD locus in an
MJD-affected subject with severe, early-onset symptoms.

Twist et al. (1995) studied 6 MJD families of Portuguese/Azorean origin
and 1 of Brazilian origin, using 9 microsatellite markers mapped to
14q24.3-q32. They showed that the MJD gene is located in the same
interval as spinocerebellar ataxia type 3 (SCA3; 183085), supporting the
suggestion that these diseases are allelic.

Coutinho et al. (1982) described the presumedly homozygotic son of 2
affected parents; the son had onset at age 8 and died of the disease at
age 15. Another son of these parents had onset at age 7. As with other
late-onset dominant spinocerebellar degenerations (notably the
olivopontocerebellar degenerations), there is considerable phenotypic
variation even within the same family. Coutinho and Andrade (1978)
proposed a 3-way phenotypic classification: cerebellar ataxia, external
ophthalmoplegia and pyramidal signs (type 2), additional predominant
extrapyramidal signs (type 1), and additional distal muscular atrophy
(type 3). Although not completely specific to MJD, dystonia, facial and
lingual fasciculations, and peculiar, bulging eyes represent a
constellation strongly suggestive of this disease. Rosenberg (1983)
added a fourth phenotype: neuropathy and parkinsonism. Joseph disease is
a fascinating case study in nosology, a contest between lumpers and
splitters. Even the name has been much debated depending, for example,
on what has been thought to be the neuropathology and the predominant
ethnic distribution of the disease. Joseph disease seems to be a
consensus designation, witness the fact that it was selected for the
name of the lay-professional single-disease society. Use of the
designation Azorean neurologic disease is acceptable, I believe; there
are many examples of eponyms that have proven inaccurate in honoring the
first description or perhaps even the predominant ethnic distribution.
In January 1976, Corino Andrade (Coutinho et al., 1977) 'went to the
Azores...to investigate a degenerative disease of the central nervous
system known to exist there. Indeed, in 1972, 2 families of Azorean
ancestry were described in the U.S. as having a peculiar hereditary
ataxia (Nakano et al., 1972; Woods and Schaumburg, 1972). We saw 40
patients belonging to 15 families (in the islands of Flores and St.
Michael)...It is our opinion that different families just mentioned,
which have been taken as separate diseases, are only clinically diverse
forms of the same disorder, of which symptomatic pleomorphism is a
conspicuous feature.' In the same year, Romanul et al. (1977) arrived at
the same conclusion. The full paper by Coutinho and Andrade (1978)
appeared the next year. Barbeau et al. (1984) gave an extensive review.
Lima and Coutinho (1980) described a mainland Portuguese family. The
possibility that the Joseph family was originally Sephardic Jewish was
raised by Sequeiros and Coutinho (1981). Mainland families originated in
a mountainous and relatively inaccessible region of northeastern
Portugal where large communities of Sephardic Jews settled at one time.
Sequeiros and Coutinho (1981) identified 9 cases of 'skipped
generations' (penetrance = 94.5%). Dawson et al. (1982) suggested that
the electrooculogram may be useful in early detection.

Takiyama et al. (1994) compared the clinical and pathologic features of
SCA1 and SCA2 to those in a large Japanese family with Machado-Joseph
disease that had previously been linked to markers on chromosome 14q.
Although many of the clinical features and the age of onset were similar
to those of SCA1 and SCA2, other features were more distinctive for
Machado-Joseph disease. These included dystonia, difficulty in opening
of the eyelids, slowness of movements, bulging eyes, and facial-lingual
fasciculations. One autopsy showed few changes in either the inferior
olive or the Purkinje cells, in sharp contrast to SCA1 and SCA2 where
such changes are pronounced. The subthalamopallidal system of the MJD
patient showed marked degeneration, which has not been described in SCA1
or SCA2.

In a nationwide survey of Japanese patients, Hirayama et al. (1994)
estimated the prevalence of all forms of spinocerebellar degeneration to
be 4.53 per 100,000; of these, 2% were thought to have Machado-Joseph
disease.

Kawaguchi et al. (1994) screened a human brain cDNA library using an
oligonucleotide probe with 13 CTG repeats, complementary to the CAG
repeats. One of the cDNA clones contained a CAG repeat and was,
therefore, subjected to further investigation. They mapped the gene to
14q32.1, the location of the gene for MJD. In normal individuals, the
gene was found to contain between 13 and 36 CAG repeats, whereas most of
the patients with clinically diagnosed MJD and all of the affected
members of a family with the clinical and pathologic diagnosis of MJD
showed expansion of the repeat number to the range of 68 to 79.
Kawaguchi et al. (1994) found a negative correlation between age of
onset and CAG repeat numbers. Southern blot analyses and genomic cloning
demonstrated the existence of related genes and raised the possibility
that similar abnormalities in related genes may give rise to diseases
similar to MJD.

Maruyama et al. (1995) examined the molecular features of the CAG
repeats and the clinical manifestations in 90 MJD individuals from 62
independent Japanese MJD families and found that the MJD1 repeat length
was inversely correlated with the age of onset (r = -0.87). The MJD
chromosomes contained 61-84 repeat units, whereas normal chromosomes
displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were
the most common and the shortest. In association with the clinical
anticipation of the disease, a parent-child analysis showed the
unidirectional expansion of CAG repeats and no case of diminution in the
affected family. The differences in CAG repeat length between parent and
child and between sibs were greater in paternal transmission than in
maternal transmission. Detailed analysis showed that a large degree of
expansion was associated with a shorter length of the MJD1 gene in
paternal transmission. On the other hand, the increments of increase
were similar for shorter and longer expansions in maternal transmission.
Among the 3 clinical subtypes, type 1 MJD with dystonia showed a larger
degree of expansion in CAG repeats of the gene and younger ages of onset
than the other types.

A form of autosomal dominant spinocerebellar ataxia, SCA3 (183085) was
mapped to 14q, close to the MJD locus. As some clinical features of MJD
overlap with those of SCA, Schols et al. (1995) sought MJD mutations in
38 German families with autosomal dominant SCA. The MJD1 (CAG)n
trinucleotide expansion was identified in 19 families. In contrast, the
trinucleotide expansion was not observed in 21 ataxia patients without a
family history of the disease. Analysis of the (CAG)n repeat length in
30 patients revealed an inverse correlation with the age of onset. The
(CAG)n stretch of the affected allele varied between 67 and 78
trinucleotide units; the normal alleles carried between 12 and 28 simple
repeats. These results demonstrated that the MJD mutation causes the
disease phenotype of most SCA patients in Germany. Schols et al. (1995)
pointed out that in SCA3 as observed in Germany, features characteristic
of Machado-Joseph disease, such as dystonia, bulging eyes, and
faciolingual fasciculations, are rare.

Takiyama et al. (1995) examined the size of the (CAG)n repeat array in
the 3-prime end of the MJD1 gene and the haplotype at a series of
microsatellite markers surrounding the MJD1 gene in a large cohort of
Japanese and Caucasian subjects with MJD. Expansion of the array from
the normal range of 14-37 repeats to 68-84 repeats was found with no
instances of expansions intermediate in size between those of the normal
and MJD affected groups. The expanded allele associated with MJD
displayed intergenerational instability, particularly in male meiosis,
and this instability was associated with the clinical phenomenon of
anticipation. The size of the expanded allele was not only inversely
correlated with the age-of-onset of MJD, but was also correlated with
the frequency of other clinical features, such as pseudoexophthalmos and
pyramidal signs were more frequent in subjects with larger repeats. The
disease phenotype was significantly more severe and had an early age of
onset (16 years) in a subject homozygous for the expanded allele, which
contrasts with Huntington disease (HD; 143100), in which the homozygous
subject has a disorder indistinguishable from that in the heterozygous
subject. The observation in MJD suggests that the expanded allele may
exert its effect either by a dominant negative effect (putatively
excluded in HD) or by a gain-of-function effect as proposed for HD.
Japanese and Caucasian subjects affected with MJD shared haplotypes at
several markers surrounding the MJD1 gene, these markers being uncommon
in the normal Japanese and Caucasian populations, thus suggesting the
existence either of common founders in these populations or of
chromosomes susceptible to pathologic expansion of the CAG repeat in the
MJD1 gene.

Size of the expanded repeat and gene dosage are factors in the severity
and early onset of MJD. Another factor pointed out by Kawakami et al.
(1995) is gender. In a total of 14 sibpairs, the mean of the differences
in age of onset between the sibs of different sexes was 12.7 +/-1.7 (n =
7) and between the sibs of the same sex was 3.9 +/-1.7 (n = 7). The
difference was statistically significant, whereas the variance in length
of CAG repeats between these 2 groups was not significant.

Ranum et al. (1995) made use of the fact that the genes involved in 2
forms of autosomal dominant ataxia, that for MJD and that for SCA1, have
been isolated to assess the frequency of trinucleotide repeat expansions
among individuals diagnosed with ataxia. They collected and analyzed DNA
from individuals with both disorders. In both cases, the genes
responsible for the disorder were found to have an expansion of an
unstable CAG trinucleotide repeat. These individuals represented 311
families with adult-onset ataxia of unknown etiology, of which 149
families had dominantly inherited ataxia. Ranum et al. (1995) found that
of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were
positive for the MJD trinucleotide expansion. For the 57 patients with
MJD trinucleotide repeat expansions, strong inverse correlation between
CAG repeat size and age at onset was observed (r = -0.838). Among the
MJD patients, the normal and affected ranges of CAG repeat size were 14
to 40 and 68 to 82 repeats, respectively. For SCA1, the normal and
affected ranges were much closer, namely 19 to 38 and 40 to 81 CAG
repeats, respectively.

Cancel et al. (1995) documented the marked phenotypic heterogeneity
associated with expansion of the CAG repeat sequence at the SCA3/MJD
locus. They studied 3 French families with type I autosomal dominant
cerebellar ataxia and a French family with neuropathologic findings
suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy.
A strong correlation was found between size of the expanded CAG repeat
and age at onset of clinical disease. Instability of the expanded
triplet repeat was not found to be affected by sex of the parent
transmitting the mutation. Both somatic and gonadal mosaicism for
alleles carrying expanded trinucleotide repeats was found. The 4 French
families had no known Portugese ancestry. Faciolingual myokymia, said to
be a hallmark of MJD, increased tendon reflexes, ophthalmoplegia and
dystonia occur significantly more frequent among Azorean MJD patients,
while decreased vibratory sense and dementia were found more often among
the French cerebellar ataxia type I patients. Myoclonus, present in 1 of
the 5 patients in the French family with the DRPLA-like disorder, had
never been reported in SCA3 or MJD kindreds.

Ikeuchi et al. (1996) analyzed segregation patterns in 80 transmissions
in 7 MJD pedigrees and in 211 transmissions in 24 DRPLA pedigrees
(125370), with the diagnoses confirmed by molecular testing. The
significant distortions in favor of transmission of the mutant alleles
were found in male meiosis, where the mutant alleles were transmitted to
73% of all offspring in MJD (P less than 0.01) and to 62% of all
offspring in DRPLA (P less than 0.01). The results were consistent with
meiotic drive in these 2 disorders. The authors commented that, since
more prominent meiotic instability of the length of the CAG
trinucleotide repeats is observed in male meiosis than in female meiosis
and meiotic drive is observed only in male meiosis, these results raised
the possibility that a common molecular mechanism underlies the meiotic
drive and the meiotic instability in male meiosis.

Rubinsztein and Leggo (1997) investigated the transmission of alleles
with larger versus smaller CAG repeat numbers in the MJD1 gene in normal
heterozygotes from the 40 CEPH families. Their data suggested that there
was no segregation distortion in male meioses, while the smaller CAG
allele was inherited in 57% of female meioses (p = less than 0.016). The
pattern of inheritance of smaller versus larger CAG alleles at this
locus was significantly different when male and female meioses were
compared. While previous data suggested that meiotic drive may be a
feature of certain human diseases, including the trinucleotide disease
MJD, myotonic dystrophy, and DRPLA, the data of Rubinsztein and Leggo
(1997) were compatible with meiotic drive also occurring among
nondisease-associated CAG sizes.

In German patients with SCA3 (183085), which is caused by mutations at
the same locus as MJD, Riess et al. (1997) likewise found transmission
distortion of the mutant alleles, but the segregation distortion was
observed during maternal transmission in German families, rather than in
paternal inheritance, as observed in Japanese pedigrees.

Ikeda et al. (1996) demonstrated the induction of apoptosis in cultured
cells expressing a portion of the MJD1 gene that included the expanded
CAG repeats. Cell death occurred only when the CAG repeat was translated
into polyglutamine residues, which apparently precipitated in large
covalently modified forms. Ikeda et al. (1996) also created ataxic
transgenic mice by expressing the expanded polyglutamine stretch in
Purkinje cells. The results demonstrated the potential involvement of
expanded polyglutamine regions as the common etiologic agent for
inherited neurodegenerative diseases with CAG expansions.

Maruyama et al. (1995) and Takiyama et al. (1995) reported an
intergenerational increase in the number of CAG repeat units and genetic
anticipation of MJD. Genetic anticipation in this disorder was reported
to be more prominent in paternal transmission than in maternal
transmission. Stevanin et al. (1995) reported strong linkage
disequilibrium of MJD chromosomes at the AFM343vf1 locus and found a
common haplotype that is frequently shared by Japanese and Azorean MJD
chromosomes, which suggests a founder effect or the presence of
predisposing chromosomes prone to expansions of the CAG repeat. Igarashi
et al. (1996) investigated the association of intergenerational
instability of the expanded CAG repeat in MJD with a CAG/CAA
polymorphism in the CAG repeat and a CGG/GGG polymorphism at the 3-prime
end of the CAG array. Their results strongly suggested that an
interallelic interaction is involved in the intergenerational
instability of the expanded CAG repeat. Igarashi et al. (1996) reported
that normal chromosomes with the CGG allele are more frequently
associated with larger CAG repeats than normal chromosomes with the GGG
allele. They also reported that 80 of 88 independent MJD chromosomes had
the CGG allele, which is in striking contrast to the CGG allele
frequency in the normal chromosome. Igarashi et al. (1996) investigated
the effect of gender on the intergenerational instability of the
expanded CAG repeat. They obtained significant evidence that the
expanded CAG repeats were less stable in paternal transmission than in
maternal transmission.

*FIELD* AV
.0001
MACHADO-JOSEPH DISEASE
SPINOCEREBELLAR ATAXIA-3
MJD, (CAG)n EXPANSION
Machado-Joseph disease and cerebellar ataxia-3 are produced by an
expansion of a (CAG)n repeat in the MJD gene. In normal individuals, the
gene contains between 13 and 36 CAG repeats, whereas most patients with
clinically diagnosed MJD and all of the affected members of a family
with clinical and pathologic MJD show expansion of the repeat number in
the range of 68 to 79 copies. The same CAG repeat in the MJD gene is
found as the cause of one form of spinocerebellar ataxia (183085).

*FIELD* SA
Boyer et al. (1962); Chazot et al. (1983); Dawson  (1977); Rosenberg
and Fowler (1981); Sachdev et al. (1982); Suite et al. (1986)
*FIELD* RF
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J.; Simpson, N. E.: Machado-Joseph disease: linkage analysis between
the loci for the disease and 18 protein markers. Cytogenet. Cell
Genet. 43: 226-228, 1986.

29. Nakano, K. K.; Dawson, D. M.; Spence, A.: Machado disease: a
hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology 22:
49-55, 1972.

30. Pogacar, S.; Ambler, M.; Conklin, W. J.; O'Neil, W. A.; Lee, H.
Y.: Dominant spinopontine atrophy: report of two additional members
of family W. Arch. Neurol. 35: 156-162, 1978.

31. Ranum, L. P. W.; Lundgren, J. K.; Schut, L. J.; Ahrens, M. J.;
Perlman, S.; Aita, J.; Bird, T. D.; Gomez, C.; Orr, H. T.: Spinocerebellar
ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions
among adult-onset ataxia patients from 311 families with dominant,
recessive, or sporadic ataxia. Am. J. Hum. Genet. 57: 603-608, 1995.

32. Riess, O.; Epplen, J. T.; Amoiridis, G.; Przuntek, H.; Schols,
L.: Transmission distortion of the mutant alleles in spinocerebellar
ataxia. Hum. Genet. 99: 282-284, 1997.

33. Romanul, F. C. A.; Fowler, H. L.; Radvany, J.; Feldman, R. G.;
Feingold, M.: Azorean disease of the nervous system. New Eng. J.
Med. 296: 1505-1508, 1977.

34. Rosenberg, R. N.: Azorean disease of the nervous system.(Letter) New
Eng. J. Med. 297: 729, 1977.

35. Rosenberg, R. N.: Dominant ataxias.In: Kety, S. S.; Rowland,
L. P.; Sidman, R. L.; Matthysse, S. W.: Genetics of Neurological
and Psychiatric Disorders.  New York: Raven Press (pub.)  1983.

36. Rosenberg, R. N.; Fowler, H. L.: Autosomal dominant motor system
disease of the Portuguese: a review. Neurology 31: 1124-1126, 1981.

37. Rosenberg, R. N.; Nyhan, W. L.; Bay, C.; Shore, P.: Autosomal
dominant striato-nigral degeneration: a clinical, pathologic and biochemical
study of a new genetic disorder. Neurology 26: 703-714, 1976.

38. Rubinsztein, D. C.; Leggo, J.: Non-Mendelian transmission at
the Machado-Joseph disease locus in normal females: preferential transmission
of alleles with smaller CAG repeats. J. Med. Genet. 34: 234-236,
1997.

39. Sachdev, H. S.; Forno, L. S.; Kane, C. A.: Joseph disease: a
multisystem degenerative disorder of the nervous system. Neurology 32:
192-195, 1982.

40. Sakai, T.; Ohta, M.; Ishino, H.: Joseph disease in a non-Portuguese
family. Neurology 33: 74-80, 1983.

41. Schols, L.; Amoiridis, G.; Langkafel, M.; Buttner, T.; Przuntek,
H.; Riess, O.; Vieira-Saecker, A. M.; Epplen, J. T.: Machado-Joseph
disease mutations as the genetic basis of most spinocerebellar ataxias
in Germany. J. Neurol. Neurosurg. Psychiat. 59: 449-450, 1995.

42. Schols, L.; Vieira-Saecker, A. M. M.; Schols, S.; Przuntek, H.;
Epplen, J. T.; Riess, O.: Trinucleotide expansion within the MJD1
gene presents clinically as spinocerebellar ataxia and occurs most
frequently in German SCA patients. Hum. Molec. Genet. 4: 1001-1005,
1995.

43. Sequeiros, J.: Personal Communication. Baltimore, Md. and Oporto,
Portugal  3/4/1985.

44. Sequeiros, J.; Coutinho, P.: Genetic aspects of Machado-Joseph
disease. Broteria-Genetica (Lisbon) 77: 137-147, 1981.

45. Sequeiros, J.; Silva, R. M.; Rosenberg, R. N.: Epidemiology of
Machado-Joseph disease.(Abstract) Clin. Res. 32: 693A, 1984.

46. Sequeiros, J.; Silveira, I.; Maciel, P.; Coutinho, P.; Manaia,
A.; Gaspar, C.; Burlet, P.; Loureiro, L.; Guimaraes, J.; Tanaka, H.;
Takiyama, Y.; Sakamoto, H.; Nishizawa, M.; Nomura, Y.; Segawa, M.;
Tsuji, S.; Melki, J.; Munnich, A.: Genetic linkage studies of Machado-Joseph
disease with chromosome 14q STRPs in 16 Portuguese-Azorean kindreds. Genomics 21:
645-648, 1994.

47. Sequeiros, J.; Suite, N. D. A.: Spinopontine atrophy disputed
as a separate entity: the first description of Machado-Joseph disease.
(Letter) Neurology 36: 1408, 1986.

48. Silveira, I.; Manaia, A.; Melki, J.; Magarino, C.; Lunkes, A.;
Hernandez, A.; Gispert, S.; Burlet, P.; Rozet, J.-M.; Coutinho, P.;
Loureiro, J. E. L.; Guimaraes, J.; Auburger, G.; Munnich, A.; Sequeiros,
J.: Machado-Joseph disease is genetically different from Holguin
dominant ataxia (SCA2). Genomics 17: 556-559, 1993.

49. St. George-Hyslop, P.; Rogaeva, E.; Huterer, J.; Tsuda, T.; Santos,
J.; Haines, J. L.; Schlumpf, K.; Rogaev, E. I.; Liang, Y.; Crapper
McLachlan, D. R.; Kennedy, J.; Weissenbach, J.; Billingsley, G. D.;
Cox, D. W.; Lang, A. E.; Wherrett, J. R.: Machado-Joseph disease
in pedigrees of Azorean descent is linked to chromosome 14. Am. J.
Hum. Genet. 55: 120-125, 1994.

50. Stevanin, G.; Cancel, G.; Didierjean, O.; Durr, A.; Abbas, N.;
Cassa, E.; Feingold, J.; Agid, Y.; Brice, A.: Linkage disequilibrium
at the Machado-Joseph disease/spinal cerebellar ataxia 3 locus: evidence
for a common founder effect in French and Portuguese-Brazilian families
as well as a second ancestral Portuguese-Azorean mutation. (Letter) Am.
J. Hum. Genet. 57: 1247-1250, 1995.

51. Suite, N. D. A.; Sequeiros, J.; McKhann, G. M.: Machado-Joseph
disease in a Sicilian-American family. J. Neurogenet. 3: 177-182,
1986.

52. Takiyama, Y.; Igarashi, S.; Rogaeva, E. A.; Endo, K.; Rogaev,
E. I.; Tanaka, H.; Sherrington, R.; Sanpei, K.; Liang, Y.; Saito,
M.; Tsuda, T.; Takano, H.; Ikeda, M.; Lin, C.; Chi, H.; Kennedy, J.
L.; Lang, A. E.; Wherrett, J. R.; Segawa, M.; Nomura, Y.; Yuasa, T.;
Weissenbach, J.; Yoshida, M.; Nishizawa, M.; Kidd, K. K.; Tsuji, S.;
St George-Hyslop, P. H.: Evidence for inter-generational instability
in the CAG repeat in the MJD1 gene and for conserved haplotypes at
flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph
disease. Hum. Molec. Genet. 4: 1137-1146, 1995.

53. Takiyama, Y.; Nishizawa, M.; Tanaka, H.; Kawashima, S.; Sakamoto,
H.; Karube, Y.; Shimazaki, H.; Soutome, M.; Endo, K.; Ohta, S.; Kagawa,
Y.; Kanazawa, I.; Mizuno, Y.; Yoshida, M.; Yuasa, T.; Horikawa, Y.;
Oyanagi, K.; Nagai, H.; Kondo, T.; Inuzuka, T.; Onodera, O.; Tsuji,
S.: The gene for Machado-Joseph disease maps to human chromosome
14q. Nature Genet. 4: 300-304, 1993.

54. Takiyama, Y.; Oyanagi, S.; Kawashima, S.; Sakamoto, H.; Saito,
K.; Yoshida, M.; Tsuji, S.; Mizuno, Y.; Nishizawa, M.: A clinical
and pathologic study of a large Japanese family with Machado-Joseph
disease tightly linked to the DNA markers on chromosome 14q. Neurology 44:
1302-1308, 1994.

55. Taniguchi, R.; Konigsmark, B. W.: Dominant spino-pontine atrophy:
report of a family through three generations. Brain 94: 349-358,
1971.

56. Twist, E. C.; Casaubon, L. K.; Ruttledge, M. H.; Rao, V. S.; Macleod,
P. M.; Radvany, J.; Zhao, Z.; Rosenberg, R. N.; Farrer, L. A.; Rouleau,
G. A.: Machado Joseph disease maps to the same region of chromosome
14 as the spinocerebellar ataxia type 3 locus. J. Med. Genet. 32:
25-31, 1995.

57. Woods, B. T.; Schaumburg, H. H.: Nigro-spino-dentatal degeneration
with nuclear ophthalmoplegia: a unique and partially treatable clinico-pathological
entity. J. Neurol. Sci. 17: 149-166, 1972.

*FIELD* CS

Neuro:
   Ataxia;
   Parkinsonian features;
   Dystonia;
   Facial and lingual fasciculations;
   Muscle fasciculation;
   Loss of leg reflexes;
   Cerebellar tremors;
   Extensor plantar responses

Eyes:
   Bulging eyes;
   Limited eye movement;
   Nystagmus

Muscle:
   Muscle atrophy

Endo:
   Diabetes mellitus

Misc:
   Onset after age 40

Lab:
   Neuronal loss and gliosis in the substantia nigra, nuclei pontis (putamen
   in one case), nuclei of vestibular and cranial nerves, columns of
   Clarke and anterior horns;
   Abnormal electrooculogram

Inheritance:
   Autosomal dominant (14q24.3-q32)

*FIELD* CN
Victor A. McKusick - updated: 04/21/1997
Victor A. McKusick - updated: 2/19/1997
Moyra Smith - updated: 8/15/1996
Orest Hurko - updated: 3/27/1996
Moyra Smith - updated: 3/26/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
alopez: 04/21/1997
alopez: 4/17/1997
terry: 4/11/1997
mark: 2/19/1997
terry: 2/11/1997
terry: 8/15/1996
mark: 8/15/1996
mark: 8/8/1996
mark: 7/22/1996
mark: 5/31/1996
terry: 5/29/1996
mark: 4/27/1996
terry: 4/19/1996
terry: 4/15/1996
mark: 3/27/1996
mark: 3/26/1996
terry: 3/19/1996
mark: 10/19/1995
carol: 12/5/1994
terry: 7/28/1994
jason: 7/1/1994
davew: 6/8/1994
mimadm: 4/14/1994

*RECORD*
*FIELD* NO
109160
*FIELD* TI
*109160 AZOTEMIA, FAMILIAL
*FIELD* TX
Hsu et al. (1978) described a family in which 6 persons in 3 generations
had elevated serum urea with normal creatine levels, renal biopsy and
all measures of renal function except urea clearance. Urea is both
filtered at the glomerulus and actively secreted by the proximal tubule
(Kawamura and Kokko, 1976). Furthermore, urea is reabsorbed actively by
the tubule; this process is apparently brought into play particularly in
states of low protein intake. Net reabsorption might be due to
exaggerated active reabsorption or to deficient secretion. Whatever the
precise nature of the defect, it appeared to be inherited as an
autosomal dominant. Four instances of father-to-son transmission were
demonstrated.

*FIELD* RF
1. Hsu, C. H.; Kurtz, T. W.; Massari, P. U.; Ponze, S. A.; Chang,
B. S.: Familial azotemia: impaired urea excretion despite normal
renal function. New Eng. J. Med. 298: 117-121, 1978.

2. Kawamura, S.; Kokko, J. P.: Urea secretion by the straight segment
of the proximal tubule. J. Clin. Invest. 58: 604-612, 1976.

*FIELD* CS

GU:
   Normal renal function

Lab:
   Azotemia;
   Normal creatinine

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/25/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
109170
*FIELD* TI
*109170 B144 PROTEIN
*FIELD* TX
In the mouse H-2 complex, the gene B144, which is transcribed
specifically in B cells and macrophages, is located 10 kb downstream
from the TNFA gene (Tsuge et al., 1987). Spies et al. (1989) found the
human B144 homolog in a corresponding position within a cosmid clone by
DNA blot hybridization with a mouse cDNA probe.

Nalabolu et al. (1996) showed that the human homolog of B144 maps within
a 200-kb region of 6p21.3 spanning the TNFA (191160) and TNFB (153440)
cluster. The gene is located between a cytokeratin pseudogene and 1C7,
which is preferentially expressed in the spleen.

*FIELD* RF
1. Nalabolu, S. R.; Shukla, H.; Nallur, G.; Parimoo, S.; Weissman,
S. M.: Genes in a 220-kb region spanning the TNF cluster in human
MHC. Genomics 31: 215-222, 1996.

2. Spies, T.; Blanck, G.; Bresnahan, M.; Sands, J.; Strominger, J.
L.: A new cluster of genes within the human major histocompatibility
complex. Science 243: 214-217, 1989.

3. Tsuge, I.; Shen, F.-W.; Steinmetz, M.; Boyse, E. A.: A gene in
the H-2S:H-2D interval of the major histocompatibility complex which
is transcribed in B cells and macrophages. Immunogenetics 26: 378-380,
1987.

*FIELD* CN
Alan F. Scott - updated: 04/09/1996

*FIELD* CD
Victor A. McKusick: 1/30/1989

*FIELD* ED
mark: 04/09/1996
terry: 4/9/1996
mark: 4/8/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 1/30/1989

*RECORD*
*FIELD* NO
109180
*FIELD* TI
*109180 BABOON VIRUS INTEGRATION; BEVI
*FIELD* TX
Baboon M7 xenotropic (type C) virus infects human cells but not Chinese
hamster cells. By human-hamster cell hybrids, Brown et al. (1978) showed
that this behavior of human cells requires chromosome 19. Thus, several
virus susceptibilities have been related to chromosome 19; see polio
virus sensitivity (173850) and Echo 11 sensitivity (129150).
Contradictory findings were reported by Lemons et al. (1977), who
assigned the locus to chromosome 6. Lemons et al. (1977) referred to the
locus as 'Bevi' for baboon endogenous virus infection, but it can
equally well stand for baboon endogenous virus integration because
Lemons et al. (1978) presented evidence that 'Bevi' is the preferred
proviral integration site in the human genome. It was the conclusion of
the fifth Human Gene Mapping Workshop in Edinburgh (1979) that BEVI is
on chromosome 6, but that chromosome 19 carries a locus, symbolized
M7VS1, which is essential to replication of the baboon virus (see
109190).

*FIELD* SA
Lemons et al. (1978)
*FIELD* RF
1. Brown, S.; Oie, H.; Francke, U.; Gazdar, A. F.; Minna, J. D.:
Assignment of a gene required for infection with endogenous baboon
virus to human chromosome 19. Cytogenet. Cell Genet. 22: 239-242,
1978.

2. Lemons, R. S.; Nash, W. G.; O'Brien, S. J.; Benveniste, R. E.;
Sherr, C. J.: A gene (Bevi) on human chromosome 6 is an integration
site for baboon type C DNA provirus in human cells. Cell 14: 995-1005,
1978.

3. Lemons, R. S.; O'Brien, S. J.; Sherr, C. J.: A new genetic locus,
Bevi, on human chromosome 6 which controls the replication of baboon
type C virus in human cells. Cell 12: 251-262, 1977.

4. Lemons, R. S.; O'Brien, S. J.; Sherr, C. J.: The Bevi locus (chromosome
6) encodes a post-penetrational cellular function required for baboon
endogenous virus replication in human cells. Cytogenet. Cell Genet. 22:
255-259, 1978.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 7/20/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 9/19/1988
carol: 9/14/1988

*RECORD*
*FIELD* NO
109190
*FIELD* TI
*109190 BABOON VIRUS RECEPTOR; M7V1
RD114 SENSITIVITY;;
RD114 VIRUS RECEPTOR; RDRC
*FIELD* TX
It was the conclusion of the fifth Human Gene Mapping Workshop in
Edinburgh (1979) that chromosome 19 carries a gene required for
replication of baboon M7 virus. The RD114 virus is an endogenous feline
type C retrovirus. By study of mouse-human hybrid cells, Schnitzer et
al. (1980) showed that the gene encoding the RD114 virus receptor is
located on human chromosome 19. They showed that the receptor is
independent of that for poliovirus, which is also encoded by chromosome
19. The feline and baboon endogenous type C retroviruses make use of the
same receptor. Replication and integration of the baboon virus are
dependent on chromosome 6 (see 109180); whether this is also true of the
feline virus is not known (Schnitzer et al., 1980). By analysis of
human-mouse hybrid cells, Kaneda et al. (1987) assigned RDRC to
19q1.1-qter.

Simian retrovirus (SRV) serotypes 1 to 5 are exogenous type D viruses
causing immune suppression in macaque monkeys. These viruses exhibit
receptor interference with each other, with 2 endogenous type D viruses
of the langur and squirrel monkey, and with 2 type C retroviruses,
feline endogenous virus (RD114/CCC) and baboon endogenous virus (BaEV),
indicating that each utilizes the same cell surface receptor (Sommerfelt
and Weiss, 1990). Sommerfelt et al. (1990) used envelope glycoproteins
from several of these strains to detect receptors expressed in
human/rodent somatic cell hybrids segregating human chromosomes. The
only human chromosome common to all the susceptible hybrids was
chromosome 19. By using hybrids retaining different fragments of
chromosome 19, a provisional subchromosomal localization of the receptor
gene was made to 19q13.1-q13.2.

*FIELD* RF
1. Kaneda, Y.; Hayes, H.; Uchida, T.; Yoshida, M. C.; Okada, Y.:
Regional assignment of five genes on human chromosome 19. Chromosoma 95:
8-12, 1987.

2. Schnitzer, T. J.; Weiss, R. A.; Juricek, D. K.; Ruddle, F. H.:
Use of vesicular stomatitis virus pseudotypes to map viral receptor
genes: assignment of RD114 virus receptor gene to human chromosome
19. J. Virol. 35: 575-580, 1980.

3. Sommerfelt, M. A.; Weiss, R. A.: Receptor interference groups
of 20 retroviruses plating on human cells. Virology 176: 58-69,
1990.

4. Sommerfelt, M. A.; Williams, B. P.; McKnight, A.; Goodfellow, P.
N.; Weiss, R. A.: Localization of the receptor gene for type D simian
retroviruses on human chromosome 19. J. Virol. 64: 6214-6220, 1990.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 7/20/1994
supermim: 3/16/1992
carol: 6/11/1991
carol: 6/10/1991
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
109195
*FIELD* TI
*109195 BACTERICIDAL PERMEABILITY INCREASING PROTEIN; BPI
*FIELD* TX
The bactericidal permeability increasing protein is associated with
human neutrophil granules and has bactericidal activity on gram-negative
organisms. Both BPI and lipopolysaccharide binding protein (LBP; 151990)
are involved in the defense against gram-negative bacterial infections
and bind LPS with high affinity. Furthermore, they show 45% amino acid
identity. Using both Southern blot analysis of human/mouse somatic cell
hybrids and in situ hybridization, Gray et al. (1993) mapped both genes
to 20q11.23-q12.

*FIELD* RF
1. Gray, P. W.; Corcorran, A. E.; Eddy, R. L., Jr.; Byers, M. G.;
Shows, T. B.: The genes for the lipopolysaccharide binding protein
(LBP) and the bactericidal permeability increasing protein (BPI) are
encoded in the same region of human chromosome 20. Genomics 15:
188-190, 1993.

*FIELD* CD
Victor A. McKusick: 2/17/1993

*FIELD* ED
carol: 2/17/1993

*RECORD*
*FIELD* NO
109200
*FIELD* TI
*109200 BALDNESS, MALE-PATTERNED; MPB
*FIELD* TX
Early baldness of the ordinary type has been thought to be autosomal
dominant in males and to be autosomal recessive in females who transmit
the trait if heterozygous but are bald only if homozygous (Osborn, 1916;
Snyder and Yingling, 1935). The transmission through many successive
generations, as in the descendants of President John Adams, suggests the
operation of a single major gene. It should be possible to map one or
more of such genes by linkage methods such as those being used with
success in plants and experimental animals and with at least promise in
connection with complex traits in the human.

Carey et al. (1992) described an autosomal dominant syndrome comprising
polycystic ovaries (PCO; 184700) and premature male-patterned baldness.
In studies of 14 Caucasian families with 81 affected individuals with
this PCO/MPB syndrome, Carey et al. (1994) found a single base change in
the 5-prime promoter region of the CYP17 gene (202110), which seemed to
modify the expression of the syndrome in some families but could be
excluded as the primary genetic defect.

Hamilton (1951) classified pattern baldness and gave incidence figures.

*FIELD* SA
Carey et al. (1993)
*FIELD* RF
1. Carey, A. H.; Chan, K. L.; Short, F.; White, D.; Williamson, R.;
Franks, S.: Evidence for a single gene effect causing polycystic
ovaries and male pattern baldness. Clin. Endocr. 38: 653-658, 1993.

2. Carey, A. H.; Waterworth, D.; Patel, K.; White, D.; Little, J.;
Novelli, P.; Franks, S.; Williamson, R.: Polycystic ovaries and premature
male pattern baldness are associated with one allele of the steroid
metabolism gene CYP17. Hum. Molec. Genet. 3: 1873-1876, 1994.

3. Hamilton, J. B.: Patterned loss of hair in man: types and incidence.
Ann. N.Y. Acad. Sci. 53: 708-728, 1951.

4. Osborn, D.: Inheritance of baldness. Various patterns due to heredity
and sometimes present at birth--a sex-limited character-dominant in
man--women not bald unless they inherit tendency from both parents.
J. Hered. 7: 347-355, 1916.

5. Snyder, L. H.; Yingling, H. C.: The application of the gene-frequency
method of analysis to sex-influenced factors, with special reference
to baldness. Hum. Biol. 7: 608-615, 1935.

*FIELD* CS

Hair:
   Early baldness

Inheritance:
   Autosomal dominant in males;
   recessive in females

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 12/13/1994
mimadm: 4/9/1994
warfield: 3/21/1994
carol: 12/14/1993
carol: 9/16/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
109270
*FIELD* TI
*109270 SOLUTE CARRIER FAMILY 4, ANION EXCHANGER, MEMBER 1; SLC4A1
BAND 3 OF RED CELL MEMBRANE; BND3;;
ERYTHROID PROTEIN BAND 3; EPB3;;
EMPB3;;
ANION EXCHANGE PROTEIN-1; AE1
ACANTHOCYTOSIS, ONE FORM OF, INCLUDED;;
ELLIPTOCYTOSIS, MALAYSIAN-MELANESIAN TYPE, INCLUDED;;
OVALOCYTOSIS, MALAYSIAN-MELANESIAN-FILIPINO TYPE, INCLUDED;;
OVALOCYTOSIS, SOUTHEAST ASIAN; SAO, INCLUDED;;
ELLIPTOCYTOSIS-4; EL4, INCLUDED;;
ERYTHROCYTOSIS, STOMATOCYTIC HEREDITARY, INCLUDED;;
HE, STOMATOCYTIC, INCLUDED
*FIELD* TX
Band 3 is the major glycoprotein of the erythrocyte membrane and
mediates exchange of chloride and bicarbonate across the phospholipid
bilayer (Palumbo et al., 1986) and plays a central role in respiration
of carbon dioxide. It is a 93,000-dalton protein composed of 2 distinct
domains that function independently. The 50,000-dalton COOH-terminal
polypeptide codes for the transmembrane domain that is involved in anion
transport. The 43,000-dalton cytoplasmic domain anchors the membrane
cytoskeleton to the membrane through an ankyrin-binding site (band 2.1)
and also contains binding sites for hemoglobin and several glycolytic
enzymes. Proteins related to red cell band 3 have been identified in
several types of nucleated somatic cells. Peptide mapping shows
substantial sequence homology between red cell band 3 protein and a band
3-like protein found in leukocytes (109280). Langdon and Holman (1988)
concluded that band 3 constitutes the major glucose transporter of human
erythrocytes. A monoclonal antibody to band 3 specifically removed band
3 and more than 90% of the reconstitutable glucose transport activity
from extracts of erythrocyte membranes; nonimmune serum removed neither.
Band 3 is probably a multifunctional transport protein responsible for
transport of glucose, anions, and water. Showe et al. (1987) localized
the gene for BND3 to 17q21-qter by Southern blot analysis of DNA from
somatic cell hybrids. Kay et al. (1987, 1988) found a high molecular
weight band 3 in 2 sibs with mild anemia, acanthocytosis, and functional
red cell aberrations. The sibs were clinically normal, the abnormality
having been detected through the acanthocytosis found on blood studies
for unrelated reasons. Kay et al. (1987, 1988) concluded that the
'disorder' was recessive. Lux et al. (1989) confirmed assignment of the
gene to chromosome 17. They showed that the protein is similar to other
anion exchanges and is divided into 3 regions: a hydrophilic,
cytoplasmic domain that interacts with a variety of membrane and
cytoplasmic proteins (residues 1-403); a hydrophobic, transmembrane
domain that forms the anion antiporter (residues 404-82); and an acidic,
C-terminal domain of unknown function (residues 883-911). They presented
a model in which the protein crosses the membrane 14 times. According to
HGM10, EPB3 is in the same large restriction fragment as RNU2 (180690),
which narrows the localization to 17q21-q22. Using RFLPs of both loci,
Stewart et al. (1989) showed that EPB3 is closely linked to NGFR
(162010) (maximum lod = 11.40 at theta = 0.00, with a confidence limit
of 0.00 to 0.04).

Senescent cell antigen (SCA), an aging antigen, is a protein that
appears on old cells and marks them for removal by the immune system.
The aging antigen is generated by the degradation of protein band 3.
Besides its role in the removal of senescent and damaged cells, SCA also
appears to be involved in the removal of erythrocytes in hemolytic
anemias and the removal of malaria-infected erythrocytes. Band 3 is
found in diverse cell types and tissues besides erythrocytes, including
hepatocytes, squamous epithelial cells, lung alveolar cells,
lymphocytes, kidney, neurons, and fibroblasts. It is also present in
nuclear, Golgi, and mitochondrial membranes. Kay et al. (1990) used
synthetic peptides to identify antigenic sites on band 3 recognized by
the IgG that binds to old cells.

Elliptocytosis (or ovalocytosis, as it is called by some) occurs in
polymorphic frequency in aborigines of Malaysia and Melanesia. Lie-Injo
(1965) first pointed out the high frequency in studies of Malaysian
Orang Asli. Lie-Injo et al. (1972), Ganesan et al. (1975), and Baer et
al. (1976) extended the observations in Malaysia, where frequencies as
high as 39% were found. Ganesan et al. (1975) reported an
extraordinarily high frequency of 'ovalocytosis' among the Land Dayaks
(12.7%) and Sea Dayaks (9.0%), the indigenous people of Sarawak. Amato
and Booth (1977), Booth et al. (1977) and Holt et al. (1981) identified
another focus of high frequency of elliptocytosis in Melanesia (Papua
New Guinea, Sarawak) where the phenotype was thought to be recessive.
The morphologic change in the red cells was apparently responsible for a
previously described depression of blood group antigens (Booth, 1972),
e.g., Gerbich blood group (110750), which was also thought to be
recessively inherited. Red cells in this condition are ovalocytes, which
are often macrocytic; some, called stomatocytes, have a longitudinal
slit in the middle. Indeed, stomatocytic hereditary elliptocytosis, or
stomatocytic HE, is a synonym. Fix et al. (1982) reported the findings
in studies of Malaysian Orang Asli families and concluded that
inheritance is autosomal dominant. They quoted Kidson et al. (1981) as
stating that 'in 3 of 4 families involving the marriage of a Melanesian
ovalocytic and a Caucasian normocytic person, we have found ovalocytic
children.' Kidson et al. (1981) found that ovalocytic erythrocytes from
Melanesians are resistant to invasion by malaria parasites, thus
providing a plausible explanation for the polymorphism (also see
Serjeantson et al., 1977). This may be a mutation of a structural
protein of the red cell that endows the bearer with a selective
advantage. Baer (1988) suggested that Malaysian elliptocytosis may be a
balanced polymorphism, i.e., that individuals homozygous for the
elliptocytosis allele, not clearly identifiable by any assay, may be
differentially susceptible to mortality, whereas the heterozygote is at
an advantage. See 110750 for evidence that this form of elliptocytosis
is indeed caused by a selective advantage of heterozygotes (vis-a-vis
falciparum malaria). Hadley et al. (1983) showed that Melanesian
elliptocytes are highly resistant to invasion by Plasmodium knowlesi and
P. falciparum in vitro. This is the only human red cell variant known to
be resistant to both.

Liu et al. (1990) found a structurally and functionally abnormal band 3
protein in Southeast Asian ovalocytosis. The abnormal protein binds
tightly to ankyrin, thus leading to increased rigidity of the red cells,
and in some way is responsible for the resistance of the red cells to
invasion by malaria parasites. Linkage studies in 14 families showed a
lod score of 7.0 for linkage between the molecular defect in the band 3
protein and ovalocytosis. One of the patients they studied was Filipino.
Jones et al. (1991) concluded that the markedly increased
phosphorylation of band 3 protein in whole red cells or isolated ghosts
from ovalocytic individuals might be explained by the following
findings. The cytoplasmic domain of the ovalocyte band 3 was found to be
approximately 3 kD larger than the normocytic protein. The N-terminal
sequence of the ovalocytic band 3 was different from the reported
sequence, suggesting that the increased size resulted from an N-terminal
extension. This is the region of band 3 that is phosphorylated and
interacts with the red cell cytoskeleton. Liu et al. (1994) suggested
that the homozygous state for the BND3 mutation in Southeast Asian
ovalocytosis (109270.0002) may be lethal. In a group of 6 families in
which both parents were heterozygous for the SAO and band 3-Memphis
mutations, there were 35 offspring; 12 of these were available for
testing and 10 were found to be heterozygous for the 2 mutations,
whereas the other 2 did not carry either. Specifically, none was
homozygous for the SAO band 3 mutation. They suggested that there was an
increased frequency of miscarriages in these families.

Coetzer et al. (1996) described a 4-generation South African kindred
with dominantly inherited ovalocytosis and hemolytic anemia. All
affected subjects exhibited varying degrees of hemolytic anemia.
Additionally, there was evidence for independent segregation of the band
3 Memphis I polymorphism (109270.0001) and the 27-bp deletion in BND3,
which constitutes the Southeast Asian ovalocytosis (SAO) mutation
(109270.0002). Six SAO subjects and all 3 normal family members were
heterozygous for the band 3 Memphis I polymorphism and one SAO subject
was homozygous for this mutation.

Mueller and Morrison (1977) and Hsu and Morrison (1985) reported variant
forms of band 3 with an elongated N terminus. Both variants are
hematologically normal with normal red cell morphologic features; the
red cells do not appear to be resistant to invasion by malaria parasites
in vitro (Ranney et al., 1990; Schulman et al., 1990). Palatnik et al.
(1990) described 3 phenotypes based on the polymorphism of band-3
protein from human red cells. Limited proteolysis of intact red cells
from most individuals (homozygotes) yields a peptide of 60 kD, but in
some persons (heterozygotes), there is also a 63-kD peptide, and rarely
only the single peptide of 63 kD is found. This was the first
description of the 63-kD homozygote. The frequency of the p63 allele was
estimated to be 0.041 +/- 0.0068 in Caucasoids and 0.125 +/- 0.0121 in
Negroids.

Tanner (1993) discussed the molecular and cellular biology of the
erythrocyte anion exchanger, band 3. It permits the high rate of
exchange of chloride ion by bicarbonate ion across the red cell
membrane: the efflux of bicarbonate from the cell in exchange for plasma
chloride ion in the capillaries of the tissues (the Hamburger shift, or
chloride ion shift) and the reverse process in lung capillaries. At
least 2 nonerythroid anion exchange genes have been characterized, AE2
(109280) and AE3 (106195), and tentative evidence for a fourth member of
the class, AE4, was mentioned. The ability of AE2 and AE3 to mediate
anion transport has been confirmed. As outlined by Tanner (1993), it is
not strictly accurate to refer to the AE1 gene as being that for the
erythroid anion exchanger because the AE1 gene is expressed in some
nonerythroid tissues, where it appears to be transcribed from different
tissue-specific promoters. Tanner (1993) also reviewed the evidence that
mutations in the AE1 gene can cause hereditary spherocytosis as well as
choreoacanthocytosis (100500, 200150; see Kay, 1991). Prchal et al.
(1991) studied 1 family with autosomal dominant hereditary spherocytosis
associated with deficiency of erythrocyte band 3 protein. By linkage
studies, they excluded alpha-spectrin (182860), beta-spectrin (182870),
and ankyrin (see 182900) as the site of the mutation. On the other hand,
linkage to EPB3 was suggested. They used RFLPs not only in the EPB3 gene
but also in the NGFR gene (162010) which, like EPB3, maps to 17q21-q22.
A maximum lod score of 11.40 at theta = 0.00 was observed. Study of 42
members from 4 generations revealed a consistent linkage of
spherocytosis with 1 particular haplotype generated by the 4 probes that
were used. Saad et al. (1991) examined the mechanism underlying band 3
deficiency in a subset of patients with hereditary spherocytosis. Kay et
al. (1989) reported a band 3 alteration in association with anemia as
determined by a reticulocyte count of 20%. The erythrocyte defect was
reflected in increased IgG binding, increased breakdown products of band
3, and altered anion- and glucose-transport activity in middle-aged
cells. IgG eluted from the red cells of the propositus appeared to have
a specificity for senescent cell antigen. This and other studies
suggested that band 3 was aging prematurely in erythrocytes of the
subject, and that the senescent cell antigen appeared on the middle-aged
red cells. Two sibs were affected. Both parents were thought to show
'subtle band 3 changes.' Autosomal recessive inheritance was postulated.

Del Giudice et al. (1992) also reported a family in which a dominantly
inherited form of hereditary spherocytosis was associated with
deficiency of band 3, resulting in an increased spectrin/band 3 ratio.
Since deficiency of spectrin is a much more frequent cause of hereditary
spherocytosis, the usual finding is a decreased spectrin/band 3 ratio.
An increased spectrin/band 3 ratio, pointing to a band 3 defect, was
found in 2 families with hereditary spherocytosis studied by Lux et al.
(1990). Reinhart et al. (1994) described a kindred in which 10
individuals had a history of otherwise unexplained jaundice or proven
hemolytic anemia due to a protein band 3 defect. A morphologic feature
was 'pincered' erythrocytes (see their fig. 3), i.e., erythrocytes that
appeared to have been pinched by pincers on one side. Splenectomy led to
improvement of the mild-to-moderate hemolysis. Del Giudice et al. (1993)
described a family in which both hereditary spherocytosis due to band 3
deficiency and beta-0-thalassemia trait due to codon 39 (C-T) mutation
(141900.0312) were segregating. Two subjects with HS alone had a typical
clinical form of spherocytosis with anemia, reticulocytosis, and
increased red cell osmotic fragility. Two who coinherited HS and
beta-thalassemia trait were not anemic and showed a slight,
well-compensated hemolysis. Thus, the beta-thalassemic trait partially
corrected or 'silenced' HS caused by band 3 deficiency.

Schofield et al. (1994) demonstrated that the EPB3 gene extends over 18
kb and consists of 20 exons. The cDNA sequence comprises 4,906
nucleotides, excluding the poly(A) tail. They found extensive similarity
between the human and mouse genes, although the latter covers 17 kb. The
additional length of the human gene is mainly caused by the presence of
6 Alu repetitive units in the human gene between intron 13 and exon 20.
Two potential promoter regions are positioned so that they could give
rise to the different transcripts found in erythroid cells and in the
kidney. The kidney transcript would lack exons 1 through 3 of the
erythroid transcript. The translation initiator downstream to the human
kidney promoter would give rise to a protein with a 20-amino acid
section at the N-terminus that is not present in the erythroid protein.
Sahr et al. (1994) concluded that the AE1 gene spans approximately 20 kb
and consists of 20 exons separated by 19 introns. Its structure showed
close similarity to that of the mouse AE1 gene. Sahr et al. (1994)
described the upstream and internal promoter sequences of the human AE1
gene used in erythroid and kidney cells, respectively.

Eber et al. (1996) found that band 3 frameshift and nonsense null
mutations occurred in dominant hereditary spherocytosis. In studies of
46 HS families, 12 ankyrin-1 mutations and 5 band 3 mutations were
identified.

ANIMAL MODEL

Inaba et al. (1996) studied a moderately uncompensated bovine anemia
associated with spherocytosis inherited in an autosomal incompletely
dominant mode and retarded growth. Using biochemical methods they showed
that the bovine red cells lacked the band 3 protein completely. Sequence
analysis of EPB3 cDNA and genomic DNA showed a C-to-T transition
resulting in a missense mutation: CGA-to-TGA; arg646-to-ter. The
location of the mutation was at the position corresponding to codon 646
in human EPB3 cDNA. The animal red cells were deficient in spectrin,
ankyrin, actin (see 102630), and protein 4.2 (177070), resulting in a
distorted and disrupted membrane skeletal network with decreased
density. Therefore, the animal's red cell membranes were extremely
unstable and showed the loss of surface area in several distinct ways
such as invagination, vesiculation, and extrusion of microvesicles,
leading to the formation of spherocytes. Inaba et al. (1996) also found
that total deficiency of bovine band 3 also resulted in defective
chloride/bicarbonate exchange, causing mild acidosis with decreases in
bicarbonate concentration and total CO(2) in the animal's blood. The
results demonstrated to the authors that bovine band 3 contributes to
red cell membrane stability, CO(2) transport, and acid-base homeostasis,
but is not always essential to the survival of this mammal.

Erythroid band 3 (AE1) is one of 3 anion exchanges that are encoded by
separate genes. The AE1 gene is transcribed by 2 promoters: the upstream
promoter used as erythroid band 3, whereas the downstream promoter
initiates transcription of the band 3 isoform in kidney. To assess the
biologic consequences of band 3 deficiency, Southgate et al. (1996)
selectively inactivated erythroid but not kidney band 3 by gene
targeting in mice. Although no death in utero occurred, most homozygous
mice died within 2 weeks after birth. The erythroid band 3 null mice
showed retarded growth, spherocytic red blood cell morphology, and
severe hemolytic anemia. Remarkably, the band 3(-/-) red blood cells
assembled normal membrane skeleton, thus challenging the notion that the
presence of band 3 is required for stable biogenesis of the membrane
skeleton. Similarly Peters et al. (1996) used targeted mutagenesis in
the mouse to assess AE1 function in vivo. RBCs lacking AE1 spontaneously
shed membrane vesicles and tubules, leading to severe spherocytosis and
hemolysis, but the levels of the major skeleton components, the
synthesis of spectrin in mutant erythroblasts, and skeletal architecture
were normal or nearly normal. Their results indicated that AE1 does not
regulate RBC membrane skeleton assembly in vivo but is essential for
membrane stability. Peters et al. (1996) postulated that stabilization
is achieved through AE1-lipid interactions and that loss of these
interactions is a key pathogenic event in hereditary spherocytosis. Jay
(1996) reviewed the role of band 3 in red cell homeostasis and cell
shape.

*FIELD* AV
.0001
BAND 3 MEMPHIS
SLC4A1, LYS56GLU
In addition to the variants of band 3 leading to abnormalities of
erythrocyte shape (Liu et al., 1990), Mueller and Morrison (1977)
identified a polymorphism tentatively described as an elongation of the
cytoplasmic domain, whose structure was still to be defined. Ranney et
al. (1990) found a silent band 3 polymorphism, called band 3 Memphis, in
all human populations with a frequency varying from one population to
another. Yannoukakos et al. (1991) demonstrated that this
electrophoretic variant is due to substitution of glutamic acid for
lysine at position 56. An A-to-G substitution in the first base of codon
56 is responsible for the change. Ideguchi et al. (1992) showed that the
prevalence of the Memphis variant is particularly high in Japanese; the
calculated gene frequency was 0.156, about 4 times higher than in
Caucasians. They found that the transport rate of phosphoenolpyruvate in
erythrocytes of homozygotes was decreased to about 80% of that in
control cells and the rate in heterozygotes was at an intermediate
level. They interpreted this as indicating that some structural changes
in the cytoplasmic domain of band 3 influence the conformation of the
anion transport system. The band 3 Memphis variant is characterized by a
reduced mobility of proteolytic fragments derived from the N-terminus of
the cytoplasmic domain of band 3 (cdb3). Jarolim et al. (1992) found the
AAG-to-GAG transition at codon 56 resulting in the lys56-to-glu
substitution in all of 12 heterozygotes including 1 white, 1 black, 1
Chinese, 1 Filipino, 1 Malay, and 7 Melanesian subjects. Since most of
the previously cloned mouse, rat, and chicken band 3 and band 3-related
proteins contain glutamic acid in the position corresponding to amino
acid 56 in the human band 3, Jarolim et al. (1992) proposed that the
Memphis variant is the evolutionarily older form of band 3.

.0002
OVALOCYTOSIS, SOUTHEAST ASIAN
SLC4A1, 24BP DEL, CODONS 400-408 DEL
Following up on the demonstration by Liu et al. (1990) that a
structurally and functionally abnormal band 3 protein shows absolute
linkage with the SAO phenotype, Jarolim et al. (1991) demonstrated that
the EPB3 gene in these cases contains a deletion of codons 400-408
resulting in deletion of 9 amino acids in the boundary of cytoplasmic
and membrane domains of the band 3 protein. The defect was detected in
all 30 ovalocytic subjects from Malaysia, the Philippines, and 2
unrelated coastal regions of Papua New Guinea, whereas it was absent in
all 30 controls from Southeast Asia and 20 subjects of different ethnic
origin from the United States. The lys56-to-glu mutation (109270.0001)
was also found in all SAO subjects; however, it was detected in 5 of 50
control subjects as well, suggesting that it represents a linked
polymorphism. Mohandas et al. (1992) likewise demonstrated the deletion
of amino acids 400-408 in the boundary between the cytoplasmic and the
first transmembrane domains of band 3. The biophysical consequences of
the mutation was a marked decrease in lateral mobility of band 3 and an
increase in membrane rigidity. Mohandas et al. (1992) suggested that the
mutation induces a conformational change in the cytoplasmic domain of
band 3, leading to its entanglement in the skeletal protein network.
This entanglement inhibits the normal unwinding and stretching of the
spectrin tetramers necessary for membrane extension, leading to
increased rigidity.

The same deletion of 9 amino acids was found by Tanner et al. (1991) in
a Mauritian Indian and by Ravindranath et al. (1994) in an
African-American mother and daughter. All cases of SAO had been
associated with the Memphis-1 polymorphism (109270.0001), which is found
in all populations but is present at higher frequency in American Indian
and African-American populations. However, SAO had not previously been
identified in African-Americans.

.0003
SPHEROCYTOSIS, HEREDITARY, DUE TO BAND 3 TUSCALOOSA
SLC4A1, PRO327ARG
Jarolim et al. (1991) studied a 28-year-old black female with congenital
spherocytic hemolytic anemia. Splenectomy corrected the anemia but only
partially normalized the reticulocyte count. Although there was partial
deficiency of protein 4.2 (177070), other findings suggested a primary
defect in band 3. By study of a PCR-amplified cDNA segment from the EPB3
gene, Jarolim et al. (1991) demonstrated a CCC-to-CGC transversion
converting pro327 to arginine. Proline-327 is located in a highly
conserved region of band 3 and its substitution by the basic arginine
was expected to change both the secondary and tertiary structure of the
cytoplasmic domain of band 3. The same allele carried a lys56-to-glu
substitution, a common asymptomatic polymorphism designated band 3
Memphis (109270.0001). Direct sequencing of genomic DNA from the
patient's unaffected mother and 2 sibs revealed neither of the 2
substitutions. Thus, the patient presumably represented a new mutation.

.0004
BAND 3 MONTEFIORE, HEMOLYTIC ANEMIA DUE TO
SLC4A1, GLU40LYS
In a 33-year-old female with episodes of clinically apparent hemolytic
anemia coincident with pregnancies and associated with splenomegaly,
Rybicki et al. (1993) of Montefiore Medical Center in the Bronx found a
glu40-to-lys mutation in the cytoplasmic domain of the EPB3 gene. The
mutation was homozygous; the proposita was the offspring of first-cousin
parents born in the Dominican Republic, largely of Spanish origin with
some black admixture. A striking feature was decreased RBC membrane
content of protein 4.2 (177070) which was thought to be a secondary
phenomenon resulting from defective interactions with band 3.

.0005
SPHEROCYTOSIS, HEREDITARY, DUE TO BAND 3 PRAGUE
SLC4A1, 10BP DUP
Jarolim et al. (1994) described duplication of 10 nucleotides
(2455-2464) in the EPB3 gene in a family from Prague, Czech Republic,
with 5 individuals affected by spherocytosis in 3 generations. Before
splenectomy, the affected subjects had a compensated hemolytic disease
with reticulocytosis, hyperbilirubinemia, and increased osmotic
fragility. There was a partial deficiency of the band 3 protein that was
reflected by decreased rate of transmembrane sulfate flux and decreased
density of intramembrane particles. The mutant allele potentially
encoded an abnormal band 3 protein with a 3.5-kD COOH-terminal
truncation; however, they did not detect the mutant protein in the
membrane of mature red blood cells. Since the mRNA levels for the mutant
and normal alleles were similar and since the band 3 content was the
same in the light and dense red cell fractions, Jarolim et al. (1994)
concluded that the mutant band 3 was either not inserted into the plasma
membrane or was lost from the membrane before release of red cells into
the circulation.

.0006
WRIGHT BLOOD GROUP ANTIGEN
BND3, GLU658LYS
Bruce et al. (1995) demonstrated that the blood group Wright antigens
(112050) are determined by mutation at amino acid residue 658 of
erythrocyte band 3.

.0007
BAND 3 CHUR
SLC4A1, GLY771ASP
In a large Swiss family with dominantly inherited spherocytosis and
deficiency of band 3, Maillet et al. (1995), by single-strand
conformation polymorphism analysis and nucleotide sequencing,
demonstrated a G771D (GGC-to-GAC) mutation in the EPB3 gene. Change was
present in all 8 affected members of the family studied but absent in 4
healthy members. It was located at a highly conserved position in the
middle of transmembrane segment 11, introducing a negative charge in a
stretch of 16 apolar or neutral residues.

.0008
SPHEROCYTOSIS, HEREDITARY, DUE TO BAND 3 NOIRTERRE
SLC4A1, GLN330TER
In a French kindred with typical autosomal dominant hereditary
spherocytosis, Jenkins et al. (1996) found a 15-20% deficiency of band
3, as well as abnormal erythrocyte membrane mechanical stability. Anion
transport studies of red cells from 2 affected individuals demonstrated
decreased sulfate flux. A sequence analysis of genomic DNA demonstrated
a nonsense mutation of the EPB3 gene, Q330X, near the end of the band 3
cytoplasmic domain. The mutation was present in genomic DNA of all HS
family members and absent in DNA of all unaffected family members. The
variant was named band 3 Noirteree after the village of residence of the
family in France. The change in codon 330 was from CAG to TAG.

.0009
BAND 3 LYON
SLC4A1, ARG150TER
Alloisio et al. (1996) described an 18-year-old man with moderate
hereditary spherocytosis. The condition was associated with a 35%
decrease in band 3. The underlying mutation was R150X due to a
CGA-to-TGA transition in codon 150. They designated the new allele band
3 Lyon. The inheritance was dominant; however, the mother, who also
carried the allele Lyon, had a milder clinical presentation and only a
16% decrease of band 3. They suspected the father had transmitted a
modifying mutation that remained silent in the heterozygous state in
him. Nucleotide sequencing after SSCP analysis of the band 3 cDNA and
promoter region revealed a G-to-A substitution at position 89 from the
cap site in the 5-prime untranslated region of the EPB3 gene (designated
89G-to-A), an allele they referred to as band 3 Genas (109270.0010). A
ribonuclease protection assay showed that: (1) the allele Genas from the
father resulted in a 33% decrease in the amount of band mRNA; (2) the
reduction caused by the allele Lyon (mother) was 42%; and (3) the
compound heterozygous state for both alleles (proband) resulted in a 58%
decrease. These results suggested that some mildly deleterious alleles
of the EPB3 gene are compensated for by the normal allele in the
heterozygous state. They become manifest, however, through the
aggravation of the clinical picture, based on molecular alterations when
they occur in 'trans' to an allele causing a manifest reduction of band
3 membrane protein concentration.

.0010
BAND 3 GENAS
SLC4A1, 89 GA
See 109270.0009 and Alloisio et al. (1996).

.0011
WALDNER BLOOD GROUP Wd(a)
SLC4A1, VAL557MET
Bruce et al. (1995) demonstrated that the low incidence blood group
antigen, Wd(a), is associated with an amino acid substitution val557met
in erythrocyte band 3.

*FIELD* SA
Kay  (1991); Mueller and Morrison (1977)
*FIELD* RF
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band-3 has an altered N terminus in malaria-resistant Melanesian ovalocytosis. Biochim.
Biophys. Acta 1096: 33-40, 1991.

26. Kay, M. M. B.: Band 3 in aging and neurological disease. Ann.
N.Y. Acad. Sci. 621: 179-204, 1991.

27. Kay, M. M. B.: Band 3 in aging and neurological disease. Ann.
N.Y. Acad. Sci. 621: 179-204, 1991.

28. Kay, M. M. B.; Bosman, G. J. C. G. M.; Lawrence, C.: Functional
topography of band 3: specific structural alteration linked to functional
aberrations in human erythrocytes. Proc. Nat. Acad. Sci. 85: 492-496,
1988.

29. Kay, M. M. B.; Flowers, N.; Goodman, J.; Bosman, G.: Alteration
in membrane protein band 3 associated with accelerated erythrocyte
aging. Proc. Nat. Acad. Sci. 86: 5834-5838, 1989.

30. Kay, M. M. B.; Lawrence, C.; Bosman, G. J. C. G. M.: Molecular
anatomy of an anemia.(Abstract) Clin. Res. 35: 599A, 1987.

31. Kay, M. M. B.; Marchalonis, J. J.; Hughes, J.; Watanabe, K.; Schluter,
S. F.: Definition of a physiologic aging autoantigen by using synthetic
peptides of membrane protein band 3: localization of the active antigenic
sites. Proc. Nat. Acad. Sci. 87: 5734-5738, 1990.

32. Kidson, C.; Lamont, G.; Saul, A.; Nurse, G. T.: Ovalocytic erythrocytes
from Melanesians are resistant to invasion by malaria parasites in
culture. Proc. Nat. Acad. Sci. 78: 5829-5832, 1981.

33. Langdon, R. G.; Holman, V. P.: Immunological evidence that band
3 is the major glucose transporter of the human erythrocyte membrane. Biochim.
Biophys. Acta 945: 23-32, 1988.

34. Lie-Injo, L. E.: Hereditary ovalocytosis and haemoglobin E-ovalocytosis
in Malayan aborigines. Nature 208: 1329, 1965.

35. Lie-Injo, L. E.; Fix, A.; Bolton, J. M.; Gilman, R. H.: Haemoglobin
E-hereditary elliptocytosis in Malayan aborigines. Acta Haemat. 47:
210-216, 1972.

36. Liu, S.-C.; Jarolim, P.; Rubin, H. L.; Palek, J.; Amato, D.; Hassan,
K.; Zaik, M.; Sapak, P.: The homozygous state for the band 3 protein
mutation in Southeast Asian ovalocytosis may be lethal.(Letter) Blood 84:
3590-3591, 1994.

37. Liu, S.-C.; Zhai, S.; Palek, J.; Golan, D. E.; Amato, D.; Hassan,
K.; Nurse, G. T.; Babona, D.; Coetzer, T.; Jarolim, P.; Zaik, M.;
Borwein, S.: Molecular defect of the band 3 protein in Southeast
Asian ovalocytosis. New Eng. J. Med. 323: 1530-1538, 1990.

38. Lux, S.; Bedrosian, C.; Shalev, O.; Morris, M.; Chasis, J.; Davies,
K.; Savvides, P.; Telen, M.: Deficiency of band 3 in dominant hereditary
spherocytosis with normal spectrin content.(Abstract) Clin. Res. 38:
300A, 1990.

39. Lux, S. E.; John, K. M.; Kopito, R. R.; Lodish, H. F.: Cloning
and characterization of band 3, the human erythrocyte anion-exchange
protein (AE1). Proc. Nat. Acad. Sci. 86: 9089-9093, 1989.

40. Maillet, P.; Vallier, A.; Reinhart, W. H.; Wyss, E. J.; Ott, P.;
Texier, P.; Baklouti, F.; Tanner, M. J. A.; Delaunay, J.; Alloisio,
N.: Band 3 Chur: a variant associated with band 3-deficient hereditary
spherocytosis and substitution in a highly conserved position of transmembrane
segment 11. Brit. J. Haemat. 91: 804-810, 1995.

41. Mohandas, N.; Winardi, R.; Knowles, D.; Leung, A.; Parra, M.;
George, E.; Conboy, J.; Chasis, J.: Molecular basis for membrane
rigidity of hereditary ovalocytosis: a novel mechanism involving the
cytoplasmic domain of band 3. J. Clin. Invest. 89: 686-692, 1992.

42. Mueller, T. J.; Morrison, M.: Detection of a variant of protein
3, the major transmembrane protein of the human erythrocyte. J. Biol.
Chem. 252: 6573-6576, 1977.

43. Mueller, T. J.; Morrison, M.: Heterogeneity of the major protein
in the human erythrocyte membrane.(Abstract) Fed. Proc. 36: 747,
1977.

44. Palatnik, M.; da Silva Simoes, M. L. M.; Alves, Z. M. S.; Laranjeira,
N. S. M.: The 60 and 63 kDa proteolytic peptides of the red cell
membrane band-3 protein: their prevalence in human and non-human primates. Hum.
Genet. 86: 126-130, 1990.

45. Palumbo, A. P.; Isobe, M.; Huebner, K.; Shane, S.; Rovera, G.;
Demuth, D.; Curtis, P. J.; Ballantine, M.; Croce, C. M.; Showe, L.
C.: Chromosomal localization of a human band 3-like gene to region
7q35-7q36. Am. J. Hum. Genet. 39: 307-316, 1986.

46. Peters, L. L.; Shivdasani, R. A.; Liu, S.-C.; Hanspal, M.; John,
K. M.; Gonzalez, J. M.; Brugnara, C.; Gwynn, B.; Mohandas, N.; Alper,
S. L.; Orkin, S. H.; Lux, S. E.: Anion exchanger 1 (band 3) is required
to prevent erythrocyte membrane surface loss but not to form the membrane
skeleton. Cell 86: 917-927, 1996.

47. Prchal, J. T.; Guan, Y.; Jarolim, P.; Palek, J.; Showe, L.; Bertoli,
L.: Hereditary spherocytosis in a large family is linked with the
band 3 gene and not with alpha-spectrin, beta-spectrin or ankyrin.
(Abstract) Blood 78 (suppl.): 81a, 1991.

48. Ranney, H. M.; Rosenberg, G. H.; Morrison, M.; Mueller, T. J.
: Frequencies of band 3 variants of human red cell membranes in some
different populations. Brit. J. Haemat. 76: 262-267, 1990.

49. Ravindranath, Y.; Goyette, G., Jr.; Johnson, R. M.: Southeast
Asian ovalocytosis in an African-American family.(Letter) Blood 84:
2823-2824, 1994.

50. Reinhart, W. H.; Wyss, E. J.; Arnold, D.; Ott, P.: Hereditary
spherocytosis associated with protein band 3 defect in a Swiss kindred. Brit.
J. Haemat. 86: 147-155, 1994.

51. Rybicki, A. C.; Qiu, J. J. H.; Musto, S.; Rosen, N. L.; Nagel,
R. L.; Schwartz, R. S.: Human erythrocyte protein 4.2 deficiency
associated with hemolytic anemia and a homozygous 40 glutamic acid-to-lysine
substitution in the cytoplasmic domain of band 3 (band 3 Montefiore). Blood 81:
2155-2165, 1993.

52. Saad, S. T. O.; Liu, S. C.; Golan, D.; Corbett, J. B.; Thatte,
H. S.; Derick, L.; Hanspal, M.; Jarolim, P.; Fibach, E.; Palek, J.
: Mechanism underlying band 3 deficiency in a subset of patients with
hereditary spherocytosis (HS).(Abstract) Blood 78 (suppl.): 81a,
1991.

53. Sahr, K. E.; Taylor, W. M.; Daniels, B. P.; Rubin, H. L.; Jarolim,
P.: The structure and organization of the human erythroid anion exchanger
(AE1) gene. Genomics 24: 491-501, 1994.

54. Schofield, A. E.; Martin, P. G.; Spillett, D.; Tanner, M. J. A.
: The structure of the human red blood cell anion exchanger (EPB3,
AE1, Band 3) gene. Blood 84: 2000-2012, 1994.

55. Schulman, S.; Roth, E. F., Jr.; Cheng, B.; Rybicki, A. C.; Sussman,
I. I.; Wong, M.; Wang, W.; Ranney, H. M.; Nagel, R. L.; Schwartz,
R. S.: Growth of Plasmodium falciparum in human erythrocytes containing
abnormal membrane proteins. Proc. Nat. Acad. Sci. 87: 7339-7343,
1990.

56. Serjeantson, S.; Bryson, K.; Amato, D.; Babona, D.: Malaria and
hereditary ovalocytosis. Hum. Genet. 37: 161-167, 1977.

57. Showe, L. C.; Ballantine, M.; Huebner, K.: Localization of the
gene for the erythroid anion exchange protein, band 3 (EMPB3), to
human chromosome 17. Genomics 1: 71-76, 1987.

58. Southgate, C. D.; Chisti, A. H.; Mitchell, B.; Yi, S. J.; Palek,
J.: Targeted disruption of the murine erythroid band 3 gene results
in spherocytosis and severe haemolytic anaemia despite a normal membrane
skeleton. Nature Genet. 14: 227-230, 1996.

59. Stewart, E. A.; Kopito, R.; Bowcock, A. M.: A PstI polymorphism
for the human erythrocyte surface protein band 3 (EPB3) demonstrates
close linkage of EPB3 to the nerve growth factor receptor. Genomics 5:
633-635, 1989.

60. Tanner, M. J. A.: Molecular and cellular biology of the erythrocyte
anion exchanger (AE1). Seminars Hemat. 30: 34-57, 1993.

61. Tanner, M. J. A.; Bruce, L.; Martin, P. G.; Rearden, D. M.; Jones,
G. L.: Melanesian hereditary ovalocytes have a deletion in red cell
band 3.(Letter) Blood 78: 2785-2786, 1991.

62. Yannoukakos, D.; Vasseur, C.; Driancourt, C.; Blouquit, Y.; Delaunay,
J.; Wajcman, H.; Bursaux, E.: Human erythrocyte band 3 polymorphism
(band 3 Memphis): characterization of the structural modification
(lys56-to-glu) by protein chemistry methods. Blood 78: 1117-1120,
1991.

*FIELD* CS

Heme:
   Hemolytic anemia (e.g. .0004 Band 3 Montefiore);
   Spherocytosis (e.g. .0003 Band 3 Tuscaloosa);
   Acanthocytosis;
   Elliptocytosis;
   Macrocytosis;
   Stomatocytosis;
   Reticulocytosis;
   Increased red cell osmotic fragility

GI:
   Splenomegaly

Skin:
   Jaundice

Lab:
   Band 3 erythrocyte membrane glycoprotein;
   Senescent cell antigen (SCA), derived from degraded band 3 marks aging
   and malaria-infected red cells for removal;
   Chloride and bicarbonate exchange function;
   Binding sites for hemoglobin and several glycolytic enzymes;
   Transport for glucose, anions, and water;
   Resistance to red cell invasion by malaria parasites;
   Hyperbilirubinemia

Inheritance:
   Autosomal dominant (17q21-q22)

*FIELD* CN
Moyra Smith - updated: 4/6/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jenny: 04/15/1997
mark: 12/26/1996
terry: 12/16/1996
jamie: 11/6/1996
terry: 11/6/1996
terry: 10/30/1996
terry: 10/28/1996
terry: 10/22/1996
mark: 10/7/1996
terry: 10/1/1996
mark: 5/31/1996
terry: 5/29/1996
mark: 5/17/1996
terry: 5/16/1996
mark: 4/6/1996
mark: 3/22/1996
terry: 3/18/1996
mark: 2/19/1996
terry: 2/15/1996
terry: 2/21/1995
carol: 1/27/1995
mimadm: 4/9/1994
carol: 10/20/1993
carol: 10/19/1993
carol: 6/3/1993

*RECORD*
*FIELD* NO
109280
*FIELD* TI
*109280 BAND 3-LIKE PROTEIN; BND3L
ERYTHROCYTE MEMBRANE PROTEIN BAND 3-LIKE 1; EPB3L1;;
NONERYTHROID BAND 3; NBND3; HKB3;;
ANION EXCHANGER, NONERYTHROID; AE2
*FIELD* TX
Demuth et al. (1986) isolated a cDNA clone, designated pHKB3, encoding a
human erythrocyte surface protein band 3-like gene product. Peptide
mapping shows substantial sequence homology between the erythrocyte band
3 protein (109270) and a band 3-like protein found in leukocytes.
Palumbo et al. (1986) described the partial sequence of a 2.7-kb human
cDNA clone encoding a band 3-related protein in nonerythroid cells.
Comparison of the predicted amino acid sequence for this cDNA with the
amino acid sequences of mouse and human erythroid band 3 proteins
confirmed that the human clone is related to but distinct from erythroid
band 3. Using somatic cell genetics and in situ hybridization, Palumbo
et al. (1986) mapped the band 3-related gene to 7q35-q36. Palumbo et al.
(1986) symbolized the gene as HKB3, in part after the name of the human
cell line studied. Showe et al. (1993) identified an MboI RFLP in the
EPB3L1 gene. White et al. (1994) demonstrated that the murine AE2 gene
is located on chromosome 5. This result was obtained by analysis of
recombinant inbred lines and by interspecific backcross analysis.

Tanner (1993) referred to this nonerythroid anion exchanger as AE2. The
ability of AE2 to mediate anion transport has been confirmed. Northern
blotting studies showed that the AE2 gene is transcribed in a wide
variety of tissues. In the mouse, Lindsey et al. (1990) found that AE2
is expressed only in choroid plexus, the site of cerebrospinal fluid
production. Kudrycki et al. (1990) found that, in the rat, AE2 is
particularly abundant in the stomach and portions of the
gastrointestinal tract.

*FIELD* RF
1. Demuth, D. R.; Showe, L. C.; Ballantine, M.; Palumbo, A.; Fraser,
P. J.; Cioe, L.; Rovera, G.; Curtis, P. J.: Cloning and structural
characterization of a human non-erythroid band 3-like protein. EMBO
J. 5: 1205-1214, 1986.

2. Kudrycki, K. E.; Newman, P. R.; Schull, G. E.: cDNA cloning and
tissue distribution of mRNAs for two proteins that are related to
the band 3 chloride-bicarbonate exchanger. J. Biol. Chem. 265:
462-471, 1990.

3. Lindsey, A. E.; Schneider, K.; Simmons, D. M.; Baron, R.; Lee,
B. S.; Kopito, R. R.: Functional expression and subcellular localization
of an anion exchanger cloned from choroid plexus. Proc. Nat. Acad.
Sci. 87: 5278-5282, 1990.

4. Palumbo, A. P.; Isobe, M.; Huebner, K.; Shane, S.; Rovera, G.;
Demuth, D.; Curtis, P. J.; Ballantine, M.; Croce, C. M.; Showe, L.
C.: Chromosomal localization of a human band 3-like gene to region
7q35-7q36. Am. J. Hum. Genet. 39: 307-316, 1986.

5. Showe, M. K.; Williams, D.; Showe, L. C.: An MboI RFLP in the
human erythrocyte surface protein band 3-like 1 gene (EPB3L1) on chromosome
7q35-7q36. Hum. Molec. Genet. 2: 337 only, 1993.

6. Tanner, M. J. A.: Molecular and cellular biology of the erythrocyte
anion exchanger (AE1). Seminars Hemat. 30: 34-57, 1993.

7. White, R. A.; Geissler, E. N.; Adkison, L. R.; Dowler, L. L.; Alper,
S. L.; Lux, S. E.: Chromosomal location of the murine anion exchanger
genes encoding AE2 and AE3. Mammalian Genome 5: 827-829, 1994.

*FIELD* CD
Victor A. McKusick: 1/7/1987

*FIELD* ED
carol: 2/17/1995
carol: 6/28/1993
carol: 4/26/1993
carol: 2/19/1993
carol: 2/18/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
109300
*FIELD* TI
109300 BANKI SYNDROME
*FIELD* TX
Banki (1965) described a Hungarian family in which members of 3
generations showed fusion of the lunate and cuneiform bones of the
wrist, clinodactyly, clinometacarpy, brachymetacarpy and leptometacarpy
(thin diaphysis). It appears to represent a unique dominant mutation.

*FIELD* RF
1. Banki, Z.: Kombination erblicher Gelenk-und Knochenanomalien an
der Hand. Zwei neue Roentgenzeichen. Fortschr. Roentgenstr. 103:
598-604, 1965.

*FIELD* CS

Limbs:
   Lunate and cuneiform bone fusion;
   Clinodactyly;
   Clinometacarpy;
   Brachymetacarpy;
   Leptometacarpy (thin diaphysis)

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 6/16/1994
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
109350
*FIELD* TI
109350 BARRETT ESOPHAGUS
GASTROESOPHAGEAL REFLUX; GER
ADENOCARCINOMA OF ESOPHAGUS, INCLUDED
*FIELD* TX
Barrett (1950) described a patient with chronic ulcerating esophagitis
in which columnar rather than squamous epithelium surrounded the ulcers.
Allison and Johnstone (1953), followed by many others, showed that the
columnar epithelium-lined intrathoracic structure is anatomically and
functionally esophagus. The proximal esophagus usually retains its
normal squamous epithelium. The Barrett esophagus is a complication of
gastroesophageal reflux. Why it develops only in some patients is not
clear; Sjogren and Johnson (1983) suggested that it 'may be congenitally
determined in part.' Familial occurrence was reported by Borrie and
Goldwater (1976). Adenocarcinoma of the esophagus has an incidence of
about 10% in the Barrett esophagus. Adenocarcinoma constitutes a
minority of esophageal cancers but most of these originate in a Barrett
esophagus. Gelfand (1983) reported Barrett esophagus in identical twins.
Everhart et al. (1978, 1983) described Barrett esophagus in 3 persons in
2 generations of a family. Crabb et al. (1985) described a family in
which the proband had both GER and Barrett esophagus, 3 of 5 children
also had both, the other 2 children had only GER, and 2 grandchildren
had GER. One of the children with both developed adenocarcinoma of the
esophagus. We have seen adenocarcinoma of the esophagus in a man (G.D.,
1474651) with the Barrett anomaly and a brother who died of esophageal
cancer. Prior and Whorwell (1986) observed 2 sisters, each of whom
presented at age 66. Jochem et al. (1992) described a family with 6
cases of Barrett esophagus, all in males, in 3 successive generations.
In 3 of the patients there was associated adenocarcinoma. Cameron (1992)
reviewed the literature.

*FIELD* SA
Mossberg  (1966)
*FIELD* RF
1. Allison, P. R.; Johnstone, A. S.: The esophagus lined with gastric
mucus membrane. Thorax 8: 87-101, 1953.

2. Barrett, N. R.: Chronic peptic ulcer of the oesophagus and esophagitis.
Brit. J. Surg. 38: 175-182, 1950.

3. Borrie, J.; Goldwater, L.: Columnar cell-lined esophagus: assessment
of etiology and treatment: a 22-year experience. J. Thorac. Cardiovasc.
Surg. 71: 825-834, 1976.

4. Cameron, A. J.: Barrett's esophagus and adenocarcinoma: from the
family to the gene.  (Editorial) Gastroenterology 102: 1421-1424,
1992.

5. Crabb, D. W.; Berk, M. A.; Hall, T. R.; Conneally, P. M.; Biegel,
A. A.; Lehman, G. A.: Familial gastroesophageal reflux and development
of Barrett's esophagus. Ann. Intern. Med. 103: 52-54, 1985.

6. Everhart, C. W.; Holtzapple, P. G.; Humphries, T. J.: Barrett's
esophagus: inherited epithelium or inherited reflex?.  (Editorial) J.
Clin. Gastroent. 5: 357-358, 1983.

7. Everhart, C. W., Jr.; Holtzapple, P. G.; Humphries, T. J.: Occurrence
of Barrett's esophagus in three members of the same family: first
report of familial incidence.  (Abstract) Gastroenterology 74: 1032
only, 1978.

8. Gelfand, M. D.: Barrett's esophagus in sexagenarian identical
twins. J. Clin. Gastroent. 5: 251-253, 1983.

9. Jochem, V. J.; Fuerst, P. A.; Fromkes, J. J.: Familial Barrett's
esophagus associated with adenocarcinoma. Gastroenterology 102:
1400-1402, 1992.

10. Mossberg, S. M.: The columnar-lined esophagus (Barrett syndrome)--an
acquired condition?. Gastroenterology 50: 671-676, 1966.

11. Prior, A.; Whorwell, P. J.: Familial Barrett's oesophagus?. Hepatogastroenterology 33:
86-87, 1986.

12. Sjogren, R. W., Jr.; Johnson, L. F.: Barrett's esophagus: a review.
Am. J. Med. 74: 313-321, 1983.

*FIELD* CS

GI:
   Chronic ulcerating esophagitis;
   Gastroesophageal reflux

Oncology:
   Adenocarcinoma of the esophagus risk about 10%

Lab:
   Columnar epithelium-lined distal esophagus

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 5/23/1994
mimadm: 4/18/1994
carol: 11/10/1993
carol: 6/17/1992
carol: 4/7/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
109390
*FIELD* TI
109390 BASAL CELL CARCINOMAS WITH MILIA AND COARSE, SPARSE HAIR
*FIELD* TX
Oley et al. (1992) described a family in which 9 individuals in 4
generations and 6 sibships had basal cell carcinomas, coarse and sparse
scalp hair, sparse body hair, and multiple milia on face and limbs
spontaneously disappearing by adolescence. Since there was no instance
of male-to-male transmission, the pedigree was consistent with either
autosomal dominant or X-linked dominant transmission. All 3 daughters of
2 males who had children were affected. The family was originally
ascertained as part of a search for examples of Gorlin-Goltz syndrome
(109400). The hair abnormalities, excessive sweating, and enormous
number of large milia in childhood were features considered as
distinguishing it from that disorder as well as the lack of keratocysts
of the jaw, plantar or palmar pits, rib or vertebral abnormalities, or
abnormal calcification on skull x-ray. Some features resembled those of
the Bazex syndrome (301845) and the Rombo syndrome (180730), both of
which have multiple basal cell carcinomas as features. The hair changes
were similar to those in the Marie Unna form of hypotrichosis except
that further loss of hair did not occur with aging. One 32-year-old
patient with multiple milia over her face had markedly increased
pigmentation of the face particularly around the eyes; she had had about
20 basal cell carcinomas removed, starting at the age of 22. Vabres and
de Prost (1993) were of the opinion that the family reported by Oley et
al. (1992) in fact had Bazex syndrome. They noted that the presence or
absence of follicular atrophoderma was not mentioned by Oley et al.
(1992) but pointed out that 'this manifestation may be undiagnosed, even
by experienced dermatologists, if not carefully sought.'

*FIELD* RF
1. Oley, C. A.; Sharpe, H.; Chenevix-Trench, G.: Basal cell carcinomas,
coarse sparse hair, and milia. Am. J. Med. Genet. 43: 799-804,
1992.

2. Vabres, P.; de Prost, Y.: Bazex-Dupre-Christol syndrome: a possible
diagnosis for basal cell carcinomas, coarse sparse hair, and milia.
(Letter) Am. J. Med. Genet. 45: 786 only, 1993.

*FIELD* CS

Skin:
   Basal cell carcinomas;
   Childhood multiple milia of face and limbs;
   Increased sweating;
   Increased facial pigmentation

Hair:
   Coarse and sparse scalp hair;
   Sparse body hair

Inheritance:
   Autosomal dominant vs. X-linked dominant

*FIELD* CD
Victor A. McKusick: 8/24/1992

*FIELD* ED
jason: 7/5/1994
davew: 6/8/1994
mimadm: 4/9/1994
carol: 4/2/1993
carol: 8/24/1992

*RECORD*
*FIELD* NO
109400
*FIELD* TI
#109400 BASAL CELL NEVUS SYNDROME; BCNS
NEVOID BASAL CELL CARCINOMA SYNDROME; NBCCS;;
MULTIPLE BASAL CELL NEVI, ODONTOGENIC KERATOCYSTS, AND SKELETAL ANOMALIES;;
FIFTH PHACOMATOSIS;;
GORLIN-GOLTZ SYNDROME
HYDROCEPHALUS, COSTOVERTEBRAL DYSPLASIA, AND SPRENGEL ANOMALY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder results from mutations in PTCH (601309), the human homolog of
the Drosophila 'patched' gene.

Nevoid basal cell carcinoma syndrome may be the most satisfactory
designation for this disorder. Gorlin and Goltz (1960) suggested
autosomal dominant inheritance. About 40% of cases represent new
mutation (Gorlin, 1982). Jones et al. (1975) found evidence of paternal
age effect in new mutations for this disorder. Herzberg and Wiskemann
(1963) described what they termed the 'fifth phakomatosis,' basal cell
nevus syndrome with medulloblastoma. A father and son had basal cell
nevi. The son had medulloblastoma and congenital thoracic scoliosis. One
of the patients studied by Cawson and Kerr (1964) had astrocytoma with
severe hydrocephalus. The palms and soles may show pits. (Palmar pits
occur also with Cowden syndrome (158350) and atypical palmar pits with
Darier disease (124200).) Other features include bridging of the sella
turcica, mild mandibular prognathism, lateral displacement of the inner
canthi, frontal and biparietal bossing, odontogenic keratocysts of the
jaws, kyphoscoliosis, bifid, missing, fused and/or splayed ribs,
imperfect segmentation of cervical vertebrae, characteristic lamellar
calcification of the falx cerebri, ovarian fibromata and
lymphomesenteric cysts which tend to calcify, and short 4th metacarpal.
The basal cell nevi occur in enormous numbers. Some may resemble
seborrheic keratoses. The nevi are rarely congenital, most often
appearing in increasing numbers around the time of puberty. Lip and/or
palatal clefts probably occur in about 5% of cases, and mental
retardation in about the same frequency.

Lile et al. (1968) observed 4 cases in 3 generations. In 2 of these
patients the terminal phalanx of the thumb was short. Ovarian carcinoma
has been observed (Berlin et al., 1966). Huge calcified ovarian fibromas
were present in a CPC case discussed by Holmes (1976) at the
Massachusetts General Hospital. The occurrence of lymphomesenteric
cysts, described by Clendenning et al. (1963), was emphasized in another
CPC case by Ottinger and Vickery (1986).

Schwartz (1978) pointed to hamartomatous polyps of the stomach and
mesenteric cyst as features of the basal cell nevus syndrome. Totten
(1980) observed a large congenital lung cyst occupying the left thoracic
cavity in a patient with the basal cell nevus syndrome. Patients with
BCNS are abnormally sensitive to radiotherapeutic doses of ionizing
radiation; several patients so-treated have developed an unusually large
number of basal cell tumors in the irradiated area a short time after
exposure. Radiosensitivity could not be detected at the cellular level,
however (Featherstone et al., 1983). Unilateral coloboma of the iris and
glaucoma occurred in a familial case known to me (GS, P19000).

Evans et al. (1993) studied the clinical complications of this disorder
in 84 cases. Basal cell carcinomas and jaw cysts occurred in more than
90% of patients by 40 years of age, but both sometimes occurred before
10 years of age. Less well-described complications included ovarian
calcification or fibroma (24%), medulloblastoma (5%), cardiac fibroma
(3%), cleft palate (5%), and ophthalmic abnormalities such as squint or
cataract (26%).

Cramer and Niederdellmann (1983) described 9 subjects from 3 families
with the syndrome of cerebral gigantism (117550); 7 of the patients also
had signs of the basal cell nevus syndrome. In 1 family, a father was
193 cm tall at age 45 and his son was 197 cm tall at age 18; both had
jaw cysts and other signs of basal cell nevus syndrome. Another son was
198 cm tall at age 17 years. Macrocephaly, mild hydrocephalus,
intracranial calcification and EEG abnormalities were described.

The basal cell nevus syndrome has features that are compatible with the
Knudson hypothesis, which has had great heuristic value in
retinoblastoma (180200), Wilms tumor (194070), and other neoplasms in
which tumor-suppressor genes have been found. It combines malformations
with neoplasia. In 6 cases from 4 families, Gibbs et al. (1986) found no
chromosomal abnormality. In 1 of 5 affected related individuals,
Fletcher and Morton (1988) found a constitutional chromosomal
rearrangement involving chromosomes 5 and 15. The site involved on
chromosome 5 was in the same approximate region on the long arm as that
involved in adenomatous polyposis coli (175100). Fletcher and Morton
(1988) pointed out similarities between BCNS and Gardner syndrome and
proposed that they may be genetically related.

Search for palmar pits is warranted in any patient with a basal cell
carcinoma before age 30. As might be expected of an autosomal dominant
disorder, a considerable proportion of persons judged to have this
syndrome in the course of family studies may have no skin lesions. Jones
et al. (1986) presented the case of a woman who at age 19 underwent
cardiac transplantation for an unresectable fibrous histiocytoma of the
left ventricle (Jamieson et al., 1981). The patient showed marfanoid
build, frontal bossing with large occipitofrontal circumference, ocular
hypertelorism, broad nasal root, enlarged jaw, glaucoma, long fingers,
multiple odontogenic keratocysts, postaxial polydactyly of right foot,
and bony bridging of right metatarsals 4 and 5. The palmar and plantar
pits are like those of the form of porokeratosis described in 175850.
Holubar et al. (1970) found basal cell epitheliomas in multiple palmar
pits in an 8-year-old girl with BCNS. Levine et al. (1987) described
subconjunctival epithelial cysts presenting a dramatic appearance of
everted upper eyelids in patients with this condition.

Farndon et al. (1992) estimated that the minimum prevalence is 1 per
57,000; 1 in 200 patients with basal cell carcinomas (one or more) had
the syndrome, but the proportion is much higher (1 in 5) among those in
whom a basal cell carcinoma develops before age 19. Only a few of the
nevi grow and become locally invasive, and basal cell carcinomas do not
develop at all in about 15% of affected persons. Radiation treatment can
result in fresh crops of aggressive basal cell carcinomas and can lead
to severe disfigurement.

Gorlin (1987) gave a comprehensive review. Evans et al. (1991) found
abnormal ribs in 2 infants delivered preterm at 29 and 25 weeks. The
finding at first was thought unimportant but subsequently was shown to
indicate that some members of their families had Gorlin syndrome. In the
first case, early routine chest radiographs showed an incidental finding
of bifid ribs. The 25-year-old father had dislocated shoulder from birth
due to Sprengel deformity (184400), pronounced frontal bossing with
enlarged head, hypertelorism, calcification of the falx cerebri,
pituitary fossa totally bridged by bone, and bilateral bifid ribs. A
5-year-old brother had calcification within the falx cerebri. A
4-year-old brother had been diagnosed as having arrested congenital
hydrocephalus, and chest radiograph showed 2 bifid ribs. In the second
index case, in addition to bifid ribs, there was possible Sprengel
deformity. The baby's mother had had 5 jaw cysts removed between ages 11
and 31; she had enlarged head with pronounced frontal bossing and pits
in the palms of her hands and feet. She had multiple milia on her
forehead and hypertelorism. Radiographs showed scoliosis, calcified
ovarian fibroma, calcification of the falx cerebri, and minor rib
anomalies.

Waaler and Aarskog (1980) reported a family in which the mother had
hydrocephalus, rib malformations, dysplasia of thoracic vertebrae and
Sprengel anomaly, and each of her 3 daughters had one or more of these 4
features. The hydrocephalus (present in the mother and a daughter) was
moderate and compensated spontaneously, making shunt operation
unnecessary. It seems probable that the family reported by Waaler and
Aarskog (1980) also suffered from Gorlin syndrome.

Goldstein et al. (1994) examined 11 African Americans from 2 families
with Gorlin syndrome (which they abbreviated NBCC for nevoid basal cell
carcinoma syndrome). They also reviewed the literature on this condition
in African Americans. They found that reduced expression of the basal
cell carcinomas but full expression of the other components of the
syndrome was characteristic in African Americans. The 3 most common
findings in their 11 cases were jaw cysts, palmar palmar and/or plantar
pits, and calcification of the falx cerebri. Only 4 of the 11 had 1 or
more confirmed basal cell carcinomas, whereas the frequency of basal
cell carcinomas in whites is estimated at 90%. In a study that aimed to
ascertain all the affected families in Australia, Shanley et al. (1994)
identified 118 cases. The frequency of most manifestations were similar
to those reported by Evans et al. (1993). A major difference, however,
was that the multiple basal cell carcinomas were manifest from an
earlier age in the Australian population, which probably reflects
greater exposure to ultraviolet radiation. Of the 64 families
ascertained, 37 represented simplex cases (that is, only the proband in
the family), and accordingly the new mutation rate appeared to be high,
a surprising finding in light of the lack of impact Gorlin syndrome
(which they abbreviated NBCCS) on reproductive capabilities. Their data
showed the occurrence of multiple BCCs or onset under 20 years of age in
90 of 118 cases (75%).

Loose linkage to Rh was suggested by Anderson (1968) and to
Charcot-Marie-Tooth disease by Heimler et al. (1978). Both mutations are
located on chromosome 1. Consequently, of considerable interest is the
finding by Bale et al. (1985) of a suggestion of linkage to amylase-2
(104650), which is located at 1p21. McConville et al. (1987)
investigated linkage of BCNS with the NRAS oncogene locus (164790).
Farndon and Simmons (1987) found negative lod scores with 5 markers on
chromosome 1, suggesting that BCNS may not be on that chromosome. By
linkage analysis, Farndon et al. (1992) localized BCNS to 9q22.3-q31.
They concluded that the most likely position was between DNA markers
D9S12 and D9S53. The maximum lod scores with these 2 markers were 3.597
at theta = 0.04 and 6.457 at theta = 0.03, respectively. Reis et al.
(1992) confirmed the assignment to chromosome 9. They concluded that
D9S43 is centromeric to BCNS and that GSN (137350) and ASS (215700) are
telomeric to BCNS in that sequence. In their collection of Australasian
pedigrees, Wicking et al. (1994) further refined the localization of the
gene to a site between markers D9S196 and D9S180, an interval reported
to be approximately 2 cM. Farndon et al. (1994) concluded that the gene
involved with NBCCS lies in a 2.6 cM interval centromeric to D9S287.
Recombinants also mapped the gene for Fanconi anemia, group C (227645)
to the same region; no recombinants were detected between FACC and
NBCCS; maximum lod = 5.601 at theta = 0.0. The gene for epithelioma,
self-healing, squamous (132800), and the gene for xeroderma pigmentosum,
complementation group A (XPAC; 278700) mapped to the same region.

Johnson et al. (1996) demonstrated 2 independent sequence changes in
exon 15 of the human homolog of the Drosophila patched gene (601309) in
patients with Gorlin syndrome. They cloned the human PTC gene (symbol =
PTCH) and mapped it by radiation hybrid analysis to band 9q22.3, a
region implicated in BCNS. It was mapped very close to D9S287, which
lies between D9S196 and D9S176. One 49-year-old man had an insertion of
9 bp at nucleotide 2445 of the coding sequence resulting in the
insertion of 3 amino-acids (pro-asn-ile) after amino acid 815
(601309.0001). This change produces a tandem duplication of 3 amino
acids. A second affected individual was heterozygous for an 11-bp
deletion that removes nucleotides 2442 to 2452 (601309.0002). The
resulting frameshift truncates the ORF by creating a stop codon 9 amino
acids after amino acid 813. Johnson et al. (1996) stated that PTC is
expressed in developing sclerotome, branchial arches, limbs and spinal
cord and in vertebrate skin. They noted that the pattern of vertebrate
PTC expression is consistent with the abnormalities found in BCNS.
Therefore, Johnson et al. (1996) concluded that human PTC is a strong
candidate gene for BCNS.

Hahn et al. (1996) isolated a human sequence with strong homology to the
Drosophila segment polarity gene PTC from a YAC and cosmid contig of the
NBCCS region. They carried out mutation analysis and demonstrated
alteration of PTC in NBCCS patients and in tumors from patients with
this condition. Of the mutations identified in unrelated patients, 4
were deletions or insertions resulting in frameshifts (e.g.,
601309.0004) and 2 were point mutations leading to premature stops
(601309.0003 and 601309.0005). An additional finding of Hahn et al.
(1996) that confirmed the relationship between mutations in PTC and the
disease was the identification of a frameshift mutation (2000insC) in a
sporadic NBCCS patient and the absence of this mutation in her
unaffected parents. The authors proposed that a reduction in the
expression of the PTC gene can lead to the developmental abnormalities
observed in this syndrome and that complete loss of PTC function
contributes to transformation of certain cell types. To analyze the role
of PTC in neoplasia, tumors related to the NBCCS were screened for
mutations. Hahn et al. (1996) reported that 2 sporadic basal-cell
carcinomas with allelic loss of the NBCCS region had inactivating
mutations of the remaining allele.

Bialer et al. (1994) made the prenatal diagnosis of Gorlin syndrome in a
pregnancy sired by a man with Gorlin syndrome. There were 2 other
affected members in the family. Polymorphic DNA markers on chromosome 9
were used and the fetal diagnosis was confirmed by ultrasound scan which
showed unilateral cleft lip, probable cleft palate, and hydrocephalus.
The parents elected to terminate the pregnancy and examination of the
fetus revealed aqueductal stenosis, cleft lip, and cleft palate with a
prominent forehead and macrocephaly.

Gailani et al. (1992) found allelic loss in the chromosome 9q31 region
in 11 of 16 sporadic basal cell carcinomas, in 2 hereditary basal cell
carcinomas, and in 1 hereditary ovarian fibroma. Furthermore, in a study
of 5 Gorlin syndrome kindreds, tight linkage was found with a genetic
marker in this region. Loss of heterozygosity implies that the gene is
homozygously inactivated and normally functions as a tumor suppressor.
In contrast, hemizygous germline mutations lead to multiple congenital
anomalies of the types seen in this disorder. D9S29 was the closest
linked marker. Gailani et al. (1992) pointed out that the Ferguson-Smith
syndrome (132800) maps to the same region and raised the possibility
that Gorlin syndrome and the Ferguson-Smith syndrome may be allelic
disorders. The tumors in Ferguson-Smith syndrome are variably described
as self-healing squamous cell carcinomas or as keratoacanthomas.
Developmental defects do not occur in that syndrome. The most important
risk factor for basal cell carcinomas in persons who are not genetically
predisposed is ultraviolet exposure. UV-radiation contributes to
carcinogenesis through production of C-to-T transitions in DNA and not
by induction of large-scale chromosome rearrangements. It is likely that
in tumors not showing allelic loss both copies of the gene on chromosome
9 have undergone point mutations. Furthermore, one might predict that
basal cell carcinomas related to exposure to ionizing radiation, which
causes chromosome breaks, would more often show allelic loss.
Chenevix-Trench et al. (1993) demonstrated that, in Australasian
pedigrees, the NBCCS gene was linked to markers in the same region of
chromosome 9 with no evidence of significant heterogeneity. Loss of
heterozygosity (LOH) was detected in half of sporadic cases of basal
cell carcinoma, a rate significantly higher than that in other skin
lesions used as controls. This suggests that sporadic basal cell
carcinomas may be due to mutation in the same gene.

Levanat et al. (1996) suggested a 2-hit mechanism for neoplasia in the
Gorlin syndrome according to the Knudson model. The authors concluded
that the causative gene probably functions as a tumor suppressor based
on deletion of the relevant region of 9q found in many neoplasms
occurring in the syndrome. They suggested that some of the associated
developmental defects may also arise through a 2-hit mechanism. Like
neoplasms in familial cancer predisposition syndromes, the jaw cysts in
Gorlin syndrome are multiple and appear in a random pattern, but similar
defects are seen occasionally as a isolated finding in the general
population. Levanat et al. (1996) examined a series of chromosome 9
polymorphisms in abnormal and matched constitutional tissue and found
that the lining of the jaw cysts lost the normal copy of the Gorlin
syndrome region while retaining the mutant copy. These results suggested
to them that a somatic mutation of a particular gene in an embryonic or
fetal cell leads to abnormal migration, or differentiation, or perhaps
failure to undergo programmed cell death, manifested later as a
developmental defect.

Shimkets et al. (1996) reported cytogenetic and molecular
characterization of germline deletions in one patient with a chromosome
9q22 deletion and a second patient with a deletion of 9q22-q31. Both had
typical features of Gorlin syndrome plus additional findings. Shimkets
et al. (1996) noted that the fact that Gorlin syndrome can be caused by
null mutations (deletions) has several implications. In conjunction with
previous analysis of allelic loss in tumors, this study provided
evidence that associated neoplasms arise with homozygous inactivation of
the gene.

(Although Gorlin has described many syndromes, several of which have
been given his name, none is more intimately connected with his name
than the basal cell nevus syndrome. See Gorlin (1993) for an
autobiography.)

Wicking et al. (1997) screened 71 unrelated individuals with NBCCS for
mutations in the PTCH exons. They identified 28 mutations that were
distributed throughout the entire gene and predicted that 86% would
cause protein truncation. Wicking et al. (1997) identified 3 families
bearing identical genotypes with variable phenotypes. From this they
concluded that phenotypic variability in NBCCS is a complex genetic
event. No phenotype/genotype correlation between the position of the
truncation mutations and major clinical features was evident. Wicking et
al. (1997) concluded that the preponderance of truncation mutations in
the germline of NBCCS patients suggests that the developmental defects
associated with NBCCS are likely due to haploinsufficiency.

Bale (1997) reviewed factors contributing to the variable expressivity
of PTCH mutations in NBCCS. He reported that clinical features of NBCCS
syndrome differ more among families than between families. Shimkets et
al. (1996) reported 2 patients with small interstitial deletions on
chromosome 9q which involved the PTCH gene. Phenotypes of the 2 patients
differed with respect to several key findings (e.g., occurrence of jaw
cysts, palmar pits, and skeletal abnormalities). Bale (1997) noted that
developmental defects may also arise through a 2-hit mechanism and he
reviewed evidence for loss of the normal allele in epithelial cells
lining jaw cysts. Bale (1997) noted the absence of genotype/phenotype
correlation in NBCCS and concluded that modifying genes and germline
variants resulting in hypomorphic or hypermorphic alleles may play an
important role in determining the phenotype.

*FIELD* SA
Anderson and Cook (1966); Anderson et al. (1967); Dahl et al. (1976);
Gorlin et al. (1976); Gorlin and Sedano (1971); Gundlach and Kiehn
(1979); Howell and Mehregan (1970); Lorenz and Fuhrmann (1978); Satinoff
and Wells (1969); Southwick and Schwartz (1979)
*FIELD* RF
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28. Gorlin, R. J.; Sedano, H. O.: The multiple nevoid basal cell
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29. Gundlach, K. K. H.; Kiehn, M.: Multiple basal cell carcinoma
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30. Hahn, H.; Wicking, C.; Zaphiropoulos, P. G.; Gailani, M. R.; Shanley,
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*FIELD* CS

Skin:
   Basal cell nevi;
   Basal cell carcinoma;
   Pits of palms and soles

Facies:
   Broad facies;
   Frontal and biparietal bossing;
   Mild mandibular prognathism;
   Odontogenic keratocysts of jaws

Eyes:
   Strabismus;
   Lateral displacement of the inner canthi;
   Hypertelorism;
   Subconjunctival epithelial cysts;
   Iris coloboma;
   Glaucoma

Nose:
   Broad nasal root

Mouth:
   Cleft lip/palate

Spine:
   Scoliosis;
   Kyphoscoliosis;
   Abnormal cervical vertebrae

Thorax:
   Bifid ribs;
   Synostotic ribs;
   Hypoplastic ribs

GU:
   Ovarian fibromata;
   Ovarian carcinoma

GI:
   Lymphomesenteric cysts, often calcified;
   Hamartomatous stomach polyps

Neuro:
   Mental retardation;
   Medulloblastoma

Limbs:
   Brachydactyly;
   Short 4th metacarpal;
   Short thumb terminal phalanx

Pulmonary:
   Congenital lung cyst

Cardiac:
   Cardiac fibroma

Misc:
   Paternal age effect;
   Abnormal sensitivity to therapeutic radiation

Radiology:
   Lamellar calcification of falx cerebri;
   Bridging of the sella turcica

Inheritance:
   Autosomal dominant (9q22.3-q31)

*FIELD* CN
Moyra Smith - updated: 1/24/1997
Moyra Smith - updated: 10/1/1996
Moyra Smith - updated: 7/1/1996
Moyra Smith - updated: 6/14/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/17/1997
terry: 1/28/1997
terry: 1/24/1997
mark: 10/1/1996
mark: 8/7/1996
mark: 7/2/1996
terry: 7/2/1996
mark: 7/1/1996
mark: 6/18/1996
terry: 6/17/1996
mark: 6/14/1996
mark: 3/14/1996
terry: 2/29/1996
mark: 1/8/1996
terry: 1/4/1996
mark: 7/26/1995
terry: 12/22/1994
davew: 7/27/1994
mimadm: 4/17/1994
warfield: 4/7/1994
carol: 4/1/1994

*RECORD*
*FIELD* NO
109480
*FIELD* TI
*109480 BASIGIN; BSG
*FIELD* TX
Basigin is a member of the immunoglobulin superfamily, with a structure
related to the putative primordial form of the family. It was cloned as
a carrier of an oncodevelopmental carbohydrate marker expressed in
teratocarcinoma stem cells. It is expressed broadly in both embryos and
adults (Miyauchi et al., 1990, 1991; Kanekura et al., 1991). As members
of the immunoglobulin superfamily play fundamental roles in
intercellular recognition involved in various immunologic phenomena,
differentiation, and development, basigin is thought also to play a role
in intercellular recognition. Kaname et al. (1993) mapped the human BSG
gene to 19p13.3 by fluorescence in situ hybridization. Using an
interspecific backcross panel and microsatellite polymorphisms as
markers, Simon-Chazottes et al. (1992) mapped the gene for basigin (Bsg)
to mouse chromosome 10.

*FIELD* RF
1. Kaname, T.; Miyauchi, T.; Kuwano, A.; Matsuda, Y.; Muramatsu, T.;
Kajii, T.: Mapping basigin (BSG), a member of the immunoglobulin
superfamily, to 19p13.3. Cytogenet. Cell Genet. 64: 195-197, 1993.

2. Kanekura, T.; Miyauchi, T.; Tashiro, M.; Muramatsu, T.: Basigin,
a new member of the immunoglobulin superfamily: genes in different
mammalian species, glycosylation changes in the molecule from adult
organs and possible variation in the N-terminal sequences. Cell
Struct. Funct. 16: 23-30, 1991.

3. Miyauchi, T.; Kanekura, T.; Yamaoka, A.; Ozawa, M.; Miyazawa, S.;
Muramatsu, T.: Basigin, a new, broadly distributed member of the
immunoglobulin superfamily, has strong homology with both the immunoglobulin
V domain and the beta-chain of major histocompatibility complex class
II antigen. J. Biochem. 107: 316-323, 1990.

4. Miyauchi, T.; Masuzawa, Y.; Muramatsu, T.: The basigin group of
the immunoglobulin superfamily: complete conservation of a segment
in and around transmembrane domains of human and mouse basigin and
chicken HT7 antigen. J. Biochem. 110: 770-774, 1991.

5. Simon-Chazottes, D.; Matsubara, S.; Miyauchi, T.; Muramatsu, T.;
Guenet, J.-L.: Chromosomal localization of two cell surface-associated
molecules of potential importance in development: midkine (Mdk) and
basigin (Bsg). Mammalian Genome 2: 269-271, 1992.

*FIELD* CD
Victor A. McKusick: 11/4/1993

*FIELD* ED
carol: 11/16/1993
carol: 11/5/1993
carol: 11/4/1993

*RECORD*
*FIELD* NO
109500
*FIELD* TI
109500 BASILAR IMPRESSION, PRIMARY
*FIELD* TX
Using a radiologic criterion, Bull et al. (1955) found primary basilar
impression in 20 subjects. Of 39 available relatives, 11 also showed
basilar impression. Although first-cousin parents were found in 1 case,
it was tentatively concluded that autosomal dominant inheritance is
likely. Of the 20 probands, 10 were asymptomatic, 7 had a previous
diagnosis of syringomyelia, and 3 had symptoms and signs explicable by a
local lesion at the level of the foramen magnum. Brocher (1955)
described affected mother and daughter. Sax (1970) tells me of a family
in which as many as 9 persons in 4 generations may have been affected,
with 1 instance of male-to-male transmission. The proband, a 32-year-old
man, presented with weakness mainly in the left arm and leg. He had a
short neck, craniofacial asymmetry, left Horner syndrome, depressed
reflexes in the arms, exaggerated reflexes in legs, Babinski sign, and
kyphoscoliosis. Cervical myelogram was thought to demonstrate
hydromyelia.

*FIELD* RF
1. Brocher, J. E. W.: Die Occipito-Cervical-Gegend.  Stuttgart:
Georg Thieme Verlag (pub.)  1955.

2. Bull, J. W. D.; Nixon, W. L. B.; Pratt, R. T. C.: The radiological
criteria and familial occurrence of primary basilar impression. Brain 78:
229-247, 1955.

3. Sax, D. S.: Personal Communication. Boston, Mass.  1970.

*FIELD* CS

Radiology:
   Primary basilar impression;
   Abnormal cervical myelogram;
   Foramen magnum lesion

Neuro:
   Syringomyelia;
   Hydromyelia;
   Horner syndrome;
   Depressed arm reflexes;
   Exaggerated leg reflexes

Muscle:
   Limb muscle weakness

Neck:
   Short neck

Head:
   Craniofacial asymmetry

Spine:
   Kyphoscoliosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
109530
*FIELD* TI
*109530 B-CELL ACTIVATION MARKER; BCM1; BLAST1
ANTIGEN CD48; CD48
*FIELD* TX
Blast-1 is the designation used for an activation-associated cell
surface glycoprotein of 40-45 kD expressed primarily in
mitogen-stimulated human lymphocytes. The protein sequence predicted by
the cDNA encoding Blast-1 indicates that Blast-1 is a member of the
immunoglobulin supergene family. By Southern blot analysis of somatic
cell hybrids, Barton et al. (1987) determined that the Blast-1 gene is
located in the region 1cen-q32. Yokoyama (1991) identified the Blast-1
activation/adhesion molecule as CD48. In the course of constructing a
physical map of human 1q21-q23, Oakey et al. (1992) determined that CD48
is located in the mid-portion of this segment.

*FIELD* RF
1. Barton, D. E.; Staunton, D.; Francke, U.: The gene for BLAST1,
encoding a B-cell activation marker, is located on chromosome 1, region
cen-q32.  (Abstract) Cytogenet. Cell Genet. 46: 577 only, 1987.

2. Oakey, R. J.; Watson, M. L.; Seldin, M. F.: Construction of a
physical map on mouse and human chromosome 1: comparison of 13 Mb
of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620,
1992.

3. Yokoyama, S.: Expression of the Blast-1 (BCM1) activation/adhesion
molecule and its identification as CD48. J. Immun. 146: 2191-2200,
1991.

*FIELD* CD
Victor A. McKusick: 8/31/1987

*FIELD* ED
carol: 10/19/1993
carol: 2/9/1993
supermim: 3/16/1992
carol: 7/9/1991
carol: 6/26/1991
carol: 6/24/1991

*RECORD*
*FIELD* NO
109535
*FIELD* TI
*109535 B-CELL ASSOCIATED MOLECULE CD40; CD40
*FIELD* TX
CD40, a 48-kD glycoprotein, is expressed on the surface of all mature B
cells, most mature B-cell malignancies, and on some early B-cell acute
lymphocytic leukemias, but is not expressed on plasma cells (Clark,
1990). Stamenkovic et al. (1989) isolated a cDNA encoding CD40 and
demonstrated by the predicted sequence of the protein that CD40 is
related to human nerve growth factor receptor (162010). It is also
closely related to the receptor for TNF-alpha (191160) and to CD27
(186711). These homologies imply that the ligand for CD40 may be a
soluble factor and that CD40 is a member of the cytokine receptor
family. CD40 is a phosphoprotein and is capable of expression as a
homodimer.

Using chromosomal in situ hybridization, Lafage-Pochitaloff et al.
(1994) localized the CD40 gene to 20q12-q13.2. This localization
correlated well with the mapping of the murine CD40 gene to the distal
region of chromosome 2 which shows rather extensive homology of synteny
to human 20q11-q13.

By analysis of lymphoblastoid cell lines carrying 20q deletions,
Asimakopoulos et al. (1996) placed CD40 within a 19-21 cM interval that
was almost coincidental with the common deleted region defined by
previous analysis of samples from patients with myeloid malignancies.

*FIELD* RF
1. Asimakopoulos, F. A.; White, N. J.; Nacheva, E. P.; Green, A. R.
: The human CD40 gene lies within chromosome 20q deletions associated
with myeloid malignancies. Brit. J. Haemat. 92: 127-130, 1996.

2. Clark, E. A.: CD40: a cytokine receptor in search of a ligand.
Tissue Antigens 35: 33-36, 1990.

3. Lafage-Pochitaloff, M.; Herman, P.; Birg, F.; Galizzi, J.-P.; Simonetti,
J.; Mannoni, P.; Banchereau, J.: Localization of the human CD40 gene
to chromosome 20, bands q12-q13.2. Leukemia 8: 1172-1175, 1994.

4. Stamenkovic, I.; Clark, E. A.; Seed, B.: A B-lymphocyte activation
molecule related to the nerve growth factor receptor and induced by
cytokines in carcinomas. EMBO J. 8: 1403-1410, 1989.

*FIELD* CD
Victor A. McKusick: 2/15/1991

*FIELD* ED
mark: 03/11/1996
terry: 3/6/1996
carol: 11/16/1994
supermim: 3/16/1992
carol: 3/8/1991
carol: 2/19/1991
carol: 2/15/1991

*RECORD*
*FIELD* NO
109540
*FIELD* TI
109540 B-CELL GROWTH FACTOR; BCGF
B-CELL GROWTH FACTOR 1; BCGF1
*FIELD* TX
B-cell growth factor is released by T lymphocytes after either lectin or
antigen stimulation as a protein of Mr 12,000-14,000. Sahasrabuddhe et
al. (1984) demonstrated that this relatively small molecule is derived
from a precursor molecule of Mr 60,000-80,000 which exists in an
intracytoplasmic pool in the T cells.

*FIELD* SA
Sharma et al. (1987)
*FIELD* RF
1. Sahasrabuddhe, C. G.; Morgan, J.; Sharma, S.; Mehta, S.; Martin,
B.; Wright, D.; Maizel, A.: Evidence for an intracellular precursor
for human B-cell growth factor. Proc. Nat. Acad. Sci. 81: 7902-7906,
1984.

2. Sharma, S.; Mehta, S.; Morgan, J.; Maizel, A.: Molecular cloning
and expression of a human B-cell growth factor gene in Escherichia
coli. Science 235: 1489-1492, 1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 4/15/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 3/25/1987

*RECORD*
*FIELD* NO
109543
*FIELD* TI
*109543 B-CELL MALIGNANCY, LOW GRADE
DISRUPTED IN B-CELL MALIGNANCY; DBM;;
LEUKEMIA, CHRONIC LYMPHOCYTIC, B-CELL
*FIELD* TX
Roughly 25% of human B-cell chronic lymphocytic leukemias (CLL) are
characterized by a chromosomal lesion involving 13q14. Brown et al.
(1993) found that in all except 1 of 11 cases of low grade B-cell
malignancy, with deletions or translocations involving 13q14, the change
was in the region of D13S25, with at least 4 cases showing homozygous
disruption. They concluded that D13S25 lies close to a tumor suppressor
locus whose inactivation contributes to the initiation or progression of
low grade B-cell malignancy. They showed that this locus is at least 530
kb telomeric to RB1. Involvement of the RB1 locus (180200) in CLL could
be excluded. They designated the new gene DBM, for 'disrupted in B-cell
malignancy.'

*FIELD* RF
1. Brown, A. G.; Ross, F. M.; Dunne, E. M.; Steel, C. M.; Weir-Thompson,
E. M.: Evidence for a new tumour suppressor locus (DBM) in human
B-cell neoplasia telomeric to the retinoblastoma gene. Nature Genet. 3:
67-72, 1993.

*FIELD* CS

Oncology:
   B-cell chronic lymphocytic leukemia (CLL)

Inheritance:
   Autosomal dominant (13q14)

*FIELD* CD
Victor A. McKusick: 1/27/1993

*FIELD* ED
mimadm: 4/9/1994
carol: 1/28/1993
carol: 1/27/1993

*RECORD*
*FIELD* NO
109545
*FIELD* TI
*109545 B-CELL MATURATION FACTOR; BCMA; BCM
*FIELD* TX
Laabi et al. (1992) found that a t(4;16)(q26;p13.1) translocation, found
in tumor cells of a patient with intestinal T-cell lymphoma, resulted in
a rearrangement of the interleukin-2 gene (IL2; 147680), normally
located on 4q26, with sequences from 16p13.1. Use of an IL2-specific
probe to screen a cDNA library of tumor cells, Laabi et al. (1992)
isolated clones that consisted, from 5-prime to 3-prime, of the 3 first
exons of the IL2 gene, followed by a 16p13 inframe sequence encoding 181
amino acids. A probe derived from this sequence detected a 1.2-kb
transcript in various cell lines exhibiting mature B lymphoid cell
features, but this sequence was not detected in other cell lines
representative of other hematopoietic lineages, or in other organs. For
this reason, the novel gene was termed BCM for B-cell maturation. The
open reading frame of normal BCM cDNA predicted a 184-amino acid protein
with a single transmembrane domain that had no homology with any protein
sequences stored in data banks. Data indicated that the expression of
BCM coincides with B-cell terminal maturation.

The patient from whose tumor cells the 4;16 translocation was derived
had a chronic intestinal malabsorption syndrome. Histologic and
immunohistochemical studies demonstrated a lymphoproliferative syndrome
of mature T cells. Monoclonality was demonstrated by the presence of a
rearranged band of the TCRB gene (186930).

*FIELD* RF
1. Laabi, Y.; Gras, M. P.; Carbonnel, F.; Brouet, J. C.; Berger, R.;
Larsen, C. J.; Tsapis, A.: A new gene, BCM, on chromosome 16 is fused
to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a
malignant T cell lymphoma. EMBO J. 11: 3897-3904, 1992.

*FIELD* CD
Victor A. McKusick: 11/16/1992

*FIELD* ED
carol: 1/25/1993
carol: 11/16/1992

*RECORD*
*FIELD* NO
109560
*FIELD* TI
*109560 B-CELL LEUKEMIA/LYMPHOMA-3; BCL3
BCL4, FORMERLY
*FIELD* TX
One of the recurring translocations found in the neoplastic cells of
patients with chronic lymphocytic leukemia is t(14;19)(q32;13.1). In 1
such patient, McKeithan et al. (1987) analyzed the leukemic cells with
probes from the immunoglobulin heavy-chain locus. Using a probe for the
IGHA1 gene (146900), they detected a rearranged band by Southern blot
analysis. By analysis of human-mouse somatic cell hybrids, they cloned
the rearranged band and mapped it to chromosome 19. Thus, they confirmed
that the rearranged band contained the translocation breakpoint
junction. (HGM 9.5 revised the symbol from BCL4 to BCL3.) Bhatia et al.
(1991) isolated cDNA clones of mouse bcl-3. They mapped the gene to the
proximal end of mouse chromosome 7, which is syntenic to human
chromosome 19.

(Although to our knowledge BCL3 is not the determinant of an inherited
autosomal phenotype, dominant or recessive, it is a specific DNA coding
segment that is involved in a specific form of neoplasia through somatic
cell mutation.)

Wulczyn et al. (1992) and Franzoso et al. (1992) found that the BCL3
gene encodes an inhibitor (antagonist) for subunit 2 of nuclear factor
kappa-B (NFKB2; 164012).

*FIELD* RF
1. Bhatia, K.; Huppi, K.; McKeithan, T.; Siwarski, D.; Mushinski,
J. F.; Magrath, I.: Mouse bcl-3: cDNA structure, mapping and stage-dependent
expression in B lymphocytes. Oncogene 6: 1569-1573, 1991.

2. Franzoso, G.; Bours, V.; Park, S.; Tomita-Yamaguchi, M.; Kelly,
K.; Siebenlist, U.: The candidate oncoprotein Bcl-3 is an antagonist
of p50/NF-kappa-B-mediated inhibition. Nature 359: 338-342, 1992.

3. McKeithan, T. W.; Rowley, J. D.; Shows, T. B.; Diaz, M. O.: Cloning
of the chromosome translocation breakpoint junction of the t(14;19)
in chronic lymphocytic leukemia. Proc. Nat. Acad. Sci. 84: 9257-9260,
1987.

4. Wulczyn, F. G.; Naumann, M.; Scheidereit, C.: Candidate proto-oncogene
bcl-3 encodes a subunit-specific inhibitor of transcription factor
NF-kappa-B. Nature 358: 597-599, 1992.

*FIELD* CS

Oncology:
   Chronic lymphocytic leukemia

Inheritance:
   Chromosome 19 rearrangement, e.g. t(14;
   19)(q32;
   13.1)

*FIELD* CD
Victor A. McKusick: 9/19/1988

*FIELD* ED
mimadm: 4/9/1994
carol: 12/8/1992
carol: 9/3/1992
supermim: 3/16/1992
carol: 12/5/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
109565
*FIELD* TI
*109565 B-CELL LYMPHOMA-6; BCL6
ZINC FINGER PROTEIN-51; ZNF51
*FIELD* TX
Chromosomal translocations involving chromosome 3q27 and immunoglobulin
gene regions are among the most common rearrangements in B-cell
non-Hodgkin lymphoma. Using a probe from the immunoglobulin heavy chain
joining region locus (147010), Baron et al. (1993) isolated genomic
clones from a bacteriophage lambda library prepared from a lymphoma
characterized by a translocation t(3;14)(q27;q32). Normal chromosome 3
sequences and the reciprocal breakpoint junction were isolated. DNA
probes on each side of the chromosome 3 breakpoint hybridized at high
stringency to the DNA of various mammalian species, demonstrating
evolutionary conservation. A probe made from partial cDNA clones
isolated from a T-cell line hybridized the genomic DNA from both sides
of the chromosome 3 breakpoint, indicating that the t(3;14) is
associated with a break within the gene on chromosome 3. In situ
chromosomal hybridization revealed that the same gene is involved in the
t(3;22)(q27;q11). Preliminary nucleotide sequencing showed no identity
of the cDNA to gene sequences in available data banks. Baron et al.
(1993) proposed the name B-cell lymphoma-6 (BCL6) for this gene, which
they presumed plays a role in the pathogenesis of certain B-cell
lymphomas. Ye et al. (1993) cloned the BCL6 gene.

Kerckaert et al. (1993) reported the isolation of a gene that was
disrupted in 2 patients with non-Hodgkin lymphoma and t(3;14) and t(3;4)
translocations. The gene, called LAZ3 (for lymphoma-associated zinc
finger gene on chromosome 3) by them, encodes a 79-kD protein containing
6 zinc-finger motifs and sharing amino terminal homology with several
transcription factors, including the Drosophila 'tramtrack' and
'Broad-complex' genes, both of which are developmental transcription
regulators. LAZ3 is transcribed as a 3.8-kb message predominantly in
normal adult skeletal muscle and in several non-Hodgkin lymphomas
carrying 3q27 chromosomal defects. Kerckaert et al. (1993) suggested
that LAZ3 may act as a transcription regulator and play an important
role in lymphoma genesis.

Ye et al. (1993) cloned a gene from chromosomal translocations affecting
band 3q27. They showed that the gene, BCL6, encodes a 79-kilodalton
protein that is homologous with zinc finger-transcription factors.
Chromosomal translocations affecting 3q27 are common in diffuse large
cell lymphoma (DLCL). In 13 of 39 DLCL samples, but not in other types
of lymphoid malignancies, Ye et al. (1993) found that the BCL6 gene was
truncated within its 5-prime noncoding sequences, suggesting that its
expression had been deregulated. Thus, BCL6 may be a protooncogene
specifically involved in the pathogenesis of DLCL. Miki et al. (1994)
cloned the gene located at the 3q27 breakpoint in a patient with Burkitt
lymphoma carrying a translocation t(3;22)(q27;q11). The immunoglobulin
lambda light chain gene was fused to the gene on 3q27, which Miki et al.
(1994) referred to as BCL5. This designation is, however, used for the
gene on 17q22 (151441). The characteristics of their BCL5 gene were like
those described by Baron et al. (1993) and Ye et al. (1993) for the
so-called BCL6 gene.

Because structural alterations of the 5-prime noncoding region of the
BCL6 gene are found in 40% of diffuse large cell lymphomas and 5 to 10%
of follicular lymphomas, deregulated BCL6 expression may play a role in
lymphomagenesis. Nucleotide sequencing of BCL6 cDNA predicts a protein
containing 6 zinc-finger domains, suggesting that it may function as a
transcription factor. Using antisera raised against N- and C-terminal
BCL6 synthetic oligopeptides, Cattoretti et al. (1995) identified the
BCL6 gene product as a 95-kD nuclear protein. Western blot analysis of
human tumor cell lines representative of various hematopoietic
lineages/stages of differentiation showed that the BCL6 protein is
predominantly expressed in the B-cell lineage where it was found in
mature B cells. Immunohistochemical analysis of normal human lymphoid
tissues indicated that BCL6 expression is topographically restricted to
germinal centers, including all centroblasts and centrocytes. The
results indicated that expression of BCL6 is specifically regulated
during B-cell differentiation and suggested a role for BCL6 in germinal
center development or function. Because diffuse large cell lymphoma
derives from germinal-center B cells, Cattoretti et al. (1995) suggested
that deregulated BCL6 expression may contribute to its genesis by
preventing postgerminal center differentiation.

Migliazza et al. (1995) reported that in 22/30 (73%) DLCL and 7/15 (47%)
follicular lymphoma, but not in other tumor types, the BCL6 gene is also
altered by multiple, often biallelic, mutations clustered in its 5-prime
noncoding region. These mutations are of somatic origin and are found in
cases displaying either normal or rearranged BCL6 alleles indicating
their independence from chromosomal rearrangements and association with
immunoglobulin genes through translocation. These alterations identify a
mechanism of genetic instability and malignant B cells and may have been
selected during lymphomagenesis for their role in altering BCL6
expression. A panel of 123 nonhematologic tumors were screened for
mutations in the sequences most frequently mutated in non-Hodkgin
lymphoma using PCR/SSCP analysis, and no SSCP variant was found accept
for previously detected population polymorphisms. Several observations
suggested to Migliazza et al. (1995) that BCL6 mutations may be the
result of the IgD hypermutation mechanism acting on non-Ig loci. In 10
cases studied in detail, a total of 59 alterations were detected in the
BCL6 gene, including single bp substitutions (n = 55), small deletions
(n = 3), and 1 insertion.

In summary, approximately 40% of diffuse large cell lymphomas are
associated with chromosomal translocations that deregulate the
expression of BCL6 by juxtaposing heterologous promoters to BCL6 coding
domain. The BCL6 gene encodes a 95-kD protein containing 6 C-terminal
zinc finger motifs and an N-terminal POZ domain, suggesting that it may
function as a transcription factor. By using a DNA sequence selected for
its ability to bind recombinant BCL6 in vitro, Chang et al. (1996)
showed that BCL6 is present in DNA-binding complexes in nuclear extracts
from various B-cell lines. In transfection experiments, BCL6 can repress
transcription from promoters linked to its DNA target sequence and this
activity is dependent upon specific DNA-binding and the presence of an
intact N-terminal half of the protein. This part of the BCL6 molecule
contains an autonomous transrepressor domain, and 2 noncontiguous
regions, including the POZ motif, mediate maximum transrepressive
activity. Thus, the BCL6 protein can function as a sequence-specific
transcriptional repressor and may have a role in normal lymphoid
development lymphomagenesis.

Liao et al. (1996) mapped the Bcl6 gene to mouse chromosome 16 by
interspecific backcross analysis.

*FIELD* SA
Miki et al. (1994); Ye et al. (1993)
*FIELD* RF
1. Baron, B. W.; Nucifora, G.; McCabe, N.; Espinosa, R., III; Le Beau,
M. M.; McKeithan, T. W.: Identification of the gene associated with
the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11)
in B-cell lymphomas. Proc. Nat. Acad. Sci. 90: 5262-5266, 1993.

2. Cattoretti, G.; Chang, C.-C.; Cechova, K.; Zhang, J.; Ye, B. H.;
Falini, B.; Louie, D. C.; Offit, K.; Chaganti, R. S. K.; Dalla-Favera,
R.: BCL-6 protein is expressed in germinal-center B cells. Blood 86:
45-53, 1995.

3. Chang, C.-C.; Ye, B. H.; Chaganti, R. S. K.; Dalla-Favera, R.:
BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional
repressor. Proc. Nat. Acad. Sci. 93: 6947-6952, 1996.

4. Kerckaert, J.-P.; Deweindt, C.; Tilly, H.; Quief, S.; Lecocq, G.;
Bastard, C.: LAZ3, a novel zinc-finger encoding gene, is disrupted
by recurring chromosome 3q27 translocations in human lymphomas. Nature
Genet. 5: 66-70, 1993.

5. Liao, X.; Gilbert, D. J.; Dent, A.; Staudt, L. M.; Jenkins, N.
A.; Copeland, N. G.: Mapping of the mouse Bcl6 gene to chromosome
16. Mammalian Genome 7: 621-622, 1996.

6. Migliazza, A.; Martinotti, S.; Chen, W.; Fusco, C.; Ye, B. H.;
Knowles, D. M.; Offit, K.; Changanti, R. S. K.; Dalla-Favera, R.:
Frequent somatic hypermutation of the 5-prime noncoding region of
the BCL6 gene in B-cell lymphoma. Proc. Nat. Acad. Sci. 92: 12520-12524,
1995.

7. Miki, T.; Kawamata, N.; Arai, A.; Ohashi, K.; Nakamura, Y.; Kato,
A.; Hirosawa, S.; Aoki, N.: Molecular cloning of the breakpoint for
3q27 translocation in B-cell lymphomas and leukemias. Blood 83:
217-222, 1994.

8. Miki, T.; Kawamata, N.; Hirosawa, S.; Aoki, N.: Gene involved
in the 3q27 translocation associated with B-cell lymphoma, BCL5, encodes
a Kruppel-like zinc-finger protein. Blood 83: 26-32, 1994.

9. Ye, B. H.; Lista, F.; Lo Coco, F.; Knowles, D. M.; Offit, K.; Chaganti,
R. S. K.; Dalla-Favera, R.: Alterations of a zinc finger-encoding
gene, BCL-6, in diffuse large-cell lymphoma. Science 262: 747-750,
1993.

10. Ye, B. H.; Rao, P. H.; Chaganti, R. S. K.; Dalla-Favera, R.:
Cloning of bcl-6, the locus involved in chromosome translocations
affecting band 3q27 in B-cell lymphoma. Cancer Res. 53: 2732-2735,
1993.

*FIELD* CD
Victor A. McKusick: 6/24/1993

*FIELD* ED
terry: 11/14/1996
mark: 10/11/1996
terry: 9/20/1996
mark: 2/5/1996
terry: 1/27/1996
mark: 9/17/1995
carol: 5/31/1994
carol: 11/11/1993
carol: 11/5/1993
carol: 9/9/1993
carol: 7/19/1993

*RECORD*
*FIELD* NO
109580
*FIELD* TI
*109580 B-CELL TRANSLOCATION GENE 1; BTG1
*FIELD* TX
Rimokh et al. (1991) cloned the breakpoint of a t(8;12) chromosomal
translocation in a case of B-cell chronic lymphocytic leukemia and
isolated a coding sequence mapping on 12q22. This sequence detected a
1.8-kb transcript in virtually all tissues tested except in the brain
and muscle where the signal was barely detectable. The putative gene
corresponding to this sequence, termed BTG1 for B-cell translocation
gene 1, was shown to be highly conserved in evolution; a similar 1.8-kb
transcript could be detected in murine and chicken tissue by using a
human BTG1 DNA probe. Rouault et al. (1992) established the genomic
organization of the gene. The full-length cDNA isolated from a
lymphoblastoid cell line contained an open reading frame of 171 amino
acids. BTG1 expression was maximal in the G(0)/G(1) phases of the cell
cycle and downregulated when cells progressed throughout G(1).
Furthermore, transfection experiments using NIH 3T3 cells indicated that
BTG1 negatively regulates cell proliferation. Rouault et al. (1992)
postulated that BTG1 is a member of a new family of antiproliferative
genes.

*FIELD* RF
1. Rimokh, R.; Rouault, J. P.; Wahbi, K.; Gadoux, M.; Lafage, M.;
Archimbaud, E.; Charrin, C.; Gentilhomme, O.; Germain, D.; Samarut,
J.; Magaud, J. P.: A chromosome 12 coding region is juxtaposed to
the MYC protooncogene locus in a t(8;12)(q24;q22) translocation in
a case of B-cell chronic lymphocytic leukemia. Genes Chromosomes
Cancer 3: 24-36, 1991.

2. Rouault, J.-P.; Rimokh, R.; Tessa, C.; Paranhos, G.; Ffrench, M.;
Duret, L.; Garoccio, M.; Germain, D.; Samarut, J.; Magaud, J.-P.:
BTG1, a member of a new family of antiproliferative genes. EMBO
J. 11: 1663-1670, 1992.

*FIELD* CD
Victor A. McKusick: 1/14/1994

*FIELD* ED
carol: 1/14/1994

*RECORD*
*FIELD* NO
109600
*FIELD* TI
109600 BEETURIA
BETACYANINURIA
*FIELD* TX
Beeturia is the urinary excretion of beet pigment (betacyanin) after
oral ingestion of beets. Allison and McWhirter (1956) suggested that the
trait is unifactorial and polymorphic. They concluded that 'nonexcreter'
is dominant to 'excreter.' Penrose (1957) challenged this idea. Watson
et al. (1963) found beeturia in 14% of persons. However, 80% of iron
deficient subjects have beeturia. They suggested that iron and
betacyanin may compete for an intestinal mucosal acceptor substance,
perhaps apoferritin. Thus, iron deficiency interferes with the
usefulness of beeturia as a genetic trait.

*FIELD* SA
Farrai et al. (1968); Farrai et al. (1971); Tunnessen et al. (1969)
*FIELD* RF
1. Allison, A. C.; McWhirter, K. G.: Two unifactorial characters
for which man is polymorphic. Nature 178: 748-749, 1956.

2. Farrai, G.; Vagujfalvi, D.; Bolosky, P.: Betaninuria in childhood.
Acta Paediat. Acad. Sci. Hung. 9: 43-51, 1968.

3. Farrai, G.; Vagujfalvi, D.; Lutter, J.; Benedek, E.; Soos, E.:
No simple association between betanin excretion and iron deficiency.
Folia Haemat. 95: 245-248, 1971.

4. Penrose, L. S.: Two new human genes.  (Letter) Brit. Med. J. 1:
282 only, 1957.

5. Tunnessen, W. W.; Smith, C.; Oski, F. A.: Beeturia. Am. J. Dis.
Child. 117: 424-426, 1969.

6. Watson, W. C.; Luke, R. G.; Inall, J. A.: Beeturia: its incidence
and a clue to its mechanism. Brit. Med. J. 2: 971-973, 1963.

*FIELD* CS

Lab:
   Urinary excretion of beet pigment (betacyanin) after oral ingestion
   of beets

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 6/24/1987

*RECORD*
*FIELD* NO
109610
*FIELD* TI
*109610 BENZODIAZEPINE RECEPTOR, PERIPHERAL TYPE; BZRP
BENZODIAZEPINE PERIPHERAL BINDING SITE; PBR
*FIELD* TX
Benzodiazepines are psychoactive drugs with sedative, anxiolytic, and
anticonvulsant properties. They exert these actions through receptors
located in the central nervous system; however, some benzodiazepines
also interact with a different type of receptor present mainly in the
mitochondrial compartment of peripheral tissues. The physiologic role of
this peripheral-type receptor is unclear. Riond et al. (1991) found that
the peripheral receptor is very similar in rat, Chinese hamster, and
human. Based on these results, they screened a human cDNA library with
oligonucleotide probes derived from the Chinese hamster sequence. One
clone contained a full-length representation of human peripheral binding
site (PBS) mRNA. The amino acid sequence of human benzodiazepine PBS
deduced from the cDNA was 79% identical to that of rat PBS. Using the
cDNA of human BPBS as a probe, the gene was localized to human 22q13.3
by in situ hybridization. Chang et al. (1992) mapped the BZRP gene to
chromosome 22 by hybridization to DNA from a somatic cell hybrid mapping
panel. With a regional panel for chromosome 22, they localized the gene
within band 22q13.31. They found that the receptor expressed in COS-1
cells had remarkably different affinities than did the endogenous human
benzodiazepine receptor. They interpreted this finding as indicating
that the host cell and/or posttranslational modification had important
influences on function of the receptor protein. They used the
abbreviation PBR for the peripheral benzodiazepine receptor. Bucan et
al. (1993) mapped the homologous murine gene to chromosome 15.

The mitochondrial benzodiazepine receptor appears to be a key factor in
the flow of cholesterol into mitochondria to permit the initiation of
steroid hormone synthesis. It consists of 3 components; the 18-kD
component on the outer mitochondrial membrane appears to contain the
benzodiazepine-binding site and is therefore termed the peripheral
benzodiazepine receptor. Using a cloned human PBR cDNA as probe, Lin et
al. (1993) cloned the gene, which they found covers 13 kb and is divided
into 4 exons, with exon 1 encoding only a short 5-prime untranslated
segment. It had been speculated that patients with congenital lipoid
adrenal hyperplasia (201710), who cannot make any steroids, might have a
genetic lesion in the BZRP gene. However, on RT-PCR analysis of
testicular RNA from such a patient, sequencing of cDNA, and blotting
analysis of genomic DNA, Lin et al. (1993) found no abnormality of the
gene or mRNA for the peripheral benzodiazepine receptor component of the
mitochondrial BZR.

*FIELD* RF
1. Bucan, M.; Gatalica, B.; Nolan, P.; Chung, A.; Leroux, A.; Grossman,
M. H.; Nadeau, J. H.; Emanuel, B. S.; Budarf, M.: Comparative mapping
of 9 human chromosome 22q loci in the laboratory mouse. Hum. Molec.
Genet. 2: 1245-1252, 1993.

2. Chang, Y. J.; McCabe, R. T.; Rennert, H.; Budarf, M. L.; Sayegh,
R.; Emanuel, B. S.; Skolnick, P.; Strauss, J. F., III: The human
'peripheral-type' benzodiazepine receptor: regional mapping of the
gene and characterization of the receptor expressed from cDNA. DNA
Cell Biol. 11: 471-480, 1992.

3. Lin, D.; Chang, Y. J.; Strauss, J. F., III; Miller, W. L.: The
human peripheral benzodiazepine receptor gene: cloning and characterization
of alternative splicing in normal tissues and in a patient with congenital
lipoid adrenal hyperplasia. Genomics 18: 643-650, 1993.

4. Riond, J.; Mattei, M. G.; Kaghad, M.; Dumont, X.; Guillemot, J.
C.; Le Fur, G.; Caput, D.; Ferrara, P.: Molecular cloning and chromosomal
localization of a human peripheral-type benzodiazepine receptor. Europ.
J. Biochem. 195: 305-311, 1991.

*FIELD* CD
Victor A. McKusick: 6/25/1991

*FIELD* ED
mimadm: 4/26/1994
carol: 2/2/1994
carol: 9/20/1993
carol: 11/3/1992
supermim: 3/16/1992
carol: 1/29/1992

*RECORD*
*FIELD* NO
109630
*FIELD* TI
*109630 BETA-1-ADRENERGIC RECEPTOR; ADRB1; ADRB1R; B1AR
*FIELD* TX
See 104210 and 109690. A number of pharmacologically well-characterized
subtypes of adrenergic receptors are known, including alpha-1, alpha-2,
beta-1, and beta-2. Of these, both B1AR and B2AR stimulate adenylate
cyclase, although they subserve different physiologic functions. A
variety of drugs, both agonists and antagonists, selective for either
beta-1 or beta-2 receptors have important applications in clinical
medicine. Frielle et al. (1987) reported the unexpected cloning of the
human B1AR cDNA from a human placenta cDNA library screened with human
genomic clone G-21. The G-21 clone, containing an intronless gene for an
as yet unidentified putative receptor, was itself obtained by its
cross-hybridization with the human gene encoding B2AR. The sequence of
the cDNA encoding human B1AR was determined. The 2.4-kb cDNA for the
human B1AR encodes a protein of 477 amino acid residues that is 69%
homologous with the avian beta-adrenergic receptor but only 54%
homologous with the human beta-2-adrenergic receptor. This suggested
that the avian gene encoding BAR and the human gene encoding B1AR
evolved from a common ancestral gene. Expression of the B1AR protein in
Xenopus laevis oocytes conveyed adenylate cyclase responsiveness to
catecholamines with a typical beta-1 specificity. This contrasts with
the typical beta-2 subtype specificity observed when B2AR cDNAs
expressed in the Xenopus laevis system. Thus, mammalian B1AR and B2AR
are products of distinct genes, both of which are apparently related to
the putative G-21 receptor. See review by Frielle et al. (1988).

By means of somatic cell hybrid analysis and in situ hybridization,
Hoehe et al. (1989) localized the beta-1 adrenergic receptor gene to
chromosome 10. Hoehe et al. (1989) concluded from linkage studies that
the ADRB1R and ADRA2R (104210) loci are closely linked in the region
10q23-q25. Pulsed field gel electrophoresis showed that the 2 loci are
in the same 250-kb segment. Linkage studies in 7 manic-depressive
families excluded linkage of this gene as well as the ADRA2C (104250),
ADRA2R, and ADRB2R (109690) genes as causative; lod scores were less
than -2. By in situ hybridization, Yang-Feng et al. (1990) regionalized
the ADRA2R and ADRB1R genes to 10q24-q26. From studies by pulsed field
gel electrophoresis, they concluded that the 2 genes are less than 225
kb apart. By linkage studies and interspecific backcrosses, Oakey et al.
(1991) assigned the Adrb1r gene to the distal region of mouse chromosome
19.

Magnusson et al. (1990) demonstrated autoantibodies against the
beta-1-adrenergic receptor in some patients with idiopathic dilated
cardiomyopathy.

*FIELD* RF
1. Frielle, T.; Collins, S.; Daniel, K. W.; Caron, M. G.; Lefkowitz,
R. J.; Kobilka, B. K.: Cloning of the cDNA for the human beta-1-adrenergic
receptor. Proc. Nat. Acad. Sci. 84: 7920-7924, 1987.

2. Frielle, T.; Kobilka, B.; Lefkowitz, R. J.; Caron, M. G.: Human
beta-1- and beta-2-adrenergic receptors: structurally and functionally
related receptors derived from distinct genes. Trends Neurosci. 11:
321-324, 1988.

3. Hoehe, M.; Berrettini, W.; Leppert, M.; Lalouel, J.-M.; Byerley,
W.; Gershon, E.; White, R.: Genetic mapping of adrenergic receptor
genes.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A143 only, 1989.

4. Magnusson, Y.; Marullo, S.; Hoyer, S.; Waagstein, F.; Andersson,
B.; Vahlne, A.; Guillet, J.-G.; Strosberg, A. D.; Hjalmarson, A.;
Hoebeke, J.: Mapping of a functional autoimmune epitope on the beta(1)-adrenergic
receptor in patients with idiopathic dilated cardiomyopathy. J.
Clin. Invest. 86: 1658-1663, 1990.

5. Oakey, R. J.; Caron, M. G.; Lefkowitz, R. J.; Seldin, M. F.: Genomic
organization of adrenergic and serotonin receptors in the mouse: linkage
mapping of sequence-related genes provides a method for examining
mammalian chromosome evolution. Genomics 10: 338-344, 1991.

6. Yang-Feng, T. L.; Xue, F.; Zhong, W.; Cotecchia, S.; Frielle, T.;
Caron, M. G.; Lefkowitz, R. J.; Francke, U.: Chromosomal organization
of adrenergic receptor genes. Proc. Nat. Acad. Sci. 87: 1516-1520,
1990.

*FIELD* CD
Victor A. McKusick: 12/2/1987

*FIELD* ED
carol: 4/7/1992
carol: 4/1/1992
supermim: 3/16/1992
carol: 2/25/1992
carol: 5/21/1991
carol: 11/16/1990

*RECORD*
*FIELD* NO
109635
*FIELD* TI
*109635 BETA-ADRENERGIC RECEPTOR KINASE 1; ADRBK1
BARK;;
G-PROTEIN-DEPENDENT RECEPTOR KINASE-2; GRK2
*FIELD* TX
Beta-adrenergic receptor kinase (BARK) phosphorylates the
beta-2-adrenergic receptor (109690) and appears to mediate
agonist-specific desensitization observed at high agonist
concentrations. BARK is a ubiquitous cytosolic enzyme that specifically
phosphorylates the activated form of the beta-adrenergic and related
G-protein-coupled receptors. Benovic et al. (1991) used the bovine BARK
cDNA to screen a human retinal library and isolate the human cDNA. They
showed that it encodes a protein of 689 amino acids with an overall 98%
amino acid and 92.5% nucleotide identity with bovine BARK. By study of
rodent/human hybrid cells retaining various human chromosomes and parts
of chromosomes, they demonstrated that the gene, symbolized ADRBK1,
segregates with the long arm of chromosome 11, centromeric to 11q13,
i.e., 11cen-q13. Benovic et al. (1991) mapped the homologous gene to
mouse chromosome 19.

Penn and Benovic (1994) reported that the ADRBK1 gene spans
approximately 23 kb and is composed of 21 exons interrupted by 20
introns. Exon sizes range from 52 bp (exon 7) to over 1200 bp (exon 21),
intron sizes from 68 bp (intron L) to 10.8 kb (intron A). The splice
sites for donor and acceptor were in agreement with the canonical GT/AG
rule. A major transcription start site was thought to be located
approximately 246 bp upstream of the start ATG. Sequence analysis of the
5-prime flanking/promoter region shows many features characteristic of
mammalian housekeeping genes; the lack of a TATA box, absent or
nonstandard positioned CAAT box, high GC content, and the presence of
Sp1-binding sites. The extraordinarily high GC content of the 5-prime
flanking region (more than 80%) helped define this region as a CpG
island that may be a principal regulator of expression of the gene.

*FIELD* RF
1. Benovic, J. L.; Stone, W. C.; Huebner, K.; Croce, C.; Caron, M.
G.; Lefkowitz, R. J.: cDNA cloning and chromosomal localization of
the human beta-adrenergic receptor kinase. FEBS Lett. 283: 122-126,
1991.

2. Penn, R. B.; Benovic, J. L.: Structure of the human gene encoding
the beta-adrenergic receptor kinase. J. Biol. Chem. 269: 14924-14930,
1994.

*FIELD* CD
Victor A. McKusick: 2/1/1993

*FIELD* ED
mark: 09/10/1996
terry: 9/9/1996
terry: 8/23/1996
carol: 10/6/1994
carol: 2/4/1993
carol: 2/1/1993

*RECORD*
*FIELD* NO
109636
*FIELD* TI
*109636 BETA-ADRENERGIC RECEPTOR KINASE-2; ADRBK2; BARK2
*FIELD* TX
In the rat and the mouse, Benovic et al. (1991) identified a second
beta-adrenergic receptor kinase. See beta-adrenergic receptor kinase-1
(ADRBK1; 109635). They isolated the receptor by screening a bovine brain
cDNA library with a catalytic domain fragment of the beta-adrenergic
receptor kinase. The enzyme, which they termed BARK2, showed overall
amino acid identity of 85% with BARK1, with the protein kinase catalytic
domain having 95% identity. In the rat, BARK2 mRNA was localized
predominantly in neuronal tissues, although low levels were also
observed in various tissues. The gene encoding BARK2 mapped to mouse
chromosome 5, whereas that encoding BARK1 was localized to mouse
chromosome 19. This may indicate that the ADRBK2 gene is located on
human chromosome 4 or chromosome 7 since these show extensive homology
of synteny with mouse chromosome 5. In fact, however, Calabrese et al.
(1994) demonstrated by fluorescence in situ hybridization that the
ADRBK2 gene is located on human 22q11.

*FIELD* RF
1. Benovic, J. L.; Onorato, J. J.; Arriza, J. L.; Stone, W. C.; Lohse,
M.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.; Caron, M. G.;
Lefkowitz, R. J.: Cloning, expression, and chromosomal localization
of beta-adrenergic receptor kinase 2: a new member of the receptor
kinase family. J. Biol. Chem. 266: 14939-14946, 1991.

2. Calabrese, G.; Sallese, M.; Stornaiuolo, A.; Stuppia, L.; Palka,
G.; De Blasi, A.: Chromosome mapping of the human arrestin (SAG),
beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2)
genes. Genomics 23: 286-288, 1994.

*FIELD* CD
Victor A. McKusick: 2/1/1993

*FIELD* ED
terry: 11/7/1994
carol: 2/4/1993
carol: 2/1/1993

*RECORD*
*FIELD* NO
109640
*FIELD* TI
*109640 BETA-GLYCEROL PHOSPHATASE; GPB
*FIELD* TX
In human-hamster hybrid cells, Wilson et al. (1986) found that
beta-glycerol phosphatase cosegregated with chromosome 8. In one clone
in which 8q was apparently present (according to karyotyping) but 8p was
apparently absent (according to absence of glutathione reductase;
138300), GPB was expressed, suggesting that the locus may be on 8q.
Wijnen et al. (1987) confirmed the assignment to chromosome 8.

*FIELD* RF
1. Wijnen, J. T.; Oldenburg, M.; Jhanwar, S. C.; Meera Khan, P.:
Confirmation of GPB assignment to chromosome 8.  (Abstract) Cytogenet.
Cell Genet. 46: 715 only, 1987.

2. Wilson, D. E.; Del Pizzo, R.; Carritt, B.; Povey, S.: Assignment
of the human gene for beta-glycerol phosphatase to chromosome 8. Ann.
Hum. Genet. 50: 217-221, 1986.

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 6/23/1988
marie: 3/25/1988
reenie: 10/16/1986

*RECORD*
*FIELD* NO
109650
*FIELD* TI
109650 BEHCET SYNDROME
*FIELD* TX
Goolamali et al. (1976) observed this syndrome of recurrent inflammatory
lesions of the mouth, genitalia and eyes in 5 persons in 4 generations
of a family. Viral and autoimmune etiologies have been suggested. In the
family reported, 2 brothers suffered from an unusual schizoaffective
disorder and their mother, who also had the Behcet syndrome, had severe
alopecia areata, Raynaud phenomenon and rheumatoid arthritis. Thus, this
may be the familial aggregation recognized with other autoimmune
diseases. Chamberlain (1978) found that first-degree relatives of
patients with definite Behcet syndrome occasionally suffer from mouth
and, less commonly, genital ulcerations, but not from uveitis and other
features of severe disease. Spouses showed no abnormality. A positive
family history was noted by Forbes and Robson (1960), Fowler et al.
(1968), Mason and Barnes (1969), among others. Behcet disease is most
frequent in Turkey and Japan. HLA-B5 has been found to predominate in
cases. Dundar et al. (1985) reported 7 families with multiple cases. In
1 family, 3 sibs, including twins, were affected. Father and son were
affected in another. They found HLA-B5 in the 3 families tested. Stewart
(1986) analyzed 15 families from the U.K. and 9 from Turkey, finding 27
affected persons. There were no affected parents. The author concluded
that the data were incompatible with a simple mendelian pattern of
inheritance and specifically incompatible with autosomal recessive
inheritance. No definite HLA association was found.

Mizuki et al. (1997) noted that Behcet disease is characterized by 4
major symptoms: oral aphthous ulcers, skin lesions, ocular symptoms, and
genital ulcerations, and occasionally by inflammation in tissues and
organs throughout the body, including the gastrointestinal tract,
central nervous system, vascular system, lungs, and kidneys. Behcet
disease is associated with the HLA-B51 molecule, which is relatively
frequent, ranging from 45% to 60% in many different ethnic groups
including Asian and Eurasian populations from Japan and the Middle East
(Ohno et al., 1982). However, it was not certain whether HLA-B51 itself
or a closely linked gene is responsible for susceptibility to Behcet
disease. Mizuki et al. (1997) presented evidence that the primary
association of Behcet disease may be, not with HLA-B, but with
polymorphism in a gene located about 40 kb centromeric to the HLA-B
gene: MICA (600169). They discovered a triplet repeat (GCT/AGC)
microsatellite polymorphism in the transmembrane region of the MICA
gene. In investigations of 77 Japanese patients with Behcet disease they
found that the microsatellite allele of MICA consisting of 6 repetitions
of GCT/AGC was present at significantly higher frequencies in the
patient population (Pc = 0.00055) than in a control population.
Furthermore, the (GCT/AGC)6 allele was present in all B51-positive
patients and in an additional 13 B51-negative patients. These results
suggested the possibility of a primary association of Behcet disease
with MICA rather than HLA-B.

*FIELD* SA
Whiteside Yim and White (1985)
*FIELD* RF
1. Chamberlain, M. A.: A family study of Behcet's syndrome. Ann.
Rheum. Dis. 37: 459-465, 1978.

2. Dundar, S. V.; Gencalp, U.; Simsek, H.: Familial cases of Behcet's
disease. Brit. J. Derm. 113: 319-321, 1985.

3. Forbes, I. J.; Robson, H. N.: Familial recurrent orogenital ulceration.
(Letter) Brit. Med. J. 1: 599 only, 1960.

4. Fowler, T.; Hampston, D. J.; Nussey, A. M.; Small, M.: Behcet's
syndrome with neurological manifestations in two sisters. Brit. Med.
J. 2: 473-474, 1968.

5. Goolamali, S. K.; Comaish, J. S.; Hassanyeh, F.; Stephens, A.:
Familial Behcet's syndrome. Brit. J. Derm. 95: 637-642, 1976.

6. Mason, R. M.; Barnes, C. G.: Behcet's syndrome with arthritis. Ann.
Rheum. Dis. 28: 95-103, 1969.

7. Mizuki, N.; Ota, M.; Kimura, M.; Ohno, S.; Ando, H.; Katsuyama,
Y.; Yamazaki, M.; Watanabe, K.; Goto, K.; Nakamura, S.; Bahram, S.;
Inoko, H.: Triplet repeat polymorphism in the transmembrane region
of the MICA gene: a strong association of six GCT repetitions with
Behcet disease. Proc. Nat. Acad. Sci. 94: 1298-1303, 1997.

8. Ohno, S.; Ohguchi, M.; Hirose, S.; Matsuda, H.; Wakisaka, A.; Aizawa,
M.: Close association of HLA-Bw51 with Behcet's disease. Arch. Ophthal. 100:
1455-1458, 1982.

9. Stewart, J. A. B.: Genetic analysis of families of patients with
Behcet's syndrome: data incompatible with autosomal recessive inheritance. Ann.
Rheum. Dis. 45: 265-268, 1986.

10. Whiteside Yim, C.; White, R. H.: Behcet's syndrome in a family
with inflammatory bowel disease. Arch. Intern. Med. 145: 1047-1050,
1985.

*FIELD* CS

Mouth:
   Mouth ulcerations

GU:
   Genital ulcerations;
   Epididymitis

Skin:
   Erythema nodosum-like eruptions;
   Superficial thrombophlebitis;
   Pustular skin lesions;
   Hyperirritability;
   Raynaud phenomenon

Hair:
   Alopecia areata

Neuro:
   Brainstem syndrome;
   Meningoencephalomyelitic syndrome;
   Organic confusional state;
   Schizoaffective disorder

Joints:
   Arthritis

Eyes:
   Uveitis;
   Hypopyon;
   Iritis;
   Iridocyclitis;
   Choreoretinitis

Inheritance:
   Familial cases reported, but probably not Mendelian

*FIELD* CN
Victor A. McKusick - updated: 3/3/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jamie: 03/04/1997
mark: 3/3/1997
terry: 2/28/1997
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 7/8/1987

*RECORD*
*FIELD* NO
109660
*FIELD* TI
*109660 BETA-AMINO ACIDS, RENAL TRANSPORT OF; AABT
TAURINE RENAL REABSORPTION
*FIELD* TX
Connolly et al. (1979) stated that urinary taurine excretion values show
three modes in normals, consistent with a polymorphic codominant
2-allele system regulating renal reabsorption. They estimated
frequencies of 0.35 and 0.65 for the high and low reabsorption,
respectively. Beta-alanine competitively inhibits reabsorption of
taurine and BAIB (beta-amino-isobutyric acid; see 210100). Thus, the
postulated system is probably homologous to the beta-amino acid renal
transport system found in mice and rats. Taurine excretion is, on the
average, low in the Down syndrome, suggesting to Connolly et al. (1979)
that the gene encoding this system is on human chromosome 21. At HGM6
(Oslo, 1981), a tentative assignment of a locus for this function to
chromosome 21 was made on the basis of dosage effect in Down syndrome.
Goodman (1981) concluded that a polymorphic codominant pair of alleles,
symbolized T(R) and T(S), for rapid and slow uptake of taurine, are the
prime regulators of taurine reabsorption at the renal level. The
subtlety of the difference (only about 20% in reabsorption between the
two homozygous genotypes) makes taurine loading essential to rigorous
demonstration. In Down syndrome subjects, four genotypes occur in
frequencies suggesting that the gene is on chromosome 21. A correlation
between primary taurine excretion and IQ in Down syndrome was observed
by Thomas et al. (1965). Thus, the same variability in uptake may occur
in brain cells. Goodman et al. (1980) claimed that taurine metabolism
may be important in epilepsy. Taurine, like gamma-aminobutyric acid
(GABA), is probably neuroinhibitory and serves a role in modulation of
neurotransmission (Barbeau and Huxtable, 1978). Taurine accounts for
more than half of the total free amino acids in brain and platelet.
Variability in platelet taurine may be a useful way to examine this
polymorphism. Goodman (1981) estimated that the frequency of the rapid
absorption gene is about 0.338.

*FIELD* RF
1. Barbeau, A.; Huxtable, R. J.: Taurine and Neurological Disorders.
New York: Raven Press (pub.)  1978.

2. Connolly, B. A.; Goodman, H. O.; Swanton, C. H.: Evidence for
inheritance of a renal beta-amino acid transport system and its localization
to chromosome 21.  (Abstract) Am. J. Hum. Genet. 31: 43A only, 1979.

3. Goodman, H. O.: Personal Communication. Winston-Salem, N. C.
7/13/1981.

4. Goodman, H. O.; Connolly, B. M.; McLean, W.; Resnick, M.: Taurine
transport in epilepsy. Clin. Chem. 26: 414-419, 1980.

5. Thomas, J. J.; Goodman, H. O.; King, J. S., Jr.; Wainer, A.: Taurine
excretion and intelligence in mongolism. Proc. Exp. Biol. Med. 119:
832-833, 1965.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 7/20/1994
pfoster: 3/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
109670
*FIELD* TI
109670 BETA-ADRENERGIC STIMULATION, RESPONSE TO; BAS
*FIELD* TX
McSwigan et al. (1981) suggested that chromosome 21 may carry genetic
information involved in regulation of the beta-adrenergic response of
human fibroblasts. They based this conclusion on the finding of a
10-fold greater response to beta-adrenergic agonists (as monitored by
intracellular cyclic AMP accumulation) in cultured fibroblasts from Down
syndrome patients than that in either normal diploid skin fibroblasts or
other aneusomic fibroblasts (trisomy 13, 18, 22). No peculiarity of
response was observed with prostaglandin E1 or cholera toxin. Monosomy
21 cells responded less than normal diploid fibroblasts to stimulation
by the beta-adrenergic agonist isoproterenol.

*FIELD* RF
1. McSwigan, J. D.; Hanson, D. R.; Lubiniecki, A.; Heston, L. L.;
Sheppard, J. R.: Down syndrome fibroblasts are hyperresponsive to
beta-adrenergic stimulation. Proc. Nat. Acad. Sci. 78: 7670-7673,
1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/24/1986
reenie: 6/4/1986

*RECORD*
*FIELD* NO
109675
*FIELD* TI
*109675 BETA-GALACTOSIDE ALPHA-2,6-SIALYLTRANSFERASE
SIALYLTRANSFERASE 1; SIAT1
*FIELD* TX
Much interest in the role and regulation of beta-galactoside
alpha-2,6-sialyltransferase (EC 2.4.99.1) in B lymphocytes stemmed from
its relation to CDw75, a human leukocyte cell-surface antigen expressed
in mature and activated B cells but not in B cells at earlier stages of
development or in plasma cells. SiaT-1 is required for the elaboration
of the CDw75 cell-surface epitope. Grundmann et al. (1990) reported the
complete cDNA sequence corresponding to the SIAT1 gene on the basis of
cDNA isolated from a human placental lambda-gt10 library. By Southern
analysis of somatic cell hybrids and by in situ hybridization, Wang et
al. (1993) demonstrated that the SIAT1 gene is located on 3q21-q28.
Comparative analysis of the human and rat sequences demonstrated precise
conservation of the intron/exon boundaries throughout the coding
domains. Furthermore, there was extensive interspecies sequence
similarity in some of the exons that contained information only for the
5-prime leader regions.

*FIELD* RF
1. Grundmann, U.; Nerlich, C.; Rein, T.; Zettlmeissl, G.: Complete
cDNA sequence encoding human beta-galactoside alpha-2,6-sialyltransferase.
Nucleic Acids Res. 18: 667 only, 1990.

2. Wang, X.; Vertino, A.; Eddy, R. L.; Byers, M. G.; Jani-Sait, S.
N.; Shows, T. B.; Lau, J. T. Y.: Chromosome mapping and organization
of the human beta-galactoside alpha-2,6-sialyltransferase gene: differential
and cell-type specific usage of upstream exon sequences in B-lymphoblastoid
cells. J. Biol. Chem. 268: 4355-4361, 1993.

*FIELD* CD
Victor A. McKusick: 6/22/1994

*FIELD* ED
jason: 6/22/1994

*RECORD*
*FIELD* NO
109684
*FIELD* TI
*109684 17-@BETA-HYDROXYSTEROID DEHYDROGENASE I
17-@BETA-HSD I;;
17-@BETA-HYDROXYSTEROID DEHYDROGENASE 1; HSD17B1;;
ESTRADIOL 17-BETA-DEHYDROGENASE II; EDH17B2
*FIELD* TX
The enzyme that is responsible for the interconversion of estrone (E1)
and estradiol (E2) as well as the interconversion of androstenedione and
testosterone is known as either 17-beta-hydroxysteroid dehydrogenase or
17-ketosteroid reductase (Migeon, 1990). Harkness et al. (1979)
concluded that there are at least 2 forms of 17-beta-hydroxysteroid
oxidoreductase (EC 1.1.1.64) under independent genetic control and that
only one of these is localized to the testis. Luu-The et al. (1990)
isolated, sequenced, and characterized 2 in-tandem
17-beta-hydroxysteroid dehydrogenase genes that reside within a 13-kb
genomic DNA fragment. In addition to being found in ovary, testis, and
placenta, appreciable levels of 17-beta-HSD mRNAs were found in
peripheral tissues such as uterus, breast, prostate, and fat. Normand et
al. (1993) determined the complete nucleotide sequence of the EDH17B2
gene in 4 unrelated individuals. Direct sequencing of PCR fragments that
span the complete gene revealed a total of 11 allelic variants that were
due to single base substitutions. Studies in 26 unrelated persons
demonstrated that 9 of these variants were frequent polymorphisms and 2
of them rare variants. Complete linkage disequilibrium was demonstrated
for 7 of the 11 polymorphisms. They suggested that these polymorphisms
could be used for further mapping of the gene and for establishing
whether EDH17B2 is a candidate gene for hereditary breast-ovarian
cancer. The second EDH17B2 gene that was mapped to chromosome 17 is, in
fact, a pseudogene (Russell, 1994), EDH17BP1.

Berube et al. (1989) mapped the gene for this enzyme to 17q11-q12 by in
situ hybridization. By Southern blotting studies, Tremblay et al. (1989)
concluded that the mRNA for estrogenic 17-KSR is encoded by 2 similar
genes, which they localized to 17cen-q25 by analysis of DNA from
mouse/human somatic hybrid cell lines. Winqvist et al. (1990) assigned
the 17-HSD gene to chromosome 17 by Southern blot analysis of
human/rodent somatic cell hybrids and independently to 17q12-q21 by
chromosomal in situ hybridization. Male pseudohermaphroditism (264300)
is caused by mutations in the testicular isoform, 17-beta-hydroxysteroid
dehydrogenase-3 (Geissler et al., 1994).

*FIELD* RF
1. Berube, D.; Luu-The, V.; Simard, J.; Gagne, R.; Labrie, F.: Localization
of the beta-estradiol dehydrogenase genes to q11-q12 of chromosome
17.  (Abstract) Cytogenet. Cell Genet. 51: 962 only, 1989.

2. Geissler, W. M.; Davis, D. L.; Wu, L.; Bradshaw, K. D.; Patel,
S.; Mendonca, B. B.; Elliston, K. O.; Wilson, J. D.; Russell, D. W.;
Andersson, S.: Male pseudohermaphroditism caused by mutations of
testicular 17-beta-hydroxysteroid dehydrogenase 3. Nature Genet. 7:
34-39, 1994.

3. Harkness, R. A.; Thistlethwaite, D.; Darling, J. A. B.; Skakkebaek,
N. E.; Corker, C. S.: Neutral 17-beta-hydroxysteroid oxidoreductase
deficiency in testes causing male pseudohermaphroditism in an infant.
J. Inherit. Metab. Dis. 2: 51-54, 1979.

4. Luu-The, V.; Labrie, C.; Simard, J.; Lachance, Y.; Zhao, H.-F.;
Couet, J.; Leblanc, G.; Labrie, F.: Structure of two in tandem human
17-beta-hydroxysteroid dehydrogenase genes. Molec. Endocr. 4: 268-275,
1990.

5. Migeon, C. J.: Personal Communication. Baltimore, Md.  10/29/1990.

6. Normand, T.; Narod, S.; Labrie, F.; Simard, J.: Detection of polymorphisms
in the estradiol 17-beta-hydroxysteroid dehydrogenase II gene at the
EDH17B2 locus on 17q11-q21. Hum. Molec. Genet. 2: 479-483, 1993.

7. Russell, D. W.: Personal Communication. Dallas, Texas  5/9/1994.

8. Tremblay, Y.; Ringler, G. E.; Morel, Y.; Mohandas, T. K.; Labrie,
F.; Strauss, J. F., III; Miller, W. L.: Regulation of the gene for
estrogenic 17-ketosteroid reductase lying on chromosome 17cen-q25.
J. Biol. Chem. 264: 20458-20462, 1989.

9. Winqvist, R.; Peltoketo, H.; Isomaa, V.; Grzeschik, K. H.; Mannermaa,
A.; Vihko, R.: The gene for 17-beta-hydroxysteroid dehydrogenase
maps to human chromosome 17, bands q12-q21, and shows an RFLP with
ScaI. Hum. Genet. 85: 473-476, 1990.

*FIELD* CD
Victor A. McKusick: 3/29/1995

*FIELD* ED
carol: 3/29/1995

*RECORD*
*FIELD* NO
109685
*FIELD* TI
*109685 17-@BETA-HYDROXYSTEROID DEHYDROGENASE II
17-@BETA-HSD II; HSD17B2
*FIELD* TX
A functional gene, designated 17-beta-hydroxysteroid dehydrogenase type
2, was cloned by Wu et al. (1993). Sequence analysis of a 1.4-kb cDNA
indicated that the type 2 protein had 387 amino acids with a predicted
molecular weight of 42,782. Because the protein contained an
amino-terminal type II signal-anchor motif and a carboxy-terminal
endoplasmic reticulum retention motif, Wu et al. (1993) suggested that
the type 2 enzyme is associated with the membranes of the endoplasmic
reticulum. The type 2 enzyme was capable of catalyzing the
interconversion of testosterone and androstenedione, as well as
estradiol and estrone. The enzyme also demonstrated 20-alpha-HSD
activity toward 20-alpha-dihydroprogesterone. The placenta was found to
have a high content of 17-beta-HSD type 2 mRNA.

Casey et al. (1994) assigned the functional HSD17B2 gene to 16q24 by in
situ hybridization. From measurements taken in 20 chromosomes 16, it was
determined that the gene is located 89% of the distance from the
centromere to the telomere, placing it in 16q24. The location at 16q24
is supported by the findings of genetic linkage studies by Durocher et
al. (1995), who used a dinucleotide CA repeat sequence in intron 1 for
genotyping in 8 CEPH reference families. This placed the HSD17B2 locus
very close to marker D16S422 located on 16q24.1-q24.2.

This and other findings were consistent with the view that the
progestin-regulated 17-beta-HSD of the glandular epithelium of the human
endometrium is primarily, if not exclusively, the product of the HSD17B2
gene.

See 264300 for discussion of polycystic ovarian disease with associated
deficiency of 17-beta-HSD. Some of the descriptions of familial
polycystic ovarian disease may represent mutation in the type 2 or the
type 1 isozyme (109684).

*FIELD* RF
1. Casey, M. L.; MacDonald, P. C.; Andersson, S.: 17-beta-hydroxysteroid
dehydrogenase type 2: chromosomal assignment and progestin regulation
of gene expression in human endometrium. J. Clin. Invest. 94: 2135-2141,
1994.

2. Durocher, F.; Morissette, J.; Labrie, Y.; Labrie, F.; Simard, J.
: Mapping of the HSD17B2 gene encoding type II 17-beta-hydroxysteroid
dehydrogenase close to D16S422 on chromosome 16q24.1-q24.2. Genomics 25:
724-726, 1995.

3. Wu, L.; Einstein, M.; Geissler, W. M.; Chan, H. K.; Elliston, K.
O.; Andersson, S.: Expression cloning and characterization of human
17-beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing
20-alpha-hydroxysteroid dehydrogenase activity. J. Biol. Chem. 268:
12964-12969, 1993.

*FIELD* CD
Victor A. McKusick: 1/2/1991

*FIELD* ED
mark: 6/15/1995
carol: 3/29/1995
terry: 2/6/1995
mimadm: 5/17/1994
carol: 12/10/1993
carol: 4/30/1993

*RECORD*
*FIELD* NO
109690
*FIELD* TI
*109690 BETA-2-ADRENERGIC RECEPTOR; ADRB2; ADRB2R; BAR
BETA-ADRENERGIC RECEPTOR; ADRBR; B2AR;;
BETA-2-ADRENOCEPTOR
*FIELD* TX
Because of a lack of beta-adrenergic receptors, Chinese hamster
fibroblasts do not respond to the beta-adrenergic agonist with an
increase in cellular cAMP. Thus, by study of hamster-human somatic cell
hybrids, Sheppard et al. (1983) could assign to human chromosome 5 the
structural gene for the beta-2-adrenergic receptor. Kobilka et al.
(1987) reported the cloning and complete nucleotide sequence of the cDNA
for human beta-2-adrenergic receptor. The deduced amino acid sequence
(413 residues) was found to be that of a protein containing 7 clusters
of hydrophobic amino acids suggestive of membrane-spanning domains.
While the protein showed 87% identity overall with the previously cloned
hamster beta-2-adrenergic receptor, the most highly conserved regions
were the putative transmembrane helices (95% identical) and cytoplasmic
loops (93% identical), suggesting that these regions of the molecule
harbor important functional domains. Whereas the rhodopsin gene (180380)
consists of 5 exons interrupted by 4 introns, the beta-adrenergic
receptor genes contain no introns in either their coding or untranslated
sequences (Kobilka et al., 1987).

By studies in somatic cell hybrids and by in situ hybridization, Kobilka
et al. (1987) localized the gene to 5q31-q32. This position is the same
as that for the gene coding for platelet-derived growth factor receptor
(173410) and is adjacent to the site of the FMS oncogene (164770), the
receptor for CSF1 (120420). Emorine et al. (1987) characterized the
promoter region of the gene. Using oligonucleotide directed
site-specific mutagenesis, Fraser et al. (1988) accomplished point
mutation at nucleotide 388 of the BAR gene. The mutation resulted in a
guanine-to-adenine substitution, exchanging an asparagine for a highly
conserved aspartic acid at residue 130 of the human beta-adrenergic
receptor. The mutant beta-adrenergic receptor appeared capable of
interacting with the stimulatory guanine nucleotide-binding regulatory
protein, but the ability of guanine nucleotides to alter agonist
affinity was attenuated. By in situ hybridization, Yang-Feng et al.
(1990) regionalized the assignment to 5q32-q34. By analysis of
interspecific backcrosses, Oakey et al. (1991) mapped the corresponding
mouse gene, symbolized Adrb2, to the proximal portion of chromosome 18.

In a study of 65 healthy and drug-free subjects, Lonnqvist et al. (1992)
demonstrated that some individuals have resistance to the lipolytic
effects of catecholamines and that this is the result of decreased ADRB2
expression in fat cells. The resistance was studied in vivo and in
isolated abdominal subcutaneous adipocytes. Some of the plotted data
demonstrated bimodality consistent with a relatively simple genetic
basis for the difference. Whether the genetic difference is located at
the ADRB2 locus or at another site is unclear. The clinical consequence
of catecholamine resistance in apparently healthy subjects was also not
clear.

Patients with nocturnal asthma represent a subset of asthmatics who
experience a marked worsening of airway obstruction and symptoms while
asleep. Nocturnal asthmatics display greater bronchial hyperreactivity
than do nonnocturnal asthmatics. Several studies had suggested that
autonomic function may be different in nocturnal asthma as compared to
nonnocturnal asthma. Szefler et al. (1991) found that circulating
neutrophil and lymphocyte beta-2-adrenergic receptors, which are
potential markers for ADRB2s of bronchial smooth muscle and other lung
cells, decrease at 4:00 a.m. as compared to 4:00 p.m. in patients with
nocturnal asthma. No such downregulation of ADRB2 was found in
nonnocturnal asthmatics or normal subjects. Reihsaus et al. (1993) found
6 different polymorphic forms of ADRB2. These polymorphisms consisted of
amino acid substitutions. When they were mimicked by site-directed
mutagenesis of the cloned human ADRB2 cDNA and expressed in Chinese
hamster fibroblasts, some were found to display different pharmacologic
properties. Specifically, they found that glycine at position 16
(109690.0001), rather than arginine, imparted enhanced agonist-promoted
downregulation. This prompted them to determine ADRB2 phenotypes of 2
well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34%
nocturnal depression of peak expiratory flow rates and 22 nonnocturnal
asthmatics with virtually no such depression (2.3%). The frequency of
the gly16 allele was 80.4% in the nocturnal group as compared to 52.2%
in the nonnocturnal group, while the arg16 allele was present in 19.6%
of the nocturnal group and 47.8% of the nonnocturnal group. Turki et al.
(1995) hypothesized that gly16 may be overrepresented in nocturnal
asthma. This overrepresentation of the gly16 allele in nocturnal asthma
was significant at P = 0.007, with a 3.8 odds ratio for having both
nocturnal asthma and the gly16 polymorphism. Comparisons of the 2
cohorts as to homozygosity for gly16, homozygosity for arg16, or
heterozygosity were also consistent with segregation of gly16 with
nocturnal asthma. There was no difference in the frequency of
polymorphisms at codons 27 (gln27 or glu27) and 164 (thr164 or ile164)
between the 2 groups.

*FIELD* AV
.0001
ASTHMA, NOCTURNAL
ADRB2, ARG16GLY
Turki et al. (1995) found an excess of gly16, as opposed to arg16, among
nocturnal asthmatics. Other evidence has suggested that the presence of
glycine at position 16 of B2AR imparts enhanced agonist-promoted
downregulation of the type that characterizes this form of asthma.

*FIELD* SA
Hoehe et al. (1989); Kobilka et al. (1987)
*FIELD* RF
1. Emorine, L. J.; Marullo, S.; Delavier-Klutchko, C.; Kaveri, S.
V.; Durieu-Trautman, O.; Strosberg, A. D.: Structure of the gene
for human beta-2 adrenergic receptor: expression and promoter characterization.
Proc. Nat. Acad. Sci. 84: 6995-6999, 1987.

2. Fraser, C. M.; Chung, F.-Z.; Wang, C.-D.; Venter, J. C.: Site-directed
mutagenesis of human beta-adrenergic receptors: substitution of aspartic
acid-130 by asparagine produces a receptor with high affinity agonist
binding that is uncoupled from adenylate cyclase. Proc. Nat. Acad.
Sci. 85: 5478-5482, 1988.

3. Hoehe, M.; Berrettini, W.; Leppert, M.; Lalouel, J.-M.; Byerley,
W.; Gershon, E.; White, R.: Genetic mapping of adrenergic receptor
genes.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A143 only, 1989.

4. Kobilka, B. K.; Dixon, R. A. F.; Frielle, T.; Dohlman, H. G.; Bolanowski,
M. A.; Sigal, I. S.; Yang-Feng, T. L.; Francke, U.; Caron, M. G.;
Lefkowitz, R. J.: cDNA for the human beta-2-adrenergic receptor:
a protein with multiple membrane-spanning domains and encoded by a
gene whose chromosomal location is shared with that of the receptor
for platelet-derived growth factor. Proc. Nat. Acad. Sci. 84: 46-50,
1987.

5. Kobilka, B. K.; Frielle, T.; Collins, S.; Yang-Feng, T.; Kobilka,
T. S.; Francke, U.; Lefkowitz, R. J.; Caron, M. G.: An intronless
gene encoding a potential member of the family of receptors coupled
to guanine nucleotide regulatory proteins. Nature 329: 75-79, 1987.

6. Lonnqvist, F.; Wahrenberg, H.; Hellstrom, L.; Reynisdottir, S.;
Arner, P.: Lipolytic catecholamine resistance due to decreased beta-2-adrenoceptor
expression in fat cells. J. Clin. Invest. 90: 2175-2186, 1992.

7. Oakey, R. J.; Caron, M. G.; Lefkowitz, R. J.; Seldin, M. F.: Genomic
organization of adrenergic and serotonin receptors in the mouse: linkage
mapping of sequence-related genes provides a method for examining
mammalian chromosome evolution. Genomics 10: 338-344, 1991.

8. Reihsaus, E.; Innis, M.; MacIntyre, N.; Liggett, S. B.: Mutations
in the gene encoding for the beta(2)-adrenergic receptor in normal
and asthmatic subjects. Am. J. Respir. Cell Molec. Biol. 8: 334-339,
1993.

9. Sheppard, J. R.; Wehner, J. M.; McSwigan, J. D.; Shows, T. B.:
Chromosomal assignment of the gene for the human beta-2-adrenergic
receptor. Proc. Nat. Acad. Sci. 80: 233-236, 1983.

10. Szefler, S. J.; Ando, R.; Cicutto, L. C.; Surs, W.; Hill, M. R.;
Martin, R. J.: Plasma histamine, epinephrine, cortisol, and leukocyte
beta-adrenergic receptors in nocturnal asthma. Clin. Pharm. Therap. 49:
59-68, 1991.

11. Turki, J.; Pak, J.; Green, S. A.; Martin, R. J.; Liggett, S. B.
: Genetic polymorphisms of the beta-2-adrenergic receptor in nocturnal
and nonnocturnal asthma: evidence that gly16 correlates with the nocturnal
phenotype. J. Clin. Invest. 95: 1635-1641, 1995.

12. Yang-Feng, T. L.; Xue, F.; Zhong, W.; Cotecchia, S.; Frielle,
T.; Caron, M. G.; Lefkowitz, R. J.; Francke, U.: Chromosomal organization
of adrenergic receptor genes. Proc. Nat. Acad. Sci. 87: 1516-1520,
1990.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 5/5/1995
carol: 1/21/1993
supermim: 3/16/1992
carol: 2/25/1992
carol: 5/21/1991
carol: 9/9/1990

*RECORD*
*FIELD* NO
109691
*FIELD* TI
*109691 BETA-3-ADRENERGIC RECEPTOR; ADRB3
*FIELD* TX
Emorine et al. (1989) isolated a third beta-adrenergic receptor,
beta-3-adrenergic receptor (ADRB3). (See ADRB1 (109630) and ADRB2
(109690).) Exposure of eukaryotic cells transfected with this gene to
adrenaline or noradrenaline promoted the accumulation of adenosine
3-prime,5-prime-monophosphate. The potency of beta-AR agonists and
inhibitors was described. Van Spronsen et al. (1993) demonstrated that
the transcription-start sites of the mouse and human ADRB3 mRNA are
located in a region comprised between 150 and 200 nucleotides 5-prime
from the ATG translation-start codon. Motifs potentially implicated in
heterologous regulation of ADRB3 expression by glucocorticoids and by
beta-adrenergic agonists were identified upstream from these cap sites.
Van Spronsen et al. (1993) also described the exon/intron structure of
the genes. Their results suggested that utilization of alternate
promoters and/or 3-prime untranslated regions may allow tissue-specific
regulation of the expression of ADRB3. Wilkie et al. (1993) presented a
list of G-protein-coupled receptor genes (their table 3), indicating
that the ADRB3 gene had been mapped to 8p12-p11.2 and the homologous
gene to mouse chromosome 8.

The beta-3-adrenergic receptor, located mainly in adipose tissue, is
involved in the regulation of lipolysis and thermogenesis. The potential
relevance of this receptor to obesity in humans led Clement et al.
(1995) to screen obese patients for the mutation in the ADRB3 gene that
results in replacement of tryptophan by arginine at position 64
(trp64-to-arg). They studied DNA extracted from leukocytes of 94 normal
subjects and 185 unrelated patients with morbid obesity, as defined by a
body-mass index (the weight in kilograms divided by the square of the
height in meters) greater than 40. The trp64-to-arg mutation was
detected by analysis of RFLPs with the restriction enzyme BstNI, which
discriminates between the normal and mutant sequences. Frequency of the
W64R allele was similar in the morbidly obese patients and the normal
subjects: 0.08 and 0.10, respectively. However, patients with morbid
obesity who were heterozygous for the trp64-to-arg mutation had an
increased capacity to gain weight: the mean weight in the 14
heterozygous patients was 140 kg, as compared with 126 kg in the 171
patients without the mutation (P = 0.03). There were no homozygotes in
this sample. The cumulative 25-year change in weight (from the age of 20
years) was 67 kg in the trp64-to-arg heterozygotes, as compared with 51
kg in those without the mutation. The maximum weight differential (the
maximal lifetime weight minus the weight at 20 years of age) in the W64R
heterozygotes was 74 kg, as compared with 59 kg in the patients without
the mutation (P = 0.02). Clement et al. (1995) interpreted the findings
as indicating that the trp64-to-arg mutation of the ADRB3 gene increases
the capacity to gain weight.

*FIELD* AV
.0001
BETA-3-ADRENERGIC RECEPTOR W64R POLYMORPHISM
ADRB3, TRP64ARG
Using a candidate gene approach to the genetics of obesity, Clement et
al. (1995) found evidence suggesting that the W64R mutation of the
beta-3-adrenergic receptor gene increases the capacity to gain weight.
Gagnon et al. (1996) failed to find an association between the trp64arg
mutation in the ADRB3 gene and obesity in studies in 2 cohorts: the
Quebec Family Study (QFS) and the Swedish Obese Subjects (SOS).

*FIELD* RF
1. Clement, K.; Vaisse, C.; Manning, B. S. J.; Basdevant, A.; Guy-Grand,
B.; Ruiz, J.; Silver, K. D.; Shuldiner, A. R.; Froguel, P.; Strosberg,
A. D.: Genetic variation in the beta-3-adrenergic receptor and an
increased capacity to gain weight in patients with morbid obesity. New
Eng. J. Med. 333: 352-354, 1995.

2. Emorine, L. J.; Marullo, S.; Briend-Sutren, M.-M.; Patey, G.; Tate,
K.; Delavier-Klutchko, C.; Strosberg, A. D.: Molecular characterization
of the human beta-3-adrenergic receptor. Science 245: 1118-1121,
1989.

3. Gagnon, J.; Mauriege, P.; Roy, S.; Sjostrom, D.; Chagnon, Y. C.;
Dionne, F. T.; Oppert, J.-M.; Perusse, L.; Sjostrom, L.; Bouchard,
C.: The trp64arg mutation of the beta-3 adrenergic receptor gene
has no effect on obesity phenotypes in the Quebec Family Study and
Swedish Obese Subjects cohorts. J. Clin. Invest. 98: 2086-2093,
1996.

4. Van Spronsen, A.; Nahmias, C.; Krief, S.; Briend-Sutren, M.-M.;
Strosberg, A. D.; Emorine, L. J.: The promoter and intron/exon structure
of the human and mouse beta-3-adrenergic-receptor genes. Europ. J.
Biochem. 213: 1117-1124, 1993.

5. Wilkie, T. M.; Chen, Y.; Gilbert, D. J.; Moore, K. J.; Yu, L.;
Simon, M. I.; Copeland, N. G.; Jenkins, N. A.: Identification, chromosomal
location, and genome organization of mammalian G-protein-coupled receptors. Genomics 18:
175-184, 1993.

*FIELD* CD
Victor A. McKusick: 12/14/1993

*FIELD* ED
jenny: 12/12/1996
terry: 12/6/1996
mark: 2/22/1996
terry: 2/19/1996
mark: 9/7/1995
carol: 12/14/1993

*RECORD*
*FIELD* NO
109700
*FIELD* TI
*109700 BETA-2-MICROGLOBULIN; B2M
*FIELD* TX
Beta-2-microglobulin is found in the serum of normal individuals and in
the urine in elevated amounts in patients with Wilson disease, cadmium
poisoning, and other conditions leading to renal tubular dysfunction
(Berggard and Bearn, 1968). Like immunoglobulins, prealbumin, and the
beta protein found in the amyloid of Alzheimer disease (104300),
beta-2-microglobulin has a predominantly beta-pleated sheet structure
that may adopt the fibrillar configuration of amyloid in certain
pathologic states. The protein is a single polypeptide chain of
molecular weight 11,600. Its complete amino acid sequence was reported
by Cunningham et al. (1973). Although the function of
beta-2-microglobulin is not known, the close homology in sequence to
immunoglobulins suggests a common evolutionary origin.
Beta-2-microglobulin also has structural relationships to HLA (being the
low molecular weight component of the HLA antigens). By somatic cell
hybridization, it was shown that a structural gene for this protein is
on chromosome 15 (Goodfellow et al., 1975; Smith et al., 1975). Evidence
for localization on 15q was presented by Manolov et al. (1979), who
reported that the Daudi cell line, which has no detectable
beta-2-microglobulin, has one normal chromosome 15 and one with a
deletion of 15q12-q21. Arce-Gomez et al. (1978) made somatic cell
hybrids between the Daudi lymphoblastoid cell line (derived from a
patient with Burkitt lymphoma and lacking both HLA antigens and
beta-2-microglobulin) and a human cell line derived from HeLa and also
showing no HLA antigens. The hybrid cells did express HLA antigens.
Since Daudi cells are known not to express beta-2-microglobulin despite
the presence of a chromosome 15, reexpression in the hybrid cells is
thought to be due to provision of beta-2-microglobulin by the other
parental cell line. The experiment shows that beta-2-microglobulin is
essential to expression of HLA. Although allelic variation is known in
the mouse (Robinson et al., 1981), such has, it seems, not been found in
man. Using high resolution banding techniques, Zhang and Zech (1981)
concluded that the abnormal chromosome 15 in the Burkitt
lymphoma-derived cell line Daudi is del(15)(q13q15). This is
inconsistent with the assignment of the B2M locus by somatic cell
hybridization; deficient production of B2M by Daudi had been considered
evidence of location of the structural gene in the deleted segment.

Cox et al. (1982) found that in the mouse, as in man, B2M is not linked
to MHC, being on chromosome 2, not 17 (which carries H2). In the mouse,
sorbitol dehydrogenase is also on chromosome 2; SORD and B2M are
syntenic in man. Ly-4 and H3 are cell surface antigens encoded by genes
on mouse chromosome 2. Nothing is yet known about the homologous
antigens in man. Arguing from comparative mapping, one might suggest
that an 'Ly-4' antigen restricted to lymphocytes is encoded by
chromosome 15 in man. In the mouse, 2 alleles that differ by an amino
acid substitution--alanine or aspartic acid at position 85--have been
demonstrated. On the basis of molecular cloning studies, Margulies et
al. (1983) suggested that the ly-m11 antigenic determinant (demonstrated
on lymphocytes by a monoclonal antibody) is on the B2M molecule. H3 and
ly-4 may be also.

Hemodialysis-related amyloidosis (HRA) is a form of systemic amyloidosis
with a predilection for the synovium and bone that occurs with a
disturbingly high frequency among patients on long-term hemodialysis.
The clinical features include carpal tunnel syndrome, erosive
arthropathy, spondyloarthropathy, lytic bone lesions, and pathologic
fractures. Gejyo et al. (1985) found that protein that accumulates in
amyloid-laden tissue obtained from a chronic hemodialysis patient with
carpal tunnel syndrome was identical to B2M in several characteristics.
Connors et al. (1985) demonstrated the in vitro creation of amyloid
fibers from B2M. Gorevic et al. (1985, 1986) reported the amino acid
sequence of the HRA subunit protein and identified it as
beta-2-microglobulin. The occurrence of amyloidosis in these patients
can be prevented by periodic use of high-permeability membranes or
intermittent hemofiltration. Charra et al. (1984) reported that 38 of 52
patients receiving hemodialysis for more than 8 years for chronic renal
failure not due to amyloid nephropathy developed carpal tunnel syndrome.
Tissues excised at surgical decompression contained amyloid. In 95% of
these patients, shoulder pain, which was presumed to be due to amyloid
deposits, was present. McClure et al. (1986) demonstrated the
beta-2-microglobulin nature of the amyloid in the 3 patients with carpal
tunnel syndrome requiring decompression surgery after long-term
hemodialysis treatment for chronic renal failure not due to amyloid
nephropathy. Zingraff et al. (1990) described a patient with severe
renal insufficiency who had beta-2-microglobulin amyloidosis despite the
fact that dialysis had never been performed. The possibility that some
B2M variants are more amyloidogenic than others should be explored.

In the human melanoma cell line FO-1, D'Urso et al. (1991) found that
the lack of expression of HLA class I antigens was the result of a
defect in the B2M gene: a deletion of the first exon of the 5-prime
flanking region and of a segment of the first intron. Bicknell et al.
(1994) used single-strand conformation polymorphism (SSCP) analysis to
screen a series of 37 established colorectal cell lines, 22 fresh tumor
samples, and 22 normal DNA samples for mutations in the B2M gene. Exon 1
(including the leader peptide sequence) and exon 2 were screened
separately. Mutations were found in 6 of 7 colorectal cell lines and 1
of 22 fresh tumors, whereas no mutations were detected in the normal DNA
samples. Sequencing of these mutations showed that an 8-bp CT repeat in
the leader peptide sequence was particularly variable, since 3 of the
cell lines and 1 fresh tumor sample had deletions in this region. In 2
related colorectal cell lines, DLD-1 and HCT-15, 2 similar mutations
were identified, a C-to-A substitution in codon 10 and a G-to-T mutation
in the splice sequence of intron 1. Expression of beta-2-microglobulin
was examined using a series of monoclonal antibodies in an ELISA system.
Reduced expression correlated with a mutation in 1 allele of the B2M
gene, whereas loss of expression was seen in instances where a line was
homozygous for a mutation or heterozygous for 2 mutations. Some tumors
lack cell surface expression of HLA class I molecules and this may be
one mechanism by which tumor cells escape immune recognition by
cytotoxic T cells. In some cases, there is loss of the heavy chain
surface expression encoded by the HLA-A, -B, and -C genes which is
responsible; in other cases, expression of the B2M gene for the light
chain is responsible, as in the G-to-C point mutation in the initiator
ATG sequence in the Burkitt lymphoma cell line Daudi (Rosa et al.,
1983).

*FIELD* AV
.0001
BURKITT LYMPHOMA CELL LINE, DAUDI
B2M, MET1ILE
The Daudi lymphoblastoid cell line (derived from a patient with Burkitt
lymphoma and lacking both HLA antigens and beta-2 microglobulin) fails
to express HLA class I molecules because of a specific defect in the B2M
component. Rosa et al. (1983) demonstrated a G-to-C transversion in the
initiator ATG sequence of the B2M gene. The mutation predicts a change
from the initiator methionine residue to isoleucine.

*FIELD* SA
Casey et al. (1986); Goodfellow et al. (1975); Lindblom et al. (1974);
Marx  (1974); Michaelson et al. (1980); Oliver et al. (1978); Reisfeld
et al. (1975)
*FIELD* RF
1. Arce-Gomez, B.; Jones, E. A.; Barnstable, C. J.; Solomon, E.; Bodmer,
W. F.: The genetic control of HLA-A and B antigens in somatic cell
hybrids: requirements for beta-2-microglobulin. Tissue Antigens 11:
96-112, 1978.

2. Berggard, I.; Bearn, A. G.: Isolation and properties of a low
molecular weight beta-2-globulin occurring in human biological fluids.
J. Biol. Chem. 243: 4095-4103, 1968.

3. Bicknell, D. C.; Rowan, A.; Bodmer, W. F.: Beta-2-microglobulin
gene mutations: a study of established colorectal cell lines and fresh
tumors. Proc. Nat. Acad. Sci. 91: 4751-4755, 1994.

4. Casey, T. T.; Stone, W. J.; DiRaimondo, C. R.; Brantley, B. D.;
DiRaimondo, C. V.; Gorevic, P. D.; Page, D. L.: Tumoral amyloidosis
of bone of beta-2-microglobulin origin in association with long-term
hemodialysis: a new type of amyloid disease. Hum. Path. 17: 731-738,
1986.

5. Charra, B.; Calemard, E.; Uzan, M.; Terrat, J. C.; Vanel, T.; Laurent,
G.: Carpal tunnel syndrome, shoulder pain and amyloid deposits in
long-term haemodialysis patients.  (Abstract) Kidney Int. 26: 549
only, 1984.

6. Connors, L. H.; Shirahama, T.; Skinner, M.; Fenves, A.; Cohen,
A. S.: In vitro formation of amyloid fibrils from intact beta-2-microglobulin.
Biochem. Biophys. Res. Commun. 131: 1063-1068, 1985.

7. Cox, D. R.; Sawicki, J. A.; Yee, D.; Appella, E.; Epstein, C. J.
: Assignment of the gene for beta-2-microglobulin (B2m) to mouse chromosome
2. Proc. Nat. Acad. Sci. 79: 1930-1934, 1982.

8. Cunningham, B. A.; Wang, J. L.; Berggard, I.; Peterson, P. A.:
The complete amino acid sequence of beta-2-microglobulin. Biochemistry 12:
4811-4821, 1973.

9. D'Urso, C. M.; Wang, Z.; Cao, Y.; Tatake, R.; Zeff, R. A.; Ferrone,
S.: Lack of HLA class I antigen expression by cultured melanoma cells
FO-1 due to a defect in B(2)m gene expression. J. Clin. Invest. 87:
284-292, 1991.

10. Gejyo, F.; Yamada, T.; Odani, S.; Nakagawa, Y.; Arakawa, M.; Kunitomo,
T.; Kataoka, H.; Suzuki, M.; Hirasawa, Y.; Shirahama, T.; Cohen, A.
S.; Schmid, K.: A new form of amyloid protein associated with chronic
hemodialysis was identified as beta-2-microglobulin. Biochem. Biophys.
Res. Commun. 129: 701-706, 1985.

11. Goodfellow, P.; Jones, E.; Van Heyningen, V.; Solomon, E.; Kennett,
R.; Bobrow, M.; Bodmer, W. F.: Linkage relationships of the HL-A
system and beta-2-microglobulin. Birth Defects Orig. Art. Ser. 11(3):
162-167, 1975. Note: Alternate: Cytogenet. Cell Genet. 14: 332-337,
1975.

12. Goodfellow, P. N.; Jones, E. A.; Van Heyningen, V.; Solomon, E.;
Bobrow, M.: The beta-2-microglobulin gene is on chromosome 15 and
not in the HL-A region. Nature 254: 267-269, 1975.

13. Gorevic, P. D.; Casey, T. T.; Stone, W. J.; DiRaimondo, C. R.;
Prelli, F. C.; Frangione, B.: Beta-2 microglobulin is an amyloidogenic
protein in man. J. Clin. Invest. 76: 2425-2429, 1985.

14. Gorevic, P. D.; Munoz, P. C.; Casey, T. T.; DiRaimondo, C. R.;
Stone, W. J.; Prelli, F. C.; Rodrigues, M. M.; Poulik, M. D.; Frangione,
B.: Polymerization of intact beta-2-microglobulin in tissue causes
amyloidosis in patients on chronic hemodialysis. Proc. Nat. Acad.
Sci. 83: 7908-7912, 1986.

15. Lindblom, J. B.; Ostberg, I.; Peterson, P.: Beta-2-microglobulin
on the cell surface: relationship to HL-A antigens and the mixed lymphocyte
culture reaction. Tissue Antigens 4: 186-196, 1974.

16. Manolov, G.; Manolova, Y.; Kieler, J.: Cytogenetic investigation
of assignment of locus for beta-2-microglobulin in K562 leukemia and
Namalwa and Daudi Burkitt lymphoma cells.  (Abstract) Cytogenet.
Cell Genet. 25: 182 only, 1979.

17. Margulies, D. H.; Parnes, J. R.; Johnson, N. A.; Seidman, J. G.
: Linkage of beta-2-microglobulin and ly-m11 by molecular cloning
and DNA-mediated gene transfer. Proc. Nat. Acad. Sci. 80: 2328-2331,
1983.

18. Marx, J. L.: Immunology: role of beta-2-microglobulin. Science 185:
428-429, 1974.

19. McClure, J.; Bartley, C. J.; Ackrill, P.: Carpal tunnel syndrome
caused by amyloid containing beta-2-microglobulin: a new amyloid and
a complication of long term haemodialysis. Ann. Rheum. Dis. 45:
1007-1011, 1986.

20. Michaelson, J.; Rothenberg, E.; Boyse, E. A.: Genetic polymorphism
of murine beta-2-microglobulin detected biochemically. Immunogenetics 11:
93-95, 1980.

21. Oliver, N.; Francke, U.; Pellegrino, M. A.: Regional assignment
of genes for mannose phosphate isomerase, pyruvate kinase-3, and beta-2-microglobulin
expression on human chromosome 15 by hybridization of cells from a
t(15;22) (q14;q13.3) translocation carrier. Cytogenet. Cell Genet. 22:
506-510, 1978.

22. Reisfeld, R. A.; Sevier, E. D.; Pellegrino, M. A.; Ferrone, S.;
Poulik, M. D.: Association of HL-A antigens and beta-2-microglobulin
at the cellular and molecular level. Immunogenetics 2: 183-197,
1975.

23. Robinson, P. J.; Graf, L.; Sege, K.: Two allelic forms of mouse
beta-2-microglobulin. Proc. Nat. Acad. Sci. 78: 1167-1170, 1981.

24. Rosa, F.; Berissi, H.; Weissenbach, J.; Maroteaux, L.; Fellous,
M.; Revel, M.: The beta-2-microglobulin mRNA in human Daudi cells
has a mutated initiation codon but is still inducible by interferon.
EMBO J. 2: 239-243, 1983.

25. Smith, M.; Gold, P.; Freedman, S. O.; Shuster, J.: Studies of
the linkage relationship of beta-2-microglobulin in man-mouse somatic
cell hybrids. Ann. Hum. Genet. 39: 21-31, 1975.

26. Zhang, S.; Zech, L.: Marker chromosomes in cell lines from Burkitt's
lymphoma: analysis of break points by high resolution techniques.
(Abstract) Sixth Int. Cong. Hum. Genet., Jerusalem 311 only, 1981.

27. Zingraff, J. J.; Noel, L.-H.; Bardin, T.; Atienza, C.; Zins, B.;
Drueke, T. B.; Kuntz, D.: Beta-2-microglobulin amyloidosis in chronic
renal failure.  (Letter) New Eng. J. Med. 323: 1070-1071, 1990.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 9/19/1994
terry: 5/13/1994
pfoster: 3/25/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 1/28/1991

*RECORD*
*FIELD* NO
109710
*FIELD* TI
*109710 BETA-2-MICROGLOBULIN REGULATOR; B2MR
*FIELD* TX
Two groups assigned the beta-2-microglobulin regulator locus to
chromosome 15 by dosage effect (Manolov et al., 1979; Zhang and Zech,
1981). The regional assignment is 15q13-15q15. Cell lines lacking this
locus through chromosomal deletion produce B2M but do not insert it into
the cell membrane.

*FIELD* RF
1. Manolov, G.; Manolova, Y.; Kieler, J.: Cytogenetical investigation
of assignment of locus for beta-2-microglobulin in K562 leukemia and
Namalwa and Daudi Burkitt lymphoma cells.  (Abstract) Cytogenet.
Cell Genet. 25: 182 only, 1979.

2. Zhang, S.; Zech, L.: Marker chromosomes in cell lines from Burkitt's
lymphoma; analysis of break points by high resolution techniques.
(Abstract) Sixth Int. Cong. Hum. Genet., Jerusalem 208 only, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 10/23/1986
reenie: 6/4/1986

*RECORD*
*FIELD* NO
109715
*FIELD* TI
*109715 3-@BETA-HYDROXYSTEROID DEHYDROGENASE/DELTA-ISOMERASE, TYPE I
3-@BETA-HSD, PLACENTAL TYPE; HSD3B1
*FIELD* TX
Rheaume et al. (1992) described the structure of 2 highly homologous
genes encoding 3-beta-HSD isoenzymes. The gene for the type I enzyme is
expressed mainly in the placenta and peripheral tissues. They found no
mutations therein. They identified a nonsense mutation and a frameshift
mutation, however, in the type II gene (HSD3B2; 201810), which is
expressed predominantly in the adrenals and gonads. These mutations give
rise to congenital adrenal hyperplasia manifested by salt-wasting and
incomplete masculinization in males, e.g., hypospadias and gynecomastia
(see 201810). Also by in situ hybridization, Berube et al. (1989)
demonstrated that a gene for 3-beta-hydroxysteroid
dehydrogenase/isomerase is located in the 1p13 band. By in situ
hybridization, Morrison et al. (1991) refined the localization to
1p13.1. Rheaume et al. (1991) demonstrated a BglII RFLP in the HSD3B1
gene and Rheaume et al. (1992) demonstrated linkage between this RFLP
and mutations in the HSD3B2 gene. Thus the 2 homologous genes are
apparently both on 1p. Bain et al. (1993) demonstrated that the genes
encoding the gonadal and nongonadal forms of 3-beta-hydroxysteroid
dehydrogenase are encoded by closely linked genes on mouse chromosome 3.
They are located within a segment that is conserved on human chromosome
1. In fact, Bain et al. (1993) pointed out that 4 isoforms of the
enzyme, and presumably 4 genes, have been identified in the mouse. The
possibility of additional genes in the human was suggested. Morissette
et al. (1995) demonstrated that the HSD3B1 and HSD3B2 genes are located
within a restriction fragment of approximately 290 kb.

*FIELD* RF
1. Bain, P. A.; Meisler, M. H.; Taylor, B. A.; Payne, A. H.: The
genes encoding gonadal and nongonadal forms of 3-beta-hydroxysteroid
dehydrogenase/delta-5-delta-4 isomerase are closely linked on mouse
chromosome 3. Genomics 16: 219-223, 1993.

2. Berube, D.; Luu The, V.; Lachance, Y.; Gagne, R.; Labrie, F.:
Assignment of the human 3 beta-hydroxysteroid dehydrogenase gene (HSDB3)
to the p13 band of chromosome 1. Cytogenet. Cell Genet. 52: 199-200,
1989.

3. Morissette, J.; Rheaume, E.; Leblanc, J.-F.; Luu-The, V.; Labrie,
F.; Simard, J.: Genetic linkage mapping of HSD3B1 and HSD3B2 encoding
human types I and II 3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4-isomerase
close to D1S514 and the centromeric D1Z5 locus. Cytogenet. Cell
Genet. 69: 59-62, 1995.

4. Morrison, N.; Nickson, D. A.; McBride, M. W.; Mueller, U. W.; Boyd,
E.; Sutcliffe, R. G.: Regional chromosomal assignment of human 3-beta-hydroxy-5-ene
steroid dehydrogenase to 1p13.1 by non-isotopic in situ hybridisation.
Hum. Genet. 87: 223-225, 1991.

5. Rheaume, E.; Leblanc, J. F.; Lachance, Y.; Labrie, F.; Simard,
J.: Detection of frequent BglII polymorphism by polymerase chain
reaction and TaqI restriction fragment length polymorphism for 3-beta-hydroxysteroid
dehydrogenase/delta-5-delta-4 isomerase at the human HSDB3 locus (1p11-p13).
Hum. Genet. 87: 753-754, 1991.

6. Rheaume, E.; Simard, J.; Morel, Y.; Mebarki, F.; Zachmann, M.;
Forest, M. G.; New, M. I.; Labrie, F.: Congenital adrenal hyperplasia
due to point mutations in the type II 3-beta-hydroxysteroid dehydrogenase
gene. Nature Genet. 1: 239-245, 1992.

*FIELD* CD
Victor A. McKusick: 8/21/1992

*FIELD* ED
mark: 4/4/1995
carol: 5/4/1993
carol: 10/5/1992
carol: 9/8/1992
carol: 8/25/1992
carol: 8/21/1992

*RECORD*
*FIELD* NO
109720
*FIELD* TI
109720 BILIARY CIRRHOSIS, PRIMARY; PBC
*FIELD* TX
In the study of patients with primary biliary cirrhosis and their
relatives, Miller et al. (1983) used a method based on the finding that
the in vitro addition of concanavalin A to pokeweed mitogen-stimulated
lymphocytes activates suppressor cells, which in turn inhibit
immunoglobulin synthesis. Significant impairment of IgG suppression was
observed in 13 of 16 patients with PBC and 6 of 23 healthy relatives;
all 6 relatives were females. No abnormal suppression was found in
unrelated household contacts, patients with other forms of cirrhosis, or
healthy controls. They suggested that the finding is not a result of the
PBC but a genetic marker of susceptibility to the disorder. Jaup and
Zettergen (1980) studied familial incidence of PBC. Hirakata et al.
(1988) described 2 unrelated patients with a combination of the CREST
syndrome (181750) and primary biliary cirrhosis. Coppel et al. (1988)
identified a human cDNA clone encoding the complete amino acid sequence
of the 70,000-MW autoantigen found in high frequency in the serum of
patients with PBC. They found that the predicted structure had great
similarity to the dihydrolipoamide acetyltransferase (EC 2.3.1.12) of
the E. coli pyruvate dehydrogenase multienzyme complex.
(Dihydrolipoamide acetyltransferase is also known as E2.) Tsuji et al.
(1992) studied 18 healthy first-degree relatives of patients with
primary biliary cirrhosis in 2 families. In each of these 2 families,
there were 2 persons with PBC: 2 sisters in one family and a brother and
sister in the other. Tsuji et al. (1992) reported findings suggesting
that impairment of concanavalin A-inducible lymphocytes, mainly
suppressor T cells, is one of the contributing factors in the
development of PBC.

Kaplan (1996) reviewed all aspects of primary biliary cirrhosis,
including the genetics.

*FIELD* RF
1. Coppel, R. L.; McNeilage, L. J.; Surh, C. D.; Van de Water, J.;
Spithill, T. W.; Whittingham, S.; Gershwin, M. E.: Primary structure
of the human M2 mitochondrial autoantigen of primary biliary cirrhosis:
dihydrolipoamide acetyltransferase. Proc. Nat. Acad. Sci. 85: 7317-7321,
1988.

2. Hirakata, M.; Akizuki, M.; Miyachi, K.; Matsushima, H.; Okano,
T.; Homma, M.: Coexistence of CREST syndrome and primary biliary
cirrhosis: serological studies of two cases. J. Rheum. 15: 1166-1170,
1988.

3. Jaup, B. H.; Zettergen, L. S. W.: Familial occurrence of primary
biliary cirrhosis associated with hypergammaglobulinemia in descendants:
a family study. Gastroenterology 78: 549-555, 1980.

4. Kaplan, M. M.: Primary biliary cirrhosis. New Eng. J. Med. 335:
1570-1580, 1996.

5. Miller, K. B.; Sepersky, R. A.; Brown, K. M.; Goldberg, M. J.;
Kaplan, M. M.: Genetic abnormalities of immunoregulation in primary
biliary cirrhosis. Am. J. Med. 75: 75-80, 1983.

6. Tsuji, H.; Murai, K.; Akagi, K.; Fujishima, M.: Familial primary
biliary cirrhosis associated with impaired concanavalin A-induced
lymphocyte transformation in relatives: two family studies. Digest.
Dis. Sci. 37: 353-360, 1992.

*FIELD* CS

GI:
   Primary biliary cirrhosis

Lab:
   Impaired in vitro IgG suppression

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/26/1996
mimadm: 4/9/1994
carol: 10/15/1993
carol: 6/19/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
109730
*FIELD* TI
109730 BICUSPID AORTIC VALVE
AORTIC VALVE, BICUSPID
*FIELD* TX
Emanuel et al. (1978) investigated the families of 41 patients with
surgically proved isolated bicuspid aortic valves. The minimum frequency
of familial occurrence was 17.1%, or 34.1% if doubtful cases were
included. Roberts (1970) found a frequency of isolated bicuspid aortic
valve of 0.9% in 1,440 autopsies. With the decline in rheumatic fever,
congenital bicuspid valve is the most frequent basis of isolated aortic
stenosis, being the substrate in over 50% of cases (Roberts, 1970). Some
of the pedigrees were consistent with autosomal dominant inheritance
with reduced penetrance particularly in females. A male preponderance
has been noted for both bicuspid aortic valve and calcific aortic
stenosis. The male preponderance of the latter entity is exaggerated by
the superimposition on bicuspid valve of the atherogenic propensity of
the male. The superior engineering of the tricuspid arterial valve as
opposed to either a quadricuspid or a bicuspid valve was recognized by
Leonardo da Vinci (McKusick, 1958). The male preponderance for bicuspid
aortic valve is of interest in relation also to the fact that this
anomaly is frequent in the XO Turner syndrome where it may be the most
common cardiac defect; Miller et al. (1983) found that 12 of 35
consecutive patients with Turner syndrome (34%) had isolated,
nonstenotic bicuspid aortic valve, as demonstrated by echocardiography.
The presence of a systolic ejection click correlated closely with
echocardiographic evidence of a bicuspid aortic valve.

Glick and Roberts (1994) could find reports of only 4 families in which
more than 1 member had a congenitally bicuspid aortic valve. On the
other hand, they had encountered 6 such families with 17 affected
members over a period of 27 years. In 3 of the families, a parent and at
least 1 child were affected, and in 3 families, 2 or more sibs were
affected. In 11 of the 17 family members, the congenital bicuspid nature
of the aortic valve was confirmed at the time of aortic valve
replacement. In a twelfth patient, the aortic valve was replaced, but
the nature of the valve involvement was unknown to Glick and Roberts
(1994). In the other 5 patients, the bicuspid aortic valve was
demonstrated by echocardiogram in 2 and strongly suggested by aortogram
in 3. In the 4 previously reported families, 9 members, all male, were
affected; in their group, Glick and Roberts (1994) found 9 males of the
17 affected.

Clementi et al. (1996) reported a family in which 4 members of 2
generations (2 brothers, 1 sister, and her son) had bicuspid aortic
valve.

*FIELD* RF
1. Clementi, M.; Notari, L.; Borghi, A.; Tenconi, R.: Familial congenital
bicuspid aortic valve: a disorder of uncertain inheritance. Am. J.
Med. Genet. 62: 336-338, 1996.

2. Emanuel, R.; Withers, R.; O'Brien, K.; Ross, P.; Feizi, O.: Congenitally
bicuspid aortic valves: clinicogenetic study of 41 families. Brit.
Heart J. 40: 1402-1407, 1978.

3. Glick, B. N.; Roberts, W. C.: Congenitally bicuspid aortic valve
in multiple family members. Am. J. Cardiol. 73: 400-404, 1994.

4. McKusick, V. A.: Cardiovascular Sound in Health and Disease.
Baltimore: Williams and Wilkins (pub.)  1958. Pp. 36-38.

5. Miller, M. J.; Geffner, M. E.; Lippe, B. M.; Itami, R. M.; Kaplan,
S. A.; DiSessa, T. G.; Isabel-Jones, J. B.; Friedman, W. F.: Echocardiography
reveals a high incidence of bicuspid aortic valve in Turner syndrome. J.
Pediat. 102: 47-50, 1983.

6. Roberts, W. C.: The congenitally bicuspid aortic valve: a study
of 85 autopsy cases. Am. J. Cardiol. 26: 72-83, 1970.

*FIELD* CS

Cardiac:
   Bicuspid aortic valve

Misc:
   Male preponderance;
   Systolic ejection click

Inheritance:
   Autosomal dominant form

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 08/14/1996
terry: 7/18/1996
jason: 7/28/1994
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
carol: 12/4/1989
ddp: 10/26/1989

*RECORD*
*FIELD* NO
109740
*FIELD* TI
109740 BIFID NOSE
*FIELD* TX
Anyane-Yeboa et al. (1984) reported 5 women in 3 generations who had
bifid nose without hypertelorism. Miles and Smith (1985) insisted that
the dominant bifid nose syndrome is a distinct entity without ocular
hypertelorism. In the family they studied, 10 persons had a bifid nasal
tip. Of these, 8 had ptosis and 2 scoliosis. Of 3 males, 2 had
cryptorchidism. A recessive form (210400) may exist.

*FIELD* RF
1. Anyane-Yeboa, K.; Raifman, M. A.; Berant, M.; Frogel, M. P.; Travers,
H.: Dominant inheritance of bifid nose. Am. J. Med. Genet. 17:
561-563, 1984.

2. Miles, J. H.; Smith, V.: Dominant bifid nose syndrome in four
generations.  (Abstract) Am. J. Hum. Genet. 37: A69 only, 1985.

*FIELD* CS

Nose:
   Bifid nose

Eyes:
   No hypertelorism;
   Ptosis

Skel:
   Soliosis

GU:
   Cryptorchidism

Inheritance:
   Autosomal dominant form;
   ? also a recessive form (210400)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
109750
*FIELD* TI
*109750 BILIVERDIN REDUCTASE A; BLVRA; BLVR
*FIELD* TX
Biliverdin reductase (EC 1.3.1.24) occurs ubiquitously in human tissues.
It catalyzes the conversion of biliverdin to bilirubin in the presence
of NADPH or NADH. Meera Khan et al. (1983) used a simple chromogenic
staining procedure for specific identification of BLVR after gel
electrophoresis. The study indicated that both NADH-dependent and
NADPH-dependent BLVR activity is due to one enzyme which is probably
coded by a single gene and is a monomer in its functional configuration.

Through a study of mouse-human hybrids, Meera Khan et al. (1982)
assigned the structural gene for biliverdin reductase to chromosome 7
(7p14-cen). Peters et al. (1989) mapped Blvr to mouse chromosome 2 using
an electrophoretic variant in linkage studies.

*FIELD* SA
Parkar et al. (1984)
*FIELD* RF
1. Meera Khan, P.; Wijnen, L. M. M.; Wijnen, J. T.; Grzeschik, K.-H.
: Assignment of a human biliverdin reductase gene (BLVR) to 7p14-cen.
(Abstract) Cytogenet. Cell Genet. 32: 298 only, 1982.

2. Meera Khan, P.; Wijnen, L. M. M.; Wijnen, J. T.; Grzeschik, K.-H.
: Electrophoretic characterization and genetics of human biliverdin
reductase (BLVR; EC 1.3.1.24); assignment of BLVR to the p14-cen region
of human chromosome 7 in mouse-human somatic cell hybrids. Biochem.
Genet. 21: 123-133, 1983.

3. Parkar, M.; Jeremiah, S. J.; Povey, S.; Lee, A. F.; Finlay, F.
O.; Goodfellow, P. N.; Solomon, E.: Confirmation of the assignment
of human biliverdin reductase to chromosome 7. Ann. Hum. Genet. 48:
57-60, 1984.

4. Peters, J.; Ball, S. T.; von Deimling, A.: Localization of Blvr,
biliverdin reductase, on mouse chromosome 2. Genomics 5: 270-274,
1989.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/13/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/3/1989
root: 5/11/1989

*RECORD*
*FIELD* NO
109760
*FIELD* TI
*109760 5-@HYDROXYTRYPTAMINE RECEPTOR 1A; HTR1A
SEROTONIN 5-HT-1A RECEPTOR;;
BETA-2-ADRENERGIC RECEPTOR-LIKE PROTEIN G-21
*FIELD* TX
Kobilka et al. (1987) cloned and sequenced a DNA fragment in the human
genome which cross-hybridizes with a full-length beta-2-adrenergic
receptor at reduced stringency. Like the beta-2-adrenergic receptor
(109690), this gene appears to be intronless, containing an
uninterrupted long open reading frame which encodes a putative protein
with all the expected structural features of a G-protein-coupled
receptor. Kobilka et al. (1987) determined the chromosomal localization
of the G-21 clone (the designation for the DNA segment) by Southern blot
analysis of DNA from 12 hamster and human somatic cell hybrids and by in
situ hybridization. By these methods it was found to be located at
5q11.2-q13. This is the same location as that of the glucocorticoid
receptor (138040). The authors thought it unlikely that G-21 represents
a pseudogene for the beta-2-adrenergic receptor or some other gene for
several reasons. Most pseudogenes do not contain uninterrupted coding
blocks because of the lack of selected pressure in preventing
termination mutations. For the same reason one would not expect to find
well-conserved regions of homology such as those observed between the
G-21 and the G-protein-coupled receptors. Finally, the G-21 gene is
expressed in several tissues as revealed by Northern blot analysis. The
tissue distribution of the mRNA is unique, being highest in lymphoid
tissues. Fargin et al. (1988) reported that the protein product of the
genomic clone G21, transiently expressed in monkey kidney cells, has all
the typical ligand-binding characteristics of the 5-hydroxytryptamine
(5-HT-1A) receptor. At least 6 subtypes of 5-HT receptors (1A, 1B, 1C,
1D, 2, and 3) have been characterized extensively by pharmacologic and
physiologic methods. See review by El Mestikawy et al. (1991). Melmer et
al. (1991) showed close linkage of HTR1A to highly polymorphic
microsatellite markers on chromosome 5. Oakey et al. (1991) mapped the
Htra1 gene to distal mouse chromosome 13.

*FIELD* RF
1. El Mestikawy, S.; Fargin, A.; Raymond, J. R.; Gozlan, H.; Hnatowich,
M.: The 5-HT(1A) receptor: an overview of recent advances. Neurochem.
Res. 16: 1-10, 1991.

2. Fargin, A.; Raymond, J. R.; Lohse, M. J.; Kobilka, B. K.; Caron,
M. G.; Lefkowitz, R. J.: The genomic clone G-21 which resembles a
beta-adrenergic receptor sequence encodes the 5-HT(1A) receptor. Nature 335:
358-360, 1988.

3. Kobilka, B. K.; Frielle, T.; Collins, S.; Yang-Feng, T.; Kobilka,
T. S.; Francke, U.; Lefkowitz, R. J.; Caron, M. G.: An intronless
gene encoding a potential member of the family of receptors coupled
to guanine nucleotide regulatory proteins. Nature 329: 75-79, 1987.

4. Melmer, G.; Sherrington, R.; Mankoo, B.; Kalsi, G.; Curtis, D.;
Gurling, H. M. D.: A cosmid clone for the 5HT1A receptor (HTR1A)
reveals a TaqI RFLP that shows tight linkage to DNA loci D5S6, D5S39,
and D5S76. Genomics 11: 767-769, 1991.

5. Oakey, R. J.; Caron, M. G.; Lefkowitz, R. J.; Seldin, M. F.: Genomic
organization of adrenergic and serotonin receptors in the mouse: linkage
mapping of sequence-related genes provides a method for examining
mammalian chromosome evolution. Genomics 10: 338-344, 1991.

*FIELD* CN
Orest Hurko - updated: 4/1/1996

*FIELD* CD
Victor A. McKusick: 12/7/1987

*FIELD* ED
terry: 04/15/1996
mark: 4/1/1996
terry: 3/26/1996
carol: 6/17/1992
supermim: 3/16/1992
carol: 10/23/1991
carol: 6/21/1991
carol: 6/7/1991
supermim: 4/28/1990

*RECORD*
*FIELD* NO
109770
*FIELD* TI
*109770 BILIARY GLYCOPROTEIN I; BGP I; BGP1; CD66
*FIELD* TX
Biliary glycoprotein I, an antigen crossreactive with carcinoembryonic
antigen (CEA; 114890), has a molecular weight of 85,000 and consists of
a single polypeptide chain containing approximately 40% carbohydrate by
weight. Hinoda et al. (1988) isolated and sequenced 4 overlapping cDNA
clones from a normal adult human colon library. BGP I is a member of the
CEA gene family, which is a subfamily in the immunoglobulin gene
superfamily. By analysis of somatic cell hybrids, Robbins et al. (1991)
mapped the Bgp-1 gene of the mouse to chromosome 7. They considered it
likely that the gene is located in the region of conservation of synteny
in chromosome 7 of the mouse and chromosome 19 of man. Location of the
BPG1 gene in the CEA cluster of genes on 19q13.2 was established by
Thompson et al. (1992) who determined the order and orientation of the
genes in the cluster by hybridization with probes from the 5-prime and
3-prime regions of the genes to large groups of ordered cosmid clones.

Biliary glycoprotein is the human homolog of a cell adhesion molecule
(CAM) of the rat designated Cell-CAM. BGP is expressed in cells of
epithelial and myeloid origin. In granulocytes, BGP is a main antigen of
the CD66 cluster of differentiation antigens that mediate the binding to
endothelial E-selectin. Neumaier et al. (1993) reported findings
suggesting that loss or reduced expression of the BGP adhesion molecule
is a major event in colorectal carcinogenesis.

Schlossman et al. (1994) provided a table of all known CD antigens, with
a list of the common names, the size in kilodaltons, and the nature of
the protein (adhesion, myeloid, platelet, B cell, T cell, etc.).

*FIELD* RF
1. Hinoda, Y.; Neumaier, M.; Hefta, S. A.; Drzeniek, Z.; Wagener,
C.; Shively, L.; Hefta, L. J. F.; Shively, J. E.; Paxton, R. J.:
Molecular cloning of a cDNA coding biliary glycoprotein I: primary
structure of a glycoprotein immunologically crossreactive with carcinoembryonic
antigen. Proc. Nat. Acad. Sci. 85: 6959-6963, 1988.

2. Neumaier, M.; Paululat, S.; Chan, A.; Matthaes, P.; Wagener, C.
: Biliary glycoprotein, a potential human cell adhesion molecule,
is down-regulated in colorectal carcinomas. Proc. Nat. Acad. Sci. 90:
10744-10748, 1993.

3. Robbins, J.; Robbins, P. F.; Kozak, C. A.; Callahan, R.: The mouse
biliary glycoprotein gene (Bgp): partial nucleotide sequence, expression,
and chromosomal assignment. Genomics 10: 583-587, 1991.

4. Schlossman, S. F.; Boumsell, L.; Gilks, W.; Harlan, J. M.; Kishimoto,
T.; Morimoto, C.; Ritz, J.; Shaw, S.; Silverstein, R. L.; Springer,
T. A.; Tedder, T. F.; Todd, R. F.: CD antigens 1993. Immun. Today 15:
98-99, 1994.

5. Thompson, J.; Zimmermann, W.; Osthus-Bugat, P.; Schleussner, C.;
Eades-Perner, A.-M.; Barnert, S.; Von Kleist, S.; Willcocks, T.; Craig,
I.; Tynan, K.; Olsen, A.; Mohrenweiser, H.: Long-range chromosomal
mapping of the carcinoembryonic antigen (CEA) gene family cluster.
Genomics 12: 761-772, 1992.

*FIELD* CD
Victor A. McKusick: 10/10/1988

*FIELD* ED
carol: 9/22/1994
jason: 6/28/1994
carol: 12/9/1993
carol: 6/9/1992
carol: 6/2/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
109780
*FIELD* TI
*109780 BKM DNA
BANDED KRAIT MINOR SATELLITE DNA; BKMA1
BKMA2, INCLUDED
*FIELD* TX
This marker for male sexual differentiation was first found in
association with the heterogametic (female) sex in the banded krait (a
venomous snake of India). Highly conserved in evolution, it shows
preferential association with the heterogametic sex. BKM probes were
useful in Sxr ('sex-reversal') in mice (McLaren et al., 1984).
Kiel-Metzger and Erickson (1984) assigned BKM homologous sequences on 2
mouse autosomes (in addition to the Y). One was on proximal 17 in a
region where deletions can cause hermaphroditism (Washburn and Eicher,
1983). (The other was on mouse 4.) Extending these in situ hybridization
studies to man, Kiel-Metzger et al. (1985) found, surprisingly, no BKM
sequences on the Y chromosome. They found the largest concentration on
6q21 (BKMA1); human chromosome 6 is homologous to mouse chromosome 17. A
lesser concentration was found at 11q13-q14 (BKMA2). On the X
chromosome, a minor aggregation at Xp21 and a major one at Xq21 were
found. The latter corresponds approximately to the site of the
postulated human X-inactivation center (314670), and females with
balanced X-autosome translocations involving a breakpoint at Xq21
frequently have amenorrhea, hypogonadism, and streak gonads (Summitt et
al., 1978). See Arnemann et al. (1986) for information of BKM sequences
on Y. DNA sequence analysis had revealed simple repeats of GATA and GACA
to be responsible for sex-specific hybridization. Singh and Jones (1986)
found BKM sequences to be polymorphic and to be present in all small
acrocentric human chromosomes including the Y. Australian aborigines
appeared to have a characteristic pattern of polymorphism (Singh and
Jones, 1986).

*FIELD* RF
1. Arnemann, J.; Jakubiczka, S.; Schmidtke, J.; Schafer, R.; Epplen,
J. T.: Clustered GATA repeats (Bkm sequences) on the human Y chromosome.
Hum. Genet. 73: 301-303, 1986.

2. Kiel-Metzger, K.; Erickson, R. P.: Regional localization of sex-specific
Bkm-related sequences on proximal chromosome 17 of mice. Nature 310:
579-581, 1984.

3. Kiel-Metzger, K.; Warren, G.; Wilson, G. N.; Erickson, R. P.:
Evidence that the human Y chromosome does not contain clustered DNA
sequences (BKM) associated with heterogametic sex determination in
other vertebrates. New Eng. J. Med. 313: 242-245, 1985.

4. McLaren, A.; Simpson, E.; Tomonari, K.; Chandler, P.; Hogg, H.
: Male sexual differentiation in mice lacking H-Y antigen. Nature 312:
552-555, 1984.

5. Singh, L.; Jones, K. W.: Bkm sequences are polymorphic in humans
and are clustered in pericentric regions of various acrocentric chromosomes
including the Y. Hum. Genet. 73: 304-308, 1986.

6. Summitt, R. L.; Tipton, R. E.; Wilroy, R. S., Jr.; Martens, P.
R.; Phelan, J. P.: X-autosome translocations: a review. Birth Defects
Orig. Art. Ser. 14(6C): 219-247, 1978.

7. Washburn, L. L.; Eicher, E. M.: Sex reversal in XY mice caused
by dominant mutation on chromosome 17. Nature 303: 338-340, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 5/15/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
109800
*FIELD* TI
#109800 BLADDER CANCER
*FIELD* TX
A number sign (#) is used with this entry because mutations at several
loci, e.g., HRAS (190020) and RB1 (180200), have been implicated as the
cause of bladder cancer.

Fraumeni and Thomas (1967) observed affected father and 3 sons. I have
encountered 2 instances of affected father and son (P0135 and P7658).
McCullough et al. (1975) found transitional cell carcinoma in 6 persons
in 3 sibships of 2 generations of a kindred. Goldfarb et al. (1982)
studied the DNA from T24, a cell line derived from a human bladder
carcinoma, which can induce the morphologic transformation of
nonmalignant cells. The gene responsible for this transformation was
cloned by techniques of gene rescue. It was shown to be human in origin
and less than 5 kb long. Blot analysis showed extensive restriction
endonuclease polymorphism near this gene in human DNAs. See Bishop
(1982) for a discussion of oncogenes. By Southern blot analysis of
human-rodent hybrid cell DNA, de Martinville et al. (1983) found that
the cellular homolog of the transforming DNA sequence isolated from the
bladder carcinoma line EJ is located on the short arm of chromosome 11.
The locus also contains sequences homologous to the Harvey ras oncogene.
No evidence of gene amplification was found. These workers also found
karyologically 'a complex rearrangement of the short arm in two of the
four copies of chromosome 11 present in this heteroploid cell line'
(EJ). Region 11p15 was the site of a breakpoint in a t(3;11)
translocation found in tumor cells from a patient with hereditary renal
cell carcinoma (144700). Shih et al. (1981) found that DNA from mouse
and rabbit bladder cancers as well as from a human bladder cancer cell
line (EJ) induced foci of transformed cells when applied to monolayer
cultures of NIH 3T3 cells. In a study of loss of heterozygosity (LOH),
Shipman et al. (1993) found no evidence of deletion at 17p13, the region
known to contain the p53 tumor suppressor gene (TP53; 191170). Analysis
of LOH at 11p13, a region containing the Wilms tumor suppressor gene
(WT1; 194070), showed deletion at the CAT locus (115500) in 13 of 18
bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), and at the
FSHB locus (136530) in 6 of 16 (38%). Risch et al. (1995) demonstrated
that the slow N-acetylation genotype (NAT2; 243400) is a susceptibility
factor in occupational and smoking-related bladder cancer. Employing
PCR-based genotyping, they investigated NAT2 type among 189 Caucasian
bladder cancer patients attending a clinic in Birmingham, U.K. The
results were compared to those from an age-matched nonmalignant
Caucasian control population from the same region. Risch et al. (1995)
found a significant excess of genotypic slow acetylators in patients
exposed to arylamines as a result of their occupation or cigarette use.
A higher proportion of slow acetylators was also found in most bladder
cancer patients without identified exposure to arylamines when compared
to the nonmalignant controls.

Patients with cancer of the urinary bladder often present with multiple
tumors appearing at different times and at different sites in the
bladder. This observation had been attributed to a 'field defect' in the
bladder that allowed the independent transformation of epithelial cells
at a number of sites. Sidransky et al. (1992) tested this hypothesis
with molecular genetic techniques and concluded that in fact multiple
bladder tumors are of clonal origin. A number of bladder tumors can
arise from the uncontrolled spread of a single transformed cell. These
tumors can then grow independently with variable subsequent genetic
alterations.

Hruban et al. (1994) did a retrospective molecular genetic analysis of
the bladder carcinoma that was the cause of death in the case of Hubert
H. Humphrey (1911-1978), U.S. senator and vice president. In 1967,
hematuria led to a diagnosis of chronic proliferative cystitis. Although
urine cytology at that time was thought by one prominent cytopathologist
to be diagnostic of carcinoma, a diagnosis of infiltrating carcinoma of
the bladder was not made until August 1976. Hruban et al. (1994)
analyzed both the invasive bladder carcinoma resected in 1976 and the
filters prepared from urine in 1967. Both showed a transversion from
adenine to thymine in codon 227, creating a cryptic splice site in exon
7 of the p53 gene. The mutation resulted in the loss of several amino
acids and in the production of a shortened, mutant p53 protein. This
mutation was not present in nonneoplastic tissue of the resected
bladder.

Deletions involving chromosome 9 represent the most frequent genetic
change identified in bladder tumors. Several independent studies had
reported overall deletion frequencies of 50 to 70% in large series of
tumors. It was of particular interest that these deletions were present
at similar frequency in bladder tumors of all grades and stages (Tsai et
al., 1990). This finding of chromosome 9 deletions as the sole genetic
change in many low-grade, early-stage tumors suggests that it may
represent an early or initiating genetic event. Keen and Knowles (1994)
used a panel of 22 highly informative microsatellite markers, evenly
distributed along chromosome 9, to analyze LOH in 95 cases of primary
transitional cell carcinoma of the bladder. In 49 tumors (53%), LOH was
demonstrated at one or more loci. Of these 49, 30 had LOH at all
informative loci, indicating probable monosomy 9. Subchromosomal
deletions were found in 19 tumors (22%), 5 of 9p only, 9 of 9q only, and
5 of both 9p and 9q with a clear region of retention of heterozygosity
between. The patterns of LOH in these tumors indicated a common region
of deletion on 9p between D9S126 (9p21) and the interferon-alpha cluster
(IFNA; 147660) located also at 9p21. A single tumor showed a second site
of deletion on 9p telomeric to IFNA, indicating the possible existence
of 2 target genes on 9p. All deletions of 9q were large, with a common
region of deletion between D9S15 (9q13-q21.1) and D9S60 (9q33-q34.1).
The results provided evidence for the simultaneous involvement of
distinct suppressor loci on 9p and 9q in bladder carcinoma.

In a review of case reports and epidemiologic studies in the literature,
Kiemeney and Schoenberg (1996) concluded that first-degree relatives
have an increased risk for transitional cell carcinoma by a factor of 2.
Familial clustering of smoking did not appear to be the cause of this
increased risk.

*FIELD* SA
Krontiris and Cooper (1981); Leklem and Brown (1976); Lynch et al.
(1979); Mahboubi et al. (1981)
*FIELD* RF
1. Bishop, J. M.: Oncogenes. Sci. Am. 246(3): 80-92, 1982.

2. de Martinville, B.; Giacalone, J.; Shih, C.; Weinberg, R. A.; Francke,
U.: Oncogene from human EJ bladder carcinoma is located on the short
arm of chromosome 11. Science 219: 498-501, 1983.

3. Fraumeni, J. F., Jr.; Thomas, L. B.: Malignant bladder tumors
in a family. J.A.M.A. 201: 507-509, 1967.

4. Goldfarb, M.; Shimizu, K.; Perucho, M.; Wigler, M.: Isolation
and preliminary characterization of a human transforming gene from
T24 bladder carcinoma cells. Nature 296: 404-409, 1982.

5. Hruban, R. H.; van der Riet, P.; Erozan, Y. S.; Sidransky, D.:
Molecular biology and the early detection of carcinoma of the bladder:
the case of Hubert H. Humphrey. New Eng. J. Med. 330: 1276-1278,
1994.

6. Keen, A. J.; Knowles, M. A.: Definition of two regions of deletion
on chromosome 9 in carcinoma of the bladder. Oncogene 9: 2083-2088,
1994.

7. Kiemeney, L. A. L. M.; Schoenberg, M.: Familial transitional cell
carcinoma. J. Urol. 156: 867-872, 1996.

8. Krontiris, T. G.; Cooper, G. M.: Transforming activity of human
tumor DNAs. Proc. Nat. Acad. Sci. 78: 1181-1184, 1981.

9. Leklem, J. E.; Brown, R. R.: Abnormal tryptophan metabolism in
a family with a history of bladder cancer. J. Nat. Cancer Inst. 56:
1101-1104, 1976.

10. Lynch, H. T.; Walzak, M. P.; Fried, R.; Domina, A. H.; Lynch,
J. F.: Familial factors in bladder carcinoma. J. Urol. 122: 458-461,
1979.

11. Mahboubi, A. O.; Ahlvin, R. C.; Mahboubi, E. O.: Familial aggregation
of urothelial carcinoma. J. Urol. 126: 691-692, 1981.

12. McCullough, D. L.; Lamm, D. L.; McLaughlin, A. P., III; Gittes,
R. F.: Familial transitional cell carcinoma of the bladder. J. Urol. 113:
629-635, 1975.

13. Risch, A.; Wallace, D. M. A.; Bathers, S.; Sim, E.: Slow N-acetylation
genotype is a susceptibility factor in occupational and smoking related
bladder cancer. Hum. Molec. Genet. 4: 231-236, 1995.

14. Shih, C.; Padhy, L. C.; Murray, M.; Weinberg, R. A.: Transforming
genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:
261-264, 1981.

15. Shipman, R.; Schraml, P.; Colombi, M.; Raefle, G.; Ludwig, C.
U.: Loss of heterozygosity on chromosome 11p13 in primary bladder
carcinoma. Hum. Genet. 91: 455-458, 1993.

16. Sidransky, D.; Frost, P.; Von Eschenbach, A.; Oyasu, R.; Preisinger,
A. C.; Vogelstein, B.: Clonal origin of bladder cancer. New Eng.
J. Med. 326: 737-740, 1992.

17. Tsai, Y. C.; Nichols, P. W.; Hiti, A. L.; Williams, Z.; Skinner,
D. G.; Jones, P. A.: Allelic losses of chromosomes 9, 11, and 17
in human bladder cancer. Cancer Res. 50: 44-47, 1990.

*FIELD* CS

GU:
   Transitional cell bladder carcinoma

Inheritance:
   Autosomal dominant (11p)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 10/22/1996
mark: 3/31/1995
carol: 9/12/1994
davew: 6/8/1994
mimadm: 4/9/1994
carol: 8/18/1993
carol: 5/11/1992

*RECORD*
*FIELD* NO
109820
*FIELD* TI
109820 BLADDER DIVERTICULUM
*FIELD* TX
Hofmann et al. (1984) described isolated (solitary) bladder diverticulum
in males of 3 and probably 4 generations. In most patients, the
diverticulum was located near the vesicoureteral junction. Moderate
sclerosis of the urethral sphincter with a prominent median bar of the
prostate was a consistent finding. Symptoms varied from gross hematuria,
diurnal frequency, infection and urinary hesitancy to only mild dysuria.
One patient was entirely asymptomatic. The diverticula consisted mainly
of mucosa covered only by a few strands of muscle. Bladder diverticula
occur also in the Ehlers-Danlos syndrome.

*FIELD* RF
1. Hofmann, R.; Hegemann, M.; Mauermayer, W.; Endres, M.: Hereditary
autosomal dominant form of bladder diverticula in male patients. J.
Urol. 131: 338-339, 1984.

*FIELD* CS

GU:
   Solitary bladder diverticulum;
   Urethral sphincter sclerosis;
   Prominent prostate median bar;
   Hematuria;
   Diurnal frequency;
   Urinary infection;
   Urinary hesitancy;
   Dysuria

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
carol: 3/6/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
109900
*FIELD* TI
109900 BLEPHAROCHALASIS AND DOUBLE LIP
ASCHER SYNDROME
*FIELD* TX
Franceschetti (1955) described the syndrome in father and daughter.
Sagging eyelids and double upper lip are features. Nontoxic goiter is a
variable feature.

*FIELD* SA
Barnett et al. (1972); Findlay  (1954)
*FIELD* RF
1. Barnett, M. L.; Bosshardt, L. L.; Morgan, A. F.: Double lip and
double lip with blepharochalasis (Ascher's syndrome). Oral Surg. 34:
727-733, 1972.

2. Findlay, G. H.: Idiopathic enlargements of the lips: cheilitis
granulomatosa, Ascher's syndrome and double lip. Brit. J. Derm. 66:
129-138, 1954.

3. Franceschetti, A.: Cas observe: manifestation de blepharochalasis
chez le pere, associe a des doubles levres apparaissant egalement
chez sa filette agee d'un mois. J. Genet. Hum. 4: 181-182, 1955.

*FIELD* CS

Eyes:
   Sagging eyelids

Mouth:
   Double upper lip

Neck:
   Nontoxic goiter

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
110000
*FIELD* TI
110000 BLEPHAROCHALASIS, SUPERIOR
*FIELD* TX
The outer portion of the upper lid is loose-skinned and pendulous.
Schulze (1965) traced the condition through 6 generations with 11 males
and 3 females affected. Bismarck showed this condition. In minor form,
this is sometimes called the Nordic type of eye fold. Panneton (1936)
found the trait in 51 of 79 members of a French-Canadian family.
Bismarck and Harold McMillan, German and British politicians,
respectively, showed this condition.

*FIELD* RF
1. Panneton, P.: La blepharo-chalazis: a propos de 51 cas dans une
meme famille. Arch. Ophtal. (Paris) 53: 729-755, 1936.

2. Schulze, F.: Beitrag zur hereditaeren Blepharochalasis. Klin.
Mbl. Augenheilk. 147: 863-877, 1965.

*FIELD* CS

Eyes:
   Loose pendulous outer upper eyelid skin

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 9/10/1991
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
110050
*FIELD* TI
110050 BLEPHARONASOFACIAL MALFORMATION SYNDROME
*FIELD* TX
Pashayan et al. (1973) described a family in which the mother and 3
children had telecanthus, lateral displacement of the lacrimal puncta,
lacrimal excretory obstruction, bulky nose, masklike facies with
weakness of facial muscles, torsion dystonia and mental retardation. The
affected children were 2 boys and a girl. Two sisters were unaffected.
No further cases have been reported (Gorlin, 1982).

*FIELD* SA
Putterman et al. (1973)
*FIELD* RF
1. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.  1982.

2. Pashayan, H.; Pruzansky, S.; Putterman, A.: A family with blepharo-naso-facial
malformations. Am. J. Dis. Child. 125: 389-396, 1973.

3. Putterman, A. M.; Pashayan, H.; Pruzansky, S.: Eye findings in
the blepharo-naso-facial malformation syndrome. Am. J. Ophthal. 76:
825-831, 1973.

*FIELD* CS

Facies:
   Masklike facies;
   Facial muscle weakness

Eyes:
   Telecanthus;
   Lateral displacement of lacrimal puncta;
   Lacrimal excretory obstruction

Nose:
   Bulky nose

Neuro:
   Torsion dystonia;
   Mental retardation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
warfield: 4/7/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
110100
*FIELD* TI
*110100 BLEPHAROPHIMOSIS, EPICANTHUS INVERSUS, AND PTOSIS; BPES
BPES1
*FIELD* TX
Vignes (1889) probably first described this entity, a dysplasia of the
eyelids. In addition to small palpebral fissures, features include
epicanthus inversus, low nasal bridge, and ptosis of the eyelids (Sacrez
et al., 1963; Johnson, 1964; Smith, 1970). The condition should be
considered distinct from congenital ptosis (178300). Smith (1970)
described affected mother and daughter. Owens et al. (1960) updated the
pedigree of a family that was first reported by Dimitry (1921) and had
affected members in 6 generations. The patients had the syndrome-triad
consisting of blepharophimosis, ptosis and epicanthus inversus (fold
curving in the mediolateral direction, inferior to the inner canthus). I
got a first-hand description of the disorder from a physician (Raviotta,
1971) who is an affected member (number 38) of the pedigree of Owens et
al. (1960).

Moraine et al. (1976) suggested that female infertility is a pleiotropic
effect of the gene. Townes and Muechler (1979) reported a family in
which all affected females had primary ovarian failure (176440). They
had a normal female karyotype and normal breast development; pubic and
axillary hair was scant, but in a normal female distribution.
Laparoscopy showed a small uterus and small atrophic ovaries. Zlotogora
et al. (1983) suggested that there are 2 forms of BPES: type I with
infertility of affected females; type II with transmission by both males
and females. The infertility is inherited as an autosomal dominant
sex-limited trait. The same type of inheritance has been suggested for
Stein-Leventhal syndrome (184700). The 'cause' of the infertility is
unknown. Whether the 2 forms are allelic or nonallelic is also unknown.

Jones and Collin (1984) reviewed 37 known cases; of the 6 females of
child-bearing age, 1 had primary amenorrhea with raised gonadotropins
and low estrogen and progesterone. Oley and Baraitser (1988) provided an
illustrated review. Fraser et al. (1988) and Smith et al. (1989)
described 4 women from 3 families with blepharophimosis, epicanthus
inversus, and ptosis who had premature ovarian failure. Two of the cases
were sisters; they had another affected sister who was not investigated.
Two of the 3 families had multiple affected members. Smith et al. (1989)
suggested that these cases, type I in the classification of Zlotogora et
al. (1983), represent a 'contiguous gene syndrome' (Schmickel, 1986)--a
combination of blepharophimosis and familial precocious ovarian failure.
Panidis et al. (1994) described blepharophimosis in 2 sisters, a
brother, and their father. The elder sister presented initially with
'resistant ovary syndrome' and thereafter true premature menopause,
while the younger sister presented with resistant ovary syndrome.

Temple and Baraitser (1989) reported a family in which an uncle and
nephew were clearly affected. The carrier mother had no abnormality as
an adult, but photographs of her as a child showed unilateral minimal
ptosis without epicanthus inversus. Finley et al. (1990) studied 14
sporadic cases of this syndrome (which they abbreviated BPEI) and found
an apparent maternal age effect, but no paternal age effect, in new
mutation.

Fukushima et al. (1990) reported a newborn infant with BPES and a de
novo balanced 3q23;4p15 reciprocal translocation. In a father and son
with typical BPES, de Die-Smulders et al. (1991) found an apparently
balanced translocation, t(3;11)(q21;q23). Since blepharophimosis,
ptosis, and microphthalmia are consistent features in patients with an
interstitial deletion of band 3q2 (Alvarado et al., 1987), the location
of the BPES gene at 3q2 seems highly likely. Fujita et al. (1992)
reported the case of a 6-year-old boy with de novo 46,XY,del(3)(q12q23)
and bilateral blepharophimosis, ptosis, epicanthus inversus, and
multiple other anomalies. Other relevant cases had been reported by
Martsolf and Ray (1983), Al-Awadi et al. (1986), and Okada et al.
(1987). Williamson et al. (1981) described an 8-year-old boy with marked
blepharophimosis, ptosis, sad fixed face, joint contractures, and
several other anomalies associated with a del(3)(q22.1-q24), and
suspected him of having Schwartz-Jampel syndrome (255800). The patient
of Fujita et al. (1992) also had joint contractures and a fixed facial
appearance, but in their patient and the patient of Williamson et al.
(1981) the diagnosis of Schwartz-Jampel syndrome was excluded by normal
EMG findings; that diagnosis was also excluded in their patient by
normal skeletal films with average stature. Fujita et al. (1992)
suggested that the blepharophimosis sequence in these patients may
represent a contiguous gene syndrome. Jewett et al. (1992) reported a
child with classic features of BPES with developmental delay and an
interstitial deletion of a single band within 3q: del(3)(q21.3-q22.3).

Cabral de Almeida et al. (1993) described an apparently balanced
translocation, t(3;8)(q23;p21.1), in a child with mild mental
retardation, blepharophimosis, ptosis, telecanthus, and epicanthus
inversus. The patient was microcephalic with mild dysmorphism and minor
anomalies. Reinforcement of the suggestion that the BPES gene is located
at 3q2 was provided by Fryns et al. (1993), who described a 6-year-old,
mentally retarded boy, born to normal parents, who had typical signs of
the disorder and a de novo interstitial deletion of chromosome 3:
del(3)(q22.3-q23). Ishikiriyama and Goto (1993) described a girl with
BPES, microcephaly of postnatal onset, mild developmental retardation,
and a de novo deletion del(3)(q22.2q23). Jewett et al. (1993) described
an interstitial deletion of 3q22. From a review of the other reported
cases, they concluded that a locus for eyelid development is situated at
the interface of bands 3q22.3 and 3q23. Wolstenholme et al. (1994)
reported a sporadic case of BPES associated with prenatally diagnosed
diaphragmatic hernia and interstitial deletion of the long arm of
chromosome 3, del(3)(q21q23). Ishikiriyama and Goto (1994) suggested
that the association of BPES with microcephaly or other manifestations
of 'general hypoplasia of the CNS' such as hypotrophy of the cerebellar
vermis may represent a contiguous gene syndrome because of the observed
association with interstitial deletions.

Boccone et al. (1994) described a de novo, apparently balanced,
reciprocal translocation between the long arms of chromosomes 3 and 7 in
a 2-year-old male with BPES; the breakpoints were 3q23 and 7q32. Warburg
et al. (1995) described 3 unrelated, mentally retarded boys with typical
BPES, each of whom had chromosomal aberrations. One of them was thought
to have a deletion of 3p25 and a second was thought to have a loss of
band 3q23. The third patient, however, had a del(7)(q34). The phenotypes
of the 2 patients with the chromosome 3 aberrations were similar, but
the third had, in addition to features of BPES, genital malformations
resembling those of the Smith-Lemli-Opitz syndrome (SLO; 270400), which
maps to 7q34-qter. Thus, the features may represent a contiguous gene
syndrome. The patient had a palatal ridge as well as a single mesial
maxillary tooth, suggesting the holoprosencephaly sequence, but CT scans
of the brain were normal. Karimi-Nejad et al. (1996) reported a sporadic
translocation t(X;3)(p22;q21) in a girl with typical manifestations of
BPES.

Small et al. (1995) studied 2 BPES families with autosomal dominant
inheritance and obtained a maximum lod score of 3.23 using the markers
rhodopsin (180380), located at 3q21-q24; prostate acid phosphatase
(171790), located at 3q21-q23; and D3S1238. No evidence of genetic
heterogeneity was observed. In a large French pedigree, Amati et al.
(1995) also mapped the BPES gene to 3q23. Fryns (1995) described a
patient in which BPES was associated with the Langer type of mesomelic
dwarfism (249700). He suggested that a submicroscopic deletion of
3q22.3-q23 was responsible for the concurrence of the 2 disorders. With
linkage studies in 2 large families, Harrar et al. (1995) confirmed the
assignment of BPES to 3q21-q24. A lod score of 3.2 was found with
D3S1237.

Amati et al. (1996) showed that the form of BPES associated with
premature ovarian failure type I of Zlotogora et al. (1983) maps to
3q22-q23, the same chromosomal region as does type II.

See also 601649, which describes a chromosome 7-linked BPES pedigree.

*FIELD* SA
Kohn and Romano (1971); Pueschel and Barsel-Bowers (1979); Stoll et
al. (1974)
*FIELD* RF
1. Al-Awadi, S. A.; Naguib, K. K.; Farag, T. I.; Teebi, A. S.; Cuschieri,
A.; Al-Othman, S. A.; Sundareshan, T. S.: Complex translocation involving
chromosomes Y, 1, and 3 resulting in deletion of segment 3q23-q25. J.
Med. Genet. 23: 91-92, 1986.

2. Alvarado, M.; Bocian, M.; Walker, A. P.: Interstitial deletion
of the long arm of chromosome 3: case report, review, and definition
of a phenotype. Am. J. Med. Genet. 27: 781-786, 1987.

3. Amati, P.; Chomel, J.-C.; Nivelon-Chevalier, A.; Gilgenkrantz,
S.; Kitzis, A.; Kaplan, J.; Bonneau, D.: A gene for blepharophimosis-ptosis-epicanthus
inversus syndrome maps to chromosome 3q23. Hum. Genet. 96: 213-215,
1995.

4. Amati, P.; Gasparini, P.; Zlotogora, J.; Zelante, L.; Chomel, J.
C.; Kitzis, A.; Kaplan, J.; Bonneau, D.: A gene for premature ovarian
failure associated with eyelid malformation maps to chromosome 3q22-q23.(Letter) Am.
J. Hum. Genet. 58: 1089-1092, 1996.

5. Boccone, L.; Meloni, A.; Falchi, A. M.; Usai, V.; Cao, A.: Blepharophimosis,
ptosis, epicanthus inversus syndrome, a new case associated with de
novo balanced autosomal translocation (46,XY,t(3;7)(q23;q32). Am.
J. Med. Genet. 51: 258-259, 1994.

6. Cabral de Almeida, J. C.; Llerena, J. C., Jr.; Neto, J. B. G.;
Jung, M.; Martins, R. R.: Another example favouring the location
of BPES at 3q2. (Letter) J. Med. Genet. 30: 86, 1993.

7. de Die-Smulders, C. E. M.; Engelen, J. J. M.; Donk, J. M.; Fryns,
J. P.: Further evidence for the location of the BPES gene at 3q2.
(Letter) J. Med. Genet. 28: 725, 1991.

8. Dimitry, T. J.: Hereditary ptosis. Am. J. Ophthal. 4: 655-658,
1921.

9. Finley, W. H.; Callahan, A.; Thompson, J. N.: Parental age in
the blepharophimosis, ptosis, epicanthus inversus, telecanthus complex. Am.
J. Med. Genet. 36: 414-417, 1990.

10. Fraser, I. S.; Shearman, R. P.; Smith, A.; Russell, P.: An association
between blepharophimosis, resistant ovary syndrome and true premature
menopause. Fertil. Steril. 50: 747-751, 1988.

11. Fryns, J. P.: The concurrence of the blepharophimosis, ptosis,
epicanthus inversus syndrome (BPES) and Langer type of mesomelic dwarfism
in the same patient: evidence of the location of Langer type of mesomelic
dwarfism at 3q22.3-q23?. (Letter) Clin. Genet. 48: 111-112, 1995.

12. Fryns, J. P.; Stromme, P.; van den Berghe, H.: Further evidence
for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23. Clin.
Genet. 44: 149-151, 1993.

13. Fujita, H.; Meng, J.; Kawamura, M.; Tozuka, N.; Ishii, F.; Tanaka,
N.: Boy with a chromosome del(3)(q12q23) and blepharophimosis syndrome. Am.
J. Med. Genet. 44: 434-436, 1992.

14. Fukushima, Y.; Wakui, K.; Nishida, T.; Ueoka, Y.: Blepharophymosis
(sic) syndrome and de novo balanced autosomal translocation [46,XY,t(3;4)(q23;p15.2)]:
possible localization of blepharophymosis (sic) syndrome to 3q23. Am.
J. Hum. Genet. 47: A29, 1990.

15. Harrar, H. S.; Jeffery, S.; Patton, M. A.: Linkage analysis in
blepharophimosis-ptosis syndrome confirms localisation to 3q21-24. J.
Med. Genet. 32: 774-777, 1995.

16. Ishikiriyama, S.; Goto, M.: Blepharophimosis, ptosis, and epicanthus
inversus syndrome (BPES) and microcephaly. (Letter) Am. J. Med. Genet. 52:
245, 1994.

17. Ishikiriyama, S.; Goto, M.: Blepharophimosis sequence (BPES)
and microcephaly in a girl with del(3)(q22.2q23): a putative gene
responsible for microcephaly close to the BPES gene?. Am. J. Med.
Genet. 47: 487-489, 1993.

18. Jewett, T.; Rao, P. N.; Weaver, R. G.; Stewart, W.; Thomas, I.
T.; Pettenati, M. J.: Blepharophimosis, ptosis, and epicanthus inversus
syndrome (BPES) associated with interstitial deletion of band 3q22:
review and gene assignment to the interface of band 3q22.3 and 3q23. Am.
J. Med. Genet. 47: 1147-1150, 1993.

19. Jewett, T.; Rao, P. N.; Weaver, R. G.; Stewart, W.; Thomas, I.
T.; Pettenati, M. J.: Blepharophimosis syndrome (BPES) associated
with del 3q22: gene assignment to the interface of band 3q22-q23.
(Abstract) Am. J. Hum. Genet. 51 (suppl.): A81, 1992.

20. Johnson, C. C.: Surgical repair of the syndrome of epicanthus
inversus, blepharophimosis and ptosis. Arch. Ophthal. 71: 510-516,
1964.

21. Jones, C. A.; Collin, J. R. O.: Blepharophimosis and its association
with female infertility. Brit. J. Ophthal. 68: 533-534, 1984.

22. Karimi-Nejad, A.; Karimi-Nejad, R.; Najafi, H.; Karimi-Nejad,
M. H.: Blepharophimosis syndrome (BPES) and additional abnormalities
in a female with a balanced X:3 translocation. (Letter) Clin. Dysmorph. 5:
259-261, 1996.

23. Kohn, R.; Romano, P. E.: Blepharoptosis, blepharophimosis, epicanthus
inversus, and telecanthus--a syndrome with no name. Am. J. Ophthal. 72:
625-632, 1971.

24. Martsolf, J. T.; Ray, M.: Interstitial deletion of the long arm
of chromosome 3. Ann. Genet. 26: 98-99, 1983.

25. Moraine, C.; Titeca, C.; Delplace, M.-P.; Grenier, B.; Lenoel,
Y.; Ribadeau-Dumas, J. L.: Blepharophimosis familial et sterilite
feminine: pleiotropisme ou genes lies?. J. Genet. Hum. 24 (suppl.):
125-132, 1976.

26. Okada, N.; Hasegawa, T.; Osawa, M.; Fukuyama, Y.: A case of de
novo interstitial deletion 3q. J. Med. Genet. 24: 305-308, 1987.

27. Oley, C.; Baraitser, M.: Blepharophimosis, ptosis, epicanthus
inversus syndrome (BPES syndrome). J. Med. Genet. 25: 47-51, 1988.

28. Owens, N.; Hadley, R. C.; Kloepfer, H. W.: Hereditary blepharophimosis,
ptosis and epicanthus inversus. J. Intern. Coll. Surg. 33: 558-574,
1960.

29. Panidis, D.; Rousso, D.; Vavilis, D.; Skiadopoulos, S.; Kalogeropoulos,
A.: Familial blepharophimosis with ovarian dysfunction. Hum. Reprod. 9:
2034-2037, 1994.

30. Pueschel, S. M.; Barsel-Bowers, G.: A dominantly inherited congenital
anomaly syndrome with blepharophimosis. J. Pediat. 95: 1010-1012,
1979.

31. Raviotta, J. J.: Personal Communication. New Orleans, Louisiana
1971.

32. Sacrez, R.; Francfort, J.; Juif, J. G.; de Grouchy, J.: Le blepharophimosis
complique familial: etude des membres de la famille Ble. Ann. Paediat. 10:
493-501, 1963.

33. Schmickel, R. D.: Contiguous gene syndromes: a component of recognizable
syndromes. J. Pediat. 109: 231-241, 1986.

34. Small, K. W.; Stalvey, M.; Fisher, L.; Mullen, L.; Dickel, C.;
Beadles, K.; Reimer, R.; Lessner, A.; Lewis, K.; Pericak-Vance, M.
A.: Blepharophimosis syndrome is linked to chromosome 3q. Hum. Molec.
Genet. 4: 443-448, 1995.

35. Smith, A.; Fraser, I. S.; Shearman, R. P.; Russell, P.: Blepharophimosis
plus ovarian failure: a likely candidate for a contiguous gene syndrome. J.
Med. Genet. 26: 434-438, 1989.

36. Smith, D. W.: Recognizable Patterns of Human Malformation. Genetic,
Embryologic, and Clinical Aspects.  Philadelphia: W. B. Saunders
(pub.)  1970. Pp. 114-115.

37. Stoll, C.; Levy, J. M.; Bigel, P.; Francfort, J. J.: Etude genetique
due blepharophimosis familial (maladie autosomique dominante). J.
Genet. Hum. 22: 353-363, 1974.

38. Temple, I. K.; Baraitser, M.: Pitfalls in counselling of the
blepharophimosis, ptosis, epicanthus inversus syndrome (BPES). J.
Med. Genet. 26: 517-519, 1989.

39. Townes, P. L.; Muechler, E. K.: Blepharophimosis, ptosis, epicanthus
inversus and primary amenorrhoea. Arch. Ophthal. 97: 1664-1666,
1979.

40. Vignes, (NI): Epicanthus hereditaire. Rev. Gen. Opthal. 8:
438, 1889.

41. Warburg, M.; Bugge, M.; Brondum-Nielsen, K.: Cytogenetic findings
indicate heterogeneity in patients with blepharophimosis, epicanthus
inversus, and developmental delay. J. Med. Genet. 32: 19-24, 1995.

42. Williamson, R. A.; Donlan, M. A.; Dolan, C. R.; Thuline, H. C.;
Harrison, M. T.; Hall, J. G.: Familial insertional translocation
of a portion of 3q into 11q resulting in duplication and deletion
of region 3q22.1-q24 in different offspring. Am. J. Med. Genet. 9:
105-111, 1981.

43. Wolstenholme, J.; Brown, J.; Masters, K. G.; Wright, C.; English,
C. J.: Blepharophimosis sequence and diaphragmatic hernia associated
with interstitial deletion of chromosome 3 (46,XY,del(3)(q21q23)). J.
Med. Genet. 31: 647-648, 1994.

44. Zlotogora, J.; Sagi, M.; Cohen, T.: The blepharophimosis, ptosis,
and epicanthus inversus syndrome: delineation of two types. Am. J.
Hum. Genet. 35: 1020-1027, 1983.

*FIELD* CS

Eyes:
   Eyelid dysplasia;
   Small palpebral fissures;
   Epicanthus inversus;
   Eyelid ptosis

Nose:
   Low nasal bridge

GU:
   Primary amenorrhea;
   Female infertility;
   Primary ovarian failure;
   Small uterus;
   Small atrophic ovaries

Thorax:
   Normal breast development

Hair:
   Scant pubic and axillary hair

Lab:
   Normal female karyotype;
   Elevated gonadotropins;
   Low estrogen and progesterone

Inheritance:
   Autosomal dominant, female sex-limited infertility features;
   ? contiguous gene syndrome at 3q2

*FIELD* CN
Moyra Smith - updated: 01/30/1997
Iosif W. Lurie - updated: 8/12/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/30/1997
carol: 8/12/1996
terry: 5/3/1996
terry: 4/29/1996
mark: 11/6/1995
terry: 4/24/1995
carol: 3/19/1995
mimadm: 4/18/1994
warfield: 4/7/1994
carol: 12/13/1993

*RECORD*
*FIELD* NO
110150
*FIELD* TI
110150 BLEPHAROPTOSIS, MYOPIA, AND ECTOPIA LENTIS
*FIELD* TX
Gillum and Anderson (1982) described a family in which a 72-year-old
woman and 2 of her daughters showed blepharoptosis from birth, high
grade myopia, and ectopia lentis, present in one of the daughters since
at least age 4 years. The globes were abnormally long. The affected
women showed abnormally high upper eyelid creases and good levator
function--a combination indicative of levator aponeurosis disinsertion.
The authors suggested that a connective tissue defect of sclera, zonules
and levator aponeurosis was the common factor underlying the clinical
features. The mother was 1 of 16 children of presumably unaffected
parents and may have represented a new mutation.

*FIELD* RF
1. Gillum, W. N.; Anderson, R. L.: Dominantly inherited blepharoptosis,
high myopia, and ectopia lentis. Arch. Ophthal. 100: 282-284, 1982.

*FIELD* CS

Eyes:
   Congenital blepharoptosis;
   Myopia;
   Ectopia lentis;
   Abnormally long globes;
   Abnormally high upper eyelid creases;
   Good levator function;
   Levator aponeurosis disinsertion

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/27/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
110250
*FIELD* TI
110250 BLOOD GROUP--ABO SUPPRESSOR
*FIELD* TX
Rubinstein et al. (1973) found a healthy blood donor with no anti-A in
his serum despite the fact that his red cells typed as O. A maternal
half-brother, whose father was unrelated, lacked anti-B. The pedigree
showed that the effect was due to dominant suppression of normal A1 and
B genes. It is not certain that the suppressor is determined by a
separate locus; as the authors indicated, there is precedence for
mutation at the same locus (ABO) to be responsible. The authors favored
a suppressor at the ABO locus. See 111150 for a Lutheran suppressor
genetically independent of the Lutheran locus. See Bombay phenotype
(211100).

*FIELD* RF
1. Rubinstein, P.; Allen, F. H., Jr.; Rosenfield, R. E.: A dominant
suppressor of A and B. Vox Sang. 25: 372-381, 1973.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/17/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/24/1986

*RECORD*
*FIELD* NO
110300
*FIELD* TI
*110300 ABO BLOOD GROUP; ABO
BLOOD GROUP--ABO SYSTEM;;
ABO HISTO-BLOOD GROUP GLYCOSYLTRANSFERASES;;
TRANSFERASE A, ALPHA 1-3-N-ACTYLGALACTOSAMINYLTRANSFERASE;;
TRANSFERASE B, ALPHA 1-3-GALACTOSYLTRANSFERASE
*FIELD* TX
This was the first blood group system discovered, by Landsteiner at the
beginning of this century. The occurrence of natural antibody permitted
identification of red cell types by agglutination of red cells when
mixed with serum from some but not all other persons. At first the
alternative genetic hypotheses were mainly: (1) multiple alleles at a
single locus, and (2) two loci with two alleles each, one locus
determining A and non-A and the other B and non-B. Application of the
Hardy-Weinberg principle to population data by Felix Bernstein
(1878-1956) and analysis of family data excluded the second alternative
and established the former. Crow (1993) reviewed this history. He
introduced his review with the following words: 'Accustomed as we now
are to thousands of polymorphisms useful as human chromosome markers, it
is hard to realize that in the the first quarter century of Mendelism
there was only one good marker. It is all the more remarkable that its
simple mode of inheritance was not understood until the trait had been
known for 25 years.'

Developments of the 1950s and 1960s included: (1) demonstration of
associations between particular disorders (peptic ulcer, gastric cancer,
thromboembolic disease) and particular ABO phenotypes, and (2) discovery
of the biochemical basis of ABO specificity. It is known that the A and
B alleles determine a specific glycosyl-transferring enzyme. The
specificity of the enzyme formed by the A allele is to add
N-acetylgalactosaminosyl units to the ends of the oligosaccharide chains
in the final stages of the synthesis of the ABO blood group
macromolecule. The enzyme determined by the B allele may differ from
that determined by the A allele by only a single amino acid, but its
function is to add D-galactosyl units to the end. The O allele appears
to be functionless.

In studies of a familial 15p+ chromosomal variant, Yoder et al. (1974)
calculated a lod score of 1.428 at theta 0.32 for linkage between the p+
region and the ABO blood group locus. Cook et al. (1978) collated
evidence that ABO and AK1 (103000) lie in band 9q34. They could exclude
MNSs, GPT and Gc from chromosome 9. Possible linkage of DBH to ABO was
indicated by a maximum lod score of 1.82 at 0% and 10% recombination
fractions for males and females, respectively (Goldin et al., 1982).
Elston et al. (1979) found a lod score of 2.32 at 0 recombination, to
give a combined score of 2.32. Narahara et al. (1986) assigned the ABO
and AK1 loci to 9q31.3-qter by studies in a family with a complex
chromosomal rearrangement. The order of loci on the distal portion of 9q
appears to be: cen--AK1--ABL--ASS--ABO--qter.

Occasionally, an O mother and an AB father may give birth to an AB
child. The interpretation is cis-AB, i.e., both alleles on the same
chromosome, or an allele with both specificities. Hummel et al. (1977)
traced such through 3 generations. Inherited mosaicism in the ABO system
consists of a situation in which, in an autosomal dominant pedigree
pattern, family members show mosaicism of A cells and O cells, or B
cells and O cells. A 'mixed field' agglutination pattern results. This
phenotype is probably caused by a weak allele rather than by a modifier
gene. Bird et al. (1978) found that in a B-O mosaic family affected
persons had low levels of B-specific transferase. A curious feature was
that one class of cells had nearly normal B antigen, whereas the second
class had none.

Watkins et al. (1981) reviewed the evidence to refute the arguments that
the genes coding for the A antigen-associated
alpha-3-N-acetyl-D-galactosaminyltransferase and the B
antigen-associated alpha-3-D-galactosyltransferase are not allelic. They
suggested that the final answer may need to await the isolation of the
pure enzymes in sufficient quantities for amino acid sequencing and
examination of the active sites (or, one might add, sequencing of the
genes themselves). The demonstration of immunologic homology of the 2
transferases indicates that the differences in structure of the 2
enzymes are relatively small and hence not incompatible with those to be
expected of the products of allelic genes. Yoshida et al. (1982)
concluded that the blood group A allele can take any of 3 common forms,
A1, A2, and Aint (for intermediate), each determining a different type
of blood group GalNAc transferase.

Yamamoto et al. (1990) cloned and sequenced cDNA encoding the specific
primary gene product that they referred to as the histo-blood group A
gene (A transferase). Nucleotide sequence showed a coding region of
1,062 basepairs encoding a protein of 41 kD. No RFLP was found to
correlate with ABO blood group type. Bands were detected in Northern
hybridization of mRNAs from cell lines expressing A, B, AB, or H
antigens, suggesting that sequences of ABO genes have only minimal
differences and that the inability of the O gene to encode A or B
transferases is probably due to a structural difference rather than to
failure of expression of the A or B transferases. Yamamoto et al. (1990)
showed that cells of the histo-blood group phenotype O express a message
similar to that of A and B alleles. Indeed, they found that the O allele
is identical in DNA sequence to the A allele, except for a single base
deletion, 258-guanine, in the coding region close to the N-terminus of
the protein. The deletion shifts the reading frame, resulting in
translation of an entirely different protein. It is therefore unlikely
that O individuals express a protein immunologically related to the A
and B transferases, which agrees with the absence of crossreacting
protein in O cells when specific monoclonal antibody directed toward
soluble A transferase is used. Yamamoto et al. (1990) also reported the
single base substitutions responsible for the 4 amino acid substitutions
that distinguish the A and B glycosyltransferases. Thus, the ABO
polymorphism, discovered by Landsteiner (1900), was finally elucidated
90 years later. (In a similar manner, the colorblindness polymorphism,
which can be said to have been described first by John Dalton in 1798,
was elucidated in molecular terms in 1986 (see 303800), and the
wrinkled/round polymorphism of the garden pea, which was studied by
Mendel (1865), was explained at the molecular level by Bhattacharyya et
al. (1990). The wrinkled trait is called 'rugosus' (symbolized r); the
pea seeds of RR or Rr genotype are round. Wrinkled seeds lack 1 isoform
of starch-branching enzyme (SBEI), present in round seeds. Bhattacharyya
et al. (1990) demonstrated that the SBEI gene in the rr genotype is
interrupted by a 0.8-kb insertion that appears to be a transposable
element. Loss of activity of SBEI leads to reduction in starch
synthesis, accompanied by failure to convert amylose to amylopectin. In
rr seeds, the levels of free sucrose are higher than in RR seeds, and
this apparently leads to the observed higher osmotic pressure and,
hence, higher water content. The seeds lose a larger proportion of their
volume during maturation, which results in the wrinkled phenotype. See
comment by Fincham (1990).) Ugozzoli and Wallace (1992) applied
allele-specific PCR to the determination of ABO blood type. Johnson and
Hopkinson (1992) showed that one could use PCR followed by denaturing
gradient gel electrophoresis (DGGE) for rapid identification of the 6
major ABO genotypes. The procedure also distinguished hitherto
undescribed polymorphisms associated with the O and B alleles, thereby
elevating the information content of the locus as a genetic marker from
3 to 70%. Its usefulness in the study of disease associations and in
forensic identification was also emphasized.

Yamamoto et al. (1995) isolated genomic DNA clones encompassing 30 kb of
the ABO locus. The locations of the exons were mapped and the nucleotide
sequences of the exon/intron boundaries determined. The human ABO genes
consist of at least 7 exons, and the coding sequence in the 7 coding
exons spans over 18 kb of genomic DNA. The exons range in size from 28
to 688 bp, with most of the coding sequence lying in exon 7.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988). The relationship between ABO blood groups
and susceptibility to a specific infectious disease is a topic of long
interest to those seeking an explanation for the variations in gene
frequencies around the world. Several studies (reviewed by Glass et al.,
1985) indicated that individuals with blood group O are at higher risk
of contracting cholera (due to Vibrio cholerae 01) than those with other
blood groups and that individuals with blood group AB are relatively
resistant to cholera. Clemens et al. (1989) demonstrated that
individuals with blood group O are at higher risk for cholera due to
only the E1 Tor biotype of V. cholerae 01. During a large field trial in
Bangladesh of killed oral cholera vaccine, persons with blood group O
were significantly less protected against severe cholera than were
persons with AB blood group. Faruque et al. (1994) found that patients
in Bangladesh who had diarrhea due to V. cholerae 0139 were nearly twice
as likely as controls to be of blood group O (64 vs 34%) and that
individuals with blood group AB were at no risk for diarrhea due to V.
cholerae 0139. Individuals with blood group O were the most susceptible
to diarrhea due to V. cholerae 0139, followed in order by groups B, A,
and AB.

*FIELD* AV
.0001
BLOOD GROUP O
ABO, G258 DEL
Yamamoto et al. (1990) demonstrated that the blood group O allele
differs from the blood group A allele by deletion of guanine-258. The
deletion, occurring in the portion of the gene encoding the part near
the NH2-terminus of the protein, causes a frameshift and results in
translation of an almost entirely different protein. The latter protein
is incapable of modifying the H antigen.

.0002
BLOOD GROUP A/B POLYMORPHISM
ABO, 7 NUCLEOTIDE SUBSTITUTIONS
Whereas A, B, and AB in individuals express glycosyltransferase
activities that convert the H antigen into A or B antigen, O(H) persons
lack such activities. Yamamoto et al. (1990) found 7 nucleotide
differences between the alleles that code for the A and B
glycosyltransferase enzymes: 4 of the nucleotide differences were
accompanied by change in amino acid residue in the transferase. The A
gene had A, C, C, G, C, G, and G as nucleotides 294, 523, 654, 700, 793,
800, and 927; the B gene was found to have G, G, T, A, A, C, and A at
these positions.

.0003
BLOOD GROUP A2
ABO, 1-BP DEL
Yamamoto et al. (1992) demonstrated that the A2 allele, which encodes a
minor subtype of A, has a single base deletion near the carboxyl
terminal. As a result of frameshifting, the A2 transferase possesses an
extra domain. Introduction of this single base deletion into the A1
transferase cDNA expression construct drastically decreased the A
transferase activity in DNA-transfected HeLa cells. The protein encoded
by the A1 allele had 21 additional amino acids. The same nucleotide
deletion was found in a total of 8 individuals with A2 blood type. (The
single base deletion in O alleles is located close to the N-terminal
(see 110300.0001), whereas that of the A2 allele is close to the
C-terminal.) All 8 A1 alleles studied also showed a single base
substitution (T in A2 and C in A1 at nucleotide position 467 counting
from the A residue of the initiation codon) resulting in an amino acid
difference (leucine in A2 transferase and proline in A1 transferase at
amino acid position 156). Based on the observed expression of chimeric
cDNAs in transfected HeLa cells, the amino acid substitution was shown
to be incapable of drastically altering enzymatic activity or
sugar-nucleotide donor specificity. The single nucleotide deletion
occurred in a stretch of 3 Cs in nucleotide positions 1059-1061 of the
A1 allele.

.0004
BLOOD GROUP CIS-AB
ABO, PRO156LEU, GLY268ALA
Seyfried et al. (1964) and Yamaguchi et al. (1965, 1966) described
instances in which blood group O was inherited from 1 parent and both
blood group A and blood group B from the other parent. This was referred
to as cis-AB to discriminate this rare phenotype from ordinary trans-AB.
Yoshida et al. (1980) reported 2 possible genetic mechanisms: unequal
chromosomal crossing over and structural mutation in the blood group
glycosyltransferase. In the latter instance, mutation in either the A or
the B gene had produced a single abnormal enzyme with bifunctional
activity. Yamamoto et al. (1993) determined the nucleotide sequence of
the coding region in the last 2 exons of the ABO genes from 2 unrelated
cis-AB individuals of the genotype cis-AB/O. They found that the cis-AB
alleles were identical to one another while different from the A1 allele
by 2 nucleotide substitutions. Both of these substitutions resulted in
amino acid replacements. The first substitution was identical to the one
previously found in the A2 allele, i.e., a C-to-T transition at
nucleotide 467 resulting in the amino acid substitution pro156-to-leu.
The other substitution was found at the fourth position of the 4 amino
acid substitutions that discriminate A1 and B transferases, i.e., a
G-to-C transversion at nucleotide 803 resulting in a gly268-to-ala amino
acid substitution. The 2 patients in the study were Japanese; judging
from the report, the cis-AB phenotype may be more common in Japanese
than in others.

*FIELD* SA
Badet et al. (1978); Ferguson-Smith and Aitken (1978); Ferguson-Smith
et al. (1976); Landsteiner  (1901); Lewis et al. (1978); Nagai and
Yoshida (1978); Oka et al. (1982); Oriol et al. (1986); Robson et
al. (1977); Salmon et al. (1968); Westerveld et al. (1976); Yamamoto
et al. (1990); Yoshida  (1982); Yoshida et al. (1980)
*FIELD* RF
1. Badet, J.; Ropars, C.; Salmon, C.: Alpha-N-acetyl-D-galactosaminyl-
and alpha-D-galactosyltransferase activities in sera of cis AB blood
group individuals. J. Immunogenet. 5: 221-231, 1978.

2. Bhattacharyya, M. K.; Smith, A. M.; Ellis, T. H. N.; Hedley, C.;
Martin, C.: The wrinkled-seed character of pea described by Mendel
is caused by a transposon-like insertion in a gene encoding starch-branching
enzyme. Cell 60: 115-122, 1990.

3. Bird, G. W. G.; Wingham, J.; Watkins, W. M.; Greenwell, P.; Cameron,
A. H.: Inherited 'mosaicism' within the ABO blood group system. J.
Immunogenet. 5: 215-219, 1978.

4. Clemens, J. D.; Sack, D. A.; Harris, J. R.; Chakraborty, J.; Khan,
M. R.; Huda, S.; Ahmed, F.; Gomes, J.; Rao, M. R.; Svennerholm, A.-M.;
Holmgren, J.: ABO blood groups and cholera: new observations on specificity
of risk and modification of vaccine efficacy. J. Infect. Dis. 159:
770-773, 1989.

5. Cook, P. J. L.; Robson, E. B.; Buckton, K. E.; Slaughter, C. A.;
Gray, J. E.; Blank, C. E.; James, F. E.; Ridler, M. A. C.; Insley,
J.; Hulten, M.: Segregation of ABO, AK(1) and ACONs in families with
abnormalities of chromosome 9. Ann. Hum. Genet. 41: 365-378, 1978.

6. Crow, J. F.: Felix Bernstein and the first human marker locus. Genetics 133:
4-7, 1993.

7. Elston, R. C.; Namboodiri, K. K.; Hames, C. G.: Segregation and
linkage analysis of dopamine-beta-hydroxylase activity. Hum. Hered. 29:
284-292, 1979.

8. Faruque, A. S. G.; Mahalanabis, D.; Hoque, S. S.; Albert, M. J.
: The relationship between ABO blood groups and susceptibility to
diarrhea due to Vibrio cholerae 0139. Clin. Infect. Dis. 18: 827-828,
1994.

9. Ferguson-Smith, M. A.; Aitken, D. A.: Gene dosage: further information
on the regional position of the ABO:Np:AK-1 linkage group on chromosome
9. Cytogenet. Cell Genet. 22: 449-451, 1978.

10. Ferguson-Smith, M. A.; Aitken, D. A.; Turleau, C.; de Grouchy,
J.: Localisation of the human ABO: Np-1: AK-1 linkage group by regional
assignment of AK-1 to 9q34. Hum. Genet. 34: 35-43, 1976.

11. Fincham, J. R. S.: Mendel--now down to the molecular level. Nature 343:
208-209, 1990.

12. Glass, R. I.; Holmgren, J.; Haley, C. E.; Khan, M. R.; Svennerholm,
A.-M.; Stoll, B. J.; Belayet Hossain, K. M.; Black, R. E.; Yunus,
M.; Barua, D.: Predisposition for cholera of individuals with O blood
group: possible evolutionary significance. Am. J. Epidemiol. 121:
791-796, 1985.

13. Goldin, L. R.; Gershon, E. S.; Lake, C. R.; Murphy, D. L.; McGinniss,
M.; Sparkes, R. S.: Segregation and linkage studies of plasma dopamine-beta-hydroxylase
(DBH), erythrocyte catechol-O-methyltransferase (COMT), and platelet
monoamine oxidase (MAO): possible linkage between the ABO locus and
a gene controlling DBH activity. Am. J. Hum. Genet. 34: 250-262,
1982.

14. Hummel, K.; Badet, J.; Bauermeister, W.; Bender, K.; Duffner,
G.; Lopez, M.; Mauff, G.; Pulverer, G.; Salmon, C.; Schmidts, W.:
Inheritance of cis-AB in three generations (family Lam.). Vox Sang. 33:
290-298, 1977.

15. Johnson, P. H.; Hopkinson, D. A.: Detection of ABO blood group
polymorphism by denaturing gradient gel electrophoresis. Hum. Molec.
Genet. 1: 341-344, 1992.

16. Landsteiner, K.: Zur Kenntnis der antifermentativen, lytischen
und agglutinierenden Wirkungen des Blutserums und der Lymphe. Zbl.
Bakt. 27: 357-362, 1900.

17. Landsteiner, K.: Ueber Agglutinationserscheinungen normalen menschlichen
Blutes. Wien. Klin. Wschr. 14: 1132-1134, 1901.

18. Lewis, M.; Kaita, H.; Giblett, E. R.; Anderson, J. E.: Genetic
linkage analyses of chromosome 9 loci ABO and AK-1. Cytogenet. Cell
Genet. 22: 452-455, 1978.

19. Mendel, G.: Versuche ueber Pflanzen-Hybriden. Verh. Naturforsch.
Ver. Brunn. 4: 3-47, 1865.

20. Nagai, M.; Yoshida, A.: Possible existence of hybrid glycosyltransferase
in heterozygous blood group AB subjects. Vox Sang. 35: 378-381,
1978.

21. Narahara, K.; Takahashi, Y.; Kikkawa, K.; Wakita, Y.; Kimura,
S.; Kimoto, H.: Assignment of ABO locus to 9q31.3-qter by study of
a family in which an intrachromosomal shift involving chromosome 9
is segregating. Jpn. J. Hum. Genet. 31: 289-296, 1986.

22. Oka, Y.; Niikawa, N.; Yoshida, A.; Matsumoto, H.: An unusual
case of blood group ABO inheritance: O from AB x O. Am. J. Hum. Genet. 34:
134-141, 1982.

23. Oriol, R.; Le Pendu, J.; Mollicone, R.: Genetics of ABO, H, Lewis,
X and related antigens. Vox Sang. 51: 161-171, 1986.

24. Robson, E. B.; Cook, P. J. L.; Buckton, K. E.: Family studies
with the chromosome 9 markers ABO, AK-1, ACON-S and 9qh. Ann. Hum.
Genet. 41: 53-60, 1977.

25. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

26. Salmon, C.; Seger, J.; Mannoni, P.; Bahno-Duchery, J.; Liberge,
G.: Une population d'erythrocytes avec anomalie simultanee des phenotypes
induits par les genes des locus A B O et adenylate kinase. Rev. Franc.
Etud. Clin. Biol. 13: 296-298, 1968.

27. Seyfried, H.; Walewska, I.; Werblinska, B.: Unusual inheritance
of ABO group in a family with weak B antigens. Vox Sang. 9: 268-277,
1964.

28. Ugozzoli, L.; Wallace, R. B.: Application of an allele-specific
polymerase chain reaction to the direct determination of ABO blood
group genotypes. Genomics 12: 670-674, 1992.

29. Watkins, W. M.; Greenwell, P.; Yates, A. D.: The genetic and
enzymic regulation of the synthesis of the A and B determinants in
the ABO blood group system. Immun. Commun. 10: 83-100, 1981.

30. Westerveld, A.; Jongsma, A. P. M.; Meera Khan, P.; Van Someren,
H.; Bootsma, D.: Assignment of the AK(1): Np: ABO linkage group to
human chromosome 9. Proc. Nat. Acad. Sci. 73: 895-899, 1976.

31. Yamaguchi, H.; Okubo, Y.; Hazama, F.: An A(2)B(3) phenotype blood
showing atypical mode of inheritance. Proc. Jpn. Acad. 41: 316-320,
1965.

32. Yamaguchi, H.; Okubo, Y.; Hazama, F.: Another Japanese A(2)B(3)
blood-group family with the propositus having O-group father. Proc.
Jpn. Acad. 42: 517-520, 1966.

33. Yamamoto, F.; Clausen, H.; White, T.; Marken, J.; Hakomori, S.
: Molecular genetic basis of the histo-blood group ABO system. Nature 345:
229-233, 1990.

34. Yamamoto, F.; Marken, J.; Tsuji, T.; White, T.; Clausen, H.; Hakomori,
S.: Cloning and characterization of DNA complementary to human UDP-GalNAc:Fuc
alpha 1--2Gal alpha 1--3GalNAc transferase (histo-blood group A transferase)
mRNA. J. Biol. Chem. 265: 1146-1151, 1990.

35. Yamamoto, F.; McNeill, P. D.; Hakomori, S.: Human histo-blood
group A2 transferase coded by A2 allele, one of the A subtypes, is
characterized by a single base deletion in the coding sequence, which
results in an additional domain at the carboxyl terminal. Biochem.
Biophys. Res. Commun. 187: 366-374, 1992.

36. Yamamoto, F.; McNeill, P. D.; Hakomori, S.: Genomic organization
of human histo-blood group ABO genes. Glycobiology 5: 51-58, 1995.

37. Yamamoto, F.; McNeill, P. D.; Kominato, Y.; Yamamoto, M.; Hakomori,
S.; Ishimoto, S.; Nishida, S.; Shima, M.; Fujimura, Y.: Molecular
genetic analysis of the ABO blood group system. 2. cis-AB alleles. Vox
Sang. 64: 120-123, 1993.

38. Yoder, F. E.; Bias, W. B.; Borgaonkar, D. S.; Bahr, G. F.; Yoder,
I. I.; Yoder, O. C.; Golomb, H. M.: Cytogenetics and linkage studies
of a familial 15p+ variant. Am. J. Hum. Genet. 26: 535-548, 1974.

39. Yoshida, A.: Biochemical genetics of human blood group ABO system. Am.
J. Hum. Genet. 34: 1-14, 1982.

40. Yoshida, A.; Dave, V.; Branch, D. R.; Yamaguchi, H.; Okubo, Y.
: An enzyme basis for blood type A intermediate status. Am. J. Hum.
Genet. 34: 919-924, 1982.

41. Yoshida, A.; Yamaguchi, H.; Okubo, Y.: Genetic mechanism of cis-AB
inheritance. I. A case associated with unequal chromosomal crossing
over. Am. J. Hum. Genet. 32: 332-338, 1980.

42. Yoshida, A.; Yamaguchi, H.; Okubo, Y.: Genetic mechanism of cis-AB
inheritance. II. Cases associated with structural mutation of blood
group glycosyltransferase. Am. J. Hum. Genet. 32: 645-650, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/29/1996
terry: 6/20/1996
terry: 6/18/1996
mark: 6/27/1995
jason: 7/1/1994
davew: 6/9/1994
warfield: 4/6/1994
mimadm: 2/11/1994
carol: 9/27/1993

*RECORD*
*FIELD* NO
110310
*FIELD* TI
110310 BLOOD GROUP--ABH ANTIGEN, TYPE 2
*FIELD* TX
From studies in cases of bone marrow transplantation, Oriol et al.
(1981) concluded that there are two types of ABH antigens with different
genetic determination, probable chemical structure, and cellular origin.

*FIELD* RF
1. Oriol, R.; Le Pendu, J.; Sparkes, R. S.; Sparkes, M. C.; Crist,
M.; Gale, R. P.; Terasaki, P. I.; Bernoco, M.: Insights into the
expression of ABH and Lewis antigens through human bone marrow transplantation.
Am. J. Hum. Genet. 33: 551-560, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
110350
*FIELD* TI
*110350 BLOOD GROUP--AHONEN; AN
*FIELD* TX
Furuhjelm et al. (1972) described a rare 'new' blood type, An(a). It
apparently is a blood group system distinct from ABO, MNS, P, Rh,
secretor, Duffy, Kidd and Dombrock. Genetic independence from Lutheran,
Kell, Yt, Diego and Colton had not been established.

*FIELD* RF
1. Furuhjelm, U.; Nevanlinna, H. R.; Gavin, J.; Sanger, R.: A rare
blood group antigen An(a) (Ahonen). J. Med. Genet. 9: 385-391,
1972.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 2/26/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
110450
*FIELD* TI
#110450 BLOOD GROUP--COLTON; CO
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
polymorphism is due to variation in the aquaporin-CHIP gene (AQP1;
107776).

Co(a) was described by Race and Sanger (1968) as 'well on the way to
establishment as a separate system.' Its independence of Lutheran, Kell,
Diego and Yt remained to be demonstrated. De la Chapelle et al. (1975)
reported the very rare Co(a-b-) phenotype in 2 of 5 cases of monosomy 7
in the bone marrow. Mohr and Eiberg (1977) found a lod score of 2.57 for
the linkage of Kidd (JK) and Colton. Each had been tentatively assigned
to chromosome 7. Lewis et al. (1984) presented further data that
weakened the previously proposed linkage of Colton with Kidd from
'probable' to 'possible.' Combined data gave a peak lod of 0.55 at theta
= 0.36. Sherman and Simpson (1985) assigned the Kidd blood group locus,
erroneously as it turned out, to 2p, and suggested that the CO locus
might be located there also. The observations of de la Chapelle et al.
(1975) prompted Zelinski et al. (1990) to revisit chromosome 7 in an
attempt to map CO. This was successfully achieved when they demonstrated
linkage to the argininosuccinate synthetase pseudogene (ASSP11) which is
located on 7p; maximum lod = 5.79 at theta = 0.07 for combined paternal
and maternal meiosis. In further linkage studies, Zelinski et al. (1991)
provided very strong evidence that the CO locus is on 7p.

Smith et al. (1994) demonstrated that the Colton blood group antigens
result from an ala-val polymorphism at residue 45, located on the first
extracellular loop of the aquaporin-1 protein. In red cells from 3
individuals who lacked Colton antigens, i.e., were Co(a-b-), Preston et
al. (1994) found mutations in the AQP1 gene that resulted in a
nonfunctioning CHIP molecule. Surprisingly, none of the 3 suffered any
apparent clinical consequences.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Heisto et al. (1967); Lewis et al. (1977); Race and Sanger (1975)
*FIELD* RF
1. de la Chapelle, A.; Vuopio, P.; Sanger, R.; Teesdale, P.: Monosomy-7
and the Colton blood-groups.  (Letter) Lancet II: 817 only, 1975.

2. Heisto, H.; Van Der Hart, M.; Madsen, G.; Moes, M.; Noades, J.;
Pickles, M. M.; Race, R. R.; Sanger, R.; Swanson, J.: Three examples
of a new red cell antibody, anti-Co-(a). Vox Sang. 12: 18-24, 1967.

3. Lewis, M.; Kaita, H.; Chown, B.; Giblett, E. R.; Anderson, J.:
Colton blood groups in Canadian Caucasians: frequencies, inheritance
and linkage analysis. Vox Sang. 32: 208-213, 1977.

4. Lewis, M.; Kaita, H.; Philipps, S.: Dwindling odds for Jk:Co linkage.
(Abstract) Cytogenet. Cell Genet. 37: 524 only, 1984.

5. Mohr, J.; Eiberg, H.: Colton blood groups: indication of linkage
with the Kidd (Jk) system as support for assignment to chromosome
7. Clin. Genet. 11: 372-374, 1977.

6. Preston, G. M.; Smith, B. L.; Zeidel, M. L.; Moulds, J. J.; Agre,
P.: Mutations in aquaporin-1 in phenotypically normal humans without
functional CHIP water channels. Science 265: 1585-1587, 1994.

7. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
Sci. Publ. (pub.)  1975.

8. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

9. Sherman, S. L.; Simpson, S. P.: Evidence for the location of JK
and CO on chromosome 2 based on family studies.  (Abstract) Cytogenet.
Cell Genet. 40: 743 only, 1985.

10. Smith, B. L.; Preston, G. M.; Spring, F.; Anstee, D. J.; Agre,
P.: Human red blood cell aquaporin CHIP. I. Molecular characterization
of ABH and Colton blood group antigens. J. Clin. Invest. 94: 1043-1049,
1994.

11. Zelinski, T.; Kaita, H.; Gilson, T.; Coghlan, G.; Philipps, S.;
Lewis, M.: Linkage between the Colton blood group locus and ASSP11
on chromosome 7. Genomics 6: 623-625, 1990.

12. Zelinski, T. A.; White, L. J.; Coghlan, G. E.; Philipps, S. E.
: Linkage relationships between CO, D7S135 and ASSP11 on chromosome
7p.  (Abstract) Cytogenet. Cell Genet. 58: 1927 only, 1991.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/1/1994
mimadm: 4/19/1994
warfield: 4/7/1994
carol: 10/14/1993
supermim: 3/16/1992
carol: 2/26/1992

*RECORD*
*FIELD* NO
110500
*FIELD* TI
*110500 BLOOD GROUP--DIEGO SYSTEM; DI
*FIELD* TX
The Diego blood group system is controlled by 2 allelic genes: Di(a) and
Di(b). The Di(a) antigen was first described in Venezuela on the basis
of an antibody that had been the cause of hemolytic disease of the
newborn (Levine et al., 1956). A second example of anti-Di(a) was found
in Buffalo in the serum of a Polish mother, whose child also suffered
from hemolytic disease of the newborn (Tatarsky et al., 1959). The Diego
system shows polymorphism mainly in Mongolian peoples, e.g., Chinese and
American Indians. In a family of Polish origin, Kusnierz-Alejska and
Bochenek (1992) found anti-Di(a) antibody in the serum of a mother who
gave birth to a newborn with severe hemolytic anemia. They identified
the Di(a) antigen in 45 of 9,661 donor blood samples from different
regions of Poland (0.46%). All 45 were of Polish ancestry.

Zelinski et al. (1993) showed that the DI blood group is tightly linked
to the erythrocyte surface protein band 3 locus (EPB3; 109270); maximum
lod = 5.42 at theta = 0.00. Looser linkage between DI and D17S41
(maximum lod = 3.14 at theta = 0.09) for combined paternal and maternal
meioses was also established. The EPB3 gene is located at 17q21-q22.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Lewis et al. (1976)
*FIELD* RF
1. Kusnierz-Alejska, G.; Bochenek, S.: Haemolytic disease of the
newborn due to anti-Di(a) and incidence of the Di(a) antigen in Poland.
Vox Sang. 62: 124-126, 1992.

2. Levine, P.; Layrisse, M.; Robinson, E. A.; Arends, T.; Domingues
Sisco, R.: The Diego blood factor. Nature 177: 40-41, 1956.

3. Lewis, M.; Kaita, H.; Chown, B.; Giblett, E. R.; Anderson, J.;
Steinberg, A. G.: The Diego blood groups: a genetic linkage analysis.
Am. J. Hum. Genet. 28: 18-21, 1976.

4. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

5. Tatarsky, J.; Stroup, M.; Levine, P.; Ernoehazy, W. S.: Another
example of anti-Diego (Di-a). Vox Sang. 4: 152-154, 1959.

6. Zelinski, T.; Coghlan, G.; White, L.; Philipps, S.: The Diego
blood group locus is located on chromosome 17q. Genomics 17: 665-666,
1993.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 2/11/1994
carol: 9/21/1993
carol: 8/11/1992
carol: 6/19/1992
carol: 6/15/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
110600
*FIELD* TI
*110600 BLOOD GROUP--DOMBROCK SYSTEM; DO
*FIELD* TX
Anti-Do(a) antibody was detected in a transfused patient, Mrs. Dombrock.
About 64% of northern Europeans are Do(a+), making the system a useful
marker in linkage study (Swanson et al., 1965). Tippett et al. (1972)
found a hint of loose linkage between Do and MNS. Lewis et al. (1983)
found a lod score of 3.56 at theta = 0.23 for the linkage of Do and PGD
(172200). They concluded that Do lies distal to PGD and that Do:PGD
recombination occurs more frequently in males than in females. No
support for Do:Gc linkage was provided by the data. New data presented
by Mohr et al. (1985) appeared to erase the previous assignment to
chromosome 1 on the basis of linkage to PGD (172200).

Telen (1996) gave a review of all erythrocyte blood group antigens that
represent polymorphisms of functionally important molecules. Of the 30
listed, the genetic locus for all except Dombrock had been determined.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Lewis et al. (1978); Molthan et al. (1973); Polesky and Swanson (1966);
Tippett  (1967); Williams and Crawford (1966)
*FIELD* RF
1. Lewis, M.; Kaita, H.; Giblett, E. R.; Anderson, J. E.: Genetic
linkage analysis of the Dombrock (Do) blood group locus. Cytogenet.
Cell Genet. 22: 313-318, 1978.

2. Lewis, M.; Kaita, H.; Philipps, S.; Giblett, E. R.; Anderson, J.
E.: Genetic linkage data for the Dombrock blood group locus relative
to chromosome 1 and chromosome 4 loci. Ann. Hum. Genet. 47: 49-53,
1983.

3. Mohr, J.; Eiberg, H.; Nielsen, L. S.: Various linkage relationships
of the Dombrock blood group system. (Abstract) Cytogenet. Cell Genet. 40:
701 only, 1985.

4. Molthan, L.; Crawford, M. N.; Tippett, P.: Enlargement of the
Dombrock blood group system: the finding of anti-Do(b). Vox Sang. 24:
382-384, 1973.

5. Polesky, H. F.; Swanson, J. L.: Studies on distribution of the
blood group antigen Do(a) (Dombrock) and the characteristics of anti-Do(a). Transfusion 6:
268-270, 1966.

6. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

7. Swanson, J. L.; Polesky, H. F.; Tippett, P.; Sanger, R.: A 'new'
blood group antigen, Do(a). Nature 206: 313 only, 1965.

8. Telen, M. J.: Erythrocyte blood group antigens: polymorphisms
of functionally important molecules. Semin. Hemat. 33: 302-314,
1996.

9. Tippett, P.: Genetics of the Dombrock blood system. J. Med. Genet. 4:
7-11, 1967.

10. Tippett, P.; Gavin, J.; Sanger, R.: The Dombrock system: linkage
relations with other blood group loci. J. Med. Genet. 9: 392-395,
1972.

11. Williams, C. H.; Crawford, M. N.: The third example of anti-Do. Transfusion 6:
310 only, 1966.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jamie: 01/15/1997
terry: 1/10/1997
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 2/28/1992
carol: 2/26/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
110700
*FIELD* TI
*110700 BLOOD GROUP--DUFFY SYSTEM; Fy
GLYCOPROTEIN D; GPD, INCLUDED
*FIELD* TX
The Duffy system enjoys the distinction of being the first blood group
whose genetic locus was assigned to a specific autosome, i.e.,
chromosome 1 (Donahue et al., 1968). On the basis of families studied in
Rochester, N.Y., Weitkamp (1972) could demonstrate no linkage of beta HB
locus and Duffy, as had been suggested by Nance et al. (1970). An
earlier suspicion of localization to chromosome 16 (Crawford et al.,
1967) was apparently in error. Duffy and the locus for a form of
hereditary cataract (116200) are closely linked. From extensive family
studies, Robson et al. (1973) arrived at a tentative map of chromosome
1. From study of a family with a pericentric inversion of chromosome 1,
Lee et al. (1974) suggested that the most probable location of the Fy
locus is close to the centromere on the short arm (favored) or near the
distal end of the centric heterochromatin on the long arm. Assuming that
each arm of chromosome 1 is 140 male cM in length, Cook et al. (1974)
concluded that, measured from the centromere, map positions are as
follows: PGD 1p124--Rh 1p109--PGM-1 1p079--Fy 1p010--PEP-C 1q030. Palmer
et al. (1977) studied a parent with transposition of segment 1q31-1q32
from the long arm to the short arm of chromosome 1 and a child in whom
crossing-over had resulted in duplication of this segment. The Duffy
type in the father and a normal son with the same transposition was
Fy(ab); in the mother, Fy(b). In the proband (with the duplication) it
was Fy(b), suggesting that the Duffy locus is situated at 1q2. In the
course of paternity testing, Herbich et al. (1985) found an apparent
maternal exclusion by the PGM1 enzyme system--mother's PGM1 type, 1;
child's PGM1 type, 2; and by the Duffy blood group system--mother, Fy
(a-b+); child, Fy (a+b-). The father was not available for testing. The
karyotype of the child showed a 'new fragile site' at 1p31. The authors
concluded that the PGM1 and Duffy loci are located in the 1p31 band,
which they stated to be 'a position supposed to carry the PGM1 and the
Duffy loci.' The last statement is incorrect and the assignment to 1p31
is inconsistent with previous well-established assignments of PGM1 and
Fy to 1p22.1 and 1q12-q21, respectively. The demonstration of close
linkage to alpha-spectrin (182860) suggests the location of Fy in the
q21 band (Raeymaekers et al., 1988). McAlpine et al. (1989) concluded
that Fy lies distal to SPTA1.

Hadley et al. (1984) found that the red cell component that carries
Duffy antigen is a 35- to 43-kilodalton protein. Some unusual physical
properties distinguished it from previously described red cell membrane
proteins. Duffy antigens appear to be multimeric erythrocyte-membrane
proteins composed of different subunits. A glycoprotein of 35-45 kD
named GPD is the major subunit of the protein complex and has the
antigenic determinants defined by anti-Fy(a), anti-Fy(b), and anti-Fy6
antibodies. Chaudhuri et al. (1993) isolated cDNA clones encoding the
major subunit of the Duffy blood group from a human bone marrow cDNA
library using a PCR-amplified DNA fragment encoding an internal peptide
sequence of the glycoprotein D protein. The open reading frame of the
1,267-bp cDNA clone indicated that GPD protein is composed of 338 amino
acids, predicting a molecular mass of 35,733, which is the same as a
deglycosylated GPD protein. In Southern blot analysis, Chaudhuri et al.
(1993) used a GPD cDNA probe to identify a single gene in Duffy-positive
and -negative individuals. Duffy-negative individuals, therefore, have
the GPD gene, but it is not expressed in bone marrow. The same or a
similar gene is active in adult kidney, adult spleen, and fetal liver of
Duffy-positive individuals. Chaudhuri et al. (1993) found a significant
protein sequence homology to human and rabbit interleukin-8 receptors
(146929). By fluorescence in situ hybridization, Chaganti (1993) mapped
the GPD gene to 1q22-q23.

An association between sickle cell trait and Duffy null blood group was
demonstrated in Saudi Arabs (Gelpi and King, 1976). Neither linkage nor
association of the usual type was the basis but rather a protection
against malaria provided by both traits. Resistance to vivax malaria and
Duffy negativity occurs in blacks. Miller et al. (1976) presented
evidence that Duffy determinants are directly involved as receptors for
the second stage of red cell invasion by the Plasmodium. Livingstone
(1984) examined the seeming paradox that the Duffy negative allele is
most frequent in areas where there is no vivax malaria. Most red cell
polymorphisms that have been considered to be due to malaria selection
are found in high frequencies in populations with endemic malaria.
Possible explanations are that vivax malaria was eliminated from West
Africa by genetic adaptations to the organism or that a prior-existing
high frequency of the Duffy negative allele prevented vivax malaria from
becoming endemic in West Africa. Livingstone (1984) suggested that 'the
temperate climate adaptations of the vivax parasite and its probable
primate malaria ancestor point to the latter possibility.'

Nichols et al. (1987) reported a new Duffy specificity, Fy6, defined by
a murine monoclonal antibody. Fy6 is related to susceptibility to
invasion of red cells by P. vivax.

Mallinson et al. (1995) presented evidence for 2 different genetic
backgrounds giving rise to the Fy(a-b-) phenotype. The most likely
genetic mechanism in most individuals is down-regulation of Duffy
glycoprotein mRNA. However, the Duffy gene from a very rare Caucasian
individual (AZ) with the Fy(a-b-) phenotype had a 14-bp deletion
(nucleotides 287-301) resulting in a frameshift that introduced a stop
codon and produced a putative truncated 118-amino acid protein. The
occurrence of this mutation in an apparently healthy individual raised
questions about the functional importance of the Duffy glycoprotein not
only in normal erythrocytes but also in all human cells and tissues. The
only known examples of the Fy(a-b-) phenotype in Caucasians were AZ and
Czech gypsies. Chaudhuri et al. (1995) found Duffy glycoprotein mRNA to
be present in lung, spleen, and colon, but not bone marrow, of
African-American individuals of the Fy(a-b-) phenotype, supporting an
erythroid-specific down-regulation of Duffy GP mRNA as the basis of this
phenotype.

Horuk et al. (1993) presented several lines of evidence indicating that
the Duffy blood group antigen is the erythrocyte receptor for the
chemokines interleukin-8 (146930) and melanoma growth stimulatory
activity (MGSA; 155730). IL-8 bound minimally to Duffy-negative
erythrocytes. A monoclonal antibody to the Duffy blood group antigen
blocked binding of IL-8 in other chemokines to Duffy-positive
erythrocytes. Both MGSA and IL-8 blocked the binding of the malaria
parasite ligand and the invasion of human erythrocytes by Plasmodium
knowlesi, suggesting the possibility of receptor blockade for
anti-malarial therapy.

Szabo et al. (1995) demonstrated that the chemokine binding junction is
conserved between mouse and man. The finding of Peiper et al. (1995)
that the Duffy antigen-erythrocyte chemokine receptor is also expressed
by endothelial cells lining postcapillary venules and splenic sinusoids
suggests additional unelucidated roles for this protein.

The Duffy glycoprotein is expressed along postcapillary venules
throughout the body, except in the liver. Erythroid cells and
postcapillary venule endothelium are the principle tissues expressing
the Duffy transcripts. The Fy(a-b-) individuals do not produce Duffy
mRNA in the bone marrow, in accordance with the absence of Duffy
glycoprotein on their erythrocytes. However, in organs other than bone
marrow of Duffy negative individuals, mRNA of the same size but less
quantity than those of Duffy positive individuals is expressed.
Chaudhuri et al. (1995) demonstrated the Duffy glycoprotein on the
endothelial cells of Fy(a-b-) individuals. Iwamoto et al. (1996)
identified a novel first exon and spliced form mRNA that was the
predominant Duffy transcript in both erythroid and postcapillary venule
endothelium. The novel exon started at nucleotide position -332 in
erythroid cells and -380 in endothelial cells. The 5-prime flanking
region of the novel first exon was regarded as a transcription
controlling unit for both tissues. The tissue-specific lack of
expression in Fy(a-b-) indicated that the transcriptional control of the
Duffy gene is under tight tissue-specific regulation. Iwamoto et al.
(1996) characterized a base substitution in the promoter of Duffy
negative individuals: a 1-bp substitution (-365T-to-C) was found in the
proximal GATA motif from 3 black Fy(a-b-) individuals. Iwamoto et al.
(1996) found that the black-type mutation abolished chloramphenicol
acetyltransferase transcription in human erythroleukemia cells but not
in human microvascular endothelial cells. Deletion mutagenesis studies
revealed that the proximal GATA motif represents the erythroid
regulatory core region for the Duffy gene. Gel shift assay showed that
the proximal GATA motif is the target sequence of GATA1 (305371). These
studies indicated that the black-type mutation abolishes Duffy gene
expression in erythroid but not in postcapillary venule endothelium,
which is compatible with the Northern blot and immunohistochemical
observation in black Fy(a-b-) individuals.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
DUFFY a/DUFFY b POLYMORPHISM
GPD, GLY44ASP
Tournamille et al. (1995) found that a single amino acid difference,
gly44-to-asp, accounts for the difference between the FY*A and FY*B
alleles at the Duffy blood group locus. This is the result of a G-to-A
transition at nucleotide 131, which also correlates with a BanI
restriction site polymorphism. This polymorphism allowed them to develop
a method for the DNA typing of the main Duffy blood group antigens by
means of PCR/restriction fragment length polymorphisms. Mallinson et al.
(1995) likewise found the gly44-to-asp difference as the basis of the
a/b polymorphism.

*FIELD* SA
Cook et al. (1978); Howard et al. (1975); Miller et al. (1975); Pasvol
and Wilson (1982); Ritter  (1967)
*FIELD* RF
1. Chaganti, R. S. K.: Personal Communication. New York, N. Y.
10/22/1993.

2. Chaudhuri, A.; Polyakova, J.; Zbrzezna, V .; Pogo, A. O.: The
coding sequence of Duffy blood group gene in humans and simians: restriction
fragment length polymorphism, antibody and malarial parasite specificities,
and expression in nonerythroid tissues in Duffy-negative individuals. Blood 85:
615-621, 1995.

3. Chaudhuri, A.; Polyakova, J.; Zbrzezna, V.; Williams, K.; Gulati,
S.; Pogo, A. O.: Cloning of glycoprotein D cDNA, which encodes the
major subunit of the Duffy blood group system and the receptor for
the Plasmodium vivax malaria parasite. Proc. Nat. Acad. Sci. 90:
10793-10797, 1993.

4. Cook, P. J. L.; Page, B. M.; Johnston, A. W.; Stanford, W. K.;
Gavin, J.: Four further families informative for 1q and the Duffy
blood group. Cytogenet. Cell Genet. 22: 378-380, 1978.

5. Cook, P. J. L.; Robson, E. B.; Buckton, K. E.; Jacobs, P. A.; Polani,
P. E.: Segregation of genetic markers in families with chromosome
polymorphisms and structural rearrangements involving chromosome no.
1. Ann. Hum. Genet. 37: 261-274, 1974.

6. Crawford, M. N.; Punnett, H. H.; Carpenter, G. G.: Deletion of
the long arm of chromosome 16 and an unexpected Duffy blood group
phenotype reveal a possible autosomal linkage. Nature 215: 1075-1076,
1967.

7. Donahue, R. P.; Bias, W. B.; Renwick, J. H.; McKusick, V. A.:
Probable assignment of the Duffy blood group locus to chromosome 1
in man. Proc. Nat. Acad. Sci. 61: 949-955, 1968.

8. Gelpi, A. P.; King, M. C.: Association of Duffy blood groups with
the sickle cell trait. Hum. Genet. 32: 65-68, 1976.

9. Hadley, T. J.; David, P. H.; McGinniss, M. H.; Miller, L. H.:
Identification of an erythrocyte component carrying the Duffy blood
group Fy-a antigen. Science 223: 597-599, 1984.

10. Herbich, J.; Szilvassy, J.; Schnedl, W.: Gene localisation of
the PGM-1 enzyme system and the Duffy blood groups on chromosome no.
1 by means of a new fragile site at 1p31. Hum. Genet. 70: 178-180,
1985.

11. Horuk, R.; Chitnis, C. E.; Darbonne, W. C.; Colby, T. J.; Rybicki,
A.; Hadley, T. J.; Miller, L. H.: A receptor for the malarial parasite
Plasmodium vivax: the erythrocyte chemokine receptor. Science 261:
1182-1184, 1993.

12. Howard, P. N.; Stoddard, G. R.; Goddard, M. W.; Seely, J. R.:
Giemsa banding of chromosome 1qh+ and linkage analysis. J. Med. Genet. 12:
44-48, 1975.

13. Iwamoto, S.; Li, J.; Sugimoto, N.; Okuda, H.; Kajii, E.: Characterization
of the Duffy gene promoter: evidence for tissue-specific abolishment
of expression in Fy(a-b-) of black individuals. Biochem. Biophys.
Res. Commun. 222: 852-859, 1996.

14. Lee, C. S. N.; Ying, K. L.; Bowen, P.: Position of the Duffy
locus on chromosome 1 in relation to breakpoints for structural rearrangements. Am.
J. Hum. Genet. 26: 93-102, 1974.

15. Livingstone, F. B.: The Duffy blood groups, vivax malaria, and
malaria selection in human populations: a review. Hum. Biol. 56:
413-425, 1984.

16. Mallinson, G.; Soo, K. S.; Schall, T. J.; Pisacka, M.; Anstee,
D. J.: Mutations in the erythrocyte chemokine receptor (Duffy) gene:
the molecular basis of the Fy(a)/Fy(b) antigens and identification
of a deletion in the Duffy gene of an apparently healthy individual
with the Fy(a-b-) phenotype. Brit. J. Haemat. 90: 823-829, 1995.

17. McAlpine, P. J.; Coopland, G.; Guy, C.; James, S.; Komarnicki,
L.; MacDonald, M.; Stranc, L.; Lewis, M.; Philipps, S.; Coghlan, G.;
Kaita, H.; Cox, D. W.; Guinto, E. R.; MacGillivray, R.: Mapping the
genes for erythrocytic alpha-spectrin 1 (SPTA1) and coagulation factor
V (F5). (Abstract) Cytogenet. Cell Genet. 51: 1042, 1989.

18. Miller, L. H.; Mason, S. J.; Clyde, D. F.; McGinnis, M. H.: The
resistance factor to Plasmodium vivax in blacks: the Duffy blood group
genotype, FyFy. New Eng. J. Med. 295: 302-304, 1976.

19. Miller, L. H.; Mason, S. J.; Dvorak, J. A.: Erythrocyte receptors
of Plasmodium knowlesi malaria: Duffy blood group determinants. Science 189:
561-562, 1975.

20. Nance, W. E.; Conneally, M.; Kang, K. W.; Reed, T. E.; Schroder,
J.; Rose, S.: Genetic linkage analysis of human hemoglobin variants. Am.
J. Hum. Genet. 22: 453-459, 1970.

21. Nichols, M. E.; Rubinstein, P.; Barnwell, J.; Rodriguez de Cordoba,
S.; Rosenfield, R. E.: A new human Duffy blood group specificity
defined by a murine monoclonal antibody: immunogenetics and association
with susceptibility to Plasmodium vivax. J. Exp. Med. 166: 776-785,
1987.

22. Palmer, C. G.; Christian, J. C.; Merritt, A. D.: Partial trisomy
1 due to a 'shift' and probable location of the Duffy (Fy) locus. Am.
J. Hum. Genet. 29: 371-377, 1977.

23. Pasvol, G.; Wilson, R. J. M.: The interaction of malaria parasites
with red blood cells. Brit. Med. Bull. 38: 133-140, 1982.

24. Peiper, S.; Wang, Z.; Neote, K.; et al. :J. Exp. Med. 181:
1311-1317, 1995.

25. Raeymaekers, P.; Van Broeckhoven, C.; Backhovens, H.; Wehnert,
A.; Muylle, L.; De Jonghe, P.; Gheuens, J.; Vandenberghe, A.: The
Duffy blood group is linked to the alpha-spectrin locus in a large
pedigree with autosomal dominant inheritance of Charcot-Marie-Tooth
disease type 1. Hum. Genet. 78: 76-78, 1988.

26. Ritter, H.: Zur formalen Genetik des Duffy-systems. Untersuchung
von 247 Familien. Humangenetik 4: 59-61, 1967.

27. Robson, E. B.; Cook, P. J. L.; Corney, G.; Hopkinson, D. A.; Noades,
J.; Cleghorn, T. E.: Linkage data on Rh, PGM, PGD, peptidase C and
Fy from family studies. Ann. Hum. Genet. 36: 393-399, 1973.

28. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

29. Szabo, M. C.; Soo, K. S.; Zlotnik, A.; Schall, T. J.: Chemokine
class differences in binding to the Duffy antigen-erythrocyte chemokine
receptor. J. Biol. Chem. 270: 25348-25351, 1995.

30. Tournamille, C.; Le Van Kim, C.; Gane, P.; Cartron, J.-P.; Colin,
Y.: Molecular basis and PCR-DNA typing of the Fya/fyb blood group
polymorphism. Hum. Genet. 95: 407-410, 1995.

31. Weitkamp, L. R.: Personal Communication. Rochester, N. Y.
1972.

*FIELD* CS

Immune:
   Duffy negative blacks are more resistant to vivax malaria

Lab:
   Duffy blood group

Gene:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 02/03/1997

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 02/03/1997
terry: 2/3/1997
mark: 10/3/1996
terry: 9/17/1996
mark: 3/4/1996
mark: 2/20/1996
mark: 12/13/1995
mark: 11/17/1995
terry: 10/30/1995
pfoster: 4/25/1994
warfield: 4/7/1994
mimadm: 2/11/1994
carol: 12/9/1993

*RECORD*
*FIELD* NO
110720
*FIELD* TI
110720 BLOOD GROUP--En
*FIELD* TX
Darnborough et al. (1969) discovered a new antibody, anti-En(a), which
reacted strongly with many cells tested, a total of 7000, but did not
react with her own cells or those of 2 of her 8 sibs. The proposita, an
English woman, was pregnant and had been transfused 2 years earlier. En
of the notation stands for envelope; the authors summarized as follows:
'The reactions of various unrelated blood group antigens are modified,
in some cases enhanced and in others depressed, the total picture being
strongly reminiscent of the effects of proteolytic enzyme treatment. It
is suggested that these effects can only be due to some factor affecting
the red cell structure possibly by modifying the cell envelope.' Two
further examples of En(a-) were found in Finland in unrelated persons.
The great rarity of the phenotype is indicated by the fact that by 1975
only these 3 families had been discovered (Race and Sanger, 1975). The
English case had parents from a small fishing port in Yorkshire. The
parents of both Finnish probands were consanguineous. Because of the
consanguinity, any locus for which the En(a-) persons were heterozygous
cannot have been responsible for the En gene. Using this reasoning, ABO,
MNSs, Rh, Duffy, Haptoglobin, Kidd, Gm, and Dombrock could be excluded
(Race and Sanger, 1975). Although En is independent of MN, MN typing
shows a profound derangement in En(a-) persons.

*FIELD* RF
1. Darnborough, J.; Dunsford, I.; Wallace, J. A.: The En(a) antigen
and antibody: a genetical modification of human red cells affecting
their blood grouping reactions. Vox Sang. 17: 241-255, 1969.

2. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
(pub.)  (6th ed.): 1975. Pp. 463-470.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/18/1994
warfield: 4/6/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 4/2/1988

*RECORD*
*FIELD* NO
110750
*FIELD* TI
*110750 BLOOD GROUP--GERBICH; Ge
GLYCOPHORIN C, INCLUDED;;
GYPC, INCLUDED;;
GPC, INCLUDED;;
GLYCOPHORIN D, INCLUDED;;
GYPD, INCLUDED;;
GPD, INCLUDED;;
DUCH BLOOD GROUP, INCLUDED;;
DH BLOOD GROUP, INCLUDED
*FIELD* TX
Antibody demonstrating this antigen was found in cases of fetomaternal
incompatibility (Barnes and Lewis, 1961). Independence from ABO, MNS, P,
Rh, Kell, Duffy, and Kidd systems has been demonstrated (Race and
Sanger, 1975). Anstee et al. (1984) studied the red cells of 2 unrelated
persons who lacked Ge blood group substance and 3 minor
sialoglycoproteins that are associated with the cytoskeleton of normal
red cells. About 10% of red cells in each subject were 'frankly
elliptocytic.' In Melanesia there are more Gerbich-negative persons than
in any other part of the world (Booth and McLoughlin, 1972). Since
Gerbich-negative red cells lack beta- and gamma-sialoglycoproteins, it
is reasonable to presume that Gerbich antigens are located on these
proteins, also called glycophorin C. Glycophorin C is a minor red cell
membrane component, representing about 4% of the membrane
sialoglycoproteins. It is a putative receptor for the merozoites of
Plasmodium falciparum (Pasvol et al., 1984). The occurrence of
elliptocytosis and Gerbich-negative red cells in Melanesia may be
related to the function of glycophorin C in relation to Plasmodium
falciparum. However, the primary defect in the Malaysian-Melanesian type
of elliptocytosis resides in the band 3 protein of the red cell membrane
(109270.0002). Glycophorin C has a role in the maintenance of red cell
shape (Bennett, 1985).

Colin et al. (1986) isolated cDNA clones for red cell glycophorin C and
deduced its complete amino acid sequence. It is a single polypeptide
chain of 128 amino acids showing very little homology with the major red
cell membrane glycophorins A and B, which carry the blood group MN
(111300) and Ss (111740) antigens, respectively, and are closely related
proteins. Mattei et al. (1986) used a cDNA clone for GYPC in studies by
in situ hybridization to assign the GYPC locus to 2q14-q21. Some rare
individuals with the Gerbich-negative phenotype lack certain minor
erythrocyte sialoglycoproteins. Anderson et al. (1986) reported such an
individual whose erythrocytes lacked beta- and gamma-sialoglycoproteins
in SDS-PAGE but had 2 additional abnormal sialoglycoproteins. Analysis
using SDS-PAGE of erythrocyte membranes from his 2 children failed to
reveal any similar abnormal sialoglycoproteins. This led to the
suggestion by Anderson et al. (1986) that in this instance the
Gerbich-negative phenotype may have resulted from other mechanisms,
possibly defective glycosylation, rather than from a crossover involving
the gene coding for the primary protein structure of the
sialoglycoproteins. Glycophorin C carries Gerbich determinants; Ge
antigens are also present on glycophorin D. Using a cDNA prepared from
the mRNA of glycophorin C, Le Van Kim et al. (1987) found that the
Ge-negative condition in donors with nonelliptocytic red cells is
associated with a 3-kb deletion in the glycophorin C gene. Their
findings also suggested that the same gene codes for glycophorin D. Reid
et al. (1987) obtained unequivocal evidence of the autosomal codominant
nature of the Ge alleles by means of protein immunoblotting using
monoclonal antibodies against what they termed the beta and gamma
sialoglycoproteins (SGPs). El-Maliki et al. (1989) concluded from the
sequence data that glycophorin D is an abridged version of glycophorin
C. Glycophorin C is a single polypeptide chain of 128 amino acid
residues. GYPD is smaller than GYPC (24 kD vs 32 kD). Amino acid
sequence showed identity of GYPD with residues of 30 to 126 of GYPC. The
mechanism generating GYPC and GYPD from the same gene may involve
translation of the same mRNA to in-phase AUGs by leaky translation
(Cartron et al., 1990). Available sequencing information on GYPD was
consistent with this model. From studies of the molecular basis of the
rare blood group An(a) antigen, Daniels et al. (1993) obtained further
evidence that glycophorin D is a product of the GYPC gene.

Winardi et al. (1993) characterized the deficiency of glycophorins C and
D in erythrocytes of the Leach phenotype. They found that the deficiency
was the consequence of deletion or marked alteration of exons 3 and 4 of
the GYPC gene. The mutant gene encoded an mRNA stable enough to be
detected in circulating reticulocytes. The protein encoded by this mRNA
would not be expected to be expressed in the cell membrane because it
would lack the transmembrane and cytoplasmic domains.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
GLYCOPHORIN C, YUS VARIANT
GYPC, 57-BP DEL, EX2DEL
Immunochemical and serologic studies identified a number of glycophorin
C variants that include the Yus, Gerbich, and Webb phenotypes. In the
Yus phenotype, Chang et al. (1991) demonstrated a 57-bp deletion that
corresponds to exon 2 of the glycophorin C gene.

.0002
GLYCOPHORIN C, GERBICH VARIANT
GYPC, 84-BP DEL, EX3DEL
In the Gerbich phenotype, Chang et al. (1991) identified deletion of the
84-bp exon 3 of the glycophorin C gene.

.0003
GLYCOPHORIN D, WEBB VARIANT
BLOOD GROUP--WEBB ANTIGEN
WB
GYPD, ASN8SER
The Webb antigen was first described by Simmons and Albrey (1963) in
Australia. It is a very rare antigen. Bloomfield et al. (1986) found 8
examples of Wb-positive antigen, 2 in the same family, among 10,117
random blood donors in South Wales. Family studies confirmed autosomal
dominant inheritance. The Webb antigen segregated independently of ABO,
Rh, MNSs, Jk, and Lu; furthermore, it was not X-linked or Y-linked.
Whereas the cDNA generated from mRNA in the Yus and Gerbich phenotypes
is shorter than normal, that from the Webb phenotype is of normal size.
Chang et al. (1991) demonstrated an A-to-G transition at nucleotide 23
of the coding sequence, resulting in substitution of asparagine by
serine. This modification accounted for the altered glycosylation of
glycophorin seen with the Webb phenotype. Telen et al. (1991) likewise
found a point mutation resulting in substitution of serine for
asparagine at amino acid position 8.

.0004
GLYCOPHORIN D, DUCH VARIANT
BLOOD GROUP DH
GYPD, LEU14PHE
Duch, Dh(a), an exceedingly rare red cell antigen, is recognized by an
antibody found in Aarhus, Denmark, in 1968 (Jorgensen et al., 1982). The
antigen was found in 5 persons in 3 generations and segregated
independently of Rh, MNSs and Kidd.

Spring (1991) detected the Duch antigen on a variant of glycophorin C
that had the same apparent molecular mass as normal GPC. The location of
Dh(a) on GPC was tentatively assigned to the sequence between residues 1
and 47. Since the Dh(a) antigen was not detected on GPD but was present
on GPC, it was presumed to reside within residues 1-21 at the N-terminal
domain of GPC. By sequencing PCR-amplified DNA, King et al. (1992)
demonstrated a C-to-T transition at nucleotide 40 responsible for a
substitution of leucine by phenylalanine at amino acid residue 14.

*FIELD* SA
Reid  (1972); Sondag et al. (1987)
*FIELD* RF
1. Anderson, S. E.; McKenzie, J. L.; McLoughlin, K.; Beard, M. E.
J.; Hart, D. N. J.: The inheritance of abnormal sialoglycoproteins
found in a Gerbich negative individual. Pathology 18: 407-412,
1986.

2. Anstee, D. J.; Parsons, S. F.; Ridgwell, K.; Tanner, M. J. A.;
Merry, A. H.; Thomson, E. E.; Judson, P. A.; Johnson, P.; Bates, S.;
Fraser, I. D.: Two individuals with elliptocytic red cells apparently
lack three minor erythrocyte membrane sialoglycoproteins. Biochem.
J. 218: 615-619, 1984.

3. Barnes, R.; Lewis, T. L. T.: A rare antibody (anti-Ge) causing
hemolytic disease of the newborn. Lancet II: 1285-1286, 1961.

4. Bennett, V.: The membrane skeleton of human erythrocytes and its
implications for more complex cells. Annu. Rev. Biochem. 54: 273-304,
1985.

5. Bloomfield, L.; Rowe, G. P.; Green, C.: The Webb (Wb) antigen
in South Wales donors. Hum. Hered. 36: 352-356, 1986.

6. Booth, P. B.; McLoughlin, K.: The Gerbich blood group system,
especially in Melanesians. Vox Sang. 22: 73-84, 1972.

7. Cartron, J.-P.; Colin, Y.; Kudo, S.; Fukuda, M.: Molecular genetics
of human erythrocyte sialoglycoproteins A, B, C, and D. In: Harris,
J. R.: Erythroid Cells. Blood Cell Biochemistry.  New York: Plenum
Press (pub.)  1: 1990. Pp. 299-335.

8. Chang, S.; Reid, M. E.; Conboy, J.; Kan, Y. W.; Mohandas, N.:
Molecular characterization of erythrocyte glycophorin C variants.
Blood 77: 644-648, 1991.

9. Colin, Y.; Rahuel, C.; London, J.; Romeo, P. H.; d'Auriol, L.;
Galibert, F.; Cartron, J.-P.: Isolation of cDNA clones and complete
amino acid sequence of human erythrocyte glycophorin C. J. Biol.
Chem. 261: 229-233, 1986.

10. Daniels, G.; King, M.-J.; Avent, N. D.; Khalid, G.; Reid, M.;
Mallinson, G.; Symthe, J.; Cedergren, B.: A point mutation in the
GYPC gene results in the expression of the blood group An(a) antigen
on glycophorin D but not on glycophorin C: further evidence that glycophorin
D is a product of the GYPC gene. Blood 82: 3198-3203, 1993.

11. El-Maliki, B.; Blanchard, D.; Dahr, W.; Beyreuther, K.; Cartron,
J.-P.: Structural homology between glycophorins C and D of human
erythrocytes. Europ. J. Biochem. 183: 639-643, 1989.

12. Jorgensen, J.; Drachmann, O.; Gavin, J.: Duch, Dh(a), a low frequency
red cell antigen. Hum. Hered. 32: 73-75, 1982.

13. King, M. J.; Avent, N. D.; Mallinson, G.; Reid, M. E.: Point
mutation in the glycophorin C gene results in the expression of the
blood group antigen Dh(a). Vox Sang. 63: 56-58, 1992.

14. Le Van Kim, C.; Colin, Y.; Blanchard, D.; Dahr, W.; London, J.;
Cartron, J.-P.: Gerbich blood group deficiency of the Ge:-1,-2,-3
and Ge:-1,-2,3 types: immunochemical study and genomic analysis with
cDNA probes. Europ. J. Biochem. 165: 571-579, 1987.

15. Mattei, M. G.; Colin, Y.; Le Van Kim, C.; Mattei, J. F.; Cartron,
J. P.: Localization of the gene for human erythrocyte glycophorin
C to chromosome 2, q14-q21. Hum. Genet. 74: 420-422, 1986.

16. Pasvol, G.; Anstee, D. J.; Tanner, M. J. A.: Glycophorin C and
the invasion of red cells by Plasmodium falciparum. Lancet I: 907-908,
1984.

17. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
Sci. Publ. (pub.)  (6th ed.): 1975. Pp. 416-421.

18. Reid, M. E.: The Gerbich blood group antigens: a review. Med.
Lab. Sci. 43: 177-182, 1972.

19. Reid, M. E.; Sullivan, C.; Taylor, M.; Anstee, D. J.: Inheritance
of human-erythrocyte Gerbich blood group antigens. Am. J. Hum. Genet. 41:
1117-1123, 1987.

20. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

21. Simmons, R. T.; Albrey, J. A.: A 'new' blood group antigen Webb
(Wb) of low frequency found in two Australian families. Med. J.
Aust. I: 8-10, 1963.

22. Sondag, D.; Alloisio, N.; Blanchard, D.; Ducluzeau, M.-T.; Colonna,
P.; Bachir, D.; Bloy, C.; Cartron, J.-P.; Delaunay, J.: Gerbich reactivity
in 4.1(-) hereditary elliptocytosis and protein 4.1 level in blood
group Gerbich deficiency. Brit. J. Haemat. 65: 43-50, 1987.

23. Spring, F. A.: Immunochemical characterisation of the low-incidence
antigen, Dh(a). Vox Sang. 61: 65-68, 1991.

24. Telen, M. J.; Le Van Kim, C.; Guizzo, M. L.; Cartron, J.-P.; Colin,
Y.: Erythrocyte Webb-type glycophorin C variant lacks N-glycosylation
due to an asparagine to serine substitution. Am. J. Hemat. 37:
51-52, 1991.

25. Winardi, R.; Reid, M.; Conboy, J.; Mohandas, N.: Molecular analysis
of glycophorin C deficiency in human erythrocytes. Blood 81: 2799-2803,
1993.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/18/1994
mimadm: 4/19/1994
pfoster: 3/31/1994
carol: 3/19/1994
carol: 10/21/1993
carol: 10/20/1993

*RECORD*
*FIELD* NO
110800
*FIELD* TI
#110800 BLOOD GROUP--I SYSTEM; Ii
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the i
and I antigens are determined by linear and branched
poly-N-acetyllactosaminoglycans, respectively; that these 2 antigens are
the fetal and adult antigens, respectively; and that a replacement
during development of i by I is dependent on the appearance of a
beta-1,6-N-acetylglucosaminyltransferase, the I-branching enzyme (GCNT2;
600429).

Tippett et al. (1960) described a Baltimore black family in which red
cells were apparently of 'i' phenotype and their serum contained
anti-'I.' This was the first direct evidence that the 'I' antigen is
under genetic control. Anti-'I' was first identified by Wiener et al.
(1956). Anti-'i' was first recognized by Marsh and Jenkins (1960),
leading to the 'reciprocal relationship hypothesis' of Marsh (1961).
Bingham (1971) concluded, on the basis of the developmental pattern of
the 'I' and 'i' antigens, that the corresponding antibodies may define
two independent blood group systems. The matter cannot be considered
resolved. Yamaguchi et al. (1972) presented evidence suggesting linkage
of the Ii blood group locus and a recessive form of congenital cataract.
In each of 4 Japanese families, 2 sibs were both homozygous for 'little
eye' (no pun intended), and affected with a recessive form of cataract
(see 212500). Ogata et al. (1979) found congenital cataract in 17 of 18
Japanese of the 'i' phenotype. Macdonald et al. (1983) reported a
Caucasian family in Australia in which a sister and brother (whose
parents were half-first-cousins, i.e., the offspring of half sisters)
had cataracts and the phenotype I-negative, i-positive. In Boston, Page
et al. (1987) observed a 19-year-old woman of Irish descent whose red
blood typed as I-negative and i-positive. The patient had bilateral
cataracts recognized at birth; there had been no maternal history of
German measles or other problems during pregnancy. Page et al. (1987)
also studied the blood of 31 white patients with congenital cataracts
and found none with the i phenotype. The pattern of inheritance of
cataracts in the 31 patients was either autosomal dominant or apparently
sporadic, with no clear instance of autosomal recessive inheritance.
Among 6 white persons with the i phenotype in New York, no ocular
abnormalities were found by Marsh and DePalma (1982).

The blood group i/I antigens were the first identified alloantigens that
display a dramatic change during human development. In human
erythrocytes during embryonic development, the fetal (i) antigen is
replaced by the adult (I) antigen as the result of the appearance of a
beta-1,6-N-acetylglucosaminyltransferase, the I-branching enzyme. This
branching enzyme, GCNT2, converts the linear
poly-N-acetyllactosaminoglycans into branched
poly-N-acetyllactosaminoglycans. Bierhuizen et al. (1993) reported the
cDNA cloning and expression of this branching enzyme. The cDNA sequence
predicted a protein of type II membrane topology as has been found for
all other mammalian glycosyltransferases cloned to that time. Comparison
of the amino acid sequence with those of other glycosyltransferases
demonstrated that this I-branching enzyme and another
beta-1,6,N-acetylglucosaminyltransferase that forms a branch in
O-glycans (GCNT1; 600391) are strongly homologous in the center of their
putative catalytic domains. Moreover, the genes encoding these 2 enzymes
were found by isotopic in situ hybridization to be located in the same
band, 9q21.

*FIELD* SA
Hakomori  (1981); Joshi and Bhatia (1984)
*FIELD* RF
1. Bierhuizen, M. F. A.; Mattei, M.-G.; Fukuda, M.: Expression of
the developmental I antigen by a cloned human cDNA encoding a member
of a beta-1,6-N-acetylglucosaminyltransferase gene family. Genes
Dev. 7: 468-478, 1993.

2. Bingham, C. P.: Anti-I and anti-i define two independent blood
group systems.  (Unpublished) 1971.

3. Hakomori, S.: Blood group ABH and Ii antigens of human erythrocytes:
chemistry, polymorphism, and their developmental change. Seminars
Hemat. 18: 39-62, 1981.

4. Joshi, S. R.; Bhatia, H. M.: I-i-phenotype in a large kindred
Indian family. Vox Sang. 46: 157-160, 1984.

5. Macdonald, E. B.; Douglas, R.; Harden, P. A.: A Caucasian family
with the i phenotype and congenital cataracts. Vox Sang. 44: 322-325,
1983.

6. Marsh, W. L.: Anti-I: a cold antibody defining the Ii relationship
in human red cells. Brit. J. Haemat. 7: 200-209, 1961.

7. Marsh, W. L.; DePalma, H.: Association between the Ii blood group
and congenital cataract. Transfusion 22: 337-338, 1982.

8. Marsh, W. L.; Jenkins, W. J.: Anti-I: a new cold antibody. Nature 188:
753 only, 1960.

9. Ogata, H.; Okubo, Y.; Akabane, T.: Phenotype i associated with
congenital cataract in Japanese. Transfusion 19: 166-168, 1979.

10. Page, P. L.; Langevin, S.; Petersen, R. A.; Kruskall, M. S.:
Reduced association between the Ii blood group and congenital cataracts
in white patients. Am. J. Clin. Path. 87: 101-102, 1987.

11. Tippett, P.; Noades, J.; Sanger, R.; Race, R. R.; Sausais, L.;
Holman, C. A.; Buttimer, R. J.: Further studies of the I antigen
and antibody. Vox Sang. 5: 107-121, 1960.

12. Wiener, A. S.; Unger, L. T.; Cohen, L.; Feldman, J.: Type specific
cold autoantibodies as a cause of acquired hemolytic anemia and hemolytic
transfusion reactions: biologic test with bovine red cells. Ann.
Intern. Med. 44: 221-240, 1956.

13. Yamaguchi, H.; Okubo, Y.; Tanaka, M.: A note on possible close
linkage between the Ii blood locus and a congenital cataract locus.
Proc. Jpn. Acad. 48: 625-628, 1972.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/27/1995
jason: 7/5/1994
mimadm: 4/2/1994
pfoster: 3/25/1994
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
110900
*FIELD* TI
*110900 BLOOD GROUP--KELL-CELLANO SYSTEM; KEL
*FIELD* TX
The Kell and Cellano blood groups are symbolized K and k, respectively.
The Kell-Cellano system illustrates nicely the manner in which the
understanding of several of the blood group systems has developed. The
Kell type was first identified using an antibody developed by Mrs. Kell
through the mechanism of maternofetal incompatibility. Later, when Mrs.
Cellano was found to have an antibody developed by the same mechanism,
it was demonstrated that these antibodies were testing for antigens
determined by allelic genes. Sutter is part of the Kell system. Linkage
data, suggestive but not conclusive, on Kell and pepsinogen (169700)
were reported by Weitkamp et al. (1975). The McLeod phenotype was
described by Allen et al. (1961) in a man of that surname. His red cells
showed unaccountably weak reactivity to Kell antisera. In 1970, his red
cells were noted to be acanthocytic in the absence of
abetalipoproteinemia. The precursor missing in McLeod's red cells is
called Kx. The X-linked locus determining this substance is called Xk.
Boys with chronic granulomatous disease (306400) lack Kx on their
phagocytic white cells and show acanthocytosis. McLeod had normal white
cell Kx and did not have granulomatous disease. He did have a
compensated hemolytic state (Wimer et al., 1976). Evidence for X-linkage
of Xk was provided by mosaicism in females for both acanthocytosis and
red cell Kx. The observations showed that some blood group antigenic
substances are important to both structure and function of cell
membranes.

Conneally et al. (1974, 1976) found Kell and PTC (171200) to be closely
linked: total lod = 10.78 at theta = 0.045. Keats et al. (1978) raised
the question of linkage of Kell and PTC to Jk-Km-Co, then thought to be
on chromosome 7. Spence et al. (1984) analyzed 2 new data sets regarding
PTC/Kell linkage and found a maximum likelihood estimate for theta (both
sexes) of 0.28. All published data including these gave a combined
maximum likelihood estimate of 0.14 (lod = 8.94) but there was
statistically significant evidence of heterogeneity among the published
studies.

See 145290 for description of a trait, hyperreflexia, that is possibly
linked to Kell (Parke et al., 1984).

Despite its high level of polymorphism with a series of serologically
distinct antigens (KEL1 to KEL24), the gene controlling KEL antigen
expression (KEL) eluded chromosomal assignment until the mapping work of
Zelinski et al. (1991). They succeeded in showing linkage with
prolactin-inducible protein (PIP; 176720), which had been assigned to
7q32-q36. No evidence of recombination was found; maximum lod = 10.36 at
theta = 0.00. The mapping of the Kell blood group to chromosome 7 means
that PTC tasting (171200), the YT blood group (112100), and
hyperreflexia (145290) are also located there. Purohit et al. (1992)
demonstrated close linkage to cystic fibrosis (CFTR; 219700);
sex-specific estimates of recombination fractions were 0.013 in males
and 0.219 in females, with a joint maximum lod score of 4.58. Lee et al.
(1993) used genomic clones as probes to confirm the assignment of the
gene to chromosome 7 by Southern analysis of human/hamster somatic cell
hybrids; by in situ hybridization, they localized the KEL gene to 7q33.
Using a biotinylated 1.1-kb DNA fragment containing the 3-prime half of
the KEL cDNA for in situ hybridization, Murphy et al. (1993) likewise
assigned the KEL gene to 7q33-q35. They suggested that since the in situ
assignment agrees with the genetic localization using antigenic
variation as the marker, KEL antigenic determinants are part of the
polypeptide chain rather than the associated sugar molecules.

KEL antigens reside on a 93-kD membrane glycoprotein that is surface
exposed and associated with the underlying cytoskeleton. Lee et al.
(1991) isolated tryptic peptides of this glycoprotein and, based on the
amino acid sequence of one of the peptides and by using PCR, prepared a
specific oligonucleotide to screen a lambda-gt10 human bone marrow cDNA
library. One clone contained cDNA with an open reading frame for a
predicted 83-kD protein. All known KEL amino acid sequences were present
in the deduced sequence; moreover, rabbit antibody to a 30-amino acid
peptide prepared from this sequence reacted on an immunoblot with
authentic KEL protein. The KEL cDNA sequence predicts a 732-amino acid
protein. A computer-based search showed that KEL has structural and
sequence homology to a family of zinc metalloglycoproteins with neutral
endopeptidase activity.

Marsh (1992) reviewed the cloning of the KEL gene and its
characterization. By Northern blot analysis of RNA from multiple
tissues, Lee et al. (1993) demonstrated that the KEL gene is expressed
only in erythroid tissues.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
KELL K/k BLOOD GROUP POLYMORPHISM
KEL, THR193MET
The importance of the Kell blood group system to transfusion medicine is
indicated by the fact that the Kell antigen (K1) is probably secondary
in importance to Rh D as an immunogen in alloimmunized pregnancies that
cause hemolytic disease of the newborn. The K/k (K1/K2) blood group
polymorphism, otherwise known as the Kell/Cellano polymorphism was shown
by Lee et al. (1995) to represent a point mutation resulting in a
thr193(k) to met193(K) amino acid substitution in the Kell glycoprotein.
The C-to-T substitution in exon 6 creates a BsmI restriction site that
was exploited by Lee et al. (1995) to form the basis of a simple PCR
assay to determine the Kell type of an individual. Avent and Martin
(1996) described a simple allele-specific PCR assay for the
determination of K1/K2 status of an individual. The assay was
successfully applied to the determination of the Kell status of fetal
material and was found suitable for use in the clinical management of
pregnancies in which the fetus is at risk for hemolytic disease of the
newborn (HDN) due to anti-K.

*FIELD* SA
Morton et al. (1965); Stroup et al. (1965); Zelinski et al. (1991)
*FIELD* RF
1. Allen, F. H., Jr.; Krabbe, S. M.; Corcoran, P. A.: A new phenotype
(McLeod) in the Kell blood-group system. Vox Sang. 6: 555-560, 1961.

2. Avent, N. D.; Martin, P. G.: Kell typing by allele-specific PCR
(ASP). Brit. J. Haemat. 93: 728-730, 1996.

3. Conneally, P. M.; Dumont-Driscoll, M.; Huntzinger, R. S.; Nance,
W. E.; Jackson, C. E.: Linkage relations of the loci for Kell and
phenylthiocarbamide (PTC) taste sensitivity. Hum. Hered. 26: 267-271,
1976.

4. Conneally, P. M.; Nance, W. E.; Huntzinger, R. S.: Linkage analysis
of Kell-Sutter and PTC loci. (Abstract) Am. J. Hum. Genet. 26: 22A
only, 1974.

5. Keats, B. J. B.; Morton, N. E.; Rao, D. C.: Possible linkages
(lod score over 1.5) and a tentative map of the Jk-Km linkage group. Cytogenet.
Cell Genet. 22: 304-308, 1978.

6. Lee, S.; Wu, X.; Reid, M. E.; Zelinski, T.; Redman, C. M.: Molecular
basis of the Kell (K1) phenotype. Blood 85: 912-916, 1995.

7. Lee, S.; Zambas, E. D.; Marsh, W. L.; Redman, C. M.: Molecular
cloning and primary structure of Kell blood group protein. Proc.
Nat. Acad. Sci. 88: 6353-6357, 1991.

8. Lee, S.; Zambas, E. D.; Marsh, W. L.; Redman, C. M.: The human
Kell blood group gene maps to chromosome 7q33 and its expression is
restricted to erythroid cells. Blood 81: 2804-2809, 1993.

9. Marsh, W. L.: Molecular biology of blood groups: cloning of the
Kell gene. Transfusion 32: 98-101, 1992.

10. Morton, N. E.; Krieger, H.; Steinberg, A. G.; Rosenfield, R. E.
: Genetic evidence confirming the localization of Sutter in the Kell
blood-group system. Vox Sang. 10: 608-613, 1965.

11. Murphy, M. T.; Morrison, N.; Miles, J. S.; Fraser, R. H.; Spurr,
N. K.; Boyd, E.: Regional chromosomal assignment of the Kell blood
group locus (KEL) to chromosome 7q33-q35 by fluorescence in situ hybridization:
evidence for the polypeptide nature of antigenic variation. Hum.
Genet. 91: 585-588, 1993.

12. Parke, J. T.; Riccardi, V. M.; Lewis, R. A.; Ferrell, R. E.:
A syndrome of microcephaly and retinal pigmentary abnormalities without
mental retardation in a family with coincidental autosomal dominant
hyperreflexia. Am. J. Med. Genet. 17: 585-594, 1984.

13. Purohit, K. R.; Weber, J. L.; Ward, L. J.; Keats, B. J. B.: The
Kell blood group locus is close to the cystic fibrosis locus on chromosome
7. Hum. Genet. 89: 457-458, 1992.

14. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

15. Spence, M. A.; Falk, C. T.; Neiswanger, K.; Field, L. L.; Marazita,
M. L.; Allen, F. H., Jr.; Siervogel, R. M.; Roche, A. F.; Crandall,
B. F.; Sparkes, R. S.: Estimating the recombination frequency for
the PTC-Kell linkage. Hum. Genet. 67: 183-186, 1984.

16. Stroup, M.; MacIlroy, M.; Walker, R.; Aydelotte, J. V.: Evidence
that Sutter belongs to the Kell blood group system. Transfusion 5:
309-314, 1965.

17. Weitkamp, L. R.; Townes, P. L.; Johnston, E.: Linkage data on
urinary pepsinogen and the Kell blood group. Birth Defects Orig.
Art. Ser. 11(3): 281-282, 1975. Note: Alternate: Cytogenet. Cell
Genet. 14: 451-452, 1975.

18. Wimer, B. M.; Marsh, W. L.; Taswell, H. F.: Clinical characteristics
of the McLeod blood group phenotype. (Abstract) Am. Soc. Hemat.,
Boston , 12/1976.

19. Zelinski, T.; Coghlan, G.; Myal, Y.; Shiu, R. P. C.; Philipps,
S.; White, L.; Lewis, M.: Genetic linkage between the Kell blood
group system and prolactin-inducible protein loci: provisional assignment
of KEL to chromosome 7. Ann. Hum. Genet. 55: 137-140, 1991.

20. Zelinski, T. A.; Coghlan, G. E.; Myal, Y.; White, L. J.; Philipps,
S. E.: Assignment of the Kell blood group locus to chromosome 7q.
(Abstract) Cytogenet. Cell Genet. 58: 1927 only, 1991.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 08/20/1996
davew: 6/9/1994
terry: 5/13/1994
mimadm: 4/13/1994
warfield: 4/6/1994
pfoster: 3/25/1994
carol: 9/14/1993

*RECORD*
*FIELD* NO
111000
*FIELD* TI
*111000 BLOOD GROUP--KIDD SYSTEM; JK
SOLUTE CARRIER FAMILY 14, MEMBER 1; SLC14A1, INCLUDED;;
UREA TRANSPORTER, ERYTHROCYTE, INCLUDED; UTE; UT11, INCLUDED
*FIELD* TX
On the basis of studies of a patient with deletion of part of the long
arm of chromosome 7, Shokeir et al. (1973) proposed that the Kidd blood
group is on the deleted segment. The parents were homozygous Jk(a) and
Jk(b) and all 9 sibs of the proband were heterozygous as one would
expect. The proband herself was Jk(a). Hulten et al. (1968) previously
suggested that the Kidd locus is on either chromosome 2 or a C group
chromosome, but banding techniques were not then available. Mace and
Robson (1974) found a hint of linkage between 'red-cell' acid
phosphatase (171500), which is coded by chromosome 2, and Kidd blood
group. Mohr and Eiberg (1977) found a lod score of plus 2.57 for the
linkage of Kidd and Colton. Each had been tentatively assigned to
chromosome 7. Under 3 different genetic models for IDDM, Hodge et al.
(1981) found evidence for linkage with 2 different sets of marker loci:
HLA, properdin factor B and glyoxalase-1 on chromosome 6, and Kidd blood
group on chromosome 2. The 71 families studied apparently did not fall
into 2 groups, one exhibiting linkage to HLA and the other to Kidd.
Thus, 2 distinct disease-susceptibility loci may be involved in IDDM, a
situation also postulated for Graves disease (275000). Field et al.
(1985) and Sherman and Simpson (1985) provided evidence for linkage of
IGK and Jk and, therefore, assignment to chromosome 2. This means that
the Colton blood group locus (110450) may also be on chromosome 2.
Sherman and Simpson (1985) published a collated maximum lod score of
3.14 at theta 0.31 for Jk:IGK. The Kidd blood group was assigned to 18p
by linkage to a polymorphic anonymous DNA probe, L2.7 (Gedde-Dahl,
1986). Leppert et al. (1987) also found linkage of blood group Kidd to 2
DNA markers on chromosome 18; the maximum lod scores were 3.61 at theta
= 0.168 and 4.18 at theta = 0.218. This is, of course, inconsistent with
linkage of Jk to Km (147200). Pausch and Mayr (1987) presented
additional data supporting linkage of Jk and IGK. Together with the data
of Field et al. (1985), the maximum lod score reached 3.0 for theta
equal to 0.32. However, the evidence from linkage studies using DNA
markers is overwhelming; HGM9 concluded provisionally that the Jk locus
is at 18q11-q12 (Geitvik et al., 1987). The L2.7 probe used in the
assignment to chromosome 18 was thought to lie on the short arm, close
to the centromere. The maximum lod score was 8.53 at recombination
fraction of 0.03 (upper probability limit 0.11). In these data also,
linkage of Jk to IGK was found (total lods = 4.12 at theta = 0.30). No
obvious explanation for the conflicting gene mapping data could be
found. Geitvik et al. (1987) quoted deletion data excluding Jk from a
considerable part of chromosome 18 and contributing to the assignment of
18q11-q12.

Olives et al. (1994) cloned the gene encoding the urea transporter of
human erythrocytes. Olives et al. (1995) assigned the gene, which they
symbolized UTE, to 18q12-q21 by isotopic in situ hybridization. (The
gene has also been symbolized HUT11 or UT11.) The JK locus is situated
in the same region. The possibility that the urea transport of human
erythrocytes may be related to Kidd blood group antigens was raised by
the observation that red cells from Jk(a-b-) individuals which lack Kidd
antigens exhibited an increased resistance to lysis in aqueous 2 M urea.
These cells exhibited a defect in urea transport, whereas chloride,
water, and ethylene glycol permeabilities, as well as
aquaporin-associated Colton blood group antigens (107776), were the same
as in control cells. Olives et al. (1995) demonstrated that, indeed, the
urea transporter of human erythrocytes is encoded by the Kidd locus. In
coupled transcription-translation assays, the UTE cDNA directed the
synthesis of a 36-kD protein that was immunoprecipitated by human
anti-Jk(3) antibody produced by immunized Jk(a-b-) donors whose red
cells lack Kidd antigens.

Nomenclature: This gene was designated SLC14A1 for solute carrier family
14, member 1.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Barbosa et al. (1982); Keats et al. (1977); Keats et al. (1978)
*FIELD* RF
1. Barbosa, J.; Rich, S.; Dunsworth, T.; Swanson, J.: Linkage disequilibrium
between insulin-dependent diabetes and the Kidd blood group Jk(b)
allele. J. Clin. Endocr. Metab. 55: 193-195, 1982.

2. Field, L. L.; Marazita, M. L.; Spence, M. A.; Crandall, B. F.;
Sparkes, R. S.: Is JK linked to IGK on chromosome 2?. (Abstract) Cytogenet.
Cell Genet. 40: 628-629, 1985.

3. Gedde-Dahl, T.: Personal Communication. Oslo, Norway  9/26/1986.

4. Geitvik, G. A.; Hoyheim, B.; Gedde-Dahl, T.; Grzeschik, K. H.;
Lothe, R.; Tomter, H.; Olaisen, B.: The Kidd (JK) blood group locus
assigned to chromosome 18 by close linkage to a DNA-RFLP. Hum. Genet. 77:
205-209, 1987.

5. Hodge, S. E.; Anderson, C. E.; Neiswanger, K.; Field, L. L.; Spence,
M. A.; Sparkes, R. S.; Sparkes, M. C.; Crist, M.; Terasaki, P. I.;
Rimoin, D. L.; Rotter, J. I.: Close genetic linkage between diabetes
mellitus and Kidd blood group. Lancet II: 893-895, 1981.

6. Hulten, M.; Lindsten, J.; Pen-Ming, L. M.; Fraccaro, M.; Mannini,
A.; Trepolo, L.; Robson, E. B.; Heiken, A.; Tellingen, K. G.: Possible
localization of the genes for the Kidd blood group on an autosome
involved in a reciprocal translocation. Nature 211: 1067-1068, 1968.

7. Keats, B. J. B.; Morton, N. E.; Rao, D. C.: Likely linkage: InV
with Jk. Hum. Genet. 39: 157-159, 1977.

8. Keats, B. J. B.; Morton, N. E.; Rao, D. C.: Possible linkages
(lod score over 1.5) and a tentative map of the Jk-Km linkage group. Cytogenet.
Cell Genet. 22: 304-308, 1978.

9. Leppert, M.; Ferrell, R.; Kamboh, M. I.; Beasley, J.; O'Connell,
P.; Lathrop, M.; Lalouel, J.-M.; White, R.: Linkage of the polymorphic
protein markers F13B, C1S, C1R, and blood group antigen Kidd in CEPH
reference families. (Abstract) Cytogenet. Cell Genet. 46: 647, 1987.

10. Mace, M. A.; Robson, E. B.: Linkage data on ACP-1 and MNSS. Cytogenet.
Cell Genet. 13: 123-125, 1974.

11. Mohr, J.; Eiberg, H.: Colton blood groups: indication of linkage
with the Kidd (Jk) system as support for assignment to chromosome
7. Clin. Genet. 11: 372-374, 1977.

12. Olives, B.; Mattei, M.-G.; Huet, M.; Neau, P.; Martial, S.; Cartron,
J.-P.; Bailly, P.: Kidd blood group and urea transport function of
human erythrocytes are carried by the same protein. J. Biol. Chem. 270:
15607-15610, 1995.

13. Olives, B.; Neau, P.; Bailly, P.; Hediger, M. A.; Rousselet, G.;
Cartron, J.-P.; Ripoche, P.: Cloning and functional expression of
a urea transporter from human bone marrow cells. J. Biol. Chem. 269:
31649-31652, 1994.

14. Pausch, V.; Mayr, W. R.: Analysis of the linkage JK-IGK, MNS-GC
and of two other possible linkage groups. Hum. Hered. 37: 260-262,
1987.

15. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

16. Sherman, S. L.; Simpson, S. P.: Evidence for the location of
JK and CO on chromosome 2 based on family studies. (Abstract) Cytogenet.
Cell Genet. 40: 743, 1985.

17. Shokeir, M. H. K.; Ying, K. L.; Pabello, P.: Deletion of the
long arm of chromosome no. 7: tentative assignment of the Kidd (Jk)
locus. Clin. Genet. 4: 360-368, 1973.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 01/06/1997
terry: 12/16/1996
terry: 5/16/1996
terry: 10/31/1995
mark: 9/10/1995
warfield: 4/7/1994
mimadm: 2/11/1994
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
111100
*FIELD* TI
*111100 FUCOSYLTRANSFERASE-3; FUT3
BLOOD GROUP--LEWIS SYSTEM; Le; Les
*FIELD* TX
The Lewis system involves genetically variable antigens in the body
fluids and only secondarily are the antigens absorbed to red cells.
Grollman et al. (1969) showed that Lewis-negative women lack a specific
fucosyltransferase which is present in the milk of Lewis-positive women.
The enzyme is apparently required for synthesis of the structural
determinants of both Lewis (a) and Lewis (b) specificity. The same
enzyme is involved in the synthesis of milk oligosaccharides, because 2
oligosaccharides containing the relevant linkage were absent from the
milk of Lewis-negative women. Grubb (1953) provided the ingenious
interpretation of the interactions between the Les locus determining
presence/absence of Lewis substance in the saliva and on red cells and
the Se locus (182100) determining secretion of ABH blood group
substances in the saliva and Le(a) or Le(b) expression in red cells.

Weitkamp et al. (1974) presented evidence that the Lewis blood group
locus and the C3 locus are linked. The assignment of C3 to chromosome 19
(see 120700) indicated that Lewis blood group is also on that
chromosome. Gedde-Dahl et al. (1984) used Les as the symbol for this
locus.

Sheinfeld et al. (1989) found an increased frequency of Lewis blood
group nonsecretor--Le(a+b-)--and of recessive Le(a-b-) phenotypes among
women with recurrent urinary tract infections. No significant difference
was found in the distribution of ABO or P phenotypes between a group of
49 white women with histories of recurrent urinary tract infections and
49 healthy control women without recurrent urinary tract infections.

The last step in the biosynthesis of Lewis antigen, the addition of a
fucose to precursor polysaccharides, can be catalyzed by at least 3
types of alpha-3-fucosyltransferases: FUT1, or Bombay (211100), FUT2, or
secretor (182100), and FUT3, or Lewis, and FUT4, which is the myeloid
form of alpha-3-fucosyltransferase (104230).

Nishihara et al. (1994) found that all le alleles had a T59G mutation,
whereas none of the Le alleles did. The le alleles were divided into 2
subtypes, le1, having a G508A mutation, and le2, having a T1067A
mutation. The T1067A mutation reduced the enzyme activity less than 10%,
whereas the G508A mutation in the catalytic domain made the enzyme
completely inactive. The frequency of Le, le1, and le2 in the Japanese
population was found to be 66%, 30%, and 4%, respectively.

Yazawa et al. (1996) demonstrated that genotyping of Le genes by
PCR-RFLP methods could be used for determining Lewis blood type on human
hairs and blood stains, as well as in paternity testing.

From linkage studies using microsatellite markers, Reguigne-Arnould et
al. (1995) concluded that FUT3 is in a cluster of loci with FUT6
(136836) and FUT5 (136835) on 19p13.3. The following gene order was
deduced: 19pter--D19S216--FUT6--FUT3--FUT5--D19S567--cen.

In transfusion medicine, it has been found that some individuals who
type as Lewis-positive on erythrocytes can change their erythrocyte
phenotype to Lewis-negative during diseases or during pregnancy. Orntoft
et al. (1996) noted that these patients have been named non-genuine
Lewis-negative individuals as they have alpha-1-4 fucosyltransferase
activity in saliva. Due to this phenomenon, the Lewis-negative phenotype
is more common among cancer patients (approximately 20%) than among
healthy individuals (approximately 8%). Orntoft et al. (1996) examined
the mutational spectrum of the Lewis gene in Denmark and found 6
different mutations. Five, 59T-G (L20R; 111100.0001), 202T-C (W68R),
314C-T (T105M), 508G-A (G170S; 111100.0001), and 1067T-A (I356K), were
frequent, and 1, 445C-A (L146M), was only detected in 1 of 40
individuals. The authors demonstrated that the nucleotide 202 and 314
mutations were colocated on the same allele. COS7 cells transfected with
an allele having the 202/314 mutations lacked enzyme activity.
Lewis-negative patients, whose erythrocytes converted from
Lewis-positive to Lewis-negative during their disease, showed FUT3
heterozygosity significantly more often than did others (p less than
0.05).

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
Le(-) PHENOTYPE
FUT3, LEU20ARG AND GLY170SER
Koda et al. (1993) examined the expression of Lewis fucosyltransferase
mRNA in gastric mucosa from 2 Lewis-positive and 2 Lewis-negative
individuals. Northern blot analysis demonstrated that levels of mRNA
were similar in the 2 different types. In the Le(-) gastric mucosa, the
sequence of cDNA showed 2 single-base substitutions: G for T at position
59 and A for G at position 508 from the A of the initiation codon. These
substitutions predicted 2 amino acid changes: arg for leu at position 20
and ser for gly at position 170 from the N-terminus. To determine
whether either or both of these base substitutions was responsible for
the Le(-) gene, Koda et al. (1993) constructed chimera cDNAs and
expressed them in COS cells. Those COS cells transfected with a chimera
cDNA containing a mutation of the nucleotide 508 did not express Lewis
antigen, whereas those cells transfected with a chimeric cDNA containing
the nucleotide 59 mutation expressed Lewis antigen, indicating that a
single-base change from G to A at position 508 is responsible for the
Le(-) phenotype. The G-to-A transition at position 508 created a new
site for the restriction enzyme PvuII. One of the Le(-) individuals were
shown to be homozygous for the PvuII site; the other Le(-) individual
was heterozygous for the site, suggesting the presence of other Le(-)
allele(s).

*FIELD* SA
Koprowski et al. (1982)
*FIELD* RF
1. Gedde-Dahl, T., Jr.; Olaisen, B.; Teisberg, P.; Wilhelmy, M. C.;
Mevag, B.; Helland, R.: The locus for apolipoprotein E (apoE) is
close to the Lutheran (Lu) blood group locus on chromosome 19. Hum.
Genet. 67: 178-182, 1984.

2. Grollman, E. F.; Kobata, A.; Ginsburg, V.: An enzymatic basis
for Lewis blood types in man. J. Clin. Invest. 48: 1489-1494, 1969.

3. Grubb, R.: Zur Genetik des Lewis-Systems. Naturwissenschaften 21:
560-561, 1953.

4. Koda, Y.; Kimura, H.; Mekada, E.: Analysis of Lewis fucosyltransferase
genes from the human gastric mucosa of Lewis-positive and -negative
individuals. Blood 82: 2915-2919, 1993.

5. Koprowski, H.; Blaszczyk, M.; Steplewski, Z.; Brockhaus, M.; Magnani,
J.; Ginsburg, V.: Lewis blood-type may affect the incidence of gastrointestinal
cancer. Lancet I: 1332-1333, 1982.

6. Nishihara, S.; Narimatsu, H.; Iwasaki, H.; Yazawa, S.; Akamatsu,
S.; Ando, T.; Seno, T.; Narimatsu, I.: Molecular genetic analysis
of the human Lewis histo-blood group system. J. Biol. Chem. 269:
29271-29278, 1994.

7. Orntoft, T. F.; Vestergaard, E. M.; Holmes, E.; Jakobsen, J. S.;
Grunnet, N.; Mortensen, M.; Johnson, P.; Bross, P.; Gregersen, N.;
Skorstengaard, K.; Jensen, U. B.; Bolund, L.; Wolf, H.: Influence
of Lewis alpha-1-3/4-L-fucosyltransferase (FUT3) gene mutations on
enzyme activity, erythrocyte phenotyping, and circulating tumor marker
sialyl-Lewis a levels. J. Biol. Chem. 271: 32260-32268, 1996.

8. Reguigne-Arnould, I.; Couillin, P.; Mollicone, R.; Faure, S.; Fletcher,
A.; Kelly, R. J.; Lowe, J. B.; Oriol, R.: Relative positions of two
clusters of human alpha-L-fucosyltransferases in 19q (FUT1-FUT2) and
19p (FUT6-FUT3-FUT5) within the microsatellite genetic map of chromosome
19. Cytogenet. Cell Genet. 71: 158-162, 1995.

9. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

10. Sheinfeld, J.; Schaeffer, A. J.; Cordon-Cardo, C.; Rogatko, A.;
Fair, W. R.: Association of the Lewis blood-group phenotype with
recurrent urinary tract infections in women. New Eng. J. Med. 320:
773-777, 1989.

11. Weitkamp, L. R.; Johnston, E.; Guttormsen, S. A.: Probable genetic
linkage between the loci for the Lewis blood group and complement
C3. Cytogenet. Cell Genet. 13: 183-184, 1974.

12. Yazawa, S.; Oh-Kawara, H.; Nakajima, T.; Hosomi, O.; Akamatsu,
S.; Kishi, K.: Histo-blood group Lewis genotyping from human hairs
and blood. Jpn. J. Hum. Genet. 41: 177-188, 1996.

*FIELD* CN
Victor A. McKusick - updated: 2/6/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/10/1997
terry: 2/6/1997
terry: 2/5/1997
terry: 5/7/1996
terry: 5/2/1996
mark: 11/13/1995
terry: 1/26/1995
carol: 1/9/1995
mimadm: 2/11/1994
carol: 12/20/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
111130
*FIELD* TI
*111130 BLOOD GROUP--LKE; LKE
*FIELD* TX
Whitehouse et al. (1988) studied the family of the fourth human example
of anti-LKE (originally called Luke) and excluded close linkage to MNS,
Rh, HLA, PI, Gm, and C6. They also showed that LKE is genetically
independent of P1, K, Xg, Au, Se, and C3.

*FIELD* RF
1. Whitehouse, D. B.; Attwood, J.; Green, C.; Bruce, M.; McQuade,
M.; Tippett, P.: Inheritance and linkage data for an unusual combination
of genes (at the LKE, PI and C6 loci) in a single large sibship. Ann.
Hum. Genet. 52: 197-201, 1988.

*FIELD* CD
Victor A. McKusick: 10/18/1988

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/18/1988

*RECORD*
*FIELD* NO
111150
*FIELD* TI
*111150 BLOOD GROUP--LUTHERAN INHIBITOR
DOMINANT LU (a-b-) PHENOTYPE; INLU
*FIELD* TX
Race and Sanger (1975) described a dominant, independently segregating
suppressor affecting the expression of Lutheran genes. The Lutheran
inhibitor, symbolized In(Lu), is responsible for Lutheran (a-b-). It
also influences the Auberger (111200), I (110800), and P (111400)
systems. (The Auberger system indeed belongs to the Lutheran system
(Daniels et al., 1991).) The Lu(a-b-) phenotype in the Lutheran blood
group system has 2 genotypic forms. One form is recessive and one
dominant. The 2 forms can be differentiated both by the pedigree and
serologically. Gibson (1976) described 2 families and confirmed the fact
that In(Lu) also inhibits the full expression of the P1 antigen. See
247420 for the recessive Lu(a-b-) phenotype. It might be speculated
whether this is a situation like 'lac' repressor in E. coli. The
regulator of TAT (314350) is another possible example. Shaw et al.
(1984) found that the dominant inhibitor of Lutheran antigens, In(Lu),
is the usual cause of the Lutheran null phenotype in southeast England
where they studied the families of 41 probands and found no proven case
of the recessive background, LuLu. The only suggestion of linkage was
with Rh (maximum lod = 1.169 in males at theta 0.1). Previously, INLU
and CD44 (or MDU3; 107269) were thought to be the same. Telen (1992),
however, knew of no evidence for this.

In South Wales, Rowe et al. (1992) found a frequency of 0.0002 for the
Lu(a-b-) phenotype. They investigated the families of 11 Lu-null
probands to determine which of the 3 known genetic backgrounds,
dominant, recessive, or X-linked recessive, was responsible for their
Lu-null phenotype. In 10 of the 11 families, the Lu-null phenotype was
caused by the dominant suppressor gene INLU. The family data permitted
them to demonstrate for the first time independence of the INLU and LU
genes. They also demonstrated suppression of P1 (111410) by the INLU
gene. Close linkage of INLU and HLA was excluded.

*FIELD* SA
Contreras and Tippett (1974); Taliano et al. (1973)
*FIELD* RF
1. Contreras, M.; Tippett, P.: The Lu(a-b-) syndrome and an apparent
upset of P1 inheritance. Vox Sang. 27: 369-371, 1974.

2. Daniels, G. L.; Le Pennec, P. Y.; Rouger, P.; Salmon, C.; Tippett,
P.: The red cell antigens Au(a) and Au(b) belong to the Lutheran
system. Vox Sang. 60: 191-192, 1991.

3. Gibson, T.: Two kindred with the rare dominant inhibitor of the
Lutheran and P1 red cell antigens. Hum. Hered. 26: 171-174, 1976.

4. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
Sci. Publ. (pub.)  (6th ed.): 1975. Pp. 267-272.

5. Rowe, G. P.; Gale, S. A.; Daniels, G. L.; Green, C. A.; Tippett,
P.: A study on Lu-null families in South Wales. Ann. Hum. Genet. 56:
267-272, 1992.

6. Shaw, M. A.; Leak, M. R.; Daniels, G. L.; Tippett, P.: The rare
Lutheran blood group phenotype Lu(a-b-): a genetic study. Ann. Hum.
Genet. 48: 229-237, 1984.

7. Taliano, V.; Guevin, R.-M.; Tippett, P.: The genetics of a dominant
inhibitor of the Lutheran antigens. Vox Sang. 24: 42-47, 1973.

8. Telen, M. J.: Personal Communication. Durham, N. C.  12/30/1992.

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
davew: 8/18/1994
mimadm: 4/19/1994
warfield: 4/7/1994
carol: 1/13/1993
carol: 12/18/1992
supermim: 3/19/1992

*RECORD*
*FIELD* NO
111200
*FIELD* TI
*111200 BLOOD GROUP--LUTHERAN SYSTEM; Lu
AUBERGER SYSTEM; Au, INCLUDED;;
B-CELL ADHESION MOLECULE; BCAM, INCLUDED
*FIELD* TX
Lutheran and Secretor (Se; see FUT2, 182100) are linked (review by Cook,
1965). Indeed this was the first autosomal linkage demonstrated in man,
by Dr. Jan Mohr (1951) in Copenhagen, using Penrose's sib-pair method.
See 111150 for description of a dominant Lutheran inhibitor comparable
to Bombay (211100) and the ABO blood groups. Myotonic dystrophy (160900)
is linked to Lutheran and Secretor, and Lewis (111100) and Bombay are in
the same linkage group with C3 (120700) on chromosome 19. Gedde-Dahl et
al. (1984) found linkage of Se and APOE (107741)--peak lod score 3.3 at
recombination fraction 0.08 in males and 1.36 at 0.22 in females, and
linkage of APOE and Lu with lod score 4.52 at zero recombination in
sexes combined. C3-APOE linkage gave lod score 4.0 at theta 0.18 in
males but 0.04 at theta 0.45 in females. Triple heterozygote families
confirmed that APOE is on the Se side and on the Lu side of C3. A
summarizing map was given (Fig. 3). Lewis et al. (1988) demonstrated
that APOC2 (207750), Lu, and Se constitute a tightly linked gene cluster
and argued that Lu and Se are on the long arm of chromosome 19.

Although the alleles of the Auberger system have a frequency that would
make it useful in linkage studies, the unavailability of antiserum
excluded it from the list of linkage markers. Whitehouse et al. (1988)
showed that the Au blood group is genetically independent of the locus
for the Kell blood group (110900) and the loci for C3, C6, Gc, HLA, PI,
and Gm groups. Daniels et al. (1991) showed, however, that the Au(a) and
Au(b) antigens belong to the Lutheran system. Although the Au(a) antigen
was found by Salmon et al. (1961), the antithetical antigen, Au(b), was
not found until 1989 (Frandson et al., 1989). Evidence that the Auberger
antigens are in the Lutheran system comes from the fact that they are
located on the glycoproteins that carry Lutheran determinants and that
they show the same linkage relationships to markers on chromosome 19
(Zelinski et al., 1990).

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

Parsons et al. (1995) isolated glycoproteins expressing the Lutheran
blood group antigens from human erythrocyte membranes and from human
fetal liver. Amino acid sequence analysis allowed the design of
redundant oligonucleotides that were used to generate a 459-bp
sequence-specific probe by PCR. They then isolated a cDNA clone of 2,400
bp from a human placental lambda-gt11 library. From the sequence of the
cDNA clone, the predicted mature protein was a type I membrane protein
of 597 amino acids with 5 potential N-glycosylation sites. There were 5
disulfide-bonded, extracellular, immunoglobulin superfamily domains (2
variable-region set and 3 constant-region set), a single hydrophobic,
membrane-spanning domain, and a cytoplasmic domain of 59 residues. The
overall structure was similar to that of the human tumor marker MUC18
(155735) and the chicken neural adhesion molecule SC1. The extracellular
domains and cytoplasmic domain contained consensus motifs with a binding
of integrin and SRC homology 3 domains, respectively, suggesting
possible receptor and signal-transduction functions. Parsons et al.
(1995) stated that immunostaining of human tissues demonstrated a wide
distribution and provided evidence that the glycoprotein is under
developmental control in liver and may also be regulated during
differentiation in other tissues.

Rahuel et al. (1996) reported that 2 previously described cDNA clones,
the Lutheran cDNA clone described by Parsons et al. (1995) and the BCAM
cDNA clone described by Campbell et al. (1994), represent alternatively
spliced transcripts of a unique gene on chromosome 19q13.2-q13.3. Rahuel
et al. (1996) demonstrated that the structure and tissue distribution of
these mRNA spliceosomes are consistent with immunocharacterization of 2
active glycoproteins, Lu and B-Cam, in various cells. Rahuel et al.
(1996) noted that the BCAM antigen was first identified by monoclonal
antibodies raised against human tumor cells and was shown to be
overexpressed in ovarian carcinomas in vivo and upregulated following
malignant transformation in certain cell types.

*FIELD* SA
Lewis et al. (1977); Lewis et al. (1978)
*FIELD* RF
1. Campbell, I. G.; Foulkes, W. D.; Senger, G.; Trowsdale, J.; Garin-Chesa,
P.; Rettig, W. J.: Molecular cloning of the B-CAM cell surface glycoprotein
of epithelial cancers: a novel member of the immunoglobulin superfamily. Cancer
Res. 54: 5761-5765, 1994.

2. Cook, P. J. L.: The Lutheran-secretor recombination fraction in
man: a possible sex difference. Ann. Hum. Genet. 28: 393-401, 1965.

3. Daniels, G. L.; Le Pennec, P. Y.; Rouger, P.; Salmon, C.; Tippett,
P.: The red cell antigens Au(a) and Au(b) belong to the Lutheran
system. Vox Sang. 60: 191-192, 1991.

4. Frandson, S.; Atkins, C. J.; Moulds, M.; Poole, J.; Crawford, M.
N.; Tippett, P.: Anti-Au(b): the antithetical antibody to anti-Au(a). Vox
Sang. 56: 54-56, 1989.

5. Gedde-Dahl, T., Jr.; Olaisen, B.; Teisberg, P.; Wilhelmy, M. C.;
Mevag, B.; Helland, R.: The locus for apolipoprotein E (apoE) is
close to the Lutheran (Lu) blood group locus on chromosome 19. Hum.
Genet. 67: 178-182, 1984.

6. Lewis, M.; Kaita, H.; Chown, B.; Giblett, E. R.; Anderson, J.;
Cote, G. B.: The Lutheran and Secretor loci: genetic linkage analysis. Am.
J. Hum. Genet. 29: 101-106, 1977.

7. Lewis, M.; Kaita, H.; Coghlan, G.; Philipps, S.; Belcher, E.; McAlpine,
P. J.; Coopland, G. R.; Woods, R. A.: The chromosome 19 linkage group
LDLR, C3, LW, APOC2, LU, SE in man. Ann. Hum. Genet. 52: 137-144,
1988.

8. Lewis, M.; Kaita, H.; Giblett, E. R.; Anderson, J. E.: Lods for
Lu:Se and other loci. Cytogenet. Cell Genet. 22: 627-628, 1978.

9. Mohr, J.: Search for linkage between Lutheran blood group and
other hereditary characters. Acta Path. Microbiol. Scand. 28: 207-210,
1951.

10. Parsons, S. F.; Mallinson, G.; Holmes, C. H.; Houlihan, J. M.;
Simpson, K. L.; Mawby, W. J.; Spurr, N. K.; Warne, D.; Barclay, A.
N.; Anstee, D. J.: The Lutheran blood group glycoprotein, another
member of the immunoglobulin superfamily, is widely expressed in human
tissues and is developmentally regulated in human liver. Proc. Nat.
Acad. Sci. 92: 5496-5500, 1995.

11. Parsons, S. F.; Mallinson, G.; Holmes, C. H.; Houlihan, J. M.;
Simpson, K. L.; Mawby, W. J.; Spurr, N. K.; Warne, D.; Barclay, A.
N.; Anstee, D. J.: The Lutheran blood group glycoprotein, another
member of the immunoglobulin superfamily, is widely expressed in human
tissues and is developmentally regulated in human liver. Proc. Nat.
Acad. Sci. 92: 5496-5500, 1995.

12. Rahuel, C.; Le Van Kim, C.; Mattei, M. G.; Cartron, J. P.; Colin,
Y.: A unique gene encodes spliceforms of the B-cell adhesion molecule
cell surface glycoprotein of epithelial cancer and of the Lutheran
blood group glycoprotein. Blood 88: 1865-1872, 1996.

13. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

14. Salmon, C.; Salmon, D.; Liberge, G.; Andre, R.; Tippett, P.; Sanger,
R.: Un nouvel antigene de groupe sanguin erythrocytaire present chez
80% des sujets de race blanche. Nouv. Rev. Franc. Hemat. 1: 649-661,
1961.

15. Whitehouse, D. B.; Attwood, J.; Green, C.; Bruce, M.; McQuade,
M.; Tippett, P.: Inheritance and linkage data for an unusual combination
of genes (at the LKE, PI and C6 loci) in a single large sibship. Ann.
Hum. Genet. 52: 197-201, 1988.

16. Zelinski, T.; Kaita, H.; Johnson, K.; Moulds, M.: Genetic evidence
that the gene controlling Au(b) is located on chromosome 19. Vox
Sang. 58: 126-128, 1990.

*FIELD* CN
Moyra Smith - updated: 12/31/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jenny: 01/07/1997
mark: 12/31/1996
mark: 6/29/1995
davew: 6/9/1994
warfield: 4/6/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 10/23/1991

*RECORD*
*FIELD* NO
111250
*FIELD* TI
*111250 LANDSTEINER-WIENER BLOOD GROUP; LW
BLOOD GROUP--LW
*FIELD* TX
LW stands for Landsteiner and Wiener, the researchers who first
discovered the LW blood group with antibody raised in guinea pigs
injected with the cells of rhesus monkeys. It was originally thought to
be identical to the anti-D first described in a woman with an
erythroblastotic infant studied by Levine and Stetson (1939). Hence, the
name of the Rh system. It was later found to be distinct; LW is the true
Rhesus blood group, but this designation had been preempted. Levine
suggested the designation LW.

Sistonen (1984) showed that the LW locus is closely linked to C3
(120700) and Lutheran (111200) on chromosome 19. The maximum lod score
was 3.61 at theta = 0.00 for LW:C3 and 3.67 at theta = 0.05 for LW:Lu.
The data suggested that the Lewis blood group locus is situated outside
the C3-LW region. Using a C3 DNA probe, Lewis et al. (1987) found no
recombinants between LW and C3 (maximum lod score = 4.216 at theta =
0.00). No recombinants were found in 16 female meioses. Combined with
the data of Sistonen (1984), the recombination fraction between LW and
C3 was estimated to be 0.09 in females (maximum lod score = 3.773).
Lewis et al. (1988) established close linkage between LW and LDLR
(143890); maximum lod = 8.43 at theta = 0.00. They concluded that LDLR,
C3, and LW constitute a tightly linked gene cluster. Their findings
supported a 19p13.2-cen position for LW.

The LW blood group antigens reside on a 42-kD erythrocyte membrane
glycoprotein. Bailly et al. (1994) isolated 2 forms of LW cDNA. The
predicted LW protein was found to exhibit sequence similarities, with
approximately 30% identity, with intercellular adhesion molecules ICAM1
(147840), ICAM2 (146630), and ICAM3 (146631), which are the
counterreceptors for the lymphocyte function-associated antigen LFA1
(116920). The extracellular domain of LW consists, like that of ICAM2,
of 2 immunoglobulin-like domains, and the critical residues involved in
the binding of LFA1 to ICAMs were partially conserved in LW. Hermand et
al. (1996) characterized the LW gene, which is organized into 3 exons
spanning approximately 2.65 kb of DNA.

In an individual with the LW(a- b-) phenotype, deficient for LW antigens
but carrying a normal Rh phenotype, Hermand et al. (1996) found a 10-bp
deletion which generated a premature stop codon and encoded a truncated
protein without the transmembrane and cytoplasmic domains. Heterogeneity
was indicated by the fact that no detectable abnormality of the LW gene
or transcript could be detected in another LW(a- b-) individual.

*FIELD* AV
.0001
LW(a)/LW(b) BLOOD GROUP POLYMORPHISM
LW, GLN70ARG
Hermand et al. (1995) demonstrated that the molecular basis for the
LW(a)/LW(b) polymorphism is a single basepair mutation (A308G) that
correlates with a PvuII restriction site and results in a gln70-to-arg
amino acid substitution. COS-7 cells transfected with LW(a) or LW(b)
cDNAs reacted with human anti-LW(a) and anti-LW(b) sera, respectively,
as well as with a murine monoclonal anti-LW(ab) antibody, as shown by
flow cytometry analysis. In addition, the LW locus was assigned to
19p13.3 by isotopic in situ hybridization. Study by Southern blot
analysis indicated that the LW locus is composed of a single gene that
is not grossly rearranged in the rare LW(a-b-) individuals or in the
Rh(null) individuals deficient for LW antigens. RFLP analysis using
PvuII indicated that these variants were homozygous for a phenotypically
silent LW(a) allele in all cases.

*FIELD* SA
Race and Sanger (1975); Sistonen and Virtaranta-Knowles (1985)
*FIELD* RF
1. Bailly, P.; Hermand, P.; Callebaut, I.; Sonneborn, H. H.; Khamlichi,
S.; Mornon, J.-P.; Cartron, J.-P.: The LW blood group glycoprotein
in homologous to intercellular adhesion molecules. Proc. Nat. Acad.
Sci. 91: 5306-5310, 1994.

2. Hermand, P.; Gane, P.; Mattei, M. G.; Sistonen, P.; Cartron, J.-P.;
Bailly, P.: Molecular basis and expression of the LW(a)/LW(b) blood
group polymorphism. Blood 86: 1590-1594, 1995.

3. Hermand, P.; Le Pennec, P. Y.; Rouger, P.; Cartron, J.-P.; Bailly,
P.: Characterization of the gene encoding the human LW blood group
protein in LW(+) and LW(-) phenotypes. Blood 87: 2962-2967, 1996.

4. Levine, P.; Stetson, R. E.: An unusual case of intragroup agglutination.
J.A.M.A. 113: 126-127, 1939.

5. Lewis, M.; Kaita, H.; Coghlan, G.; Philipps, S.; Belcher, E.; McAlpine,
P. J.; Coopland, G. R.; Woods, R. A.: The chromosome 19 linkage group
LDLR, C3, LW, APOC2, LU, SE in man. Ann. Hum. Genet. 52: 137-144,
1988.

6. Lewis, M.; Kaita, H.; Philipps, S.; Coghlan, G.; McAlpine, P. J.;
Coopland, G. R.; Woods, R. A.: The LW:C3 recombination fraction in
female meioses. Ann. Hum. Genet. 51: 201-203, 1987.

7. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
(pub.)  (6th ed.): 1975. Pp. 228-232.

8. Sistonen, P.: Linkage of the LW blood group locus with the complement
C3 and Lutheran blood group loci. Ann. Hum. Genet. 48: 239-242,
1984.

9. Sistonen, P.; Virtaranta-Knowles, K.: Evidence for linkage of
LW blood group locus with the complement C3, and Le, Lu and Se loci
with assignment to chromosome 19.    (Abstract) Cytogenet. Cell Genet. 40:
747, 1985.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 05/10/1996
terry: 5/10/1996
terry: 5/2/1996
mark: 2/13/1996
mark: 10/16/1995
davew: 8/18/1994
jason: 6/22/1994
supermim: 3/16/1992
carol: 2/26/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
111300
*FIELD* TI
*111300 BLOOD GROUP--MN LOCUS; MN
GLYCOPHORIN A, INCLUDED;;
GPA, INCLUDED;;
GYPA, INCLUDED
*FIELD* TX
On the basis of studies in the family of a child with a translocation
chromosome, German et al. (1968) suggested that the MN locus is either
in the middle of chromosome 2 or near the distal end of the long arm of
chromosome 4. Using 'banding techniques,' German and Chaganti (1973)
restudied the translocation they reported in 1968 and concluded that MN
can be tentatively assigned to the area of band q14 in the proximal
portion of the long arm of chromosome 2. Weitkamp et al. (1972)
presented data suggesting that the MN locus and the beta hemoglobin
locus (141900) are linked. (This has, of course, been disproved.)
Barbosa et al. (1975) excluded a recombination fraction of less than
0.30 for MN and Hb beta. The results supported a lower recombination
fraction for males. Linkage with the Alzheimer locus (104300) and with
colonic polyposis (175100) has been suspected. Recombinational data
suggested that the MN and acid phosphatase (ACP1; 171500) loci are far
apart (Weitkamp et al., 1975). Cook et al. (1978) excluded MNSs from
chromosome 9 by exclusion mapping that incorporated data both from
families with chromosome markers and from linkage studies with firmly
assigned markers. MNSs was subsequently assigned to chromosome 4. In a
further study of the propositus of the 2q;4q translocation family,
German et al. (1979) showed by banding that the breaks had occurred at
2q14 and 4q29 and that a minute segment had been lost at the site of
break. Whether the loss was from chromosome 2 or 4 was not certain
because both have several short bands at these sites and only one band
was missing in the proband. The proband lacked blood type 's' (GPB;
111740) which he should have received from his 'ss' father, had signs of
a modified red cell membrane, and had developmental abnormalities. Since
the abnormalities of phenotype appeared at the same time as the
chromosomal abnormality, German et al. (1979) suggested that deletion
was the basis of all the changes. Since Weitkamp (1978) reported
observations indicating strongly that MNSs is not near 2q14, German et
al. (1979) concluded that it must be in a band near 4q29. Cook et al.
(1980) favored 4q28 over 4q31. For males, Bias and Meyers (1979) found a
maximal lod score of 3.99 at theta 0.18 for linkage of Stoltzfus
(111800) and MNS. Acid phosphatase and Kidd both gave lods of 0.32 with
Stoltzfus at a male-theta of 0.20. Linkage of Gc and MNSs at
recombination frequencies of less than 25% in males and 30% in females
was excluded by Weitkamp (1978). For MN vs Gc, Falk et al. (1979) found
a male lod score of 3.75 at a recombination fraction of 0.30. In females
the maximal lod score was 0.34 at a recombination fraction of 0.42. From
analysis of MNSs blood groups in families with chromosome 4
rearrangements, both deletion analysis and family linkage study, Cook et
al. (1981) concluded that the MNSs 'locus' lies in the region 4q28-q31.

Blumenfeld and Adamany (1978) found that the MM blood group polypeptide
differs from the NN polypeptide in two amino acids, these being serine
and glycine in MM and leucine and glutamic acid in NN. The MN individual
shows all four amino acids. The two major sialoglycoproteins of the
human red cell membrane, alpha and delta (glycophorins A and B), carry
the MNSs antigenic specificities. They have identical amino acid
sequences for the first 26 residues from the amino terminus. Alpha
expresses M or N blood group activity; delta carries only blood group N
activity. Furthermore, the asparagine at position 26 of the alpha
carries an oligosaccharide chain which is absent from the same position
of delta. The two sialoglycoproteins differ in their remaining amino
acid sequence and delta expresses Ss activity. Using antibodies directed
against different structural regions of the major sialoglycoprotein
alpha, Mawby et al. (1981) confirmed that two variant forms
(Miltenberger class V and Ph) represented hybrid sialoglycoprotein
molecules, which arose from anomalous crossover events between the genes
coding for alpha and delta. The genes appear to be closely linked, in
the order alpha-delta (5-prime to 3-prime). Thus the family data on
close linkage are confirmed. The sequence may be MN--Ss--Gc (Gedde-Dahl
and Olaisen, 1981).

One of the longest genetic intervals measured in man in the pre-RFLP era
was that between GC and MN with a lod score, in males, of 3.79 at a
recombination fraction of 0.32 (Falk, 1984). In a linkage analysis of
146 informative families for MN and Ss, Spence et al. (1984) found 7
recombinant children out of 467, including 1 confirmed recombinant
(retested and HLA-compatible) and 6 not verified. The 95% confidence
interval of the estimate of recombination was 0.0033-0.1167. By in situ
hybridization using a glycophorin A cDNA probe, Mattei et al. (1987)
mapped the gene to 4q28-q31, thus confirming the mapping by other
methods. By in situ hybridization and RFLP studies in a case of balanced
de novo translocation between chromosomes 2 and 4, Divelbiss et al.
(1989) concluded that the fibrinogen gene cluster (134830) lies proximal
to the GYPA/GYPB loci and that all of these loci lie in the 4q28 band.
In a malformed female infant with de novo interstitial deletion of 4q,
Wakui et al. (1991) found that the MN locus was intact. On the basis of
this finding and previous mapping data, they concluded that the MN locus
is in the 4q28.2-q31.1 segment.

Onda and Fukuda (1995) isolated several P1 plasmid clones with which
they characterized the organization of the glycophorin A (GPA), B (GPB),
and E (GPE) gene cluster which spans about 330 kb of chromosome 4q31.
For each gene, the first intron varies in size from 25 to 29 kb, while
the intergenic interval is approximately 80 kb. The authors proposed
that the GPA-GPB-GPE cluster arose by 2 successive duplications and a
number of subsequent events, including a gene conversion between the
exon 2 region of GPA and GPE.

Red cells with the rare En(a-) variant are resistant to falciparum
malaria (Pasvol et al., 1982). Such cells lack glycophorin A, the major
red cell sialoglycoprotein (Siebert and Fukuda, 1986). The rare U(-)
variant of the Ss system, which lacks the other major sialoglycoprotein,
glycophorin B, is relatively resistant to invasion. Wr(b)-negative cells
are also resistant to invasion by P. falciparum despite the fact that
they have normal amounts of glycophorins A and B on their surface. All
of these observations, as well as experiments using antibodies to
glycophorins and certain sugars, particularly N-acetylglucosamine, have
led to a tentative model of the role of glycophorin in the red cell
invasion of P. falciparum (Pasvol and Wilson, 1982). Langlois et al.
(1986) studied the frequency of red cells with loss of expression at the
glycophorin A locus (GPA). Glycophorin A is present in about 500,000
copies per red cell. The 2 allelic forms of GPA, blood group M and blood
group N, are identical except for 2 amino acid substitutions at
positions 1 and 5 from the amino terminus (Prohaska et al., 1986). Using
monoclonal antibodies, Langlois et al. (1986) identified expression loss
mutants. They found a frequency of about 1 in 100,000 cells in normals
and a significant increase in the variant cells in cancer patients after
exposure to mutagenic chemotherapy drugs. Langlois et al. (1987)
demonstrated a linear relationship between frequency of mutations at the
glycophorin A locus and radiation exposure in atomic bomb survivors.
Grant and Bigbee (1994) discussed the use of the GPA assay to evaluate
the creation of somatic mutations by cancer chemotherapy.

Rahuel et al. (1988) characterized 2 cDNA clones encoding glycophorin A
from human fetal cDNA libraries. They used these clones to locate the
structural gene to 4q28-q32. They concluded further, by Southern blot
analysis of genomic DNA from normal En(a+) and rare En(a-) persons, that
the glycophorin A gene has a complex organization and is largely deleted
in persons of the En(a-) phenotype (Finnish type), who lack glycophorin
A on their red cells. Rahuel et al. (1988) concluded that the Finnish
variant is homozygous for a complete deletion of the glycophorin A gene
without any detectable abnormality of the genes encoding glycophorins B
or C. In the genome of the UK variant of En(a-), Rahuel et al. (1988)
identified several abnormalities of the glycophorin A and B genes,
leading them to conclude that both are largely deleted, being replaced
by a gene fusion product composed of the N-terminal portion of a blood
group M-type glycophorin A and of the C-terminal portion of glycophorin
B. Okubo et al. (1988) described 2 Japanese sisters with consanguineous
parents who were apparently homozygous for M(k). Total absence of
sialoglycoproteins A (alpha) and B (delta) from red cell membranes was
demonstrated in 1 of the sisters. This is the third reported family; one
of the other families was also Japanese. All affected individuals had
been healthy except for the proposita in the present study who had
Hodgkin disease. Huang et al. (1988) studied a family in which 3
different glycophorin mutations were present in 2 individuals of a
16-member family. The variant Dantu glycophorin showed properties
consistent with a delta-alpha (HBB/HBA) hybrid glycophorin. This gene
was linked to a gene coding for the M-specific alpha glycophorin.
Another variant glycophorin, Mi-III glycophorin, was transmitted as an
autosomal dominant trait and was associated with N blood group activity.
The inheritance pattern indicated that it could be a variant of delta
glycophorin (glycophorin B). In the persons with both Dantu and Mi-III
glycophorins, a delta glycophorin deficiency was observed, suggesting
that a deletion or alteration of the delta gene may exist on the same
chromosome as the Dantu gene. Huang et al. (1989) showed that the St(a)
antigen is likewise determined by a fusion hybrid of the glycophorin A
and B genes.

As noted earlier, the glycophorin variant Miltenberger class V-like
molecule (MiV) is a hybrid: Kudo et al. (1990) showed that the 5-prime
half of the gene is derived from the GPA gene, whereas the 3-prime half
is derived from the GPB gene. This structure is reciprocal to another
glycophorin variant, Sta, which has a GPB-GPA hybrid structure. Huang et
al. (1992) identified the molecular nature of the change responsible for
the Miltenberger class I (MiI) phenotype in a white family in which the
first homozygote was observed.

Rothman et al. (1995) used the GPA assay to evaluate the effects of
occupational exposure to benzene. The GPA assay measures the frequency
of variant erythrocytes that have lost expression of the blood type M in
blood samples from heterozygous (MN) individuals. Variant cells are
detected by treating sphered, fixed erythrocytes with
fluorescent-labeled monoclonal antibodies specific for the M and N forms
and, by flow cytometry, counting variant cells that bind the anti-N
antibody but not the anti-M antibody. The variant cells possess the
phenotype N-zero (single-copy expression of N and no expression of M) or
NN (double-copy expression of N and no expression of M). These
phenotypic variants arise from different mutational mechanisms in
precursor cells: N-zero cells are thought to arise from point mutations,
deletions, or gene inactivation, whereas NN cells presumably arise from
mitotic recombination, chromosome loss and reduplication, or gene
conversion. Rothman et al. (1995) used this GPA assay to evaluate DNA
damage produced by benzene in 24 heavily exposed workers in Shanghai,
China and 23 matched controls. A significant increase in the MN GPA
variant cell frequency was found in benzene-exposed workers, but no
significant difference existed between the 2 groups for N-zero cells.
Furthermore, lifetime cumulative occupational exposure to benzene was
associated with the NN frequency, but not with the N-zero frequency,
suggesting that NN mutations occur in longer-lived bone marrow stem
cells.

Blumenfeld and Huang (1995) reviewed the molecular genetics of 25
variants of the glycophorin gene family, whose common denominator is
that they arise from unequal gene combinations or gene conversions
coupled to splice-site mutations. Most rearrangements occur within a
2-kb region mainly within GPA and GPB and only rarely within the third
member, GPE. They observed that the key feature is the shuffling of
sequences within 2 specific exons (1 of which is silent), which are
homologous in the 2-parent genes. This results in expression of a mosaic
of sequences within the region, leading to polymorphism.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
BLOOD GROUP ERIK
GPErik
GPA, GLY59ARG
Huang et al. (1993) identified a G-to-A transition at the last
nucleotide position of exon 3 of the GYPA gene, which affected pre-mRNA
splicing because of partial inactivation of the adjacent 5-prime splice
site and skipping of various exons involving the alternative use of
other constitutive splice sites. Characterization of the resultant
transcripts allowed Huang et al. (1993) to elucidate the molecular basis
for the coexpression of ERIK and St(a) antigens on the erythrocyte
membrane. The full-length transcript encoded a variant glycophorin with
an arginine replacing a glycine at position 59 and defining the ERIK
epitope, whereas the exon 3-deleted transcript specified a shorter
glycophorin carrying the St(a) antigen. Whereas most mutations leading
to aberrant splicing occur as single nucleotide substitutions in the
5-prime and 3-prime splicing consensus sequences, the G-to-A change at
position -1 from the splice donor site, in the allele the authors'
referred to as GPErik, has been found in a few other cases, e.g., in the
COL1A1 gene causing Ehlers-Danlos syndrome, type VII-A (120150.0026).

*FIELD* SA
Anstee  (1981); Furthmayr et al. (1981); German et al. (1969); Heiberg
and Berg (1975); Mayr  (1976); Rahuel et al. (1988); Springer and
Tegtmeyer (1981); Walker et al. (1977)
*FIELD* RF
1. Anstee, D. J.: The blood group MNSs-active sialoglycoproteins.
Seminars Hemat. 18: 13-31, 1981.

2. Barbosa, C. A. A.; Koury, W. H.; Krieger, H.: Linkage data on
MN and the Hb beta locus. Am. J. Hum. Genet. 27: 797-801, 1975.

3. Bias, W. B.; Meyers, D. A.: Segregation and linkage analysis of
the Stoltzfus blood group (SF).     (Abstract) Cytogenet. Cell Genet. 25:
137, 1979.

4. Blumenfeld, O. O.; Adamany, A. M.: Structural (glycophorins) of
the human erythrocyte membrane. Proc. Nat. Acad. Sci. 75: 2727-2731,
1978.

5. Blumenfeld, O. O.; Huang, C.-H.: Molecular genetics of the glycophorin
gene family, the antigens for MNSs blood groups: multiple gene rearrangements
and modulation of splice site usage result in extensive diversification. Hum.
Mutat. 6: 199-209, 1995.

6. Cook, P. J. L.; Lindenbaum, R. H.; Salonen, R.; de la Chapelle,
A.; Daker, M. G.; Buckton, K. E.; Noades, J. E.; Tippett, P.: The
MNSs blood groups of families with chromosome 4 rearrangements. Ann.
Hum. Genet. 45: 39-47, 1981.

7. Cook, P. J. L.; Noades, J. E.; Lomas, C. G.; Buckton, K. E.; Robson,
E. B.: Exclusion mapping illustrated by the MNSs blood group. Ann.
Hum. Genet. 44: 61-73, 1980.

8. Cook, P. J. L.; Robson, E. B.; Buckton, K. E.; Slaughter, C. A.;
Gray, J. E.; Blank, C. E.; James, F. E.; Ridler, M. A. C.; Insley,
J.; Hulten, M.: Segregation of ABO, AK-1 and ACON-S in families with
abnormalities of chromosome 9. Ann. Hum. Genet. 41: 365-377, 1978.

9. Divelbiss, J.; Shiang, R.; German, J.; Moore, J.; Murray, J. C.;
Patil, S. R.: Refinement of the physical location of glycophorin
A and beta fibrinogen using in situ hybridization and RFLP analysis.
(Abstract) Cytogenet. Cell Genet. 51: 991, 1989.

10. Falk, C. T.: New family data supporting the MN/GC linkage.
(Abstract) Cytogenet. Cell Genet. 37: 466, 1984.

11. Falk, C. T.; Martin, M. D.; Walker, M. E.; Chen, T.; Rubinstein,
P.; Allen, F. H., Jr.: Family data suggesting a linkage between MN
and Gc.     (Abstract) Cytogenet. Cell Genet. 25: 152, 1979.

12. Furthmayr, H.; Metaxas, M. N.; Metaxas-Buhler, M.: M(g) and M(c):
mutations within the amino-terminal region of glycophorin A. Proc.
Nat. Acad. Sci. 78: 631-635, 1981.

13. Gedde-Dahl, T., Jr.; Olaisen, B.: MN:Ss--GC more likely than
Ss:MN--GC?.     (Abstract) Cytogenet. Cell Genet. 32: 277-278, 1981.

14. German, J.; Chaganti, R. S. K.: Mapping human autosomes: assignment
of the MN locus to a specific segment in the long arm of chromosome
no. 2. Science 182: 1261-1262, 1973.

15. German, J.; Metaxas, M. N.; Metaxas-Buhler, M.; Louie, E.; Chaganti,
R. S. K.: Further evaluation of a child with the M(k) phenotype and
a translocation affecting the long arms of chromosomes 2 and 4.
(Abstract) Cytogenet. Cell Genet. 25: 160, 1979.

16. German, J.; Walker, M. E.; Steifel, F. H.; Allen, F. H., Jr.:
Autoradiographic studies of human chromosomes. II. Data concerning
the position of the MN locus. Vox Sang. 16: 130-145, 1969.

17. German, J.; Walker, M. E.; Stiefel, F. H.; Allen, F. H., Jr.:
MN blood-group locus: data concerning the possible chromosomal location.
Science 162: 1014-1015, 1968.

18. Grant, S. G.; Bigbee, W. L.: Bone marrow somatic mutation after
genotoxic cancer therapy.     (Letter) Lancet 343: 1507-1508, 1994.

19. Heiberg, A.; Berg, K.: Linkage data on the MNSs blood group-red
cell acid phosphatase relationship. Hum. Hered. 25: 93-94, 1975.

20. Huang, C.-H.; Guizzo, M. L.; Kikuchi, M.; Blumenfeld, O. O.:
Molecular genetic analysis of a hybrid gene encoding St(a) glycophorin
of the human erythrocyte membrane. Blood 74: 836-843, 1989.

21. Huang, C.-H.; Puglia, K. V.; Bigbee, W. L.; Guizzo, M. L.; Hoffman,
M.; Blumenfeld, O. O.: A family study of multiple mutations of alpha
and delta glycophorins (glycophorins A and B). Hum. Genet. 81:
26-30, 1988.

22. Huang, C.-H.; Reid, M.; Daniels, G.; Blumenfeld, O. O.: Alteration
of splice site selection by an exon mutation in the human glycophorin
A gene. J. Biol. Chem. 268: 25902-25908, 1993.

23. Huang, C.-H.; Spruell, P.; Moulds, J. J.; Blumenfeld, O. O.:
Molecular basis for the human erythrocyte glycophorin specifying the
Miltenberger class I (MiI) phenotype. Blood 80: 257-263, 1992.

24. Kudo, S.; Chagnovich, D.; Rearden, A.; Mattei, M. G.; Fukuda,
M.: Molecular analysis of a hybrid gene encoding human glycophorin
variant Miltenberger V-like molecule. J. Biol. Chem. 265: 13825-13829,
1990.

25. Langlois, R. G.; Bigbee, W. L.; Jensen, R. H.: Measurements of
the frequency of human erythrocytes with gene expression loss phenotypes
at the glycophorin A locus. Hum. Genet. 74: 353-362, 1986.

26. Langlois, R. G.; Bigbee, W. L.; Kyoizumi, S.; Nakamura, N.; Bean,
M. A.; Akiyama, M.; Jensen, R. H.: Evidence for increased somatic
cell mutations at the glycophorin A locus in atomic bomb survivors.
Science 236: 445-448, 1987.

27. Mattei, M. G.; London, J.; Rahuel, C.; d'Auriol, L.; Colin, Y.;
Le Van Kim, C.; Mattei, J. F.; Galibert, F.; Cartron, J. P.: Chromosome
localization by in situ hybridization of the gene for human erythrocyte
glycophorin to region 4q28-q31.     (Abstract) Cytogenet. Cell Genet. 46:
658, 1987.

28. Mawby, W. J.; Anstee, D. J.; Tanner, M. J. A.: Immunochemical
evidence for hybrid sialoglycoproteins of human erythrocytes. Nature 291:
161-162, 1981.

29. Mayr, W. R.: No close linkage between MNSs and red cell acid
phosphatase. Hum. Hered. 26: 1-3, 1976.

30. Okubo, Y.; Daniels, G. L.; Parsons, S. F.; Anstee, D. J.; Yamaguchi,
H.; Tomita, T.; Seno, T.: A Japanese family with two sisters apparently
homozygous for M(k). Vox Sang. 54: 107-111, 1988.

31. Onda, M.; Fukuda, M.: Detailed physical mapping of the genes
encoding glycophorins A, B, and E, as revealed by P1 plasmids containing
human genomic DNA. Gene 159: 225-230, 1995.

32. Pasvol, G.; Wainscoat, J. S.; Weatherall, D. J.: Erythrocytes
deficient in glycophorin resist invasion by the malarial parasite
Plasmodium falciparum. Nature 297: 64-66, 1982.

33. Pasvol, G.; Wilson, R. J. M.: The interaction of malaria parasites
with red blood cells. Brit. Med. Bull. 38: 133-140, 1982.

34. Prohaska, R.; Koerner, T. A. W., Jr.; Armitage, I. M.; Furthmayr,
H.: Chemical and carbon-13 nuclear magnetic resonance studies of
the blood group M and N active sialoglycopeptides from human glycophorin
A. J. Biol. Chem. 256: 5781-5791, 1986.

35. Rahuel, C.; London, J.; d'Auriol, L.; Mattei, M.-G.; Tournamille,
C.; Skrzynia, C.; Lebouc, Y.; Galibert, F.; Cartron, J.-P.: Characterization
of cDNA clones for human glycophorin A: use for gene localization
and for analysis of normal of glycophorin-A-deficient (Finnish type)
genomic DNA. Europ. J. Biochem. 172: 147-153, 1988.

36. Rahuel, C.; London, J.; Vignal, A.; Cherif-Zahar, B.; Colin, Y.;
Siebert, P.; Fukuda, M.; Cartron, J.-P.: Alteration of the genes
for glycophorin A and B in glycophorin-A-deficient individuals. Europ.
J. Biochem. 177: 605-614, 1988.

37. Rothman, N.; Haas, R.; Hayes, R. B.; Li, G.-L.; Wiemels, J.; Campleman,
S.; Quintana, P. J. E.; Xi, L.-J.; Dosemeci, M.; Titenko-Holland,
N.; Meyer, K. B.; Lu, W.; Zhang, L. P.; Bechtold, W.; Wang, Y.-Z.;
Kolachana, P.; Yin, S.-N.; Blot, W.; Smith, M. T.: Benzene induces
gene-duplicating but not gene-inactivating mutations at the glycophorin
A locus in exposed humans. Proc. Nat. Acad. Sci. 92: 4069-4073,
1995.

38. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

39. Siebert, P. D.; Fukuda, M.: Isolation and characterization of
human glycophorin A cDNA clones by a synthetic oligonucleotide approach:
nucleotide sequence and mRNA structure. Proc. Nat. Acad. Sci. 83:
1665-1669, 1986.

40. Spence, M. A.; Field, L. L.; Marazita, M. L.; Joseph, J.; Sparkes,
M.; Crist, M.; Crandall, B. F.; Anderson, C. E.; Bateman, J. B.; Rotter,
J. I.; Kidd, K. K.; Hodge, S. E.; Sparkes, R. S.: Estimating the
recombination frequency for the MN and the Ss loci. Hum. Hered. 34:
343-347, 1984.

41. Springer, G. F.; Tegtmeyer, H.: Further evidence that carbohydrates
are the immunodeterminant structures of blood group M and N specificities.
Immun. Commun. 10: 157-171, 1981.

42. Wakui, K.; Nishida, T.; Masuda, J.; Itoh, T.; Katsumata, D.; Ohno,
T.; Fukushima, Y.: De novo interstitial deletion of 4q[46,XX,del(4)(q27q28.2)]
with intact blood group-MN locus, confining its locus to 4q28.2-4q31.1.
Jpn. J. Hum. Genet. 36: 149-153, 1991.

43. Walker, M. E.; Rubinstein, P.; Allen, F. H., Jr.: Biochemical
genetics of MN. Vox Sang. 32: 111-120, 1977.

44. Weitkamp, L. R.: Concerning the linkage relationships of the
Gc and MNSs loci. Hum. Genet. 43: 215-220, 1978.

45. Weitkamp, L. R.; Adams, M. S.; Rowley, P. T.: Linkage between
the MN and Hb beta loci. Hum. Hered. 22: 566-572, 1972.

46. Weitkamp, L. R.; Lovrien, E. W.; Olaisen, B.; Fenger, K.; Gedde-Dahl,
T., Jr.; Sorensen, S. A.; Conneally, P. M.; Bias, W. B.; Ott, J.:
Linkage relations of the loci for the MN blood group and red cell
phosphate. Birth Defects Orig. Art. Ser. XI(3): 276-280, 1975.
Note: Alternate: Cytogenet. Cell Genet. 14: 446-450, 1975.....

*FIELD* CN
Alan F. Scott - updated: 8/9/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/17/1996
mark: 3/7/1996
mark: 2/7/1996
terry: 1/31/1996
terry: 5/25/1995
jason: 6/16/1994
davew: 6/9/1994
carol: 3/29/1994
pfoster: 3/25/1994

*RECORD*
*FIELD* NO
111360
*FIELD* TI
111360 BLOOD GROUP--NEWFOUNDLAND; NFLD
*FIELD* TX
Lewis et al. (1984) described a 'new' low incidence red cell antigen
dubbed NFLD which was found in a Caucasian Newfoundland family under
study because of the transmission of an inversion 3 chromosome. It was
defined by a serum called Mess that contained multiple antibodies
against many red cell antigens. The NFLD specificity was purified by
absorption of the other specificities. The antigen is not part of the
ABO, MNSs, Duffy, Kidd, or Yt blood group systems and probably does not
belong to the Rh or Kell system.

*FIELD* RF
1. Lewis, M.; Kaita, H.; Allderdice, P. W.; Bergren, M.; McAlpine,
P. J.: A 'new' low incidence red cell antigen, NFLD. Hum. Genet. 67:
270-271, 1984.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
111380
*FIELD* TI
*111380 BLOOD GROUP--OK; OK
*FIELD* TX
A murine monoclonal antibody produced in response to immunization with a
human teratocarcinoma cell line recognizes a cell surface antigen
expressed by all human cells including red blood cells. All red cell
samples tested reacted positively with the monoclonal antibody except
those of a very rare phenotype called OK(a-). Only 3 unrelated OK(a-)
propositi were known to Williams et al. (1987), who found that the cells
in all 3 were negative for the monoclonal antibody. Further tests
suggested that the immune antibody found in the serum of some OK(a-)
persons recognized the same cell surface determinant as did the
monoclonal antibody. The determinant was found on the red cells of
gorillas and chimpanzees but not on the red cells of rhesus monkeys,
baboons, and marmosets. Indirect radioimmunoassay of reactivity to the
monoclonal antibody by somatic cell hybrids located the gene to
19pter-p13.2.

*FIELD* RF
1. Williams, B. P.; Pym, B.; Tippett, P.; Sher, D.; Povey, S.; Andrews,
P. W.; Goodfellow, P. N.; Daniels, G.; Okubo, Y.: Another red cell
surface antigen, OK(a), is encoded by a gene on chromosome 19.  (Abstract) Cytogenet.
Cell Genet. 46: 717 only, 1987.

*FIELD* CD
Victor A. McKusick: 8/31/1987

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/13/1989
root: 6/9/1988
marie: 3/25/1988

*RECORD*
*FIELD* NO
111400
*FIELD* TI
*111400 BLOOD GROUP--P SYSTEM
P GLOBOSIDE
*FIELD* TX
Naiki and Marcus (1975) suggested from immunochemical studies that P1
and P2 (P and P1 in the newer nomenclature) are not allelic, i.e., that
there are at least two loci determining P blood type. The red cell
antigens with various P specificities actually belong to two different
glycosphingolipid chains. One series, called the globoside series, has
the structures characteristic of the P2 phenotype. A second, called the
paragloboside series, carries P1 specificity. Marcus et al. (1976)
suggested that P and P(k) antigens are the glycosphingolipids globoside
and trihexosyl ceramide, respectively. They confirmed this by chemical
analysis of the red cells lacking these antigens. P(k) red cells contain
only traces of globoside and a marked excess of trihexosyl ceramide,
whereas P cells lack both globoside and trihexosyl ceramide and contain
an excess of lactosyl ceramide and the other complex glycolipids.
Phillips and Rodey (1975) reported a large family that gave strongly
negative lod scores for linkage of HLA and P, which had previously been
suggested by cell hybrid studies (Fellous et al., 1971). In a large
kindred studied in connection with acrokeratoelastoidosis (101850),
Greiner et al. (1983) found a suggestion of linkage of HLA and P
(maximum lod score=1.48 at theta 0.27). Similar data were reported by
Keats et al. (1979). Data suggesting linkage of the P blood group locus
and the NADH-diaphorase locus (250800), on chromosome 22, were presented
by McAlpine et al. (1978). The P blood group locus, which was assigned
to chromosome 6 by somatic cell hybridization, is nonpolymorphic (in
terms of conventional blood typing). It is the P1 blood group locus
which is polymorphic; it may be coded by chromosome 22. The chromosome 6
locus codes for globoside expression; the chromosome 22 locus for
paragloboside. See 111410.

The ability of bacteria to adhere to epithelial cells of the host is a
prerequisite for many bacterial infections. In human urinary tract
infections, there is a high correlation between the ability of bacteria
to adhere to the urinary epithelium and their virulence (Svanborg Eden
et al., 1976, 1978). The adhesive capacity is likely to endow the
bacteria with higher resistance to mechanical elimination by the flow of
urine and thus aid in their ascent to the upper urinary tract and
kidney. The receptors on human uroepithelial cells and red cells to
which pyelonephritogenic Escherichia coli bind are glycosphingolipids
related to the human P blood group system (see Korhonen et al., 1982).
Svanborg Eden et al. (1983) presented evidence suggesting that P(1)
blood group phenotype is a factor in susceptibility to urinary tract
infection. Bacterial adhesion is the mechanism. In the uroepithelium,
antigens in the P blood group system are glycolipid receptors for
bacteria. Persons of blood group P(1) have a higher density of receptor
glycolipids in their red cell membrane than do persons of the P(2)
phenotype. Svanborg Eden et al. (1983) found the P(1) phenotype
overrepresented among patients with recurrent pyelonephritis without
reflux: 97% as compared to 75% in healthy children. This patient group
also showed a higher frequency of 'attaching bacteria.' In cases of
recurrent pyelonephritis with reflux, no significant increase in
prevalence of P(1) or of attaching bacteria was seen. Lomberg et al.
(1983) presented evidence that the P1 blood group phenotype and bacteria
that attach to glycolipid epithelial cell receptors are especially
common in girls with recurrent pyelonephritis if they do not have
vesicoureteral reflux. The P(1) blood group phenotype is not more common
in patients with reflux and recurrent pyelonephritis than in the healthy
population. In the nonreflux group, bacteria causing the pyelonephritis
were often of the type with adhesions, whereas these were rare in
patients with reflux. The presence of reflux appears to compensate for
the defect in the capacity of the bacteria to attach. Sheinfeld et al.
(1989) reviewed work on the relationship between P blood group phenotype
and recurrent urinary tract infections. In their own studies they could
find no peculiarity in the distribution of P phenotypes in a group of 49
white women with histories of recurrent urinary tract infections.

Lichodziejewska-Niemierko et al. (1995) examined the distribution of P
antigen, Lewis blood group phenotypes, and secretor status in 65
patients with E. coli UTI (20 asymptomatic bacteriuria, 20 cystitis with
normal radiology, and 25 reflux nephropathy) and 45 controls who had
never experienced a UTI episode. The distribution of Lewis blood group
antigens was similar in all UTI groups and in the controls. The
incidence of nonsecretors in the reflux nephropathy group was similar to
that in controls. P1 phenotype was present in 100% of patients with
asymptomatic bacteriuria, 80% with cystitis and in controls, and only
44% with reflux nephropathy. Combined P1/nonsecretor phenotype was
observed in 45% of patients with asymptomatic bacteriuria, 30% with
cystitis, 12% with reflux nephropathy, and 22% of control healthy
individuals. P2/secretor phenotype was demonstrated in 44% of patients
with reflux nephropathy and in only 11% of controls. The data suggested
to the authors that having the P2 blood group protects against
asymptomatic colonization of urinary tract, but is associated with the
type of infection responsible for scarring in reflux nephropathy. It
also appears that being a nonsecretor does not predispose to renal
scarring and that the combined E2/secretor phenotype may be linked with
susceptibility to reflux nephropathy.

*FIELD* SA
Bosker and Nijenhuis (1975); Graham and Williams (1980); Marcus et
al. (1981); Nielson et al. (1984); O'Hanley et al. (1985)
*FIELD* RF
1. Bosker, H.; Nijenhuis, L. E.: Possible linkage between a gene
causing reinclusion of molar I and blood group P. Birth Defects
Orig. Art. Ser. XI(3): 85-86, 1975. Note: Alternate: Cytogenet. Cell
Genet. 14: 255-256, 1975...

2. Fellous, M.; Billardon, C.; Dausset, J.; Frezal, J.: Linkage probable
between locus HL-A and P. Comp. Rend. Acad. Sci. (Paris) 272: 3356-3359,
1971.

3. Graham, H. A.; Williams, A. N.: A genetic model for the inheritance
of P, P(1) and P(k) antigens. Immun. Commun. 9: 191-201, 1980.

4. Greiner, J.; Kruger, J.; Palden, L.; Jung, E. G.; Vogel, F.: A
linkage study of acrokeratoelastoidosis: possible mapping to chromosome
2. Hum. Genet. 63: 222-227, 1983.

5. Keats, B. J. B.; Morton, N. E.; Rao, D. C.; Williams, W. R.: A
Source Book for Linkage in Man.  Baltimore: Johns Hopkins Univ.
Press (pub.)  1979.

6. Korhonen, T. K.; Vaisanen, V.; Saxen, H.; Hultberg, H.; Svenson,
S. B.: P-antigen-recognizing fimbriae from human uropathogenic Escherichia
coli strains. Infect. Immun. 37: 286-291, 1982.

7. Lichodziejewska-Niemierko, M.; Topley, N.; Smith, C.; Verrier-Jones,
K.; Williams, J. D.: P1 blood group phenotype, secretor status in
patients with urinary tract infections. Clin. Nephrol. 44: 376-381,
1995.

8. Lomberg, H.; Hanson, L. A.; Jacobsson, B.; Jodal, U.; Leffler,
H.; Svanborg Eden, C.: Correlation of P blood group, vesicoureteral
reflux, and bacterial attachment in patients with recurrent pyelonephritis.
New Eng. J. Med. 308: 1189-1192, 1983.

9. Marcus, D. M.; Kundu, S. K.; Suzuki, A.: The P blood group system:
recent progress in immunochemistry and genetics. Seminars Hemat. 18:
63-71, 1981.

10. Marcus, D. M.; Naiki, M.; Kundu, S. K.: Abnormalities in the
glycosphingolipid content of human Pk and P erythrocytes. Proc.
Nat. Acad. Sci. 73: 3263-3267, 1976.

11. McAlpine, P. J.; Kaita, H.; Lewis, M.: Is the DIA-1 locus linked
to the P blood group locus?. Cytogenet. Cell Genet. 22: 629-632,
1978.

12. Naiki, M.; Marcus, D. M.: An immunochemical study of the human
blood group P1, P and P(k) antigens. Biochemistry 14: 4837-4841,
1975.

13. Nielson, L. S.; Mohr, J.; Eiberg, H.: Data concerning the linkage
relationship of the HLA and P systems.    (Abstract) Cytogenet. Cell
Genet. 37: 555, 1984.

14. O'Hanley, P.; Low, D.; Romero, I.; Lark, D.; Vosti, K.; Falkow,
S.; Schoolnik, G.: Gal-Gal binding and hemolysin phenotypes and genotypes
associated with uropathogenic Escherichia coli. New Eng. J. Med. 313:
414-420, 1985.

15. Phillips, R. B.; Rodey, G.: Negative evidence for linkage between
HL-A and P blood group. Immunogenetics 2: 395-396, 1975.

16. Sheinfeld, J.; Schaeffer, A. J.; Cordon-Cardo, C.; Rogatko, A.;
Fair, W. R.: Association of the Lewis blood-group phenotype with
recurrent urinary tract infections in women. New Eng. J. Med. 320:
773-777, 1989.

17. Svanborg Eden, C.; Eriksson, B.; Hanson, L. A.; Jodal, U.; Kaijser,
B.; Lidin-Janson, G.; Lindberg, U.; Olling, S.: Adhesion to normal
human uroepithelial cells of Escherichia coli from children with various
forms of urinary tract infection. J. Pediat. 93: 398-403, 1978.

18. Svanborg Eden, C.; Hagberg, L.; Hanson, L. A.; Hull, S.; Hull,
R.; Jodal, U.; Leffler, H.; Lomberg, H.; Straube, E.: Bacterial adherence--a
pathogenetic mechanism in urinary tract infections caused by Escherichia
coli. Prog. Allergy 33: 175-188, 1983.

19. Svanborg Eden, C.; Hanson, L. A.; Jodal, U.; Lindberg, U.; Sohl-Akerlund,
A.: Variable adherence to normal human urinary tract epithelial cells
of Escherichia coli strains associated with various forms of urinary
tract infections. Lancet II: 490-492, 1976.

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 03/14/1996
terry: 3/5/1996
mimadm: 4/19/1994
pfoster: 3/25/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 11/18/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
111410
*FIELD* TI
*111410 BLOOD GROUP--P SYSTEM, SECOND LOCUS
P-ONE ANTIGEN; P1
*FIELD* TX
See 111400 for evidence of two nonallelic series of antigens in the P
blood group system. The P1 blood group is polymorphic and codes for
paragloboside expression. The possible assignment of P1 to chromosome 22
was first suggested by McAlpine et al. (1978) who found linkage to DIA1
(250800). Julier et al. (1985) presented family linkage data in support
of this assignment: maximum lod of 1.66 at theta 0.03 with SIS (190040).
Julier et al. (1985) found evidence for linkage of P1 to RFLPs of
myoglobin (160000) and the SIS oncogene (190040) although the scores
were not yet significant. The data suggested the following order on 22q:
IGL--0.10--D22S1--0.20--MB--0.07--(SIS, P1)--ter.

The phenotype p, originally called Tj(a-), is rare (Race and Sanger,
1975). There is a relatively high frequency in Vasterbotten County,
Sweden (Cedergren, 1973) and the same rare blood type has been found in
the Old Order Amish of Holmes County, Ohio (Lehmann, 1991). (The Tj(a-)
gene was traced through several generations of a Schwartzentruber Amish
kindred.) The Tj(a) antigen is present in the vast majority of people
and the corresponding antibody, anti-Tj(a), occurs regularly in the
individual who is Tj(a-), like anti-A and anti-B in the ABO system. The
hemolytic power of the antibody, however, is much more violent than that
of anti-A and anti-B.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Julier et al. (1985)
*FIELD* RF
1. Cedergren, B.: Population studies in northern Sweden. IV. Frequency
of the blood type p. Hereditas 73: 27-30, 1973.

2. Julier, C.; Lathrop, M.; Lalouel, J. M.; Reghis, A.; Szajnert,
M. F.; Kaplan, J. C.: Use of multi-locus tests of gene order: example
for chromosome 22.  (Abstract) Cytogenet. Cell Genet. 40: 663-664,
1985.

3. Julier, C.; Reghis, A.; Szajnert, M. F.; Kaplan, J. C.; Lathrop,
G. M.; Lalouel, J. M.: A preliminary linkage map of human chromosome
22.  (Abstract) Cytogenet. Cell Genet. 40: 665 only, 1985.

4. Lehmann, E. D.: Personal Communication. Mount Eaton, Ohio  11/15/1991.

5. McAlpine, P. J.; Kaita, H.; Lewis, M.: Is the DIA-1 locus linked
to the P blood group locus?. Cytogenet. Cell Genet. 22: 629-632,
1978.

6. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
Sci. Publ. (pub.)  (6th ed.): 1975. Pp. 149-155.

7. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/18/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 11/22/1991
carol: 11/18/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
111500
*FIELD* TI
#111500 BLOOD GROUP--PRIVATE SYSTEMS
ANTIGENIC DETERMINANTS OF LOW FREQUENCY IN THE POPULATION
*FIELD* TX
A number sign (#) is used with this entry because it does not represent
a single gene locus.

Many of these blood groups have been found only in a single family. They
include Levay, Jobbins, Becker, Ven, Cavaliere, Berrens, Wright, Batty,
Romunde, Chr, Swann (601550), Good, Bi, Froese (601551), and Tr. The
relation, if any, of each to the major systems is not known, mainly
because the one or few families in which they have been found do not
contribute enough information.

*FIELD* SA
Yvart et al. (1974)
*FIELD* RF
1. Yvart, J.; Gerbal, A.; Salmon, C.: A new 'private' antigen: Hey. Vox
Sang. 26: 41-44, 1974.

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 12/05/1996
supermim: 3/16/1992
carol: 2/6/1992
supermim: 3/20/1990
carol: 3/6/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
111600
*FIELD* TI
#111600 BLOOD GROUP--PUBLIC SYSTEMS
ANTIGENIC DETERMINANTS OF HIGH FREQUENCY IN THE POPULATION
*FIELD* TX
A number sign (#) is used with this entry because it does not represent
a single gene locus.

These include Vel, Lan, and Sm. The relation, if any, of each to the
major systems listed earlier is not known. The I ('eye') blood group
system may also be considered a public system. A listing of public
systems, which may represent so-called monomorphic loci, was given by
Nei and Roychoudhury (1974).

*FIELD* RF
1. Nei, M.; Roychoudhury, A. K.: Genic variation within and between
the three major races of man, Caucasoids, Negroids, and Mongoloids.
Am. J. Hum. Genet. 26: 421-443, 1974.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 7/5/1994
supermim: 3/16/1992
carol: 3/4/1992
supermim: 3/20/1990
carol: 3/6/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
111620
*FIELD* TI
111620 BLOOD GROUP--RADIN ANTIGEN; Rd
*FIELD* TX
Radin is a rare red cell antigen, symbolized Rd(a), which was discovered
by Rausen et al. (1967), who found it in 3 persons among 562 New York
Jews, but in none of over 6000 others. It was found in 62 of 14,301
Danes, not known to be Jewish, and in 1 of 529 Icelanders. Lewis and
Kaita (1979) found linkage with Rh (lods of +3.89 at a recombination
fraction of 0.10). This suggests that Radin may in fact be part of the
Scianna system, since the latter locus is on 1p in the region of Rh.
Lewis et al. (1980) presented evidence that the Radin blood group
antigen is governed by a locus called Rd, which is located between PGM-1
(171900) and alpha-fucosidase--Rh, and is either very closely linked to
or identical with Sc.

*FIELD* SA
Hilden et al. (1985); Mourant et al. (1978)
*FIELD* RF
1. Hilden, J.-O.; Shaw, M.-A.; Whitehouse, D. B.; Monteiro, M.; Tippett,
P.: Linkage information from nine more Radin families.  (Abstract) Cytogenet.
Cell Genet. 40: 650-651, 1985.

2. Lewis, M.; Kaita, H.: Genetic linkage between the Radin and Rh
blood group loci. Vox Sang. 37: 286-289, 1979.

3. Lewis, M.; Kaita, H.; Philipps, S.; Giblett, E. R.; Anderson, J.
E.; McAlpine, P. J.; Nickel, B.: The position of the Radin blood
group locus in relation to other chromosome 1 loci. Ann. Hum. Genet. 44:
179-184, 1980.

4. Mourant, A. E.; Kopec, A. C.; Domaniewska-Sobczak, K.: The Genetics
of Jews.  Oxford: Clarendon Press (pub.)  1978. Pp. 7 only.

5. Rausen, A. R.; Rosenfield, R. E.; Alter, A. A.; Hakim, S.; Graven,
S. N.; Apollon, C. J.; Dallman, P. R.; Dalziel, J. C.; Konugres, A.
A.; Francis, B.; Gavin, J.; Cleghorn, T. E.: A 'new' infrequent red
cell antigen, Rd (Radin). Transfusion 7: 336-342, 1967.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
111680
*FIELD* TI
*111680 RHESUS BLOOD GROUP, D ANTIGEN; RHD
BLOOD GROUP--RHESUS SYSTEM D POLYPEPTIDE
*FIELD* TX
Individuals are classified as Rh-positive and Rh-negative according to
the presence or the absence of the major D antigen on the surface of
their erythrocytes, but more than 46 other antigens, including those of
the CcEe series, have been identified (Issitt, 1989). By Southern blot
analysis, Colin et al. (1991) showed that the Rh 'locus' is composed of
2 homologous structural genes, one encoding the Rh D polypeptide and the
other encoding both the Cc and the Ee polypeptides (111700). Alternative
splicing of a primary transcript was considered the likely mechanism of
the encoding of the Cc and Ee polypeptides by a single gene (Le Van Kim
et al., 1992). Le Van Kim et al. (1992) cloned cDNAs for representing
the RHD gene. They found that the predicted translation product is a
417-amino acid protein of molecular mass 45,500 with a membrane
organization of 13 bipolar-spanning domains similar to that of the
polypeptide encoded by the CcEe gene. The D and CeEe polypeptides differ
by 36 amino acids (8.4% divergence), but the NH2- and COOH-terminal
regions of the 2 proteins are well conserved. The sequence homology
supports the concept that the genes evolve by duplication of a common
ancestral gene. It is evident that the controversy between Wiener
(1944), who espoused the existence of a single gene with multiple
epitopic sites, and the Fisher-Race school (Race, 1944), which held to
the existence of 2 closely linked genes, has now been resolved with the
conclusion that each view was partially right and partially wrong. None
of the 3 researchers survived to see the definitive resolution of the
issue. Arce et al. (1993) likewise cloned the RHD gene.

Bennett et al. (1993) demonstrated that DNA testing can be used to
determine RhD type in chorionic villus samples or amniotic cells. An
RhD-negative woman whose partner is heterozygous may have preexisting
anti-RhD antibodies that may or may not affect a subsequent fetus,
depending on whether it is heterozygous. A safe method of determining
fetal RhD type early in pregnancy would eliminate the risks to an
RhD-negative fetus of fetal blood sampling or serial amniocenteses.

Cartron (1994) provided a comprehensive review of the molecular genetics
of the Rh blood group antigens. These antigens are carried by a family
of nonglycosylated hydrophobic transmembrane proteins of 30 to 32 kD,
which are missing from the red cells of rare Rh-null individuals. The Rh
proteins are erythroid-specific and share no sequence homology with any
known protein. The RhD and non-D proteins exhibit 92% sequence identity.
The RhD and RhCE genes are organized in tandem on 1p36-p34 and
presumably originated by duplication of a common ancestral gene. This
concept is supported by the identification of RH-like genes in nonhuman
primates. The C/c and E/e proteins are presumably produced through
alternative splicing of a pre-messenger RNA; most RhD-negative
haplotypes represent absence of the RHD gene and the presence of only 1
structural gene, RHCE. The correlation between the blood group D
epitopes and the amino acid polymorphism of the Rh proteins had not been
established, but in the case of the RHCE gene, the polymorphism
ser103-to-pro had been shown to be responsible for the C/c specificity
(111700.0002) and pro226-to-ala for the E/e specificity (111700.0001).
Gene conversion appears to be the principal mechanism responsible for
polymorphism and gene diversity in the RH system; however, gene
deletions have also been identified.

In his review of the molecular genetics of the Rh blood group antigens,
Cartron (1994) pointed out the desirability of an early and safe
prenatal diagnosis of Rh status for use in pregnancies at risk of Rh
alloimmunization. Such became possible when the structure and
organization of the RH locus in RhD-positive and RhD-negative
individuals was determined. The general approach was based on the
detection of D genomic sequences by PCR in fetal DNA samples from
chorionic villus biopsy or amniocentesis. Huang et al. (1996) used a set
of SphI RFLPs that are tightly linked with the Rh structural genes to
demonstrate linkage disequilibrium that allowed determination of
Rh-positive or Rh-negative status (D/D, D/d, and d/d).

Smythe et al. (1996) provided definitive proof that the RHD gene encodes
the D and G antigens and the RHCE gene (111700) encodes the c and E
antigens. They did this by retroviral-mediated gene transfer using cDNA
transcripts of the RHD and RHCE genes and isolated clones that expressed
one or the other of these pairs of antigens. Both c and E antigens were
expressed after transduction of the test cells with a single cDNA,
indicating that the c antigen does not arise by alternative splicing
(exon skipping) of the product of the RHCE gene, as had been suggested.

Huang et al. (1996) described a family study of the Evans (also known as
'D..') phenotype, a codominant trait associated with both qualitative
and quantitative changes in D-antigen expression. A cataract-causing
mutation was also inherited in this family and was apparently
cotransmitted with Evans, suggesting chromosomal linkage of these 2
otherwise unrelated traits. Southern blot analysis and allele-specific
PCR showed the linkage of Evans with a SphI RFLP marker and the presence
of a hybrid gene in the RH locus. To delineate the pattern of gene
expression, Huang et al (1996) characterized the composition and
structure of RH-polypeptide transcripts were characterized by RT-PCR and
nucleotide sequencing. They identified a novel Rh transcript expressed
only in the Evans-positive erythroid cells. Sequence analysis showed
that the transcript maintained a normal open reading frame but occurred
as a CE-D-CE composite in which exons 2-6 of the CE gene (111700) were
replaced by the homologous counterpart of the D gene. This hybrid gene
was predicted to encode a CD-D-CE fusion protein whose surface
expression correlates with the Evans phenotype. The mode and consequence
of such a recombination of events suggested the occurrence, in the RH
locus, of a segmental DNA transfer via the mechanism of gene conversion,
although unequal homologous recombination through double crossover could
not be excluded formally. Congenital cataract of the Volkmann type (CCV;
115665) has been mapped to the RH region, specifically to 1pter-p36.13.
The family studied by Huang et al. (1996) was ascertained through the
East of Scotland Blood Transfusion Service, in Dundee, Scotland (Huang,
1996).

Race and Sanger (1975) referred to the unpublished observations on the
Evans antigen in an English family by Weiner in 1966. The antibody
against the Evans antigen caused hemolytic disease of the newborn in the
Evans family. Outside the original family, one positive was found in 480
random British people. All 4 Evans-positive members of the original
family had an Rh complex like, but not identical to, --D--, whereas all
3 Evans-negative blood relatives did not. The Evans antibody did not
react with cells of true --D-- homozygotes or heterozygotes.

Kemp et al. (1996) examined 5 unrelated Rh D-- homozygotes and found
that, in 4 of them, RHCE sequences have been replaced by Rh D sequences.
The 5-prime end of these rearrangements all occurred within a 4.2-kb
interval around exon 2. There was, however, heterogeneity at the 3-prime
end of the rearranged genes, indicating that they were not identical by
descent, but rather that independent recombination events had occurred
within a small genomic interval.

*FIELD* AV
.0001
RHD-NEGATIVE POLYMORPHISM
RHD, DEL
Colin et al. (1991) showed that Rh-negative (dd) individuals are
homozygous for a deletion of the RHD gene.

.0002
RHD CATEGORY D-VII
RHD, LEU110PRO
Although the presence or absence of the major antigen, D, at the red
blood cell surface determines the Rh-positive or Rh-negative phenotypes,
respectively, some rare Rh-positive variants that belong to 1 of the 7 D
category phenotypes, D(II) to D(VII) and DFR, can develop anti-D
antibodies following immunization by pregnancy or transfusion; their
RBCs do not express some of the 9 determinants (epD1 through epD9),
which normally compose the so-called D mosaic structure. Rouillac et al.
(1995) analyzed the modification of the RHD gene associated with the
D(VII) category, characterized by the lack of epD8 and the expression of
the low frequency antigen Rh40. They showed that Rh40 and the lack of
epD8 are associated with a single point mutation, T329C, in exon 2 of
the RHD gene. This nucleotide polymorphism resulted in a leucine to
proline substitution at amino acid position 110 of the RhD polypeptide.

*FIELD* SA
Le Van Kim et al. (1992)
*FIELD* RF
1. Arce, M. A.; Thompson, E. S.; Wagner, S.; Coyne, K. E.; Ferdman,
B. A.; Lublin, D. M.: Molecular cloning of RhD cDNA derived from
a gene present in RhD-positive, but not RhD-negative individuals. Blood 82:
651-655, 1993.

2. Bennett, P. R.; Le Van Kim, C.; Colin, Y.; Warwick, R. M.; Cherif-Zahar,
B.; Fisk, N. M.; Cartron, J.-P.: Prenatal determination of fetal
RhD type by DNA amplification. New Eng. J. Med. 329: 607-610, 1993.

3. Cartron, J.-P.: Defining the Rh blood group antigens: biochemistry
and molecular genetics. Blood Rev. 8: 199-212, 1994.

4. Colin, Y.; Cherif-Zahar, B.; Le Van Kim, C.; Raynal, V.; Van Huffel,
V.; Cartron, J.-P.: Genetic basis of the RhD-positive and RhD-negative
blood group polymorphism as determined by Southern analysis. Blood 78:
2747-2752, 1991.

5. Huang, C.-H.: Personal Communication. New York City, N. Y.
10/11/1996.

6. Huang, C.-H.; Chen, Y.; Reid, M.; Ghosh, S.: Genetic recombination
at the human RH locus: a family study of the red-cell Evans phenotype
reveals a transfer of exons 2-6 from the RHD to the RHCE gene. Am.
J. Hum. Genet. 59: 825-833, 1996.

7. Huang, C.-H.; Reid, M. E.; Chen, Y.; Coghlan, G.; Okubo, Y.: Molecular
definition of red cell Rh haplotypes by tightly linked SphI RFLPs. Am.
J. Hum. Genet. 58: 133-142, 1996.

8. Issitt, P. D.: The Rh blood group system, 1988: eight new antigens
in nine years and some observations on the biochemistry and genetics
of the system. Transfusion Med. Rev. 3: 1-12, 1989.

9. Kemp, T. J.; Poulter, M.; Carritt, B.: A recombination hot spot
in the Rh genes revealed by analysis of unrelated donors with the
rare D-- phenotype. Am. J. Hum. Genet. 59: 1066-1073, 1996.

10. Le Van Kim, C.; Cherif-Zahar, B.; Raynal, V.; Mouro, I.; Lopez,
M.; Cartron, J. P.; Colin, Y.: Multiple Rh messenger RNA isoforms
are produced by alternative splicing. Blood 80: 1074-1078, 1992.

11. Le Van Kim, C.; Mouro, I.; Cherif-Zahar, B.; Raynal, V.; Cherrier,
C.; Cartron, J.-P.; Colin, Y.: Molecular cloning and primary structure
of the human blood group RhD polypeptide. Proc. Nat. Acad. Sci. 89:
10925-10929, 1992.

12. Race, R. R.: An 'incomplete' antibody in human serum. (Letter) Nature 153:
771-772, 1944.

13. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
(pub.)  (6th ed.): 1975.

14. Rouillac, C.; Le Van Kim, C.; Beolet, M.; Cartron, J.-P.; Colin,
Y.: Leu110-to-pro substitution in the RhD polypeptide is responsible
for the D(VII) category blood group phenotype. Am. J. Hemat. 49:
87-88, 1995.

15. Smythe, J. S.; Avent, N. D.; Judson, P. A.; Parsons, S. F.; Martin,
P. G.; Anstee, D. J.: Expression of RHD and RHCE gene products using
retroviral transduction of K562 cells establishes the molecular basis
of Rh blood group antigens. Blood 87: 2968-2973, 1996.

16. Wiener, A. S.: The Rh series of allelic genes. Science 100:
595-597, 1944.

*FIELD* CN
Moyra Smith - updated: 10/26/1996

*FIELD* CD
Victor A. McKusick: 12/6/1988

*FIELD* ED
mark: 12/29/1996
terry: 12/20/1996
mark: 11/9/1996
mark: 10/26/1996
terry: 10/17/1996
mark: 5/9/1996
terry: 5/2/1996
mark: 1/25/1996
terry: 1/22/1996
mark: 11/14/1995
carol: 2/13/1995
pfoster: 5/12/1994
warfield: 3/15/1994
carol: 10/19/1993
carol: 9/28/1993

*RECORD*
*FIELD* NO
111690
*FIELD* TI
#111690 BLOOD GROUP--RHESUS SYSTEM E POLYPEPTIDE; RHE
*FIELD* TX
A number sign (#) is used with this entry because Colin et al. (1991)
presented evidence indicating that one gene codes both C/c and E/e
specificities (see 111700), whereas another gene codes Rh D specificity
(111680).

*FIELD* RF
1. Colin, Y.; Cherif-Zahar, B.; Le Van Kim, C.; Raynal, V.; Van Huffel,
V.; Cartron, J.-P.: Genetic basis of the RhD-positive and RhD-negative
blood group polymorphism as determined by Southern analysis. Blood 78:
2747-2752, 1991.

*FIELD* CD
Victor A. McKusick: 12/6/1988

*FIELD* ED
carol: 9/13/1993
supermim: 3/16/1992
carol: 3/4/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 12/6/1988

*RECORD*
*FIELD* NO
111700
*FIELD* TI
*111700 RHESUS BLOOD GROUP, CcEe ANTIGENS; RHCE
BLOOD GROUP--RHESUS SYSTEM Cc/Ee POLYPEPTIDES;;
RHC;;
RHE;;
RH-NULL HEMOLYTIC ANEMIA, INCLUDED
*FIELD* TX
Rh, elliptocytosis, PGM(1), and 6PGD are all on the same chromosome. The
first two loci appear to lie between the latter two (Renwick, 1971).
Information from cell hybridization studies placed the
Rh-elliptocytosis-PGM(1)-6PGD linkage group on chromosome 1. Jacobs et
al. (1970) reported data suggesting a loose linkage between a
translocation breakpoint near the end of the long arm of chromosome 1
and Rh. Lamm et al. (1970) published family data consistent with loose
linkage of Duffy and PGM(1). Renwick (1971) suggested that PGM(1) is on
the side of Rh, remote from 6PGD and about 30 centimorgans from Rh. Cook
et al. (1972) confirmed this interval. Although the Rh and Duffy loci
are both on chromosome 1, they are too far apart to demonstrate linkage
in family studies (Sanger et al., 1973). Marsh et al. (1974) found
Rh-negative erythrocytes in an Rh-positive man suffering from
myelofibrosis. Nucleated hemopoietic precursors were circulating in his
blood, and these cells had an abnormal chromosome complement from which
part of the short arm of chromosome 1 had been deleted. They concluded
that the Rh locus probably lies on the distal segment of the short arm
at some point between 1p32 and the end of the short arm. The conclusion
is consistent with the finding of Douglas et al. (1973) that the PGM(1)
locus, which is linked to Rh, is on the short arm of chromosome 1. Since
the patient of Marsh et al. (1974) did not have deletion of the PGM(1)
locus in the mutant clone, the Rh locus is probably distal to the PGM(1)
locus. Corney et al. (1977) observed only 1 recombination in 58
opportunities between the alpha-fucosidase locus and the Rh locus. Rh
antigen still eludes chemical definition (Tippett, 1978), but it is
thought to be a lipoprotein. No completely certain example of
recombination within a postulated gene complex has been described.
Steinberg (1965) described a Hutterite family in which the father was
CDe-cde, mother cde-cde, 4 children cde-cde, 3 children CDe-cde, and 1
child (the 6th born) Cde-cde. Steinberg (1965) thought this was an
instance of crossingover. Mutation and, much less likely, a recessive
suppressor of the D antigen were mentioned as other possibilities. Race
and Sanger (1975) considered a recessive suppressor likely.
(Illegitimacy was excluded by the mores of the sect and by marker
studies.) Rosenfield (1981) wrote: 'We still know nothing about Rh.
Except for Steinberg's one crossover, there have been no exceptions to
the inheritance of Rh antigens in tight haplotype packages. Hopefully,
Rh antigen will be isolated for characterisation but there has been
nothing published since the report of Plapp et al. (1979).' Steinberg et
al. (1984) reexamined the Hutterite family, making use of other markers
thought to be on 1p (6PGD, Colton, UMPK1) and concluded that crossover
or mutation indeed had occurred. (Colton is probably not on chromosome
1p; UMPK1 was not informative in the critical parent (Lewis, 1989).)
They concluded further that if, as seems likely from other evidence, C
lies between D and E, their data indicate that the D gene (116800) is
distal (telomeric) in the Rh complex. This order is consistent with the
rare Rh haplotype D. Race et al. (1950, 1951) considered this haplotype
to represent a probable or possible deletion in a human Rh chromosome.
Race and Sanger (1975) listed 20 homozygotes for this haplotype.
Originating from various populations, they were, in about 80% of the
cases, the products of consanguineous matings. Olafsdottir et al. (1983)
concluded that this Rhesus haplotype is not very rare in Iceland. They
estimated the frequency to be about 1 in 214 persons. They discovered
the haplotype in 2 unrelated women because of difficulty with
crossmatching. Both had formed Rh antibodies, one provoked by
transfusions and the other by 3 pregnancies.

Saboori et al. (1988) purified Rh protein in relatively large amounts
from Rh(D)-positive and -negative blood. Differences in the peptide maps
of the 2 proteins were found. Blanchard et al. (1988) presented indirect
data based on immunologic and biochemical investigations demonstrating
that the Rh D, c, and E polypeptides of the erythrocyte membrane are
homologous but distinct molecular species that can be physically
separated and analyzed. These polypeptides have a molecular weight of
about 32,000. Polypeptides c and E were found by Blanchard et al. (1988)
to be more closely related to each other than to D. All the observations
were consistent with partial divergence among homologous members of a
family of Rh proteins. In a review completed in early 1988, Issitt
(1988) suggested that current molecular genetic methods could finally
end 50 years of speculation as to the genetic determination of the Rh
blood groups. Cherif-Zahar et al. (1990) isolated cDNA clones encoding a
human blood group Rh polypeptide from a human bone marrow cDNA library
using a PCR amplified DNA fragment encoding the known common N-terminal
region of the Rh proteins. Translation of the open reading frame
indicated that the Rh protein is composed of 417 amino acids, including
the initiator methionine, which is removed in the mature protein, that
it lacks a cleavable N-terminal sequence, and that it has no consensus
site for potential N-glycosylation. Hydropathy analysis and predictions
of secondary structure suggested the presence of 13 membrane-spanning
domains, indicating that the Rh polypeptide is highly hydrophobic and
deeply buried within the phospholipid bilayer. In Northern analysis, the
Rh cDNA probe detected a major 1.7-kb and a minor 3.5-kb mRNA species in
erythroid tissues but not in adult liver and kidney tissues or lymphoid
and promyelocytic cell lines. By in situ hybridization using an Rh
protein probe, Cherif-Zahar et al. (1991) mapped the Rh gene to
1p36.1-p34.3.

Whether the 3 sets of Rh antigens--D, Cc, and Ee--that are inherited en
bloc represent separate epitopes on a single protein (as maintained by
Wiener, 1944) or multiple independent proteins encoded by closely linked
genes (as first suggested by Fisher in 1944 (Race, 1944)) has been
controversial since the discovery of the Rh antigens in the early 1940s.
Cherif-Zahar et al. (1990) quoted work of Blanchard et al. (1988)
suggesting that the Rh D, c, and E antigens are carried by 3 distinct
but homologous membrane proteins that share a common N-terminal protein
sequence. It is possible that these are the product of one gene with
multiple splicing alternatives. See also review by Agre and Cartron
(1991). Colin et al. (1991) used Rh cDNA as a probe in Southern analysis
of the Rh locus. They demonstrated that in all Rh D-positive persons 2
strongly related Rh genes are present per haploid genome, whereas 1 of
these 2 genes is missing in Rh D-negative donors. Colin et al. (1991)
concluded that 1 of the 2 genes of the Rh locus encodes the Rh C/c and
Rh E/e polypeptides while the other encodes the Rh D protein. (Both
Fisher and Wiener were partly right.) The absence of any D gene and of
its postulated allelic form d in the Rh D-negative genome explains why
no Rh d antigen has ever been demonstrated.

Using cDNAs amplified from reticulocyte mRNA, Mouro et al. (1993)
investigated CcEe gene differences in Rh-negative individuals homozygous
for dCe, dcE, and dce haplotypes. The RNA analysis was followed by PCR
amplification of specific exons using genomic DNA from donors carrying a
range of common Rh haplotypes. The Ee polypeptide was shown to be
synthesized from the full-length transcript of the CcEe gene and to be
identical in length (417 residues) and very similar in sequence to the D
polypeptide. The Cc polypeptides were synthesized from shorter
transcripts of the same CcEe gene sequence, but spliced so as to exclude
exons 4, 5, and 6 or exons 4, 5 and 8. In both cases, the residue at 226
in exon 5 associated with Ee antigenicity was omitted from the
polypeptide product; see 111700.0001 and 111700.0002. Also see review by
Hopkinson (1993).

The Rh-null phenotype is of 2 types. The most common type, called the
'regulator type,' occurs by an inhibition mechanism; see 268150. This
form is caused by homozygosity for an autosomal recessive suppressor
gene that is genetically independent of the Rh locus, mapping to
chromosome 3 rather than to chromosome 1. The second type of Rh-null,
which was first described in a Japanese family (Ishimori and Hasekura,
1967), is called the 'amorph type' and results from homozygosity for a
silent allele at the Rh locus. In a survey of 42 examples of the Rh-null
phenotype, Nash and Shojania (1987) found that only 5 were of the amorph
type. Perez-Perez et al. (1992) described a Spanish family in which a
silent Rh gene was segregating, giving rise to the amorph type of
Rh-null in the proposita whose parents were first cousins. She suffered
from severe hemolytic anemia. Western blot analysis carried out with
glycosylation-independent antibodies directed against the Rh polypeptide
and the LW glycoprotein, respectively, confirmed that these protein
components were absent from the red cells of the proposita.

Investigations by Cherif-Zahar et al. (1993) failed to reveal any
alteration of the RH genes and transcripts in Rh(null) of the silent
type, and they suspected that these variants have a transcriptional or
post-transcriptional alteration of RH genes. Cherif-Zahar et al. (1996)
analyzed the RH locus and sequenced the Rh transcripts from 5
Rh-deficient phenotypes caused by an autosomal suppressor gene (reg and
mod types). They were unable to detect any abnormality; these variants
did not express RH genes but did convey a functional RH locus from one
generation to the next. They also detected no gross alteration in the
CD47 gene structure; transcripts were easily amplified and the
nucleotide sequence was identical to that from controls. This agreed
with binding studies indicating that CD47 is present on the red cell
surface of Rh-deficient cells, although severely reduced (10-15% of
controls). In general, their findings suggested that the low expression
of CD47 on Rh(null) erythrocytes results from the defective assembly or
transport to the cell surface when Rh proteins are absent.

Cherif-Zahar et al. (1994) demonstrated that the RHCE gene has 10 exons
distributed over 75 kb. Exons 4 to 8 are alternatively spliced in the
different RNA isoforms. Primary extension analysis indicated that the
transcription initiation site is located 83 bp upstream of the
initiation codon. Study of hematopoietic and nonhematopoietic (HeLa)
cell lines and Northern blot analysis suggested that the expression of
the RH locus is restricted to the erythroid/megakaryocytic lineage.
Consistent with this, putative binding sites for SP1, GATA-1, and Ets
proteins, nuclear factors known to be involved in erythroid and
megakaryocytic gene expression, were identified in the promoter of the
RHCE gene.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

Mollison (1994) reviewed the genetic basis of the Rh blood group system,
giving a brief survey of the early history. Rosenfield (1989) had
described the bitter disagreements between Wiener and Levine,
particularly over priority of discovery. Mollison (1994) reviewed the
disagreement between A. S. Wiener, who postulated multiple alleles at a
single locus (Wiener, 1943), and R. A. Fisher, who interpreted the data
of R. R. Race (1944) as most compatible with the existence of 3 closely
linked genes. Cartron and Agre (1993) reviewed the protein and gene
structure of the Rh blood group antigens. In summary, Rh-positive
persons have 2 Rh genes, 1 encoding the Cc- and Ee-bearing protein or,
more likely, proteins, and a second encoding the D-bearing protein,
while Rh-negative persons have only 1 Rh gene, the first of the 2
described above.

Cartron et al. (1995) defended the 2-gene model of the Rh blood group
system. They suggested that the RHCE gene encodes the C/c and E/e
proteins through alternative splicing of the primary transcript.
D-positive and D-negative individuals differ on the basis of the
presence or absence of the RHD gene, as a rule; in some Australian
Aborigines and Blacks, the fragment of the RHD gene or a nonfunctional
RHD gene is present. Smythe et al. (1996) found that both c and E
antigens were expressed after transduction of K562 cells with a single
cDNA, indicating that the c antigen does not arise by alternative
splicing (exon skipping) of the product of the RHCE gene.

Valenzuela et al. (1991) reported a strong association between plasma
total iron binding capacity (TIBC) and Cc Rh specificity in a Chilean
primary school population in Santiago. Valenzuela et al. (1995) found
similar results in university students from Medellin, Colombia.

In a 3-generation family ascertained through the East of Scotland Blood
Transfusion Service in Dundee, Scotland, Huang et al. (1996) found that
a cataract-causing mutation was cosegregating with an autosomal dominant
anomaly of Rh type known as the Evans phenotype. The geography and the
genetic linkage suggested that the form of cataract may be the same as
that in the Danish family. The red cell Evans phenotype is produced by a
hybrid RH gene in which exons 2-6 from the RHD gene (111680) is
transferred to the RHCE gene. Kemp et al. (1996) also examined 5
unrelated Rh D-- homozygotes and found that, in 4 of them, RHCE
sequences had been replaced by RHD sequences. The 5-prime end of these
rearrangements occurred within a 4.2-kb interval around exon 2. There
was, however, heterogeneity at the 3-prime end of the rearranged genes,
indicating that they were not identical by descent, but rather that
independent recombination events had occurred within a small genomic
interval--a recombination hot spot.

*FIELD* AV
.0001
RH E/e POLYMORPHISM
RHCE, PRO226ALA
Mouro et al. (1993) showed that the difference between the classic
allelic antithetical E and e antigens depends on a point mutation in
exon 5 which changes proline to alanine at residue 226 in the e allele.

.0002
RH C/c POLYMORPHISM
RHCE, CYS16TRP, ILE60LEU, SER68ASN, AND SER103PRO
Mouro et al. (1993) showed that the difference between the classic
allelic antithetical C and c antigens depends on point mutations leading
to 4 amino acid substitutions in exons 1 and 2 in the c allele.

*FIELD* SA
Levine et al. (1963); Lewis et al. (1976); Lewis et al. (1977); Rosenfield
et al. (1973); Schmidt  (1979); Sturgeon  (1970)
*FIELD* RF
1. Agre, P.; Cartron, J.-P.: Molecular biology of the Rh antigens. Blood 78:
551-563, 1991.

2. Blanchard, D.; Bloy, C.; Hermand, P.; Cartron, J.-P.; Saboori,
A. M.; Smith, B. L.; Agre, P.: Two-dimensional iodopeptide mapping
demonstrates that erythrocyte Rh D, c, and E polypeptides are structurally
homologous but nonidentical. Blood 72: 1424-1427, 1988.

3. Cartron, J.-P.; Agre, P.: Rh blood group antigens: protein and
gene structure. Semin. Hemat. 30: 193-208, 1993.

4. Cartron, J.-P.; Le Van Kim, C.; Cherif-Zahar, B.; Mouro, I.; Rouillac,
C.; Colin, Y.: The two-gene model of the RH blood-group locus. (Letter) Biochem.
J. 306: 877-878, 1995.

5. Cherif-Zahar, B.; Bloy, C.; Le Van Kim, C.; Blanchard, D.; Bailly,
P.; Hermand, P.; Salmon, C.; Cartron, J.-P.; Colin, Y.: Molecular
cloning and protein structure of a human blood group Rh polypeptide. Proc.
Nat. Acad. Sci. 87: 6243-6247, 1990.

6. Cherif-Zahar, B.; Le Van Kim, C.; Rouillac, C.; Raynal, V.; Cartron,
J.-P.; Colin, Y.: Organization of the gene (RHCE) encoding the human
blood group RhCcEe antigens and characterization of the promoter region. Genomics 19:
68-74, 1994.

7. Cherif-Zahar, B.; Mattei, M. G.; Le Van Kim, C.; Bailly, P.; Cartron,
J.-P.; Colin, Y.: Localization of the human Rh blood group gene structure
to chromosome region 1p34.3-1p36.1 by in situ hybridization. Hum.
Genet. 86: 398-400, 1991.

8. Cherif-Zahar, B.; Raynal, V.; Gane, P.; Mattei, M.-G.; Bailly,
P.; Gibbs, B.; Colin, Y.; Cartron, J.-P.: Candidate gene acting as
a suppressor of the RH locus in most cases of Rh-deficiency. Nature
Genet. 12: 168-173, 1996.

9. Cherif-Zahar, B.; Raynal, V.; Le Van Kim, C.; D'Ambrosio, A. M.;
Bailly, P.; Cartron, J. P.; Colin, Y.: Structure and expression of
the RH locus in the Rh-deficiency syndrome. Blood 82: 656-662, 1993.

10. Colin, Y.; Cherif-Zahar, B.; Le Van Kim, C.; Raynal, V.; Van Huffel,
V.; Cartron, J.-P.: Genetic basis of the RhD-positive and RhD-negative
blood group polymorphism as determined by Southern analysis. Blood 78:
2747-2752, 1991.

11. Cook, P. J. L.; Noades, J.; Hopkinson, D. A.; Robson, E. B.; Cleghorn,
T. E.: Demonstration of a sex difference in recombination fraction
in the loose linkage, Rh and PGM(1). Ann. Hum. Genet. 35: 239-242,
1972.

12. Corney, G.; Fisher, R. A.; Cook, P. J. L.; Noades, J.; Robson,
E. B.: Linkage between alpha-fucosidase and rhesus blood groups. Ann.
Hum. Genet. 40: 403-405, 1977.

13. Douglas, G. R.; McAlpine, P. J.; Hamerton, J. L.: Sub-regional
localization of human Pep C, PGM1 and PGD on chromosome 1 using Chinese
hamster-human somatic cell hybrids. (Abstract) Genetics 74: S65,
1973.

14. Hopkinson, D. A.: The long [E/e] and the short [C/c] of the rhesus
polymorphism. Nature Genet. 5: 6-7, 1993.

15. Huang, C.-H.; Chen, Y.; Reid, M.; Ghosh, S.: Genetic recombination
at the human RH locus: a family study of the red-cell Evans phenotype
reveals a transfer of exons 2-6 from the RHD to the RHCE gene. Am.
J. Hum. Genet. 59: 825-833, 1996.

16. Ishimori, T.; Hasekura, H.: A Japanese with no detectable Rh
blood group antigens due to silent Rh alleles or deleted chromosomes. Transfusion 7:
84-87, 1967.

17. Issitt, P. D.: Genetics of the Rh blood group system: some current
concepts. Med. Lab. Sci. 45: 395-404, 1988.

18. Jacobs, P. A.; Brunton, M.; Frackiewicz, A.; Newton, M.; Cook,
P. J. L.; Robson, E. B.: Studies on a family with three cytogenetic
markers. Ann. Hum. Genet. 33: 325-336, 1970.

19. Kemp, T. J.; Poulter, M.; Carritt, B.: A recombination hot spot
in the Rh genes revealed by analysis of unrelated donors with the
rare D-- phenotype. Am. J. Hum. Genet. 59: 1066-1073, 1996.

20. Lamm, L. U.; Kissmeyer-Nielsen, F.; Henningsen, K.: Linkage and
association studies of two phosphoglucomutase loci (PGM-1 and PGM-3)
to eighteen other markers. Hum. Hered. 20: 305-318, 1970.

21. Levine, P.; Celano, M. J.; Wallace, J.; Sanger, R.: A human 'D-like'
antibody. Nature 198: 596-597, 1963.

22. Lewis, M.: Personal Communication. Winnipeg, Manitoba, Canada
3/1989.

23. Lewis, M.; Kaita, H.; Chown, B.: Genetic linkage between the
human blood group loci Rh and Sc (Scianna). (Letter) Am. J. Hum.
Genet. 28: 619-620, 1976.

24. Lewis, M.; Kaita, H.; Chown, B.; Giblett, E. R.; Anderson, J.
E.: Relative positions of chromosome 1 loci Fy, PGM-1, Sc, UMPK,
Rh, PGD and ENO-1 in man. Canad. J. Genet. Cytol. 19: 695-709, 1977.

25. Marsh, W. L.; Chaganti, R. S. K.; Gardner, F. H.; Mayer, K.; Nowell,
P. C.; German, J.: Mapping human autosomes: evidence supporting assignment
of Rhesus to the short arm of chromosome no. 1. Science 183: 966-968,
1974.

26. Mollison, P. L.: The genetic basis of the Rh blood group system. Transfusion 34:
539-541, 1994.

27. Mouro, I.; Colin, Y.; Cherif-Zahar, B.; Cartron, J.-P.; Le Van
Kim, C.: Molecular genetic basis of the human Rhesus blood group
system. Nature Genet. 5: 62-65, 1993.

28. Nash, R.; Shojania, A. M.: Hematological aspect of Rh deficiency
syndrome: a case report and a review of the literature. Am. J. Hemat. 24:
267-275, 1987.

29. Olafsdottir, S.; Jensson, O.; Thordarson, G.; Sigurdardottir,
S.: An unusual Rhesus haplotype, -D-, in Iceland. Forensic Sci.
Int. 22: 183-187, 1983.

30. Perez-Perez, C.; Taliano, V.; Mouro, I.; Huet, M.; Salat-Marti,
A.; Martinez, A.; Rouger, P.; Cartron, J.-P.: Spanish Rh-null family
caused by a silent Rh gene: hematological, serological, and biochemical
studies. Am. J. Hemat. 40: 306-312, 1992.

31. Plapp, F. V.; Kowalski, M. M.; Tilzer, L.; Brown, P. J.; Evans,
J.; Chiga, M.: Partial purification of Rh-0(D) antigen from Rh positive
and negative erythrocytes. Proc. Nat. Acad. Sci. 76: 2964-2968,
1979.

32. Race, R. R.: An 'incomplete' antibody in human serum. (Letter) Nature 153:
771-772, 1944.

33. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
(pub.)  (6th ed.): 1975. Pp. 188-212.

34. Race, R. R.; Sanger, R.; Selwyn, J. G.: A possible deletion in
human Rh chromosome: a serological and genetical study. Brit. J.
Exp. Path. 32: 124-135, 1951.

35. Race, R. R.; Sanger, R.; Selwyn, J. G.: A probable deletion in
a human Rh chromosome. Nature 166: 520, 1950.

36. Renwick, J. H.: The Rhesus syntenic group in man. Nature 234:
475, 1971.

37. Rosenfield, R. E.: Who discovered Rh? A personal glimpse of the
Levine-Wiener argument. Transfusion 29: 355-357, 1989.

38. Rosenfield, R. E.: Personal Communication. New York, N. Y.
6/30/1981.

39. Rosenfield, R. E.; Allen, F. H., Jr.; Rubenstein, P.: Genetic
model for the Rh blood-group system. Proc. Nat. Acad. Sci. 70: 1303-1307,
1973.

40. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

41. Saboori, A. M.; Smith, B. L.; Agre, P.: Polymorphism in the M(r)
32,000 Rh protein purified from Rh(D)-positive and -negative erythrocytes. Proc.
Nat. Acad. Sci. 85: 4042-4045, 1988.

42. Sanger, R.; Tippett, P.; Gavin, J.; Race, R. R.: Failure to demonstrate
linkage between the loci for the Rh and Duffy blood groups. Ann.
Hum. Genet. 38: 353-354, 1973.

43. Schmidt, P. J.: Hereditary hemolytic anemias and the null blood
types. Arch. Intern. Med. 139: 570-571, 1979.

44. Smythe, J. S.; Avent, N. D.; Judson, P. A.; Parsons, S. F.; Martin,
P. G.; Anstee, D. J.: Expression of RHD and RHCE gene products using
retroviral transduction of K562 cells establishes the molecular basis
of Rh blood group antigens. Blood 87: 2968-2973, 1996.

45. Steinberg, A. G.: Evidence for a mutation or crossing over at
the Rh locus. Vox Sang. 10: 721-724, 1965.

46. Steinberg, A. G.; Giblett, E. R.; Lewis, M.; Zachary, A. A.:
A crossover or mutation in the Rh region revisited. Am. J. Hum. Genet. 36:
700-703, 1984.

47. Sturgeon, P.: Hematological observations on the anemia associated
with blood type Rh-null. Blood 36: 310-320, 1970.

48. Tippett, P.: Depressed Rh phenotypes. Rev. Franc. Transfusion 21:
135-150, 1978.

49. Valenzuela, C. Y.; Avendano, A.; Harb, Z.: Association between
Rh and plasma iron binding (transferrin). Hum. Genet. 87: 438-440,
1991.

50. Valenzuela, C. Y.; Bravo, M. L.; Alarcon, J. C.: Rh-plasma iron
binding capacity association: new evidence. Hum. Genet. 96: 219-220,
1995.

51. Wiener, A. S.: Genetic theory of the Rh blood types. Proc. Soc.
Exp. Biol. Med. 54: 316-319, 1943.

52. Wiener, A. S.: The Rh series of allelic genes. Science 100:
595-597, 1944.

*FIELD* CN
Moyra Smith - updated: 10/26/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/29/1996
terry: 12/20/1996
mark: 10/26/1996
terry: 10/17/1996
mark: 5/9/1996
terry: 5/2/1996
terry: 3/26/1996
mark: 2/1/1996
terry: 1/30/1996
mark: 8/22/1995
davew: 8/18/1994
terry: 5/13/1994
mimadm: 4/29/1994
pfoster: 4/25/1994
warfield: 4/7/1994

*RECORD*
*FIELD* NO
111730
*FIELD* TI
*111730 BLOOD GROUP--Sd SYSTEM; Sd
*FIELD* TX
Sd blood group substance, like ABO and Lewis substances, is secreted
into the saliva.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
MacVie et al. (1967); Renton et al. (1967)
*FIELD* RF
1. MacVie, S. I.; Morton, J. A.; Pickles, M. M.: The reactions and
inheritance of a new blood group antigen, Sd(a). Vox Sang. 13:
485-492, 1967.

2. Renton, P. H.; Howell, P.; Ikin, E. W.; Giles, C. M.; Goldsmith,
K. L. G.: Anti-Sd(a), a new blood group antibody. Vox Sang. 13:
493-501, 1967.

3. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 2/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 4/20/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
111740
*FIELD* TI
*111740 BLOOD GROUP--Ss LOCUS; Ss
GLYCOPHORIN B, INCLUDED;;
GYPB, INCLUDED;;
GPB, INCLUDED
*FIELD* TX
Ss and MN (GPA; 111300) are closely linked but separate gene loci on
chromosome 4 (4q28-q31). Several instances of recombination between the
loci have been observed (see review by Race and Sanger, 1975). Close
linkage of the genes for the two sialoglycoproteins that carry the MN
and Ss specificities, respectively, is also indicated by the
identification of hybrid molecules that appear to have arisen by a
Lepore-type mechanism (Mawby et al., 1981). The erythrocyte
glycophorins, which lie partly within the cell membrane and partly
exposed to the exterior, contain 203 amino acids. The amino-terminal
half is exposed and is the one that bears the oligosaccharide complexes
that determine blood-group antigen specificities and serve as receptors
for viruses and plant agglutinins. As indicated in 111300, the Ss blood
group antigens are located on glycophorin B. The structural difference
between SS and ss specificities is a methionine-to-threonine
polymorphism at position 29. Ferrari and Pavia (1986) synthesized 2
peptides, each 8 amino acids long, carrying the Ss specificities: SS,
asn-gly-glu-met-gly-gln-leu-val; ss, asn-gly-glu-thr-gly-gln-leu-val.
Glycophorin C is the site of the Gerbich blood group antigen specificity
(110750). Siebert and Fukuda (1987) isolated a cDNA for human
glycophorin B and determined its nucleotide sequence. They used RNA blot
hybridization with both cDNA and synthetic oligonucleotide probes to
prove that glycophorins A and B are negatively and coordinately
regulated by a tumor-promoting phorbol ester. They established,
furthermore, the intron/exon structure of the glycophorin A and B genes
by oligonucleotide mapping. The results suggested a complex evolution of
the glycophorin genes. Huang et al. (1987) presented evidence derived
from protein and genomic DNA analyses that erythrocytes of 2 unrelated
persons homozygous for the S--s--U-- blood group phenotype lack
delta-glycophorin as a result of a delta-glycophorin gene deletion.
Dantu and Stones are 2 variant antigens carried by hybrid glycoproteins
that appear to be products of delta and alpha glycophorin fusion genes.
In Stones, symbolized St(a), the junction is from amino acid residue 26
or 28 of delta to residue 59 or 61 of alpha, whereas in Dantu, residue
38 or 39 of delta is joined to residue 71 or 72 of alpha.

Huang and Blumenfeld (1988) delineated the structure of the alpha and
delta glycophorins at the genomic level in the DNA from a 3-generation
black family in which both the presence of Dantu and Mi-III (another
rare MNs antigen) and the absence of delta-glycophorin were seen. Kudo
and Fukuda (1989) compared the genomic structures of GPA and GPB; they
consist of 7 and 5 exons, respectively, and both genes have more than
95% identical sequence from the 5-prime flanking region to the region
about 1 kb downstream from the exon encoding the transmembrane region.
In this homologous part of the genes, GPB lacks 1 exon due to a point
mutation at the 5-prime splicing site of the third intron, which
inactivates the 5-prime cleavage event of splicing and leads to ligation
of the second to the fourth exon. No homology could be detected in the
3-prime ends of the 2 genes. The transition from homologous to
nonhomologous sequences is located within Alu repeat sequences. An
ancestral genomic structure appears to have been maintained in the GPA
gene, whereas the GPB gene acquired 3-prime sequences different from
those of the GPA gene by homologous recombination at the Alu repeats
during or after gene duplication. Onda et al. (1993) identified the
putative precursor genomic segment located downstream from the GPA gene.
The isolated genomic clones contained an Alu sequence that appeared to
be involved in the recombination. Downstream from the Alu sequence, the
nucleotide sequence of the precursor genomic segment was almost
identical to that of the GPB or GPE gene (138590). In contrast, the
upstream sequence of the genomic segment differed entirely from that of
the GPA, GPB, and GPE genes. They interpreted the results as indicating
that one of the duplicated ancestral glycophorin genes acquired a unique
3-prime sequence by unequal crossingover through its Alu sequence and
the further downstream Alu sequence present in the duplicated gene.
Further duplication and divergence of this gene yielded the GPB and GPE
genes. Onda et al. (1993) mapped the precursor genomic sequence to
4q28-q31 by in situ hybridization.

Onda and Fukuda (1995) isolated several P1 plasmid clones with which
they characterized the organization of the glycophorin A (GPA), B, and E
gene cluster which spans about 330 kb of chromosome 4q31. For each gene,
the first intron varies in size from 25 to 29 kb, while the intergenic
interval is approximately 80 kb. The authors proposed that the
GPA-GPB-GPE cluster arose by 2 successive duplications and a number of
subsequent events, including a gene conversion between the exon 2 region
of GPA and GPE.

*FIELD* SA
Marchesi et al. (1972)
*FIELD* RF
1. Ferrari, B.; Pavia, A. A.: Blood group antigens: synthesis of
Ss antigenic peptides related to human glycophorin B. Int. J. Peptide
Protein Res. 28: 456-461, 1986.

2. Huang, C.-H.; Blumenfeld, O. O.: Characterization of a genomic
hybrid specifying the human erythrocyte antigen Dantu: Dantu gene
is duplicated and linked to a delta glycophorin gene deletion. Proc.
Nat. Acad. Sci. 85: 9640-9644, 1988.

3. Huang, C.-H.; Johe, K.; Moulds, J. J.; Siebert, P. D.; Fukuda,
M.; Blumenfeld, O. O.: Delta-glycophorin (glycophorin B) gene deletion
in two individuals homozygous for the S--s--U-- blood group phenotype.
Blood 70: 1830-1835, 1987.

4. Kudo, S.; Fukuda, M.: Structural organization of glycophorin A
and B genes: glycophorin B gene evolved by homologous recombination
at Alu repeat sequences. Proc. Nat. Acad. Sci. 86: 4619-4623, 1989.

5. Marchesi, V. T.; Tillack, T. M.; Jackson, R. L.; Segrest, J. P.;
Scott, R. E.: Chemical characterization and surface orientation of
the major glycoprotein of the human erythrocyte membrane. Proc.
Nat. Acad. Sci. 69: 1445-1449, 1972.

6. Mawby, W. J.; Anstee, D. J.; Tanner, M. J. A.: Immunochemical
evidence for hybrid sialoglycoproteins of human erythrocytes. Nature 291:
161-162, 1981.

7. Onda, M.; Fukuda, M.: Detailed physical mapping of the genes encoding
glycophorins A, B, and E, as revealed by P1 plasmids containing human
genomic DNA. Gene 159: 225-230, 1995.

8. Onda, M.; Kudo, S.; Rearden, A.; Mattei, M.-G.; Fukuda, M.: Identification
of a precursor genomic segment that provided a sequence unique to
glycophorin B and E genes. Proc. Nat. Acad. Sci. 90: 7220-7224,
1993.

9. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
(pub.)  (6th ed.): 1975. Pp. 92-138.

10. Siebert, P. D.; Fukuda, M.: Molecular cloning of a human glycophorin
B cDNA: nucleotide sequence and genomic relationship to glycophorin
A. Proc. Nat. Acad. Sci. 84: 6735-6739, 1987.

*FIELD* CN
Alan F. Scott - updated: 8/9/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/17/1996
mark: 3/7/1996
davew: 8/18/1994
terry: 5/13/1994
carol: 10/4/1993
supermim: 3/16/1992
carol: 3/20/1991

*RECORD*
*FIELD* NO
111750
*FIELD* TI
*111750 BLOOD GROUP--SCIANNA SYSTEM; Sc
*FIELD* TX
The Scianna locus is represented by 2 blood group antigens called Sc-1
(formerly Sm) and Sc-2 (formerly Bu-a). The Rh laboratory at Winnipeg
has lods greater than +3.0 for Scianna on human chromosome 1 (Cote,
1976). Concerning the Rh:Sc linkage, Lewis et al. (1976) found that at a
recombination fraction of 0.10, the lod score was +5.34 for sibships
with the father as the double heterozygote and -5.955 for those with the
mother as the double heterozygote. Using data on 13 loci, Rao et al.
(1979) derived a maximum likelihood map of chromosome 1. Confirmation of
the assignment of Scianna to chromosome 1 was achieved thereby. Noades
et al. (1979) found recombination between UMPK (191710) and Sc,
suggesting that UMPK lies between Sc and PGM-1 (171900).

*FIELD* SA
Lewis et al. (1974)
*FIELD* RF
1. Cote, G. B.: Personal Communication. Athens, Greece  5/10/1976.

2. Lewis, M.; Kaita, H.; Chown, B.: Scianna blood group system. Vox
Sang. 27: 261-264, 1974.

3. Lewis, M.; Kaita, H.; Chown, B.: Genetic linkage between the human
blood group loci Rh and Sc (Scianna).  (Letter) Am. J. Hum. Genet. 28:
619-620, 1976.

4. Noades, J. E.; Corney, G.; Cook, P. J. L.; Putt, W.; King, J.;
Fisher, R. A.; Spowart, G.; Lee, M.; Bowell, P. J.: The Scianna blood
group lies distal to uridine monophosphate kinase on chromosome 1p.
Ann. Hum. Genet. 43: 121-132, 1979.

5. Rao, D. C.; Keats, B. J.; Lalouel, J. M.; Morton, N. E.; Yee, S.
: A maximum likelihood map of chromosome 1. Am. J. Hum. Genet. 31:
680-696, 1979.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 2/9/1987
marie: 12/15/1986

*RECORD*
*FIELD* NO
111800
*FIELD* TI
*111800 BLOOD GROUP--STOLTZFUS SYSTEM; Sf
*FIELD* TX
An antibody that tests for an antigen in a seemingly 'new' blood group
system was found in the Lancaster County Amish (Bias et al., 1969). It
has been designated Stoltzfus, symbolized Sf. For males, Bias and Meyers
(1979) found a maximal lod score of 3.99 at theta 0.18 for Stoltzfus and
MNS. Acid phosphatase and Kidd both gave lods of 0.32 with Stoltzfus at
a male theta of 0.20. Bias and Meyers (1982) presented additional data
bringing the maximum lods to 5.01 for theta 0.25 in males and 3.05 for
theta 0.27 in females.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* RF
1. Bias, W. B.; Light-Orr, J. K.; Krevans, J. R.; Humphrey, R. L.;
Hamill, P. V. V.; Cohen, B. H.; McKusick, V. A.: The Stoltzfus blood
group, a new polymorphism in man. Am. J. Hum. Genet. 21: 552-558,
1969.

2. Bias, W. B.; Meyers, D. A.: Segregation and linkage analysis of
the Stoltzfus blood group (SF).  (Abstract) Cytogenet. Cell Genet. 25:
137 only, 1979.

3. Bias, W. B.; Meyers, D. A.: Further data on the linkage between
MNS and Stoltzfus blood group systems.  (Abstract) Cytogenet. Cell
Genet. 32: 254 only, 1982.

4. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 5/13/1994
mimadm: 2/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 4/20/1989

*RECORD*
*FIELD* NO
112000
*FIELD* TI
*112000 BLOOD GROUP--Ul SYSTEM; UL
*FIELD* TX
In Finland Furuhjelm et al. (1968) found an antibody that tests for a
previously unknown antigen called Ul(a). The antigen was present in 2.6%
of Helsinki donors. Independence from Kell, Yt and Diego systems was not
yet proved but it was independent of other systems. The Ul(a) locus may
be within measurable distance of the ABO and adenylate kinase loci.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* RF
1. Furuhjelm, U.; Nevanlinna, H. R.; Nurkka, R.; Gavin, J.; Tippett,
P.; Gooch, A.; Sanger, R.: The blood group antigen Ul(a) (Karhula).
Vox Sang. 15: 118-124, 1968.

2. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 2/11/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
johnj: 4/24/1989
carol: 3/26/1988

*RECORD*
*FIELD* NO
112010
*FIELD* TI
#112010 BLOOD GROUP--WALDNER TYPE; WD
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Wd(a) antigenic expression is due to a point mutation in the SLC4A1 gene
(109270.0011).

Lewis and Kaita (1981) found a 'new' red cell antigen in Hutterites of
the surname Waldner. It is not part of the ABO, Chido, Colton, Dombrock,
Duffy, Kidd, MN, P or Rh blood group systems. Zelinski et al. (1995)
stated that the WD blood group antigen had been identified in Khoisans
in South Africa and in a family in Holland. By genetic linkage analysis,
they showed that WD is loosely linked to the reference marker D17S41 at
17q12-q24 and closely linked to the anion exchange protein-1 locus
(SLC4A1; 109270) at 17q12-q21.

Bruce et al. (1995) demonstrated that the Wd(a) results from a point
mutation with substitution of methionine for valine-557 in erythrocyte
band 3 (SLC4A1).

*FIELD* RF
1. Bruce, L. J.; Tanner, M. J.; Zelinski, T.: The low incidence blood
group antigen, Wd(a), is associated with the substitution val557-to-met
in human erythrocyte band 3. (Abstract) Transfusion 35 (Suppl.):
52S only, 1995.

2. Lewis, M.; Kaita, H.: A 'new' low incidence 'Hutterite' blood
group antigen Waldner (Wd-a). Am. J. Hum. Genet. 33: 418-420, 1981.

3. Zelinski, T.; Coghlan, G.; White, L.; Phillips, S.: Assignment
of the Waldner blood group locus (WD) to 17q12-q21. Genomics 25:
320-322, 1995.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/26/1996
terry: 12/16/1996
carol: 2/10/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/28/1988

*RECORD*
*FIELD* NO
112050
*FIELD* TI
#112050 BLOOD GROUP--WRIGHT ANTIGEN; Wr
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
blood group Wright antigens are associated with a mutation at amino acid
658 in human erythrocyte band 3 (BND3; 109270).

The Wright antigen, a 'private' blood group (111500), was found by
Holman (1953). Although it is very rare, the early date of its discovery
and the ready availability of testing sera led to a large number of
persons and variety of populations being tested. The frequency of the
gene for the Wr(a) antigen was found to be about 3 in 10,000 among
Europeans (Mourant et al., 1978).

Because the Wr(b) antigen appeared to involve both red blood cell band 3
and glycophorin A (GPA; 111300), Bruce et al. (1995) examined the cDNA
sequences of band 3 and GPA of 1 of the 2 known Wr(a+b-) individuals.
They showed that this person was homozygous for a glu658-to-lys mutation
in the BND3 gene, but had normal GPA. Putative heterozygotes with
Wr(a+b+) RBCs had both glu and lys at residue 658 of band 3, whereas the
common Wr(a-b+) RBC phenotype had only band 3 with glu658. Thus, the
Wr(a) and Wr(b) antigens are determined by the amino acid at residue 658
of band 3 and are antithetical. Bruce et al. (1995) proposed that arg61
of GPA interacts with glu658 of band 3 to form the Wr(b) antigen.

*FIELD* RF
1. Bruce, L. J.; Ring, S. M.; Anstee, D. J.; Reid, M. E.; Wilkinson,
S.; Tanner, M. J. A.: Changes in the blood group Wright antigens
are associated with a mutation at amino acid 658 in human erythrocyte
band 3: a site of interaction between band 3 and glycophorin A under
certain conditions. Blood 85: 541-547, 1995.

2. Holman, C. A.: A new rare human blood group antigen, Wr(a). Lancet II:
119-120, 1953.

3. Mourant, A. E.; Kopec, A. C.; Domaniewska-Sobczak, K.: The Genetics
of Jews.  Oxford: Clarendon Press (pub.)  1978. Pp. 7 only.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/20/1995
supermim: 3/16/1992
carol: 2/6/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
112100
*FIELD* TI
#112100 BLOOD GROUP--Yt SYSTEM; YT
CARTWRIGHT
*FIELD* TX
A number sign (#) is used with this entry because of the finding that
this blood group system is an antigenic expression of the
acetylcholinesterase molecule (ACHE; 100740).

The antibody defining the very common antigen Yt(a) was the cause of a
cross-matching difficulty investigated by Eaton et al. (1956). It was
presumed to be the result of previous transfusions. Among 1,051 English
people, 4 negatives were found. Positives showed 2 grades of strength of
reaction; on the assumption that the weaker reactors represented
heterozygotes, an estimate of gene frequency simply by counting was
possible. Independence of the ABO, MN, Ph, Lutheran, P, Kell, Lewis,
secretor, Duffy, Kidd, Dombrock, and Colton systems has been achieved
(Race and Sanger, 1975). Coghlan et al. (1989) found loose linkage of Yt
and the Kell blood group locus (110900); the maximum lod score was 3.48
at theta = 0.28. The mapping of the Kell blood group locus (see 110900)
to chromosome 7 means that the YT locus is also on 7q. This was directly
demonstrated by Zelinski et al. (1991) who found close linkage to COL1A2
(120160); peak lod = 3.61 at theta = 0.00. It was also tightly linked to
DNA marker D7S13; peak lod = 3.31 at theta = 0.00.

The Cartwright (Yt) red cell antigen was shown to reside on an
unidentified phosphatidylinositol (PI)-linked protein (Telen et al.,
1990). Telen and Whitsett (1992) identified a patient with the hitherto
unreported Yt(a-b-) phenotype in whom studies allowed localization of
the Yt antigens to the acetylcholinesterase molecule. Telen and Whitsett
(1992) found that binding of antibodies to several membrane proteins
including CD55 (125240), CD58 (153420), and CD59 (107271) were normal,
whereas 4 monoclonal antibodies to different acetylcholinesterase
epitopes reacted only weakly with Yt(a-b-) erythrocytes. In addition,
enzymatic assay of acetylcholinesterase activity of Yt(a-b-)
erythrocytes demonstrated only 15% of the normal amount of enzyme
activity. The use of anti-Yt(a) in radioimmunoprecipitation experiments
demonstrated the expected 160 kD of the acetylcholinesterase molecule
from normal erythrocyte membrane proteins, but not from Yt(a-b-)
erythrocytes. Spring et al. (1992) obtained similar results. Thus,
acetylcholinesterase is the PI-linked protein that represents the Yt
antigen.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Giles et al. (1967)
*FIELD* RF
1. Coghlan, G.; Kaita, H.; Belcher, E.; Philipps, S.; Wong, P.; McAlpine,
P. J.; Zelinski, T.; Lewis, M.: Genetic linkage between the Kell
and Yt blood group loci.  (Abstract) Cytogenet. Cell Genet. 51:
978 only, 1989.

2. Eaton, B. R.; Morton, J. A.; Pickles, M. M.; White, K. E.: A new
antibody anti-Yt(a), characterizing a blood group antigen of high
incidence. Brit. J. Haemat. 2: 333-341, 1956.

3. Giles, C. M.; Metaxas-Buhler, M.; Romanski, Y.; Metaxas, M. N.
: Studies on the Yt blood group system. Vox Sang. 13: 171-180,
1967.

4. Race, R. R.; Sanger, R.: Blood Groups in Man.  Oxford: Blackwell
Sci. Publ. (pub.)  (6th ed.): 1975. Pp. 379-382.

5. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

6. Spring, F. A.; Gardner, B.; Anstee, D. J.: Evidence that the antigens
of the Yt blood group system are located on human erythrocyte acetylcholinesterase.
Blood 80: 2136-2141, 1992.

7. Telen, M. J.; Rosse, W. F.; Parker, C. J.; Moulds, M. K.; Moulds,
J. J.: Evidence that several high-frequency human blood group antigens
reside on phosphatidylinositol-linked erythrocyte membrane proteins.
Blood 75: 1404-1407, 1990.

8. Telen, M. J.; Whitsett, C. F.: Erythrocyte acetylcholinesterase
bears the Cartwright blood group antigens.  (Abstract) Clin. Res. 40:
170A only, 1992.

9. Zelinski, T.; White, L.; Coghlan, G.; Philipps, S.: Assignment
of the YT blood group locus to chromosome 7q. Genomics 11: 165-167,
1991.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/18/1994
mimadm: 2/11/1994
carol: 10/19/1993
carol: 7/13/1993
carol: 12/1/1992
carol: 10/13/1992

*RECORD*
*FIELD* NO
112200
*FIELD* TI
*112200 BLUE RUBBER BLEB NEVUS
BEAN SYNDROME
*FIELD* TX
This is a bladderlike variety of hemangioma found particularly on the
trunk and upper arms. Nocturnal pain and regional hyperhidrosis are
features. Bleeding hemangiomas of the gastrointestinal tract are an
important complication. Berlyne and Berlyne (1960) demonstrated
transmission through 5 generations. Other cases have been sporadic,
perhaps new dominant mutations. Fretzin and Potter (1965) described a
particularly dramatic case with involvement of the skin and
gastrointestinal tract and angiomatous gigantism of the right arm
requiring amputation in infancy. In a single case in a Japanese woman,
Sakurane et al. (1967) described cavernous hemangiomas characteristic of
blue rubber bleb nevi over the entire surface of the body and in the
mucosa of the oropharynx, esophagus, distal ileum and anus. In addition
the patient had multiple enchondromatosis. This, then, had many of the
features of Maffucci syndrome (see 166000). Two families with affected
persons in 3 and 5 successive generations, supporting autosomal dominant
inheritance, were reported by Walshe et al. (1966). Bean (1958) gave the
name to this condition which, furthermore, he was mainly instrumental in
delineating. Rice and Fischer (1962) observed the association of
cerebellar medulloblastoma. They illustrated the extraordinary
appearance of the skin lesions. Intestinal hemangiomas were found at
autopsy. Munkvad (1983) reported a family with 7 affected persons in 3
generations, including father-to-son transmission. The skin tumors are
rubberlike nipples, easily compressible and promptly refilling after
compression. They vary in color, size, shape and number and may be
tender. The affected persons in Munkvad's pedigree had no evidence of
visceral abnormality. Satya-Murti et al. (1986) described a 19-year-old
man with extensive central nervous involvement who had a chronic, slowly
progressive, and nonfatal course.

See 600195 for a familial venous malformation syndrome (VMCM) that may
be the same as the blue rubber bleb nevus syndrome of Bean (1958), which
maps to 9p. Gallione et al. (1995) suggested that VMCM is identical to
the Bean syndrome. Several members of the family they studied had
gastrointestinal bleeding from vascular lesions just as did the family
originally described by Bean (1958).

*FIELD* SA
Fine et al. (1961); Hoffman et al. (1978); McCauley et al. (1979);
Morris et al. (1978); Nakagawara et al. (1977); Talbot and Wyatt (1970)
*FIELD* RF
1. Bean, W. B.: Vascular Spiders and Related Lesions of the Skin.
Springfield, Ill.: Charles C Thomas (pub.)  1958. Pp. 178-185.

2. Berlyne, G. M.; Berlyne, N.: Anaemia due to 'blue-rubber-bleb'
naevus disease. Lancet II: 1275-1277, 1960.

3. Fine, R. M.; Derbes, V. J.; Clark, W. H.: Blue rubber bleb nevus.
Arch. Derm. 84: 802-805, 1961.

4. Fretzin, D. F.; Potter, B.: Blue rubber bleb nevus. Arch. Intern.
Med. 116: 924-929, 1965.

5. Gallione, C. J.; Pasyk, K. A.; Boon, L. M.; Lennon, F.; Johnson,
D. W.; Helmbold, E. A.; Markel, D. S.; Vikkula, M.; Mulliken, J. B.;
Warman, M. L.; Pericak-Vance, M. A.; Marchuk, D. A.: A gene for familial
venous malformations maps to chromosome 9p in a second large kindred.
J. Med. Genet. 32: 197-199, 1995.

6. Hoffman, T.; Chasko, S.; Safai, B.: Association of blue rubber
bleb nevus syndrome with chronic lymphocytic leukemia and hypernephroma.
Johns Hopkins Med. J. 142: 91-94, 1978.

7. McCauley, R. G. K.; Leonidas, J. C.; Bartoshesky, L. E.: Blue
rubber bleb nevus syndrome. Radiology 133: 375-377, 1979.

8. Morris, S. J.; Kaplan, S. R.; Ballan, K.; Tedesco, F. J.: Blue
rubber-bleb nevus syndrome. J.A.M.A. 239: 1887 only, 1978.

9. Munkvad, M.: Blue rubber bleb nevus syndrome. Dermatologica 167:
307-309, 1983.

10. Nakagawara, G.; Asano, E.; Kimura, S.; Akimoto, R.; Miyazaki,
I.: Blue rubber bleb nevus syndrome: report of a case. Dis. Colon
Rectum 20: 421-427, 1977.

11. Rice, J. S.; Fischer, D. S.: Blue rubber bleb nevus syndrome.
Arch. Derm. 86: 503-511, 1962.

12. Sakurane, H. F.; Sugai, T.; Saito, T.: The association of blue
rubber bleb nevus and Maffucci's syndrome. Arch. Derm. 95: 28-36,
1967.

13. Satya-Murti, S.; Navada, S.; Eames, F.: Central nervous system
involvement in blue-rubber-bleb-nevus syndrome. Arch. Neurol. 43:
1184-1186, 1986.

14. Talbot, S.; Wyatt, E. H.: Blue rubber bleb naevi (report of a
family in which only males were affected). Brit. J. Derm. 82: 37-39,
1970.

15. Walshe, M. M.; Evans, C. D.; Warin, R. P.: Blue rubber bleb naevus.
Brit. Med. J. 2: 931-932, 1966.

*FIELD* CS

Skin:
   Bladderlike skin hemangiomas, esp. of trunk and upper arms;
   Nocturnal pain and regional hyperhidrosis

GI:
   Bleeding gastrointestinal hemangiomas

Limbs:
   Angiomatous gigantism

Neuro:
   Cerebellar medulloblastoma

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 4/19/1995
mimadm: 4/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
112203
*FIELD* TI
*112203 CD80 ANTIGEN; CD80
CD28 ANTIGEN LIGAND 1; CD28LG1;;
B-LYMPHOCYTE ACTIVATION ANTIGEN B7-1; LAB7;;
B7-1 ANTIGEN
*FIELD* TX
The B-lymphocyte activation antigen B7-1 (formerly referred to as B7)
provides regulatory signals for T lymphocytes as a consequence of
binding to the CD28 (186760) and CTLA-4 (123890) ligands of T cells. The
cDNA for B7-1 predicts a type I membrane protein, i.e., one synthesized
with a signal peptide that is cleaved upon translocation across the
endoplasmic membrane. The protein is predicted to contain 2
extracellular domains structurally similar to those of Ig, a hydrophobic
transmembrane region, and a short cytoplasmic domain. Selvakumar et al.
(1992) found that the gene has 6 exons that span approximately 32 kb of
genomic DNA. Exon 1 is not translated, and exon 2 contains the
initiation ATG codon and encodes a predicted signal peptide. Exons 3 and
4 correspond to 2 Ig-like domains, whereas exons 5 and 6, respectively,
encode the transmembrane portion and the cytoplasmic tail. This close
relationship between exons and functional domains is a characteristic
feature of genes of the Ig superfamily.

By DNA blot analysis of human/rodent somatic cell hybrids, Selvakumar et
al. (1992) demonstrated that the LAB7 gene is located on chromosome 3 in
the q21-qter region. Cell surface expression of the presumed B7 gene
product had previously been mapped to human chromosome 12 by antibody
reactivity with the B7-specific monoclonal antibody BB-1 (Katz et al.,
1985). Freeman et al. (1992) corroborated the assignment to chromosome
3, using the technique of PCR on a panel of hamster/human somatic cell
hybrid DNAs. They further localized the gene to 3q13.3-q21 by in situ
hybridization. Freeman et al. (1992) pointed out that trisomy of
chromosome 3 is a recurrent chromosome change seen in various lymphomas
and lymphoproliferative disorders and that chromosomal defects involving
3q21 have been described in leukemia and myelodysplastic states.

As the ligand for CD28, LAB7-1 is also symbolized CD28LG1.

*FIELD* RF
1. Freeman, G. J.; Disteche, C. M.; Gribben, J. G.; Adler, D. A.;
Freedman, A. S.; Dougery, J.; Nadler, L. M.: The gene for B7, a costimulatory
signal for T-cell activation, maps to chromosomal region 3q13.3-3q21.
Blood 79: 489-494, 1992.

2. Katz, F. E.; Parkar, M.; Stanley, K.; Murray, L. J.; Clark, E.
A.; Greaves, M. F.: Chromosome mapping of cell membrane antigens
expressed on activated B cells. Europ. J. Immun. 15: 103-106, 1985.

3. Selvakumar, A.; Mohanraj, B. K.; Eddy, R. L.; Shows, T. B.; White,
P. C.; Dupont, B.: Genomic organization and chromosomal location
of the human gene encoding the B-lymphocyte activation antigen B7.
Immunogenetics 36: 175-181, 1992.

*FIELD* CN
Alan F. Scott - updated: 1/29/1996

*FIELD* CD
Victor A. McKusick: 8/27/1992

*FIELD* ED
terry: 04/17/1996
mark: 1/29/1996
jason: 7/5/1994
carol: 4/29/1994
carol: 12/22/1993
carol: 12/14/1993
carol: 1/13/1993
carol: 8/27/1992

*RECORD*
*FIELD* NO
112205
*FIELD* TI
*112205 B-LYMPHOCYTE-SPECIFIC MB-1 PROTEIN; MB1
*FIELD* TX
The mouse mb-1 gene was originally identified on the basis of its
restricted expression in lymphocytes of B lineage. Predicted structural
homology with the gamma chain of the CD3 complex of T cells (186740) led
to the suggestion that the MB-1 protein may associate with surface
immunoglobulin on B cells and be involved in signal transduction. To
identify genes specifically expressed in normal human B cells, Ha et al.
(1992) constructed a B minus T lymphocyte subtraction library and
isolated a cDNA clone highly homologous to murine mb-1. The full-length
cDNA was found to encode a membrane glycoprotein of 226 amino acids
which showed striking homology to the mouse mb-1 through much of its
structure.

*FIELD* RF
1. Ha, H.; Kubagawa, H.; Burrows, P. D.: Molecular cloning and expression
pattern of a human gene homologous to the murine mb-1 gene. J. Immun. 148:
1526-1531, 1992.

*FIELD* CD
Victor A. McKusick: 5/5/1992

*FIELD* ED
carol: 5/5/1992

*RECORD*
*FIELD* NO
112210
*FIELD* TI
*112210 B-LYMPHOCYTE SURFACE ANTIGEN B1; CD20
*FIELD* TX
B1, also known as CD20, is a human B-lymphocyte surface molecule that is
widely expressed during B-cell ontogeny, from early pre-B-cell
developmental stages until final differentiation into plasma cells.
Although the exact role of B1 in vivo is unknown, functional studies
using monoclonal antibodies have shown that antibody binding to B1
inhibits B-cell proliferation caused by mitogens and inhibits B-cell
differentiation. Tedder et al. (1988) described the primary structure of
CD20. Tedder et al. (1989) showed that the CD20 gene is 16 kb long and
composed of 8 exons.

Using in situ hybridization and Southern blotting of hybrid cell DNA,
Tedder et al. (1989) showed that the CD20 gene is located on 11q12-q13.
This localization places the CD20 gene near the site of the
t(11;14)(q13;q32) translocation that is found in a subgroup of B cell
malignancies. (See BCL1 (151400).) The CD20 gene was found to lie on the
centromeric side of BCL1 and to be separated from BCL1 by at least 50 kb
of DNA. The proximal location of CD20 was indicated by the fact that it
is not translocated to chromosome 14 in the translocation. It must be
located between the centromere of chromosome 11 and the 3-prime end of
BCL1. Richard et al. (1991) described a high-resolution radiation hybrid
map of 11q12-q13. They found that the CD20 locus was not separated from
the CD5 locus (153340) and that the 2 loci lie between OSBP (167040) and
the pepsinogen cluster (see 169710). Szepetowski et al. (1993) studied
amplification of the BCL1 region in breast cancer to map genes in the
11q13 band. CD20 was the most proximal of 13 genes located centromeric
to BCL1 and was in the same group as CD5, PGA4 (169720), and FTH1
(134770). Distal to this cluster was a group of 3 genes, COX8 (123870),
PYGM (232600), and SEA (165110), of which the most proximal was COX8.

*FIELD* SA
Tedder et al. (1989)
*FIELD* RF
1. Richard, C. W.; Withers, D. A.; Meeker, T. C.; Myers, R. M.: A
radiation hybrid map of the proximal long arm of human chromosome
11 containing the MEN-1 and bcl-1 disease locus.  (Abstract) Cytogenet.
Cell Genet. 58: 1970 only, 1991.

2. Szepetowski, P.; Perucca-Lostanlen, D.; Gaudray, P.: Mapping genes
according to their amplification status in tumor cells: contribution
to the map of 11q13. Genomics 16: 745-750, 1993.

3. Tedder, T. F.; Disteche, C. M.; Louie, E.; Adler, D. A.; Croce,
C. M.; Schlossman, S. F.; Saito, H.: The gene that encodes the human
CD20 (B1) differentiation antigen is located on chromosome 11 near
the t(11;14)(q13;q32) translocation site. J. Immun. 142: 2555-2559,
1989.

4. Tedder, T. F.; Klejman, G.; Schlossman, S. F.; Saito, H.: Structure
of the gene encoding the human B lymphocyte differentiation antigen
CD20 (B1). J. Immun. 142: 2560-2568, 1989.

5. Tedder, T. F.; Streuli, M.; Schlossman, S. F.; Saito, H.: Isolation
and structure of a cDNA encoding the B1 (CD20) cell-surface antigen
of human B lymphocytes. Proc. Nat. Acad. Sci. 85: 208-212, 1988.

*FIELD* CD
Victor A. McKusick: 2/12/1988

*FIELD* ED
carol: 6/24/1993
supermim: 3/16/1992
carol: 2/26/1992
carol: 2/21/1992
carol: 10/10/1991
carol: 9/19/1991

*RECORD*
*FIELD* NO
112240
*FIELD* TI
112240 BONE FRAGILITY WITH CRANIOSYNOSTOSIS, OCULAR PROPTOSIS, HYDROCEPHALUS,
AND DISTINCTIVE FACIAL FEATURES
*FIELD* TX
Cole and Carpenter (1987) described a seemingly new osteogenesis
imperfecta-like disorder in 2 unrelated infants. Both had bone
deformities and multiple fractures reminiscent of OI but also had ocular
proptosis with orbital craniosynostosis, hydrocephalus, and distinctive
facial features. Both infants were normal at birth; before the first
birthday, however, recurrent diaphyseal fractures of the weight-bearing
bones had occurred. Despite the craniosynostosis and hydrocephalus,
intellectual development was unimpaired. The parents were unrelated in
each case; their ages were not stated. In the first case the mother was
noted to have somewhat shallow orbits and her father and grandmother had
similar features; a paternal aunt had been examined for hyperthyroidism
because of clinically evident proptosis. In this patient, frontal
craniectomy was performed at age 9 months to relieve compression of the
ocular globes because of an alarming progression of proptosis and
frontal bossing. Progressive communicating hydrocephalus was noted by
computer tomography at 12 months of age and a lumboperitoneal shunt was
established to be replaced later by a ventriculoperitoneal shunt.

MacDermot et al. (1995) reported the case of a male infant thought to
represent either the more severe end of the spectrum of type IV
osteogenesis imperfecta (166220) or the mild end of the spectrum of
Cole-Carpenter syndrome. Severe hydrops fetalis developed between 19 and
28 weeks of gestation. After delivery at 32 weeks, he was treated by
hemofiltration, prolonged ventilation, and intravenous feeding. He had
hypertelorism, orbital hypoplasia without proptosis, brachydactyly,
frontal and temporal bossing of the skull, central hypotonia,
communicating hydrocephalus, and severe delay in psychomotor
development. Signs of connective tissue disorder included osteopenia,
pathologic fracture, yellow/gray discolored teeth, blue sclerae, and
easy bruising.

*FIELD* RF
1. Cole, D. E. C.; Carpenter, T. O.: Bone fragility, craniosynostosis,
ocular proptosis, hydrocephalus, and distinctive facial features:
a newly recognized type of osteogenesis imperfecta. J. Pediat. 110:
76-80, 1987.

2. MacDermot, K. D.; Buckley, B.; Van Someren, V.: Osteopenia, abnormal
dentition, hydrops fetalis and communicating hydrocephalus. Clin.
Genet. 48: 217-220, 1995.

*FIELD* CS

Skel:
   Bone deformities;
   Multiple fractures

Eyes:
   Ocular proptosis;
   Shallow orbits

Skull:
   Orbital craniosynostosis;
   Frontal bossing

Neuro:
   Hydrocephalus;
   Normal intellectual development

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/26/1987

*FIELD* ED
mark: 12/13/1995
terry: 12/11/1995
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 3/26/1987

*RECORD*
*FIELD* NO
112250
*FIELD* TI
*112250 BONE DYSPLASIA WITH MEDULLARY FIBROSARCOMA
HEREDITARY BONE DYSPLASIA WITH MALIGNANT FIBROUS HISTIOCYTOMA
*FIELD* TX
Arnold (1973) described several generations of a Vermont and New York
kindred demonstrating multiple areas of necrosis in the diaphyses of the
large tubular bones. The radiographic appearance of this skeletal
condition resembled radiation osteitis, a highly premalignant condition;
however, no source of radiation exposure was found in this family.
Medullary fibrosarcoma, an uncommon bone tumor, was noted in 4 of the 12
affected members. Death had occurred from widespread metastases at ages
varying from 23 to 48 years. Occurrence of fibrosarcoma in idiopathic
bone infarcts (Furey et al., 1960) and in an infarct in a caisson worker
(Dorfman et al., 1966) has been reported. Hardcastle et al. (1986) gave
follow-up information on the original American family and reported 2
other families, one English and the other Australian. They could find no
reports of any hereditary or acquired condition similar to that in these
3 families. They suggested that the malignant change should be labelled
'malignant fibrous histiocytoma' rather than fibrosarcoma because the
tumors were markedly aggressive. The malignancy occurred generally in
the second to fifth decades of life. They defined the skeletal dysplasia
as a diaphyseal medullary stenosis with overlying cortical bone
thickening. The occurrence with minimal trauma was emphasized.

*FIELD* RF
1. Arnold, W. H.: Hereditary bone dysplasia with sarcomatous degeneration.
Ann. Intern. Med. 78: 902-906, 1973.

2. Dorfman, H. D.; Norman, A.; Wolff, H.: Fibrosarcoma complicating
bone infarction in a caisson worker. J. Bone Joint Surg. 48A: 528-532,
1966.

3. Furey, J. G.; Ferrer-Torells, M.; Reagan, J. W.: Fibrosarcoma
arising at the site of bone infarcts. J. Bone Joint Surg. 42A:
802-810, 1960.

4. Hardcastle, P.; Nade, S.; Arnold, W.: Hereditary bone dysplasia
with malignant change: report of three families. J. Bone Joint Surg. 68A:
1079-1089, 1986.

*FIELD* CS

Skel:
   Skeletal dysplasia

Oncology:
   Malignant fibrous histiocytoma

Misc:
   Bone lesions follow minimal trauma

Radiology:
   Multiple necrosis in large tubular bone diaphyses;
   Diaphyseal medullary stenosis with overlying cortical bone thickening

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986

*RECORD*
*FIELD* NO
112260
*FIELD* TI
*112260 BONE GAMMA-CARBOXYGLUTAMIC ACID PROTEIN
BONE GLA PROTEIN; BGLAP; BGP;;
OSTEOCALCIN
*FIELD* TX
Bone gamma-carboxyglutamic acid (Gla) protein (BGP) is a small, highly
conserved molecule associated with the mineralized matrix of bone. Its
interaction with synthetic hydroxyapatite in vitro is absolutely
dependent on its content of 3 residues of gamma-carboxyglutamic acid,
the amino acid formed posttranslationally from glutamic acid by a
vitamin K-dependent process. Pan and Price (1985) studied cDNA of the
rat protein. They found that a stretch of 9 residues proximal to the
NH2-terminus of secreted BGP is strikingly similar to the corresponding
regions in known propeptides of the gamma-carboxyglutamic
acid-containing blood coagulation factors. They suggested that this
common structural feature may be involved in the posttranslational
targeting of these polypeptides for vitamin K-dependent
gamma-carboxylation. See 277450 and 118650 for a discussion of
chondrodysplasia punctata, coagulation defects, and coumarin embryopathy
which have, it seems, a common link in BGP. Celeste et al. (1986) used
mouse and rat cDNA clones to isolate the human BGP gene. It has 4 exons.
Comparison of the exon structure of the BGP gene and the factor IX gene
(306900), which is a gamma-carboxylated clotting factor, suggested that
the exons encoding the part of the leader peptides presumably directing
gamma-carboxylation arose from a common ancestral sequence. Kerner et
al. (1989) described regions within the BGP promoter that contribute to
basal expression of the osteocalcin gene in osteoblast-like cells in
culture. Further, they defined a 21-base pair element that acts in cis
to mediate vitamin D inducibility of the osteocalcin gene.

See 277440 for a discussion of the work of Morrison et al. (1992)
indicating that allelic variation in the vitamin D receptor gene is
related to serum concentrations of osteocalcin and in turn probably to
bone density.

Puchacz et al. (1989) assigned the osteocalcin gene to chromosome 1 by
Southern blot analysis of DNAs from a panel of mouse-human somatic cell
hybrids. Furthermore, by Southern blot analysis of DNAs from mouse-human
hybrids that retain specific segments of human chromosome 1, they
determined that the locus is on 1q, telomeric to the alpha-spectrin gene
(182860). Johnson et al. (1991) mapped the Bglap gene to mouse
chromosome 3 by study of somatic whole cell hybrids and microcell
hybrids. Desbois et al. (1994) confirmed this assignment by analyzing
the segregation of restriction fragment length variants (RFLVs) in an
interspecific backcross.

*FIELD* SA
Kaplan et al. (1990); Tabas et al. (1991)
*FIELD* RF
1. Celeste, A. J.; Rosen, V.; Buecker, J. L.; Kriz, R.; Wang, E. A.;
Wozney, J. M.: Isolation of the human gene for bone gla protein utilizing
mouse and rat cDNA clones. EMBO J. 5: 1885-1890, 1986.

2. Desbois, C.; Seldin, M. F.; Karsenty, G.: Localization of the
osteocalcin gene cluster on mouse chromosome 3. Mammalian Genome 5:
321-322, 1994.

3. Johnson, T. L.; Sakaguchi, A. Y.; Lalley, P. A.; Leach, R. J.:
Chromosomal assignment in mouse of matrix GLA protein and bone GLA
protein genes. Genomics 11: 770-772, 1991.

4. Kaplan, F. S.; Tabas, J. A.; Zasloff, M. A.: Fibrodysplasia ossificans
progressiva: a clue from the fly?. Calcif. Tissue Int. 47: 117-125,
1990.

5. Kerner, S. A.; Scott, R. A.; Pike, J. W.: Sequence elements in
the human osteocalcin gene confer basal activation and inducible response
to hormonal vitamin D(3). Proc. Nat. Acad. Sci. 86: 4455-4459,
1989.

6. Morrison, N. A.; Yeoman, R.; Kelly, P. J.; Eisman, J. A.: Contribution
of trans-acting factor alleles to normal physiological variability:
vitamin D receptor gene polymorphisms and circulating osteocalcin.
Proc. Nat. Acad. Sci. 89: 6665-6669, 1992.

7. Pan, L. C.; Price, P. A.: The propeptide of rat bone gamma-carboxyglutamic
acid protein shares homology with other vitamin K-dependent protein
precursors. Proc. Nat. Acad. Sci. 82: 6109-6113, 1985.

8. Puchacz, E.; Lian, J. B.; Stein, G. S.; Wozney, J.; Huebner, K.;
Croce, C.: Chromosomal localization of the human osteocalcin gene.
Endocrinology 124: 2648-2650, 1989.

9. Tabas, J. A.; Zasloff, M.; Wasmuth, J. J.; Emanuel, B. S.; Altherr,
M. R.; McPherson, J. D.; Wozney, J. M.; Kaplan, F. S.: Bone morphogenetic
protein: chromosomal localization of human genes for BMP1, BMP2A,
and BMP3. Genomics 9: 283-289, 1991.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 6/16/1994
carol: 3/23/1994
carol: 9/10/1992
supermim: 3/16/1992
carol: 2/26/1992
carol: 10/23/1991

*RECORD*
*FIELD* NO
112261
*FIELD* TI
*112261 BONE MORPHOGENETIC PROTEIN-2; BMP2
BONE MORPHOGENETIC PROTEIN-2A; BMP2A
*FIELD* TX
Transforming growth factor-beta (TGFB) superfamily encodes at least 12
members, including TGFB1 (190180), TGFB2 (190220), TGFB3 (190230),
Mullerian inhibitory substance (600957), the bone morphogenetic proteins
2A, 2B, and 3, and the VG-1-related gene product. Wozney et al. (1988)
purified bone morphogenetic proteins BMP-2A and BMP-3 from demineralized
bone on the basis of their ability to induce the formation of ectopic
cartilage when implanted subcutaneously. Wang et al. (1990) showed that
when BMP-2A produced by recombinant DNA techniques was implanted into
rats, bone formation occurred by day 14. Dickinson et al. (1990)
demonstrated that in the mouse the Bmp-2a gene is located on chromosome
2 in a segment that shows homology of synteny with human 20p. They
suggested, therefore, that the human BMP2A gene may be located on 20p.
They pointed out that in the mouse 5 of the 8 loci (Tgfb-1, Bmp-2a,
Bmp-2b1, Bmp-2b2, and Vgr-1) map near mutant loci associated with
connective tissue and skeletal disorders, raising the possibility that
at least some of these mutations result from defects in TGFB-related
genes. The Bmp-2a gene is situated close to the tight skin (Tsk) locus
(see 184900), raising the question that this gene may be the site for
the mutation in 'tight skin.' Using cDNA probes for the analysis of
somatic cell hybrid lines, Tabas et al. (1991) confirmed the assignment
of BMP2A to chromosome 20. By both in situ hybridization and FISH, Gopal
Rao et al. (1992) assigned BMP2A to 20p12.

Tabas et al. (1991) stated that 'BMP2A has been suggested as a
reasonable candidate for the human condition fibrodysplasia (myositis)
ossificans progressiva (FOP, 135100), on the basis of observations in a
Drosophila model (Kaplan et al., 1990).'

*FIELD* RF
1. Dickinson, M. E.; Kobrin, M. S.; Silan, C. M.; Kingsley, D. M.;
Justice, M. J.; Miller, D. A.; Ceci, J. D.; Lock, L. F.; Lee, A.;
Buchberg, A. M.; Siracusa, L. D.; Lyons, K. M.; Derynck, R.; Hogan,
B. L. M.; Copeland, N. G.; Jenkins, N. A.: Chromosomal localization
of seven members of the murine TGF-beta superfamily suggests close
linkage to several morphogenetic mutant loci. Genomics 6: 505-520,
1990.

2. Gopal Rao, V. V. N.; Loffler, C.; Wozney, J. M.; Hansmann, I.:
The gene for bone morphogenetic protein 2A (BMP2A) is localized to
human chromosome 20p12 by radioactive and nonradioactive in situ hybridization.
Hum. Genet. 90: 299-302, 1992.

3. Kaplan, F. S.; Tabas, J. A.; Zasloff, M. A.: Fibrodysplasia ossificans
progressiva: a clue from the fly?. Calcif. Tissue Int. 47: 117-125,
1990.

4. Tabas, J. A.; Zasloff, M.; Wasmuth, J. J.; Emanuel, B. S.; Altherr,
M. R.; McPherson, J. D.; Wozney, J. M.; Kaplan, F. S.: Bone morphogenetic
protein: chromosomal localization of human genes for BMP1, BMP2A,
and BMP3. Genomics 9: 283-289, 1991.

5. Wang, E. A.; Rosen, V.; D'Alessandro, J. S.; Bauduy, M.; Cordes,
P.; Harada, T.; Israel, D. I.; Hewick, R. M.; Kerns, K. M.; LaPan,
P.; Luxenberg, D. P.; McQuaid, D.; Moutsatsos, I. K.; Nove, J.; Wozney,
J. M.: Recombinant human bone morphogenetic protein induces bone
formation. Proc. Nat. Acad. Sci. 87: 2220-2224, 1990.

6. Wozney, J. M.; Rosen, V.; Celeste, A. J.; Mitsock, L. M.; Whitters,
M. J.; Kriz, R. W.; Hewick, R. M.; Wang, E. A.: Novel regulators
of bone formation: molecular clones and activities. Science 242:
1528-1534, 1988.

*FIELD* CD
Victor A. McKusick: 5/15/1990

*FIELD* ED
mark: 07/03/1996
mark: 12/12/1995
mimadm: 2/11/1994
carol: 9/21/1993
carol: 1/22/1993
carol: 11/5/1992
supermim: 3/16/1992
carol: 9/10/1991

*RECORD*
*FIELD* NO
112262
*FIELD* TI
*112262 BONE MORPHOGENETIC PROTEIN-4; BMP4
BONE MORPHOGENETIC PROTEIN-2B; BMP2B;;
BMP2B1
*FIELD* TX
Dickinson et al. (1990) demonstrated that in the mouse the Bmp-2b1 gene
is located on chromosome 14 and maps to the same area as 'pug nose'
(pn). The mutation in the latter disorder may reside in the Bmp-2b1
gene. Arguing from homology of synteny, Dickinson et al. (1990)
suggested that the human BMP2B1 gene may be located on human chromosome
14. Furthermore, they suggested that the human homolog of the murine
Bmp-2b2 gene (see 301880) resides on the X chromosome, as it does in the
mouse. There is, however, no direct evidence of a second BMP2B gene in
the human (McAlpine, 1992). BMP2B was also designated BMP4. By analysis
of human/rodent somatic cell hybrids, Tabas et al. (1993) assigned the
BMP4 gene to human chromosome 14. By fluorescence in situ hybridization,
van den Wijngaard et al. (1995) localized the BMP4 gene to 14q22-q23.

The transcriptional unit of the human BMP4 gene is encoded by 5 exons
and spans approximately 7 kb (van den Wijngaard et al., 1996). The human
BMP4 gene has at least 2 functional promoters, which are used in a cell
type specific manner.

Shafritz et al. (1996) found overexpression of BMP4 in lymphoblastoid
cell lines from 26 of 32 patients with fibrodysplasia ossificans
progressiva (FOP; 135100), but from only 1 of 12 normal subjects (P less
than 0.001). Furthermore, BMP4 and its mRNA were detected in the
lymphoblastoid cell lines from a man with FOP and his 3 affected
children, but not from the children's unaffected mother. Cosegregation
of DNA markers for the BMP4 locus on chromosome 14 in the rare families
in which FOP is inherited would strengthen the candidacy of BMP4, and
the demonstration of mutations in the BMP4 gene, especially in the
promoter sequences, would be confirmatory.

Connor (1996) speculated that transgenic mice with selective
overexpression of BMP4 may serve as animal models of FOP and may make it
possible to evaluate potential therapies directed at influencing the
expression of BMP4 or its 2 types of cell-surface receptors. Not only
may this knowledge provide a rational basis for therapy for FOP, but
possibly also measures for the control of local ectopic bone development
which occurs in 10% to 20% of patients who have undergone surgical hip
replacement. According to Connor (1996), there appears to be an
individual propensity to the phenomenon of secondary ectopic
ossification of soft tissue. In the 10% to 20% of patients who develop
local ectopic bone formation after hip replacement, if surgical removal
of that bone is attempted or the opposite hip is replaced, ectopic bone
almost invariably recurs or occurs.

*FIELD* RF
1. Connor, J. M.: Fibrodysplasia ossificans progressiva: lessons
from rare maladies. (Editorial) New Eng. J. Med. 335: 591-593, 1996.

2. Dickinson, M. E.; Kobrin, M. S.; Silan, C. M.; Kingsley, D. M.;
Justice, M. J.; Miller, D. A.; Ceci, J. D.; Lock, L. F.; Lee, A.;
Buchberg, A. M.; Siracusa, L. D.; Lyons, K. M.; Derynck, R.; Hogan,
B. L. M.; Copeland, N. G.; Jenkins, N. A.: Chromosomal localization
of seven members of the murine TGF-beta superfamily suggests close
linkage to several morphogenetic mutant loci. Genomics 6: 505-520,
1990.

3. McAlpine, P. J.: Personal Communication. Winnipeg, Manitoba,
Canada  7/15/1992.

4. Shafritz, A. B.; Shore, E. M.; Gannon, F. H.; Zasloff, M. A.; Taub,
R.; Muenke, M.; Kaplan, F. S.: Overexpression of an osteogenic morphogen
in fibrodysplasia ossificans progressiva. New Eng. J. Med. 335:
555-561, 1996.

5. Tabas, J. A.; Hahn, G. V.; Cohen, R. B.; Seaunez, H. N.; Modi,
W. S.; Wozney, J. M.; Zasloff, M.; Kaplan, F. S.: Chromosomal assignment
of the human gene for bone morphogenetic protein 4. Clin. Orthop.
Rel. Res. 293: 310-316, 1993.

6. van den Wijngaard, A.; Olde Weghuis, D.; Boersma, C. J. C.; van
Zoelen, E. J. J.; Geurts van Kessel, A.; Olijve, W.: Fine mapping
of the human bone morphogenetic protein-4 gene (BMP4) to chromosome
14q22-q23 by in situ hybridization. Genomics 27: 559-560, 1995.

7. van den Wijngaard, A.; van Kraay, M.; van Zoelen, E. J. J.; Olijve,
W.; Boersma, C. J. C.: Genomic organization of the human bone morphogenetic
protein-4 gene: molecular basis for multiple transcripts. Biochem.
Biophys. Res. Commun. 219: 789-794, 1996.

*FIELD* CD
Victor A. McKusick: 5/15/1990

*FIELD* ED
mark: 12/31/1996
jenny: 12/19/1996
terry: 12/13/1996
mark: 4/28/1996
terry: 4/22/1996
mark: 7/31/1995
terry: 7/24/1995
mimadm: 4/29/1994
warfield: 4/7/1994
carol: 12/13/1993
carol: 11/4/1993

*RECORD*
*FIELD* NO
112263
*FIELD* TI
*112263 BONE MORPHOGENETIC PROTEIN-3; BMP3
*FIELD* TX
Dickinson et al. (1990) showed that in the mouse the Bmp-3 gene is
located on chromosome 5. Arguing from homology of synteny, they
suggested that the cognate gene in man is located on either chromosome 4
or chromosome 7. Indeed, using cDNA probes for the analysis of somatic
cell hybrid lines, Tabas et al. (1991) assigned the BMP3 gene to
4p14-q21. BMP2A (112261) and BMP3 are members of the transforming growth
factor-beta supergene family; BMP1 (112264) is a novel regulatory
protein.

*FIELD* RF
1. Dickinson, M. E.; Kobrin, M. S.; Silan, C. M.; Kingsley, D. M.;
Justice, M. J.; Miller, D. A.; Ceci, J. D.; Lock, L. F.; Lee, A.;
Buchberg, A. M.; Siracusa, L. D.; Lyons, K. M.; Derynck, R.; Hogan,
B. L. M.; Copeland, N. G.; Jenkins, N. A.: Chromosomal localization
of seven members of the murine TGF-beta superfamily suggests close
linkage to several morphogenetic mutant loci. Genomics 6: 505-520,
1990.

2. Tabas, J. A.; Zasloff, M.; Wasmuth, J. J.; Emanuel, B. S.; Altherr,
M. R.; McPherson, J. D.; Wozney, J. M.; Kaplan, F. S.: Bone morphogenetic
protein: chromosomal localization of human genes for BMP1, BMP2A,
and BMP3. Genomics 9: 283-289, 1991.

*FIELD* CD
Victor A. McKusick: 5/15/1990

*FIELD* ED
supermim: 3/16/1992
carol: 9/10/1991
carol: 2/21/1991
supermim: 1/26/1991
supermim: 5/15/1990

*RECORD*
*FIELD* NO
112264
*FIELD* TI
*112264 BONE MORPHOGENETIC PROTEIN-1; BMP1
TOLLOID, DROSOPHILA, HUMAN HOMOLOG OF; TLD;;
PROCOLLAGEN C-PROTEINASE
*FIELD* TX
The BMP1 locus encodes a protein that is capable of inducing formation
of cartilage in vivo (Wozney et al., 1988). Although other bone
morphogenetic proteins are members of the TGF-beta (190180) superfamily,
BMP1 encodes a novel protein that is not closely related to other known
growth factors. Ceci et al. (1990) mapped murine Bmp1 to a region of
mouse chromosome 14 close to esterase-10 and the murine homolog of the
human retinoblastoma gene (180200); thus, it was considered possible for
the human homolog of Bmp1 to be located on 13q14. However, using cDNA
probes in the analysis of somatic cell hybrid lines, Tabas et al. (1991)
demonstrated that the BMP1 gene maps to chromosome 8. By in situ
hybridization, Yoshiura et al. (1993) mapped the BMP1 gene to 8p21. Thus
it is not likely to be involved in the causation of multiple exostoses,
either as an isolated finding (133700) or as part of the Langer-Giedion
syndrome (150230), both of which map to 8q.

In mammals a single BMP1 gene apparently encodes alternatively spliced
transcripts not only for BMP1 but also for a longer protein with a
domain structure identical to that of the Drosophila dorsal-ventral
patterning gene product tolloid (Tld), and for a third species of low
abundance. Takahara et al. (1995) described the organization of the
46-kb, 22-exon human BMP1/TLD gene. Exons corresponding to each of the
alternatively spliced transcripts were identified and comparison with
the Drosophila Tld gene revealed alignment of introns at only 3
positions. The major BMP1/TLD transcription start site was found only
706 bp downstream of the polyadenylation site of the SFTP2 surfactant
gene (178620), and a previously reported highly polymorphic CA repeat
was found within the BMP1/TLD first intron. These 2 findings placed the
BMP1/TLD gene between markers D8S298 and D8S5 on the genetic map.

Kessler et al. (1996) showed that recombinantly expressed BMP1 and
purified procollagen C proteinase (PCP), a secreted metalloprotease
requiring calcium and needed for cartilage and bone formation, are, in
fact, identical. PCP cleaves the C-terminal propeptides of procollagen I
(120150), II (120140), and III (120180) and its activity is increased by
the procollagen C-endopeptidase enhancer protein (600270). Reddi (1996)
discussed the significance of the finding that BMP-1 is the same as
procollagen C-proteinase. Procollagen N-proteinase is thought to be the
site of the basic defect in a form of Ehlers-Danlos syndrome (225410).

*FIELD* RF
1. Ceci, J. D.; Kingsley, D. M.; Silan, C. M.; Copeland, N. G.; Jenkins,
N. A.: An interspecific backcross linkage map of the proximal half
of mouse chromosome 14. Genomics 6: 673-678, 1990.

2. Kessler, E.; Takahara, K.; Biniaminov, L.; Brusel, M.; Greenspan,
D.: Bone morphogenic protein-1: the type I procollagen C-proteinase. Science 271:
360-362, 1996.

3. Reddi, A. H.: BMP-1: resurrection as procollagen C-proteinase. Science 271:
5-6, 1996.

4. Tabas, J. A.; Zasloff, M.; Wasmuth, J. J.; Emanuel, B. S.; Altherr,
M. R.; McPherson, J. D.; Wozney, J. M.; Kaplan, F. S.: Bone morphogenetic
protein: chromosomal localization of human genes for BMP1, BMP2A,
and BMP3. Genomics 9: 283-289, 1991.

5. Takahara, K.; Lee, S.; Wood, S.; Greenspan, D. S.: Structural
organization and genetic localization of the human bone morphogenetic
protein 1/mammalian tolloid gene. Genomics 29: 9-15, 1995.

6. Wozney, J. M.; Rosen, V.; Celeste, A. J.; Mitsock, L. M.; Whitters,
M. J.; Kriz, R. W.; Hewick, R. M.; Wang, E. A.: Novel regulators
of bone formation: molecular clones and activities. Science 242:
1528-1534, 1988.

7. Yoshiura, K.; Tamura, T.; Hong, H.-S.; Ohta, T.; Soejima, H.; Kishino,
T.; Jinno, Y.; Niikawa, N.: Mapping of the bone morphogenetic protein
1 gene (BMP1) to 8p21: removal of BMP1 from candidacy for the bone
disorder in Langer-Giedion syndrome. Cytogenet. Cell Genet. 64:
208-209, 1993.

*FIELD* CN
Alan F. Scott - updated: 1/18/1996

*FIELD* CD
Victor A. McKusick: 6/13/1990

*FIELD* ED
terry: 04/17/1996
mark: 2/6/1996
terry: 2/6/1996
mark: 1/18/1996
mark: 10/3/1995
carol: 11/17/1993
carol: 11/3/1993
supermim: 3/16/1992
carol: 2/21/1991
carol: 2/11/1991

*RECORD*
*FIELD* NO
112265
*FIELD* TI
*112265 BONE MORPHOGENETIC PROTEIN-5; BMP5
*FIELD* TX
Bone morphogenetic proteins were originally identified by an ability of
demineralized bone extract to induce endochondral osteogenesis in vivo
in an extraskeletal site (Urist, 1965). Through molecular cloning, 7 BMP
cDNAs, designated BMP1 through BMP7, have been recovered. Recombinant
protein products from 6 of these clones, BMP2 through BMP7, are members
of the transforming growth factor-beta superfamily of regulatory
molecules. From a high degree of amino acid sequence homology, BMP5,
BMP6, and BMP7 are recognized as a subfamily of the BMPs. Using
human-rodent somatic cell hybrid lines and cDNA probes, Hahn et al.
(1992) mapped BMP5 and BMP6 to human chromosome 6, while BMP7 was found
to be syntenic with the previously localized BMP2 on human chromosome
20. Sequence analysis suggested that the 60A gene of Drosophila is the
dipteran homolog of this BMP subfamily and may provide clues to the
physiologic function of the products of these genes.

Kingsley et al. (1992) showed that mutations at the classic mouse locus
short ear (se) on chromosome 9 disrupt the mouse homolog of the BMP5
gene. Complete deletion of BMP5 coding sequences is compatible with
viability. Mutations at the 'short ear' locus are associated with a
specific spectrum of morphologic alterations in the ear and many
internal skeletal structures, suggesting that bone morphogenetic
proteins have been aptly named. The mutant animals also show a defect in
repair of bone fractures and a number of soft tissue abnormalities
including lung cysts, liver granulomas, and hydrotic kidneys. Further
study of these mice should be useful for determining how BMPs control
the growth and patterning of skeletal tissue, and what roles these genes
play in other organ systems as well.

*FIELD* RF
1. Hahn, G. V.; Cohen, R. B.; Wozney, J. M.; Levitz, C. L.; Shore,
E. M.; Zasloff, M. A.; Kaplan, F. S.: A bone morphogenetic protein
subfamily: chromosomal localization of human genes for BMP5, BMP6,
and BMP7. Genomics 14: 759-762, 1992.

2. Kingsley, D. M.; Bland, A. E.; Grubber, J. M.; Marker, P. C.; Russell,
L. B.; Copeland, N. G.; Jenkins, N. A.: The mouse short ear skeletal
morphogenesis locus is associated with defects in a bone morphogenetic
member of the TGF-beta superfamily. Cell 71: 399-410, 1992.

3. Urist, M. R.: Bone: formation by autoinduction. Science 150:
893-899, 1965.

*FIELD* CD
Victor A. McKusick: 11/6/1992

*FIELD* ED
carol: 2/24/1993
carol: 12/4/1992
carol: 11/6/1992

*RECORD*
*FIELD* NO
112266
*FIELD* TI
*112266 BONE MORPHOGENETIC PROTEIN-6; BMP6
*FIELD* TX
See 112265. Hahn et al. (1992) mapped both BMP5 and BMP6 to human
chromosome 6 by study of human-rodent somatic cell hybrid lines with
cDNA probes.

*FIELD* RF
1. Hahn, G. V.; Cohen, R. B.; Wozney, J. M.; Levitz, C. L.; Shore,
E. M.; Zasloff, M. A.; Kaplan, F. S.: A bone morphogenetic protein
subfamily: chromosomal localization of human genes for BMP5, BMP6,
and BMP7. Genomics 14: 759-762, 1992.

*FIELD* CD
Victor A. McKusick: 11/6/1992

*FIELD* ED
carol: 11/6/1992

*RECORD*
*FIELD* NO
112267
*FIELD* TI
*112267 BONE MORPHOGENETIC PROTEIN-7; BMP7
OSTEOGENIC PROTEIN-1; OP1
*FIELD* TX
See 112265. Hahn et al. (1992) mapped BMP7 to human chromosome 20 by
study of human-rodent somatic cell hybrid lines with cDNA probes. BMP2
(112261) also maps to chromosome 20.

Marker et al. (1995) assigned mouse Bmp7 to distal chromosome 2 by
interspecific backcross mapping. Marker et al. (1995) studied the
distribution of BMP7 transcripts at various anatomical sites disrupted
by Holt-Oram syndrome (142900) mutations. They found BMP7 expression in
all structures that are altered in Holt-Oram patients, including the
heart, proximal and distal forelimb, clavicle, and scapula, as well as
other unaffected tissues. Marker et al. (1995) suggested that the human
BMP7 gene may be on 20q13.1-q13.3, extrapolating from the fact that the
Bmp7 gene in the mouse is between Ada (localized to 20q12-q13.11) and
Pck1 (localized to 20q13.2-q13.31).

BMP7 is also termed osteogenic protein-1 (OP1).

Solursh et al. (1996) examined developmental and temporal expression of
OP1 by hybridization with histological sections of rat embryos during a
3-day period comprising the primitive streak stages to early limb bud
stages. OP1 expression was detected in the neuroepithelium of the optic
vesicle at day E11.5 and was limited to the presumptive neural retina
and developing lens placode. From E12.5-E13.5, they found expression in
the neural retina, lens, and developing cornea.

*FIELD* RF
1. Hahn, G. V.; Cohen, R. B.; Wozney, J. M.; Levitz, C. L.; Shore,
E. M.; Zasloff, M. A.; Kaplan, F. S.: A bone morphogenetic protein
subfamily: chromosomal localization of human genes for BMP5, BMP6,
and BMP7. Genomics 14: 759-762, 1992.

2. Marker, P. C.; King, J. A.; Copeland, N. G.; Jenkins, N. A.; Kingsley,
D. M.: Chromosomal localization, embryonic expression, and imprinting
tests for Bmp7 on distal mouse chromosome 2. Genomics 28: 576-580,
1995.

3. Marker, P. C.; King, J. A.; Copeland, N. G.; Jenkins, N. A.; Kingsley,
D. M.: Chromosomal localization, embyronic expression, and imprinting
tests for Bmp7 on distal mouse chromosome 2. Genomics 28: 576-580,
1995.

4. Solursh, M.; Langille, R. M.; Wood, J.; Sampath, T. K.: Osteogenic
protein-1 is required for mammalian eye development. Biochem. Biophys.
Res. Commun. 218: 438-443, 1996.

*FIELD* CN
Alan F. Scott - updated: 09/24/1996
Alan F. Scott - updated: 9/26/1995

*FIELD* CD
Victor A. McKusick: 11/6/1992

*FIELD* ED
mark: 09/24/1996
terry: 4/17/1996
mark: 3/7/1996
mark: 1/18/1996
terry: 1/16/1996
mark: 9/27/1995
carol: 11/6/1992

*RECORD*
*FIELD* NO
112270
*FIELD* TI
112270 BONE PAIN, PERIODIC
*FIELD* TX
Reimann and Angelides (1951) reported a kindred in which many members
had episodic pain which the authors termed 'periodic arthralgia.' The
kindred was studied further by Thompson and Merritt (1974), who
concluded that the pain was located in the shafts of the long bones. It
was reminiscent of the pain of sickle cell anemia. No instance of
male-to-male transmission was noted. Thirty-three persons in 7
generations were considered affected.

*FIELD* RF
1. Reimann, H. A.; Angelides, A. P.: Periodic arthralgia in twenty-three
members of five generations of a family. J.A.M.A. 146: 713-716,
1951.

2. Thompson, B. H.; Merritt, A. D.: Dominantly inherited periodic
bone pain. Birth Defects Orig. Art. Ser. 10: 245-248, 1974.

*FIELD* CS

Skel:
   Episodic pain in the shafts of long bones

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
112300
*FIELD* TI
*112300 BOOK SYNDROME
PHC SYNDROME
*FIELD* TX
Book (1950) reported 25 affected persons in 4 generations of a Swedish
family. The features are premolar aplasia (P), hyperhidrosis (H), and
canities prematura (C). Inheritance is clearly autosomal dominant with
high penetrance. No other family has been reported and there is no other
report of this particular syndromal association.

*FIELD* RF
1. Book, J. A.: Clinical and genetical studies of hypodontia. I.
Premolar aplasia, hyperhidrosis, and canities prematura. A new hereditary
syndrome in man. Am. J. Hum. Genet. 2: 240-263, 1950.

*FIELD* CS

Skin:
   Hyperhidrosis

Teeth:
   Premolar aplasia;
   Hypodontia;
   Canities prematura

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 6/9/1994
mimadm: 4/9/1994
warfield: 4/6/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
112310
*FIELD* TI
112310 BOOMERANG DYSPLASIA
*FIELD* TX
Kozlowski et al. (1981), Tenconi et al. (1983), and Kozlowski et al.
(1985) each described 1 case of a disorder termed boomerang dysplasia
because of the unusual shape of the long bones of the legs. All 3
subjects died in the neonatal period. They had dwarfism with short,
bowed, rigid limbs and characteristic facies. In particular, the nose
had a broad root and severe hypoplasia of the nares and septum.
Radiographically, the radii and fibulae were absent, while the remaining
long bones had the boomerang configuration. The iliac bodies were small
and ossification in the lower spine and digits was retarded. All 3
patients were sporadic males, derived from Japan, Italy, and Australia.
Winship et al. (1990) described a fourth case, again in a male infant.
Shortened boomerang-shaped radii, femora, and tibias were noted. The
vertebral borders showed coronal clefts. The genetic basis of the
syndrome is unknown. Hunter and Carpenter (1991) described a patient
with apparent manifestations of both type I atelosteogenesis (108720)
and boomerang dysplasia and concluded that these disorders are 'part of
a spectrum, probably reflecting a common etiology.' Greally et al.
(1993) presented a case that supported the hypothesis of Hunter and
Carpenter (1991).

*FIELD* SA
Beighton  (1988)
*FIELD* RF
1. Beighton, P.: Inherited Disorders of the Skeleton.  London:
Churchill Livingstone (pub.)  (2nd ed.): 1988. Pp. 99-100.

2. Greally, M. T.; Jewett, T.; Smith, W. L., Jr.; Penick, G. D.; Williamson,
R. A.: Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis
I and boomerang dysplasia. Am. J. Med. Genet. 47: 1086-1091, 1993.

3. Hunter, A. G. W.; Carpenter, B. F.: Atelosteogenesis I and boomerang
dysplasia: a question of nosology. Clin. Genet. 39: 471-480, 1991.

4. Kozlowski, K.; Sillence, D.; Cortis-Jones, R.; Osborn, R.: Boomerang
dysplasia. Brit. J. Radiol. 58: 369-371, 1985.

5. Kozlowski, K.; Tsuruta, T.; Kameda, Y.; Kan, A.; Leslie, G.: New
forms of neonatal death dwarfism: report of 3 cases. Pediat. Radiol. 10:
155-160, 1981.

6. Tenconi, R.; Kozlowski, K.; Largaiolli, G.: Boomerang dysplasia:
a new form of neonatal death dwarfism. Fortschr. Geb. Roentgenstr. 138:
378-380, 1983.

7. Winship, I.; Cremin, B.; Beighton, P.: Boomerang dysplasia. Am.
J. Med. Genet. 36: 440-443, 1990.

*FIELD* CS

Growth:
   Congential dwarfism

Limbs:
   Short, bowed, rigid limbs

Nose:
   Broad nasal root;
   Hypoplastic nares and septum

Misc:
   Neonatal death

Radiology:
   Absent radii and fibulae with boomerang shaped remaining long bones;
   Small iliac bodies;
   Retarded ossification of lower spine and digits

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 12/9/1989

*FIELD* ED
davew: 7/28/1994
mimadm: 4/9/1994
carol: 11/22/1993
supermim: 3/16/1992
carol: 9/16/1991
carol: 8/20/1990

*RECORD*
*FIELD* NO
112350
*FIELD* TI
112350 BOWING OF LEGS, ANTERIOR, WITH DWARFISM
WEISMANN-NETTER SYNDROME;;
TOXOPACHYOSTEOSE DIAPHYSAIRE TIBIO-PERONIERE
*FIELD* TX
The presenting manifestations are dwarfism and sabre shins, mental
retardation, mild involvement of the arms, and dural calcification.
Familial incidence was noted by Larcan et al. (1963). Hoefnagel (1969)
and Keats and Alavi (1970) reported cases in this country. The changes
in the legs resemble 'sabre shins' of congenital syphilis. Diaphyseal
bowing occurs in other long bones, suggesting that this is a form of
diaphyseal dysplasia. 'Squaring' of the iliac bones is also a feature.
Mental retardation, goiter, and anemia, previously noted associations,
are probably only coincidental. Patients are short (adult height, 47 to
61 inches). According to Amendola et al. (1980), family history has been
documented in 14 instances, including mother and 3 children
(Weismann-Netter and Stuhl, 1954); sibs and identical twins (Krewer,
1961) and 5 females in 3 generations of a family (Breuzard et al.,
1960). There is, however, no gender predominance in the 40 reported
cases (23 male, 17 female). Robinow and Johnson (1988) reported a
patient who showed anterior bowing of the tibias and lateral bowing of
the femurs. The patient, his mother, and several maternally related
males had X-linked ichthyosis. Serum calcium phosphorus, alkaline
phosphatase, and vitamin D metabolite levels were normal. Bryke et al.
(1990) described 3 unrelated children with this disorder.

*FIELD* SA
Alavi and Keats (1973); Stuve and Wiedemann (1971); Weismann-Netter
and Rouaux (1956)
*FIELD* RF
1. Alavi, S. M.; Keats, T. E.: Toxopachyosteose diaphysaire tibio-peroniere:
Weismann-Netter syndrome. Am. J. Roentgen. 118: 314-317, 1973.

2. Amendola, M. A.; Brower, A. C.; Tisnado, J.: Weismann-Netter-Stuhl
syndrome: toxopachyosteose diaphysaire tibio-peroniere. Am. J. Roentgen. 135:
1211-1215, 1980.

3. Breuzard, J.; Tixier, P.; Sallet, J.: A propos des incurvations
non rachitiques des membres inferieurs: deux nouveaux cas de toxopachyosteose
tibio-peroniere observes chez l'adulte. Bull. Soc. Med. Hop. Paris 76:
165-170, 1960.

4. Bryke, C.; Oliphant, M.; Thomson, L.; Robinow, M.; Bankier, A.
: Weismann-Netter syndrome in childhood.  (Abstract) Am. J. Hum.
Genet. 47 (suppl.): A50 only, 1990.

5. Hoefnagel, D.: Malformation syndromes with mental deficiency.
In: The Clinical Delineation of Birth Defects. II. Malformation Syndromes.
New York: National Foundation-March of Dimes (pub.)  1969. Pp.
11-14.

6. Keats, T. E.; Alavi, S. M.: Toxopachyosteose diaphysaire tibio-peroniere
(Weismann-Netter syndrome). Am. J. Roentgen. 109: 568-574, 1970.

7. Krewer, B.: Dysmorphie jambiere de Weismann-Netter (toxo-pachy-osteose
diaphysaire tibio-peroniere) chez deux vrais jumeaux. Presse Med. 69:
419-420, 1961.

8. Larcan, A.; Cayotte, J. L.; Gaucher, A.; Bertheau, J. M.: La toxopachyosteose
de Weismann-Netter. Ann. Med. 2: 1724-1732, 1963.

9. Robinow, M.; Johnson, G. F.: The Weismann-Netter syndrome. Am.
J. Med. Genet. 29: 573-579, 1988.

10. Stuve, A.; Wiedemann, H.-R.: Angeborene Verbiegungen langer Roehrenknochen--eine
Geschwisterbeobachtung. Z. Kinderheilk. 111: 184-192, 1971.

11. Weismann-Netter, R.; Rouaux, Y.: Toxopachyosteose diaphysaire
tibio-peroniere: chex deux soeurs. Presse Med. 64: 799-800, 1956.

12. Weismann-Netter, R.; Stuhl, L.: D'une osteopathie congenitale
eventuellement familiale. Presse Med. 62: 1618-1622, 1954.

*FIELD* CS

Growth:
   Congenital dwarfism

Limbs:
   Sabre shins;
   Mild arm involvement

Neuro:
   Mental retardation

Radiology:
   Dural calcification;
   Diaphyseal bowing of long bones;
   Squaring of iliac bones

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
davew: 8/15/1994
terry: 5/10/1994
mimadm: 4/9/1994
pfoster: 3/29/1994
carol: 3/31/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
112370
*FIELD* TI
112370 BRACHMANN-DE LANGE-LIKE FACIAL CHANGES WITH MICROCEPHALY, METATARSUS
ADDUCTUS, AND DEVELOPMENTAL DELAY
*FIELD* TX
Halal and Silver (1992) described the cases of 3 sibs (2 boys, 1 girl)
and their father. The children had growth retardation, microcephaly,
minor facial anomalies reminiscent of mild Brachmann-de Lange syndrome
(BDLS; 122470), severe metatarsus adductus, developmental delay, and
unusual dermatoglyphics. The father was thought to show some of the same
features.

*FIELD* RF
1. Halal, F.; Silver, K.: Syndrome of microcephaly, Brachmann-de
Lange-like facial changes, severe metatarsus adductus, and developmental
delay: mild Brachmann-de Lange syndrome?. Am. J. Med. Genet. 42:
381-386, 1992.

*FIELD* CS

Growth:
   Growth retardation

Head:
   Microcephaly

Facies:
   Mild Brachmann-de Lange like facies

Limbs:
   Metatarsus adductus

Neuro:
   Developmental delay

Skin:
   Unusual dermatoglyphics

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 2/17/1992

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/17/1992

*RECORD*
*FIELD* NO
112410
*FIELD* TI
*112410 BRACHYDACTYLY WITH HYPERTENSION
HTNB
*FIELD* TX
Bilginturan et al. (1973) described a 'new' form of brachydactyly
manifested by shortening of both phalanges and metacarpals and
associated, probably as a pleiotropic effect, with hypertension. An
extensive pedigree was well documented.

Schuster et al. (1996) undertook a linkage study of this family
motivated by the possibility that identification of the genetic basis of
this rare monogenic form of hypertension might assist in elucidation of
the multifactorial causation of essential hypertension. By linkage
analysis they succeeded in localizing the responsible gene to 12p in a
region defined by markers D12S364 and D12S87. (From the location of
these markers the gene probably lies in the region 12p12.2-p11.2.) As
the renin-angiotensin system and sympathetic nervous system respond
normally in this form of hypertension, the condition resembles essential
hypertension (see also 145500). This feature also distinguishes this
form of hypertension from glucocorticoid-remediable aldosteronism
(103900) and Liddle syndrome (177200), which are salt-sensitive forms of
monogenic hypertension with very low plasma renin activity. The family
lived in a remote area on the northeastern Black Sea coast of Turkey.
Some members were residing in Germany.

Bahring et al. (1996) demonstrated loops in the posterior/inferior
cerebellar artery by magnetic resonance imaging (MRI) angiography of the
posterior fossa vessels in 15 patients with this syndrome. It was
present bilaterally or unilaterally in all affected individuals and in
none of the unaffected members of the kindred. Bahring et al. (1996)
speculated that neurovascular compression resulting from the looping
might be responsible for the hypertension. A reported deletion in 12p in
a Japanese family with similar brachydactyly narrowed attention to a
3-Mb fragment which was mapped to a YAC contig.

Schuster et al. (1996) performed a comprehensive medical examination on
6 members (5 affected and 1 unaffected) of a Turkish family with this
disease, first reported by Bilginturan et al. (1973). None of them were
being treated for hypertension at the time of the study. The affected
individuals were not salt sensitive and the humoral responses (including
renin, aldosterone, and catecholamine) to volume expansion and
contraction were normal, suggesting that the
renin-angiotensin-aldosterone and the sympathetic nervous systems may
not be responsible for the hypertension. Schuster et al. (1996)
suggested that a not-yet-appreciated mechanism of blood pressure
elevation was possibly involved.

Bahring et al. (1997) restudied a 5-year-old Japanese boy reported by
Nagai et al. (1995) and described in 208500. The boy had brachydactyly
remarkably similar to that exhibited by the affected Turkish kindred
with HTNB reported by Schuster et al. (1996). The Japanese child's blood
pressure was 110/74 mm Hg. This value was at the upper limit of normal
for age; however, it was lower than the blood pressures of similarly
aged affected children from the Turkish family. A de novo chromosomal
deletion, 12(p11.21p12.2), was identified in the Japanese child by Nagai
et al. (1995). The deleted segment overlapped the segment to which the
HTNB gene had been mapped. Bahring et al. (1997) reported precise
mapping of the deletion in the Japanese boy, using microsatellite
markers. They gave extensive descriptions of the changes in the patient
of Nagai et al. (1995), pointing out the remarkable similarities to the
changes in the Turkish family.

*FIELD* RF
1. Bahring, S.; Nagai, T.; Toka, H. R.; Nitz, I.; Toka, O.; Aydin,
A.; Muhl, A.; Wienker, T. F.; Schuster, H.; Luft, F. C.: Deletion
at 12p in a Japanese child with brachydactyly overlaps the assigned
locus of brachydactyly with hypertension in a Turkish family. (Letter) Am.
J. Hum. Genet. 60: 732-735, 1997.

2. Bahring, S.; Schuster, H.; Wienker, T. F.; Haller, H.; Toka, H.;
Toka, O.; Naraghi, R.; Luft, F. C.: Construction of a physical map
and additional phenotyping in autosomal-dominant hypertension and
brachydactyly, which maps to chromosome 12. (Abstract) Am. J. Hum.
Genet. 59 (suppl.): A55 only, 1996.

3. Bilginturan, N.; Zileli, S.; Karacadag, S.; Pirnar, T.: Hereditary
brachydactyly associated with hypertension. J. Med. Genet. 10: 253-259,
1973.

4. Nagai, T.; Nishimura, G.; Kato, R.; Hasegawa, T.; Ohashi, H.; Fukushima,
Y.: Del(12)(p11.21p12.2) associated with an asphyxiating thoracic
dystrophy or chondroectodermal dysplasia-like syndrome. Am. J. Med.
Genet. 55: 16-18, 1995.

5. Schuster, H.; Wienker, T. F.; Bahring, S.; Bilginturan, N.; Toka,
H. R.; Neitzel, H.; Jeschke, E.; Toka, O.; Gilbert, D.; Lowe, A.;
Ott, J.; Haller, H.; Luft, F. C.: Severe autosomal dominant hypertension
and brachydactyly in a unique Turkish kindred maps to human chromosome
12. Nature Genet. 13: 98-100, 1996.

6. Schuster, H.; Wienker, T. F.; Toka, H. R.; Bahring, S.; Jeschke,
E.; Toka, O.; Busjahn, A.; Hempel, A.; Tahlhammer, C.; Oelkers, W.;
Kunze, J.; Bilginturan, N.; Haller, H.; Luft, F. C.: Autosomal dominant
hypertension and brachydactyly in a Turkish kindred resembles essential
hypertension. Hypertension 28: 1085-1092, 1996.

*FIELD* CS

Limbs:
   Brachydactyly;
   Short phalanges;
   Short metacarpals

Endocrine:
   Hypertension

Inheritance:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 03/13/1997
Wilson H. Y. Lo - updated: 2/18/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/13/1997
terry: 3/12/1997
mark: 2/18/1997
jenny: 12/3/1996
terry: 11/22/1996
mark: 5/15/1996
terry: 5/14/1996
terry: 5/6/1996
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
112430
*FIELD* TI
112430 BRACHYDACTYLY, LONG-THUMB TYPE
*FIELD* TX
Hollister and Hollister (1981) described a family in which members of 3
generations showed skeletal and joint anomalies and cardiac conduction
defects. Male-to-male transmission occurred in 1 instance. A unique
feature was symmetric brachydactyly with relatively long thumbs. The tip
of the thumb extended distal to the proximal interphalangeal joint of
the index finger when these digits were apposed.

*FIELD* RF
1. Hollister, D. W.; Hollister, W. G.: The 'long-thumb' brachydactyly
syndrome. Am. J. Med. Genet. 8: 5-16, 1981.

*FIELD* CS

Limbs:
   Symmetric brachydactyly;
   Long thumbs

Joints:
   Joint anomalies

Cardiac:
   Cardiac conduction defects

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
112440
*FIELD* TI
112440 BRACHYDACTYLY, COMBINED B AND E TYPES
PITT-WILLIAMS BRACHYDACTYLY
*FIELD* TX
In 12 members of 4 generations, Pitt and Williams (1985) found a 'new'
type of brachydactyly combining features of types B and E: hypoplasia of
the distal phalanges of the ulnar side of the hand and shortening of 1
or more metacarpals. The subjects were, however, not short of stature as
in type E. Male-to-male transmission was noted in several instances.

*FIELD* RF
1. Pitt, P.; Williams, I.: A new brachydactyly syndrome with similarities
to Julia Bell types B and E. J. Med. Genet. 22: 202-204, 1985.

*FIELD* CS

Limbs:
   Brachydactyly;
   Hypoplastic ulnar side hand distal phalanges;
   Short metacarpals

Growth:
   Normal stature

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
112450
*FIELD* TI
112450 BRACHYDACTYLY, PREAXIAL, WITH HALLUX VARUS AND THUMB ABDUCTION
*FIELD* TX
Christian et al. (1972) described short thumbs and first toes with
abduction of these digits. The shortening involves the metacarpals,
metatarsals, and distal phalanges, while the proximal and middle
phalanges are of normal length. Although no male-to-male transmission
was observed, males and females were affected to a similar degree. Four
successive generations and 6 sibships were affected. All 8 affected
members were mentally retarded. Sharma et al. (1994) described a father
and daughter with the same form of brachydactyly but without mental
retardation. The changes in the hands and feet were much like those
reported by Mononen et al. (1992) (see 301940), but Sharma et al. (1994)
considered that to be a different entity because it showed missing
phalanges, short stature, and epiphyseal and metaphyseal changes
indicative of a skeletal dysplasia.

*FIELD* RF
1. Christian, J. C.; Cho, K. S.; Franken, E. A.; Thompson, B. H.:
Dominant preaxial brachydactyly with hallux varus and thumb abduction.
Am. J. Hum. Genet. 24: 694-701, 1972.

2. Mononen, T. K.; Karnes, P. S.; Senas, M., Jr.; Falk, R. E.: New
skeletal dysplasia with unique brachydactyly. Am. J. Med. Genet. 42:
706-713, 1992.

3. Sharma, A. K.; Haldar, A.; Phadke, S. R.; Agarwal, S. S.: Preaxial
brachydactyly with abduction of thumbs and hallux varus: a distinct
entity. Am. J. Med. Genet. 49: 274-277, 1994.

*FIELD* CS

Limbs:
   Short abducted thumbs;
   Short abducted first toes;
   Short distal phalanges;
   Short metacarpals;
   Short metatarsals;
   Normal proximal and middle phalanges

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 6/1/1994
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
112500
*FIELD* TI
*112500 BRACHYDACTYLY, TYPE A1; BDA1
FARABEE TYPE BRACHYDACTYLY
*FIELD* TX
In the classification of the brachydactylies, the analysis by Bell
(1951) proved highly useful. The type A brachydactylies of Bell have the
shortening confined mainly to the middle phalanges. In the A1 type the
middle phalanges of all the digits are rudimentary or fused with the
terminal phalanges. The proximal phalanges of the thumbs and big toes
are short. This trait has the distinction of being the first in man to
be interpreted in mendelian dominant terms (by Farabee, 1903). Haws and
McKusick (1963) followed up on Farabee's family. The subjects are short
of stature. Julia Bell (1879-1979) died 3 months after her 100th
birthday (obituary, 1979). Type A1 brachydactyly was present in the
women of 3 successive generations who also had ankylosis of the thumbs,
which was not accompanied by synostosis on x-ray, and mental retardation
(Piussan et al., 1983); see 188201. Stiff thumbs occur also with the
C.S. Lewis type of symphalangism (185650).

Fukushima et al. (1995) found a de novo apparently balanced reciprocal
translocation between 5q11.2 and 17q23 in a Japanese child with type A1
brachydactyly, Klippel-Feil anomaly most closely resembling type II
(148900), and unusual facies: midfacial hypoplasia, low nasal bridge,
short nasal septum, long philtrum, thin upper lip, micrognathia, low
posterior hairline, and short and wide neck.

Studying 2 families with multiple affected members, Mastrobattista et
al. (1995) excluded the following candidate genes: HOXD (see 142980),
MSX1 (142983), MSX2 (123101), FGF1 (131220), and FGF2 (134920).

*FIELD* SA
Fitch  (1979)
*FIELD* RF
1. Bell, J.: On brachydactyly and symphalangism.In: Penrose, L. S.
: Treasury of Human Inheritance.  London: Cambridge Univ. Press (pub.)
5: 1951. Pp. 1-31.

2. Farabee, W. C.: Hereditary and sexual influence in meristic variation:
a study of digital malformations in man.  Ph.D. Thesis: Harvard Univ.
(pub.)  1903.

3. Fitch, N.: Classification and identification of inherited brachydactylies. J.
Med. Genet. 16: 36-44, 1979.

4. Fukushima, Y.; Ohashi, H.; Wakui, K.; Nishimoto, H.; Sato, M.;
Aihara, T.: De novo apparently balanced reciprocal translocation
between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and
type A1 brachydactyly. Am. J. Med. Genet. 57: 447-449, 1995.

5. Haws, D. V.; McKusick, V. A.: Farabee's brachydactylous kindred
revisited. Bull. Johns Hopkins Hosp. 113: 20-30, 1963.

6. Mastrobattista, J. M.; Dolle, P.; Blanton, S. H.; Northrup, H.
: Evaluation of candidate genes for familial brachydactyly. J. Med.
Genet. 32: 851-854, 1995.

7. Obituary: Julia Bell, M. A., F.R.C.P. Lancet I: 1152, 1979.

8. Piussan, C.; Lenaerts, C.; Mathieu, M.; Boudailliez, B.: Dominance
reguliere d'une ankylose des pouces avec retard mental se transmettant
sur trois generations. J. Genet. Hum. 31: 107-114, 1983.

*FIELD* CS

Growth:
   Short stature

Limbs:
   Brachydactyly;
   Hypoplastic middle phalanges;
   Occasional terminal symphalangism;
   Short first digit proximal phalanges

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
mark: 1/31/1996
terry: 1/24/1996
mark: 7/16/1995
davew: 7/28/1994
jason: 7/5/1994
terry: 5/13/1994
mimadm: 4/17/1994
pfoster: 3/25/1994

*RECORD*
*FIELD* NO
112600
*FIELD* TI
*112600 BRACHYDACTYLY, TYPE A2; BDA2
BRACHYMESOPHALANGY II;;
MOHR-WRIEDT TYPE BRACHYDACTYLY
*FIELD* TX
Shortening of the middle phalanges is confined to the index finger and
the second toe, all other digits being more or less normal. Because of a
rhomboid or triangular shape of the affected middle phalanx, the end of
the second finger usually deviates radially. This rare form of
brachydactyly has been described only 3 times in the literature. Temtamy
and McKusick (1978) added a fourth family, the first cases in blacks.
The family of Mohr and Wriedt (1919) contained a possible homozygote.

*FIELD* SA
Edelson  (1972); Freire-Maia et al. (1980); Ziegner  (1903)
*FIELD* RF
1. Edelson, P. J.: Brachydactyly type A2 in an American Negro family. Clin.
Genet. 3: 59 only, 1972.

2. Freire-Maia, N.; Maia, N. A.; Pacheco, C. N. A.: Mohr-Wriedt (A2)
brachydactyly: analysis of a large Brazilian kindred. Hum. Hered. 30:
225-231, 1980.

3. Mohr, O. L.; Wriedt, C.: A New Type of Hereditary Brachyphalangy
in Man.  Washington: Carnegie Inst. (pub.)  1919. Pp. 5-64. Note:
Publ. 295.

4. Temtamy, S. A.; McKusick, V. A.: The Genetics of Hand Malformations.
New York: Alan R. Liss (pub.)  1978.

5. Ziegner, H.: Kasuistischer Beitrag zu den symmetrischen Missbildungen
der Extremitaeten. Muench. Med. Wschr. 50: 1386-1387, 1903.

*FIELD* CS

Growth:
   Normal

Limbs:
   Brachydactyly;
   Hypoplastic middle phalanges of index finger and second toe;
   Radial deviation of distal index finger;
   Clinodactyly of fifth finger;
   Delta phalanx

Radiology:
   Rhomboid or triangular shaped affected middle phalanx

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
terry: 5/12/1994
pfoster: 4/4/1994
carol: 3/31/1992
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
112700
*FIELD* TI
*112700 BRACHYDACTYLY, TYPE A3; BDA3
BRACHYMESOPHALANGY V;;
BRACHYDACTYLY-CLINODACTYLY
*FIELD* TX
Shortening is limited to the middle phalanx of the fifth finger. Because
of rhomboid or triangular shape of the rudimentary middle phalanx,
radial curvature (clinodactyly) of the fifth finger results.
(Camptodactyly is flexure contracture of fingers, usually the fifth.
Clinodactyly, which also involves the fifth finger, is a radial
curvature.) Dutta (1965) described 'simple radial deviation of the
distal phalanx' without bony deformity of the middle or distal phalanx
and with normal length of the digit. Whether this is a separate trait is
not certain. Type A3 brachydactyly is variable and may encompass the
cases described by Dutta. (See also dystelephalangy, 128000.) Bauer
(1907) described the anomaly in 4 generations. Defining shortened fifth
medial phalanges as those less than half the length of the fourth medial
phalanx, Hertzog (1967) found the state much more frequent in Chinese
than in Blacks. Population surveys suggest that the trait is more
frequent in Mongoloids and American Indians than in whites or Blacks.
The condition is more frequent in females. (Note that brachymesophalangy
V and brachytelophalangy I are 'normal' forms of brachydactyly and that
each has characteristic sex and population distributions.) X-ray changes
consist of cone-shaped epiphyses with early union.

*FIELD* SA
Hersh et al. (1953)
*FIELD* RF
1. Bauer, B.: Eine bisher nicht beobachtete kongenitale, hereditaere
Anomalie des Fingerskelettes. Dtsch. Z. Chir. 86: 252-259, 1907.

2. Dutta, P.: The inheritance of the radially curved little finger. Acta
Genet. Statist. Med. 15: 70-76, 1965.

3. Hersh, A. H.; DeMarinis, F.; Stecher, R. M.: On the inheritance
and development of clinodactyly. Am. J. Hum. Genet. 5: 257-268,
1953.

4. Hertzog, K. P.: Shortened fifth medial phalanges. Am. J. Phys.
Anthrop. 27: 113-118, 1967.

*FIELD* CS

Growth:
   Normal

Limbs:
   Brachydactyly;
   Hypoplastic fifth finger middle phalanx;
   Fifth finger clinodactyly;
   Clinomicrodactyly

Radiology:
   Cone-shaped epiphyses;
   Rhomboid or triangular shaped fifth finger middle phalanx

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/8/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
112800
*FIELD* TI
*112800 BRACHYDACTYLY, TYPE A4; BDA4
BRACHYMESOPHALANGY II AND V;;
TEMTAMY TYPE BRACHYDACTYLY
*FIELD* TX
Temtamy and McKusick (1978) studied a pedigree with an unusual type of
brachydactyly in 4 generations. The main features were
brachymesophalangy affecting mainly the 2nd and 5th digits. When the 4th
digit was affected, it showed an abnormally shaped middle phalanx
leading to radial deviation of the distal phalanx. The feet also showed
absence of middle phalanges of the lateral four toes. The propositus had
congenital talipes calcaneovalgus. A pedigree reported by Jeanselme et
al. (1923) had affected members in 4 generations and could represent the
same type of brachydactyly. It was one of Bell's unclassified pedigrees.
The affected members had brachydactyly of the 2nd and 5th fingers due to
brachymesophalangy, and one affected member had club foot. Stiles and
Schalck (1945) described a family in which many members of 4 generations
had ulnar curvature of the second finger. Usually the 5th finger, and
sometimes also the 4th, showed at least mild radial curvature. This is
really a form of clinodactyly. Ohzeki et al. (1993) reported this form
of brachydactyly in a Japanese mother and daughter who were also short
of stature.

*FIELD* RF
1. Jeanselme, (NI); Blamoutier, (NI); Joannon, (NI): Brachydactylie
symetrique familiale: etude des lesions anatomique et de la transmission
hereditaire. Rev. Anthrop. 33: 1-23, 1923.

2. Ohzeki, T.; Hanaki, K.; Motozumi, H.; Ohtahara, H.; Shiraki, K.;
Yoshioka, K.: Brachydactyly type A-4 (Temtamy type) with short stature
in a Japanese girl and her mother. Am. J. Med. Genet. 46: 260-262,
1993.

3. Stiles, K. A.; Schalck, J.: A pedigree of curved forefingers. J.
Hered. 36: 211-216, 1945.

4. Temtamy, S. A.; McKusick, V. A.: The Genetics of Hand Malformations.
New York: Alan R. Liss (pub.)  1978.

*FIELD* CS

Growth:
   Normal

Limbs:
   Brachydactyly;
   Hypoplastic middle phalanges;
   Brachymesophalangy affecting mainly the 2nd and 5th digits;
   Absent middle phalanges of the lateral four toes;
   Congenital talipes calcaneovalgus

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
mimadm: 4/18/1994
warfield: 3/31/1994
carol: 12/6/1993
carol: 10/21/1993
carol: 5/19/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
112900
*FIELD* TI
*112900 BRACHYDACTYLY, TYPE A5, WITH NAIL DYSPLASIA
ABSENT MIDDLE PHALANGES OF DIGITS 2-5 WITH NAIL DYSPLASIA
*FIELD* TX
In 13 persons in 4 generations, with male-to-male transmission, Bass
(1968) found absence of the middle phalanges and nail dysplasia. The
terminal phalanx of the thumb was duplicated. Cuevas-Sosa and
Garcia-Segur (1971) reported a family.

*FIELD* RF
1. Bass, H. N.: Familial absence of middle phalanges with nail dysplasia:
a new syndrome. Pediatrics 42: 318-323, 1968.

2. Cuevas-Sosa, A.; Garcia-Segur, F.: Brachydactyly with absence
of middle phalanges and hypoplastic nails: a new hereditary syndrome.
J. Bone Joint Surg. 53B: 101-105, 1971.

*FIELD* CS

Growth:
   Normal

Nails:
   Nail dysplasia

Limbs:
   Brachydactyly;
   Absent middle phalanges;
   Duplicated terminal phalanx of thumb

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
carol: 2/3/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
112910
*FIELD* TI
112910 BRACHYDACTYLY, TYPE A6; BDA6
BRACHYMESOPHALANGY WITH MESOMELIC SHORT LIMBS AND CARPAL AND TARSAL;;
OSSEOUS ABNORMALITIES;;
OSEBOLD-REMONDINI SYNDROME
*FIELD* TX
Osebold et al. (1985) described a kindred in which 7 members had a
constellation of skeletal anomalies which appeared to constitute a 'new'
syndrome. The middle phalanges of the hands and feet were hypoplastic or
absent. The limbs showed mesomelic shortening, and the affected persons
were in general somewhat short. The terminal phalanges of the index
fingers deviated radially. In younger members x-rays showed delayed
coalescence of bipartite calcanei. All were of normal intelligence. In
the wrist the hamate and capitate bones were joined. Male-to-male
transmission was observed and affected persons were found in 3
generations. Sheffield et al. (1987) pointed to similarities between the
OR syndrome and the mild type of chondrodysplasia punctata, and Osebold
(1987) reviewed differences between the two.

*FIELD* SA
Opitz and Gilbert (1985)
*FIELD* RF
1. Opitz, J. M.; Gilbert, E. F.: Autopsy findings in a still-born
female infant with the Osebold-Remondini syndrome. Am. J. Med. Genet. 22:
811-819, 1985.

2. Osebold, W. R.: Reply to Sheffield et al. . (Letter) Am. J. Med.
Genet. 28: 509 only, 1987.

3. Osebold, W. R.; Remondini, D. J.; Lester, E. L.; Spranger, J. W.;
Opitz, J. M.: An autosomal dominant syndrome of short stature with
mesomelic shortness of limbs, abnormal carpal and tarsal bones, hypoplastic
middle phalanges, and bipartite calcanei. Am. J. Med. Genet. 22:
791-809, 1985.

4. Sheffield, L. J.; Mayne, V. M.; Danks, D. M.: Osebold-Remondini
syndrome vs chondrodysplasia punctata. (Letter) Am. J. Med. Genet. 28:
507 only, 1987.

*FIELD* CS

Limbs:
   Mesomelic shortening;
   Short, broad and angulated digits;
   Hypoplastic/absent middle phalanges of hands and feet;
   Radial deviation of index finger terminal phalanges;
   Fused hamate and capitate bones

Growth:
   Short stature

Neuro:
   Normal intelligence

Radiology:
   Delayed coalescence of bipartite calcanei

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 12/15/1988
marie: 3/25/1988

*RECORD*
*FIELD* NO
113000
*FIELD* TI
*113000 BRACHYDACTYLY, TYPE B; BDB
*FIELD* TX
In this form, as in the four A types, the middle phalanges are short but
in addition the terminal phalanges are rudimentary or absent. Both
fingers and toes are affected. The thumbs and big toes are usually
deformed. This type of hand malformation presents the severest deformity
in the brachydactyly group. Symphalangism is also a feature. There is
also mild syndactyly between the digits, leading some authors to
describe this deformity as symbrachydactyly. In the feet there is
syndactyly usually of the 2nd and 3rd toes. The first description of
this hand deformity was in the premendelian era by MacKinder (1857) in 6
generations. MacArthur and McCullough (1932) described the same
deformity in 3 generations and preferred the term 'apical dystrophy.'
(See also coloboma of macula with type B brachydactyly.) Goeminne et al.
(1970) observed affected persons in 5 generations. Lenz (1977) made
brief reference (with photographs) to peripheral defects simulating
amniogenic ('constriction band') defects but distinct from those and
from type B brachydactyly. Five persons in 4 generations were affected.
Failing penetrance was observed in 2 persons.

Houlston and Temple (1994) raised the question of a distinctive facial
appearance associated with type B brachydactyly in an English family
with at least 11 affected members of 4 generations. Affected members
showed wide-spaced, down-slanting palpebral fissures, a prominent nose
with bulbous tip, and a short philtrum.

Sorsby (1935) described the association of congenital coloboma of the
macula with type B coloboma (120400).

*FIELD* SA
Battle et al. (1973); Thompson and Baraitser (1988)
*FIELD* RF
1. Battle, H. I.; Walker, N. F.; Thompson, M. W.: MacKinder's hereditary
brachydactyly: phenotypic, radiological, dermatoglyphic and genetic
observations in an Ontario family. Ann. Hum. Genet. 36: 415-424,
1973.

2. Goeminne, L.; Agneessens, A.; Kunnen, M.: Perodactylie of apicale
dystrofie: brachydactylie door hypofalangie II-V met bifide telefalangie
I, in vijf generaties. Tijdschr. Geneeskunde 9: 469-472, 1970.

3. Houlston, R. S.; Temple, I. K.: Characteristic facies in type
B brachydactyly?. Clin. Dysmorph. 3: 224-227, 1994.

4. Lenz, W.: Comment. Birth Defects Orig. Art. Ser. XIII(1): 267-268,
1977.

5. MacArthur, J. W.; McCullough, E.: Apical dystrophy as inherited
defect of hands and feet. Hum. Biol. 4: 179-207, 1932.

6. MacKinder, D.: Deficiency of fingers transmitted through six generations. Brit.
Med. J. 1: 845-846, 1857.

7. Sorsby, A.: Congenital coloboma of the macula: together with an
account of the familial occurrence of bilateral macular coloboma in
association with apical dystrophy of hands and feet. Brit. J. Ophthal. 19:
65-90, 1935.

8. Thompson, E. M.; Baraitser, M.: Sorsby syndrome: a report on further
generations of the original family. J. Med. Genet. 25: 313-321,
1988.

*FIELD* CS

Limbs:
   Brachydactyly;
   Hypoplastic middle phalanges;
   Hypoplastic/absent terminal phalanges;
   Symphalangism;
   Mild syndactyly;
   Deformed thumbs and big toes

Growth:
   Normal

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
terry: 6/8/1995
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 7/14/1989

*RECORD*
*FIELD* NO
113100
*FIELD* TI
*113100 BRACHYDACTYLY, TYPE C; BDC
BRACHYDACTYLY, HAWS TYPE
*FIELD* TX
Haws (1963) described an extensively affected Mormon kindred. The
anomalies of the digits are of many types: brachydactyly of the middle
phalanx of the index and middle fingers, triangulation of the fifth
middle phalanx, brachymetapody, hyperphalangy (more than 3 phalanges per
finger), symphalangism (q.v.), etc. About 600 family members were
examined, of whom 86 were affected. The characteristic change should be
considered a deformity of the middle and proximal phalanges of the
second and third fingers, sometimes with hypersegmentation of the
proximal phalanx. The ring finger may be essentially normal and project
beyond the others. In a kindred with brachydactyly considered by the
authors as type C, Robinson et al. (1968) found Legg-Perthes disease of
the hip in 3 affected persons, 2 sisters and their maternal uncle. The
family reported by Ventruto et al. (1976) may have had type C
brachydactyly, but Fitch (1980) favored type B (as part of a syndrome).

Baraitser and Burn (1983) described affected brother and sister whose
Iraqi, first-cousin parents were unaffected. This raised the possibility
of autosomal recessive inheritance of this phenotype.

Sanz and Gilgenkrantz (1988) described affected individuals in 4
generations of a family. Rowe-Jones et al. (1992) described
brachydactyly type C in 4 generations of a family. Characteristic
hypersegmentation producing an extra, wedge-shaped bone at the base of
the proximal phalanx in the index and middle fingers was found with
ulnar deviation of the index finger. Members of this family also had
shortening of the hallux with hypersegmentation. All affected members
had similar small cupped-shaped ears.

In a reevaluation of the kindred reported by Haws (1963), Polymeropoulos
et al. (1996) was able to demonstrate linkage to DNA markers in the
12q24 region.

*FIELD* SA
Fitch et al. (1979); Pol  (1921)
*FIELD* RF
1. Baraitser, M.; Burn, J.: Recessively inherited brachydactyly type
C. J. Med. Genet. 20: 128-129, 1983.

2. Fitch, N.: Personal Communication. Montreal, Quebec, Canada
1980.

3. Fitch, N.; Jequier, S.; Costom, B.: Brachydactyly C, short stature,
and hip dysplasia. Am. J. Med. Genet. 4: 157-165, 1979.

4. Haws, D. V.: Inherited brachydactyly and hypoplasia of the bones
of the extremities. Ann. Hum. Genet. 26: 201-212, 1963.

5. Pol, D.: 'Brachydactylie,' 'Klinodaktylie,' Hyperphalangie und
ihre Grundlagen. Virchows Arch. Path. Anat. 229: 388-530, 1921.

6. Polymeropoulos, M. H.; Ide, S. E.; Magyari, T.; Francomano, C.
A.: Brachydactyly type C gene maps to human chromosome 12q24. Genomics 38:
45-50, 1996.

7. Robinson, G. C.; Wood, B. J.; Miller, J. R.; Baillie, J.: Hereditary
brachydactyly and hip disease. Unusual radiological and dermatoglyphic
findings in a kindred. J. Pediat. 72: 539-543, 1968.

8. Rowe-Jones, J. M.; Moss, A. L. H.; Patton, M. A.: Brachydactyly
type C associated with shortening of the hallux. J. Med. Genet. 29:
346-348, 1992.

9. Sanz, J.; Gilgenkrantz, S.: Type C brachydactyly transmitted through
four generations. Ann. Genet. 31: 43-46, 1988.

10. Ventruto, V.; DiGirolamo, R.; Festa, B.; Romano, A.; Sebastio,
L.: Family study of inherited syndrome with multiple congenital deformities:
symphalangism, carpal and tarsal fusion, brachydactyly, craniosynostosis,
strabismus, hip osteochondritis. J. Med. Genet. 13: 394-398, 1976.

*FIELD* CS

Growth:
   Normal

Limbs:
   Brachydactyly;
   Brachymetapody;
   Hyperphalangy;
   Abnormal middle and proximal phalanges of index and middle fingers;
   Hypersegmentation of the proximal phalanges;
   Characteristic ulnar deflection of the index finger;
   Symphalangism

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
terry: 10/30/1996
mimadm: 4/9/1994
warfield: 4/7/1994
carol: 6/23/1992
carol: 3/31/1992
supermim: 3/16/1992
carol: 8/23/1990

*RECORD*
*FIELD* NO
113200
*FIELD* TI
*113200 BRACHYDACTYLY, TYPE D; BDD
STUB THUMB
*FIELD* TX
This type is characterized by short and broad terminal phalanges of the
thumbs and big toes. Thomsen (1928) described this anomaly. In a
unilateral case he pointed out that the epiphyseal line at the base of
the anomalous phalanx was obliterated but was still demonstrable in the
corresponding position on the normal thumb. Goodman et al. (1965) also
studied this 'normal' morphologic trait in detail. The trait has
picturesque designations such as 'potter's thumb' and 'murderer's
thumb.' It occurs as part of the Rubinstein syndrome (180849). Gray and
Hurt (1984) concluded that penetrance is complete in females and
incomplete in males. About three-fourths of affected persons, both males
and females, express the trait bilaterally.

*FIELD* SA
Breitenbecher  (1923); Hefner  (1924); Sayles and Jailer (1934)
*FIELD* RF
1. Breitenbecher, J. K.: Hereditary shortness of thumbs. J. Hered. 14:
15-21, 1923.

2. Goodman, R. M.; Adam, A.; Sheba, C.: A genetic study of stub thumbs
among various ethnic groups in Israel. J. Med. Genet. 2: 116-121,
1965.

3. Gray, E.; Hurt, V. K.: Inheritance of brachydactyly type D. J.
Hered. 75: 297-299, 1984.

4. Hefner, R. A.: Inherited abnormalities of the fingers. II. Short
thumbs (brachymegalodactylism). J. Hered. 15: 433-440, 1924.

5. Sayles, L. P.; Jailer, J. W.: Four generations of short thumbs. J.
Hered. 25: 377-378, 1934.

6. Thomsen, O.: Hereditary growth anomaly of the thumb. Hereditas 10:
261-273, 1928.

*FIELD* CS

Growth:
   Normal

Limbs:
   Brachydactyly;
   Short and broad distal phalanges of thumbs and great toes

Radiology:
   Obliterated epiphyseal line at base of distal thumb phalanx

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 12/13/1996
terry: 12/10/1996
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 10/22/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
113300
*FIELD* TI
*113300 BRACHYDACTYLY, TYPE E; BDE
*FIELD* TX
In type E brachydactyly, shortening of the fingers is mainly in the
metacarpals and metatarsals. Wide variability in the number of digits
affected occurs from person to person, even in the same family. The
patients are moderately short of stature and have round facies but do
not have ectopic calcification (or ossification), mental retardation or
cataract as in pseudo-pseudohypoparathyroidism (300800) which is
otherwise a clinically similar entity. Male-to-male transmission of type
E brachydactyly has been observed (McKusick and Milch, 1964). This
phenotype is a useful example of genetic heterogeneity, because in
addition to the autosomal dominant isolated type and the X-linked
Albright hereditary osteodystrophy, it also occurs with a chromosomal
aberration, the XO Turner syndrome. Also see
brachydactyly-nystagmus-cerebellar ataxia (Biemond syndrome I), a
probable dominant trait. Hertzog (1968) suggested that there are at
least 3 subtypes: E1, in which shortening is limited to fourth
metacarpals and/or metatarsals (Hortling et al., 1960); E2, in which
variable combinations of metacarpals are involved, with shortening also
of the first and third distal and the second and fifth middle phalanges
(McKusick and Milch, 1964); and E3, a dubious category which may have a
variable combination of short metacarpals without phalangeal
involvement. Newcombe and Keats (1969) described an extensively affected
kindred with a dominant pedigree pattern (their pedigree II) as having
peripheral dysostosis. The description resembles that in the family of
McKusick and Milch (1964) except for cone epiphyses. The authors felt
that the presence of cone epiphyses in their family was a distinguishing
feature. In a family reported by Gorlin and Sedano (1971), type E
brachydactyly was associated with multiple impacted teeth. Gorlin and
Sedano (1971) gave the designation 'cryptodontic metacarpalia' to type E
brachydactyly associated with multiple impacted teeth. The clavicles
were unusually straight and short. Whether this is a distinct entity is
not clear. Poznanski et al. (1977) concluded that 'brachydactyly E is
indistinguishable radiologically from the PHP-PPHP syndrome' (300800).
Bale et al. (1985) raised a question of linkage of Wolfram syndrome
(222300) and brachydactyly E on the basis of a family in which 3 sisters
had both, their mother and a brother had only brachydactyly E, and
another brother had neither.

Wilson et al. (1995) found a cytogenetically visible de novo deletion of
2q37 in 4 patients in whom brachydactyly type E was combined with mental
retardation to produce a picture simulating Albright hereditary
osteodystrophy (see 600430). A fifth patient, who was cytogenetically
normal, was found to have a microdeletion at 2q37. It is likely that
these patients suffered from a contiguous gene syndrome involving the
locus for brachydactyly type E and one or more other loci.

*FIELD* SA
Cartwright et al. (1980); Gnamey et al. (1975)
*FIELD* RF
1. Bale, A. E.; Ludwig, I. H.; Effron, L. A.; Zakov, Z. N.: Linkage
between the genes for Wolfram syndrome and brachydactyly E.  (Letter) Am.
J. Med. Genet. 20: 733-734, 1985.

2. Cartwright, J. D.; Rosin, M.; Robertson, C.: Brachydactyly type
E: a report of a family. S. Afr. Med. J. 58: 255-257, 1980.

3. Gnamey, D.; Walbaum, R.; Fossati, P.; Prouvost, J.-M.: Brachydactylie
hereditaire de type E: a propos d'une observation familiale. Pediatrie 30:
153-169, 1975.

4. Gorlin, R. J.; Sedano, H. O.: Cryptodontic brachymetacarpalia.
Birth Defects Orig. Art. Ser. VII(7): 200-203, 1971.

5. Hertzog, K. P.: Brachydactyly and pseudo-pseudohypoparathyroidism.
Acta Genet. Med. Gemellol. 17: 428-437, 1968.

6. Hortling, H.; Puupponen, E.; Koski, K.: Short metacarpal or metatarsal
bones: pseudo-pseudohypoparathyroidism. J. Clin. Endocr. 20: 466-472,
1960.

7. McKusick, V. A.; Milch, R. A.: The clinical behavior of genetic
disease: selected aspects. Clin. Orthop. 33: 22-39, 1964.

8. Newcombe, D. S.; Keats, T. E.: Roentgenographic manifestations
of hereditary peripheral dysostosis. Am. J. Roentgen. 106: 178-189,
1969.

9. Poznanski, A. K.; Werder, E. A.; Giedion, A.: The pattern of shortening
of the bones of the hand in PHP and PPHP--a comparison with brachydactyly
E, Turner syndrome, and acrodysostosis. Radiology 123: 707-718,
1977.

10. Wilson, L. C.; Leverton, K.; Oude Luttikhuis, M. E. M.; Oley,
C. A.; Flint, J.; Wolstenholme, J.; Duckett, D. P.; Barrow, M. A.;
Leonard, J. V.; Read, A. P.; Trembath, R. C.: Brachydactyly and mental
retardation: an Albright hereditary osteodystrophy-like syndrome localized
to 2q37. Am. J. Hum. Genet. 56: 400-407, 1995.

*FIELD* CS

Growth:
   Moderately short stature

Limbs:
   Brachydactyly;
   Short metacarpals;
   Variable short metatarsals

Facies:
   Round facies

Teeth:
   Multiple impacted teeth

Skel:
   Straight and short clavicles

Radiology:
   Radiologically indistinguishable from the PHP-PPHP syndrome

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/27/1995
mimadm: 4/9/1994
carol: 10/21/1993
supermim: 3/16/1992
carol: 3/22/1991
carol: 9/19/1990

*RECORD*
*FIELD* NO
113301
*FIELD* TI
113301 BRACHYDACTYLY, TYPE E, WITH ATRIAL SEPTAL DEFECT, TYPE II
*FIELD* TX
In a kindred in which multiple members had somewhat short stature, round
facies, and brachydactyly type E (113300), Czeizel and Goblyos (1989)
described also the appearance of the secundum type of atrial septal
defect (ASD II). The shortening of the metacarpals was most pronounced
in the 4th metacarpal, but not limited to that bone.

*FIELD* RF
1. Czeizel, A.; Goblyos, P.: Familial combination of brachydactyly,
type E and atrial septal defect, type II. Europ. J. Pediat. 149:
117-119, 1989.

*FIELD* CS

Growth:
   Short stature

Facies:
   Round facies

Limbs:
   Brachydactyly;
   Short metacarpals, esp. 4th;
   Variable short metatarsals

Cardiac:
   Atrial septal defect (ASD II)

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 2/9/1990

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/9/1990

*RECORD*
*FIELD* NO
113310
*FIELD* TI
113310 BRACHYDACTYLY-ECTRODACTYLY WITH FIBULAR APLASIA OR HYPOPLASIA
*FIELD* TX
In a 25-year-old woman, Genuardi et al. (1990) observed hypoplasia of
the phalanges of both hands, ectrodactyly in both feet, and nearly
complete bilateral absence of the fibula. In a male second cousin, very
mild defects of the hands and feet were observed. The fibulas were
normal. In the proposita, the middle phalanx was particularly small in
the right index finger. In the left hand, the second and third fingers
had only rudimentary phalanges. Genuardi et al. (1990) referred to a
similar deformity reported by Deragna et al. (1966) in 7 members of a
family. Lewin and Opitz (1986) gave a general discussion of fibular
aplasia/hypoplasia.

*FIELD* RF
1. Deragna, S.; Zucco, V.; Ferrante, E.: Trasmissione ereditaria
di aplasia del perone e di ectrodattilia: studio di una famiglia.
Quad. Clin. Ostet. Ginec. 21: 1295-1308, 1966.

2. Genuardi, M.; Zollino, M.; Bellussi, A.; Fuhrmann, W.; Neri, G.
: Brachy/ectrodactyly and absence or hypoplasia of the fibula: an
autosomal dominant condition with low penetrance and variable expressivity.
Clin. Genet. 38: 321-326, 1990.

3. Lewin, S. O.; Opitz, J. M.: Fibular a/hypoplasia: review and documentation
of the fibular developmental field. Am. J. Med. Genet. 25 (suppl.
2): 215-238, 1986.

*FIELD* CS

Limbs:
   Hypoplastic phalanges of hands;
   Ectrodactyly of feet;
   Fibular aplasia/hypoplasia

*FIELD* CD
Victor A. McKusick: 12/13/1990

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 2/27/1992
carol: 3/22/1991
carol: 12/14/1990
carol: 12/13/1990

*RECORD*
*FIELD* NO
113400
*FIELD* TI
113400 BRACHYDACTYLY-NYSTAGMUS-CEREBELLAR ATAXIA
*FIELD* TX
Biemond (1934) described a syndrome consisting of brachydactyly (due to
one short metacarpal and metatarsal), nystagmus and cerebellar ataxia in
4 generations of a family. Mental deficiency and strabismus were also
present. Only a few members of the family had the full syndrome.
Additional families are needed before this combination can be considered
a single gene syndrome.

*FIELD* RF
1. Biemond, A.: Brachydactylie, Nystagmus en cerebellaire Ataxie
als familiair Syndroom. Nederl. T. Geneesk. 78: 1423-1431, 1934.

*FIELD* CS

Limbs:
   Brachydactyly (one short metacarpal and metatarsal)

Eyes:
   Nystagmus;
   Strabismus

Neuro:
   Cerebellar ataxia;
   Mental deficiency

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
113450
*FIELD* TI
113450 BRACHYDACTYLY-DISTAL SYMPHALANGISM SYNDROME
*FIELD* TX
Sillence (1978) described a kindred in which grandfather, mother and 3
granddaughters, i.e., 5 persons in 3 successive generations, had
brachydactyly, distal symphalangism producing a distal phalanx with the
shape of a chess pawn, scoliosis, and clubfoot. The disorder resembled
type A1 brachydactyly (112500), but affected persons were tall. In
another symphalangism-brachydactyly syndrome (186500), the symphalangism
is proximal.

*FIELD* RF
1. Sillence, D. O.: Brachydactyly, distal symphalangism, scoliosis,
tall stature, and club feet: a new syndrome. J. Med. Genet. 15:
208-211, 1978.

*FIELD* CS

Limbs:
   Brachydactyly;
   Distal symphalangism;
   Clubfoot

Spine:
   Scoliosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
carol: 11/27/1989
ddp: 10/26/1989
root: 10/17/1989

*RECORD*
*FIELD* NO
113470
*FIELD* TI
113470 BRACHYMESOMELIA-RENAL SYNDROME
*FIELD* TX
Langer et al. (1983) reported a single case of a Japanese infant who
died in the newborn period of cardiac and renal failure. X-rays showed
bizarre deformities of the forearm and lower leg. The corneas were
clouded and the kidneys enlarged. Renal biopsies showed glomerulocystic
kidneys. A noncyanotic cardiac malformation was thought to be present.
Autopsy was refused. The parents were apparently unrelated--mother aged
31 and father aged 36.

*FIELD* RF
1. Langer, L. O., Jr.; Nishino, R.; Yamaguchi, A.; Ito, Y.; Ueke,
T.; Togari, H.; Kato, T.; Opitz, J. M.; Gilbert, E. F.: Brachymesomelia-renal
syndrome. Am. J. Med. Genet. 15: 57-65, 1983.

*FIELD* CS

Limbs:
   Short distal limbs

Eyes:
   Cloudy corneas

GU:
   Enlarged kidneys;
   Renal failure

Cardiac:
   Congenital heart defect;
   Congestive heart failure

Misc:
   Neonatal death

Radiology:
   Bizarre deformities of the forearm and lower leg

Lab:
   Glomerulocystic kidneys on renal biopsy

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
113475
*FIELD* TI
113475 BRACHYMETATARSUS IV
METATARSUS IV, SHORT;;
TOE, FOURTH, SHORT
*FIELD* TX
Before his death on December 1, 1964, J. B. S. Haldane, with A. K. Ray,
prepared a paper describing short fourth metatarsus resulting in
unilateral or bilateral short fourth toes identified in 206 persons in
Northeastern India (Ray and Haldane, 1965). This was Haldane's only
publication in an American journal (Ray, 1989). From a study of 61
pedigrees Ray and Haldane (1965) concluded that the trait is autosomal
dominant with approximately 27% penetrance. The wearing of sandals
facilitated the population survey. In an initial survey they found the
trait in 3 unrelated men among 2,500 in Orissa. Although short terminal
phalanx of the thumb was found in 3 of 117 persons with short fourth
toes, 2 bilateral and 1 unilateral, there was apparently no instance of
short metacarpals, thus indicating that the trait is distinct from type
E brachydactyly (113300).

*FIELD* RF
1. Ray, A. K.: Personal Communication. Toronto, Canada  12/11/1989.

2. Ray, A. K.; Haldane, J. B. S.: The genetics of a common Indian
digital abnormality. Proc. Nat. Acad. Sci. 53: 1050-1053, 1965.

*FIELD* CS

Limbs:
   Short fourth metatarsus;
   Short fourth toes

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 1/12/1990

*FIELD* ED
mimadm: 4/9/1994
warfield: 4/7/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/12/1990

*RECORD*
*FIELD* NO
113477
*FIELD* TI
113477 BRACHYMORPHISM-ONYCHODYSPLASIA-DYSPHALANGISM SYNDROME
BOD SYNDROME
*FIELD* TX
Senior (1971) described 6 'short children with tiny fingernails.' Pre-
and postnatal short stature, hypoplastic fifth digits with abnormal
phalanges and tiny fingernails, facial dysmorphism, and, in some, mild
intellectual impairment were observed. Mace and Gotlin (1973) reported a
single case. As noted in connection with the Coffin-Siris syndrome
(135900), the condition reported by Senior (1971) resembles that
disorder except that mental retardation is milder. Verloes et al. (1993)
reported 3 unrelated children with intrauterine proportionate growth
retardation and facial dysmorphism (broad nose, flat malar area, large
mouth, pointed chin), microcephaly, hypo/aplasia of the terminal fifth
digits, and normal or only mildly reduced intelligence. Radiologic
findings included hypo/aplasia or fusion of the distal phalanges of the
fifth finger and toe, brachymesophalangism V, and nail dysplasia or
aplasia. One of the 3 children had cystic adenomatoid disease of the
lung. This disorder may be a mild form of Coffin-Siris syndrome or an
independent entity. Verloes et al. (1993) suggested that it be called
the brachymorphism-onychodysplasia-dysphalangism syndrome (BOD syndrome)
because 'Senior syndrome' runs the risk of confusion with the
Senior-Loken syndrome (266900).

*FIELD* RF
1. Mace, J. W.; Gotlin, R. W.: Short stature and onychodysplasia:
report of a case resembling Senior syndrome. Am. J. Dis. Child. 125:
114-116, 1973.

2. Senior, B.: Impaired growth and onychodysplasia: short children
with tiny toenails. Am. J. Dis. Child. 122: 7-9, 1971.

3. Verloes, A.; Bonneau, D.; Guidi, O.; Berthier, M.; Oriot, D.; Van
Maldergem, L.; Koulischer, L.: Brachymorphism-onychodysplasia-dysphalangism
syndrome. J. Med. Genet. 30: 158-161, 1993.

*FIELD* CS

Nails:
   Nail dysplasia/aplasia;
   Tiny fingernails

Growth:
   Pre- and postnatal short stature

Limbs:
   Hypo/aplasia of terminal fifth digits;
   Abnormal phalanges

Facies:
   Facial dysmorphism;
   Broad nose;
   Flat malar area;
   Large mouth;
   Pointed chin

Neuro:
   Normal or only mildly reduced intelligence

Head:
   Microcephaly

Pulmonary:
   Cystic adenomatoid lung disease

Radiology:
   Hypo/aplasia or fusion of the distal phalanges of the fifth finger
   and toe;
   Brachymesophalangism V

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/20/1993

*FIELD* ED
mimadm: 4/9/1994
carol: 3/20/1993

*RECORD*
*FIELD* NO
113480
*FIELD* TI
113480 BRACHYTELEPHALANGY WITH CHARACTERISTIC FACIES AND KALLMANN SYNDROME
*FIELD* TX
Hunter et al. (1986) described mother and son with identical facies
(square forehead, telecanthus, flat nasal bridge, thin upper lip,
'smooth' philtrum), and marked brachytelephalangy. The son had Kallmann
syndrome (147950, 244200, 308700).

*FIELD* RF
1. Hunter, A. G. W.; Feldman, W.; Miller, J.: Characteristic craniofacial
appearance and brachytelephalangy in a mother and son with Kallmann
syndrome in the son. Am. J. Med. Genet. 24: 527-532, 1986.

*FIELD* CS

Limbs:
   Brachytelephalangy

Facies:
   Square forehead;
   Telecanthus;
   Flat nasal bridge;
   Thin upper lip;
   Smooth philtrum

GU:
   Hypogonadotropic hypogonadism

Nose:
   Anosmia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 3/4/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
113500
*FIELD* TI
113500 BRACHYRACHIA
BRACHYOLMIA
*FIELD* TX
Brown (1933) described as Morquio disease the condition in a mother and
2 daughters. Lenz (1964) observed father and son with a very short spine
and deformity of the anterior chest rather like that in Morquio disease.
Except for marked changes in the femoral epiphyses, the extremities were
normal. The vertebral bodies were small, irregular, and radiolucent.
Perhaps the family of Lomas and Boyle (1959) in which 3 generations were
affected had the same condition. See the dominant type of
spondyloepiphyseal dysplasia tarda (184100) and spondylodysplasia with
pure brachyolmia (271530). Kozlowski et al. (1982) stated that pure
brachyolmia does not exist and that metaphyseal involvement may be
minimal and scattered but always is present along with involvement of
the spine in cases labeled brachyolmia. Shohat et al. (1989), however,
described a mother and son with severe spinal changes with no
metaphyseal or epiphyseal changes in the long bones. These patients
showed the most severe scoliosis of the patients they studied, and
demonstrated marked cervical vertebral flattening and irregularity.
Gardner and Beighton (1994) investigated the cases of a mother and son
of South African Xhosa stock who presented with short-trunk dwarfism and
kyphoscoliosis. Radiographs showed the marked platyspondyly and
vertebral irregularity characteristic of brachyolmia. In the mother, the
femoral necks were very short with a varus deformity; in the 6-year-old
son, the femoral necks were likewise short and their metaphyseal regions
were irregular, with areas of patchy lucency and sclerosis.

*FIELD* SA
Brown and MacDonald (1933)
*FIELD* RF
1. Brown, D. O.: Morquio's disease. Med. J. Aust. 1: 598-600,
1933.

2. Brown, D. O.; MacDonald, C.: Three cases of familial osseous dystrophy.
Aust. New Zeal. J. Surg. 3: 78-88, 1933.

3. Gardner, J.; Beighton, P.: Brachyolmia: an autosomal dominant
form. Am. J. Med. Genet. 49: 308-312, 1994.

4. Kozlowski, K.; Beemer, F. A.; Bens, G.; Dijkstra, P. F.; Iannaccone,
G.; Emons, D.; Lopez-Ruiz, P.; Masel, J.; van Nieuwenhuizen, O.; Rodriguez-Barrionuevo,
C.: Spondylo-metaphyseal dysplasia: report of 7 cases and essay of
classification. In: Papadatos, C. J.; Bartsocas, C. S.: Skeletal
Dysplasias.  New York: Alan R. Liss (pub.)  1982. Pp. 89-101.

5. Lenz, W.: Anomalien des Wachstums und der Koerperform. In: Becker,
P. E.: Ein kurzes Handbuch in fuenf Baenden.  Stuttgart: Georg
Thieme Verlag (pub.)  2: 1964. Pp. 88-89. Note: Fig. 30.

6. Lomas, J. J. P.; Boyle, A. C.: Osteo-chondrodystrophy (Morquio's
disease) in three generations. Lancet II: 430-432, 1959.

7. Shohat, M.; Lachman, R.; Gruber, H. E.; Rimoin, D. L.: Brachyolmia:
radiographic and genetic evidence of heterogeneity. Am. J. Med.
Genet. 33: 209-219, 1989.

*FIELD* CS

Spine:
   Short spine;
   Scoliosis

Thorax:
   Anterior chest deformity

Radiology:
   Abnormal femoral epiphyses;
   Small, irregular and radiolucent vertebral bodies;
   Variable long bone metaphyseal abnormality

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 6/1/1994
mimadm: 4/9/1994
pfoster: 3/25/1994
carol: 10/26/1993
supermim: 3/16/1992
carol: 8/23/1990

*RECORD*
*FIELD* NO
113503
*FIELD* TI
*113503 BRADYKININ RECEPTOR B2; BDKRB2
BRADYKININ RECEPTOR-2; BKR2
*FIELD* TX
Bradykinin (BK), a 9-amino acid peptide, is generated from
high-molecular-weight precursors, the kininogens (228960), by limited
proteolysis in tissues and body fluids. It elicits numerous responses
including vasodilation, edema, smooth muscle spasm, and stimulation of
pain fibers. When activated in pathophysiologic conditions such as
inflammation, trauma, burns, shock, and allergy, the kininogens release
bradykinin, kallidin (KD or lys-BK), and met-lys bradykinin. Kinin
receptors are classified as B1 and B2 on the basis of relative potencies
of agonists in isolated vascular smooth muscle preparations. Hess et al.
(1992) cloned a human BK-2 bradykinin receptor from a lung fibroblast
cell line. The cDNA clone encoded a 364-amino acid protein that had the
characteristics of a 7-transmembrane domain G-protein coupled receptor.
The predicted amino acid sequence showed 81% identity to smooth muscle
rat BK-2 receptor. Transfection of the cDNA into COS-7 cells resulted in
the expression of high levels of specific BK binding sites. Powell et
al. (1993) used the published rat bradykinin B2 sequence to design PCR
amplimers. The full-length cDNA that they obtained also coded for a
364-amino acid protein with a molecular mass of 41,442 Da that was 81%
similar to rat bradykinin B2 receptor cDNA. Kammerer et al. (1995)
obtained both a full-length cDNA and a genomic clone and Braun et al.
(1995) described 3 polymorphic sites in the BKR2 gene.

Using PCR for specific amplification of DNA from somatic cell hybrids,
Powell et al. (1993) mapped the gene to chromosome 14. By fluorescence
in situ hybridization, Ma et al. (1994) mapped the BDKRB2 gene to 14q32.
Powell et al. (1993) stated that 'the genomic clone of the gene is
intronless;' however, Ma et al. (1994) demonstrated that the gene
contains 3 exons separated by 2 introns. The first and second exons are
noncoding, while the third exon contains the full-length coding region.
Genomic Southern blot analysis showed that the B(2) receptor is encoded
by a single copy gene and is expressed in most human tissues. Taketo et
al. (1995) demonstrated that the mouse homolog maps to the distal
portion of mouse chromosome 12.

*FIELD* RF
1. Braun, A.; Kammerer, S.; Bohme, E.; Muller, B.; Roscher, A. A.
: Identification of polymorphic sites of the human bradykinin B(2)
receptor gene. Biochem. Biophys. Res. Commun. 211: 234-240, 1995.

2. Hess, J. F.; Borkowski, J. A.; Young, G. S.; Strader, C. D.; Ransom,
R. W.: Cloning and pharmacological characterization of a human bradykinin
(BK-2) receptor. Biochem. Biophys. Res. Commun. 184: 260-268, 1992.

3. Kammerer, S.; Braun, A.; Arnold, N.; Roscher, A. A.: The human
bradykinin B(2) receptor gene: full length cDNA, genomic organization
and identification of the regulatory region. Biochem. Biophys. Res.
Commun. 211: 226-233, 1995.

4. Ma, J.; Wang, D.; Ward, D. C.; Chen, L.; Dessai, T.; Chao, J.;
Chao, L.: Structure and chromosomal localization of the gene (BDKRB2)
encoding human bradykinin B-2 receptor. Genomics 23: 362-369, 1994.

5. Powell, S. J.; Slynn, G.; Thomas, C.; Hopkins, B.; Briggs, I.;
Graham, A.: Human bradykinin B2 receptor: nucleotide sequence analysis
and assignment to chromosome 14. Genomics 15: 435-438, 1993.

6. Taketo, M.; Yokoyama, S.; Rochelle, J.; Kimura, S.; Higashida,
H.; Taketo, M.; Seldin, M. F.: Mouse B2 bradykinin receptor gene
maps to distal chromosome 12. Genomics 27: 222-223, 1995.

*FIELD* CD
Victor A. McKusick: 6/9/1992

*FIELD* ED
mark: 02/07/1996
mark: 9/27/1995
carol: 11/30/1994
carol: 5/12/1993
carol: 3/18/1993
carol: 6/9/1992

*RECORD*
*FIELD* NO
113505
*FIELD* TI
*113505 BRAIN-DERIVED NEUROTROPHIC FACTOR; BDNF
*FIELD* TX
During normal vertebral development, up to 80% of the neurons in diverse
cell populations within the forming nervous system die. This is thought
to be a mechanism that ensures that adequate numbers of neurons
establish appropriate innervation densities with effector organs or
other neuronal populations. In several instances, the innervation target
of a population of neurons has been shown to have a crucial role in
regulating the number of surviving neurons. Targets of neuronal
innervation produce a limited supply of neurotrophic factors, and
competition between neurons responsive to these factors determines which
neurons survive (Jones and Reichardt, 1990). In addition to nerve growth
factor (NGF; 162030), brain-derived neurotrophic factor (BDNF) has been
purified and shown in vivo to reduce the amount of naturally occurring
neuronal cell death in portions of the peripheral nervous system. NGF
and BDNF show considerable amino acid and nucleotide sequence similarity
(Hofer and Barde, 1988). Maisonpierre et al. (1991) cloned the human and
rat genes encoding BDNF. They demonstrated that the mature form was
identical in all mammals examined. Furthermore, the tissue distributions
and neuronal specificities are conserved among mammals. They localized
the BDNF gene to 11p13. Ozcelik et al. (1991) also mapped BDNF to human
chromosome 11p15.5-p11.2 by analysis of somatic cell hybrids. They
assigned the mouse gene to chromosome 2. By deletion analysis of somatic
cell hybrids containing human chromosome 11 with deletion or
translocation breakpoints, Hanson et al. (1992) showed that BDNF maps
between FSHB (136530) and HVBS1 (114550) at the boundary of 11p13 and
11p14.

Conover et al. (1995) and Liu et al. (1995) performed studies in mice
rendered deficient in BDNF and/or neurotrophin-4 (NT4; 162661) by the
use of homologous recombination targeting vectors in embryonic stem
cells. Conover et al. (1995) found that NT4-deficient mice were
long-lived and showed no obvious neurologic defects. Further analysis of
distinct neuronal populations demonstrated that vestibular and
trigeminal sensory neurons required BDNF but not NT4, whereas
nodose-petrosal sensory neurons required both BDNF and NT4. Liu et al.
(1995) likewise found that NT4-deficient mice were viable but exhibited
a loss of sensory neurons in the nodose-petrosal and geniculate ganglia.
In contrast, motor neurons of the facial nucleus and sympathetic neurons
of the superior cervical ganglion were unaffected. In mice lacking both
NF4 and BDNF, facial motor neurons remained unaffected, whereas the loss
of sensory neurons was more severe than with either mutation alone.

*FIELD* RF
1. Conover, J. C.; Erickson, J. T.; Katz, D. M.; Bianchi, L. M.; Poueymirou,
W. T.; McClain, J.; Pan, L.; Helgren, M.; Ip, N. Y.; Boland, P.; Friedman,
B.; Wiegand, S.; Vejsada, R.; Kato, A. C.; DeChiara, T. M.; Yancopoulos,
G. D.: Neuronal deficits, not involving motor neurons, in mice lacking
BDNF and/or NT4. Nature 375: 235-238, 1995.

2. Hanson, I. M.; Seawright, A.; van Heyningen, V.: The human BDNF
gene maps between FSHB and HVBS1 at the boundary of 11p13-p14. Genomics 13:
1331-1333, 1992.

3. Hofer, M. M.; Barde, Y.-A.: Brain-derived neurotrophic factor
prevents neuronal death in vivo. Nature 331: 261-262, 1988.

4. Jones, K. R.; Reichardt, L. F.: Molecular cloning of a human gene
that is a member of the nerve growth factor family. Proc. Nat. Acad.
Sci. 87: 8060-8064, 1990.

5. Liu, X.; Ernfors, P.; Wu, H.; Jaenisch, R.: Sensory but not motor
neuron deficits in mice lacking NT4 and BDNF. Nature 375: 238-241,
1995.

6. Maisonpierre, P. C.; Le Beau, M. M.; Espinosa, R., III; Ip, N.
Y.; Belluscio, L.; de la Monte, S. M.; Squinto, S.; Furth, M. E.;
Yancopoulos, G. D.: Human and rat brain-derived neurotrophic factor
and neurotrophin-3: gene structures, distributions and chromosomal
localizations. Genomics 10: 558-568, 1991.

7. Ozcelik, T.; Rosenthal, A.; Francke, U.: Chromosomal mapping of
brain-derived neurotrophic factor and neurotrophin-3 genes in man
and mouse. Genomics 10: 569-575, 1991.

*FIELD* CD
Victor A. McKusick: 11/19/1990

*FIELD* ED
mark: 6/19/1995
carol: 8/14/1992
supermim: 3/16/1992
carol: 2/18/1992
carol: 5/21/1991
carol: 4/2/1991

*RECORD*
*FIELD* NO
113508
*FIELD* TI
*113508 TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN,
ETA POLYPEPTIDE; YWHAH
BRAIN PROTEIN 14-3-3, ETA CHAIN;;
TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN;;
1; YWHA1
*FIELD* TX
Protein 14-3-3 is a protein kinase-dependent activator of tyrosine and
tryptophan hydroxylases (191290, 191060) and an endogenous inhibitor of
protein kinase C (176960). It was first described as a brain-specific
bovine protein. It consists of acidic dimeric subunits of about 27 kD.
Immunohistochemical analyses showed that the 14-3-3 protein is located
exclusively in the cytoplasm of neurons in the cerebral cortex and is
axonally transported to the nerve terminals. Electrophoresis and
chromatography demonstrated that the 14-3-3 protein exists in at least 7
distinct forms: alpha, beta, gamma, delta, epsilon, zeta, and eta.
Watanabe et al. (1994) found mRNA corresponding to an eighth subtype,
which they termed theta, in rat brain. The mRNA theta subtype was found
in the gray matter of cerebellar cortex and the hippocampus, as well as
in white matter where cell bodies of glial cells predominate. In
contrast, mRNA of the zeta subtype was distributed widely in the brain
gray matter with high levels of transcripts in the neocortex,
hippocampus, caudate-putamen, thalamus, cerebellar cortex, and several
brainstem nuclei. A human protein with phospholipase A2 activity was
shown to be the zeta subtype of the 14-3-3 protein (Zupan et al., 1992).
The gene is also symbolized YWHAH.

Ichimura-Ohshima et al. (1992) reported a cDNA clone of mRNA encoding
human 14-3-3 protein. The 1,730-nucleotide sequence of the cDNA
contained a 191-bp 5-prime noncoding region, the complete 738-bp coding
region, and an 801-bp 3-prime noncoding region with 3 canonical
polyadenylation signals. The eta chain encoded by the cDNA is a
246-amino acid polypeptide with a predicted molecular weight of 28,196.
The predicted amino acid sequence of the human 14-3-3 protein eta was
highly homologous to that of previously reported bovine and rat proteins
with only 2 amino acid differences. Northern blot analysis demonstrated
widespread expression of the eta chain in cultured cell lines derived
from various human tumors.

Muratake et al. (1996) determined that the human YWHAH gene has 2 exons
separated by an intron of approximately 8 kb. Using S1 nuclease mapping,
primer extension, and RACE PCR, Muratake et al. (1996) identified the
transcription initiation site. They also identified several regulatory
element sequences, including CRE, in the 5-prime noncoding region.
Muratake et al. (1996) noted that the presence of a CRE binding element
may indicate that this gene is involved in brain responses to narcotics.
The authors also found changes in a 7-bp repeat sequence (GCCTGCA)
located in the noncoding region of exon 1 and they speculated that these
changes, or other changes in the sequence of this gene, may be
associated with neuropsychiatric disorders.

Ichimura-Ohshima et al. (1992) used spot blot hybridization analysis
with flow sorted chromosomes to show that the eta chain is located on
chromosome 22. Tommerup and Leffers (1996) mapped the YWHAH gene to
22q12 by fluorescence in situ hybridization (FISH). Muratake et al.
(1996) used FISH to refine the mapping of the YWHAH gene to
22q12.1-q13.1.

*FIELD* RF
1. Ichimura-Ohshima, Y.; Morii, K.; Ichimura, T.; Araki, K.; Takahashi,
Y.; Isobe, T.; Minoshima, S.; Fukuyama, R.; Shimizu, N.; Kuwano, R.
: cDNA cloning and chromosome assignment of the gene for human brain
14-3-3 protein eta chain. J. Neurosci. Res. 31: 600-605, 1992.

2. Muratake, T.; Hayashi, S.; Ichikawa, T.; Kumanishi, T.; Ichimura,
Y.; Kuwano, R.; Isobe, T.; Wang, Y.; Minoshima, S.; Shimizu, N.; Takahashi,
Y.: Structural organization and chromosomal assignment of the human
14-3-3-eta chain gene (YWHAH). Genomics 36: 63-69, 1996.

3. Tommerup, N.; Leffers, H.: Assignment of the human genes encoding
14-3-3 eta (YWHAH) to 22q12, 14-3-3 zeta (YWHAZ) to 2p25.1-p25.2,
and 14-3-3 beta (YWHAB) to 20q13.1 by in situ hybridization. Genomics 33:
149-150, 1996.

4. Watanabe, M.; Isobe, T.; Ichimura, T.; Kuwano, R.; Takahashi, Y.;
Kondo, H.; Inoue, Y.: Molecular cloning of rat cDNAs for the zeta
and theta subtypes of 14-3-3 protein and differential distributions
of their mRNAs in the brain. Molec. Brain Res. 25: 113-121, 1994.

5. Zupan, L. A.; Steffens, D. L.; Berry, C. A.; Landt, M.; Gross,
R. W.: Cloning and expression of a human 14-3-3 protein mediating
phospholipolysis. J. Biol. Chem. 267: 8707-8710, 1992.

*FIELD* CN
Jennifer P. Macke - updated: 10/16/1996
Alan F. Scott - updated: 6/3/1996

*FIELD* CD
Victor A. McKusick: 7/1/1992

*FIELD* ED
mark: 12/31/1996
carol: 10/16/1996
mark: 6/3/1996
carol: 1/26/1995
carol: 8/25/1992
carol: 7/1/1992

*RECORD*
*FIELD* NO
113510
*FIELD* TI
*113510 BRAIN SPECIFIC PROTEIN: Pc-1
DUARTE BRAIN SPECIFIC PROTEIN
*FIELD* TX
This was the first described polymorphism of a human brain specific
protein. Comings (1979) demonstrated the polymorphism by means of
two-dimensional gel electrophoresis of 0.1 M perchloric acid extracts of
human caudate and putamen. He called the wildtype protein Pc-1A and the
variant, Pc-1 Duarte. Comings et al. (1981) found that all of 32 feral
(wild-born) baboons were homozygous for a Pc-1 (Duarte)-like protein.
The variant occurs in 32% of normals, with 2.6% being homozygous. The
frequency of the variant protein was increased among individuals with
some form of depression who committed suicide and to a less significant
extent among persons dying of multiple sclerosis or subacute sclerosing
polioencephalitis (SSPE), suggesting an association with a
predisposition to brain damage from viral infection.

*FIELD* RF
1. Comings, D. E.: Pc1 Duarte, a common polymorphism of a human brain
protein, and its relationship to depressive illness and multiple sclerosis.
Nature 277: 28-32, 1979.

2. Comings, D. E.; Jalanko, A.; Kuehl, T. J.: Homozygosity for Pc1
Duarte-like protein in primates and other animals. Am. J. Hum. Genet. 33:
134-137, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 2/26/1992
supermim: 9/28/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
113520
*FIELD* TI
*113520 BRANCHED-CHAIN AMINOTRANSFERASE-1; BCT1
*FIELD* TX
Jones and Moore (1976) isolated an auxotrophic mutant in Chinese-hamster
ovary cells that lacks the ability to grow if alpha-ketoisovaleric acid,
alpha-ketoisocaproic acid and alpha-keto-beta-methylvaleric acid are
substituted for valine, leucine and isoleucine in the culture medium.
This auxotroph, called TRANS-minus, is caused by lack of the enzyme
branched-chain amino acid transaminase (BCT). Jones and Moore (1979)
provisionally assigned the gene to 12pter-12q12. Naylor and Shows (1979,
1980) also assigned BCT1 to chromosome 12 and BCT2 (113530) to
chromosome 19. It is possible that there are 2 different clinical
disorders due to defect of BCAA transamination, hypervalinemia (277100)
and hyperleucine-isoleucinemia (238340). Since there are 2 distinct BCAA
transaminases (see 113530), it is possible that one is mutant in each of
these 2 conditions.

*FIELD* SA
Jones and Moore (1984); Tanaka and Rosenberg (1983)
*FIELD* RF
1. Jones, C.; Moore, E. E.: Isolation of mutants lacking branched-chain
amino acid transaminase. Somat. Cell Genet. 2: 235-243, 1976.

2. Jones, C.; Moore, E. E.: Assignment of the human gene complementing
the auxotrophic marker TRANS-minus (BCT1) to chromosome 12.  (Abstract) Cytogenet.
Cell Genet. 25: 168 only, 1979.

3. Jones, C.; Moore, E. E.: Localization of a gene which complements
branched-chain amino acid transaminase deficiency to the short arm
of human chromosome 12. Hum. Genet. 66: 206-211, 1984.

4. Naylor, S. L.; Shows, T. B.: Branched-chain aminotransferase genes
(BCT-1 and BCT-2) assigned to human chromosomes 12 and 19 using alpha-keto
acid selection media.  (Abstract) Cytogenet. Cell Genet. 25: 191-192,
1979.

5. Naylor, S. L.; Shows, T. B.: Branched-chain aminotransferase deficiency
in Chinese hamster cells complemented by two independent genes on
human chromosomes 12 and 19. Somat. Cell Genet. 6: 641-652, 1980.

6. Tanaka, K.; Rosenberg, L. E.: Disorders of branched chain amino
acid and organic acid metabolism. In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S.: The Metabolic
Basis of Inherited Disease.  New York: McGraw-Hill (pub.)  (5th
ed.): 1983. Pp. 450-451.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 7/26/1994
carol: 8/28/1992
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
113530
*FIELD* TI
*113530 BRANCHED-CHAIN AMINOTRANSFERASE-2; BCT2
*FIELD* TX
By study of somatic cell hybrids, Naylor and Shows (1979, 1980) assigned
the gene for BCT2 to chromosome 19. See 113520 for further details and
discussion of possible involvement of deficiency of this enzyme in an
inborn error of metabolism.

*FIELD* RF
1. Naylor, S. L.; Shows, T. B.: Branched-chain aminotransferase genes
(BCT-1 and BCT-2) assigned to human chromosomes 12 and 19 using alpha-keto
acid selection media.  (Abstract) Cytogenet. Cell Genet. 25: 191-192,
1979.

2. Naylor, S. L.; Shows, T. B.: Branched-chain aminotransferase deficiency
in Chinese hamster cells complemented by two independent genes on
human chromosomes 12 and 19. Somat. Cell Genet. 6: 641-652, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 8/28/1992
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/20/1989

*RECORD*
*FIELD* NO
113600
*FIELD* TI
*113600 BRANCHIAL CLEFT ANOMALIES
BRANCHIAL CYSTS, INCLUDED
*FIELD* TX
The abnormality may be in the form of cysts, sinuses or fistulas, the
last term being reserved for those instances in which there is
communication between the skin and the pharynx. These are considered to
be anomalies of the second branchial cleft. Although ear pits (125100)
were also present in at least one family, these are listed as separate
mutations because most families show either one or the other. Wheeler et
al. (1958) found branchial cysts and sinuses in 4 members of 3
generations of a family. Cysts, sinuses and skin tabs containing
cartilage occurred in a line extending from a point anterior to the ear
to the anterior border of the sternomastoid muscle at the level of the
angle of the mandible and thence along the anterior border of this
muscle to a point near its attachment to the sternum. One must exclude
the branchiootorenal syndrome (113650).

*FIELD* SA
Anand et al. (1979); Muckle  (1961)
*FIELD* RF
1. Anand, T. S.; Anand, C. S.; Chaurasia, B. D.: Seven cases of branchial
cyst and sinuses in four generations. Hum. Hered. 29: 213-216,
1979.

2. Muckle, T. J.: Hereditary branchial defects in a Hampshire family.
Brit. Med. J. 1: 1297-1299, 1961.

3. Wheeler, C. E.; Shaw, R. F.; Cawley, E. P.: Branchial anomalies
in three generations of one family. Arch. Derm. 77: 715-719, 1958.

*FIELD* CS

Neck:
   Cysts, sinuses or fistulas

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
113610
*FIELD* TI
113610 BRANCHIAL MYOCLONUS WITH SPASTIC PARAPARESIS AND CEREBELLAR ATAXIA
*FIELD* TX
De Yebenes et al. (1988) described a syndrome of branchial myoclonus,
spastic paraparesis, and cerebellar ataxia in 6 members of 2 generations
of a family that lived in the province of Toledo in Spain. Male-to-male
transmission occurred. Rhythmic myoclonus involving the palate, pharynx,
larynx, and face was followed by truncal ataxia and spastic paraparesis.
Age of onset ranged from 40 to 50 years. Computerized tomography and
magnetic resonance imaging showed mild atrophy of the cerebral and
cerebellar cortex and severe atrophy of the medulla and spinal cord. The
pons appeared normal, and the olives did not seem hypertrophic.
Reduction of the serotonin metabolite 5-hydroxyindoleacetic acid was
found in the cerebrospinal fluid. Treatment with 5-hydroxytryptophan and
carbidopa at maximal tolerated doses improved ataxia mildly but did not
modify the myoclonus. Treatment with other agents was unsuccessful. The
clinical symptoms were progressive, leading to death or severe
disability 5 to 10 years after onset of the disease. Branchial myoclonus
is rare but has been observed with a variety of disorders including
demyelinating disease, infarction, arteritis, neoplasm, and trauma
involving the lower brainstem or the dentato-rubro-olivary pathways.
Sperling and Hermann (1985), Leger et al. (1986), and Sasaki et al.
(1987) described branchial myoclonus in patients with spinocerebellar
degeneration and olivopontocerebellar atrophy, but de Yebenes et al.
(1988) thought that the disorder in their family was different from that
reported in any of these 3 publications.

Howard et al. (1993) described a Kuwaiti family that came to attention
because of 2 sisters and a brother, out of a sibship of 10, who
presented with a progressive neurologic disorder beginning in the third
decade of life and characterized by palatal myoclonus, nystagmus, bulbar
weakness, and spastic tetraparesis. There was no evidence of
intellectual deterioration or seizures. CT scan showed marked brainstem
atrophy in 2 patients and basal ganglia calcification in 1. MRI scan in
1 showed high signal in the brainstem and periventricular region, and
cerebral biopsy in this patient showed myelin loss and the presence of
Rosenthal fibers, which are particularly characteristic of Alexander
disease (203450). A similar disease affected the mother, who died at age
45, a maternal aunt, who died at age 50, and 2 daughters of the aunt who
were still living. Howard et al. (1993) suggested autosomal dominant
inheritance. It may be noteworthy that the parents of the 3 sibs were
consanguineous, as were also the parents of the 'mother' and 'maternal
aunt.' Palatal myoclonus, which also occurs in Machado-Joseph disease
(109150) and in spinocerebellar ataxia type 2 (183090), is characterized
by rhythmic oscillations of the soft palate. It is also called branchial
myoclonus because it may be associated with synchronous contractions of
muscles derived from the branchial arches, including the diaphragm,
tongue, and sternomastoids.

*FIELD* RF
1. de Yebenes, J. G.; Vazquez, A.; Rabano, J.; de Seijas, E. V.; Urra,
D. G.; Obregon, M. C. D.; Barquero, M. S.; Arribas, M. A.; Moreno,
J. L.; Alenda, J. R.: Hereditary branchial myoclonus with spastic
paraparesis and cerebellar ataxia: a new autosomal dominant disorder.
Neurology 38: 569-572, 1988.

2. Howard, R. S.; Greenwood, R.; Gawler, J.; Scaravilli, F.; Marsden,
C. D.; Harding, A. E.: A familial disorder associated with palatal
myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal
fibre formation. J. Neurol. Neurosurg. Psychiat. 56: 977-981, 1993.

3. Leger, J. M.; Duyckaerts, C.; Brunet, P.: Syndrome of palatal
myoclonus and progressive ataxia: report of a case. Neurology 36:
1409-1410, 1986.

4. Sasaki, H.; Sudoh, K.; Hamada, K.; Hamada, T.; Tashiro, K.: Skeletal
myoclonus in olivopontocerebellar atrophy: treatment with trihexyphenidyl.
Neurology 37: 1258-1262, 1987.

5. Sperling, M. R.; Hermann, C.: Syndrome of palatal myoclonus and
progressive ataxia: two cases with magnetic resonance imaging. Neurology 35:
1212-1214, 1985.

*FIELD* CS

Neuro:
   Rhythmic myoclonus of palate, pharynx, larynx, and face;
   Truncal ataxia;
   Spastic paraparesis;
   Nystagmus

Misc:
   Onset age 40 to 50 years;
   Death or severe disability 5 to 10 years after onset

Radiology:
   CT and MRI show mild atrophy of the cerebral and cerebellar cortex
   and severe atrophy of the medulla and spinal cord, with normal pons
   and olives

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 8/22/1988

*FIELD* ED
terry: 5/13/1994
mimadm: 4/9/1994
carol: 12/16/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
113620
*FIELD* TI
*113620 BRANCHIAL CLEFTS WITH CHARACTERISTIC FACIES, GROWTH RETARDATION, IMPERFORATE
NASOLACRIMAL DUCT, AND PREMATURE AGING
BRANCHIOOCULOFACIAL SYNDROME;;
BOF SYNDROME; BOFS;;
HEMANGIOMATOUS BRANCHIAL CLEFTS-LIP PSEUDOCLEFT SYNDROME;;
LIP PSEUDOCLEFT-HEMANGIOMATOUS BRANCHIAL CYST SYNDROME
*FIELD* TX
Lee et al. (1982) described a 38-year-old woman and her 8-year-old son
who had low birth weight for dates and retarded postnatal growth,
bilateral branchial cleft sinuses, congenital strabismus, obstructed
nasolacrimal ducts, broad nasal bridge, protruding upper lip, and carp
mouth. Graying of the mother's hair occurred at age 18. Intelligence was
normal. The same disorder may have been reported by Hall et al. (1983)
and Fujimoto et al. (1987). Hall et al. (1983) described 2 unrelated
children (1 male, 1 female) with hemangiomatous branchial clefts and
pseudocleft of the upper lip (resembling a surgically repaired cleft or
a fused cleft). They found reports of 2 additional patients who, they
suspected, also represented sporadic cases of this syndrome. In several
persons in 3 families, Fujimoto et al. (1987) observed an autosomal
dominant disorder of abnormal upper lip, which resembled a poorly
repaired median cleft lip, malformed nose with broad bridge and
flattened tip, lacrimal duct obstruction, malformed ears, and branchial
cleft sinuses and/or linear skin lesions behind the ears. In each of the
3 families an affected parent had at least 1 affected child, and
father-to-son transmission was observed in 1. Other anomalies included
coloboma, microphthalmia, auricular pits, lip pits, highly arched
palate, dental anomalies, and subcutaneous cysts of the scalp. Premature
greying of hair occurred in affected adults. The abnormality of the
upper lip might be described as an unusually broad and prominent
philtrum.

Mazzone et al. (1992) reported a patient who, in addition to typical
features of BOFS, had partial agenesis of the cerebellar vermis. Lin et
al. (1992) concluded that the father and son reported by Legius et al.
(1990) had the BOF syndrome and that this additional finding of
male-to-male transmission confirmed autosomal dominant inheritance.
Fielding and Fryer (1992) described 2 sibs with this syndrome, each of
whom also had orbital hemangiomatous cysts. Both parents were clinically
normal and unrelated. Thus this may have represented an autosomal
recessive form of the disorder or germline mosaicism for the dominant
gene. Schmerler et al. (1992) reviewed the development of an affected
child over a 12-year period of observation. Normal intelligence, regular
class placement, hypernasal speech, and continued growth along the third
centile were noted. The infant had been referred at the age of 5 months
for evaluation of his facial appearance and 'burn-like' lesions behind
both ears. McCool and Weaver (1994) observed the BOF syndrome in a
mother and her son who lacked the ocular and branchial abnormalities but
had bilateral supraauricular sinuses and hearing loss. The son had
bilateral cleft lip and right alveolar cleft; the mother had asymmetric
nostrils and upper lip. The supraauricular sinuses were thought to
represent persistence of the otic vesicle sinus tract.

Lin et al. (1995) described 15 new observations of the BOF syndrome and
reviewed previously reported cases (28 with typical and 5 with atypical
manifestations) in detail. Postauricular cervical branchial defects were
found in 40 of 43 patients, and supraauricular defects were found in 6.
Pathologic findings of the excised branchial defects showed thymic
remnants in several cases. Colobomata were found in 16 of 35 patients,
cataracts in 8 of 33, deafness in 14 of 38, scalp cysts in 4 of 38, and
premature graying of hair in 9 of 38. Pseudoclefts were observed in 23
patients, and cleft lip and/or palate in 20. Urologic examination of 19
patients revealed kidney abnormalities (agenesis, cysts, hydronephrosis)
in 7. Autosomal dominant inheritance of the BOF syndrome is supported by
a 3-generation German family, 2 instances of father-to-son transmission,
and 7 other parent-offspring families (Fujimoto et al., 1987; Lin et
al., 1995).

Richardson et al. (1996) described a boy with cleft lip and palate,
microphthalmos, colobomata of optic nerves and irides, and cystic
dysplasia of the left kidney. His mother had similar ocular
abnormalities (plus polycoria), obstruction of nasolacrimal ducts, bifid
nasal tip, abnormal philtrum, hypodontia, and premature graying of the
hair. His maternal grandmother had the same facial defects and
nasolacrimal duct obstruction, but normal eyes. The spectrum of
abnormalities in this family fits the BOF syndrome, although cervical
hemangiomata or branchial sinuses were not found in affected persons in
this family.

*FIELD* SA
Legius and Fryns (1992)
*FIELD* RF
1. Fielding, D. W.; Fryer, A. E.: Recurrence of orbital cysts in
the branchio-oculo-facial syndrome. J. Med. Genet. 29: 430-431,
1992.

2. Fujimoto, A.; Lipson, M.; Lacro, R. V.; Shinno, N. W.; Boelter,
W. D.; Jones, K. L.; Wilson, M. G.: New autosomal dominant branchio-oculo-facial
syndrome. Am. J. Med. Genet. 27: 943-951, 1987.

3. Hall, B. D.; deLorimier, A.; Foster, L. H.: A new syndrome of
hemangiomatous branchial clefts, lip pseudoclefts, and unusual facial
appearance. Am. J. Med. Genet. 14: 135-138, 1983.

4. Lee, W. K.; Root, A. W.; Fenske, N.: Bilateral branchial cleft
sinuses associated with intrauterine and postnatal growth retardation,
premature aging, and unusual facial appearance: a new syndrome with
dominant transmission. Am. J. Med. Genet. 11: 345-352, 1982.

5. Legius, E.; Fryns, J.-P.: Reply to Dr. Lin. (Letter) Clin. Genet. 41:
223 only, 1992.

6. Legius, E.; Fryns, J. P.; Van Den Berghe, H.: Dominant branchial
cleft syndrome with characteristics of both branchio-oto-renal and
branchio-oculo-facial syndrome. Clin. Genet. 37: 347-350, 1990.

7. Lin, A. E.; Doherty, R.; Lea, D.: Branchio-oculo-facial and branchio-oto-renal
syndromes are distinct entities. (Letter) Clin. Genet. 41: 221-222,
1992.

8. Lin, A. E.; Gorlin, R. J.; Lurie, I. W.; Brunner, H. G.; van der
Burgt, I.; Naumchik, I. V.; Rumyantseva, N. V.; Stengel-Rutkowski,
S.; Rosenbaum, K.; Meinecke, P.; Muller, D.: Further delineation
of the branchio-oculo-facial syndrome. Am. J. Med. Genet. 56: 42-59,
1995.

9. Mazzone, D.; Milana, A.; Carpinato, C.: Branchio-oculo-facial
syndrome: report of a new case with agenesis of cerebellar vermis. Europ.
J. Pediat. 151: 312 only, 1992.

10. McCool, M.; Weaver, D. D.: Branchio-oculo-facial syndrome: broadening
the spectrum. Am. J. Med. Genet. 49: 414-421, 1994.

11. Richardson, E.; Davison, C.; Moore, A.: Colobomatous microphthalmia
with midfacial clefting: part of the spectrum of branchio-oculo-facial
syndrome? Ophthal. Genet. 17: 59-65, 1996.

12. Schmerler, S.; Kushnick, T.; Desposito, F.: Long-term evaluation
of a child with the branchio-oculo-facial syndrome. Am. J. Med. Genet. 44:
177-178, 1992.

*FIELD* CS

Neck:
   Branchial cleft sinuses

Growth:
   Low birth weight for dates;
   Retarded postnatal growth

Eyes:
   Congenital strabismus;
   Nasolacrimal duct obstruction;
   Coloboma;
   Microphthalmia;
   Orbital hemangiomatous cysts

Nose:
   Broad nasal bridge;
   Flattened nasal tip;
   Broad and prominent philtrum

Mouth:
   Protruding upper lip;
   Pseudocleft of upper lip;
   Lip pits;
   Carp mouth;
   Highly arched palate

Teeth:
   Dental anomalies

Ears:
   Malformed ears;
   Auricular pits

Skin:
   Postauricular linear skin lesions;
   Supraauricular sinuses;
   Hemangiomatous branchial cleft;
   Subcutaneous scalp cysts

Hair:
   Premature graying

Neuro:
   Normal intelligence

Voice:
   Hypernasal speech

*FIELD* CN
Iosif W. Lurie - updated: 12/4/1996
Iosif W. Lurie - updated: 7/18/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jamie: 12/06/1996
jamie: 12/4/1996
carol: 7/18/1996
terry: 5/13/1994
mimadm: 4/9/1994
carol: 3/7/1994
carol: 10/9/1992
carol: 7/1/1992
carol: 6/8/1992

*RECORD*
*FIELD* NO
113630
*FIELD* TI
*113630 BREAKPOINT CLUSTER REGION-LIKE 2; BCRL2
*FIELD* TX
See 151410.

*FIELD* CD
Victor A. McKusick: 6/29/1988
*FIELD* ED
supermim: 3/16/1992
carol: 3/9/1992
carol: 3/8/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 6/29/1988
*RECORD*
*FIELD* NO
113640
*FIELD* TI
*113640 BREAKPOINT CLUSTER REGION-LIKE 3; BCRL3
*FIELD* TX
See 151410.

*FIELD* CD
Victor A. McKusick: 6/29/1988
*FIELD* ED
supermim: 3/16/1992
carol: 3/9/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 6/29/1988
*RECORD*
*FIELD* NO
113650
*FIELD* TI
#113650 BRANCHIOOTORENAL DYSPLASIA
BOR SYNDROME; BOR;;
BRANCHIOOTIC SYNDROME;;
MELNICK-FRASER SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder results from mutation in the EYA1 gene (601653).

Melnick et al. (1976) described a family in which the father and 3 of 6
living children (a son and 2 daughters) had mixed hearing loss
associated with a Mondini-type cochlear malformation (hypoplasia of
cochlear apex shown by tomography) and stapes fixation, cup-shaped,
anteverted pinnae, bilateral prehelical pits, bilateral branchial cleft
fistulas, and bilateral renal dysplasia with anomalies of the collecting
system. The father and affected son had aplasia of the lacrimal ducts
also. A fourth child, who died at 5 months of age, was said to have had
branchial cleft fistulas and bilateral polycystic kidneys. Conditions in
the same nosoembryologic community were discussed. Fitch and Srolovitz
(1976) reported a woman with preauricular pits, cervical fistulae, and
partial deafness who gave birth to 2 children with preauricular pits and
severe renal dysgenesis. Fraser et al. (1978) described a kindred with
the BOR syndrome. Lacrimal duct stenosis occurs in some. Fraser et al.
(1980) suggested that the frequency of the BOR syndrome may be higher
than generally realized. Of 421 white children in Montreal schools for
the deaf, 19 had preauricular pits. The BOR syndrome was identified in 4
of the 9 families that agreed to family investigations, including
audiograms and intravenous pyelograms. They estimated that about 6% of
heterozygotes have severe renal dysplasia and that a preauricular pit at
birth suggests that the child has at least 1 chance in 200 of severe
hearing loss. Melnick et al. (1978) maintained that the BOR syndrome is
distinct from branchiootic dysplasia (BO syndrome; 113600, 125100)
because in the latter condition renal anomaly is absent and deafness is
not a constant feature. Cremers and Fikkers-van Noord (1980) concluded,
however, that the BOR syndrome and the BO syndrome are one entity.

Carmi et al. (1983) observed a man with the BOR syndrome and crossed
renal ectopia who fathered 3 children born with bilateral renal agenesis
and the Potter syndrome. Preisch et al. (1985) reported affected father,
son and daughter. The father and daughter showed tearing with eating,
i.e., gustatory lacrimation (GL). The father had absent reflex tearing
in one eye and GL in the other. The daughter's GL was apparently also
unilateral. Another family was said to show the phenomenon. GL,
sometimes described as 'crocodile tears,' is said by Gorlin (1976) to
have been observed in over 100 cases but never in multiple members of
families. Most cases are unilateral and often follow facial trauma or
surgery but can occur as a congenital defect in innervation as was
probably the case in this family. Heimler and Lieber (1986) observed a
family in which some persons had duplication of the collecting system as
the renal anomaly, others had branchial and ear anomalies with normal
kidneys, and yet others had complete failure of penetrance. Legius et
al. (1990) described father and son with a branchial cleft syndrome
mixing characteristics of the BOR syndrome with those of the
branchiooculofacial syndrome (BOFS; 113620). The 2 subjects showed
several anomalies common to both syndromes, namely, abnormally shaped
ears with deafness, cervical fistulae, preauricular ear pits, and
lacrimal duct stenosis. Unilateral renal hypoplasia and dysplasia in the
son were typical of the BOR syndrome. On the other hand, cleft palate
and mild 'mental problems' in the father, and bilateral microphthalmia
and high-arched palate in the son are characteristic of the BOF
syndrome. Neither the father nor the son showed the findings that are
more or less constant in BOFS: lip 'pseudoclefts,' abnormal nose,
premature graying, or skin abnormalities. The father had been operated
on for arteria lusoria (left subclavian artery passing behind the
esophagus) causing dysphagia. He had also had unexplained atrial
fibrillation. Lin et al. (1992) concluded that the patients of Legius et
al. (1990) indeed had the BOF syndrome and that this entity is distinct
from the BOR syndrome. Legius and Fryns (1992) remained dubious of a
distinction. Chitayat et al. (1992) made the diagnosis of BOR syndrome
in a woman who had had 2 pregnancies complicated by oligohydramnios due
to renal hypoplasia and agenesis. Both babies died neonatally of
pulmonary hypoplasia. Histopathology of the temporal bones of the second
child showed marked immaturity of the middle ear cleft, ossicles, facial
nerve and canal, and cochlear nerve. The mother's renal ultrasound study
was normal although intravenous pyelography indicated renal hypoplasia.
The mother had a hearing problem first recognized at age 5 when
abnormality of the right ossicular mass and antral region was found. A
preauricular pit on the right in the mother was pictured.

It is noteworthy that preauricular skin tags and/or pits constitute the
most consistent feature of the cat eye syndrome (115470) and that renal
malformations, such as unilateral absence, unilateral or bilateral
hypoplasia, and cystic dysplasia, are frequent. Schinzel et al. (1981)
concluded that trisomy or tetrasomy of 22pter-q11 is the usual basis of
the cat eye syndrome. Is the BOR gene in this chromosomal segment?

In an extensively affected Australian family, Haan et al. (1989) found
many members who had a complex inherited rearrangement of 8q associated
with both trichorhinophalangeal syndrome (190350) and the branchiootic
syndrome. Preauricular pits or branchial sinuses were present in all 8
members studied in detail; 7 of these had deafness, the exception being
the youngest. Three breakpoints in 8q were identified. One of them was
consistent with the previously assigned location of the gene for the
trichorhinophalangeal syndrome. Haan et al. (1989) suggested that the
branchiootic syndrome is caused by mutation at one or the other
breakpoints, either 8q13.3 or 8q21.13. Confirmatory evidence that the
BOR gene is located on 8q was provided by Kumar et al. (1992), who found
linkage to genetic markers in that region in a 4-generation family;
maximum lod = 4.0 at theta = 0.05 with the D8S165 microsatellite marker.
The availability of linkage information now permits determination as to
whether the branchiootorenal dysplasia is determined by mutation at the
same locus as the branchiootic syndrome and the syndrome designated as
the branchiootoureteral syndrome by Fraser et al. (1983) on the basis of
a family in which renal involvement was limited to duplication of the
collecting system and bifid renal pelves. In the 4-generation family of
Heimler and Lieber (1986), the phenotype was that of branchiootic
syndrome in some persons and branchiootoureteral syndrome in others. By
multipoint analysis in 2 families, Smith et al. (1992) found a maximum
lod score of 3.79 at theta = 0.084 for location of BOR telomeric to a
marker at 8q12-q13. The diagnosis of BOR syndrome was based on the
presence of at least 2 of the following features: preauricular pits,
lop-ear deformity, branchial fistulae, hearing loss, and renal
anomalies. Wang et al. (1994), who referred to this disorder
alternatively as the Melnick-Fraser syndrome, used multipoint linkage
analysis based on microsatellite markers (Weissenbach et al., 1992) to
map the BOR gene to a region of 8q flanked by D8S543 and D8S84. The
interval between these 2 markers was estimated to be 6 cM. Ni et al.
(1994) concluded that BOR is flanked by D8S530 and D8S279. Based on
multipoint analysis using a set of 13 polymorphic markers from the BOR
region in 2 large, clinically well-characterized families, Kumar et al.
(1996) concluded that the BOR gene is between markers D8S543 and D8S530,
a distance of about 2 cM. They identified YACs that map in the critical
region and characterized them by fluorescence in situ hybridization and
pulsed field gel electrophoresis.

Chen et al. (1995) described the phenotype in 45 individuals,
highlighting differences and similarities to findings reported by
others. Characteristic temporal bone findings included hypoplasia of the
cochlea, which was four-fifths of normal size with only 2 turns,
dilation of the vestibular aqueduct, bulbous internal auditory canals,
deep posterior fossa, and acutely angled promontories. They pictured a
3-generation family with various manifestations.

Gu et al. (1996) made use of a cell line from one of the affected
members of the family reported by Haan et al. (1989) with both BO and
trichorhinophalangeal syndrome I. YACs spanning the BOR interval from
D8S543 to D8S541 were used as fluorescence in situ hybridization probes.
In addition to the cytogenetically defined direct insertion of material
from 8q13.3-q21.13 into 8q24.11, a previously unidentified deletion of
just under 1 megabase was found in 8q13.3. These data narrowed the most
likely location of the BOR gene to a region corresponding to the
proximal two-thirds of YAC 869E10 between D8S543 and D8S279.

Kalatzis et al. (1996) likewise used the cell line first described by
Haan et al. (1989) and identified an associated deletion by fluorescence
in situ hybridization analysis of the 8q translocation breakpoint. The
generation of a YAC contig and the isolation of overlapping recombinant
P1 and lambda phage clones from the region allowed further
characterization of the deletion. Its size was estimated to be between
470 and 650 kb, and it was flanked by the polymorphic markers D8S1060
and D8S1807.

See 600257 for a discussion of the BOR-Duane-hydrocephalus contiguous
gene syndrome as described by Vincent et al. (1994).

By positional cloning, Abdelhak et al. (1997) identified a candidate
gene for BOR syndrome at 8q13.3 and showed that mutations in the gene
(e.g., 601653.0001) underlie the disorder. The gene is a human homolog
of the Drosophila 'eyes absent' gene (eya); the human gene was
symbolized EYA1 (601653). They also found a highly conserved 271-amino
acid C-terminal region in the products of 2 other human genes, which
were subsequently called EYA2 (601654) and EYA3 (601655), demonstrating
the existence of a novel gene family. The expression pattern of the
murine EYA1 ortholog, Eya1, suggested a role in the development of all
components of the inner ear, from the emergence of the otic placode. In
the developing kidney, the expression pattern was indicative of a role
for Eya1 in the metanephric cells surrounding the 'just-divided'
ureteric branches.

*FIELD* SA
Cremers et al. (1981); Gimsing and Dyrmose (1986); Lindsay and Hinojosa
(1978); Melnick et al. (1975)
*FIELD* RF
1. Abdelhak, S.; Kalatzis, V.; Heilig, R.; Compain, S.; Samson, D.;
Vincent, C.; Weil, D.; Cruaud, C.; Sahly, I.; Leibovici, M.; Bitner-Glindzicz,
M.; Francis, M.; Lacombe, D.; Vigneron, J.; Charachon, R.; Boven,
K.; Bedbeder, P.; Van Regemorter, N.; Weissenbach, J.; Petit, C.:
A human homologue of the drosophila eyes absent gene underlies branchio-oto-renal
(BOR) syndrome and identifies a novel gene family. Nature Genet. 15:
157-164, 1997.

2. Carmi, R.; Binshtock, M.; Abeliovich, D.; Bar-Ziv, J.: The branchio-oto-renal
(BOR) syndrome: report of bilateral renal agenesis in three sibs. Am.
J. Med. Genet. 14: 625-627, 1983.

3. Chen, A.; Francis, M.; Ni, L.; Cremers, C. W. R. J.; Kimberling,
W. J.; Sato, Y.; Phelps, P. D.; Bellman, S. C.; Wagner, M. J.; Pembrey,
M.; Smith, R. J. H.: Phenotypic manifestations of branchiootorenal
syndrome. Am. J. Med. Genet. 58: 365-370, 1995.

4. Chitayat, D.; Hodgkinson, K. A.; Chen, M.-F.; Haber, G. D.; Nakishima,
S.; Sando, I.: Branchio-oto-renal syndrome: further delineation of
an underdiagnosed syndrome. Am. J. Med. Genet. 43: 970-975, 1992.

5. Cremers, C. W. R. J.; Fikkers-van Noord, M.: The earpits-deafness
syndrome: clinical and genetic aspects. Int. J. Pediat. Otorhinolaryng. 2:
309-322, 1980.

6. Cremers, C. W. R. J.; Thijssen, H. O. M.; Fischer, A. J. E. M.;
Marres, E. H. M. A.: Otological aspects of the earpit-deafness syndrome. ORL 43:
223-239, 1981.

7. Fitch, N.; Srolovitz, H.: Severe renal dysplasia produced by a
dominant gene. Am. J. Dis. Child. 130: 1356-1357, 1976.

8. Fraser, F. C.; Ayme, S.; Halal, F.; Sproule, J.: Autosomal dominant
duplication of the renal collection system, hearing loss, and external
ear anomalies: a new syndrome. Am. J. Med. Genet. 14: 473-478, 1983.

9. Fraser, F. C.; Ling, D.; Clogg, D.; Nogrady, B.: Genetic aspects
of the BOR syndrome--branchial fistulas, ear pits, hearing loss, and
renal anomalies. Am. J. Med. Genet. 2: 241-252, 1978.

10. Fraser, F. C.; Sproule, J. R.; Halal, F.: Frequency of the branchio-oto-renal
(BOR) syndrome in children with profound hearing loss. Am. J. Med.
Genet. 7: 341-349, 1980.

11. Gimsing, S.; Dyrmose, J.: Branchio-oto-renal dysplasia in three
families. Ann. Otol. Rhinol. Laryng. 95: 421-426, 1986.

12. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.
1976.

13. Gu, J. Z.; Wagner, M. J.; Haan, E. A.; Wells, D. E.: Detection
of a megabase deletion in a patient with branchio-oto-renal syndrome
(BOR) and tricho-rhino-phalangeal syndrome (TRPS): implications for
mapping and cloning of the BOR gene. Genomics 31: 201-206, 1996.

14. Haan, E. A.; Hull, Y. J.; White, S.; Cockington, R.; Charlton,
P.; Callen, D. F.: Tricho-rhino-phalangeal and branchio-oto syndromes
in a family with an inherited rearrangement of chromosome 8q. Am.
J. Med. Genet. 32: 490-494, 1989.

15. Heimler, A.; Lieber, E.: Branchio-oto-renal syndrome: reduced
penetrance and variable expressivity in four generations of a large
kindred. Am. J. Med. Genet. 25: 15-27, 1986.

16. Kalatzis, V.; Abdelhak, S.; Compain, S.; Vincent, C.; Petit, C.
: Characterization of a translocation-associated deletion defines
the candidate region for the gene responsible for branchio-oto-renal
syndrome. Genomics 34: 422-425, 1996.

17. Kumar, S.; Kimberling, W. J.; Kenyon, J. B.; Smith, R. J. H.;
Marres, E. H. M. A.; Cremers, C. W. R. J.: Autosomal dominant branchio-oto-renal
syndrome--localization of a disease gene to chromosome 8q by linkage
in a Dutch family. Hum. Molec. Genet. 1: 491-495, 1992.

18. Kumar, S.; Kimberling, W. J.; Lanyi, A.; Sumegi, J.; Pinnt, J.;
Ing, P.; Tinley, S.; Marres, H. A. M.; Cremers, C. W. R. J.: Narrowing
the genetic interval and yeast artificial chromosome map in the branchio-oto-renal
region on chromosome 8q. Genomics 31: 71-79, 1996.

19. Legius, E.; Fryns, J.-P.: Reply to Dr. Lin. (Letter) Clin. Genet. 41:
223, 1992.

20. Legius, E.; Fryns, J. P.; Van Den Berghe, H.: Dominant branchial
cleft syndrome with characteristics of both branchio-oto-renal and
branchio-oculo-facial syndrome. Clin. Genet. 37: 347-350, 1990.

21. Lin, A. E.; Doherty, R.; Lea, D.: Branchio-oculo-facial and branchio-oto-renal
syndromes are distinct entities. (Letter) Clin. Genet. 41: 221-222,
1992.

22. Lindsay, J. R.; Hinojosa, R.: Ear anomalies associated with renal
dysplasia and immunodeficiency disease: a histopathological study. Ann.
Otol. 87: 10-17, 1978.

23. Melnick, M.; Bixler, D.; Nance, W. E.; Silk, K.; Yune, H.: Familial
branchio-oto-renal dysplasia: a new addition to the branchial arch
syndromes. Clin. Genet. 9: 25-34, 1976.

24. Melnick, M.; Bixler, D.; Silk, K.; Yune, H.; Nance, W. E.: Autosomal
dominant branchiootorenal dysplasia. Birth Defects Orig. Art. Ser. XI(5):
121-128, 1975.

25. Melnick, M.; Hodes, M. E.; Nance, W. E.; Yune, H.; Sweeney, A.
: Branchio-oto-renal dysplasia and branchio-oto dysplasia: two distinct
autosomal dominant disorders. Clin. Genet. 13: 425-442, 1978.

26. Ni, L.; Wagner, M. J.; Kimberling, W. J.; Pembrey, M. E.; Grundfast,
K. M.; Kumar, S.; Daiger, S. P.; Wells, D. E.; Johnson, K.; Smith,
R. J. H.: Refined localization of the branchiootorenal syndrome gene
by linkage and haplotype analysis. Am. J. Med. Genet. 51: 176-184,
1994.

27. Preisch, J. W.; Bixler, D.; Ellis, F. D.: Gustatory lacrimation
in association with the branchio-oto-renal syndrome. Clin. Genet. 27:
506-509, 1985.

28. Schinzel, A.; Schmid, W.; Fraccaro, M.; Tiepolo, L.; Zuffardi,
O.; Opitz, J. M.; Lindsten, J.; Zetterqvist, P.; Enell, H.; Baccichetti,
C.; Tenconi, R.; Pagon, R. A.: The 'cat-eye syndrome': dicentric
small marker chromosome probably derived from a no. 22 (tetrasomy
22pter-to-q11) associated with a characteristic phenotype; report
of 11 patients and delineation of the clinical picture. Hum. Genet. 57:
148-158, 1981.

29. Smith, R. J. H.; Coppage, K. B.; Ankerstjerne, J. K. B.; Capper,
D. T.; Kumar, S.; Kenyon, J.; Tinley, S.; Comeau, K.; Kimberling,
W. J.: Localization of the gene for branchiootorenal syndrome to
chromosome 8q. Genomics 14: 841-844, 1992.

30. Vincent, C.; Kalatzis, V.; Compain, S.; Levilliers, J.; Slim,
R.; Graia, F.; de Lurdes Pereira, M.; Nivelon, A.; Croquette, M.-F.;
Lacombe, D.; Vigneron, J.; Helias, J.; Broyer, M.; Callen, D. F.;
Haan, E. A.; Weissenbach, J.; Lacroix, B.; Bellane-Chantelot, C.;
Le Paslier, D.; Cohen, D.; Petit, C.: A proposed new contiguous gene
syndrome on 8q consists of branchio-oto-renal (BOR) syndrome, Duane
syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications
for the mapping of the BOR gene. Hum. Molec. Genet. 3: 1859-1866,
1994.

31. Wang, Y.; Treat, K.; Schroer, R. J.; O'Brien, J. E.; Stevenson,
R. E.; Schwartz, C. E.: Localization of branchio-oto-renal (BOR)
syndrome to a 3 Mb region of chromosome 8q. Am. J. Med. Genet. 51:
169-175, 1994.

32. Weissenbach, J.; Gyapay, G.; Dib, C.; Vignal, A.; Morissette,
J.; Millasseau, P.; Vaysseix, G.; Lathrop, M.: A second-generation
linkage map of the human genome. Nature 359: 794-801, 1992.

*FIELD* CS

Ears:
   Mixed hearing loss;
   Cochlear malformation;
   Stapes fixation;
   Cup-shaped, anteverted pinnae;
   Preauricular pits

GU:
   Renal dysplasia/aplasia;
   Renal collecting system anomalies;
   Polycystic kidneys

Neck:
   Branchial cleft fistulas

Pulmonary:
   Pulmonary hypoplasia

Radiology:
   Hypoplasia of cochlear apex on tomography

Inheritance:
   Autosomal dominant (8q13.3 vs. 8q21.13)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/31/1997
terry: 1/29/1997
mark: 7/8/1996
terry: 6/26/1996
mark: 3/11/1996
terry: 3/6/1996
mark: 2/7/1996
terry: 2/2/1996
mark: 11/1/1995
terry: 12/21/1994
jason: 6/28/1994
mimadm: 4/14/1994
carol: 3/18/1994
carol: 10/28/1993

*RECORD*
*FIELD* NO
113660
*FIELD* TI
*113660 BREAKPOINT CLUSTER REGION-LIKE 4; BCRL4
*FIELD* TX
See 151410.

*FIELD* CD
Victor A. McKusick: 6/29/1988
*FIELD* ED
carol: 7/9/1993
supermim: 3/16/1992
carol: 3/9/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 6/29/1988
*RECORD*
*FIELD* NO
113670
*FIELD* TI
113670 BREAST, UNILATERAL GIANT
GIGANTOMASTIA, UNILATERAL
*FIELD* TX
In Nigeria, Badejo (1984) observed unilateral giant breast in 4 females
out of 7 female children in 2 unrelated families. The condition has been
described before by surgeons in Africa who attributed it to lymphedema
or consider it to be related in part to pregnancy. However, in this
study, onset occurred well before pregnancy. Unilateral breast
enlargement was suspected in the 4-year-old child of an affected female.
The author suspected that the father in each family might be a carrier
of a sex-limited autosomal dominant gene.

*FIELD* RF
1. Badejo, O. A.: Familial occurrence of unilateral giant breasts
in Nigeria: a possible new genetic entity. J. Med. Genet. 21: 114-116,
1984.

*FIELD* CS

Thorax:
   Unilateral giant breast

Inheritance:
   Sex-limited autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
113700
*FIELD* TI
113700 BREASTS AND NIPPLES, ABSENCE OF
ATHELIA
*FIELD* TX
Pedigrees consistent with dominant inheritance have been reported.
Fraser (1956) found absent breasts in 7 members of 3 generations.
Goldenring and Crelin (1961) described it in mother and daughter.
Recessive inheritance seemed more likely in the family of Kowlessar and
Orti (1968) in which brother and sister were affected and the parents
were first cousins. Hypoplasia or aplasia of the breasts and nipples
occurs in anhidrotic ectodermal dysplasia. Trier (1965) observed
affected mother and daughter. Wilson et al. (1972) described 7 persons
with absence or hypoplasia of the breasts in 4 generations. The
observations do not permit distinction between autosomal and X-linked
inheritance. Absence of the breast also occurs with Poland syndrome
(173800). A Biblical writer provided the first report: 'We have a little
sister, and she hath no breast. What shall we do for our sister in the
day when she shall be spoken for?' (Song of Solomon VIII: 8). Greenberg
(1987) described an infant girl with athelia and choanal atresia, born
to a woman treated for hyperthyroidism throughout pregnancy with
methimazole and propranolol. The possibility of methimazole
teratogenicity was raised.

*FIELD* RF
1. Fraser, F. C.: Dominant inheritance of absent nipples and breasts.
In: Novant' Anni Delle Leggi Mendeliane.  Rome: Istituto Gregorio
Mendel (pub.)  1956. Pp. 360 only.

2. Goldenring, H.; Crelin, E. S.: Mother and daughter with bilateral
congenital amastia. Yale J. Biol. Med. 33: 466-467, 1961.

3. Greenberg, F.: Choanal atresia and athelia: methimazole teratogenicity
or a new syndrome?. Am. J. Med. Genet. 28: 931-934, 1987.

4. Kowlessar, M.; Orti, E.: Complete breast absence in siblings.
Am. J. Dis. Child. 115: 91-92, 1968.

5. Trier, W. C.: Complete breast absence: case report and review
of the literature. Plast. Reconst. Surg. 36: 431-439, 1965.

6. Wilson, M. G.; Hall, E. B.; Ebbin, A. J.: Dominant inheritance
of absence of the breast. Humangenetik 15: 268 only, 1972.

*FIELD* CS

Thorax:
   Breast and nipple hypoplasia/aplasia

Inheritance:
   Autosomal dominant vs. X-linked

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 4/19/1994
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
113703
*FIELD* TI
113703 BREAST BASIC CONSERVED GENE 1; BBC1
*FIELD* TX
Adams et al. (1992) identified a novel cDNA representing an mRNA showing
significantly higher levels of expression in benign breast lesions than
in carcinomas. In both tissues, the expression was highest in epithelial
cells as determined by in situ hybridization to tissue sections. The
protein deduced from the nucleotide sequence was highly basic with no
signal or transmembrane sequence, but 2 potential nuclear localization
signals. No significant homology was found with known DNA or protein
sequences. The cDNA hybridized to multiple sequences within both human
and other mammalian genomes and to single genomic sequences in
Drosophila, Physarum, and Schizosaccharomyces pombe. Thus the cDNA
represents a highly conserved gene sequence. Only one major transcript
was identified in human cells, but the existence of several pseudogenes
was suspected.

*FIELD* RF
1. Adams, S. M.; Helps, N. R.; Sharp, M. G. F.; Brammar, W. J.; Walker,
R. A.; Varley, J. M.: Isolation and characterization of a novel gene
with differential expression in benign and malignant human breast
tumours. Hum. Molec. Genet. 1: 91-96, 1992.

*FIELD* CD
Victor A. McKusick: 10/2/1992

*FIELD* ED
carol: 10/2/1992

*RECORD*
*FIELD* NO
113705
*FIELD* TI
*113705 BREAST CANCER, TYPE 1; BRCA1
BREAST CANCER 1, EARLY-ONSET
BREAST-OVARIAN CANCER, INCLUDED
*FIELD* TX
Hall et al. (1990) studied 23 extended families with 146 cases of breast
cancer. All were Caucasian and came from a variety of ancestries. The
329 participating relatives lived in 40 states of the United States,
Puerto Rico, Canada, the United Kingdom, and Columbia. The families
shared the epidemiologic features characteristic of familial, versus
sporadic, breast cancer: younger age at diagnosis, frequent bilateral
disease, and frequent occurrence of disease among men. Hall et al.
(1990) found a lod score of 5.98 for linkage of breast cancer
susceptibility in early-onset families to D17S74, which is located in
band 17q21. Negative lod scores were found in families with late-onset
disease. Likelihood ratios in favor of linkage heterogeneity among
families ranged from 2000:1 to greater than 10(6):1 on the basis of
multipoint analysis of 4 loci in the region of 17q21. Candidate genes in
the region include HER2 (164870), which is thought to be identical to
ERBB2; estradiol-17-beta-dehydrogenase (109684); a cluster of homeo box
2 genes (e.g., 142960); retinoic acid receptor alpha (180240); and INT4
(165330). In studies of 103 women from 20 kindreds that were selected
for the presence of 2 first-degree relatives with breast cancer and of
31 control women, Skolnick et al. (1990) found, by 4-quadrant
fine-needle breast aspirates, evidence of proliferative breast disease
(PBD) in 35% of clinically normal female first-degree relatives of
breast cancer cases and in 13% of controls. Genetic analysis suggested
that genetic susceptibility caused both PBD, a precursor lesion, and
breast cancer in these kindreds. The study supported the hypothesis that
this susceptibility is responsible for a considerable proportion of
breast cancer, including unilateral and postmenopausal breast cancer.
Linkage analyses failed to show linkage with D17S74 in either early- or
late-age onset.

The gene mapped by Hall et al. (1990) may be the same as that deduced by
Claus et al. (1991). In a data-set based on 4,730 histologically
confirmed breast cancer patients aged 20 to 54 years and on 4,688
controls, the latter group of workers presented evidence for the
existence of a rare autosomal dominant allele (q = 0.0033) leading to
increased susceptibility to breast cancer. The cumulative lifetime risk
of breast cancer for women who carry the susceptibility allele was
predicted to be approximately 92%, while the cumulative lifetime risk
for noncarriers was estimated to be approximately 10%. Narod et al.
(1991) investigated 5 large families with a hereditary predisposition to
cancer of the breast and ovary. Three families showed linkage with the
D17S74 marker used by Hall et al. (1990). For the largest family the lod
score was 2.72 at a recombination fraction of 0.07. Narod et al. (1991)
suggested that about 60% of breast cancer families have linkage of the
susceptibility to the chromosome 17q locus. Lynch and Watson (1992)
reported extension of the linkage work to 19 families, most of which
showed the HBOC (hereditary breast-ovarian cancer) syndrome. In 70% of
families, linkage to 17q was demonstrated. Lynch and Watson (1992)
reported the first experience with genetic counseling and targeted
management of patients demonstrated to be at risk for HBOC by use of
multipoint linkage analysis in the largest and most informative of the
kindreds studied to date. The single family provided a lod score of
3.03. In those persons shown by linkage to be at risk, they recommended
completing their families before the age of 35 so that prophylactic
oophorectomy could be performed at an early age. Margaritte et al.
(1992) found that when account is made for the higher relative
probability of sporadic rather than inherited disease for late-onset
cases of breast cancer, later-onset families are much less informative
and linkage heterogeneity based on age at onset is no longer
significant. Furthermore, for the sample of families as a whole, linkage
is significant at a recombination fraction in the 17q21 region. Although
there is probably more than one gene for inherited breast cancer, age at
onset may not be a reflection of this heterogeneity.

Hall et al. (1992) indicated that the proportion of older-onset breast
cancer attributable to BRCA1 was not yet determinable, because both
inherited and sporadic cases occur in older-onset families. Hall et al.
(1992) found that the most closely linked marker in their repertoire was
D17S579, a highly informative CA repeat polymorphism located at 17q21.
There were no recombinants with inherited breast or ovarian cancer in 79
informative meioses in the 7 families with early-onset disease; lod
score = 9.12 at 0 recombination. Sobol et al. (1992) also pointed to
genetic heterogeneity of early-onset familial breast cancer; in an
extensively affected family they found no evidence of linkage to markers
on 17q. Goldgar et al. (1992) identified a Utah kindred in which the
BRCA1 locus was linked to 17q markers with odds in excess of a million
to one. The kindred included 170 descendents of 2 Utah pioneers of 1847,
containing a total of 24 cancer cases (16 breast, 8 ovarian). The median
age of onset was 48 for breast cancer and 53 for ovarian cancer. The
penetrance of the BRCA1 gene was estimated to be 0.92 by age 70. Easton
et al. (1993) reported the results of genetic linkage analysis in 214
families. In 15 accompanying papers, confirmatory evidence on the
linkage was reported from Icelandic, Scottish, Dutch, Swedish, and other
families including one African-American family. In Icelandic studies,
Arason et al. (1993) suggested that male carriers of the BRCA1 gene may
have an increased risk of prostatic cancer.

If the gene predisposing to breast cancer (and ovarian cancer) mapped to
17q12-q21 is a tumor suppressor gene, one would expect, based on the
Knudson hypothesis, that tumors from affected family members would show
loss of heterozygosity affecting the wildtype chromosome. In 4 multiple
case breast-ovarian cancer families, Smith et al. (1992) indeed found
that in each of 9 tumors that showed allele loss, the losses were from
the wildtype chromosome. Kelsell et al. (1993) found the same for each
of 7 breast tumors from a single multi-affected breast/ovarian cancer
pedigree. In the same family, they generated linkage data which, in
combination with previously published information, suggested that the
BRCA1 gene is contained in a region estimated to be 1-1.5 Mb in length.

Because of the finding of genetic recombination between the BRCA1 locus
and the gene for retinoic acid receptor alpha (180240), Simard et al.
(1993) was able to exclude that candidate gene. BRCA1 and the gene for
estradiol 17-beta-hydroxysteroid dehydrogenase II (109685) map to a 6-cM
interval (between THRA1 and D17S579) and no recombination was observed
between the 2 genes; however, direct sequencing of overlapping PCR
products containing the entire EDH17B2 gene in 4 unrelated affected
woman did not uncover any sequence variation other than previously
described polymorphisms. They concluded, therefore, that mutations in
the EDH17B2 gene are probably not responsible for hereditary
breast-ovarian cancer syndrome. Kelsell et al. (1993) sequenced the two
17-beta-estradiol dehydrogenase genes (EDH17B1, EDH17B2), which had been
suggested as candidate genes for BRCA1, in 4 members of the same family;
no germline mutations were detected. (Actually, the EDH17B1 and EDH17B2
genes appear to map proximal to the BRCA1 locus.)

Piver et al. (1993) presented data suggesting that mucinous carcinomas
of the ovary may be underrepresented in familial ovarian cancer.
Mutations in the BRCA1 gene account for most families with the
hereditary breast-ovarian cancer syndrome. To address whether or not
there is an association between the presence of a BRCA1 mutation and the
subtype of epithelial ovarian carcinoma, Narod et al. (1994) reviewed
the histology of 49 ovarian cancers seen in 16 hereditary breast-ovarian
cancer families shown to be linked to BRCA1 markers. Of the 49 cancers,
5 (10.2%) were mucinous. By haplotype analysis with 17q markers, they
determined the BRCA1 carrier status of 40 of the cases; 36 occurred in
women who were BRCA1 mutation carriers and 4 were sporadic in that they
occurred in noncarriers. Only 2 of the 36 ovarian cancers found in BRCA1
carriers were mucinous, compared with 3 or 4 mucinous carcinomas
observed in BRCA1 noncarriers. Albertsen et al. (1994) used simple
sequence repeat (SSR) markers to construct a high-resolution genetic map
of a 40-cM region around 17q21. For 5 of the markers, genotypes were
'captured' by using an ABI sequencing instrument and stored in a locally
developed database as a step toward automated genotyping. In a second
report, Albertsen et al. (1994) described construction of a physical map
of a 4-cM region containing the BRCA1 gene. The map comprised a contig
of 137 overlapping YACs and P1 clones, onto which they had placed 112
PCR markers. They localized more than 20 genes on the map, 10 of which
had not been mapped to the region previously, and isolated 30 cDNA
clones representing partial sequences of as yet unidentified genes. They
failed to find any deleterious mutations on sequencing of 2 genes that
lie within a narrow region defined by meiotic breakpoints in BRCA1
patients. O'Connell et al. (1994) developed a radiation hybrid map of
the BRCA1 region as the basis of YAC cloning and pulsed field gel
electrophoretic mapping of the candidate region for the BRCA1 gene.

Miki et al. (1994) identified a strong candidate for the BRCA1 gene by
positional cloning methods. Probable predisposing mutations were
detected in 5 of 8 kindreds thought to segregate BRCA1 susceptibility
alleles. The mutations included an 11-bp deletion, a 1-bp insertion, a
stop codon, a missense substitution, and an inferred regulatory
mutation. The BRCA1 gene is expressed in numerous tissues, including
breast and ovary, and encodes a predicted protein of 1,863 amino acids.
The protein contains a zinc finger domain in its amino-terminal region,
but is otherwise unrelated to previously described proteins. Futreal et
al. (1994) extended the observations to studies of primary breast and
ovarian tumors that show allele loss at the BRCA1 locus. Mutations were
detected in 3 of 32 breasts and 1 of 12 ovarian carcinomas; all 4
mutations were germline alterations and occurred in cancers of
early-onset type. These results were interpreted as indicating that
mutation in the BRCA1 gene may not be critical to the development of
most breast and ovarian cancers that arise in the absence of a mutant
germline allele. This situation is unlike that in the APC gene (175100),
which is involved in both hereditary polyposis coli and sporadic
colorectal cancer, and that of some other genes involved in both
familial and sporadic cancer.

Using single-strand conformation polymorphism (SSCP) analysis on
PCR-amplified genomic DNA in an analysis of 50 probands with a family
history of breast and/or ovarian cancer, Castilla et al. (1994) found 8
putative disease-causing alterations: 4 frameshift mutations, 2 nonsense
mutations, and 2 missense mutations. The data were considered consistent
with a tumor suppressor model. The heterogeneity of mutations, coupled
with the large size of the gene, indicated that clinical application of
BRCA1 mutation testing would be technically challenging. Simard et al.
(1994) identified mutations in the BRCA1 gene in 12 of 30 Canadian
families. Six frameshift mutations accounted for all 12 mutant alleles,
including nucleotide insertions (2 mutations) and deletions (4
mutations). The same 1-bp insertion mutation in codon 1,755 was found in
4 independent families, whereas 4 other families shared a 2-bp deletion
mutation in codons 22 to 23. These families were not known to be
related, but haplotype analysis suggested that the carriers of each of
these mutations had common ancestors. Friedman et al. (1994) likewise
used SSCP analysis and direct sequencing to identify 9 different
mutations in 10 families. The mutations in 7 instances led to protein
truncation at sites throughout the gene. A missense mutation, which
occurred independently in 2 families, led to loss of a cysteine in the
zinc-binding domain. An intronic single basepair substitution destroyed
an acceptor site and activated a cryptic splice site, leading to a 59-bp
insertion and chain termination. In 4 families with both breast and
ovarian cancer, chain termination mutations were found in the N-terminal
half of the protein.

In 4 of 47 sporadic ovarian cancers, Merajver et al. (1995) examined
tumor DNAs by SSCP and found 4 somatic mutations in the BRCA1 gene; all
4 had loss of heterozygosity at a BRCA1 intragenic marker. The findings
supported a tumor-suppressor mechanism for BRCA1; somatic mutation on
one chromosome and LOH on the other may result in inactivation of BRCA1
in some sporadic ovarian cancers. In sporadic breast cancer, Thompson et
al. (1995) found that BRCA1 mRNA levels are markedly decreased during
the transition from carcinoma in situ to invasive cancer. Thompson et
al. (1995) found that experimental inhibition of BRCA1 expression with
antisense oligonucleotides produced accelerated growth of normal and
malignant mammary cells but had no effect on nonmammary epithelial
cells. They interpreted these results as indicating that BRCA1 may
normally serve as a negative regulator of mammary epithelial cell growth
and that this function is compromised in breast cancer either by direct
mutation or by alterations in gene expression.

Bennett et al. (1995) found that the mouse Brca1 gene shares 75%
identity of the coding region with the human sequence at the nucleotide
level, whereas the predicted amino acid identity was only 58%. By an
intersubspecific backcross using a DNA sequence variant in the Brca1
locus, they mapped the gene to distal mouse chromosome 11 in a region of
extensive homology of synteny to human chromosome 17. Schrock et al.
(1996) likewise mapped the Brca1 gene to mouse chromosome 11,
specifically 11D. De Gregorio et al. (1996) also mapped the gene to
mouse chromosome 11.

Cornelis et al. (1995) sought criteria that would identify breast cancer
families with a high prior probability that the tumors were caused by a
BRCA1 mutation. They performed a linkage study in 59 consecutively
collected Dutch breast cancer families, including 16 families with at
least 1 case of ovarian cancer. They used a family intake cutoff of at
least 3 first-degree relatives with breast and/or ovarian cancer at any
age. Significant evidence for linkage was found only among the 13 breast
cancer families with a mean age at diagnosis of less than 45 years. An
unexpectedly low proportion of breast-ovarian cancer families were
estimated to be linked to BRCA1, which could be due to a founder effect
in the Dutch population. Cornelis et al. (1995) proposed that, during an
interim period, BRCA1 mutation testing be offered only to families with
a strong positive family history for early onset breast and/or ovarian
cancer. Tonin et al. (1995) studied 26 Canadian families with hereditary
breast or ovarian cancer for linkage to markers flanking BRCA1. Of the
15 families that contained cases of ovarian cancer, 94% were estimated
to be linked to BRCA1. In contrast, there was no overall evidence of
linkage in the group of 10 families with breast cancer without ovarian
cancer.

Since more than 75% of the reported mutations in the BRCA1 gene result
in truncated proteins, Hogervorst et al. (1995) used the protein
truncation test (PTT) to screen for mutations in exon 11 which encodes
61% of the BRCA1 protein. In 45 patients from breast and/or ovarian
cancer families, they found 6 novel mutations: 2 single nucleotide
insertions, 3 small deletions (of 1-5 bp), and a nonsense mutation
identified in 2 unrelated families. Furthermore, they were able to
amplify the remaining coding region by RT-PCR using lymphocyte RNA.
Combined with the protein truncation test, they detected aberrantly
spliced products affecting exons 5 and 6 in 1 of 2 BRCA1-linked families
examined.

Struewing et al. (1995) stated that more than 50 unique mutations had
been detected in the BRCA1 gene in the germline of individuals with
breast and ovarian cancer. In high-risk pedigrees, female carriers of a
BRCA1 mutation had an 80%-90% lifetime risk of breast cancer and a
40%-50% risk of ovarian cancer. Not known, however, was the mutation
status of women unselected for breast or ovarian cancer, and it was not
known whether mutations in such women confer the same risk of cancer as
in women from the high-risk families. Following the finding of a
185delAG frameshift mutation (113705.0003) in several Ashkenazi Jewish
breast/ovarian families, Struewing et al. (1995) determined the
frequency of this mutation in 858 Ashkenazim seeking genetic testing for
conditions unrelated to cancer, and in 815 reference persons not
selected for ethnic origin. They found the 185delAG mutation in 0.9% of
Ashkenazim (95% confidence limit, 0.4%-1.8%) and in none of the
reference samples. The results suggested that 1 in 100 women of
Ashkenazi descent may be at especially high risk of developing breast
and/or ovarian cancer. The possibility was raised in an accompanying
editorial by Goldgar and Reilly (1995) that a high frequency of
mortality from breast cancer in Nassau County, New York over the last 2
decades might be related to the high proportion of Ashkenazim (roughly
16%) in that population; the pathogenetic collaboration of exposure to
an environmental pollutant was also raised. Ethical, legal, and social
issues raised by these findings were also discussed by Goldgar and
Reilly (1995).

In a study of 37 families with 4 or more cases of breast cancer or
breast and ovarian cancer, Friedman et al. (1995) found that 5 families
of Ashkenazi Jewish descent carried the 185delAG mutation and shared the
same haplotype at 8 polymorphic markers spanning approximately 850 kb at
BRCA1. Expressivity of 185delAG in these families varied from
early-onset bilateral breast cancer and ovarian cancer to late-onset
breast cancer without ovarian cancer. Overall, BRCA1 mutations were
detected in 26 of the families: 16 with positive BRCA1 linkage lod
scores, 7 with negative lod scores (reflecting multiple sporadic breast
cancers), and 3 not tested for linkage.

Stratton et al. (1994) examined 22 families with at least 1 case of male
breast cancer for linkage to the BRCA1 locus. They found strong evidence
against linkage to BRCA1 (lod score, -16.63) and the best estimate of
the proportion of linked families was 0% (95% confidence interval,
0-18%).

Narod et al. (1995) reported the results of linkage analysis of 145
breast-ovarian families, each of which had 3 or more cases of
early-onset breast cancer (age less than 60) or of ovarian cancer. All
families had at least 1 case of ovarian cancer (there were 9
site-specific ovarian cancer families). Overall, they estimated that 76%
of families were linked to the BRCA1 locus. At that time, the group
stated that none of the 13 families with cases of male breast cancer
appeared to be linked to BRCA1. In their letter, Narod et al. (1995)
summarized their updated findings and reported a family with male breast
cancer that showed a mutation (113705.0003) in BRCA1; Struewing et al.
(1995) had also reported such a family. Their final results indicated
that BRCA1 and BRCA2 account for the most breast-ovarian cancer
families. Although a third breast cancer locus may be found, Narod et
al. (1995) felt it unlikely that it would account for a significant
proportion of breast-ovarian cancer families.

Chen et al. (1995) identified the BRCA1 gene product as a 220-kD nuclear
phosphoprotein in normal cells, including breast ductal epithelial
cells, and in 18 of 20 tumor cell lines derived from tissues other than
breast and ovary. However, in 16 of 17 breast and ovarian cancer lines
and in 17 of 17 samples of cells obtained from malignant effusions,
BRCA1 localized mainly in the cytoplasm. Absence of BRCA1 or aberrant
subcellular location was also observed to a variable extent in
histologic sections of many breast cancer biopsies. The findings
suggested to the authors that BRCA1 abnormalities may be involved in the
pathogenesis of many breast cancers, sporadic as well as familial.
Scully et al. (1996), however, reported results that did not support the
hypothesis that wildtype BRCA1 is specifically excluded from the nucleus
in sporadic breast and ovarian cancer.

Chen et al. (1996) raised mouse polyclonal antibodies to 3 regions of
the human BRCA1 protein and confirmed their earlier finding of a 220-kD
nuclear phosphoprotein. They reported that expression and
phosphorylation of the BRCA1 gene and protein are cell cycle dependent
in a synchronized population of bladder carcinoma cells. The greatest
levels of both expression and phosphorylation occurred in S and M
phases.

Gayther et al. (1995) analyzed 60 families with a history of breast
and/or ovarian cancer for germline mutations in BRCA1. In 32 families
(53%), a total of 22 different mutations were detected, of which 14 were
previously unreported. They observed a significant correlation between
the location of the mutation in the gene and the ratio of breast to
ovarian cancer incidence within the family. The data suggested to the
authors a transition in risk such that mutations in the 3-prime third of
the gene are associated with a lower proportion of ovarian cancer.
Haplotype analysis supported previous data suggesting that some BRCA1
mutation carriers have common ancestors; however, Gayther et al. (1995)
found at least 2 examples where recurrent mutations appeared to have
arisen independently, judging from the different haplotype background.

Serova et al. (1996) analyzed 20 breast-ovarian cancer families, most of
which showed evidence of linkage to 17q12, for germline mutations in
BRCA1. Mutations in this gene cosegregating with breast and ovarian
cancer susceptibility were identified in 16 of the 20 families,
including 1 family with a case of male breast cancer. Nine of these
mutations had not been reported previously. Most of them generated a
premature stop codon leading to the formation of a truncated BRCA1
protein of 2 to 88% of the expected normal length. The RING-finger
domain was altered by 2 of the mutations. A reduced quantity of BRCA1
transcript was associated with 8 of the mutations. Of the 4 families
with no detectable BRCA1 mutation, only 1 was clearly linked to the
BRCA1 locus.

Holt et al. (1996) demonstrated that retroviral transfer of the wildtype
BRCA1 gene inhibits growth in vitro of all breast cancer and ovarian
cancer cell lines tested, but not colon or lung cancer cells or
fibroblasts. Mutant BRCA1, however, had no effect on growth of breast
cancer cells; ovarian cancer cell growth was not affected by BRCA1
mutations in the 5-prime portion of the gene but was inhibited by
3-prime BRCA1 mutations. Development of MCF-7 tumors in nude mice was
inhibited when MCF-7 cells were transfected with wildtype, but not
mutant, BRCA1. Among mice with established MCF-7 tumors, peritoneal
treatment with a retroviral vector expressing wildtype BRCA1
significantly inhibited tumor growth and increased survival. The results
of Holt et al. (1996) were consistent with the previous observation that
the site of BRCA1 mutation is associated with relative susceptibility to
ovarian versus breast cancer.

Jensen et al. (1996) demonstrated that BRCA1 encodes a 190-kD protein
with sequence homology and biochemical analogy to the granin protein
family. BRCA2 also includes a motif similar to the granin consensus at
the C terminus of the protein. Both BRCA1 and the granins localized to
secretory vesicles, are secreted by a regulated pathway, are
posttranslationally glycosylated, and are responsive to hormones. The
authors stated that, as a regulated secretory protein, BRCA1 appears to
function by a mechanism not previously described for tumor suppressor
products. The granins with which BRCA1 and BRCA2 were compared included
chromogranin A (118910), chromogranin B (118920), and secretogranin II,
also known as chromogranin C (118930). As reviewed by Steeg (1996),
granins are a family of acidic proteins that bind calcium and aggregate
in its presence. Known members of the granin family have been solely
neuroendocrine or endocrine in origin; if BRCA1 is a granin it will
necessarily expand the families boundaries.

Studies of a number of diseases have indicated that fine-structure
haplotype analysis can provide insight into the 'genetic history' of a
particular mutation (or presumed mutation for rare diseases where the
disease gene is not yet identified). To address both the question of
mutation origin and the relationship between mutation and phenotype,
Neuhausen et al. (1996) constructed a haplotype of 9 polymorphic STR
markers within or immediately flanking the BRCA1 locus in a set of 61
families (selected to contain 1 of 6 BRCA1 mutations that had been
identified a minimum of 4 times). The mutation appeared to have an
affect on the relative proportion of cases of breast and ovarian cancer:
57% of women presumed affected because of the 1294 del 40 mutation had
ovarian cancer, compared with 14% of affected women with the splice-site
mutation in intron 5 of BRCA1. A high degree of haplotype conservation
across the region was observed. Any haplotype differences found were
most often due to mutations in the short-tandem-repeat markers, although
some likely instances of recombination also were observed. One mutation,
4184 del 4, had the same ancestral haplotype in two-thirds of the
families studied. Neuhausen et al. (1996) estimated that this mutation
had arisen 170 generations ago.

Langston et al. (1996) found germline BRCA1 mutations in 6 of 80 women
in whom breast cancer was diagnosed before the age of 35 and who were
not selected on the basis of family history. Four additional rare
sequence variants of unknown functional significance were also
identified. Two of the mutations and 3 of the rare sequence variants
were found among the 39 women who reported no family history of breast
or ovarian cancer. None of the mutations and only 1 of the rare variants
was identified in a reference population of 73 unrelated subjects.
Similar results were found by Fitzgerald et al., 1996 in a study of 30
women with breast cancer before the age of 30: 4 (13%) had
chain-terminating mutations and 1 had a missense mutation. The 185delAG
mutation (113705.0003) was found in 2 of the 4 Jewish women in this
cohort. Among the 39 Jewish women with breast cancer before the age of
40, Fitzgerald et al. (1996) found that 8 (21%) carried the 185delAG
mutation (95% confidence interval, 9-36%). Fitzgerald et al. (1996)
concluded that germline BRCA1 mutations can be present in young women
with breast cancer who do not belong to families with multiple affected
members.

Women who carry a mutation in the BRCA1 gene have an 80% risk of breast
cancer and a 40% risk of ovarian cancer by the age of 70 years. Phelan
et al. (1996) demonstrated that a modifier of this risk is the HRAS1
(190020) variable number of tandem repeats (VNTR) polymorphism, located
1 kb downstream of the HRAS1 oncogene. Individuals who have rare alleles
of this VNTR had been found to have an increased risk of certain types
of cancer, including breast cancer. Phelan et al. (1996) claimed that
this was the first study to show the effect of a modifying gene on the
penetrance of an inherited cancer syndrome.

Johannsson et al. (1996) identified 9 different germline mutations in
the BRCA1 gene in 15 of 47 kindreds from southern Sweden, by use of SSCP
and heteroduplex analysis of all exons and flanking intron region and by
a protein-truncation test for exon 11, followed by direct sequencing.
All but one of the mutations were predicted to give rise to premature
translation termination and included 7 frameshift insertions or
deletions, a nonsense mutation, and a splice acceptor site mutation. The
remaining mutation was a missense mutation (cys61-to-gly) in the
zinc-binding motif. They also identified 4 novel Swedish founding
mutations: deletion of 2595A in 5 families, the C-to-T nonsense mutation
of nt1806 in 3 families, the insertion of TGAGA after nt3166 in 3
families, and the deletion of 11 nucleotides after nt1201 in 2 families.
Analysis of the intragenic polymorphism D17S855 supported common origins
of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations
were breast-ovarian cancer families, several of which had a predominant
ovarian cancer phenotype. Among the 32 families in which no BRCA1
alteration was detected, there was 1 breast-ovarian cancer kindred
showing clear linkage to the BRCA1 region and loss of the wildtype
chromosome in associated tumors. Other tumor types found in BRCA1
mutation or haplotype carriers included prostatic, pancreas, skin, and
lung cancer, a malignant melanoma, an oligodendroglioma, and a
carcinosarcoma. In all, 12 of the 16 kindreds manifesting BRCA1 mutation
or linkage contained ovarian cancer, as compared with only 6 of the
remaining 31 families. Gayther et al. (1996) stated that more than 65
distinct mutations scattered throughout the coding region of BRCA1 had
been detected.

Langston et al. (1996) studied the BRCA1 gene in 61 men who met one or
more of these criteria: (1) under 53 years of age at diagnosis of
prostate cancer; (2) a family history of breast cancer in a first-degree
female relative diagnosed under 51 years of age; or (3) a family history
of prostate cancer in 2 or more male relatives, with at least 1 relative
diagnosed at less than 56 years of age. They found 1 germline mutation,
DEL185AG (113705.0003) in 1 subject and 5 different rare sequence
variants (1 of which was detected in 2 unrelated men). None of the rare
variants were found in population-based controls. Isaacs et al. (1995)
failed to identify a significantly increased risk of breast cancer among
relatives of prostate cancer probands. The findings of Langston et al.
(1996) are not necessarily in conflict, since the contribution of
germline BRCA1 mutations to the overall incidence of prostate cancer
appears to be small, at most, and may be limited to specific subgroups
of patients.

Couch et al. (1996) reported a total of 254 BRCA1 mutations, 132 (52%)
of which were unique. These represented mutations entered into a
database established by the Breast Cancer Information Core (BIC). A
total of 221 (87%) of all mutations or 107 (81%) of the unique mutations
are small deletions, insertions, nonsense point mutations, splice
variants, and regulatory mutations that result in truncation or absence
of the BRCA1 protein. A total of 11 disease-associated missense
mutations (5 unique) and 21 variants (19 unique) as yet unclassified as
missense mutations or polymorphisms had been detected. Thirty-five
independent benign polymorphisms had been described. The most common
mutations were 185delAG (113705.0003) and 5382insC (113705.0018), which
accounted for 30 (11.7%) and 26 (10.1%), respectively, of all the
mutations.

Stoppa-Lyonnet et al. (1996) described 2 independent BRCA1 mutations in
a single family. A woman with breast cancer diagnosed at age 25
inherited a deleterious allele from her father. Her mother had ovarian
and breast cancer caused by a separate mutation, which was the basis of
breast cancer in 5 or more of her relatives. The authors pointed out
that the segregation of 2 BRCA1 mutations resulted in the failure to
demonstrate linkage to either chromosome 17 or chromosome 13 and could
leads to the erroneous hypothesis of the involvement of a third locus in
familial breast cancer. Narod et al. (1995) suggested that the fraction
of familial breast cancer that is not accounted for by BRCA1 or BRCA2
may be small.

Rebbeck et al. (1996) performed specific studies of 23 families
identified through 2 high-risk breast cancer research programs. In 14
(61%) it was possible to attribute the pattern of hereditary cancer to
BRCA1 by a combination of linkage and mutation analyses. No families
were attributed to BRCA2. In 5 families (22%), evidence against linkage
to both BRCA1 and BRCA2 was found; no BRCA1 or BRCA2 mutations were
detected in these 5 families. The BRCA1 or BRCA2 status of the 4
remaining families (17%) could not be determined.

Brown et al. (1996) determined the detailed structure of the BRCA1
genomic region. They showed that this region of chromosome 17 contains a
tandem duplication of approximately 30 kb which results in 2 copies of
BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent gene that Brown et
al. (1994) designated 1A1-3B (M17S2; 166945), and of a previously
reported 295-bp intergenic region. Sequence analysis of the duplicated
exons of BRCA1, 1A1-3B, and flanking genomic DNA revealed to Brown et
al. (1996) that there was maintenance of exon/intron structure and a
high degree of nucleotide sequence identity, which suggested that these
duplicated exons are non-processed pseudogenes. They noted that these
findings could not only confound BRCA1 mutation analysis but could have
implications for the normal and abnormal regulation of BRCA1
transcription, translation and function.

Although many distinct mutations were identified in the breast-ovarian
cancer susceptibility gene BRCA1 with loss of the wildtype allele in
more than 90% of tumors from patients with inherited BRCA1 mutation, a
very low incidence of somatic mutations were found in sporadic tumors,
suggesting the BRCA1 inactivation occurs by alternative mechanisms, such
as interstitial chromosomal deletion or reduced transcription. To
identify possible features of the BRCA1 genomic region that may
contribute to chromosomal instability as well as potential
transcriptional regulatory elements, Smith et al. (1996) sequenced
117,143 bp from human chromosome 17 encompassing BRCA1. The 24 exons of
BRCA1 spanned an 81-kb region that had an unusually high density of Alu
repetitive DNA (41.5%), but a relatively low density (4.8%) of other
repetitive sequences. BRCA1 intron lengths ranged in size from 403 bp to
9.2 kb and contained 3 intragenic microsatellite markers located in
introns 12, 19, and 20. In addition to BRCA1, the contig contained 2
complete genes which they called RHO7 (601555) and VAT1. RHO7 is a
member of the RHO family of GTP binding proteins and VAT1 is an abundant
membrane protein of cholinergic synaptic vesicles. The order of genes on
the chromosome was found to be as follows: centromere-IFP 35
(600735)-VAT1-RHO7-BRCA1-1A1-3B-telomere.

In an effort to understand the function of BRCA1, Wu et al. (1996) used
a yeast 2-hybrid system to identify proteins that associate with BRCA1
in vivo. This analysis led to the identification of a novel protein that
interacts with the N-terminal region of BRCA1. Wu et al. (1996)
designated this protein BARD1 (601593) and determined that it maps to
chromosome 2q.

In a population-based series of 54 breast cancer cases from southern
California, Friedman et al. (1997) found no instance of germline
mutation in the BRCA1 gene but found 2 male breast cancer patients who
carried novel truncating mutations in the BRCA2 gene. Only 1 of the 2
had a family history of cancer, namely, ovarian cancer in a first-degree
relative.

In addition to the deletion mutations in BRCA1 and BRCA2 genes that
appear to be highly penetrant in the causation of young onset breast
cancer and ovarian cancer, there are several common polymorphisms in the
BRCA1 gene that generate amino acid substitutions. Dunning et al. (1997)
raised the question whether these common variants may confer more modest
individual risks which might, however, be of significance. They examined
the frequency of 4 of these polymorphisms in a large series of breast
and ovarian cancer cases and matched controls. Due to strong linkage
disequilibrium, the 4 sites generated only 3 haplotypes with a frequency
more than 1.3%. The 2 most common haplotypes had frequencies of 0.57 and
0.32, respectively, and these frequencies did not differ significantly
between patient and control groups. Thus, Dunning et al. (1997)
concluded that the most common polymorphisms of BRAC1 gene do not make a
significant contribution to breast or ovarian cancer risk. However, the
data suggested that the arg356 allele may have a different genotype
distribution in breast cancer patients than that in controls; arg356
homozygotes were more frequent in the control group (P = 0.01),
indicating that it may be protective against breast cancer.

The detection of inactivating mutations in tumor suppressor genes is
critical to their characterization, as well as to the development of
diagnostic testing. Most approaches for mutational screening of germline
specimens are complicated by the fact that mutations are heterozygous
and that missense mutations are difficult to interpret in the absence of
information about protein function. Ishioka et al. (1997) described a
novel method using Saccharomyces cerevisiae for detecting
protein-truncating mutations in any gene of interest. In their
procedure, the PCR-amplified coding sequence of the gene is inserted by
homologous recombination into a yeast URA3 fusion protein, and
transformants are assayed for growth in the absence of uracil. The high
efficiency of homologous recombination in yeast ensures that both
alleles are represented among transformants and achieves separation of
alleles, which facilitates subsequent nucleotide sequencing of the
mutated transcript. The specificity of translational initiation of the
URA3 gene lead to minimal enzymatic activity in transformants harboring
an inserted stop codon, and hence to reliable distinction between
specimens with wildtype alleles and those with a heterozygous truncating
mutation. This yeast-based codon assay accurately detected heterozygous
truncating mutations in the BRCA1 gene in patients with early onset of
breast cancer and in the APC gene (175100) in patients with familial
adenomatous polyposis.

ANIMAL MODEL

Gowen et al. (1996) described homozygous mice lacking the mouse Brca1
gene. The mice, possessing a deletion of the large exon 11, died between
days 10 and 13 of embryonic development, suffering from a variety of
neuroepithelial defects. Hakem et al. (1996) described another strain of
homozygous mice for a putative Brca1 null mutation produced by targeted
deletion of exons 5 and 6. These mutant mice were more severely
affected, dying at about embryonic day 7.5 with no signs of mesoderm
formation and exhibiting reduced cell proliferation. There were also
strong signs of disruptive cell cycle regulation via altered expression
levels of cyclin E (123837), mdm2 (164785) and p21 (116899). Hakem et
al. (1996) speculated that the death of mutant embryos was due to
failure of the proliferative burst required for germ layer development.
Hakem et al. (1996) reported that after about 1 year of age, Brca1
heterozygous female mice showed no evidence of cancer. Gowen et al.
(1996) also had been unable to detect tumors in its 1-year-old
heterozygotes.

*FIELD* AV
.0001
BREAST-OVARIAN CANCER
BRCA1, CYS64GLY
In a kindred in which 8 members had breast cancer and 5 members ovarian
cancer, Castilla et al. (1994) found a TGT-to-GGT transversion in codon
64 leading to substitution of glycine for cysteine. Analysis of tumor
DNA in 2 affected members of this kindred showed that the wildtype
allele had been lost and only the cys64-to-gly mutant allele remained,
thus supporting the tumor suppressor model.

.0002
OVARIAN CANCER, SPORADIC
BRCA1, CYS61GLY
Merajver et al. (1995) analyzed genomic DNA of tumor and normal
fractions of 47 ovarian cancers for mutations in BRCA1 using the SSCP
technique. In the DNA of 4 tumors, which also had loss of heterozygosity
at a BRCA1 intragenic marker, they found somatic mutations. One of
these, found in an endometrioid ovarian carcinoma in a 53-year-old
woman, was a cys61-to-gly substitution in the zinc-finger motif. The
data supported a tumor-suppressor mechanism for BRCA1; a combination of
somatic mutation on 1 allele and LOH on the other may result in
inactivation of BRCA1 in at least a small number of ovarian cancers.

.0003
BREAST-OVARIAN CANCER
BRCA1, 2-BP DEL, FS39TER
Simard et al. (1994) studied 30 Canadian families with breast and/or
ovarian cancer for germline mutations in the coding region of the BRCA1
candidate gene. They identified a 2-bp (AG185) deletion of the normal
sequence TTA GAG of codons 22-23 in exon 3. This mutation changes the
reading frame of the mRNA and causes a premature termination codon at
position 39. This mutation was detected in index cases from 4 families
that were not known to be related and originated from different areas in
Canada. In these 4 families there were a total of 12 cases of breast
cancer and 11 cases of ovarian cancer.

Struewing et al. (1995) pointed out that all 10 published families with
the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of
Eastern European origin). They knew of an eleventh Ashkenazi
breast/ovarian cancer family with the 185delAG mutation; furthermore,
only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other
than 185delAG. In addition, Ashkenazi families with the 185delAG
mutation appeared to share a common haplotype. In a study of 858
Ashkenazim seeking genetic testing for conditions unrelated to cancer,
they observed the 185delAG mutation in 0.9% (95% confidence limit,
0.4%-1.8%), and in 815 reference individuals not selected for ethnic
origin, none had the mutation.

Roa et al. (1996) found the 185delAG mutation in 1.09% of approximately
3,000 Ashkenazi Jewish individuals and found the 5382insC mutation
(113705.0018) in 0.13%. BRCA2 analysis on 3,085 individuals from the
same population showed a carrier frequency of 1.52% for the 6174delT
mutation (600185.0009). The expanded population-based study confirmed
that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation
constituted the 2 most frequent mutant alleles predisposing to
hereditary breast cancer among Ashkenazim and suggested a relatively
lower penetrance for the 6174delT mutation in BRCA2.

.0004
BREAST-OVARIAN CANCER
BRCA1, 59-BP INS
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a T-to-G transition at nucleotide 332 in exon 5, leading
to a premature termination codon at position 75 and a truncated protein.

.0005
BREAST-OVARIAN CANCER
BRCA1, 1-BP INS, FS345TER
Simard et al. (1994) studied 30 Canadian families with breast and/or
ovarian cancer for germline mutations in the coding region of the BRCA1
candidate gene. They identified a 1-bp (A) insertion in the normal
sequence GAA AAA AAG of codons 337-339 in exon 11, changing the reading
frame of the mRNA and causing a premature termination codon at position
345. This mutation was detected in the index case of a Canadian family
with a total of 4 cases of breast cancer and 3 cases of ovarian cancer,
bringing the probability of linkage to BRCA1 to 98.3%.

.0006
BREAST-OVARIAN CANCER
BRCA1, 40-BP DEL, FS397TER
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. Simard et al. (1994) studied 30 Canadian
families with breast and/or ovarian cancer for germline mutations in the
coding region of the BRCA1 candidate gene. They both identified a 40-bp
deletion from position 1294 to 1333, which led to a premature
termination codon that was 5 codons distal to the deletion and predicted
a truncated BRCA1 protein of 396 amino acids.

.0007
BREAST-OVARIAN CANCER
BRCA1, SER766TER
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a 2-bp (AG) deletion at nucleotide 2415 in exon 11,
leading to a premature termination codon in place of serine-766 and a
truncated protein.

.0008
BREAST-OVARIAN CANCER
BRCA1, 2-BP DEL, FS901TER
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a 2-bp (AA) deletion at nucleotide 2800 in exon 11,
leading to a premature termination codon at position 901 and a truncated
protein.

.0009
BREAST-OVARIAN CANCER
BRCA1, SER915TER
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a 2-bp (TC) deletion at nucleotide 2863 in exon 11,
leading to a premature termination codon in place of serine-915 and a
truncated protein.

.0010
BREAST-OVARIAN CANCER
BRCA1, 1-BP DEL, FS1023TER
Simard et al. (1994) studied 30 Canadian families with breast and/or
ovarian cancer for germline mutations in the coding region of the BRCA1
candidate gene. They identified a 1-bp (A3121) deletion in the normal
sequence GAA AAC of codons 1001-1002 in exon 11, changing the reading
frame of the mRNA and causing a premature termination codon at position
1023. This mutation was detected in the index case of a Canadian family
with a total of 5 cases of breast cancer and 1 case of ovarian cancer,
bringing the probability of linkage to BRCA1 to 90%.

.0011
BREAST-OVARIAN CANCER
BRCA1, SER1040ASN
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a G-to-A transition at nucleotide 3238 in exon 11 of the
BRCA1 gene, changing serine to asparagine at position 1040.

.0012
BREAST-OVARIAN CANCER
BRCA1, ARG1203TER
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a C-to-T substitution in exon 11 at position 3726,
leading to a premature termination codon in place of arginine-1203 and a
truncated protein.

.0013
BREAST-OVARIAN CANCER
BRCA1, GLU1250TER
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. They identified a G-to-T substitution in
exon 11 at position 3867, leading to a premature termination codon in
place of glutamic acid-1250 and a truncated protein.

.0014
BREAST-OVARIAN CANCER
BRCA1, 4-BP DEL, FS1252TER
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. They identified a 4-bp deletion at position
3875, leading to a premature termination codon at position 1252 and a
truncated protein.

.0015
BREAST-OVARIAN CANCER
BRCA1, 4-BP DEL, FS1364TER
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
Simard et al. (1994) studied 30 Canadian families with breast and/or
ovarian cancer for germline mutations in the coding region of the BRCA1
candidate gene. They both identified a 4-bp (TCAA) deletion in exon 11
at position 4184, leading to a premature termination codon at position
1364 and a truncated protein.

.0016
BREAST-OVARIAN CANCER
BRCA1, ARG1443TER
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. They identified a C-to-T substitution at
position 4446 of the BRCA1 gene, leading to a premature termination
codon in place of arginine-1443 and a truncated protein.

.0017
BREAST-OVARIAN CANCER
BRCA1, ARG1443GLY
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. They identified a C-to-G transition at
position 4446, changing arginine1443 to glycine.

.0018
BREAST-OVARIAN CANCER
BRCA1, 1-BP INS, FS1829TER
Simard et al. (1994) studied 30 Canadian families with breast and/or
ovarian cancer for germline mutations in the coding region of the BRCA1
candidate gene. They identified a 1-bp (C) insertion at position 5382 in
exon 20, changing the reading frame of the mRNA and causing a premature
termination codon at position 1829 in exon 24. This mutation was
detected in the index case of 4 Canadian families. In 1 of these
families, 10 cases of cancer appeared in a single large sibship,
including 3 cases of breast cancer, 2 ovarian cancers, 2 leukemias, 2
pancreatic cancers, and 1 prostate cancer. A case of leukemia and a case
of Hodgkin disease were seen in more recent generations. In the 4
families with the 5382insC mutation, there were 14 cases of breast
cancer and 5 cases of ovarian cancer.

.0019
BREAST-OVARIAN CANCER
BRCA1, TYR1853TER
Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian
cancer patients in 10 families with cancer linked to chromosome 17q21.
They identified a 1-bp (A) insertion in exon 24 of the BRCA1 gene at
position 5677, leading to a premature termination codon in place of
tyrosine-1853 and a truncated protein.

.0020
BREAST-OVARIAN CANCER
BRCA1, 19-BP DEL, FS1656TER
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. They identified a 19-bp deletion between
basepairs 5085 and 5103, leading to a termination codon at position 1656
and a truncated protein.

.0021
BREAST-OVARIAN CANCER
BRCA1, 1-BP INS, FS1773TER
Castilla et al. (1994) studied 50 probands with a family history of
breast and/or ovarian cancer for germline mutations in the coding region
of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at
nucleotide 5438, leading to a termination codon at position 1773 and a
truncated protein.

*FIELD* SA
Albertsen et al. (1994); Narod et al. (1991); Struewing et al. (1995)
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T.; Lynch, J.; Lenoir, G. M.: Familial breast-ovarian cancer locus
on chromosome 17q12-q23. Lancet 338: 82-83, 1991.

47. Neuhausen, S. L.; Mazoyer, S.; Friedman, L.; Stratton, M.; Offit,
K.; Caligo, A.; Tomlinson, G.; Cannon-Albright, L.; Bishop, T.; Kelsell,
D.; Solomon, E.; Weber, B.; Couch, F.; Struewing, J.; Tonin, P.; Durocher,
F.; Narod, S.; Skolnick, M. H.; Lenoir, G.; Serova, O.; Ponder, B.;
Stoppa-Lyonnet, D.; Easton, D.; King, M.-C.; Goldgar, D. E.: Haplotype
and phenotype analysis of six recurrent BRCA1 mutations in 61 families:
results of an international study. Am. J. Hum. Genet. 58: 271-280,
1996.

48. O'Connell, P.; Albertsen, H.; Matsunami, N.; Taylor, T.; Hundley,
J. E.; Johnson-Pais, T. L.; Reus, B.; Lawrence, E.; Ballard, L.; White,
R.; Leach, R. J.: A radiation hybrid map of the BRCA1 region. Am.
J. Hum. Genet. 54: 526-534, 1994.

49. Phelan, C. M.; Rebbeck, T. R.; Weber, B. L.; Devilee, P.; Ruttledge,
M. H.; Lynch, H. T.; Lenoir, G. M.; Stratton, M. R.; Easton, D. F.;
Ponder, B. A. J.; Cannon-Albright, L.; Larsson, C.; Goldgar, D. E.;
Narod, S. A.: Ovarian cancer risk in BRCA1 carriers is modified by
the HRAS1 variable number of tandem repeat (VNTR) locus. Nature Genet. 12:
309-311, 1996.

50. Piver, M. S.; Baker, T. R.; Jishi, M. F.; Sandecki, A. M.; Tsukada,
Y.; Natarajan, N.; Mettlin, C. J.; Blake, C. A.: Familial ovarian
cancer: a report of 658 families from the Gilda Radner Familial Ovarian
Cancer Registry 1981-1991. Cancer 71: 582-588, 1993.

51. Rebbeck, T. R.; Couch, F. J.; Kant, J.; Calzone, K.; DeShano,
M.; Peng, Y.; Chen, K.; Garber, J. E.; Weber, B. L.: Genetic heterogeneity
in hereditary breast cancer: role of BRCA1 and BRCA2. Am. J. Hum.
Genet. 59: 547-553, 1996.

52. Roa, B. B.; Boyd, A. A.; Volcik, K.; Richards, C. S.: Ashkenazi
Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nature
Genet. 14: 185-187, 1996.

53. Schrock, E.; Badger, P.; Larson, D.; Erdos, M.; Wynshaw-Boris,
A.; Ried, T.; Brody, L.: The murine homolog of the human breast and
ovarian cancer susceptibility gene Brca1 maps to mouse chromosome
11D. Hum. Genet. 97: 256-259, 1996.

54. Scully, R.; Ganesan, S.; Brown, M.; De Caprio, J. A.; Cannistra,
S. A.; Feunteun, J.; Schnitt, S.; Livingston, D. M.: Location of
BRCA1 in human breast and ovarian cancer cells. Science 272: 123-125,
1996.

55. Serova, O.; Montagna, M.; Torchard, D.; Narod, S. A.; Tonin, P.;
Sylla, B.; Lynch, H. T.; Feunteun, J.; Lenoir, G. M.: A high incidence
of BRCA1 mutations in 20 breast-ovarian cancer families. Am. J. Hum.
Genet. 58: 42-51, 1996.

56. Simard, J.; Feunteun, J.; Lenoir, G.; Tonin, P.; Normand, T.;
The, V. L.; Vivier, A.; Lasko, D.; Morgan, K.; Rouleau, G. A.; Lynch,
H.; Labrie, F.; Narod, S. A.: Genetic mapping of the breast-ovarian
cancer syndrome to a small interval on chromosome 17q12-21: exclusion
of candidate genes EDH17B2 and RARA. Hum. Molec. Genet. 2: 1193-1199,
1993.

57. Simard, J.; Tonin, P.; Durocher, F.; Morgan, K.; Rommens, J.;
Gingras, S.; Samson, C.; Leblanc, J.-F.; Belanger, C.; Dion, F.; Liu,
Q.; Skolnick, M.; Goldgar, D.; Shattuck-Eidens, D.; Labrie, F.; Narod,
S. A.: Common origins of BRCA1 mutations in Canadian breast and ovarian
cancer families. Nature Genet. 8: 392-398, 1994.

58. Skolnick, M. H.; Cannon-Albright, L. A.; Goldgar, D. E.; Ward,
J. H.; Marshall, C. J.; Schumann, G. B.; Hogle, H.; McWhorter, W.
P.; Wright, E. C.; Tran, T. D.; Bishop, D. T.; Kushner, J. P.; Eyre,
H. J.: Inheritance of proliferative breast disease in breast cancer
kindreds. Science 250: 1715-1720, 1990.

59. Smith, S. A.; Easton, D. F.; Evans, D. G. R.; Ponder, B. A. J.
: Allele losses in the region 17q12-21 in familial breast and ovarian
cancer involve the wild-type chromosome. Nature Genet. 2: 128-131,
1992.

60. Smith, T. M.; Lee, M. K.; Szabo, C. I.; Jerome, N.; McEuen, M.;
Taylor, M.; Hood, L.; King, M.-C.: Complete genomic sequence and
analysis of 117 kb of human DNA containing the gene BRCA1. Genome
Res. 6: 1029-1049, 1996.

61. Sobol, H.; Mazoyer, S.; Narod, S. A.; Smith, S. A.; Black, D.
M.; Kerbrat, P.; Jamot, B.; Solomon, E.; Ponder, B. A. J.; Guerin,
D.: Genetic heterogeneity of early-onset familial breast cancer. Hum.
Genet. 89: 381-383, 1992.

62. Steeg, P. S.: Granin expectations in breast cancer? Nature Genet. 12:
223-225, 1996.

63. Stoppa-Lyonnet, D.; Fricker, J. P.; Essioux, L.; Pages, S.; Limacher,
J. M.; Sobol, H.; Laurent-Puig, P.; Thomas, G.: Segregation of two
BRCA1 mutations in a single family. (Letter) Am. J. Hum. Genet. 59:
479-481, 1996.

64. Stratton, M. R.; Ford, D.; Neuhasen, S.; Seal, S.; Wooster, R.;
Friedman, L. S.; King, M.-C.; Egilsson, V.; Devilee, P.; McManus,
R.; Daly, P. A.; Smyth, E.; Ponder, B. A. J.; Peto, J.; Cannon-Albright,
L.; Easton, D. F.; Goldgar, D. E.: Familial male breast cancer is
not linked to the BRCA1 locus on chromosome 17q. Nature Genet. 7:
103-107, 1994.

65. Struewing, J. P.; Abeliovich, D.; Peretz, T.; Avishai, N.; Kaback,
M. M.; Collins, F. S.; Brody, L. C.: The carrier frequency of the
BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish
individuals. Nature Genet. 11: 198-200, 1995.

66. Struewing, J. P.; Brody, L. C.; Erdos, M. R.; Kase, R. G.; Giambarresi,
T. R.; Smith, S. A.; Collins, F. S.; Tucker, M.A.: Detection of eight
BRCA1 mutations in 10 breast/ovarian cancer families, including 1
family with male breast cancer. Am. J. Hum. Genet. 57: 1-7, 1995.

67. Thompson, M. E.; Jensen, R. A.; Obermiller, P. S.; Page, D. L.;
Holt, J. T.: Decreased expression of BRCA1 accelerates growth and
is often present during sporadic breast cancer progression. Nature
Genet. 9: 444-450, 1995.

68. Tonin, P.; Moslehi, R.; Green, R.; Rosen, B.; Cole, D.; Boyd,
N.; Cutler, C.; Margolese, R.; Carter, R.; McGillivray, B.; Ives,
E.; Labrie, F.; Gilchrist, D.; Morgan, K.; Simard, J.; Narod, S. A.
: Linkage analysis of 26 Canadian breast and breast-ovarian cancer
families. Hum. Genet. 95: 545-550, 1995.

69. Wu, L. C.; Wang, Z. W.; Tsan, J. T.; Spillman, M. A.; Phung, A.;
Xu, X. L.; Yang, M.-C. W.; Hwang, L.-Y.; Bowcock, A. M.; Baer, R.
: Identification of a RING protein that can interact in vivo with
the BRCA1 gene product. Nature Genet. 14: 430-440, 1996.

*FIELD* CS

Oncology:
   Breast cancer;
   Ovarian cancer;
   ? Increased risk of prostatic cancer

Misc:
   Younger age at diagnosis;
   Frequent bilateral disease;
   Frequent male breast cancer

Inheritance:
   Autosomal dominant (17q21)

*FIELD* CN
Victor A. McKusick - updated: 04/21/1997
Victor A. McKusick - updated: 4/15/1997
Victor A. McKusick - updated: 4/8/1997
Moyra Smith - updated: 3/3/1997
Moyra Smith - updated: 12/20/1996
Lori M. Kelman - updated: 11/8/1996
Moyra Smith - updated: 10/4/1996
Stylianos E. Antonarakis - updated: 7/15/1996

*FIELD* CD
Victor A. McKusick: 12/20/1990

*FIELD* ED
mark: 04/21/1997
jenny: 4/15/1997
terry: 4/9/1997
jenny: 4/8/1997
terry: 4/4/1997
mark: 3/3/1997
terry: 1/17/1997
mark: 12/20/1996
terry: 12/16/1996
terry: 11/20/1996
jamie: 11/20/1996
jamie: 11/8/1996
mark: 11/7/1996
mark: 10/24/1996
mark: 10/5/1996
mark: 10/4/1996
mark: 9/18/1996
mark: 9/10/1996
terry: 9/3/1996
terry: 8/22/1996
mark: 8/10/1996
terry: 8/9/1996
terry: 8/5/1996
carol: 7/15/1996
terry: 7/12/1996
mark: 4/27/1996
mark: 4/25/1996
terry: 4/22/1996
mark: 4/19/1996
terry: 4/15/1996
mark: 3/6/1996
terry: 3/4/1996
mark: 2/29/1996
terry: 2/26/1996
mark: 2/23/1996
terry: 2/19/1996
mark: 2/16/1996
mark: 2/13/1996
mark: 1/25/1996
terry: 1/23/1996
mark: 12/15/1995
terry: 12/13/1995
mark: 12/7/1995
terry: 12/7/1995
mark: 11/17/1995
terry: 11/16/1995
jason: 6/7/1994
mimadm: 4/12/1994
pfoster: 3/25/1994
warfield: 3/23/1994

*RECORD*
*FIELD* NO
113710
*FIELD* TI
*113710 TREFOIL FACTOR 1; TFF1
BREAST CANCER ESTROGEN-INDUCIBLE SEQUENCE; BCEI;;
GASTROINTESTINAL TREFOIL PROTEIN PS2; HPS2
*FIELD* TX
The BCEI gene, which codes for a small secreted protein and is expressed
only in human breast cancer, was cloned, sequenced, and assigned to
chromosome 21 (Cohen-Haguenauer et al., 1985; Moisan et al., 1985).
Furthermore, Moisan et al. (1985) showed by in situ hybridization that
the gene is located in the segment 21q22.3 (the critical segment in Down
syndrome) and demonstrated a RFLP with BamHI. Moisan et al. (1988) also
mapped the gene to chromosome 21 using a panel of somatic hybrid lines
and described a BstE2 RFLP. It will be of interest to use these
polymorphisms to investigate families with a high frequency of breast
cancer. Watkins et al. (1987) found that the BCEI gene is closely linked
to 2 DNA markers located at 21q22.3 (theta = 0.0 with high lod scores
for both).

In order to elucidate the function of the pS2 trefoil peptide which is
normally expressed in gastric mucosa and occurs in the epithelial cell
cytoplasm, Lefebvre et al. (1996) disrupted the mouse pS2 gene by
homologous recombination. They demonstrated that mpS2(+/+) mice and
mpS29(+/-) mice expressed high and intermediate levels of mpS2 protein
respectively, whereas the mpS(-/-) mice showed no detectable expression.
When interbred, the mpS2(-/-) mice were fertile and there was no
evidence of embryonic lethality. Histological examination of tissues
from mpS2(-/-) mice revealed that organs were normal except for the
stomach. In 3-week-old pups the antral and pyloric mucosa was thicker.
At 5 months, all examined mPS2(-/-) mice exhibited circumferential
adenoma encompassing the whole antropyloric mucosa. The epithelial cells
lining the surface and the elongated mucosal pits showed high grade
dysplasia. In 30% of 5 month old mpS2(-/-) mice 2 to 5 foci of carcinoma
were observed within the adenoma. Histological findings were
characteristic of intraepithelial and intramucosal carcinoma. Lefebvre
et al. (1996) reported that in the small intestine of mpS2(-/-) mice the
lamina propria (LP) was thickened and contained inflammatory cells.
Epithelial cells lining the intestinal villi were normal. The authors
suggested that the pS2 protein may exert a protective function and that
its absence may lead to intestine mucosal barrier defects accompanied by
a local lymphoproliferative response. Lefebvre et al. (1996) concluded
that since all mpS2(-/-) mice developed gastric adenoma but only 30%
developed gastric carcinoma the loss of pS2 protein may not be
sufficient for malignancy.They noted that about 50% of human gastric
carcinomas have lost expression of pS2, and that aberrant pS2
transcripts have been isolated from gastric carcinomas.

*FIELD* RF
1. Cohen-Haguenauer, O.; Van Cong, N.; Prud'homme, J. F.; Jegou-Foubert,
C.; Gross, M. S.; De Tand, M. F.; Milgrom, E.; Frezal, J.: A gene
expressed in human breast cancer and regulated by estrogen in MCF-7
cells is located on chromosome 21. (Abstract) Cytogenet. Cell Genet. 40:
606 only, 1985.

2. Lefebvre, O.; Chenard, M.-P.; Masson, R.; Linares, J.; Dierich,
A.; LeMeur, M.; Wendling, C.; Tomasetto, C.; Chambon, P.; Rio, M.-C.
: Gastric mucosa abnormalities and tumorigenesis in mice lacking the
pS2 trefoil protein. Science 274: 259-262, 1996.

3. Moisan, J.-P.; Mattei, M.-G.; Mandel, J.-L.: Chromosome localization
and polymorphism of an oestrogen-inducible gene specifically expressed
in some breast cancers. Hum. Genet. 79: 168-171, 1988.

4. Moisan, J. P.; Mattei, M. G.; Baeteman-Volkel, M. A.; Mattei, J.
F.; Brown, A. M. C.; Garnier, J. M.; Jeltsch, J. M.; Masiakowsky,
P.; Roberts, M.; Mandel, J. L.: A gene expressed in human mammary
tumor cells under estrogen control (BCEI) is located in 21q223 and
defines an RFLP. (Abstract) Cytogenet. Cell Genet. 40: 701-702,
1985.

5. Watkins, P. C.; Tanzi, R. E.; Roy, J.; Stuart, N.; Stanislovitis,
P.; Gusella, J. F.: A cosmid genetic linkage map of chromosome 21
and localization of the breast cancer estrogen-inducible (BCEI) gene.
(Abstract) Am. J. Hum. Genet. 41: A189 only, 1987.

*FIELD* CN
Moyra Smith  - updated: 10/10/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/14/1996
mark: 10/10/1996
supermim: 3/16/1992
carol: 2/26/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/22/1988
carol: 3/26/1988

*RECORD*
*FIELD* NO
113720
*FIELD* TI
*113720 BREAST CANCER-ASSOCIATED DF3 ANTIGEN
*FIELD* TX
Using the murine monoclonal antibody DF3 prepared against human breast
carcinoma, Kufe et al. (1984) showed that DF3 antigen levels are
elevated in the plasma of patients with breast cancer and that the
monoclonal antibody reacts with circulating glycoproteins of different
molecular weights ranging from approximately 300 to 450 kD. Hayes et al.
(1988) showed electrophoretic polymorphism of plasma DF3 antigen. DF3
antigen was demonstrated in the urine, where the electrophoretic
mobility of the protein moieties was similar but not identical to that
in plasma. Family studies suggested that the electrophoretic
heterogeneity of plasma DF3 antigen is determined by codominant
expression of multiple alleles at a single locus, which presumably codes
for the core protein of DF3 antigen. DF3 antigen is present also in
human milk. It is expressed on the surface of epithelial cells but is
absent from erythrocytes and granulocytes. See Becker et al. (1982) for
description of an antigen associated with transforming genes in human
and mouse breast cancer. Siddiqui et al. (1988) isolated and sequenced a
cDNA coding for human DF3.

*FIELD* RF
1. Becker, D.; Lane, M.-A.; Cooper, G. M.: Identification of an antigen
associated with transforming genes of human and mouse mammary carcinomas.
Proc. Nat. Acad. Sci. 79: 3315-3319, 1982.

2. Hayes, D. F.; Sekine, H.; Marcus, D.; Alper, C. A.; Kufe, D. W.
: Genetically determined polymorphism of the circulating human breast
cancer-associated DF3 antigen. Blood 71: 436-440, 1988.

3. Kufe, D.; Inghirami, G.; Abe, M.; Hayes, D.; Justi-Wheeler, H.;
Schlom, J.: Differential reactivity of a novel monoclonal antibody
(DF3) with human malignant versus benign breast tumors. Hybridoma 3:
223-232, 1984.

4. Siddiqui, J.; Abe, M.; Hayes, D.; Shani, E.; Yunis, E.; Kufe, D.
: Isolation and sequencing of a cDNA coding for the human DF3 breast
carcinoma-associated antigen. Proc. Nat. Acad. Sci. 85: 2320-2323,
1988.

*FIELD* CD
Victor A. McKusick: 3/26/1988

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 4/26/1988
carol: 3/26/1988

*RECORD*
*FIELD* NO
113721
*FIELD* TI
*113721 BREAST CANCER-RELATED REGULATOR OF TP53; BCPR
BREAST CANCER SUPPRESSOR
*FIELD* TX
Coles et al. (1990) demonstrated loss of constitutional heterozygosity
(LOH) at 17p13.3 in a large proportion of breast cancers. LOH was less
frequent in band 17p13.1, which contains the TP53 gene (191170). There
was no correlation between allele loss at the 2 sites on 17p.
Nevertheless, loss of heterozygosity at 17p13.3 was associated with
overexpression of p53 mRNA, suggesting to Coles et al. (1990) the
existence of a gene some 20 megabases telomeric of TP53 that regulates
its expression. Lesions of this regulatory gene seem to be involved in
most breast cancers (114480).

Stack et al. (1995) commented on the high frequency of LOH (50-75%) in
the 17p13.3 region distal to TP53 in sporadic breast cancer and also the
high frequency in a number of other malignancies including ovarian
cancer, astrocytomas, bladder cancer, medulloblastoma, neuroectodermal
cancer, and osteosarcoma. LOH was found to be independent of loss at the
TP53 gene locus situated some 20 Mb proximal. Stack et al. (1995)
investigated loss of heterozygosity in a panel of 40 sporadic breast
tumor patients using 8 polymorphic markers which they had ordered within
the 17p13.3 region by fluorescence in situ hybridization. Their findings
demonstrated a region of high loss (60%) within distal 17p13.3, defined
by markers D17S926, D17S695, and D17S849, which map close together. The
study presented further evidence for the existence of a breast cancer
suppressor locus distal to known genes within 17p13.3.

*FIELD* RF
1. Coles, C.; Thompson, A. M.; Elder, P. A.; Cohen, B. B.; Mackenzie,
I. M.; Cranston, G.; Chetty, U.; Mackay, J.; Macdonald, M.; Nakamura,
Y.; Hoyheim, B.; Steel, C. M.: Evidence implicating at least two
genes on chromosome 17p in breast carcinogenesis. Lancet 336: 761-763,
1990.

2. Stack, M.; Jones, D.; White, G.; Liscia, D. S.; Venesio, T.; Casey,
G.; Crichton, D.; Varley, J.; Mitchell, E.; Heighway, J.; Santibanez-Koref,
M.: Detailed mapping and loss of heterozygosity analysis suggests
a suppressor locus involved in sporadic breast cancer within a distal
region of chromosome band 17p13.3. Hum. Molec. Genet. 4: 2047-2055,
1995.

*FIELD* CD
Victor A. McKusick: 12/18/1990

*FIELD* ED
mark: 01/19/1996
terry: 1/17/1996
supermim: 3/16/1992
carol: 2/18/1992
carol: 12/18/1990

*RECORD*
*FIELD* NO
113725
*FIELD* TI
*113725 POU DOMAIN, CLASS 4, TRANSCRIPTION FACTOR 2; POU4F2
BRN3B POU-DOMAIN TRANSCRIPTION FACTOR; BRN3B
*FIELD* TX
BRN3B (POU4F2) is a member of the POU-domain family of transcription
factors. POU-domain proteins have been observed to play important roles
in control of cell identity in several systems. See also POU4F1
(601632). A class IV POU-domain protein, BRN3B is found in human retina
exclusively within a subpopulation of ganglion cells where it may play a
role in determining or maintaining the identities of a small subset of
visual system neurons. Xiang et al. (1993) used an 800-bp cDNA insert
for Southern blot analysis of a panel of 31 HindIII-digested DNAs from
human-mouse somatic cell hybrids. The BRN3B gene segregated concordantly
with chromosome 4. Xiang et al. (1993) mapped the BRN3B gene to 4q31.2
by fluorescence in situ hybridization.

*FIELD* RF
1. Xiang, M.; Zhou, L.-J.; Peng, Y.-W.; Byers, M. G.; Eddy, R. L.;
Shows, T. B.; Nathans, J.: The gene for Brn-3b: a POU-domain protein
expressed in retinal ganglion cells is assigned to the q31.2 region
of chromosome 4. (Abstract) Human Genome Mapping Workshop 93 7 only,
1993.

*FIELD* CD
Victor A. McKusick: 12/2/1993

*FIELD* ED
jamie: 01/16/1997
jamie: 1/16/1997
carol: 12/2/1993

*RECORD*
*FIELD* NO
113730
*FIELD* TI
*113730 UNCOUPLING PROTEIN; UCP
UCP1;;
BROWN ADIPOSE TISSUE UNCOUPLING PROTEIN;;
THERMOGENIN
*FIELD* TX
The uncoupling protein (UCP) of mitochondria in brown adipose tissue is
a specific component unique to mammalian cells. Complementary DNAs for
rat and mouse UCP were isolated in several laboratories (Jacobson et
al., 1985; Bouillaud et al., 1986; Ridley et al., 1986). The cDNAs have
been used to determine the sequence of rat UCP and to monitor changes in
UCP mRNA levels under various physiologic, pathologic, and pharmacologic
circumstances. A controversy exists concerning the physiologic
significance of brown adipose tissue in humans and its possible
contribution to resistance to obesity (see 601665). There is, however, a
large amount of evidence that this tissue is present in young infants
and also in human adults in certain pathologic and nonpathologic
situations.

Bouillaud et al. (1988) screened a human genomic library with a cDNA
corresponding to the UCP of rat brown adipose tissue mitochondria. They
succeeded in cloning a 0.5-kb fragment containing 2 intronic regions and
2 exonic regions. Exonic regions encoded a sequence of 84 amino acids
with a strong homology to the central domain of rat UCP. Southern
analysis experiments suggested that there is 1 copy of the gene in the
human, as there is in rodents. In Northern analysis experiments, the
probe detected a specific 1.8-kb mRNA in human brown adipose tissue
obtained from 6 patients with pheochromocytoma and from 1 patient with a
hibernoma.

Fletcher et al. (1991) mapped the Ucp gene to mouse chromosome 8 in a
location between a segment that carries genes homologous to genes on
human 8p, on the centromeric side, and a segment that carries genes
homologous to human genes on 16q, in the telomeric direction. Thus, the
human homolog of Ucp is probably on either 8p or 16q. Cassard et al.
(1990) found that the human UCP gene spans 13 kb and contains a
transcribed region that covers 9 kb. It has 6 exons. The uncoupling
protein has 305 amino acids and a molecular weight of 32,786. Using in
situ hybridization, Cassard et al. (1990) assigned the human UCP gene to
4q31. They found that the primary structure of UCP is similar to that of
ADP/ATP translocator of skeletal muscle (103220), the gene for which is
also located on chromosome 4. Thus, the prediction from homology to the
mouse did not hold up.

Brown adipose tissue, because of its capacity for uncoupled
mitochondrial respiration, is an important site of facultative energy
expenditure. It has been speculated that this tissue normally functions
to prevent obesity. Surgical efforts to ablate or denervate the brown
adipose tissue have been unsuccessful because of the diffuse deposits
and substantial capacity for regeneration and hypertrophy. Lowell et al.
(1993) used a transgenic toxigene approach to create 2 lines of
transgenic mice with primary deficiency of brown adipose tissue. In
constructing these transgenic mice, Lowell et al. (1993) used the
regulatory elements of the gene for uncoupling protein to drive
expression of the diphtheria toxin A chain (UCP-DTA) or an attenuated
mutant. At 16 days, both lines had deficient brown fat and obesity. In
one line, brown fat subsequently regenerated and obesity resolved. In
the other line, the deficiency persisted and obesity, with its morbid
complications, advanced. Obesity developed in the absence of
hyperphagia, indicating that brown fat deficient mice have increased
metabolic efficiency. As obesity progressed, transgenic animals
developed hyperphagia. See also UCP2 (601693).

Uncoupling protein is a mitochondrial proton channel that is not coupled
to oxidative phosphorylation. Therefore, when a proton gradient is
established across the inner mitochondrial membrane, activation of the
uncoupling protein leads to the uncoupled passage of protons through the
channel and the generation of heat. Expression and activation of
uncoupling proteins is usually mediated by the sympathetic nervous
system and is directly controlled by norepinephrine. This mechanism is
part of the adaptive response to cold temperatures. It also regulates
energy balance. Manipulation of thermogenesis could be an effective
strategy against obesity (Lowell et al., 1993). Enerbeck et al. (1997)
determined the role of UCP in the regulation of body mass by targeted
inactivation of the UCP gene in mice. They found that UCP-deficient mice
consumed less oxygen after treatment with a beta-3-adrenergic receptor
agonist and that they were sensitive to cold, indicating that
thermoregulation was defective. However, this deficiency caused neither
hyperphagia nor obesity in mice fed on either a standard or a high-fat
diet. Enerbeck et al. (1997) proposed that the loss of UCP may be
compensated by UCP2, a homolog of UCP that is ubiquitously expressed and
is induced in the brown fat of UCP-deficient mice.

Adrenaline and noradrenaline, the main effectors of the sympathetic
nervous system and adrenal medulla, respectively, are thought to control
adiposity and energy balance through several mechanisms. They promote
catabolism of triglycerides and glycogen, stimulate food intake when
injected into the central nervous system, activate thermogenesis in
brown adipose tissue, and regulate heat loss through modulation of
peripheral vasoconstriction and piloerection. Thermogenesis in brown
adipose occurs in response to cold and overeating, and there is an
inverse relationship between diet-induced thermogenesis and obesity both
in humans and animal models. As a potential model for obesity, Thomas
and Palmiter (1997) generated mice that could not synthesize
noradrenaline or adrenaline by inactivating the gene that encodes
dopamine beta-hydroxylase (DBH; 223360). These mice were cold intolerant
because they had impaired peripheral vasoconstriction and were unable to
induce thermogenesis in brown adipose tissue through uncoupling protein
(UCP1). The mutants had increased food intake but did not become obese
because their basal metabolic rate (BMR) was also elevated. The
unexpected increase in BMR was not due to hyperthyroidism, compensation
by the widely expressed UCP2, or shivering.

*FIELD* RF
1. Bouillaud, F.; Villarroya, F.; Hentz, E.; Raimbault, S.; Cassard,
A.-M.; Ricquier, D.: Detection of brown adipose tissue uncoupling
protein mRNA in adult patients by a human genomic probe. Clin. Sci. 75:
21-27, 1988.

2. Bouillaud, F.; Weissenbach, J.; Ricquier, D.: Complete cDNA-derived
amino acid sequence of rat brown fat uncoupling protein. J. Biol.
Chem. 261: 1487-1491, 1986.

3. Cassard, A. M.; Bouillaud, F.; Mattei, M. G.; Hentz, E.; Raimbault,
S.; Thomas, M.; Ricquier, D.: Human uncoupling protein gene: structure,
comparison with rat gene, and assignment to the long arm of chromosome
4. J. Cell. Biochem. 43: 255-264, 1990.

4. Enerbeck, S.; Jacobsson, A.; Simpson, E. M.; Guerra, C.; Yamashita,
H.; Harper, M.-E.; Kozak, L. P.: Mice lacking mitochondrial uncoupling
protein are cold-sensitive but not obese. Nature 387: 90-93, 1997.

5. Fletcher, C.; Norman, D. J.; Germond, E.; Heintz, N.: A multilocus
linkage map of mouse chromosome 8. Genomics 9: 737-741, 1991.

6. Jacobson, A.; Stadler, U.; Glotzer, M. A.; Kozak, L. P.: Mitochondrial
uncoupling protein from mouse brown fat: molecular cloning, genetic
mapping and mRNA expression. J. Biol. Chem. 260: 16250-16254, 1985.

7. Lowell, B. B.; S-Susulic, V.; Hamann, A.; Lawitts, J. A.; Himms-Hagen,
J.; Boyer, B. B.; Kozak, L. P.; Flier, J. S.: Development of obesity
in transgenic mice after genetic ablation of brown adipose tissue. Nature 366:
740-742, 1993.

8. Ridley, R. G.; Patel, H. V.; Gerber, G. E.; Morton, R. C.; Freeman,
K. B.: Complete nucleotide and derived amino acid sequence of cDNA
encoding the mitochondrial uncoupling protein of rat brown adipose
tissue: lack of mitochondrial targeting presequence. Nucleic Acids
Res. 14: 4025-4035, 1986.

9. Thomas, S. A.; Palmiter, R. D.: Thermoregulatory and metabolic
phenotypes of mice lacking noradrenaline and adrenaline. Nature 387:
94-97, 1997.

*FIELD* CN
Victor A. McKusick - updated: 05/02/1997

*FIELD* CD
Victor A. McKusick: 2/28/1988

*FIELD* ED
mark: 05/02/1997
terry: 5/2/1997
mark: 3/2/1997
terry: 2/28/1997
carol: 1/28/1994
supermim: 3/16/1992
carol: 9/24/1991
carol: 3/22/1991
carol: 3/20/1991
carol: 2/13/1991

*RECORD*
*FIELD* NO
113750
*FIELD* TI
*113750 BROWN HAIR COLOR; HCL1; BRHC
*FIELD* TX
Eiberg and Mohr (1987) found a lod score of 5.06 for linkage of green
eye color (GEY; 227240) to brown hair color (BRHC). Of interest is the
fact that 6 loci on chromosome 19 in man have their homologs on
chromosome 7 in the mouse. Chromosome 7 carries at least 3 'pigment
loci,' namely, ruby-2 (ru-2), pink-eyed dilution (p), and albino (c).

*FIELD* RF
1. Eiberg, H.; Mohr, J.: Major genes of eye color and hair color
linked to LU and SE. Clin. Genet. 31: 186-191, 1987.

*FIELD* CS

Hair:
   Brown hair color

Inheritance:
   Autosomal dominant (? Chrom 19)

*FIELD* CD
Victor A. McKusick: 4/15/1987

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 2/13/1989
root: 1/19/1989

*RECORD*
*FIELD* NO
113800
*FIELD* TI
#113800 BULLOUS ERYTHRODERMA ICHTHYOSIFORMIS CONGENITA OF BROCQ
BULLOUS ICHTHYOSIFORM ERYTHRODERMA; BIE;;
EPIDERMOLYTIC HYPERKERATOSIS; EHK
*FIELD* TX
A number sign (#) is used with this entry inasmuch as point mutations in
keratin genes (KRT1, 139350; KRT10, 148080) have been identified in this
disorder.

Heimendinger and Schnyder (1962) described this disorder in a man and 2
of his 3 children, a son and a daughter. The condition is distinct from
the nonbullous form inherited as a recessive (242100). Among 17 families
with 2 or more affected persons, Gasser (1964) found only sibs affected
in 2 families, 2 successive generations affected in 12, and 3
generations affected in 3. Goldsmith (1976) used the designation of
epidermolytic hyperkeratosis for the condition that is called bullous
congenital ichthyosiform erythroderma when generalized, and ichthyosis
hystrix (146600) when localized. They are presumably distinct entities.

Tonofibrils are fibrillar structural proteins in keratinocytes. They are
the morphologic equivalent of the biochemically well-characterized
prekeratin and precursors of the alpha-keratin of horn cells. Four
genetic disorders of keratinization are known to have a structural
defect of tonofibrils (Anton-Lamprecht, 1978): 1) In the harlequin
fetus, an abnormal x-ray diffraction pattern of the horn material points
to a cross-beta-protein structure instead of the normal alpha-protein
structure of keratin. 2) Bullous ichthyosiform erythroderma is
characterized by an early formation of clumps and perinuclear shells due
to an abnormal arrangement of tonofibrils. 3) In the Curth-Macklin form
of ichthyosis hystrix, concentric unbroken shells of abnormal
tonofilaments form around the nucleus. 4) In ichthyosis hystrix gravior
(146600) only rudimentary tonofilaments are found with compensatory
production of mucous granules.

Ninety-four percent of patients with bullous ichthyosiform erythroderma
present with skin lesions before the first birthday and 71% have lesions
at birth. There is notable perinatal mortality and childhood morbidity
from epidermal erosions and infections. A positive family history is
obtained in about half of cases. We have observed affected brother and
sister with normal parents. Golbus et al. (1980) achieved prenatal
diagnosis by fetal skin biopsy through the amnioscope. See also
Anton-Lamprecht (1981). Eady et al. (1986) achieved prenatal diagnosis
of BIE at 20 weeks' gestation by electron microscopic identification of
the characteristic aggregates of tonofilaments within skin-derived
amniocytes and in fetal skin. The mother was affected, an earlier born
child was severely affected and died at 6 days of age with generalized
candidiasis, and the fetus diagnosed as affected was aborted at 21
weeks. Generalized redness and blistering are usually manifest at birth.
The hyperkeratosis, which is the most troublesome feature throughout
life, begins later. The variation in the height of the scale along
normal skin markings produces a ridgelike appearance, particularly in
the bends of the elbows and knees, that has led to the designation
'porcupine man' (146600). The rate of new cell formation is abnormally
high; keratinocytes traverse the epidermis from the basal layer to the
stratum corneum in as little as 4 days, a journey that takes 2 weeks in
normal skin. Several kindreds have been reported in which the first
affected member, presumably a mosaic for the new mutation, had linear or
patchy lesions and produced children with generalized bullous
ichthyosiform erythroderma (Epstein, 1992). The changes in the
suprabasal keratinocytes in BIE resemble those in the basal
keratinocytes in epidermolysis bullosa simplex (131760) in which keratin
mutations have been identified (e.g., 148066.0001). In both diseases,
the intermediate filament (IF) aggregates contain the keratins normally
present in the particular cells: keratins 5 and 14 in the basal cells of
Dowling-Meara EBS and keratins 1 and 10 in the suprabasal cells of BIE.
This fact prompted Epstein (1992) and his colleagues to use linkage
analysis to test whether keratin gene mutations might also underlie BIE.
Bonifas et al. (1992) indeed found that the BIE phenotype was linked to
markers in the 12q region containing genes encoding type II keratins.
Expression of a modified truncated human keratin 10 gene (K10; 148080)
in transgenic mice gives rise to skin with the morphologic and
biochemical characteristics of epidermolytic hyperkeratosis. As in K5
and K14 mutations that give rise to epidermolysis bullosa, mutant K10
interferes with proper filament network formation and leads to cell
degeneration, but in this case the phenotype is manifested in the
suprabasal layers of the epidermis. As epidermal cells differentiate, K1
and K10 protein levels increase, and K14 and K5 protein levels decrease.
Therefore, as differentiation proceeds, an increasing gradient of
mutant/wildtype keratin is established, yielding epidermal layers with
progressively greater levels of filament disorganization and cell
degeneration. Compton et al. (1992) demonstrated complete linkage of
epidermolytic hyperkeratosis with the K1 gene on 12q11-q13.

Letai et al. (1993) reported that clinical severity of EHK and EBS is
related to the location of point mutations within the keratin
polypeptides and the degree to which these mutations perturb keratin IF
structure. Point mutations in the most severe forms have been clustered
in the highly conserved ends of the K5 or K14 rod domains in EBS (e.g.,
148066.0002) and in the corresponding regions of the K10 and K1 rod in
EHK (e.g., 148080.0003). Mutations in milder cases have been found in
less-conserved regions, either within or outside the rod domain. Of 11
known EBS or EHK mutations, 6 affected a single, highly evolutionarily
conserved arginine residue which, when mutated, markedly disturbs
keratin filament structure and network formation. The site also appeared
to be a hot spot for mutation by CpG methylation and deamination. Letai
et al. (1993) suggested that arg156 of K10 and arg125 of K14 must play a
special role in maintaining keratin network integrity.

*FIELD* SA
Barker and Sachs (1953); Bonifas et al. (1992)
*FIELD* RF
1. Anton-Lamprecht, I.: Electron microscopy in the early diagnosis
of genetic disorders of the skin. Dermatologica 157: 65-85, 1978.

2. Anton-Lamprecht, I.: Prenatal diagnosis of genetic disorders of
the skin by means of electron microscopy. Hum. Genet. 59: 392-405,
1981.

3. Barker, L. P.; Sachs, W.: Bullous congenital ichthyosiform erythrodermia.
Arch. Derm. 67: 443-455, 1953.

4. Bonifas, J. M.; Bare, J. W.; Chen, M. A.; Lee, M. K.; Slater, C.
A.; Goldsmith, L. A.; Epstein, E. H., Jr.: Linkage of the epidermolytic
hyperkeratosis phenotype and the region of the type II keratin gene
cluster on chromosome 12. J. Invest. Derm. 99: 524-527, 1992.

5. Bonifas, J. M.; Bare, W.; Chen, M. A.; Niemi, K. M.; Epstein, E.
H., Jr.: Epidermolytic hyperkeratosis: linkage to keratin gene regions
on chromosomes 12q and 17q in two families. J. Invest. Derm. 98:
573 only, 1992.

6. Compton, J. G.; DiGiovanna, J. J.; Santucci, S. K.; Kearns, K.
S.; Amos, C. I.; Abangan, D. L.; Korge, B. P.; McBride, O. W.; Steinert,
P. M.; Bale, S. J.: Linkage of epidermolytic hyperkeratosis to the
type II keratin gene cluster on chromosome 12q. Nature Genet. 1:
301-305, 1992.

7. Eady, R. A. J.; Gunner, D. B.; Carbone, L. D. L.; Dagna Bricarelli,
F.; Gosden, C. M.; Rodeck, C. H.: Prenatal diagnosis of bullous ichthyosiform
erythroderma: detection of tonofilament clumps in fetal epidermal
and amniotic fluid cells. J. Med. Genet. 23: 46-51, 1986.

8. Epstein, E. H., Jr.: Personal Communication. San Francisco, Calif.
5/29/1992.

9. Gasser, V.: Zur Klinik, Histologie und Genetik der 'Erythrodermie
congenitale ichthyosiforme bulleuse (Brocq.)'. Arch. Klaus Stift.
Vererbungsforsch. 38: 23-59, 1964.

10. Golbus, M. S.; Sagebiel, R. W.; Filly, R. A.; Gindhart, T. D.;
Hall, J. G.: Prenatal diagnosis of congenital bullous ichthyosiform
erythroderma (epidermolytic hyperkeratosis) by fetal skin biopsy.
New Eng. J. Med. 302: 93-95, 1980.

11. Goldsmith, L. A.: The ichthyoses. Prog. Med. Genet. 1: 185-210,
1976.

12. Heimendinger, J.; Schnyder, U. W.: Bullose 'Erythrodermie ichthyosiforme
congenitale' in zwei Generationen. Helv. Paediat. Acta 17: 47-55,
1962.

13. Letai, A.; Coulombe, P. A.; McCormick, M. B.; Yu, Q.-C.; Hutton,
E.; Fuchs, E.: Disease severity correlates with position of keratin
point mutations in patients with epidermolysis bullosa simplex. Proc.
Nat. Acad. Sci. 90: 3197-3201, 1993.

*FIELD* CS

Skin:
   Epidermolytic hyperkeratosis;
   Bullous erythroderma ichthyosiformis

Lab:
   Abnormal arrangement of tonofibrils

Inheritance:
   Autosomal dominant (12q11-q13)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/14/1994
carol: 4/12/1994
warfield: 4/7/1994
carol: 12/14/1993
carol: 5/21/1993
carol: 12/23/1992

*RECORD*
*FIELD* NO
113810
*FIELD* TI
*113810 BULLOUS PEMPHIGOID ANTIGEN-1; BPAG1
BP240
*FIELD* TX
One of the components of the basement membrane zone of the skin is a
230- to 240-kD glycoprotein that serves as an autoantigen in the
blistering disease bullous pemphigoid. Stanley et al. (1988) isolated a
2.2-kb cDNA coding for the carboxyl-terminal region of the bullous
pemphigoid antigen by immunoscreening a human epidermal keratinocyte
cDNA library. Tamai et al. (1993) showed that the BPAG1 gene has a
coding sequence of approximately 9 kb and consists of 22 exons varying
in size from 78 to 2,810 bp. The 5-prime region, upstream from the ATG
translation initiation codon, was found to contain several putative
transcriptional response elements. They detected 2 motifs potentially
conferring keratinocyte-specific expression to the gene. The presence of
such elements was suggested by an approximately 20-fold higher
expression of a promoter/chloramphenicol acetyltransferase (CAT)
construct in normal human epidermal keratinocytes that expressed the
endogenous gene, as compared to several nonexpressing cell types.
Transient transfections with 5-prime deletion clones of the
promoter/reporter gene constructs identified a region containing a
putative tissue-specific element, KRE2, which also conferred tissue
specificity to the expression of the truncated promoter downstream from
this element; however, a mutated derivative of KRE2 was not functional.

Sawamura et al. (1990) isolated cDNAs coding for a human BPAG1 and used
them for chromosomal in situ hybridization. They concluded that the gene
is located in the region 6p12-p11. The assignment was supported by
Southern analysis of hybrid cell DNAs. Minoshima et al. (1991) likewise
assigned the BPAG1 gene to 6p using spot-blot hybridization of
flow-sorted chromosomes. Minoshima et al. (1991) also studied cells
carrying a reciprocal translocation t(6;16)(q15;q24) which permitted
localization of the BPAG1 gene to 6pter-q15. Copeland et al. (1993)
demonstrated that the homologous murine gene, Bpag1, is located in the
proximal region of chromosome 1, thus identifying a new region of
homology between human chromosome 6 and mouse chromosome 1.

Ryynanen et al. (1991) identified RFLPs of both BPAG1 and BPAG2 (113811)
and used them for linkage studies in a large kindred with epidermolysis
bullosa simplex of the generalized, or Koebner, type (EBS; 131900).
Linkage analysis excluded the EBS locus in this pedigree approximately 9
cM and 5 cM on either side of the BPAG1 and BPAG2 loci, respectively,
with a lod score of -2.0. Thus, these genes were excluded as the primary
genetic defect in this family.

BPAG1 is made by stratified squamous epithelia, where it localizes to
the inner surface of specialized integrin-mediated adherens junctions
(hemidesmosomes). Guo et al. (1995) explored the function of BPAG1 and
its relationship to bullous pemphigoid by targeting the knockout of the
Bpag1 gene in mice. Hemidesmosomes were otherwise normal but they lacked
the inner plate and had no cytoskeleton attached. Though not affecting
cell growth or adhesion to substrate, this change compromised mechanical
integrity and influenced migration. Unexpectedly, the mice also
developed severe dystonia and sensory nerve degeneration typical of
homozygous dystonia musculorum (dt/dt) mice. Guo et al. (1995) showed
that the Bpag1 gene is defective in at least one strain of mice with
spontaneous homozygous dystonia musculorum. As indicated elsewhere, a
human homolog of the dystonia musculorum gene (600088) has been mapped
to 6p12, the same region as the BPAG1 gene. The dt/dt locus is on mouse
chromosome 1 in the same region as the Bpag1 locus. Guo et al. (1995)
discussed the evidence that they may one and the same. Brown et al.
(1995) cloned a candidate dt gene, called dystonin, that is
predominantly expressed in the dorsal root ganglia and other sites of
neurodegeneration in dt mice. They showed that the dystonin gene encodes
an N-terminal actin-binding domain and a C-terminal portion comprised of
the bullous pemphigoid antigen 1 protein; dt and bpag1 are part of the
same transcription unit which is partially deleted in a transgenic
strain of mice that harbors an insertional mutation at the dt locus and
in mice that carry a spontaneous dt mutation. They also demonstrated
abnormal dystonin transcripts in a second dt mutant. Thus, they
concluded that mutations in the dystonin gene are the primary genetic
lesion in dt mice.

In mice, dystonin cDNAs occur as at least 2 neural isoforms generated by
alternative splicing of exons at the 5-prime end of the gene. These
cDNAs contain N-terminal domains with significant sequence similarity to
the actin binding motifs of dystrophin (310200), alpha-actinin (102575
and 102573) and beta-spectrin (182870). Brown et al. (1995) proposed
that mutations in dystonin lead to neurodegeneration due to disruption
of actin or neurofilament networks. Brown et al. (1995) cloned the
5-prime neural-specific exons of the human dystonin-1 and dystonin-2
isoforms and showed that the predicted proteins are 98 and 96%
identical, respectively, to their mouse homologs.

*FIELD* SA
Brown et al. (1995); Diaz et al. (1990); Minoshima et al. (1991)
*FIELD* RF
1. Brown, A.; Bernier, G.; Mathieu, M.; Rossant, J.; Kothary, R.:
The mouse dystonia musculorum gene is a neural isoform of bullous
pemphigoid antigen 1. Nature Genet. 10: 301-306, 1995.

2. Brown, A.; Dalpe, G.; Mathieu, M.; Kothary, R.: Cloning and characterization
of the neural isoforms of human dystonin. Genomics 29: 777-780,
1995.

3. Copeland, N. G.; Gilbert, D. J.; Li, K.; Sawamura, D.; Giudice,
G. J.; Chu, M.-L.; Jenkins, N. A.; Uitto, J.: Chromosomal localization
of mouse bullous pemphigoid antigens, BPAG1 and BPAG2: identification
of a new region of homology between mouse and human chromosomes. Genomics 15:
180-181, 1993.

4. Diaz, L. A.; Ratrie, H., III; Saunders, W. S.; Futamura, S.; Squiquera,
H. L.; Anhalt, G. J.; Giudice, G. J.: Isolation of a human epidermal
cDNA corresponding to the 180-kD autoantigen recognized by bullous
pemphigoid and herpes gestationis sera: immunolocalization of this
protein to the hemidesmosome. J. Clin. Invest. 86: 1088-1094, 1990.

5. Guo, L.; Degenstein, L.; Dowling, J.; Yu, Q.-C.; Wollmann, R.;
Perman, B.; Fuchs, E.: Gene targeting of BPAG1: abnormalities in
mechanical strength and cell migration in stratified epithelia and
neurologic degeneration. Cell 81: 233-243, 1995.

6. Minoshima, S.; Amagai, M.; Kudoh, J.; Fukuyama, R.; Hashimoto,
T.; Nishikawa, T.; Shimizu, N.: Localization of the human gene for
230-kDa bullous pemphigoid autoantigen to the pter-q15 region of chromosome
6.   (Abstract) Cytogenet. Cell Genet. 58: 1914-1915, 1991.

7. Minoshima, S.; Amagai, M.; Kudoh, J.; Fukuyama, R.; Hashimoto,
T.; Nishikawa, T.; Shimizu, N.: Localization of the human gene for
230-kDal bullous pemphigoid autoantigen (BPAG1) to chromosome 6pter-q15.
Cytogenet. Cell Genet. 57: 30-32, 1991.

8. Ryynanen, M.; Knowlton, R. G.; Kero, M.; Sawamura, D.; Li, K.;
Giudice, G. J.; Diaz, L. A.; Uitto, J.: Bullous pemphigoid antigens
(BPAGs): identification of RFLPs in human BPAG1 and BPAG2, and exclusion
as candidate genes in a large kindred with dominant epidermolysis
bullosa simplex. Genomics 11: 1025-1029, 1991.

9. Sawamura, D.; Nomura, K.; Sugita, Y.; Mattei, M.-G.; Chu, M.-L.;
Knowlton, R.; Uitto, J.: Bullous pemphigoid antigen (BPAG1): cDNA
cloning and mapping of the gene to the short arm of human chromosome
6. Genomics 8: 722-726, 1990.

10. Stanley, J. R.; Tanaka, T.; Mueller, S.; Klaus-Kovtun, V.; Roop,
D.: Isolation of complementary DNA for bullous pemphigoid antigen
by use of patients' autoantibodies. J. Clin. Invest. 82: 1864-1870,
1988.

11. Tamai, K.; Sawamura, D.; Do, H. C.; Tamai, Y.; Li, K.; Uitto,
J.: The human 230-kD bullous pemphigoid antigen gene (BPAG1): exon-intron
organization and identification of regulatory tissue specific elements
in the promoter region. J. Clin. Invest. 92: 814-822, 1993.

*FIELD* CN
Alan F. Scott - updated: 11/8/1995

*FIELD* CD
Victor A. McKusick: 8/23/1990

*FIELD* ED
mark: 05/30/1996
mark: 5/29/1996
terry: 4/17/1996
mark: 3/7/1996
mark: 7/2/1995
carol: 9/16/1993
carol: 3/11/1993
supermim: 3/16/1992
carol: 2/21/1992

*RECORD*
*FIELD* NO
113811
*FIELD* TI
*113811 COLLAGEN, TYPE XVII, ALPHA-1 POLYPEPTIDE; COL17A1
BULLOUS PEMPHIGOID ANTIGEN-2; BPAG2;;
BP180
*FIELD* TX
Autoantibodies present in the sera of patients with bullous pemphigoid
(BP) bind to the basement membrane zone. In addition to recognizing the
240-kD basement membrane protein (113810), they recognize a 180-kD
protein in about 50% of all BP sera and in most sera from patients with
herpes gestationis. Diaz et al. (1990) isolated a cDNA for the 180-kD
autoantigen and showed by Northern blot analysis that the BP180 and
BP240 antigens are encoded by distinct RNA transcripts with lengths of
6.0 and 8.5 kb, respectively. They demonstrated by immunoelectron
microscopy that, like the BP240 antigen, the BP180 antigen is located on
the hemidesmosome. The BPAG2 gene was mapped to 10q24.3 (Sawamura et
al., 1991; Li et al., 1991) by in situ hybridization. Copeland et al.
(1993) demonstrated that the homologous murine gene, Bpag-2, is located
on the distal end of chromosome 19 in a region of homology to human
chromosome 10q.

Li et al. (1991) found that the cDNA encoding BPAG2 predicts an amino
acid sequence with 2 collagenous domains characterized by Gly-X-Y
repeats. The gene was found to span approximately 12 kb of genomic DNA.
The coding segment consisted of 19 exons varying in size from 27 to 222
basepairs. The organization of these exons and the splice sites at the
intron-exon junctions were clearly different from other fibrillar and
nonfibrillar collagen genes previously described. The findings suggested
that BPAG2 is a novel collagen present in stratified squamous epithelia.

Sawamura et al. (1992) reviewed data unequivocally demonstrating that
BPAG1 and BPAG2 are distinct gene products without structural homology.

Generalized atrophic benign epidermolysis bullosa (GABEB; 226650) is a
form of nonlethal junctional EB characterized by universal alopecia and
atrophy of the skin. Jonkman et al. (1995) found that the BP180 antigen
is deficient and the BPAG2 mRNA is reduced in this disorder, suggesting
that the BPAG2 gene is the site of the mutation. This was established to
be the case by McGrath et al. (1995) who demonstrated a mutation in the
BPAG2 gene in this disorder. In a series of 18 patients with nonlethal
junctional epidermolysis bullosa from unrelated families studied by
Jonkman et al. (1996), 9 presented with the clinical characteristics of
GABEB. From immunofluorescence studies with monoclonal antibodies to
BP180 and laminin-5, they concluded that the defect was in BP180 in 8
patients and laminin-5 (150310) in 1. Both BP180 and laminin-5 antigens
were normally expressed in the other 9 patients.

The work of Li et al. (1993) indicated that the 180-kD bullous
pemphigoid antigen is a transmembranous hemidesmosomal collagen which
has been designated type XVII collagen (COL17A1).

Gatalica et al. (1997) cloned the entire human COL17A1 gene and
elucidated its intron/exon organization. They demonstrated that the gene
comprises 56 distinct exons, which span approximately 52 kb of the
genome. The alpha-1 (XVII) chain consists of an intracellular globular
domain, a transmembrane segment, and an extracellular domain that
contains 15 separate collagenous subdomains, the largest consisting of
242 amino acids. Gatalica et al. (1997) described novel mutations
(113811.0003 and 113811.0004) in the COL17A1 gene in the disorder they
referred to as generalized atrophic benign epidermolysis bullosa and
defined as a nonlethal variant of junctional epidermolysis bullosa.

Jonkman et al. (1995, 1996) observed a mosaic pattern of immunoreactive
type XVII collagen in clusters of basal cells in patches of clinically
unaffected skin in a Dutch GABEB patient, in whom the remainder of the
skin demonstrated characteristic blistering from mechanical trauma.
Jonkman et al. (1997) demonstrated that the mosaic phenotype in this
compound heterozygote patient was caused by reversion of one of the
mutations in the COL17A1 gene. They also demonstrated that the reverse
mutation was the result of the nonreciprocal transfer of a part of 1
parental allele for the other by a mitotic gene conversion mechanism.
The maternal allele, carrying a 1706delA mutation (113811.0005), showed
reversion of the mutation and loss of heterozygosity (LOH) along a tract
of at least 381 bp in revertant keratinocytes derived from clinically
unaffected skin patches. The paternal mutation, R1226X (113811.0001),
remained present in all cell samples. Jonkman et al. (1997) stated that
the natural gene therapy reported here has implications for the design
of gene therapy, since reversion of the affected genotype to carrier
genotype of approximately 50% of the basal keratinocytes appeared to be
sufficient to normalize the function of the skin, as noted in clinically
unaffected skin patches of the patient with this autosomal recessive
disorder. (See 308380.0010 for an example of revertant mosaicism
involving the gene mutant in X-linked SCID.)

*FIELD* AV
.0001
EPIDERMOLYSIS BULLOSA, GENERALIZED ATROPHIC BENIGN
GABEB
COL17A1, ARG1226TER
Generalized atrophic benign epidermolysis bullosa (226650), a rare
variant of junctional EB, is usually inherited as an autosomal
recessive. McGrath et al. (1995) described a 14-year-old male with
typical clinical features of the disorder. The parents, who were not
related, were clinically normal. The patient was found to be a compound
heterozygote for a premature termination mutation of both alleles of the
BPAG2 gene: a paternally inherited C-to-T transition at nucleotide 3781
of their clone that converted an arginine residue to a nonsense codon,
and a maternally inherited 1-bp insertion of G at nucleotide position
4150 (113811.0002) that resulted in a frameshift and premature
termination codon 50 nucleotides downstream from the site of insertion.
The 2 mutations in BPAG2 were symbolized R1226X and 4150insG by the
authors.

.0002
EPIDERMOLYSIS BULLOSA, GENERALIZED ATROPHIC BENIGN
GABEB
COL17A1, 1-BP INS, 4150INSG, FS, TER
See 113811.0001 and McGrath et al. (1995).

.0003
EPIDERMOLYSIS BULLOSA, GENERALIZED ATROPHIC BENIGN
GABEB
COL17A1, 5-BP DEL, FS, TER
In 2 Finnish families with GABEB, Gatalica et al. (1997) found mutations
in the COL17A1 gene. The probands in both families showed negative
immunofluorescence staining with an anti-type XVII collagen antibody. In
one family the proband was homozygous for a 5-bp deletion, 2944del5,
which resulted in frameshift and a premature termination of translation
45 nucleotides downstream of the deletion in exon 43.

.0004
EPIDERMOLYSIS BULLOSA, GENERALIZED ATROPHIC BENIGN
GABEB
COL17A1, GLN1023TER
In a second Finnish family, Gatalica et al. (1997) demonstrated that the
proband with GABEB was a compound heterozygote, with one allele
containing the 2944del5 mutation (113811.0003) of COL17A1 and the other
containing a nonsense mutation, Q1023X. The results expanded the
information on variants of junctional epidermolysis bullosa (JEB), and
attested to the functional importance of type XVII collagen as a
transmembrane component of the hemidesmosomes at the dermal/epidermal
junction.

.0005
EPIDERMOLYSIS BULLOSA, GENERALIZED ATROPHIC BENIGN
GABEB
COL17A1, 1-BP DEL, 1706A DEL
In a compound heterozygote with the R1226X mutation (113811.0001) on the
paternal chromosome, Jonkman et al. (1997) identified a 176delA mutation
on the maternal chromosome. The patient showed patches of clinically
unaffected skin, whereas the remainder of the skin demonstrated
characteristic blistering from mechanical trauma. They showed that the
mosaic phenotype was caused by reversion of one of the mutations, as a
result of the nonreciprocal transfer of a part of 1 paternal allele for
the other by a mechanism designated mitotic gene conversion. Revertant
keratinocytes derived from clinically unaffected skin patches showed LOH
along a tract of at least 381 bp.

*FIELD* RF
1. Copeland, N. G.; Gilbert, D. J.; Li, K.; Sawamura, D.; Giudice,
G. J.; Chu, M.-L.; Jenkins, N. A.; Uitto, J.: Chromosomal localization
of mouse bullous pemphigoid antigens, BPAG1 and BPAG2: identification
of a new region of homology between mouse and human chromosomes. Genomics 15:
180-181, 1993.

2. Diaz, L. A.; Ratrie, H., III; Saunders, W. S.; Futamura, S.; Squiquera,
H. L.; Anhalt, G. J.; Giudice, G. J.: Isolation of a human epidermal
cDNA corresponding to the 180-kD autoantigen recognized by bullous
pemphigoid and herpes gestationis sera: immunolocalization of this
protein to the hemidesmosome. J. Clin. Invest. 86: 1088-1094, 1990.

3. Gatalica, B.; Pulkkinen, L.; Li, K.; Kuokkanen, K.; Ryynanen, M.;
McGrath, J. A.; Uitto, J.: Cloning of the human type XVII collagen
gene (COL17A1), and detection of novel mutations in generalized atrophic
benign epidermolysis bullosa. Am. J. Hum. Genet. 60: 352-365, 1997.

4. Jonkman, M. F.; de Jong, M. C. J. M.; Heeres, K.; Pas, H. H.; van
der Meer, J. B.; Owaribe, K.; Martinez de Velasco, A. M.; Niessen,
C. M.; Sonnenberg, A.: 180-kD bullous pemphigoid antigen (BP180)
is deficient in generalized atrophic benign epidermolysis bullosa. J.
Clin. Invest. 95: 1345-1352, 1995.

5. Jonkman, M. F.; De Jong, M. C. J. M.; Heeres, K.; Steijlen, P.
M.; Owaribe, K.; Kuster, W.; Meurer, M.; Gedde-Dahl, T., Jr.; Sonnenberg,
A.; Bruckner-Tuderman, L.: Generalized atrophic benign epidermolysis
bullosa: either 180-kd bullous pemphigoid antigen or laminin-5 deficiency. Arch.
Derm. 132: 145-150, 1996.

6. Jonkman, M. F.; Scheffer, H.; Stulp, R.; Pas, H. H.; Nijenhuis,
M.; Heeres, K.; Owaribe, K.; Pulkkinen, L.; Uitto, J.: Revertant
mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 88:
543-551, 1997.

7. Li, K.; Sawamura, D.; Giudice, G. J.; Diaz, L. A.; Mattei, M.-G.;
Chu, M.-L.; Uitto, J.: Genomic organization of collagenous domains
and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2,
a novel collagen of stratified squamous epithelium. J. Biol. Chem. 266:
24064-24069, 1991.

8. Li, K.; Tamai, K.; Tan, E. M. L.; Uitto, J.: Cloning of type XVII
collagen: complementary and genomic sequences of mouse 180-kDa bullous
pemphigoid antigen (BPAG2) predict an interrupted collagenous domain,
a transmembranous segment, and unusual features in the 5-prime end
of the gene and the 3-prime-untranslated region of the mRNA. J. Biol.
Chem. 268: 8825-8834, 1993.

9. McGrath, J. A.; Gatalica, B.; Christiano, A. M.; Li, K.; Owaribe,
K.; McMillan, J. R.; Eady, R. A. J.; Uitto, J.: Mutations in the
180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane
collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa. Nature
Genet. 11: 83-86, 1995.

10. Sawamura, D.; Li, K.; Nomura, K.; Sugita, Y.; Christiano, A. M.;
Uitto, J.: Bullous pemphigoid antigen: cDNA cloning, cellular expression,
and evidence for polymorphism of the human gene. J. Invest. Derm. 96:
908-915, 1991.

11. Sawamura, D.; Li, K.; Uitto, J.: 230-kD and 180-kD bullous pemphigoid
antigens are distinct gene products. (Letter) J. Invest. Derm. 98:
942-943, 1992.

*FIELD* CN
Victor A. McKusick - updated: 04/07/1997
Victor A. McKusick - updated: 2/17/1997

*FIELD* CD
Victor A. McKusick: 11/13/1990

*FIELD* ED
mark: 04/07/1997
terry: 4/2/1997
mark: 2/17/1997
terry: 2/10/1997
mark: 3/28/1996
terry: 3/21/1996
mark: 3/4/1996
mark: 2/20/1996
mark: 8/31/1995
carol: 2/11/1993
supermim: 3/16/1992
carol: 2/12/1992
carol: 2/4/1992
carol: 1/10/1992

*RECORD*
*FIELD* NO
113900
*FIELD* TI
*113900 BUNDLE BRANCH BLOCK
HEART BLOCK, PROGRESSIVE FAMILIAL, TYPE I; HB1
PROGRESSIVE FAMILIAL HEART BLOCK, TYPE I, INCLUDED;;
PFHB1, INCLUDED
*FIELD* TX
DeForest (1956) studied a kindred in which uncomplicated left bundle
branch block occurred in 4 persons in 2 generations. Segall (1961)
described an instance of father, son and daughter (of French-Canadian
and Black intermixture) with right bundle branch block (RBBB) and
repeated Stokes-Adams attacks with various atrial arrhythmias and
ventricular extrasystoles. The father died at 74 years, 14 years after
the first fainting episode. Two asymptomatic brothers showed the
electrocardiographic changes of Wolff-Parkinson-White. Combrink et al.
(1962) described a South African family in which the mother had RBBB and
died at age 35 years in a Stokes-Adams attack. Of 4 children, 3 had
RBBB. The mother's parents had both died suddenly in their 30s. One of
her brothers was said to have a cardiac conduction disturbance, another
had dextrocardia, while 3 other sibs were apparently normal. Follow-up
of this kindred revealed RBBB in 1 of 7 grandchildren (Myburgh et al.,
1980). Steenkamp (1972) described a South African family in which 6 of
17 members studied showed disturbance of rhythm or conduction. Brink and
Torrington (1977) suggested that the disorder they referred to as
progressive familial heart block, type I, is prevalent in South Africa
and is the same disorder as that reported by Combrink et al. (1962) and
Steenkamp (1972). Type I heart block in their description tends to have
the pattern of a right bundle branch block and/or left anterior
hemiblock, manifesting clinically when complete heart block supervenes
with syncopal episodes, Stokes-Adams seizures, or sudden death. The risk
to life appeared to be greatest at or soon after birth, during puberty
and the early twenties, and again toward middle age. (In contrast to
this form of progressive familial heart block, type II is characterized
by sinus bradycardia and left posterior hemiblock progressing to
complete heart block; the QRS complexes are narrow rather than wide as
in type I. See 140400.) In two studies, van der Merwe et al. (1986) and
van der Merwe et al. (1988) provided follow-up information on the
kindred reported by Brink et al. (1977) and documented progression of
the disorder.

Greenspahn et al. (1976) presented evidence suggesting that a
susceptibility to disorder in conduction that is expressed late in life
is inherited. Stephan (1978) reported a Lebanese kindred descended from
a man who died presumably with heart block and who left more than 260
descendants by 3 wives. Of the 209 family members examined, 32 showed
abnormalities of the conduction system: complete RBBB in 12, incomplete
RBBB in 7, RBBB with left axis deviation in 6, RBBB with right axis
deviation in 4, and complete heart block in 2. These families may
represent a heterogeneous group of conduction disturbances, distinct
from conditions in which a specific conduction defect occurs (e.g.,
113950, 115080). Lorber et al. (1988) observed a father and 2 sons with
an electrocardiographic pattern of pseudo left posterior hemiblock and
incomplete right bundle branch block that resulted in right axis
deviation.

Brink et al. (1995) did linkage studies in the kindred reported by Brink
et al. (1977) and demonstrated that the gene for progressive familial
heart block, type I (PFHB1) maps to 19q13.2-q13.3. They pointed out that
this large kindred descended from an ancestor who emigrated from
Portugal in 1696. It had been estimated that there may be between 1,000
and 9,000 gene carriers among his descendants. Maximum 2-point lod
scores were 6.49 at theta = 0.0 for kallikrein (KLK1; 147910), 5.72 at
theta = 0.01 for the myotonic dystrophy locus (DM; 160900), 3.44 at
theta = 0.0 for the creatine kinase muscle-type locus (CKM; 123310), and
4.51 at theta = 0.10 for the apolipoprotein C2 locus (APOC2; 207750).
Brink et al. (1995) noted that the gene for myotonin protein kinase,
which is implicated as a cause of myotonic dystrophy, lies within this
region and that myotonic dystrophy is a disease complicated by heart
block and other conduction abnormalities. A recombination event ruled
out the myotonic dystrophy locus from direct involvement with PFHB1.

*FIELD* RF
1. Brink, A. J.; Torrington, M.: Progressive familial heart block--two
types. S. Afr. Med. J. 52: 53-59, 1977.

2. Brink, P. A.; Ferreira, A.; Moolman, J. C.; Weymar, H. W.; van
der Merwe, P.-L.; Corfield, V. A.: Gene for progressive familial
heart block type I maps to chromosome 19q13. Circulation 91: 1633-1640,
1995.

3. Combrink, J. M.; Davis, W. H.; Snyman, H. W.: Familial bundle
branch block. Am. Heart J. 64: 397-400, 1962.

4. DeForest, R. E.: Four cases of 'benign' left bundle branch block
in the same family. Am. Heart J. 51: 398-404, 1956.

5. Greenspahn, B. R.; Denes, P.; Daniel, W.; Rosen, K. M.: Chronic
bifascicular block: evaluation of familial factors. Ann. Intern.
Med. 84: 521-525, 1976.

6. Lorber, A.; Maisuls, E.; Naschitz, J.: Hereditary right axis deviation:
electrocardiographic pattern of pseudo left posterior hemiblock and
incomplete right bundle branch block. Int. J. Cardiol. 20: 399-402,
1988.

7. Myburgh, D. P.; Steenkamp, W. F.; Combrink, J. M.: Familial right
bundle branch block.  (Letter) S. Afr. Med. J. 58: 393 only, 1980.

8. Segall, H. N.: Congenital arrhythmias and conduction abnormalities
in a father and four children. Canad. Med. Assoc. J. 84: 1283-1296,
1961.

9. Steenkamp, W. F. J.: Familial trifascicular block. Am. Heart
J. 84: 758-760, 1972.

10. Stephan, E.: Hereditary bundle branch system defect: survey of
a family with four affected generations. Am. Heart J. 95: 89-95,
1978.

11. van der Merwe, P.-L.; Weymar, H. W.; Torrington, M.; Brink, A.
J.: Progressive familial heart block. part II. Clinical and ECG confirmation
of progression: report on 4 cases. S. Afr. Med. J. 70: 356-357,
1986.

12. van der Merwe, P.-L.; Weymar, H. W.; Torrington, M.; Brink, A.
J.: Progressive familial heart block (type I): a follow-up study
after 10 years. S. Afr. Med. J. 73: 275-276, 1988.

*FIELD* CS

Cardiac:
   Bundle branch block;
   Atrial arrhythmias;
   Ventricular extrasystoles;
   Wolff-Parkinson-White syndrome

Misc:
   Syncopal episodes;
   Repeated Stokes-Adams attacks;
   Sudden death

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 5/11/1995
terry: 5/13/1994
mimadm: 4/9/1994
carol: 10/26/1993
supermim: 3/16/1992
carol: 1/8/1991

*RECORD*
*FIELD* NO
113950
*FIELD* TI
*113950 BUNDLE BRANCH BLOCK, FAMILIAL ISOLATED COMPLETE RIGHT
*FIELD* TX
Esscher et al. (1975) reported an entity with clear autosomal dominant
inheritance that is probably distinct from the disorder in any of the
families discussed in 113900. They studied the families of 2 presumably
unrelated children with isolated complete right bundle branch block and
found that each showed several cases of classical complete right bundle
branch block in 3 generations. Subsequently they discovered that both
kindreds traced their ancestry to a glass-blower who immigrated to
Sweden in the 1700s. Penetrance was somewhat reduced. Although no
male-to-male transmission was demonstrated in the persons they studied,
by inference it had occurred. The anomaly seems to have had no ill
effects on physical capacity or life expectancy. Reports of 2 other
families, both Italian, were referenced by Esscher et al. (1975).

*FIELD* RF
1. Esscher, E.; Hardell, L.-I.; Michaelsson, M.: Familial, isolated,
complete right bundle-branch block. Brit. Heart J. 37: 745-747,
1975.

*FIELD* CS

Cardiac:
   Complete right bundle branch block

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
113955
*FIELD* TI
*113955 BUNGAROTOXIN, ALPHA, RECEPTOR FOR; BGTXR
*FIELD* TX
See 254210 for a description of defective alpha-bungarotoxin binding in
familial myasthenia gravis. Alpha-bungarotoxin receptors are known to be
present in normal and neoplastic thymic epithelial cells and in a
variety of other cell types (Chini et al., 1992). The endogenous ligand
for these widely expressed BGTX receptors is unknown.

*FIELD* RF
1. Chini, B.; Clementi, F.; Hukovic, N.; Sher, E.: Neuronal-type
alpha-bungarotoxin receptors and the alpha-5-nicotinic receptor subunit
gene are expressed in neuronal and nonneuronal human cell lines. Hum.
Genet. 89: 1572-1576, 1992.

*FIELD* CD
Victor A. McKusick: 3/27/1992

*FIELD* ED
carol: 3/27/1992

*RECORD*
*FIELD* NO
113960
*FIELD* TI
113960 BUTYRYLESTERASE-1
*FIELD* TX
Von Deimling and de Looze (1983) characterized butyrylesterase-1 in 14
mammalian species including man. They could not group it with any of the
known esterases within the system of enzymes recommended by the
International Union for Biochemistry (IUB) and therefore proposed that
this enzyme be assigned to a new esterase subclass.

*FIELD* RF
1. von Deimling, O.; de Looze, S.: Human red cell butyrylesterase,
and its homologies in thirteen other mammalian species. Hum. Genet. 63:
241-246, 1983.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 11/5/1991
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
113970
*FIELD* TI
#113970 BURKITT LYMPHOMA; BL
*FIELD* TX
A number sign (#) is used with this entry because the phenotype does not
reflect a single gene locus but rather the interaction of 2 separately
discussed gene loci.

Burkitt lymphoma results from chromosomal translocations that involve
the MYC gene (190080) and either the lambda or the kappa light chain
immunoglobulin genes (147200, 147220). Burkitt lymphoma is causally
related to the Epstein-Barr virus although the pathogenetic mechanisms
are not clear. Most BL cell lines show a specific translocation
involving chromosome 8 (breakpoint at 8q24) and either 2, 14 or 22. The
type of immunoglobulins produced by this B-cell tumor correlates with
the type of translocation (Lenoir et al., 1982): those with the 8;2
translocation produce predominantly kappa light chains; those with the
8;22 translocation produce lambda light chains; those with the 8;14
translocation produce immunoglobulins with both types of light chains.
Furthermore, the kappa and lambda light chains map to the regions of 2p
and 22q, respectively, that are involved in the breakpoint creating the
translocations; in the 8;14 translocations, the breakpoint is the 14q32
band where the genes for immunoglobulin heavy chains map (Kirsch et al.,
1982). Klein (1981) suggested that the consistent involvement of 8q24
may indicate that activation of an onc gene underlies this tumor. In
this connection, it is noteworthy that the mos onc gene (190060) has
been assigned to chromosome 8; the regional localization will be of
interest, as well as information on mos DNA sequences in BL. In Burkitt
lymphoma of the t(8;22) type, the breakpoint in chromosome 22 is
proximal to the lambda immunoglobulin constant gene cluster (147220),
whereas in the CML t(9;22) it is distal (Emanuel et al., 1984). Burkitt
lymphoma and related neoplasms have their analog in murine plasmacytomas
(also referred to as myelomas) in which a specific translocation occurs
between mouse chromosome 15 and either mouse chromosome 12 (which in the
mouse carries the heavy chain genes) or mouse chromosome 6 (which
carries the kappa light chain genes). Calame et al. (1982) identified a
region of DNA on mouse chromosome 15 that is commonly rearranged in
transformed mouse lymphocytes.

Anderson et al. (1986) described 2 sisters in an American family who
died of Burkitt lymphoma at ages 11 and 22 years. The mother and 2
healthy brothers had abnormality of lymphocyte subsets. An inherited
disturbance of lymphocytes was thought to underlie the familial
aggregation for Burkitt lymphoma. Haluska et al. (1987) suggested the
following scenario for African Burkitt lymphoma: EBV is a polyclonal
activator of B lymphocytes, and infection of normal B cells in vitro by
EBV is associated with immortalization. In regions of equatorial Africa
where Burkitt lymphoma is endemic, 80% of children demonstrate evidence
of EBV infection. Malaria is also hyperendemic in the area and causes
immunosuppression. Polyclonal B-lymphocyte proliferation therefore
proceeds unchecked in the absence of T-cell suppression, probably
enlarging the population of cells susceptible to translocation.
Translocation involving the IgH locus leads to deregulation of the MYC
oncogene. In Europe and North America, childhood EBV infection is less
frequent, as is malaria. Burkitt lymphoma appears to occur in mature B
cells following antigenic stimulation and during isotype switching.
Haluska et al. (1987) presented evidence that the t(8;14) chromosome
translocation of the Burkitt lymphoma cell line Daudi occurred during
immunoglobulin gene rearrangement and involved the heavy chain diversity
region (146910). They suggested that the translocation resulted from a
recombinase error. Neri et al. (1988) showed that the endemic, sporadic,
and AIDS-associated forms of Burkitt lymphoma carrying t(8;14)
chromosomal translocations display different breakpoints within the
immunoglobulin heavy-chain locus. Cloning and sequencing of the t(8;14)
chromosomal junctions from 2 endemic BL cell lines and 1 endemic BL
biopsy sample showed that the recombinations did not involve
IGH-specific recombination signals on chromosome 14 or homologous
sequences on chromosome 8. Thus, these events probably were not mediated
by the same mechanisms or enzymes as in IGH rearrangement.

Denis Parsons Burkitt, who died in 1993 at the age of 82, was famed for
the distinctive lymphoma he described and for the dietary fiber
hypothesis which he developed and espoused (Heaton, 1993).

*FIELD* SA
Burkitt  (1958); Burkitt  (1983); Haluska et al. (1987); Pelicci et
al. (1986); Zech et al. (1976)
*FIELD* RF
1. Anderson, K. C.; Jamison, D. S.; Peters, W. P.; Li, F. P.: Familial
Burkitt's lymphoma: association with altered lymphocyte subsets in
family members. Am. J. Med. 81: 158-162, 1986.

2. Burkitt, D.: A sarcoma involving the jaws in African children.
Brit. J. Surg. 46: 218-223, 1958.

3. Burkitt, D. P.: The discovery of Burkitt's lymphoma. Cancer 51:
1777-1786, 1983.

4. Calame, K.; Kim, S.; Lalley, P.; Hill, R.; Davis, M.; Hood, L.
: Molecular cloning of translocations involving chromosome 15 and
the immunoglobulin C-alpha gene from chromosome 12 in two murine plasmacytomas.
Proc. Nat. Acad. Sci. 79: 6994-6998, 1982.

5. Emanuel, B. S.; Selden, J. R.; Wang, E.; Nowell, P. C.; Croce,
C. M.: In situ hybridization and translocation breakpoint mapping.
I. Nonidentical 22q11 breakpoints for the t(9;22) of Burkitt lymphoma.
Cytogenet. Cell Genet. 38: 127-131, 1984.

6. Haluska, F. G.; Tsujimoto, Y.; Croce, C. M.: Mechanisms of chromosome
translocation in B- and T-cell neoplasia. Trends Genet. 3: 11-15,
1987.

7. Haluska, F. G.; Tsujimoto, Y.; Croce, C. M.: The t(8;14) chromosome
translocation of the Burkitt lymphoma cell line Daudi occurred during
immunoglobulin gene rearrangement and involved the heavy chain diversity
region. Proc. Nat. Acad. Sci. 84: 6835-6839, 1987.

8. Heaton, K.: Denis Burkitt. Lancet 341: 951-952, 1993.

9. Kirsch, I. R.; Morton, C. C.; Nakahara, K.; Leder, P.: Human immunoglobulin
heavy chain genes map to a region of translocations in malignant B
lymphocytes. Science 216: 301-303, 1982.

10. Klein, G.: The role of gene dosage and genetic transpositions
in carcinogenesis. Nature 294: 313-318, 1981.

11. Lenoir, G. M.; Preud'homme, J. L.; Bernheim, A.; Berger, R.:
Correlation between immunoglobulin light chain expression and variant
translocation in Burkitt's lymphoma. Nature 298: 474-476, 1982.

12. Neri, A.; Barriga, F.; Knowles, D. M.; Magrath, I. T.; Dalla-Favera,
R.: Different regions of the immunoglobulin heavy-chain locus are
involved in chromosomal translocations in distinct pathogenetic forms
of Burkitt lymphoma. Proc. Nat. Acad. Sci. 85: 2748-2752, 1988.

13. Pelicci, P.-G.; Knowles, D. M., II; Magrath, I.; Dalla-Favera,
R.: Chromosomal breakpoints and structural alterations of the c-myc
locus differ in endemic and sporadic forms of Burkitt lymphoma. Proc.
Nat. Acad. Sci. 83: 2984-2988, 1986.

14. Zech, L.; Haglund, U.; Nilsson, K.; Klein, G.: Characteristic
chromosomal abnormalities in biopsies and lymphoid-cell lines from
patients with Burkitt and non-Burkitt lymphomas. Int. J. Cancer 17:
47-56, 1976.

*FIELD* CS

Oncology:
   Burkitt lymphoma;
   Causally related to the Epstein-Barr virus

Inheritance:
   Chromosomal translocations involving the MYC gene (8q24) and the lambda
   (22q) or the kappa (2p) light chain or heavy chain (14q32) immunoglobulin
   genes

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 7/27/1994
mimadm: 4/9/1994
warfield: 4/6/1994
carol: 7/13/1993
carol: 4/30/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
113995
*FIELD* TI
*113995 C5a ANAPHYLATOXIN RECEPTOR; C5AR
COMPLEMENT COMPONENT-5 RECEPTOR 1; C5R1
*FIELD* TX
Using a panel of somatic cell hybrids, Bao et al. (1992) mapped the
receptor for the chemotactic ligand C5a to chromosome 19. This receptor,
like those for the formyl peptides (136537, 136538) and interleukin-8
(146929), is structurally related to rhodopsin (RHO; 180380) and
transduces signals via intracellular GTP-binding proteins.

Hopken et al. (1996) deleted the murine C5a receptor (C5ar) through
homologous recombination. They reported that the C5ar-deficient mice
showed no developmental or biologic defects in cells in which C5a is
expressed (e.g., myeloid cell lineages, hepatocytes, and epithelial
cells) apart from the ability to bind and signal to exogenous C5a.
Hopken et al. (1996) reported that C5ar-deficient mice bred normally and
displayed no gross defects when maintained under barrier conditions.
When mice were challenged with intratracheal Pseudomonas aeruginosa, the
C5ar-deficient mice, in contrast to their littermates, were unable to
clear the bacteria and they succumbed to pneumonia. On the basis of
these studies, Hopken et al. (1996) concluded that C5ar has a
nonredundant function and is required for mucosal host cell defense in
the lung.

*FIELD* RF
1. Bao, L.; Gerard, N. P.; Eddy, R. L., Jr.; Shows, T. B.; Gerard,
C.: Mapping of genes for the human C5a receptor (C5AR), human FMLP
receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1,
FPRH2) to chromosome 19. Genomics 13: 437-440, 1992.

2. Hopken, U. E.; Lu, D.; Gerard, N. P.; Gerard, C.: The C5a chemoattractant
receptor mediates mucosal defence to infection. Nature 383: 86-89,
1996.

*FIELD* CN
Moyra Smith - updated: 9/5/1996

*FIELD* CD
Victor A. McKusick: 6/24/1992

*FIELD* ED
terry: 11/05/1996
terry: 10/18/1996
terry: 9/5/1996
jason: 6/17/1994
carol: 8/25/1992
carol: 6/24/1992

*RECORD*
*FIELD* NO
114000
*FIELD* TI
*114000 CAFFEY DISEASE
INFANTILE CORTICAL HYPEROSTOSIS
*FIELD* TX
This condition has somewhat unusual features for a hereditary disorder.
It rarely if ever appears after 5 months of age; it is sometimes present
at birth and has been identified by x-ray in the fetus in utero. The
acute manifestations are inflammatory in nature, with fever and hot,
tender swelling of involved bones (e.g., mandible, ribs). Despite
striking radiologic changes in the acute stages, previously affected
bones are often completely normal on restudy. However, Taj-Eldin and
Al-Jawad (1971) described a case followed since infancy with recurrences
documented up to 19 years of age (1971). (Incontinentia pigmenti
(308300) is another familial condition in which 'active' lesions at
birth and early in life may leave little or no residue.) Pickering and
Cuddigan (1969) suggested that vascular occlusion secondary to
thrombocytosis may be involved in the pathogenesis. Autosomal dominant
inheritance is suggested by the reports of Gerrard et al. (1961), Van
Buskirk et al. (1961), Holman (1962), and others. Male-to-male
transmission was observed by Van Buskirk et al. (1961). Bull and
Feingold (1974) reported 2 affected sisters, one of whom had affected
son and daughter and the other a normal daughter and affected son. Fried
et al. (1981) observed 9 affected persons in 3 sibships of 2 generations
of a family. One instance of male-to-male transmission and one of
apparent nonpenetrance were reported. X-ray findings in 3 members of the
family were reported by Pajewski and Vure (1967). Newberg and Tampas
(1981) gave a follow-up on a family with 11 cases reported in 1961
(Tampas et al., 1961; Van Buskirk et al., 1961). Since then, 10 new
cases had occurred, confirming autosomal dominant inheritance. Emmery et
al. (1983) described 8 affected persons in 3 generations. MacLachlan et
al. (1984) followed up on the French-Canadian kindred reported by
Gerrard et al. (1961). To the 14 affected children identified in the
original report, 20 new cases were added. MacLachlan et al. (1984)
commented that the sporadic form of the disorder is disappearing with no
such cases seen in the last 7 years. In sporadic cases the bones most
often affected are mandible, ulna and clavicle with fairly frequent
involvement of ribs and scapulae. In their radiographic studies of 14
familial cases, no involvement of ribs or scapulae was encountered.
Clavicular involvement was found in only 3 children. The tibia was most
often involved in familial cases. Borochowitz et al. (1991) described 2
affected sibs in a nonconsanguineous family; a girl had involvement of
the fibula at the age of 5 months and a recurrence with tibial
involvement at the age of 11 years. Her brother was hospitalized at the
age of 4 months because of swelling of the face, fever, and
restlessness.

Lecolier et al. (1992) described a case of prenatal Caffey disease.
Ultrasound examination at 20 weeks of gestation detected major
angulation of the long bones. Although no fractures were seen,
irregularities of the ribs suggested multiple callus formation and the
diagnosis of lethal osteogenesis imperfecta was entertained.
Cordocentesis showed marked leukocytosis, mainly due to neutrophils, as
well as increased serum levels of hepatic enzymes. Because of a rapid
appearance of 'feto-placental anasarca' and a probable diagnosis of
osteogenesis imperfecta, pregnancy was terminated at 23 weeks of
gestation. Special x-ray views showed a double contour of the diaphyseal
cortex of the long bones. Histologic examination confirmed the diagnosis
of Caffey disease by demonstration of thickened periosteum and
infiltration of the deeper layers of the periosteum with round cells.
Lecolier et al. (1992) suggested that this form should be referred to as
lethal prenatal cortical hyperostosis. Stevenson (1993) described a case
indicating that Caffey disease can be detected in utero in familial
nonlethal cases. Ultrasound examination at age 35.5 weeks showed
curvature of the tibia and irregularity of the cortex of the radius.
Mild leg curvature was present at birth at 39 weeks; involvement of all
long bones was documented radiographically at the age of 2.5 months. A
sister, the mother, and a maternal uncle had documented Caffey disease.

Perinatal death in 2 sibs with Caffey disease was described by de Jong
and Muller (1995). Antenatal sonographic diagnosis was short-limb
dwarfism and thoracic dysplasia of a nonspecific type, possibly
osteogenesis imperfecta, in the first sib. The second sib had a similar
appearance on ultrasonography. The thickened irregularly echodense
diaphyses were an aid to diagnosis. de Jong and Muller (1995) agreed
with LeColier et al. (1992) that pheto-placental anasarca and
polyhydramnios are helpful prognostic signs. The presence of both seems
to indicate a very poor prognosis. Autosomal dominant inheritance with
subclinical Caffey disease in one of the parents during infancy could
not be excluded since incidental discovery of the disease has been
reported (Cayler and Peterson, 1956). Parental gonadal mosaicism is
another possibility. In spite of the absence of parental consanguinity,
the occurrence of the condition in a male and a female sib born to
healthy parents suggested autosomal Recessive inheritance of the lethal
prenatal onset type of cortical hyperostosis.

See Griscom (1995) for a biographic account of John Caffey (born 1895,
died 1978).

*FIELD* SA
Caffey and Silverman (1945); Clemett and Williams (1963); Langewisch
(1975); Sherman and Hellyer (1950); Sidbury  (1957)
*FIELD* RF
1. Borochowitz, Z.; Gozal, D.; Misselevitch, I.; Aunallah, J.; Boss,
J. H.: Familial Caffey's disease and late recurrence in a child.
Clin. Genet. 40: 329-335, 1991.

2. Bull, M. J.; Feingold, M.: Autosomal dominant inheritance of Caffey
disease. Birth Defects Orig. Art. Ser. X: 139-146, 1974.

3. Caffey, J.; Silverman, W.: Infantile cortical hyperostosis, preliminary
report on new syndrome. Am. J. Roentgen. 54: 1-16, 1945.

4. Cayler, G. G.; Peterson, C. A.: Infantile cortical hyperostosis:
report of seventeen cases. Am. J. Dis. Child. 91: 119-125, 1956.

5. Clemett, A. R.; Williams, J. H.: The familial occurrence of infantile
cortical hyperostosis. Radiology 80: 409-416, 1963.

6. de Jong, G.; Muller, L. M. M.: Perinatal death in two sibs with
infantile cortical hyperostosis (Caffey disease). Am. J. Med. Genet. 59:
134-138, 1995.

7. Emmery, L.; Timmermans, J.; Christens, J.; Fryns, J. P.: Familial
infantile cortical hyperostosis. Europ. J. Pediat. 141: 56-58,
1983.

8. Fried, K.; Manor, A.; Pajewski, M.; Starinsky, R.; Vure, E.: Autosomal
dominant inheritance with incomplete penetrance of Caffey disease
(infantile cortical hyperostosis). Clin. Genet. 19: 271-274, 1981.

9. Gerrard, J. W.; Holman, G. H.; Gorman, A. A.; Morrow, I. H.: Familial
infantile cortical hyperostosis. J. Pediat. 59: 543-548, 1961.

10. Griscom, N. T.: John Caffey and his contributions to radiology.
Radiology 194: 513-518, 1995.

11. Holman, G. H.: Infantile cortical hyperostosis: a review. Quart.
Rev. Pediat. 17: 24-31, 1962.

12. Langewisch, W. H.: Infantile cortical hyperostosis--familial
occurrence in a mother and daughter. J. Pediat. 87: 323-324, 1975.

13. Lecolier, B.; Bercau, G.; Gonzales, M.; Afriat, R.; Rambaud, D.;
Mulliez, N.; de Kermadec, S.: Radiographic, haematological, and biochemical
findings in a fetus with Caffey disease. Prenatal Diag. 12: 637-641,
1992.

14. MacLachlan, A. K.; Gerrard, J. W.; Houston, C. S.; Ives, E. J.
: Familial infantile cortical hyperostosis in a large Canadian family.
Canad. Med. Assoc. J. 130: 1172-1174, 1984.

15. Newberg, A. H.; Tampas, J. P.: Familial infantile cortical hyperostosis:
an update. Am. J. Roentgen. 137: 93-96, 1981.

16. Pajewski, M.; Vure, E.: Late manifestations of infantile cortical
hyperostosis (Caffey's disease). Brit. J. Radiol. 40: 90-95, 1967.

17. Pickering, D.; Cuddigan, B.: Infantile cortical hyperostosis
associated with thrombocythaemia. Lancet II: 464-465, 1969.

18. Sherman, M. S.; Hellyer, D. T.: Infantile cortical hyperostosis:
review of the literature and report of 5 cases. Am. J. Roentgen. 63:
212-222, 1950.

19. Sidbury, J. B., Jr.: Infantile cortical hyperostosis. Postgrad.
Med. J. 22: 211-215, 1957.

20. Stevenson, R. E.: Findings of heritable Caffey disease on ultrasound
at 35 1/2 weeks gestation. Proc. Greenwood Genet. Center 12: 16-18,
1993.

21. Taj-Eldin, S.; Al-Jawad, J.: Cortical hyperostosis: infantile
and juvenile manifestations in a boy. Arch. Dis. Child. 46: 565-566,
1971.

22. Tampas, J. P.; Van Buskirk, F. W.; Peterson, O. S.; Soule, A.
B.: Infantile cortical hyperostosis. J.A.M.A. 175: 491-493, 1961.

23. Van Buskirk, F. W.; Tampas, J. P.; Peterson, O. S.: Infantile
cortical hyperostosis: an inquiry into its familial aspects. Am.
J. Roentgen. 85: 613-632, 1961.

*FIELD* CS

Skel:
   Hot, tender swelling of involved bones (e.g., mandible, ribs)

Limbs:
   Mild congenital leg curvature

Misc:
   Usually appears by 5 months of age;
   Fever;
   Specific bones involved different in familial and sporadic cases

Radiology:
   Identified by x-ray in the fetus in utero;
   Cortical hyperostosis;
   Curved tibia;
   Irregularity of bone cortex

Lab:
   Thickened periosteum and infiltration of the deeper layers of the
   periosteum with round cells

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/26/1996
mark: 1/16/1996
terry: 1/11/1996
carol: 3/7/1995
davew: 6/9/1994
terry: 5/13/1994
mimadm: 4/9/1994
warfield: 4/6/1994
carol: 10/26/1993

*RECORD*
*FIELD* NO
114010
*FIELD* TI
*114010 CAD TRIFUNCTIONAL PROTEIN
CARBAMOYLPHOSPHATE SYNTHETASE/ASPARTATE TRANSCARBAMOYLASE/DIHYDROOROTASE;;
; CAD;;
CPSase/ATCase/DHOase
*FIELD* TX
The CAD gene encodes a trifunctional protein which is associated with
the enzymatic activity of the first 3 enzymes in the 6-step pathway of
pyrimidine biosynthesis: carbamoylphosphate synthetase (EC 6.3.5.5),
aspartate transcarbamoylase (EC 2.1.3.2), and dihydroorotase (EC
3.5.2.3). Simmer et al. (1990) suggested that all DHOases are
descendents of a common ancestor. In some organisms, the enzyme has
remained monofunctional. Simmer et al. (1990) suggested that in mammals
DHOase gene duplication and insertion into an ancestral bifunctional
locus occurred. Chen et al. (1987, 1989) mapped the CAD gene to 2p22-p21
by in situ hybridization, by Southern analysis of DNA from somatic cell
hybrids, and by nutritional complementation tests in hamster/human
somatic cell hybrids containing reduced numbers of human chromosomes.
There is another carbamoylphosphate synthetase enzyme, that involved in
the urea cycle, which is also coded by 2p--a mere coincidence. By a
study of cells from 2 patients with holoprosencephaly and a 2p
interstitial deletion, Muenke et al. (1989) excluded CAD from the
segment 2p23.3-p21.01. Bertoni et al. (1993) used fluorescence in situ
hybridization to localize the Chinese hamster CAD gene to a region of
chromosome 7 where other genes homologous to genes on human chromosome
2p have been mapped.

(The carbamoylphosphate synthetase activity of the CAD trifunctional
protein is designated CPS II (CPS2). CPS I is encoded by the CPS1 gene
(237300), which maps to 2q.)

*FIELD* RF
1. Bertoni, L.; Attolini, C.; Simi, S.; Giulotto, E.: Localization
of the Chinese hamster CAD gene reveals homology between human chromosome
2p and Chinese hamster 7q. Genomics 16: 779-781, 1993.

2. Chen, K.-C.; Vannais, D. B.; Jones, C.; Patterson, D.; Davidson,
J. N.: Chromosomal localization of the human CAD gene to 2p21-22.
(Abstract) Am. J. Hum. Genet. 41: A161 only, 1987.

3. Chen, K.-C.; Vannais, D. B.; Jones, C.; Patterson, D.; Davidson,
J. N.: Mapping of the gene encoding the multifunctional protein carrying
out the first three steps of pyrimidine biosynthesis to human chromosome
2. Hum. Genet. 82: 40-44, 1989.

4. Muenke, M.; Sosnoski, D. M.; Wilson, W. G.; Wassman, E. R.; Davidson,
J. N.; Patterson, D.; Nussbaum, R. L.: Exclusion of the CAD locus
from 2p2101-p23.3 using 2p interstitial deletions from patients with
holoprosencephaly.  (Abstract) Am. J. Hum. Genet. 45 (suppl.): A84
only, 1989.

5. Simmer, J. P.; Kelly, R. E.; Rinker, A. G., Jr.; Zimmermann, B.
H.; Scully, J. L.; Kim, H.; Evans, D. R.: Mammalian dihydroorotase:
nucleotide sequence, peptide sequences, and evolution of the dihydroorotase
domain of the multifunctional protein CAD. Proc. Nat. Acad. Sci. 87:
174-178, 1990.

*FIELD* CD
Victor A. McKusick: 10/28/1987

*FIELD* ED
mark: 7/19/1995
carol: 6/24/1993
supermim: 3/16/1992
supermim: 4/25/1990
supermim: 3/20/1990
carol: 3/6/1990

*RECORD*
*FIELD* NO
114019
*FIELD* TI
*114019 CADHERIN 14; CDH14
CADHERIN, MUSCLE TYPE;;
M-CADHERIN; MCAD;;
CDHM;;
CADHERIN 3; CDH3, FORMERLY
*FIELD* TX
Cadherins are a multigene family of Ca(2+)-dependent cell adhesion
molecules. They are transmembrane glycoproteins consisting of an
extracellular domain, a transmembrane region, and a cytoplasmic domain.
The extracellular domains mediate Ca(2+)-dependent intercellular
adhesion by homophilic interactions. The binding properties and
specificities of the adhesive function are located in the N-terminal
part of the molecules. Neural (114020), placental (114021), and
epithelial (192090) forms of cadherin have been characterized. Donalies
et al. (1991) identified a member of the cadherin family in myogenic
mouse cells and referred to it as M-cadherin. It was not found in
fibroblasts and was expressed at low levels in myoblasts. It is
upregulated after induction of myotube formation, indicating a specific
function in skeletal muscle cell differentiation.

Kaupmann et al. (1992) used a mouse myotube-derived cDNA encoding
M-cadherin to demonstrate linkage of the Cdh3 gene to the gene for
E-cadherin (uvomorulin) in a mouse interspecific backcross. The linkage
group is located on chromosome 8 in a region of conserved synteny with
human chromosome 16q. The gene order was
cen--Junb--Um--Tat--(Cdh3/Aprt). The human homolog, CDH3, was mapped to
16q24.1-qter by analyzing human/mouse somatic cell hybrids.

Nomenclature: The preferred symbol for this cadherin gene is CDH14;
P-cadherin (114021) was symbolized CDH3.

*FIELD* RF
1. Donalies, M.; Cramer, M.; Ringwald, M.; Starzinski-Powitz, A.:
Expression of M-cadherin, a member of the cadherin multigene family,
correlates with differentiation of skeletal muscle cells. Proc. Nat.
Acad. Sci. 88: 8024-8028, 1991.

2. Kaupmann, K.; Becker-Follmann, J.; Scherer, G.; Jockusch, H.; Starzinski-Powitz,
A.: The gene for the cell adhesion molecule M-cadherin maps to mouse
chromosome 8 and human chromosome 16q24.1-qter and is near the E-cadherin
(uvomorulin) locus in both species. Genomics 14: 488-490, 1992.

*FIELD* CD
Victor A. McKusick: 10/30/1991

*FIELD* ED
mark: 01/18/1997
mark: 12/31/1996
mark: 8/23/1995
carol: 5/12/1994
carol: 10/15/1992
carol: 8/21/1992
carol: 4/7/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
114020
*FIELD* TI
*114020 CADHERIN, NEURAL TYPE
N-CADHERIN;;
CALCIUM-DEPENDENT ADHESION PROTEIN, NEURAL TYPE; NCAD; CDHN;;
CADHERIN 2; CDH2
*FIELD* TX
A gene family encoding proteins that mediate calcium-ion-dependent
adhesion and are therefore called cadherins has been identified
(Takeichi, 1987). Three members of the group are epithelial (E-cadherin;
CDH1; 192090), neural (N-cadherin), and placental (P-cadherin; CDH3;
114021). E-cadherin appears to be identical to the protein called
uvomorulin. N-cadherin is expressed in the brain and skeletal and
cardiac muscle. In Southern analysis of a panel of somatic cell hybrids,
Walsh et al. (1990) mapped the NCAD gene to chromosome 18. By
interspecific backcross analysis, Miyatani et al. (1992) found that the
gene in the mouse is located in the proximal region of chromosome 18.
Furthermore, in the mouse the gene consists of 16 exons dispersed over
more than 200 kb of genomic DNA. The large size of the N-cadherin gene,
compared with its cDNA (4.3 kb), was ascribed to the fact that the first
and second introns are 34.2 kb and more than 100 kb long, respectively.
Using YAC analysis and a PCR and cosmid subcloning strategy, Wallis et
al. (1994) mapped the human N-cadherin gene to a 250-kb region. The gene
contains 16 exons and its sequence is highly similar to both the mouse
NCAD gene (including the large first and second introns) and other
cadherin genes. By in situ hybridization, Wallis et al. (1994) refined
the map position of N-cadherin to 18q11.2.

Miyatani et al. (1992) compared the NCAD, liver cell adhesion molecule
(LCAM), and PCAD genes and showed that the exon-intron boundaries were
fully conserved between them, except that the P-cadherin first exon
included the first and second exons of the other 2 genes. Also, the
second intron, which is equivalent to the first intron in P-cadherin, is
exceptionally large and this structural feature is conserved in all 3 of
these genes.

Hermiston and Gordon (1995) noted that the mouse intestinal epithelium
expresses a sequence of 'developmental events'--proliferation, lineage
allocation, migration, differentiation, and death--throughout life.
Proliferation is confined to the crypts of Lieberkuhn. The crypt's
multipotent stem cell gives rise to enterocytes, mucus-producing goblet
cells, enteroendocrine cells, and Paneth cells. Cells of these 4
lineages differentiate during an orderly migration and are frequently
eliminated by apoptosis and exfoliation or phagocytosis. Renewal is
rapid (3 to 20 days). Results from cell culture studies indicate that
cadherin-catenin complexes regulate cell polarity, formation of
junctional complexes, migration, and proliferation. Hermiston and Gordon
(1995) transfected embryonic stem cells with a dominant-negative
N-cadherin mutant under the control of promoters active in small
intestinal epithelial cells and introduced them into C57BL/6
blastocysts. Analysis of adult chimeric mice revealed that expression of
the mutant along the entire crypt-villus axis, but not in the villus
epithelium alone, produced an inflammatory bowel disease resembling
Crohns disease (266600). The mutation perturbed proliferation,
migration, and death patterns in crypts, leading to adenomas. The model
provided insights into cadherin function in an adult organ and the
factors underlying inflammatory bowel disease and intestinal neoplasia.

*FIELD* RF
1. Hermiston, M. L.; Gordon, J. I.: Inflammatory bowel disease and
adenomas in mice expressing a dominant negative N-cadherin. Science 270:
1203-1206, 1995.

2. Miyatani, S.; Copeland, N. G.; Gilbert, D. J.; Jenkins, N. A.;
Takeichi, M.: Genomic structure and chromosomal mapping of the mouse
N-cadherin gene. Proc. Nat. Acad. Sci. 89: 8443-8447, 1992.

3. Takeichi, M.: Cadherins: a molecular family essential for selective
cell-cell adhesion and animal morphogenesis. Trends Genet. 3: 213-217,
1987.

4. Wallis, J.; Fox, M. F.; Walsh, F. S.: Structure of the human N-cadherin
gene: YAC analysis and fine chromosomal mapping to 18q11.2. Genomics 22:
172-179, 1994.

5. Walsh, F. S.; Barton, C. H.; Putt, W.; Moore, S. E.; Kelsell, D.;
Spurr, N.; Goodfellow, P. N.: N-cadherin gene maps to human chromosome
18 and is not linked to the E-cadherin gene. J. Neurochem. 55:
805-812, 1990.

*FIELD* CD
Victor A. McKusick: 7/24/1991

*FIELD* ED
mark: 11/16/1995
terry: 8/8/1994
carol: 5/12/1994
carol: 10/7/1992
supermim: 3/16/1992
carol: 11/6/1991

*RECORD*
*FIELD* NO
114021
*FIELD* TI
*114021 CADHERIN 3; CDH3
CADHERIN, PLACENTAL TYPE;;
P-CADHERIN; PCAD;;
CALCIUM-DEPENDENT ADHESION PROTEIN, PLACENTAL TYPE;;
CDHP
*FIELD* TX
Nose and Takeichi (1986) identified a novel cadherin cell adhesion
molecule expressed in placenta. The E-cadherin (uvomorulin; UVO; 192090)
and P-cadherin genes are tightly linked on chromosome 8 of the mouse
(Hatta et al., 1991). Since the human UVO locus is on 16q22.1, the
P-cadherin gene is probably in the same location.

Nomenclature: The preferred symbol for this cadherin gene is CDH3. The
gene previously symbolized CDH3 (i.e., M-cadherin, 114019) is symbolized
CDH14.

*FIELD* SA
Miyatani et al. (1992)
*FIELD* RF
1. Hatta, M.; Miyatani, S.; Copeland, N. G.; Gilbert, D. J.; Jenkins,
N. A.; Takeichi, M.: Genomic organization and chromosomal mapping
of the mouse P-cadherin gene. Nucleic Acids Res. 19: 4437-4441,
1991.

2. Miyatani, S.; Copeland, N. G.; Gilbert, D. J.; Jenkins, N. A.;
Takeichi, M.: Genomic structure and chromosomal mapping of the mouse
N-cadherin gene. Proc. Nat. Acad. Sci. 89: 8443-8447, 1992.

3. Nose, A.; Takeichi, M.: A novel cadherin cell adhesion molecule:
its expression patterns associated with implantation and organogenesis
of mouse embryos. J. Cell Biol. 103: 2649-2658, 1986.

*FIELD* CD
Victor A. McKusick: 7/24/1991

*FIELD* ED
mark: 01/18/1997
mark: 8/23/1995
carol: 10/20/1993
carol: 10/1/1992
carol: 9/30/1992
supermim: 3/16/1992
carol: 11/6/1991

*RECORD*
*FIELD* NO
114025
*FIELD* TI
*114025 CADHERIN-ASSOCIATED PROTEIN, RELATED; CAP-R; CAPR
CATENIN, ALPHA 2; CTNNA2
*FIELD* TX
Cell-cell and cell-matrix adhesions involve transmembrane glycoproteins
such as cell adhesion molecules and integrins, which are thought to
function via interactions of their cytoplasmic domains with proteins
associated with the cytoskeleton. Vinculin (193065) and talin (186745)
are examples. The activity of cadherins (e.g., 114020), which mediate
homophilic cell-cell Ca(2+)-dependent association, depends on their
anchorage to cytoskeleton via proteins termed catenins (Herrenknecht et
al., 1991).

Claverie et al. (1993) characterized a human cDNA encoding a protein 80%
identical to CAP102 (see 116805) and referred to as CAP-R (R = related).
Despite the homology, the protein was probably not the actual human
homolog of alpha-catenin because of atypical mouse/human mutation rates
computed from the 2 sequences and because of the finding of a partial
cDNA sequence 89% identical to CAP102 within a human expressed sequence
tag (EST) library. CAP-R also differed from CAP102 by the presence of a
48-residue insert, suggesting the situation previously described for the
metavinculin/vinculin system (Gimona et al., 1988). Using in situ
hybridization, the CAP-R gene was mapped to human 2p12-p11.1 and to the
homologous B3-D region of mouse chromosome 6.

*FIELD* SA
Nagafuchi et al. (1991)
*FIELD* RF
1. Claverie, J.-M.; Hardelin, J.-P.; Legouis, R.; Levilliers, J.;
Bougueleret, L.; Mattei, M.-G.; Petit, C.: Characterization and chromosomal
assignment of a human cDNA encoding a protein related to the murine
102-kDa cadherin-associated protein (alpha-catenin). Genomics 15:
13-20, 1993.

2. Gimona, M.; Small, J. V.; Moeremans, M.; Van Damme, J.; Puype,
M.; Vandekerckhove, J.: Porcine vinculin and metavinculin differ
by a 68-residue insert located close to the carboxy-terminal part
of the molecule. EMBO J. 7: 2329-2334, 1988.

3. Herrenknecht, K.; Ozawa, M.; Eckerskorn, C.; Lottspeich, F.; Lenter,
M.; Kemler, R.: The uvomorulin-anchorage protein alpha-catenin is
a vinculin homologue. Proc. Nat. Acad. Sci. 88: 9156-9160, 1991.

4. Nagafuchi, A.; Takeichi, M.; Tsukita, S.: The 102 kd cadherin-associated
protein: similarity to vinculin and posttranscriptional regulation
of expression. Cell 65: 849-857, 1991.

*FIELD* CD
Victor A. McKusick: 2/11/1993

*FIELD* ED
carol: 9/2/1993
carol: 2/11/1993

*RECORD*
*FIELD* NO
114030
*FIELD* TI
*114030 CAFE-AU-LAIT SPOTS, MULTIPLE; CALM
NEUROFIBROMATOSIS, TYPE 6; NF6
*FIELD* TX
Although multiple cafe-au-lait spots are the diagnostic hallmark of
neurofibromatosis-1 (162200), they have been observed in families in
which there have been no other changes of NF1 (Whitehouse, 1966;
Riccardi, 1980). The absence of neurofibromas and Lisch nodules of the
iris suggests that these families are expressing a trait genetically
distinct from NF1. Support for this suggestion was presented by Charrow
et al. (1993) who studied a family with multiple cafe-au-lait spots in 4
generations, with male-to-male transmission in the first 2 generations,
and excluded linkage to NF1 on chromosome 17. Thus they excluded this
disorder as an allelic mutation or as the result of mutation at a
closely linked locus. Brunner et al. (1993) likewise excluded the NF1
locus as the site of the mutation in this disorder by demonstrating that
an affected woman had transmitted a different haplotype for markers
flanking the NF1 gene to each of her 2 affected daughters. On the other
hand, Abeliovich et al. (1995) showed close linkage between multiple
cafe au lait spots and the NF1 locus in a 3-generation family with 1
affected subject. They concluded that the trait was allelic to NF1, that
it is fully penetrant, and that it does not confer a risk of other NF1
symptoms. Thus, there may be 2 forms of multiple cafe-au-lait spot, a
form linked to NF1 and an unlinked form.

*FIELD* RF
1. Abeliovich, D.; Gelman-Kohan, Z.; Silverstein, S.; Lerer, I.; Chemke,
J.; Merlin, S.; Zlotogora, J.: Familial cafe au lait spots: a variant
of neurofibromatosis type 1. J. Med. Genet. 32: 985-986, 1995.

2. Brunner, H. G.; Hulsebos, T.; Steijlen, P. M.; der Kinderen, D.
J.; v.d. Steen, A.; Hamel, B. C. J.: Exclusion of the neurofibromatosis
1 locus in a family with inherited cafe-au-lait spots. Am. J. Med.
Genet. 46: 472-474, 1993.

3. Charrow, J.; Listernick, R.; Ward, K.: Autosomal dominant multiple
cafe-au-lait spots and neurofibromatosis-1: evidence of non-linkage.
Am. J. Med. Genet. 45: 606-608, 1993.

4. Riccardi, V. M.: Pathophysiology of neurofibromatosis. IV. Dermatologic
insights into heterogeneity and pathogenesis. J. Am. Acad. Derm. 3:
157-166, 1980.

5. Whitehouse, D.: Diagnostic value of the cafe-au-lait spot in children.
Arch. Dis. Child. 41: 316-319, 1966.

*FIELD* CS

Skin:
   Multiple cafe-au-lait spots;
   No neurofibromas

Eyes:
   No Lisch nodules of the iris

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/24/1993

*FIELD* ED
mark: 03/01/1996
terry: 3/1/1996
mark: 1/20/1996
mark: 1/19/1996
mimadm: 4/9/1994
warfield: 3/31/1994
carol: 6/30/1993
carol: 3/24/1993

*RECORD*
*FIELD* NO
114050
*FIELD* TI
*114050 CALBINDIN 1; CALB1
CALB;;
CALBINDIN, 28-KD;;
CALBINDIN D28K
*FIELD* TX
Calbindin is a calcium-binding protein belonging to the troponin C
superfamily (see 191040). It was originally described as a 27-kD protein
induced by vitamin D in the duodenum of the chick. Calbindin
immunoreactivity was further detected by radioimmunoassay and
immunohistochemistry in the kidney, pancreatic islets, and brain. In the
brain, its synthesis is independent of vitamin-D-derived hormones. Two
different proteins presenting calbindin immunoreactivity, one of
molecular mass 27 kD (now known to be 28 kD) and the other of 29 kD
(114051), were identified in the central nervous system. Both molecular
species are present in the brain of all vertebrates except fish.
Parmentier et al. (1987) selected human 28-kD calbindin cDNA clones by
antibody screening of lambda-gt11 brain libraries. The sequence showed
an open reading frame coding for a protein of 261 amino acids,
containing 4 active calcium-binding domains, and 2 modified domains that
presumably have lost their calcium-binding capacity. The preliminary
data suggested that the 29-kD protein in brain is encoded by a different
gene. By means of immunohistochemical methods, Seto-Ohshima et al.
(1988) demonstrated a dearth of neurons containing calbindin in the
brains of patients with Huntington disease. Calbindin depletion was
particularly notable in the neostriatum (caudate nucleus and putamen) of
these patients. Parmentier and Vassart (1988) described a HindIII RFLP
of the calbindin 28-kilodalton gene. Parmentier et al. (1989) cloned and
sequenced the 5-prime and 3-prime regions of the calbindin 28-kD gene
and assigned it to chromosome 8 using human-rodent hybrid cell lines. By
Southern analysis of somatic cell hybrids and in situ hybridization,
Modi et al. (1991) assigned the CALB1 gene to 8p12-q11.2 Parmentier et
al. (1991) mapped the CALB1 gene to 8q21.3-q22.1 by in situ
hybridization. At the same time, they mapped the CALB2 gene, called by
them calretinin, to 16q22-q23, also by in situ hybridization. These
localizations matched the chromosomal regions where the carbonic
anhydrase isozyme gene cluster (CA1, 114800; CA2, 259730; CA3, 114750)
and the related gene CA7 (114770) have been described, respectively.
This suggests that in evolution a common duplication of the
calbindin/calretinin and carbonic anhydrase ancestral genes occurred.

*FIELD* RF
1. Modi, W. S.; Dean, M.; Pollock, D. D.; Seuanez, H. N.; Christakos,
S.: Chromosomal localization of the calbindin gene. (Abstract) Cytogenet.
Cell Genet. 58: 1930 only, 1991.

2. Parmentier, M.; De Vijlder, J. J. M.; Muir, E.; Szpirer, C.; Islam,
M. Q.; Geurts van Kessel, A.; Lawson, D. E. M.; Vassart, G.: The
human calbindin 27 kDa gene: structural organization of the 5-prime
and 3-prime regions, chromosomal assignment and restriction fragment
length polymorphism. Genomics 4: 309-319, 1989.

3. Parmentier, M.; Lawson, D. E. M.; Vassart, G.: Human 27-kDa calbindin
complementary DNA sequence: evolutionary and functional implications. Europ.
J. Biochem. 170: 207-215, 1987.

4. Parmentier, M.; Passage, E.; Vassart, G.; Mattei, M.-G.: The human
calbindin D28k (CALB1) and calretinin (CALB2) genes are located at
8q21.3-q22.1 and 16q22-q23, respectively, suggesting a common duplication
with the carbonic anhydrase isozyme loci. Cytogenet. Cell Genet. 57:
41-43, 1991.

5. Parmentier, M.; Vassart, G.: HindIII RFLP on chromosome 8 detected
with a calbindin 27 kDa cDNA probe, HBSC21. Nucleic Acids Res. 16:
9373 only, 1988.

6. Seto-Ohshima, A.; Emson, P. C.; Lawson, E.; Mountjoy, C. Q.; Carrasco,
L. H.: Loss of matrix calcium-binding protein-containing neurons
in Huntington's disease. Lancet I: 1252-1254, 1988.

*FIELD* CD
Victor A. McKusick: 2/23/1988

*FIELD* ED
mark: 03/05/1997
carol: 12/13/1994
supermim: 3/16/1992
carol: 2/21/1992
carol: 9/24/1991
carol: 8/8/1991
carol: 6/5/1991

*RECORD*
*FIELD* NO
114051
*FIELD* TI
*114051 CALBINDIN 2; CALB2
CALBINDIN, 29-KD;;
CALBINDIN D29K;;
CALRETININ
*FIELD* TX
Using a genomic fragment containing exon 2 of the brain calcium-binding
protein, calbindin 29 kD, in the study of human/rodent somatic cell
hybrids, Parmentier et al. (1989) assigned the gene to chromosome 16.
Chen et al. (1991) mapped the CALB2 gene and 11 others to the long arm
of chromosome 16 by the use of 14 mouse/human hybrid cell lines and the
fragile site FRA16B. The CALB2 gene was found to be in the distal
portion of band 16q22.1, just proximal to HP (140100) and just distal to
NMOR1 (DIA4; 125860). By in situ hybridization, Parmentier et al. (1991)
mapped the CALB2 gene, called by them calretinin, to 16q22-q23.

*FIELD* RF
1. Chen, L. Z.; Harris, P. C.; Apostolou, S.; Baker, E.; Holman, K.;
Lane, S. A.; Nancarrow, J. K.; Whitmore, S. A.; Stallings, R. L.;
Hildebrand, C. E.; Richards, R. I.; Sutherland, G. R.; Callen, D.
F.: A refined physical map of the long arm of human chromosome 16. Genomics 10:
308-312, 1991.

2. Parmentier, M.; Passage, E.; Vassart, G.; Mattei, M.-G.: The human
calbindin D28k (CALB1) and calretinin (CALB2) genes are located at
8q21.3-q22.1 and 16q22-q23, respectively, suggesting a common duplication
with the carbonic anhydrase isozyme loci. Cytogenet. Cell Genet. 57:
41-43, 1991.

3. Parmentier, M.; Szpirer, J.; Levan, G.; Vassart, G.: The human
genes for calbindin 27 and 29 kDa proteins are located on chromosomes
8 and 16, respectively. Cytogenet. Cell Genet. 52: 85-87, 1989.

*FIELD* CD
Victor A. McKusick: 3/27/1990

*FIELD* ED
mark: 03/05/1997
carol: 12/13/1994
supermim: 3/16/1992
carol: 10/10/1991
carol: 9/24/1991
carol: 6/5/1991
carol: 5/30/1991

*RECORD*
*FIELD* NO
114065
*FIELD* TI
114065 CALCIFIC AORTIC DISEASE WITH IMMUNOLOGIC ABNORMALITIES, FAMILIAL
*FIELD* TX
Tentolouris et al. (1993) described 2 sisters, aged 53 and 61 years, and
the 31-year-old son of the youngest sister who had linear calcification
of the ascending aorta and severe calcific mixed (stenotic and
regurgitant) aortic valve disease associated with increased levels of
globulins, lambda-chain gammopathy, an increased T4/T8 lymphocyte ratio,
and other immunologic abnormalities. A 38-year-old daughter of the older
sister had a history of severe aortic valve calcification with stenosis,
for which she underwent open heart surgery. The surgeon described a
peculiar severe nodular calcification that was 'scooped out' from the
aortic ring; the aortic valve was thought to be normally formed. The
findings were thought to resemble particularly those reported by
Goldbaum et al. (1986) who described a young woman with nodular
aggregates of amorphous calcific material on the aortic valve and
referred to a possible familial basis. Similar idiopathic calcification
of the ascending aorta and aortic valve was described in a young woman
by McLoughlin et al. (1974) and by Rose and Forman (1976). The first
case reported by McLoughlin et al. (1974) was studied also by Theman et
al. (1979), who reported on the pathologic findings: extensive medial
necrosis with secondary calcification of elastic tissue without evidence
of previous inflammation or other destructive or reparative processes.
Aortic calcification is an important feature of the Singleton-Merten
syndrome (182250), which is characterized also by dental dysplasia and
osteoporosis and other bone changes. Although syphilitic aortitis is
characterized by 'bark-like' linear calcification of the ascending aorta
caused by destruction of the media and resulting in dilatation and
aortic valve regurgitation without stenosis, these patients had no
clinical or serologic evidence of syphilis and had no risk factors or
signs pointing to precocious atherosclerosis.

*FIELD* RF
1. Goldbaum, T. S.; Lindsay, J., Jr.; Garcia, J. M.; Pichard, A. D.
: Ascending aortic calcification and calcific aortic stenosis in a
young woman. Am. Heart J. 111: 992-993, 1986.

2. McLoughlin, M. J.; Pasternac, A.; Morch, J.; Wigle, E. D.: Idiopathic
calcification of the ascending aorta and aortic valve in two young
women. Brit. Heart J. 36: 96-100, 1974.

3. Rose, A. G.; Forman, R.: Idiopathic aortitis with calcification
of ascending aorta, and aortic and mitral valves. Brit. Heart J. 38:
650-652, 1976.

4. Tentolouris, C.; Kontozoglou, T.; Toutouzas, P.: Familial calcification
of aorta and calcific aortic valve disease associated with immunologic
abnormalities. Am. Heart J. 126: 904-909, 1993.

5. Theman, T. E.; Silver, M. D.; Haust, M. D.; McLoughlin, M. J.;
Wigle, E. D.; Williams, W. R.: Morphological findings in idiopathic
calcification of the ascending aorta and aortic valve affecting a
young woman. Histopathology 3: 181-190, 1979.

*FIELD* CS

Cardiac:
   Nodular calcific aortic valve disease;
   Aortic stenosis;
   Aortic regurgitaton

Immunology:
   Increased levels of globulins;
   Lambda-chain gammopathy;
   Increased T4/T8 lymphocyte ratio

Lab:
   Extensive aortic medial necrosis with secondary calcification of elastic
   tissue without evidence of previous inflammation or other destructive
   or reparative processes

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 11/10/1993

*FIELD* ED
mimadm: 4/9/1994
carol: 11/15/1993
carol: 11/12/1993
carol: 11/10/1993

*RECORD*
*FIELD* NO
114070
*FIELD* TI
*114070 CALCIUM-BINDING PROTEIN p68; CBP68
ANNEXIN VI; ANX6;;
CALELECTRIN
*FIELD* TX
The calelectrins are abundant, evolutionarily conserved proteins, the
cellular function of which is unknown. They are distinguished by their
ability to bind reversibly to phospholipids and cell membranes in
physiologic concentrations of calcium ion. Three members of this protein
family with apparent molecular masses of 67 kD, 35 kD, and 32.5 kD have
been purified to homogeneity. Sudhof et al. (1988) reported the cDNA
cloning and primary structure of human 67 kD calelectrin. The deduced
sequence contains 8 similar repeats, each consisting of about 68 amino
acids. Comparison of the 67-kD calelectrin sequence with the protein
sequences of lipocortins I and II (151690, 151710) demonstrated a close
relationship (42-45% identity).

The protein p68 is a member of a family of proteins that bind membrane
or cytoskeleton in a Ca(2+)-dependent manner. They are characterized by
homologous amino acid sequences that are present in multiple copies in
each protein. The family is variously known as calelectrins, annexins,
calpactins, endonexins, and lipocortins. p68 is an intracellular
monomeric protein of approximately 68,000 MW. Davies et al. (1989)
assigned the gene to 5q32-q34 by use of a cDNA clone to probe genomic
DNA from rodent-human somatic cell hybrids and for in situ
hybridization. The corresponding gene in the mouse was assigned to
chromosome 11 by probing DNA from rodent-rodent somatic cell hybrids.
Warrington and Bengtsson (1994) used 3 physical mapping methods
(radiation hybrid mapping, pulsed field gel electrophoresis, and
fluorescence in situ hybridization of interphase nuclei) to determine
the order and relative distances between 12 loci in the 5q31-q33 region.
ANX6 was one of those loci.

Smith et al. (1994) demonstrated that the ANX6 gene is approximately 60
kb long and contains 26 exons. The genomic sequence at the 3-prime end
does not contain a canonical polyadenylylation signal. The genomic
sequence upstream of the transcription start site contains TATAA and
CAAT motifs. The spatial organization of the exons revealed no obvious
similarities between the 2 halves of the ANX6 gene. Comparison of the
intron/exon boundary positions of ANX6 with those of ANX1 (151690) and
ANX2 (151740) revealed that within the repeated domains the breakpoints
are perfectly conserved except for exon 8, which is 1 codon smaller in
ANX2. The corresponding point in the second half of ANX6 is represented
by 2 exons, exons 20 and 21. The latter exon is alternatively spliced,
giving rise to annexin VI isoforms that differ with respect to a 6-amino
acid insertion at the start of repeat 7.

*FIELD* RF
1. Davies, A. A.; Moss, S. E.; Crompton, M. R.; Jones, T. A.; Spurr,
N. K.; Sheer, D.; Kozak, C.; Crumpton, M. J.: The gene coding for
the p68 calcium-binding protein is localized to bands q32-q34 of human
chromosome 5, and to mouse chromosome 11. Hum. Genet. 82: 234-238,
1989.

2. Smith, P. D.; Davies, A.; Crumpton, M. J.; Moss, S. E.: Structure
of the human annexin VI gene. Proc. Nat. Acad. Sci. 91: 2713-2717,
1994.

3. Sudhof, T. C.; Slaughter, C. A.; Leznicki, I.; Barjon, P.; Reynolds,
G. A.: Human 67-kDa calelectrin contains a duplication of four repeats
found in 35-kDa lipocortins. Proc. Nat. Acad. Sci. 85: 664-668,
1988.

4. Warrington, J. A.; Bengtsson, U.: High-resolution physical mapping
of human 5q31-q33 using three methods: radiation hybrid mapping, interphase
fluorescence in situ hybridization, and pulsed-field gel electrophoresis.
Genomics 24: 395-398, 1994.

*FIELD* CD
Victor A. McKusick: 8/7/1989

*FIELD* ED
terry: 1/9/1995
jason: 7/15/1994
carol: 11/3/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/9/1990

*RECORD*
*FIELD* NO
114078
*FIELD* TI
*114078 CALMODULIN-DEPENDENT PROTEIN KINASE TYPE IIA; CAMK2A
*FIELD* TX
Using a molecular probe in the analysis of an interspecific backcross
between C57BL/6J and Mus spretus, Justice et al. (1992) mapped the gene
encoding calmodulin-dependent protein kinase IIA to mouse chromosome 18
in a region between that showing homology of synteny to human 5q and
that showing homology to human chromosome 18. Calmodulin-dependent
protein kinase type IV (CAMK4; 114080) maps to human chromosome 5.

Chen et al. (1994) showed that knockout mice deficient in the CAMK2A
gene showed behavioral abnormalities. The heterozygous mice exhibited a
well-circumscribed syndrome consisting primarily of a decreased fear
response and an increase in defensive aggression, in the absence of any
measured cognitive deficits. Unlike the heterozygote, the homozygote
displayed abnormal behavior in all paradigms tested. At the cellular
level, both extracellular and whole-cell patch clamp recordings
indicated that serotonin release in putative serotonergic neurons of the
dorsal raphe was reduced. Thus, the CAMK2A knockout mice, in particular
the heterozygote, may provide a model for studying the molecular and
cellular basis underlying emotional disorders involving fear and
aggression.

Rotenberg et al. (1996) studied the effects of an activated form
(CaMKII-Asp286) of Ca(2+)/calmodulin-dependent protein kinase in
transgenic mice. Normally, spatial location is encoded in the pattern of
firing of individual hippocampal pyramidal cells. When an animal moves
around in a familial environment, different place cells in the
hippocampus fire as the animal enters different regions of space.
Rotenberg et al. (1996) found that the CaMKII-Asp286 transgenic mice
lacked low frequency LTP and did not form stable 'place cells' in the
CA1 region of the hippocampus. Behaviorally, the mice were impaired in
spatial memory tasks. See 138249 for similar studies of mouse behavior
in NMDAR1-knockout mice.

*FIELD* RF
1. Chen, C.; Rainnie, D. G.; Greene, R. W.; Tonegawa, S.: Abnormal
fear response and aggressive behavior in mutant mice deficient for
alpha-calcium-calmodulin kinase II. Science 266: 291-294, 1994.

2. Justice, M. J.; Gilbert, D. J.; Kinzler, K. W.; Vogelstein, B.;
Buchberg, A. M.; Ceci, J. D.; Matsuda, Y.; Chapman, V. M.; Patriotis,
C.; Makris, A.; Tsichlis, P. N.; Jenkins, N. A.; Copeland, N. G.:
A molecular genetic linkage map of mouse chromosome 18 reveals extensive
linkage conservation with human chromosomes 5 and 18. Genomics 13:
1281-1288, 1992.

3. Rotenberg, A.; Mayford, M.; Hawkins, R. D.; Kandel, E. R.; Muller,
R. U.: Mice expressing activated CaMKII lack low frequency LTP and
do not form stable place cells in the CA1 region of the hippocampus. Cell 87:
1351-1361, 1996.

*FIELD* CN
Victor A. McKusick - updated: 2/6/1997

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
terry: 02/06/1997
terry: 2/6/1997
carol: 11/22/1994
terry: 11/21/1994
carol: 8/14/1992

*RECORD*
*FIELD* NO
114080
*FIELD* TI
*114080 CALMODULIN-DEPENDENT PROTEIN KINASE TYPE IV; CAMK4
BRAIN Ca(2+)/CALMODULIN-DEPENDENT PROTEIN KINASE TYPE IV
*FIELD* TX
Protein phosphorylation, a prominent activity in the brain, apparently
plays an important role in several neural functions such as neural
transmitter release, ion channel modulation, and axoplasmic transport.
Sikela et al. (1989) identified cDNA clones corresponding to a brain
Ca(2+)/calmodulin-dependent protein kinase, which they referred to as
brain CaM kinase IV. On the basis of Western blot analysis, this kinase
appeared to be restricted to brain in the rat; interestingly, it was not
detected in the brain of the newborn, but became detectable within a few
days after birth. Southern blot analysis showed the gene to be present
in single copy in the mouse and human genomes. Analysis of DNA from
hybrid cells showed that the gene is located on human chromosome 5 and
in situ hybridization indicated that the location is 5q21-q23. By
Southern blot analysis of Chinese hamster x mouse somatic cell hybrids,
Sikela et al. (1990) demonstrated that the homologous mouse locus,
Camk-4, maps to chromosome 18. Analysis of interspecific backcrosses
positioned Camk-4 in the centromeric region near 2 mutations known to
affect neurologic function and fertility. Sikela et al. (1990) raised
the possibility that a defect in Camk-4 may be responsible for 1 of
these mutant phenotypes.

*FIELD* RF
1. Sikela, J. M.; Adamson, M. C.; Wilson-Shaw, D.; Kozak, C. A.:
Genetic mapping of the gene for Ca(2+)/calmodulin-dependent protein
kinase IV (Camk-4) to mouse chromosome 18. Genomics 8: 579-582,
1990.

2. Sikela, J. M.; Law, M. L.; Kao, F.-T.; Hartz, J. A.; Wei, Q.; Hahn,
W. E.: Chromosomal localization of the human gene for brain Ca(2+)/calmodulin-dependent
protein kinase type IV. Genomics 4: 21-27, 1989.

*FIELD* CD
Victor A. McKusick: 6/12/1989

*FIELD* ED
carol: 3/26/1993
supermim: 3/16/1992
carol: 2/27/1992
carol: 2/4/1991
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
114085
*FIELD* TI
*114085 S100 CALCIUM-BINDING PROTEIN A10; S100A10
CALPACTIN I, LIGHT CHAIN; CAL1L;;
CALPACTIN I, p11 SUBUNIT; CLP11;;
ANNEXIN II LIGAND; ANX2LG
*FIELD* TX
The response to elevation of cytoplasmic Ca(2+) levels following extra-
or intracellular stimuli is mediated by proteins that are capable of
binding divalent calcium ions. A particular class of these proteins is
characterized by the so-called EF-hand, a helix-loop-helix motif
involved in coordinating the Ca(2+) ion. Within the EF-hand superfamily,
a distinct set of proteins is grouped in the so-called S-100 protein
family (see S100A1; 176940 and S100B; 176990), whose members share a
high degree of sequence similarity with S-100A and S-100B,
Ca(2+)-binding proteins originally isolated from cerebrospinal fluid.
Protein p11 (calpactin I, light chain) is a member of the S-100 family
but has several unique features. It has suffered crucial deletions and
amino acid substitutions which are thought to render both Ca(2+)-binding
sites inactive. In all tissues and cells studied, p11 is found in a
heterotetrameric complex with another Ca(2+)-binding protein, annexin II
(ANX2, LIP2; 151740). Some of the biochemical properties of annexin II
are modulated by p11-induced complex formation, which involves the
binding of one p11 dimer to 2 annexin II monomers. The p11 calpactin I
light chain is an intracellular polypeptide of 97 amino acid residues
that associates with the calpactin I heavy chain, p36, to form a
calcium-binding complex (Saris et al., 1987). The p11 subunit is a
protein kinase substrate and likely plays a role in the regulation of
p36 phosphorylation/activity.

Harder et al. (1992) isolated the gene encoding p11 (CLP11) from a human
genomic library. Restriction mapping and sequencing showed that CLP11
covers a stretch of approximately 11 kb. As in other genes encoding
S-100 proteins, the transcribed region is divided by 2 introns, one in
the 5-prime untranslated portion and the other in the protein coding
region. As in all other S-100 genes, the second intron separates the
codons for 2 corresponding amino acids which reside in the sequence
connecting the 2 helix-loop-helix (EF-hand) motifs. The 5-prime
untranslated region, which most likely represents the CLP11 promoter, is
characterized by high G+C content and is probably part of a CpG island.
Several putative binding sites for transcription factors were identified
in the 5-prime untranslated region. Among them, the beta-DRE element,
which was first described in the beta-globin promoter (141900), is most
notable, since it is also present in the promoter of the ANX2 gene. It
could be responsible for the simultaneous induction of CLP11 and ANX2
expression during certain cell differentiation processes.

Kube et al. (1991) and Dooley et al. (1992) cloned and sequenced the
cDNA for the full-length human p11 calpactin I light chain. In
connection with the possible location of the gene on human chromosome 1
(predicted by homology with the mouse), it is notable that several
S100-related genes--CAGA (S100A8; 123885), CAGB (S100A9; 123886), CACY
(S100A6; 114110), and CAPL (S100A4; 114210)--are also located on 1q in
its proximal portion. Dooley (1992) indicated that the calpactin I light
chain (p11) is distinct from calgranulin A (CAGA; also known as S100A8).
The CAGA gene codes for the 11-kD subunit of a cystic fibrosis antigen.
Volz et al. (1993) demonstrated that the human CAL1L gene is indeed on
1q21, physically linked within 2.05 Mb of DNA to the genes encoding
trichohyalin (190370), filaggrin (135940), involucrin (147360), loricrin
(152445), and calcyclin (S100A6; 114110), in that order.

The mouse p11 gene is located on chromosome 3 in a region of homology
with human chromosome 1, i.e., 1q21. The mouse gene is highly expressed
in a number of epithelial-containing tissues such as intestine, kidney,
and lung.

Schafer et al. (1995) isolated a YAC from 1q21 on which 9 different
genes coding for S100 calcium-binding proteins could be localized. The
clustered organization of S100 genes allowed introduction of a new
logical nomenclature based on their physical arrangement on the
chromosome, with S100A1 (176940) being closest to the telomere and
S100A9 being closest to the centromere. In the new nomenclature, CAL1L
became S100A10.

*FIELD* RF
1. Dooley, T. P.: Personal Communication. San Antonio, Tex.  7/21/1992.

2. Dooley, T. P.; Weiland, K. L.; Simon, M.: cDNA sequence of human
p11 calpactin I light chain. Genomics 13: 866-868, 1992.

3. Harder, T.; Kube, E.; Gerke, V.: Cloning and characterization
of the human gene encoding p11: structural similarity to other members
of the S-100 gene family. Gene 113: 269-274, 1992.

4. Kube, E.; Weber, K.; Gerke, V.: Primary structure of human, chicken,
and Xenopus laevis p11, a cellular ligand of the Src-kinase substrate,
annexin II. Gene 102: 255-259, 1991.

5. Saris, C. J. M.; Kristensen, T.; D'Eustachio, P.; Hicks, L. J.;
Noonan, D. J.; Hunter, T.; Tack, B. F.: cDNA sequence and tissue
distribution of the mRNA for bovine and murine p11, the S100-related
light chain of the protein-tyrosine kinase substrate p36 (calpactin
I). J. Biol. Chem. 262: 10663-10671, 1987.

6. Schafer, B. W.; Wicki, R.; Engelkamp, D.; Mattei, M.-G.; Heizmann,
C. W.: Isolation of a YAC clone covering a cluster of nine S100 genes
on human chromosome 1q21: rationale for a new nomenclature of the
S100 calcium-binding protein family. Genomics 25: 638-643, 1995.

7. Volz, A.; Korge, B. P.; Compton, J. G.; Ziegler, A.; Steinert,
P. M.; Mischke, D.: Physical mapping of a functional cluster of epidermal
differentiation genes on chromosome 1q21. Genomics 18: 92-99, 1993.

*FIELD* CD
Victor A. McKusick: 9/16/1992

*FIELD* ED
mark: 12/21/1996
mark: 6/15/1995
jason: 7/14/1994
warfield: 4/7/1994
carol: 10/14/1993
carol: 10/5/1993
carol: 9/16/1992

*RECORD*
*FIELD* NO
114090
*FIELD* TI
*114090 CALPASTATIN; CAST
*FIELD* TX
Calpastatin is the natural inhibitor of calpain (114170). In
erythrocytes of patients with essential hypertension (145500), the level
of calpastatin activity has been found to be significantly lower than in
the red cells of normotensive subjects. Pontremoli et al. (1988)
demonstrated by Western blot analysis that the decreased inhibitor
activity is the result of a decrease in the amount of the inhibitor
protein. Calpastatin isolated and purified from erythrocytes of
normotensive and hypertensive patients had identical specific
activities. Pontremoli et al. (1988) also presented evidence indicating
that the decreased level of calpastatin cannot be ascribed to
accelerated decay during the red cell life span. Using a cDNA probe
encoding the 5-prime terminal region of CAST for spot-blot analysis of
sorted chromosomes and chromosomal in situ hybridization, Inazawa et al.
(1990) assigned the CAST gene to 5q14-q22. Inazawa et al. (1991) mapped
CAST to 5q15-q21 by 2 methods of in situ hybridization and confirmed the
results by spot-blot analysis of sorted chromosomes. Mimori et al.
(1995) demonstrated that anti-calpastatin autoantibodies are present in
as many as 57% of rheumatoid arthritis patients and concluded that they
may participate in pathogenic mechanisms of this and other rheumatic
diseases which showed a lower frequency.

*FIELD* RF
1. Inazawa, J.; Nakagawa, H.; Misawa, S.; Abe, T.; Minoshima, S.;
Fukuyama, R.; Maki, M.; Murachi, T.; Hatanaka, M.; Shimizu, N.: Assignment
of the human calpastatin gene (CAST) to chromosome 5 at region q14-q22.
Cytogenet. Cell Genet. 54: 156-158, 1990.

2. Inazawa, J.; Nakagawa, H.; Misawa, S.; Abe, T.; Minoshima, S.;
Fukuyama, R.; Maki, M.; Murachi, T.; Hatanaka, M.; Shimizu, N.: Assignment
of the human calpastatin gene (CAST) to chromosome 5 at region q15-q21.
(Abstract) Cytogenet. Cell Genet. 58: 1898 only, 1991.

3. Mimori, T.; Suganuma, K.; Tanami, Y.; Nojima, T.; Matsumura, M.;
Fujii, T.; Yoshizawa, T.; Suzuki, K.; Akizuki, M.: Autoantibodies
to calpastatin (an endogenous inhibitor for calcium-dependent neutral
protease, calpain) in systemic rheumatic diseases. Proc. Nat. Acad.
Sci. 92: 7267-7271, 1995.

4. Pontremoli, S.; Salamino, F.; Sparatore, B.; De Tullio, R.; Pontremoli,
R.; Melloni, E.: Characterization of the calpastatin defect in erythrocytes
from patients with essential hypertension. Biochem. Biophys. Res.
Commun. 157: 867-874, 1988.

*FIELD* CD
Victor A. McKusick: 3/20/1989

*FIELD* ED
mark: 9/19/1995
supermim: 3/16/1992
carol: 2/21/1992
carol: 8/8/1991
carol: 2/26/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
114100
*FIELD* TI
114100 CALCIFICATION OF BASAL GANGLIA WITH OR WITHOUT HYPOCALCEMIA
BASAL GANGLION CALCIFICATION
*FIELD* TX
Nichols et al. (1961) reported a family in 3 generations of which
members had a syndrome of calcification of the basal ganglia and
hypocalcemia. It is not clear what relation these cases may have to
pseudohypoparathyroidism. Roberts (1959) had reported a rather similar
family with 6 affected persons in 2 generations, including an instance
of male-to-male transmission. Nigra (1970) restudied the family of
Nichols et al. (1961) and found no evidence of parathormone
unresponsiveness. Moskowitz et al. (1971) studied 5 cases in 3 sibships
in 2 generations with male-to-male transmission. A greater than normal
response of 3 prime, 5 prime-AMP to parathormone was observed. Moskowitz
et al. (1971) concluded that there are both autosomal dominant and
autosomal recessive forms of idiopathic basal ganglion calcification.
Male-to-male transmission was noted in some families, parental
consanguinity in others. Significant neurologic abnormality related to
basal ganglion dysfunction (choreoathetosis, parkinsonism-like state,
etc.) was observed. Hypocalcemia was not present, as it was in Nichol's
family. Boller et al. (1973) described palilalia (compulsive repetition
of a phrase or word) in mother and son with intracranial calcifications.
Asymptomatic intracranial calcifications were present in other members
of the family. In a later report, Boller et al. (1977) showed that 9
members of this family spanning 3 generations had bilateral
calcifications of the basal ganglia. There were examples of male-to-male
transmission. The palilalia in the mother and son was accompanied by
chorea and dementia beginning in the third or fourth decade. A third
member was thought to show initial stages of a similar syndrome. Six
members with calcifications but without neurologic signs were younger
than 25 years. All 9 patients had normal calcium and phosphorus, and no
evidence of endocrinologic or somatic abnormalities. An apparently
recessive form of basal ganglion calcification was associated with
steatorrhea and mental retardation in 4 of 16 sibs in a family reported
by Cockel et al. (1973). Autopsy showed normal parathyroid glands.
Francis (1979) described a family in which schizophreniform psychosis
was associated with basal ganglia consistent with either autosomal or
X-linked dominance. There were no skeletal or biochemical signs of
pseudohypoparathyroidism. Calcification first became evident by x-ray at
puberty. Developmental delay occurred in 2 brothers whose mother was
affected. One person had progressive parkinsonism and 4 had
extrapyramidal symptoms attributed to phenothiazine medication, to whose
unwanted effects the patients may be unusually sensitive. The authors
pointed out that a schizophrenia-like psychosis has been noted with
other disorders of the basal ganglia including Wilson disease and
Huntington chorea.

*FIELD* SA
Puvanendran and Wong (1980); Schlafroth  (1958)
*FIELD* RF
1. Boller, F.; Boller, M.; Denes, G.; Timberlake, W. H.; Zieper, I.;
Albert, M. S.: Familial palilalia. Neurology 23: 1117-1125, 1973.

2. Boller, F.; Boller, M.; Gilbert, J.: Familial idiopathic cerebral
calcifications. J. Neurol. Neurosurg. Psychiat. 40: 280-285, 1977.

3. Cockel, R.; Hill, E. E.; Rushton, D. I.; Smith, B.; Hawkins, C.
F.: Familial steatorrhoea with calcification of the basal ganglia
and mental retardation. Quart. J. Med. 42: 771-783, 1973.

4. Francis, A. F.: Familial basal ganglia calcification and schizophreniform
psychosis. Brit. J. Psychiat. 135: 360-362, 1979.

5. Moskowitz, M. A.; Winickoff, R. N.; Heinz, E. R.: Familial calcification
of the basal ganglions: a metabolic and genetic study. New Eng.
J. Med. 285: 72-77, 1971.

6. Nichols, F. L.; Holdsworth, D. E.; Reinfrank, R. F.: Familial
hypocalcemia, latent tetany and calcification of the basal ganglia.
Am. J. Med. 30: 518-528, 1961.

7. Nigra, T. P.: Personal Communication. Bethesda, Md.  1970.

8. Puvanendran, K.; Wong, P. K.: Idiopathic familial basal ganglia
calcification associated with juvenile hypertension.  (Letter) J.
Neurol. Neurosurg. Psychiat. 43: 288 only, 1980.

9. Roberts, P. D.: Familial calcification of the cerebral basal ganglia
and its relation to hypoparathyroidism. Brain 82: 599-609, 1959.

10. Schlafroth, H. J.: Familiaere symmetrische Gehirnverkalkung.
Schweiz. Med. Wschr. 88: 1269-1273, 1958.

*FIELD* CS

Radiology:
   Basal ganglia calcification

Neuro:
   Choreoathetosis;
   Parkinsonism-like state;
   Palilalia;
   Dementia

Misc:
   Steatorrhea and mental retardation in recessive form;
   ? unusually sensitive to side effects of phenothiazine

Lab:
   Variable hypocalcemia

Inheritance:
   Autosomal dominant and autosomal recessive forms

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
warfield: 4/7/1994
carol: 4/7/1992
supermim: 3/16/1992
carol: 2/28/1992
carol: 2/11/1992

*RECORD*
*FIELD* NO
114105
*FIELD* TI
*114105 PROTEIN PHOSPHATASE 3, CATALYTIC SUBUNIT, ALPHA ISOFORM; PPP3CA
CALCINEURIN A; CALNA;;
CALCINEURIN A1; CALNA1;;
CALCINEURIN A-ALPHA;;
PROTEIN PHOSPHATASE 2B, CATALYTIC SUBUNIT, ALPHA ISOFORM; PPP2B, FORMERLY
*FIELD* TX
Calcineurin, the Ca(2+)/calmodulin-regulated protein phosphatase, first
detected in skeletal muscle and brain, has been found in all cells from
yeast to mammals. It is a heterodimer of a 19-kD Ca(2+)-binding protein,
calcineurin B, and a 61-kD calmodulin-binding catalytic subunit,
calcineurin A. Guerini and Klee (1989) presented evidence that the
different forms of calcineurin A result from alternative splicing.

Multiple catalytic subunits of calcineurin are derived from at least 2
structural genes, type 1 (calcineurin A-alpha) and type 2 (calcineurin
A-beta), each of which can produce alternatively spliced transcripts. By
the analysis of genomic DNA from human/hamster hybrid cell lines using
probes designed to bind selectively to exon 3 of the open reading frame,
Giri et al. (1991) found from hybridization to Southern blots that CNA1
mapped to chromosome 4, whereas CNA2 mapped to chromosome 10.

By Southern analysis of somatic cell hybrids, Wang et al. (1996)
confirmed assignment of the CALNA gene to chromosome 4 and used the
approved gene symbol PPP3CA.

*FIELD* RF
1. Giri, P.; Higuchi, S.; Kincaid, R. L.: Chromosomal mapping of
the human genes for the calmodulin-dependent protein phosphatase (calcineurin)
catalytic subunit. Biochem. Biophys. Res. Commun. 181: 252-258,
1991.

2. Guerini, D.; Klee, C. B.: Cloning of human calcineurin A: evidence
for two isozymes and identification of a polyproline structural domain.
Proc. Nat. Acad. Sci. 86: 9183-9187, 1989.

3. Wang, M. G.; Yi, H.; Guerini, D.; Klee, C. B.; McBride, O. W.:
Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin
B (PPP3R1) are located on human chromosomes 4, 10q21-q22 and 2p16-p15
respectively. Cytogenet. Cell Genet. 72: 236-241, 1996.

*FIELD* CD
Victor A. McKusick: 1/10/1990

*FIELD* ED
mark: 06/11/1996
terry: 6/6/1996
mark: 8/21/1995
carol: 4/28/1994
carol: 10/21/1993
carol: 4/2/1993
supermim: 3/16/1992
carol: 1/22/1992

*RECORD*
*FIELD* NO
114106
*FIELD* TI
*114106 PROTEIN PHOSPHATASE 3, CATALYTIC SUBUNIT, BETA ISOFORM; PPP3CB
CALCINEURIN A-BETA;;
CALCINEURIN A2; CALNA2;;
CALCINEURIN B; CALNB, FORMERLY;;
PROTEIN PHOSPHATASE 2B, CATALYTIC SUBUNIT, BETA ISOFORM, FORMERLY
*FIELD* TX
See 114105. Guerini et al. (1989) identified and cloned human cDNA for
the Ca(2+)-binding subunit of calcineurin, the brain isozyme of the
Ca(2+)/calmodulin-stimulated protein phosphatase. The 2.5-kb cDNA had an
open reading frame of 510 bp, a leader sequence of at least 500 bp, and
a 1,277-bp 3-prime-noncoding sequence. As was observed with protein
levels, mRNA abundance in brain was 20 to 60 times that found in other
tissues with the exception of HeLa cells which, like brain, contained
abundant calcineurin B mRNA.

By Southern analysis of human/hamster hybrid cell lines, Giri et al.
(1991) demonstrated that the CNA2 gene is located on chromosome 10. Wang
et al. (1996) confirmed the assignment to chromosome 10 by Southern blot
analysis and regionalized the assignment to 10q21-q22 by isotopic in
situ hybridization.

*FIELD* RF
1. Giri, P.; Higuchi, S.; Kincaid, R. L.: Chromosomal mapping of
the human genes for the calmodulin-dependent protein phosphatase (calcineurin)
catalytic subunit. Biochem. Biophys. Res. Commun. 181: 252-258,
1991.

2. Guerini, D.; Krinks, M. H.; Sikela, J. M.; Hahn, W. E.; Klee, C.
B.: Isolation and sequence of a cDNA clone for human calcineurin
B, the Ca(2+)-binding subunit of the Ca(2+)/calmodulin-stimulated
protein phosphatase. DNA 8: 675-682, 1989.

3. Wang, M. G.; Yi, H.; Guerini, D.; Klee, C. B.; McBride, O. W.:
Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin
B (PPP3R1) are located on human chromosomes 4, 10q21-q22 and 2p16-p15
respectively. Cytogenet. Cell Genet. 72: 236-241, 1996.

*FIELD* CD
Victor A. McKusick: 1/22/1992

*FIELD* ED
mark: 06/11/1996
terry: 6/6/1996
carol: 4/28/1994
carol: 10/21/1993
carol: 4/2/1993
supermim: 3/16/1992
carol: 1/22/1992

*RECORD*
*FIELD* NO
114107
*FIELD* TI
*114107 CALCINEURIN A3; CALNA3
CALCINEURIN A-GAMMA;;
CALCINEURIN, TESTIS-SPECIFIC CATALYTIC SUBUNIT;;
PROTEIN PHOSPHATASE 2B, CATALYTIC SUBUNIT, GAMMA ISOFORM;;
PROTEIN PHOSPHATASE 3, CATALYTIC SUBUNIT, GAMMA ISOFORM; PPP3CC
*FIELD* TX
Calmodulin-dependent protein phosphatase, calcineurin, is involved in a
wide range of biologic activities, acting as a Ca(2+)-dependent modifier
of phosphorylation status. In testis, the motility of the sperm is
thought to be controlled by cAMP-dependent phosphorylation and a unique
form of calcineurin appears to be associated with the flagellum. The
calcineurin holoenzyme is composed of catalytic and regulatory subunits
of 60 and 18 kD, respectively. At least 3 genes have been cloned for the
catalytic subunit. Two of these genes, calcineurin A-alpha (CALNA1;
114105) and calcineurin A-beta (CALNA2; 114106), are highly expressed in
brain and alternatively spliced variants are known. These genes have
been identified in humans, mice, and rats, and are highly conserved
between species (90-95% amino acid identity).

Muramatsu and Kincaid (1992) cloned from a human testis library a cDNA
for an alternatively spliced variant of the testis-specific catalytic
subunit, calcineurin A-gamma. The nucleotide sequence of 2,134 bp
encoded a protein of 502 amino acids. The cDNA sequence differed from
the murine form of the gene by a 30-bp deletion in the coding region,
the position of which matched those in the 2 other genes for the
catalytic subunit. The findings indicated that the alternative splicing
event occurred before divergence of the 3 genes. The deduced sequence of
the human protein was only 88% identical to the homologous murine form;
this indicated a more rapid rate of evolution for the testis-specific
gene. Analysis of Southern blots containing DNA from human-hamster
somatic cell hybrids showed that the gene is located on human chromosome
8.

*FIELD* RF
1. Muramatsu, T.; Kincaid, R. L.: Molecular cloning and chromosomal
mapping of the human gene for the testis-specific catalytic subunit
of calmodulin-dependent protein phosphatase (calcineurin A). Biochem.
Biophys. Res. Commun. 188: 265-271, 1992.

*FIELD* CD
Victor A. McKusick: 11/24/1992

*FIELD* ED
carol: 5/10/1994
carol: 4/2/1993
carol: 11/24/1992

*RECORD*
*FIELD* NO
114110
*FIELD* TI
*114110 S100 CALCIUM-BINDING PROTEIN A6; S100A6
CALCYCLIN; CACY
*FIELD* TX
Calcyclin was originally defined as a cDNA clone (2A9) whose cognate RNA
was found to be growth-regulated and whose sequence showed strong
similarities to that of the S-100 protein, a calcium-binding protein, as
well as to a subunit of the major cellular substrate for tyrosine
kinase. Using a full-length cDNA, Ferrari et al. (1987) isolated the
entire calcyclin gene plus extensive flanking sequences. They found that
the calcyclin gene is present in single copy and has 3 exons. By in situ
hybridization, they determined that the CACY gene is located in the
1q21-q25 segment. By linkage studies of interspecific backcrosses of Mus
spretus and Mus musculus domesticus, Seldin (1989) demonstrated that the
Cacy gene is located on mouse chromosome 3. Using cDNA probes for CACY,
van Heyningen et al. (1989) and Dorin et al. (1990) showed that the gene
cosegregates with CAGA (S100A8; 123885) and CAGB (S100A9; 123886), which
are located on 1q12-q21.

In the course of constructing a physical map of human 1q21-q23, Oakey et
al. (1992) determined that the CACY gene is located at the centromeric
end of that segment, proximal to SPTA1 (182860).

Schafer et al. (1995) isolated a YAC from 1q21 on which 9 different
genes coding for S100 calcium-binding proteins could be localized. The
clustered organization of S100 genes allowed introduction of a new
logical nomenclature based on their physical arrangement on the
chromosome with S100A1 (176940) being closest to the telomere and S100A9
being closest to the centromere. In the new nomenclature, CACY became
S100A6.

*FIELD* RF
1. Dorin, J. R.; Emslie, E.; van Heyningen, V.: Related calcium-binding
proteins map to the same subregion of chromosome 1q and to an extended
region of synteny on mouse chromosome 3. Genomics 8: 420-426, 1990.

2. Ferrari, S.; Calabretta, B.; deRiel, J. K.; Battini, R.; Ghezzo,
F.; Lauret, E.; Griffin, C.; Emanuel, B. S.; Gurrieri, F.; Baserga,
R.: Structural and functional analysis of a growth-regulated gene,
the human calcyclin. J. Biol. Chem. 262: 8325-8332, 1987.

3. Oakey, R. J.; Watson, M. L.; Seldin, M. F.: Construction of a
physical map on mouse and human chromosome 1: comparison of 13 Mb
of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620,
1992.

4. Schafer, B. W.; Wicki, R.; Engelkamp, D.; Mattei, M.-G.; Heizmann,
C. W.: Isolation of a YAC clone covering a cluster of nine S100 genes
on human chromosome 1q21: rationale for a new nomenclature of the
S100 calcium-binding protein family. Genomics 25: 638-643, 1995.

5. Seldin, M. F.: Personal Communication. Durham, N. C.  3/13/1989.

6. van Heyningen, V.; Emslie, E.; Dorin, J. R.: Related calcium binding
proteins map to the same sub-region of chromosome 1q and to an extended
region of synteny on mouse chromosome 3. (Abstract) Cytogenet. Cell
Genet. 51: 1095 only, 1989.

*FIELD* CD
Victor A. McKusick: 6/30/1987

*FIELD* ED
mark: 12/21/1996
mark: 6/15/1995
carol: 1/23/1995
carol: 10/21/1993
carol: 2/9/1993
supermim: 3/16/1992
carol: 11/28/1990

*RECORD*
*FIELD* NO
114120
*FIELD* TI
114120 CALCINOSIS, TUMORAL
*FIELD* TX
Most findings point to autosomal recessive inheritance of
hyperphosphatemic tumoral calcinosis (see 211900). However, Lyles et al.
(1985) studied a kindred in which they concluded that the disorder was
inherited as an autosomal dominant. Nine affected persons were
identified in 4 generations. They used a unique dental lesion as a
phenotypic marker. The teeth are hypoplastic but have fully developed
enamel of normal color. Panoramic x-rays showed short, bulbous roots and
almost complete obliteration of pulp cavities. By histology dentin in
the radicular portion was deposited in swirls, and true pulp stones
almost completely filled the pulp cavity. Elevated serum
1,25-dihydroxyvitamin D levels were found in all affected persons even
though some did not show classic findings of tumoral calcinosis.

*FIELD* RF
1. Lyles, K. W.; Burkes, E. J.; Ellis, G. J.; Lucas, K. J.; Dolan,
E. A.; Drezner, M. C.: Genetic transmission of tumoral calcinosis:
autosomal dominant with variable clinical expressivity. J. Clin.
Endocr. Metab. 60: 1093-1096, 1985.

*FIELD* CS

Oncology:
   Hyperphosphatemic tumoral calcinosis

Teeth:
   Hypoplastic teeth with normal enamel and color

Radiology:
   Short, bulbous tooth roots with almost complete obliteration of pulp
   cavities

Lab:
   Histology shows dentin deposited in swirls in the radicular portion,
   and true pulp stones almost completely filling the pulp cavity;
   Elevated serum 1,25-dihydroxyvitamin D levels

Inheritance:
   Autosomal dominant and autosomal recessive forms

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
114130
*FIELD* TI
*114130 CALCITONIN/CALCITONIN-RELATED POLYPEPTIDE, ALPHA; CALCA
CALCITONIN; CALC1; CT;;
CALCITONIN GENE-RELATED PEPTIDE; CGRP
KATACALCIN, INCLUDED
*FIELD* TX
Calcitonin is a peptide hormone synthesized by the parafollicular cells
of the thyroid. It causes reduction in serum calcium--an effect opposite
to that of parathyroid hormone (PTH; 168450). Human calcitonin contains
32 amino acids and has a molecular weight of 3,421. See Dayhoff (1972)
for amino acid sequence data. Multiple calcitonin polypeptides are
encoded in a single messenger RNA (Jacobs et al., 1981). Rosenfeld et
al. (1982) presented evidence that alternative RNA splicing of the
transcripts of the calcitonin gene is responsible for the production of
different polypeptide products. See Amara et al. (1982). Genomic mapping
results are consistent with the existence of a single calcitonin gene
(Rosenfeld et al., 1982).

Katacalcin (kata-, Gr. down) was the name given by A. P. Waterson to a
21-amino acid peptide that flanks calcitonin on its C-terminal side in
the large precursor polyprotein from which calcitonin is cleaved. Its
concentration is higher in males than in females and approximately
equimolar with calcitonin; doubles within 5 min of calcium infusion; and
is markedly raised in cases of medullary thyroid carcinoma. Katacalcin
is a new hormone discovered by use of recombinant DNA technology rather
than by traditional techniques of tissue extraction and purification
based on biologic assay; like calcitonin, it may be involved in both
plasma calcium regulation and skeletal maintenance (Hillyard et al.,
1983). Rosenfeld et al. (1983) showed that alternative processing of the
RNA transcribed from the calcitonin gene results in the production of an
mRNA in neural tissue distinct from that in thyroidal 'C' cells. The
novel neuropeptide was referred to as calcitonin gene-related peptide
(CGRP). The distribution of CGRP-producing cells and pathways in the
brain and other tissues suggests functions for CGRP in nociception,
ingestive behavior, and modulation of the autonomic and endocrine
systems. The approach described here has general applicability, viz.,
the use of recombinant DNA technology to analyze complex neurobiologic
systems in the absence of prior structural or biologic information.
CGRP-containing neurons were detected particularly in association with
heart and blood vessels. CGRP was shown to have potent vasodilator
action and probably is an important regulator of vascular tone and blood
flow (Tippins, 1986). Tschopp et al. (1985) determined the location of
CGRP and its binding sites in the CNS and pituitary. Goltzman and
Mitchell (1985) identified discrete receptors for CT and CGRP in the
nervous system and in peripheral tissues. Tiller-Borcich et al. (1988)
found that CGRP is concentrated in the locus caeruleus in the human.
CGRP has very potent hemodynamic activity, and the locus caeruleus is
the main source of noradrenergic neurotransmission in the CNS.

Using a molecular probe containing a 584-basepair sequence corresponding
to part of the human calcitonin mRNA in the study of somatic cell
hybrids, Hoppener et al. (1984) assigned the calcitonin gene to
11p14-qter. The calcitonin gene was found to contain a polymorphic site
for restriction endonuclease TaqI. Przepiorka et al. (1984) mapped the
calcitonin gene to 11p by molecular hybridization of a human calcitonin
cDNA probe to DNA from human-rodent hybrid cells. In situ hybridization
narrowed the assignment to 11p15-p13. In a cell line derived from a
particular virulent medullary carcinoma of the thyroid, Testa (1984)
found a chromosomal rearrangement affecting 11p. Simpson et al. (1984)
assigned the calcitonin gene to chromosome 11 by use of a cDNA clone
isolated from medullary thyroid carcinoma and a somatic cell hybrid
panel. With a TaqI RFLP detected by this probe, they studied linkage of
the calcitonin locus and MEN2; negative lod scores were found at all
recombination values. In 2 tumors with mitotic deletions, Henry et al.
(1989) found that CALCA must lie distal to PTH in 11p15.5; in both
tumors the CALCA locus was lost and the PTH locus retained. It may be of
functional significance that the PTH and calcitonin genes are close
together, since they are the yin and the yang of the control of calcium
metabolism. In the mouse, both PTH and calcitonin are coded by
chromosome 7 (Lalley et al., 1987). Hoppener et al. (1988) described a
calcitonin pseudogene and reviewed information on the CALC genes. The
CALC1 gene produces calcitonin (encoded by exon 4) or calcitonin
gene-related peptide (encoded by exon 5) in a tissue-specific fashion.
The CALC2 gene (CALCB; 114160) produces a second calcitonin gene-related
peptide, but probably not a second calcitonin. The presumed pseudogene
CALC3 does not seem to encode either peptide. Like the other 2 CALC
genes, the CALC3 gene was found to be located on human chromosome 11
(Hoppener et al., 1988). Hoovers et al. (1993) used fluorescence in situ
hybridization to prometaphase chromosomes, pulsed field gel
electrophoresis analysis, and 2-color in situ hybridization to
interphase nuclei to map CALCA, CALCB, and the pseudogene CALC3 to a
220-kb SacII fragment on 11p15.2-p15.1. The related islet amyloid
polypeptide (IAPP; 147940) gene was assigned to 12p12.3-p12.1 by the
same methods. The results supported the evolutionary relationship
between the calcitonin/CGRP genes and the IAPP gene and between parts of
human chromosomes 11 and 12.

Breimer et al. (1988) reviewed the organization, expression, and
splicing of the calcitonin genes and the structure and function of the
peptides they encode. The alpha-calcitonin/CGRP gene stretches over
approximately 6.5 kb and consists of 6 exons. The first 3 exons are
present in both calcitonin and CGRP mRNA, although exon 1 is not
translated. Exon 4 contains the calcitonin-coding sequence. Exon 5
encodes the CGRP sequence. The organization of the beta gene is similar
to that of the alpha gene, and it is likely that the 2 arose by
duplication. There is no evidence for the production of calcitonin mRNA
from the beta gene. Perhaps the beta gene allows the expression of CGRP
at sites or in circumstances where the inadvertent production of
calcitonin could be deleterious. Mathe et al. (1994) examined the
concentration of calcitonin gene-related peptide immunoreactivity in the
cerebrospinal fluid of 63 patients with major depression (cf., 125480)
with that found in cerebrospinal fluid of 28 patients with schizophrenia
(e.g., 181510) and 20 controls. Patients with all forms of major
depression had higher levels of this peptide in the spinal fluid than
did patients with schizophrenia or controls. The authors suggested that
the increased concentration of CGRP may be a marker trait of major
depressive disorder.

*FIELD* AV
.0001
OSTEOPOROSIS
CALCA, 1-BP INS, IVS4
In a young male patient with osteoporosis, Alevizaki et al. (1989) found
a 1-bp (T) insertion in the calcitonin gene. The patient had no
detectable plasma concentrations of calcitonin and had responded well to
calcitonin replacement treatment for 9 years. Genomic Southern blots
with various restriction enzymes showed no large abnormalities in his
calcitonin gene. The extra nucleotide was inserted at position 462 in
the intron separating exons 4 and 5. The extra base was contiguous to a
CTGAC sequence that is the consensus sequence for formation of a branch
point during splicing, as shown by a similar intronic sequence in the
beta-globin gene. Presumably the mutation interferes with the splice
that leads to production of CGRP.

*FIELD* SA
Edbrooke et al. (1985); Girgis et al. (1985); Jonas et al. (1985);
Kittur et al. (1985); MacIntyre et al. (1982); Neher et al. (1968);
New and Mudge (1986); Struthers et al. (1986)
*FIELD* RF
1. Alevizaki, M.; Stevenson, J. C.; Girgis, S. I.; MacIntyre, I.;
Legon, S.: Altered calcitonin gene in a young patient with osteoporosis.
Brit. Med. J. 298: 1215-1216, 1989.

2. Amara, S. G.; Jonas, V.; Rosenfeld, M. G.; Ong, E. S.; Evans, R.
M.: Alternative RNA processing in calcitonin gene expression generates
mRNAs encoding different polypeptide products. Nature 298: 240-244,
1982.

3. Breimer, L. H.; MacIntyre, I.; Zaidi, M.: Peptides from the calcitonin
genes: molecular genetics, structure and function. Biochem. J. 255:
377-390, 1988.

4. Dayhoff, M. O.: Atlas of Protein Sequence and Structure. Hormones,
active peptides and toxins.  Washington: National Biomedical Research
Foundation (pub.)  5: 1972. Pp. D205 only.

5. Edbrooke, M. R.; Parker, D.; McVey, J. H.; Riley, J. H.; Sorenson,
G. D.; Pettengill, O. S.; Craig, R. K.: Expression of the human calcitonin/CGRP
gene in lung and thyroid carcinoma. EMBO J. 4: 715-724, 1985.

6. Girgis, S. I.; Macdonald, D. W. R.; Stevenson, J. C.; Bevis, P.
J. R.; Lynch, C.; Wimalawansa, S. J.; Self, C. H.; Morris, H. R.;
MacIntyre, I.: Calcitonin gene-related peptide: potent vasodilator
and major product of calcitonin gene. Lancet II: 14-16, 1985.

7. Goltzman, D.; Mitchell, J.: Interaction of calcitonin and calcitonin
gene-related peptide at receptor sites in target tissues. Science 227:
1343-1345, 1985.

8. Henry, I.; Grandjouan, S.; Barichard, F.; Huerre-Jeanpierre, C.;
Junien, C.: Mitotic deletions of 11p15.5 in two different tumors
indicate that the CALCA locus is distal to the PTH locus. Cytogenet.
Cell Genet. 50: 155-157, 1989.

9. Hillyard, C. J.; Myers, C.; Abeyasekera, G.; Stevenson, J. C.;
Craig, R. K.; MacIntyre, I.: Katacalcin: a new plasma calcium-lowering
hormone. Lancet I: 846-848, 1983.

10. Hoovers, J. M. N.; Redeker, E.; Speleman, F.; Hoppener, J. W.
M.; Bhola, S.; Bliek, J.; van Roy, N.; Leschot, N. J.; Westerveld,
A.; Mannens, M.: High-resolution chromosomal localization of the
human calcitonin/CGRP/IAPP gene family members. Genomics 15: 525-529,
1993.

11. Hoppener, J. W. M.; Steenbergh, P. H.; Zandberg, J.; Adema, G.
J.; Geurts van Kessel, A. H. M.; Lips, C. J. M.; Jansz, H. S.: A
third human CALC (pseudo)gene on chromosome 11. FEBS Lett. 233:
57-63, 1988.

12. Hoppener, J. W. M.; Steenbergh, P. H.; Zandberg, J.; Bakker, E.;
Pearson, P. L.; Geurts van Kessel, A. H. M.; Jansz, H. S.; Lips, C.
J. M.: Localization of the polymorphic human calcitonin gene on chromosome
11. Hum. Genet. 66: 309-312, 1984.

13. Jacobs, J. W.; Goodman, R. H.; Chin, W. W.; Dee, P. C.; Habener,
J. F.; Bell, N. H.; Potts, J. T., Jr.: Calcitonin messenger RNA encodes
multiple polypeptides in a single precursor. Science 213: 457-459,
1981.

14. Jonas, V.; Lin, C. R.; Kawashima, E.; Semon, D.; Swanson, L. W.;
Mermod, J.-J.; Evans, R. M.; Rosenfeld, M. G.: Alternative RNA processing
events in human calcitonin/calcitonin gene-related peptide gene expression.
Proc. Nat. Acad. Sci. 82: 1994-1998, 1985.

15. Kittur, S. D.; Hoppener, J. W. M.; Antonarakis, S. E.; Daniels,
J. D. J.; Meyers, D. A.; Maestri, N. E.; Jansen, M.; Korneluk, R.
G.; Nelkin, B. D.; Kazazian, H. H., Jr.: Linkage map of the short
arm of human chromosome 11: location of the genes for catalase, calcitonin,
and insulin-like growth factor II. Proc. Nat. Acad. Sci. 82: 5064-5067,
1985.

16. Lalley, P. A.; Sakaguchi, A. Y.; Eddy, R. L.; Honey, N. H.; Bell,
G. I.; Shen, L.-P.; Rutter, W. J.; Jacobs, J. W.; Heinrich, G.; Chin,
W. W.; Naylor, S. L.: Mapping polypeptide hormone genes in the mouse:
somatostatin, glucagon, calcitonin, and parathyroid hormone. Cytogenet.
Cell Genet. 44: 92-97, 1987.

17. MacIntyre, I.; Hillyard, C. J.; Murphy, P. K.; Reynolds, J. J.;
Gaines-Das, R. E.; Craig, R. K.: A second plasma calcium-lowering
peptide from the human calcitonin precursor. Nature 300: 460-462,
1982.

18. Mathe, A. A.; Agren, H.; Lindstrom, L.; Theodorsson, E.: Increased
concentration of calcitonin gene-related peptide in cerebrospinal
fluid of depressed patients: a possible trait marker of major depressive
disorder. Neurosci. Lett. 182: 138-142, 1994.

19. Neher, R.; Riniker, B.; Rittel, W.; Zuber, H.: Thyrocalcitonin.
II. Struktur von alpha-Thyrocalcitonin. Helv. Chim. Acta 51: 917-924,
1968.

20. New, H. V.; Mudge, A. W.: Calcitonin gene-related peptide regulates
muscle acetylcholine receptor synthesis. Nature 323: 809-811, 1986.

21. Przepiorka, D.; Baylin, S. B.; McBride, D. W.; Testa, J. R.; de
Bustros, A.; Nelkin, B. D.: The human calcitonin gene is located
on the short arm of chromosome 11. Biochem. Biophys. Res. Commun. 120:
493-499, 1984.

22. Rosenfeld, M. G.; Lin, C. R.; Amara, S. G.; Stolarsky, L.; Roos,
B. A.; Ong, E. S.; Evans, R. M.: Calcitonin mRNA polymorphism: peptide
switching associated with alternative RNA splicing events. Proc.
Nat. Acad. Sci. 79: 1717-1721, 1982.

23. Rosenfeld, M. G.; Mermod, J.-J.; Amara, S. G.; Swanson, L. W.;
Sawchencko, P. E.; Rivier, J.; Vale, W. W.; Evans, R. M.: Production
of a novel neuropeptide encoded by the calcitonin gene via tissue-specific
RNA processing. Nature 304: 129-135, 1983.

24. Simpson, N. E.; Goodfellow, P. J.; Riddell, D. C.; Hamerton, J.
L.; Holden, J. J. A.; White, B. N.: Assignment of the calcitonin
gene to chromosome 11 and probable exclusion of linkage between the
gene and the locus for multiple endocrine neoplasia type 2.   (Abstract) Am.
J. Hum. Genet. 36: 153S, 1984.

25. Struthers, A. D.; Brown, M. J.; Macdonald, D. W. R.; Beacham,
J. L.; Stevenson, J. C.; Morris, H. R.; MacIntyre, I.: Human calcitonin
gene related peptide: a potent endogenous vasodilator in man. Clin.
Sci. 70: 389-393, 1986.

26. Testa, J. R.: Personal Communication. Baltimore, Md.  3/1984.

27. Tiller-Borcich, J. K.; Capili, H.; Gordan, G. S.: Human brain
calcitonin gene-related peptide (CGRP) is concentrated in the locus
caeruleus. Neuropeptides 11: 55-61, 1988.

28. Tippins, J. R.: CGRP: a novel neuropeptide from the calcitonin
gene is the most potent vasodilator known. J. Hypertension 4 (suppl.
5): S102-S105, 1986.

29. Tschopp, F. A.; Henke, H.; Petermann, J. B.; Tobler, P. H.; Janzer,
R.; Hokfelt, T.; Lundberg, J. M.; Cuello, C.; Fischer, J. A.: Calcitonin
gene-related peptide and its binding sites in the human central nervous
system and pituitary. Proc. Nat. Acad. Sci. 82: 248-252, 1985.

*FIELD* CN
Orest Hurko - updated: 8/15/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 07/11/1996
carol: 6/29/1996
joanna: 4/4/1996
mark: 9/7/1995
davew: 8/5/1994
warfield: 4/7/1994
pfoster: 4/4/1994
mimadm: 2/11/1994

*RECORD*
*FIELD* NO
114131
*FIELD* TI
*114131 CALCITONIN RECEPTOR; CALCR; CTR; CTR1
*FIELD* TX
Gorn et al. (1992) cloned a human calcitonin receptor cDNA from a
eukaryotic expression library prepared from an ovarian small cell
carcinoma cell line. A cell line had been shown to respond to calcitonin
with increases in content of cellular cAMP. Transfection of this cDNA
into COS cells resulted in expression of receptors with high affinity
for salmon and human calcitonin. The expressed CALCR was coupled to
adenylate cyclase. Northern analysis indicated a single transcript of
about 4.2 kb. The cloned cDNA encoded a putative peptide of 490 amino
acids with 7 potential transmembrane domains. The amino acid sequence
was 73% identical to porcine CALCR, although the human CALCR contained
an inset of 16 amino acids between transmembrane domains I and II. CALCR
is closely related to the parathyroid hormone receptor (168468) and the
secretin receptor (182098); these receptors comprise a distinct family
of G protein-coupled 7-transmembrane domain receptors. A comparison of
the human CALCR sequence to protein sequences in databases suggested
that the receptor for calcitonin is evolutionarily related to the
chemoattractant receptor of the primitive eukaryote Dictyostelium
discoideum.

Gorn et al. (1995) cloned and characterized 2 distinct calcitonin
receptor-encoding cDNAs from a giant cell tumor of bone. Both differed
structurally from the human ovarian cell CTR cloned previously but
differed from each other only by the presence or absence of a predicted
16-amino acid inset in the putative first intracellular domain. In situ
hybridization on giant cell tumor tissue sections demonstrated CTR mRNA
expression in osteoclast-like cells. By isotopic in situ hybridization
to metaphase chromosomes and by PCR analysis of somatic cell hybrid
DNAs, Gorn et al. (1995) demonstrated that the CALCR gene is located on
7q22. The distinct functional characteristics of the 2 isoforms, which
differ in structure only in the first intracellular domain, indicated
that the domain plays a previously unidentified role in modulating
ligand binding and signal transduction via the G-protein/adenylate
cyclase system.

Perez Jurado et al. (1995) also used PCR analysis of somatic cell
hybrids as well as fluorescence in situ hybridization (FISH) to map the
CALCR gene to 7q21.3. By two-color FISH cohybridizing CALCR and the
elastin gene (ELN; 130160), they demonstrated that CALCR maps telomeric
to ELN. Subsequent analysis of chromosome spreads from 4 patients with
Williams syndrome (194050) demonstrated deletion of the ELN locus in all
of them but normal hybridization of CALCR probes to both chromosome 7
homologs, indicating that CALCR lies outside the deleted region.

*FIELD* RF
1. Gorn, A. H.; Lin, H. Y.; Yamin, M.; Auron, P. E.; Flannery, M.
R.; Tapp, D. R.; Manning, C. A.; Lodish, H. F.; Krane, S. M.; Goldring,
S. R.: Cloning, characterization, and expression of a human calcitonin
receptor from an ovarian carcinoma cell line. J. Clin. Invest. 90:
1726-1735, 1992.

2. Gorn, A. H.; Rudolph, S. M.; Flannery, M. R.; Morton, C. C.; Weremowicz,
S.; Wang, J.-T.; Krane, S. M.; Goldring, S. R.: Expression of two
human skeletal calcitonin receptor isoforms cloned from a giant cell
tumor of bone. J. Clin. Invest. 95: 2680-2691, 1995.

3. Perez Jurado, L. A.; Li, X.; Francke, U.: The human calcitonin
receptor gene (CALCR) at 7q21.3 is outside the deletion associated
with the Williams syndrome. Cytogenet. Cell Genet. 70: 246-249,
1995.

*FIELD* CD
Victor A. McKusick: 12/21/1992

*FIELD* ED
mark: 10/20/1995
carol: 12/21/1992

*RECORD*
*FIELD* NO
114140
*FIELD* TI
*114140 CALLOSITIES, HEREDITARY PAINFUL
CALLOSITIES, PAINFUL PLANTAR
*FIELD* TX
Roth et al. (1978) described a family with many cases of painful
callosities over pressure points in the hands and feet. There were
several instances of male-to-male transmission and affected persons were
present in 5 generations. Dupre et al. (1979) suggested that the
disorder is not rare. In France the condition is referred to as
'keratoderma palmo-plantaire disseminee type Brauer' or 'type
Buschke-Fischer.' Successful treatment with aromatic tretinoin by mouth
was noted. Rachid et al. (1987) described a large Brazilian kindred with
plantar callosities that begin with walking and persist life-long. They
are present over pressure points of the soles with excessive walking.
Bullae, which form at the edge of the callosities, are filled with a
foul-smelling fluid. Thirty-one affected persons were observed. Four
affected males transmitted the gene to 7 sons and 9 daughters. Normal
persons had only normal children. No instance of palmar callosities was
mentioned, even in persons engaged in heavy labor. Baden et al. (1984)
reported a family. Though Rachid et al. (1987) claimed that the disorder
they described was distinct from that reported by Roth et al. (1978),
this is by no means clear.

*FIELD* RF
1. Baden, H. P.; Bronstein, B. R.; Rand, R. E.: Hereditary callosities
with blisters: report of a family and review. J. Am. Acad. Derm. 11:
409-415, 1984.

2. Dupre, A.; Bonafe, J.-L.; Christol, B.: Treatment of hereditary
painful callosities with tretinoin.  (Letter) Arch. Derm. 115: 638-639,
1979.

3. Rachid, A.; Freire-Maia, N.; Pinheiro, M.: Autosomal dominant
painful plantar callosities. Am. J. Med. Genet. 26: 185-187, 1987.

4. Roth, W.; Penneys, N. S.; Fawcett, N.: Hereditary painful callosities.
Arch. Derm. 114: 591-592, 1978.

*FIELD* CS

Skin:
   Painful callosities over pressure points of hands and feet;
   Fluid-filled bullae at edges of foot callosities

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
carol: 10/21/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 4/20/1988

*RECORD*
*FIELD* NO
114150
*FIELD* TI
*114150 CAMPTOBRACHYDACTYLY
*FIELD* TX
In the large kindred reported by Edwards and Gale (1972) brachydactyly
involved the hands and the feet in combination with congenital flexion
contractures of the fingers. Syndactyly, polydactyly, septate vagina and
urinary incontinence were present in some. Two severely affected
children of affected first cousins were thought to be homozygotes.

*FIELD* RF
1. Edwards, J. A.; Gale, R. P.: Camptobrachydactyly: a new autosomal
dominant trait with two probable homozygotes. Am. J. Hum. Genet. 24:
464-474, 1972.

*FIELD* CS

Limbs:
   Brachydactyly of hands and feet;
   Congenital finger flexion contractures;
   Syndactyly;
   Polydactyly

GU:
   Septate vagina;
   Urinary incontinence

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
114160
*FIELD* TI
*114160 CALCITONIN-RELATED POLYPEPTIDE, BETA; CALCB
CALCITONIN GENE-RELATED PEPTIDE-2; CGRP2; CALC2
*FIELD* TX
The calcitonin gene (CALCA; 114130) is alternatively expressed in a
tissue-specific fashion producing either the calcium regulatory hormone
calcitonin or the neuropeptide CGRP (calcitonin gene-related peptide).
Both CT and CGRP are produced in medullary carcinoma of the thyroid. By
Southern blot analysis of DNA from human rodent somatic cell hybrids,
Hoppener et al. (1985) assigned the CALC2 gene to 11pter-q12. By
alternative RNA processing events, a single rat (and presumably human)
gene can generate mRNAs encoding either calcitonin or a neuropeptide
referred to as alpha-type calcitonin gene-related peptide (alpha-CGRP).
Amara et al. (1985) identified in rat brain and thyroid an mRNA product
of a related gene that differs from alpha-CGRP by only a single amino
acid. The RNA encoding this peptide, called beta-CGRP, appeared to be
the only mature transcript of the beta-CGRP gene. Hoovers et al. (1993)
demonstrated that the CALCB gene is in the same 220-kb SacII fragment as
CALCA.

*FIELD* SA
Steenbergh et al. (1985)
*FIELD* RF
1. Amara, S. G.; Arriza, J. L.; Leff, S. E.; Swanson, L. W.; Evans,
R. M.; Rosenfeld, M. G.: Expression in brain of a messenger RNA encoding
a novel neuropeptide homologous to calcitonin gene-related peptide.
Science 229: 1094-1097, 1985.

2. Hoovers, J. M. N.; Redeker, E.; Speleman, F.; Hoppener, J. W. M.;
Bhola, S.; Bliek, J.; van Roy, N.; Leschot, N. J.; Westerveld, A.;
Mannens, M.: High-resolution chromosomal localization of the human
calcitonin/CGRP/IAPP gene family members. Genomics 15: 525-529,
1993.

3. Hoppener, J. W. M.; Steenbergh, P. H.; Zandberg, J.; Geurts van
Kessel, A. H. M.; Baylin, S. B.; Nelkin, B. D.; Jansz, H. S.; Lips,
C. J. M.: The second human calcitonin/CGRP gene is located on chromosome
11. Hum. Genet. 70: 259-263, 1985.

4. Steenbergh, P. H.; Hoppener, J. W. M.; Zandberg, J.; Lips, C. J.
M.; Jansz, H. S.: A second human calcitonin/CGRP gene. FEBS Lett. 183:
403-407, 1985.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 06/29/1996
carol: 3/19/1993
supermim: 3/16/1992
carol: 6/13/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
114170
*FIELD* TI
*114170 CALCIUM-DEPENDENT PROTEASE, SMALL SUBUNIT; CDPS
CALPAIN, SMALL SUBUNIT; CANPS; CAPN4
*FIELD* TX
Calcium-dependent cysteine proteinases, collectively called calpain (EC
3.4.22.17), are widely distributed in mammalian cells. There are 2
distinct molecular forms, calpains I and II, which differ in the
quantity of calcium required. Both calpains I and II are heterodimeric;
each is composed of one heavy (about 80 kD) and one light (about 30 kD)
subunit. The heavy subunit has a catalytic function, whereas the
function of the light subunit is largely unknown but is probably
regulatory. Ohno et al. (1986) gave the nucleotide sequence for a nearly
full-length cDNA coding for the small subunit of human calcium-dependent
protease. A human spleen cDNA library was the source. The human protein
has 268 amino acids. By a combination of spot blot hybridization with
sorted chromosomes and of Southern hybridization with human-mouse cell
hybrid DNAs, using in each case a cDNA probe, Ohno et al. (1989)
assigned the CANPS gene to chromosome 19.

*FIELD* SA
Ohno et al. (1990); Sakihama et al. (1985)
*FIELD* RF
1. Ohno, S.; Emori, Y.; Suzuki, K.: Nucleotide sequence of a cDNA
coding for the small subunit of human calcium-dependent protease.
Nucleic Acids Res. 14: 5559 only, 1986.

2. Ohno, S.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Ohmi-Imajoh,
S.; Suzuki, K.; Shimizu, Y.; Shimizu, N.: Four genes for the calpain
family locate on four distinct human chromosomes.  (Abstract) Cytogenet.
Cell Genet. 51: 1054-1055, 1989.

3. Ohno, S.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Shimizu, Y.;
Ohmi-Imajoh, S.; Shimizu, N.; Suzuki, K.: Four genes for the calpain
family locate on four distinct human chromosomes. Cytogenet. Cell
Genet. 53: 225-229, 1990.

4. Sakihama, T.; Kakidani, H.; Zenita, K.; Yumoto, N.; Kikuchi, T.;
Sasaki, T.; Kannagi, R.; Nakanishi, S.; Ohmori, M.; Takio, K.; Titani,
K.; Murachi, T.: A putative Ca(2+)-binding protein: structure of
the light subunit of porcine calpain elucidated by molecular cloning
and protein sequence analysis. Proc. Nat. Acad. Sci. 82: 6075-6079,
1985.

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
supermim: 3/16/1992
carol: 4/29/1991
supermim: 3/20/1990
carol: 12/19/1989
ddp: 10/27/1989

*RECORD*
*FIELD* NO
114180
*FIELD* TI
*114180 CALMODULIN 1; CALM1
PHOSPHORYLASE KINASE, DELTA SUBUNIT; PHKD
*FIELD* TX
Calmodulin is the archetype of the family of calcium-modulated proteins
of which nearly 20 members have been found. They are identified by their
occurrence in the cytosol or on membranes facing the cytosol and by a
high affinity for calcium. Kretsinger et al. (1986) described the
crystal structure of calmodulin to 3.6 Angstrom resolution. Calmodulin
contains 148 amino acids and has 4 calcium-binding domains. Its
functions include roles in growth and the cell cycle as well as in
biological signal transduction and the synthesis and release of
neurotransmitters. Until the studies of Sen Gupta et al. (1987), only 1
human calmodulin cDNA had been reported. These authors found evidence of
a second actively transcribed calmodulin gene in man. Calmodulin is the
delta subunit of phosphorylase kinase, which has 3 other types of
subunits. Although only 1 form of calmodulin has been found in humans, 3
distinct human cDNAs have been isolated that encode the identical
polypeptide (Koller et al., 1990; Pegues and Friedberg, 1990). The
existence of 3 expressible genes for calmodulin may indicate that one is
a housekeeping gene and that the additional copies are differentially
regulated to modulate calmodulin function.

McPherson et al. (1991) used a panel of human/rodent somatic cell
hybrids to demonstrate that the cDNA probe for calmodulin 1 (CALM1) was
localized to chromosome 14 with cross-hybridization evident on
chromosome 7 and very weak on the X chromosome. The assignments to
chromosomes 14 and 7 confirmed an earlier report by Scambler et al.
(1987). McPherson et al. (1991) tentatively assigned the calmodulin 2
(CALM2; 114182) gene to chromosome 10, but the gene was subsequently
shown to be on chromosome 2. They assigned the cDNA probe for calmodulin
3 (CALM3; 114183) unequivocally to chromosome 19. There was no apparent
cross-hybridization to other chromosomes. A calmodulin pseudogene is
located on chromosome 17 (Sen Gupta et al., 1989) and there are probably
more on several other chromosomes. Berchtold et al. (1993) assigned the
CALM1 gene to chromosome 14 by PCR-based amplification of CALM1-specific
sequences using DNA from human/hamster cell hybrids as template.
Regional sublocalization was performed by in situ hybridization using
CALM1-specific DNA probes of intronic or flanking parts of the gene; the
regional localization was found to be 14q24-q31.

Rhyner et al. (1994) found that the CALM1 gene contains 6 exons spread
over about 10 kb of genomic DNA. The exon-intron structure was identical
to that of CALM3. A cluster of transcription-start sites was identified
200 bp upstream of the ATG translation-start codon, and several putative
regulatory elements were found in the 5-prime flanking region, as well
as in intron 1. A short CAG trinucleotide repeat region was identified
in the 5-prime untranslated region of the gene. Expression of CALM1 was
detected in all human tissues tested, although at varying levels. They
identified 2 different CALM1-related pseudogenes.

*FIELD* RF
1. Berchtold, M. W.; Egli, R.; Rhyner, J. A.; Hameister, H.; Strehler,
E. E.: Localization of the human bona fide calmodulin genes CALM1,
CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3. Genomics 16:
461-465, 1993.

2. Koller, M.; Schnyder, B.; Strehler, E. E.: Structural organization
of the human CaMIII calmodulin gene. Biochim. Biophys. Acta 1087:
180-189, 1990.

3. Kretsinger, R. H.; Rudnick, S. E.; Weissman, L. J.: Crystal structure
of calmodulin. J. Inorganic Biochem. 28: 289-302, 1986.

4. McPherson, J. D.; Hickie, R. A.; Wasmuth, J. J.; Meyskens, F. L.;
Perham, R. N.; Strehler, E. E.; Graham, M. T.: Chromosomal localization
of multiple genes encoding calmodulin. (Abstract) Cytogenet. Cell
Genet. 58: 1951 only, 1991.

5. Pegues, J. C.; Friedberg, F.: Multiple mRNAs encoding human calmodulin. Biochem.
Biophys. Res. Commun. 172: 1145-1149, 1990.

6. Rhyner, J. A.; Ottiger, M.; Wicki, R.; Greenwood, T. M.; Strehler,
E. E.: Structure of the human CALM1 calmodulin gene and identification
of two CALM1-related pseudogenes CALM1P1 and CALM1P2. Europ. J. Biochem. 225:
71-82, 1994.

7. Scambler, P. J.; McPherson, M. A.; Bates, G.; Bradbury, N. A.;
Dormer, R. L.; Williamson, R.: Biochemical and genetic exclusion
of calmodulin as the site of the basic defect in cystic fibrosis. Hum.
Genet. 76: 278-282, 1987.

8. Sen Gupta, B.; Detera-Wadleigh, S. D.; McBride, O. W.; Friedberg,
F.: A calmodulin pseudogene on human chromosome 17. Nucleic Acids
Res. 17: 2868 only, 1989.

9. Sen Gupta, B.; Friedberg, F.; Detera-Wadleigh, S. D.: Molecular
analysis of human and rat calmodulin complementary DNA clones: evidence
for additional active genes in these species. J. Biol. Chem. 262:
16663-16670, 1987.

*FIELD* CD
Victor A. McKusick: 2/9/1987

*FIELD* ED
mark: 12/29/1996
carol: 1/19/1995
carol: 12/23/1993
carol: 5/26/1993
carol: 8/14/1992
supermim: 3/16/1992
carol: 3/9/1992

*RECORD*
*FIELD* NO
114181
*FIELD* TI
*114181 CALMODULIN-LIKE 1; CALML1
*FIELD* TX
In the course of investigating the possible role of calmodulin in the
etiopathogenesis of cystic fibrosis (219700), Scambler et al. (1987)
showed that there was no gross structural abnormality in the calmodulin
protein from CF submandibular glands and that none of the 3 distinct
sequences in the human genome that cross-hybridized with a calmodulin
cDNA probe was located on 7q where the CF gene was known to be. One of
the 3 sequences was assigned to 7pter-p13 by study of somatic cell
hybrids. A RFLP was demonstrated in that sequence. McPherson et al.
(1991) also mapped a calmodulin-like sequence to chromosome 7.

*FIELD* RF
1. McPherson, J. D.; Hickie, R. A.; Wasmuth, J. J.; Meyskens, F. L.;
Perham, R. N.; Strehler, E. E.; Graham, M. T.: Chromosomal localization
of multiple genes encoding calmodulin.  (Abstract) Cytogenet. Cell
Genet. 58: 1951 only, 1991.

2. Scambler, P. J.; McPherson, M. A.; Bates, G.; Bradbury, N. A.;
Dormer, R. L.; Williamson, R.: Biochemical and genetic exclusion
of calmodulin as the site of the basic defect in cystic fibrosis.
Hum. Genet. 76: 278-282, 1987.

*FIELD* CD
Victor A. McKusick: 3/8/1992

*FIELD* ED
supermim: 3/16/1992
carol: 3/8/1992

*RECORD*
*FIELD* NO
114182
*FIELD* TI
*114182 CALMODULIN 2; CALM2
PHKD2
*FIELD* TX
McPherson et al. (1991) tentatively assigned the CALM2 gene to
chromosome 10 by study of somatic cell hybrids. However, by PCR-based
amplification of CALM2-specific sequences using DNA from human/hamster
cell hybrids as template, Berchtold et al. (1993) found that the CALM2
gene is located on chromosome 2. They regionalized the gene to
2p21.3-p21.1 by in situ hybridization.

*FIELD* RF
1. Berchtold, M. W.; Egli, R.; Rhyner, J. A.; Hameister, H.; Strehler,
E. E.: Localization of the human bona fide calmodulin genes CALM1,
CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3. Genomics 16:
461-465, 1993.

2. McPherson, J. D.; Hickie, R. A.; Wasmuth, J. J.; Meyskens, F. L.;
Perham, R. N.; Strehler, E. E.; Graham, M. T.: Chromosomal localization
of multiple genes encoding calmodulin. (Abstract) Cytogenet. Cell
Genet. 58: 1951 only, 1991.

*FIELD* CD
Victor A. McKusick: 3/8/1992

*FIELD* ED
terry: 10/31/1996
carol: 5/26/1993
supermim: 3/16/1992
carol: 3/8/1992

*RECORD*
*FIELD* NO
114183
*FIELD* TI
*114183 CALMODULIN 3; CALM3
PHKD3
*FIELD* TX
McPherson et al. (1991) assigned the CALM3 gene to chromosome 19 by
study of somatic cell hybrids. By PCR-based amplification of
CALM3-specific sequences using DNA from human/hamster cell hybrids as
template, Berchtold et al. (1993) confirmed the assignment to chromosome
19 and regionalized the gene to 19q13.2-q13.3 by in situ hybridization.

*FIELD* RF
1. Berchtold, M. W.; Egli, R.; Rhyner, J. A.; Hameister, H.; Strehler,
E. E.: Localization of the human bona fide calmodulin genes CALM1,
CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3. Genomics 16:
461-465, 1993.

2. McPherson, J. D.; Hickie, R. A.; Wasmuth, J. J.; Meyskens, F. L.;
Perham, R. N.; Strehler, E. E.; Graham, M. T.: Chromosomal localization
of multiple genes encoding calmodulin. (Abstract) Cytogenet. Cell
Genet. 58: 1951 only, 1991.

*FIELD* CD
Victor A. McKusick: 3/8/1992

*FIELD* ED
terry: 10/31/1996
carol: 5/26/1993
supermim: 3/16/1992
carol: 3/8/1992

*RECORD*
*FIELD* NO
114184
*FIELD* TI
*114184 CALMODULIN-LIKE 3; CALML3
*FIELD* TX
Berchtold et al. (1993) mapped a functional intronless gene coding for a
calmodulin-like protein to 10pter-p13. Chromosomal assignment was
performed by Southern blot analysis of DNA from human/rodent somatic
cell hybrids and amplification of a gene-specific 1,090-bp DNA fragment
by PCR from DNA of human/hamster cell hybrids. Chromosomal
sublocalization was carried out by in situ hybridization.

*FIELD* RF
1. Berchtold, M. W.; Koller, M.; Egli, R.; Rhyner, J. A.; Hameister,
H.; Strehler, E. E.: Localization of the intronless gene coding for
calmodulin-like protein CLP to human chromosome 10p13-ter. Hum.
Genet. 90: 496-500, 1993.

*FIELD* CD
Victor A. McKusick: 12/23/1993

*FIELD* ED
carol: 12/23/1993

*RECORD*
*FIELD* NO
114190
*FIELD* TI
114190 CALCITONIN GENE-RELATED PEPTIDE RECEPTOR; CGRPR
*FIELD* TX
Studies of the structure and expression of the calcitonin gene have
demonstrated the generation of alternative mRNA species from a single
gene in a tissue-specific manner. The mRNA species produced encode
polyproteins cleaved by posttranslational events to yield either
calcitonin, the major gene product in the thyroid, or a predicted
37-amino-acid amidated peptide, the calcitonin gene-related peptide
(CALCA; 114130). A second gene encoding a similar peptide (CALCB;
114160) has been identified in man as well as in the rat. Receptors for
CGRP have been located in the central nervous system by receptor-binding
studies and visualized by optoradiography. Foord and Craig (1987)
described the identification and purification of a receptor for CGRP in
human term placenta.

Aiyar et al. (1996) cloned a cDNA encoding a calcitonin gene-related
peptide receptor, which shares significant peptide sequence homology
with the calcitonin receptor (114131), a member of the G protein-coupled
receptor superfamily. The receptor is predominantly expressed in the
lung and heart.

*FIELD* RF
1. Aiyar, N.; Rand, K.; Elshourbagy, N. A.; Zeng, Z.; Adamou, J. E.;
Bergsma, D. J.; Li, Y.: A cDNA encoding the calcitonin gene-related
peptide type 1 receptor. J. Biol. Chem. 271: 11325-11329, 1996.

2. Foord, S. M.; Craig, R. K.: Isolation and characterisation of
a human calcitonin-gene-related-peptide receptor. Europ. J. Biochem. 170:
373-379, 1987.

*FIELD* CN
Jon B. Obray - updated: 06/29/1996

*FIELD* CD
Victor A. McKusick: 2/18/1988

*FIELD* ED
carol: 06/29/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 2/18/1988

*RECORD*
*FIELD* NO
114200
*FIELD* TI
*114200 CAMPTODACTYLY
STREBLODACTYLY, INCLUDED
*FIELD* TX
Camptodactyly is a hand malformation characterized by a contracture
deformity of the proximal interphalangeal joints of the fingers. The
little finger is the most frequently affected, though any finger may be
involved. This deformity is inherited as an autosomal dominant trait
with variable penetrance. Hefner (1929, 1941) reported its occurrence in
4 generations. Camptodactyly, though often occurring as an isolated
anomaly, is occasionally a feature of genetically distinct disorders
(see craniocarpotarsal dystrophy, 193700). Symptoms include
streblodactyly, congenital contracture of fingers, and congenital
Dupuytren contracture. Parish et al. (1963) described flexion
contractures of the fingers (streblodactyly: streblos = Gr. twisted,
crooked) and aminoaciduria in 10 females of 3 generations of a family.
In 2 females the hands were normal but the same aminoaciduria was
present. Nine males were normal. Since all females in the direct line
were affected by one or both of the traits mentioned, this is by
definition hologynic. However, it is not, at least not necessarily, a
sex-linked dominant as the authors proposed. In most patients fingers 2
to 5 were affected. This entity may not be different from camptodactyly.
Nevin et al. (1966) also found taurinuria in association with
camptodactyly. The increased excretion of taurine seemed to be renal in
origin. Taurine is not an amino acid but a sulfonated amine which arises
as an end product of the metabolism of sulfur-containing amino acids.
Several instances of male-to-male transmission were noted in the 4
families they studied. In a rural area of western North Carolina, Murphy
(1926) described camptodactyly in many members of 5 generations. Eleven
of the affected persons also had knee-joint subluxation which was
usually easily reduced. Donofrio and Ayala (1983) reported a family in
which 4 females in 2 generations were affected with the disorder
reported by Parish et al. (1963) and called streblodactyly. No increase
of abortions was noted in these families. The authors suggested
sex-limited autosomal dominant inheritance. Streblodactyly is
characterized by a permanent flexion contracture of all fingers at the
proximal interphalangeal joints. Donofrio and Ayala (1983) suggested
that camptodactyly (which often affects only the fifth finger and is
clearly an autosomal dominant trait with variable penetrance) is
distinct from streblodactyly.

*FIELD* SA
Dutta  (1965); Moore and Messina (1936); Welch and Temtamy (1966)
*FIELD* RF
1. Donofrio, P.; Ayala, F.: Familial streblodactyly. Acta Derm.
Venerol. 63: 361-363, 1983.

2. Dutta, P.: The inheritance of the radially curved little finger.
Acta Genet. Statist. Med. 15: 70-76, 1965.

3. Hefner, R. A.: Inheritance of crooked little fingers (minor streblomicrodactyly).
J. Hered. 20: 395-398, 1929.

4. Hefner, R. A.: Crooked little finger (minor streblomicrodactyly).
J. Hered. 32: 37-38, 1941.

5. Moore, W. G.; Messina, P.: Camptodactylism and its variable expression.
J. Hered. 27: 27-30, 1936.

6. Murphy, D. P.: Familial finger contracture and associated familial
knee-joint subluxation. J.A.M.A. 86: 395-397, 1926.

7. Nevin, N. C.; Hurwitz, L. J.; Neill, D. W.: Familial camptodactyly
with taurinuria. J. Med. Genet. 3: 265-268, 1966.

8. Parish, J. G.; Horn, D. B.; Thompson, M.: Familial streblodactyly
with amino-aciduria. Brit. Med. J. 2: 1247-1250, 1963.

9. Welch, J. P.; Temtamy, S. A.: Hereditary contractures of the fingers
(camptodactyly). J. Med. Genet. 3: 104-113, 1966.

*FIELD* CS

Limbs:
   Camptodactyly;
   Proximal interphalangeal finger joint contractures

Joints:
   Knee-joint subluxation

Misc:
   Fifth finger most frequently affected

Lab:
   Associated taurinuria

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/14/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
supermim: 2/17/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
114204
*FIELD* TI
*114204 CALCIUM CHANNEL, SKELETAL MUSCLE VOLTAGE-DEPENDENT, ALPHA-2 SUBUNIT
CALCIUM CHANNEL, L TYPE, ALPHA-2 POLYPEPTIDE; CACNL2A;;
CALCIUM CHANNEL, ALPHA-2/DELTA SUBUNIT
*FIELD* TX
The skeletal muscle L-type voltage-dependent calcium channel is a
heteromultimer complex containing 4 subunits: alpha-1 (114205, 114206,
114208), alpha-2/delta, beta-1 (114207), and gamma (114209). The
alpha-2/delta subunit appears to modulate the channel kinetics. The gene
encoding the alpha-2/delta subunit (CACNL2A) is expressed in many
tissues, including skeletal muscle, brain, heart, and lung. A comparison
of sequences of cDNAs representing the skeletal muscle and brain
isoforms showed that they are encoded by a single gene. By PCR assay of
Chinese hamster/human somatic cell hybrid DNAs, Powers et al. (1994)
assigned the CACNL2A gene to chromosome 7. They refined the localization
to 7q21-q22 by analysis of a panel of human/rodent somatic cell hybrids
containing defined regions of human chromosome 7.

A close association is formed at the skeletal muscle triadic junctions
between the ryanodine receptor (RYR1; 180901) and the L-type
voltage-dependent calcium channel, also referred to as the
dihydropyridine receptor (DHPR), and the 2 channel complexes appear to
function together in excitation-contraction coupling. Iles et al. (1994)
cloned and partially sequenced the CACNL2A gene. They found that the
gene and a neighboring polymorphic dinucleotide repeat marker, D7S849,
were linked to the gene encoding the hepatocyte growth factor (HGF;
142409). Using a human chromosome 7-specific YAC library, they found
that HGF was within approximately 110 to 380 kb of CACNL2A. They also
mapped CACNL2A to 7q11.23-q21.1 by fluorescence in situ hybridization,
the same location where D7S849 had been placed by analysis of
human/hamster somatic cell hybrids. Because of the association with the
ryanodine receptor, one of the subunits of the L-type voltage-dependent
calcium channel has been under suspicion as the site of a mutation
causing malignant hyperthermia susceptibility (MHS). The alpha-1-,
beta-1-, and gamma-subunits had been previously excluded as the site of
the mutation in MHS that does not show linkage to the RYR1 locus on
chromosome 19. In order to test the possible association of mutations in
the CACNL2A gene with MHS, Iles et al. (1994) tested D7S849 and adjacent
markers for linkage in a group of 6 MHS families that were not linked to
chromosome 19. No recombination was observed between MHS and D7S849 and
2 other markers through 11 meioses in 1 well-characterized 3-generation
pedigree.

*FIELD* RF
1. Iles, D. E.; Lehmann-Horn, F.; Scherer, S. W.; Tsui, L.-C.; Olde
Weghuis, D.; Suijkerbuijk, R. F.; Heytens, L.; Mikala, G.; Schwartz,
A.; Ellis, F. R.; Stewart, A. D.; Deufel, T.; Wieringa, B.: Localization
of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent
calcium channel to chromosome 7q and analysis of the segregation of
flanking markers in malignant hyperthermia susceptible families. Hum.
Molec. Genet. 3: 969-975, 1994.

2. Powers, P. A.; Scherer, S. W.; Tsui, L.-C.; Gregg, R. G.; Hogan,
K.: Localization of the gene encoding the alpha-2/delta subunit (CACNL2A)
of the human skeletal muscle voltage-dependent Ca(2+) channel to chromosome
7q21-q22 by somatic cell hybrid analysis. Genomics 19: 192-193,
1994.

*FIELD* CD
Victor A. McKusick: 2/9/1994

*FIELD* ED
jason: 7/27/1994
mimadm: 5/18/1994
carol: 2/9/1994

*RECORD*
*FIELD* NO
114205
*FIELD* TI
*114205 CALCIUM CHANNEL, L TYPE, ALPHA-1 POLYPEPTIDE, ISOFORM 1, CARDIAC MUSCLE;
CACNL1A1;;
CALCIUM CHANNEL, CARDIAC DIHYDROPYRIDINE-SENSITIVE, ALPHA-1 SUBUNIT
CCHL1A1;;
DHPR, ALPHA-1 SUBUNIT
*FIELD* TX
Activation of voltage-sensitive calcium channels by membrane
depolarization triggers key cellular responses such as contraction,
secretion, excitation, and electrical signaling (Tsien et al., 1991).
The L-type currents produced by voltage-sensitive calcium channels are
blocked by 1,4-dihydropyridine (DHP) derivatives; thus, the channels
responsible for these currents are referred to as DHP-sensitive. The
skeletal muscle DHP-sensitive calcium channel is a complex of 5
subunits: alpha-1, alpha-2, beta, gamma, and delta. The DHP-sensitive
calcium channels from cardiac muscle and the brain have pharmacologic
and electrophysiologic properties that differ from those of the skeletal
muscle channel. Powers et al. (1991) isolated a clone for the human
CCHL1A1 gene and partially sequenced it. Oligonucleotides based on the
human sequence were constructed and used in PCR to amplify specifically
this human gene in human-rodent somatic cell hybrids. In this way, the
gene was assigned to 12pter-p12. Using a dinucleotide repeat for linkage
analysis in the CEPH panel of families, Powers et al. (1992) narrowed
the assignment to 12pter-p13.2. The data placed CACNL1A1 distal to PRB1
(180989). By study of somatic cell hybrids, Sun et al. (1992) likewise
assigned the CACNL1A1 gene to 12pter-p13. Schultz et al. (1993)
localized the CCHL1A1 gene to 12p13.3 by study of a 12p somatic cell
hybrid mapping panel and by fluorescence in situ hybridization.

Calcium channels can be classified according to their pharmacologic
types, i.e., L, T, N, and P. To reflect this, McAlpine (1992)
recommended that the presently discussed locus be entitled 'calcium
channel, L type, alpha-1 polypeptide, isoform 1 (cardiac muscle)' with
the symbol CACNL1A1. Studying 2 somatic cell hybrids containing either
the der(12) or the der(X) from a mesothelioma with a translocation
t(X;12)(q22;p13) as the only chromosomal change and applying PCR
analysis based on genomic sequences, Aerssens et al. (1994) mapped the
CACNL1A1 distal to the 12p13 breakpoint and to VWF (193400).

Soldatov (1994) investigated the genomic organization of the CACNL1A1
gene by DNA sequencing of genomic and cDNA clones and PCR products. The
gene spans an estimated 150 kb of the human genome and is composed of 44
invariant and 6 alternative exons. Data on cDNA cloning from both human
fibroblasts and hippocampus indicated several regions of heterogeneity
due to alternative splicing sites of the CACNL1A1 primary transcript. In
addition, Southern blotting followed by partial sequencing indicated at
least 3 different isoforms of L-type Ca(2+) channels. Soldatov (1994)
suggested that the human L-type Ca(2+) channels are genetically
regulated through generation of multiple splice variants of the mRNA,
some of them in a tissue-specific manner, as well as via expression of
different gene isoforms.

O'Brien et al. (1995) found no defects in several functional segments
(II-III loop or IS3/IS3-IS4 segment) of this gene in a malignant
hyperthermia kindred.

*FIELD* RF
1. Aerssens, J.; Chaffanet, M.; Baens, M.; Matthijs, G.; Van Den Berghe,
H.; Cassiman, J.-J.; Marynen, P.: Regional assignment of seven loci
to 12p13.2-pter by PCR analysis of somatic cell hybrids containing
the der(12) or the der(X) chromosome from a mesothelioma showing t(X;12)(q22;p13). Genomics 20:
119-121, 1994.

2. McAlpine, P. J.: Personal Communication. Winnipeg, Manitoba,
Canada  2/14/1992.

3. O'Brien, R. O.; Taske, N. L.; Hansbro, P. M.; Matthaei, K. I.;
Hogan, S. P.; Denborough, M. A.; Foster, P. S.: Exclusion of defects
in the skeletal muscle specific regions of the DHPR alpha-1 subunit
as frequent causes of malignant hyperthermia. J. Med. Genet. 32:
913-914, 1995.

4. Powers, P. A.; Gregg, R. G.; Hogan, K.: Linkage mapping of the
human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+)
channel (CACNL1A1) to chromosome 12p13.2-pter using a dinucleotide
repeat. Genomics 14: 206-207, 1992.

5. Powers, P. A.; Gregg, R. G.; Lalley, P. A.; Liao, M.; Hogan, K.
: Assignment of the human gene for the alpha-1 subunit of the cardiac
DHP-sensitive Ca(2+) channel (CCHL1A1) to chromosome 12p12-pter. Genomics 10:
835-839, 1991.

6. Schultz, D.; Mikala, G.; Yatani, A.; Engle, D. B.; Iles, D. E.;
Segers, B.; Sinke, R. J.; Weghuis, D. O.; Klockner, U.; Wakamori,
M.; Wang, J.-J.; Melvin, D.; Varadi, G.; Schwartz, A.: Cloning, chromosomal
localization, and functional expression of the alpha-1 subunit of
the L-type voltage-dependent calcium channel from normal human heart. Proc.
Nat. Acad. Sci. 90: 6228-6232, 1993.

7. Soldatov, N. M.: Genomic structure of human L-type Ca(2+) channel. Genomics 22:
77-87, 1994.

8. Sun, W.; McPherson, J. D.; Hoang, D. Q.; Wasmuth, J. J.; Evans,
G. A.; Montal, M.: Mapping of a human brain voltage-gated calcium
channel to human chromosome 12p13-pter. Genomics 14: 1092-1094,
1992.

9. Tsien, R. W.; Ellinor, P. T.; Horne, W. A.: Molecular diversity
of voltage-dependent Ca(2+) channels. Trends Pharm. Sci. 12: 349-354,
1991.

*FIELD* CD
Victor A. McKusick: 2/26/1991

*FIELD* ED
mark: 12/29/1996
mark: 1/31/1996
terry: 1/24/1996
carol: 11/18/1994
jason: 7/19/1994
mimadm: 4/29/1994
warfield: 4/7/1994
carol: 7/9/1993
carol: 1/8/1993

*RECORD*
*FIELD* NO
114206
*FIELD* TI
*114206 CALCIUM CHANNEL, NEUROENDOCRINE/BRAIN-TYPE, ALPHA-1 SUBUNIT
CALCIUM CHANNEL, L TYPE, ALPHA-1 POLYPEPTIDE, ISOFORM 2;;
CACNL1A2
*FIELD* TX
Voltage-sensitive Ca(2+) channels play an important role in regulating
hormone and neurotransmitter release, muscle contraction, and a large
number of other cellular functions. The voltage-sensitive Ca(2+)
channels are multisubunit proteins. For example, in skeletal muscle the
complex has 4 distinct subunits, alpha-1 (170 kD), alpha-2/delta (175
kD), beta (52 kD), and gamma (32 kD). The alpha-1 and beta subunits are
members of gene families; cDNAs encoding 4 structurally related alpha-1
subunits and 2 beta subunits have been reported (Tsien et al., 1991).
The alpha-1 subunits were termed the skeletal muscle, heart, brain, and
neuroendocrine/brain isoforms. On the basis of their kinetics and
pharmacology, 4 types of Ca(2+) currents have been described. The Ca(2+)
channel activity associated with the skeletal muscle, heart, and
neuroendocrine/brain alpha-1 subunit isoforms is inhibited by
dihydropyridine drugs, indicating that these represent L-type currents.
By contrast, the activity of the brain isoform is not inhibited by
dihydropyridine drugs and thus may represent a P-type current.

Chin et al. (1991) used a rat brain cDNA probe to localize the alpha-1
subunit of neuronal dihydropyridine-sensitive L-type calcium channels in
the mouse and human genomes. The gene was assigned to mouse chromosome
14 by Southern analysis of Chinese hamster/mouse somatic cell hybrid
DNAs. It was mapped to a position 7.5 cM proximal to Np-1 by Southern
analysis of DNAs from an intersubspecies cross. Southern analysis of
human/rodent somatic cell hybrids indicated that the CCHL1A2 gene maps
to human chromosome 3. Because of the homology between proximal mouse
chromosome 14 and human 3p, the CCHL1A2 gene may be on 3p. Seino et al.
(1992) isolated cDNA from pancreatic beta cells that encodes the human
neuroendocrine/brain-type alpha-1 subunit. By fluorescence in situ
hybridization, Seino et al. (1992) mapped the CACNL1A2 gene to 3p14.3.
Seino et al. (1992) suggested that the alpha-1 subunit gene termed brain
L-type calcium channel subunit mapped to 3p by Chin et al. (1991) may in
fact have been the neuroendocrine/brain isoform rather than the brain
isoform described by Mori et al. (1991). The fact that it was
dihydropyridine sensitive supports this conclusion.

McAlpine (1992) recommended that the gene symbols for the calcium
channel genes reflect their classification according to pharmacologic
type, i.e., L, T, N, and P. For the form discussed here, the suggested
title is 'calcium channel, L type, alpha-1 polypeptide, isoform 2,' with
symbol CACNL1A2.

*FIELD* SA
Seino et al. (1992)
*FIELD* RF
1. Chin, H.; Kozak, C. A.; Kim, H.-L.; Mock, B.; McBride, O. W.:
A brain L-type calcium channel alpha-1 subunit gene (CCHL1A2) maps
to mouse chromosome 14 and human chromosome 3. Genomics 11: 914-919,
1991.

2. McAlpine, P. J.: Personal Communication. Winnipeg, Manitoba,
Canada  2/14/1992.

3. Mori, Y.; Friedrich, T.; Kim, M.-S.; Mikami, A.; Nakai, J.; Ruth,
P.; Bosse, E.; Hofmann, F.; Flockerzi, V.; Furuichi, T.; Mikoshiba,
K.; Imoto, K.; Tanabe, T.; Numa, S.: Primary structure and functional
expression from complementary DNA of a brain calcium channel. Nature 350:
398-402, 1991.

4. Seino, S.; Chen, L.; Seino, M.; Blondel, O.; Takeda, J.; Johnson,
J. H.; Bell, G. I.: Cloning of the alpha-1 subunit of a voltage-dependent
calcium channel expressed in pancreatic beta-cells. Proc. Nat. Acad.
Sci. 89: 584-588, 1992.

5. Seino, S.; Yamada, Y.; Espinosa, R., III; Le Beau, M. M.; Bell,
G. I.: Assignment of the gene encoding the alpha-1 subunit of the
neuroendocrine/brain-type calcium channel (CACNL1A2) to human chromosome
3, band p14.3. Genomics 13: 1375-1377, 1992.

6. Tsien, R. W.; Ellinor, P. T.; Horne, W. A.: Molecular diversity
of voltage-dependent Ca(2+) channels. Trends Pharm. Sci. 12: 349-354,
1991.

*FIELD* CD
Victor A. McKusick: 12/5/1991

*FIELD* ED
mimadm: 4/29/1994
warfield: 4/7/1994
carol: 4/7/1993
carol: 8/31/1992
carol: 6/22/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
114207
*FIELD* TI
*114207 CALCIUM CHANNEL, L TYPE, BETA-1 POLYPEPTIDE; CACNLB1
CALCIUM CHANNEL, NEURONAL DIHYDROPYRIDINE-SENSITIVE, BETA SUBUNIT;;
; CCHLB; CCHLB1
*FIELD* TX
Pragnell et al. (1991) isolated a cDNA clone encoding a protein with
high homology to the beta subunit of the rabbit skeletal muscle
dihydropyridine-sensitive calcium channel from a rat brain cDNA library.
This rat brain beta-subunit cDNA hybridized to a 3.4-kb message that was
expressed in high levels in the cerebral hemispheres and hippocampus and
much lower levels in cerebellum. The open reading frame encoded 597
amino acids with a predicted mass of 65,679 Da which was 82% homologous
with the skeletal muscle beta subunit. The corresponding human
beta-subunit gene was localized to chromosome 17 by analysis of somatic
cell hybrids. Pragnell et al. (1991) suggested that the encoded brain
beta subunit, which has a primary structure highly similar to its
isoform in skeletal muscle, may have a comparable role as an integral
regulatory component of a neuronal calcium channel. Powers et al. (1992)
demonstrated that the skeletal muscle and brain isoforms of the beta
subunit are encoded by a single gene. The human skeletal muscle beta-1
cDNA encodes a protein of 523 amino acids that is 97% identical to the
rabbit skeletal muscle beta subunit. Two different cDNAs were obtained
from the human hippocampus library. One encoded a protein of 478 amino
acids that was identical to the skeletal muscle beta subunit except for
an internal region of 52 amino acids. The other encoded a protein of 596
amino acids, which was identical to the 478-amino acid skeletal muscle
beta subunit at amino acids 1-444; however, it had a unique 152-amino
acid carboxyl terminus. All 3 cDNAs represented transcripts encoded by a
single gene. Iles et al. (1993) mapped the CACNLB1 gene to 17q11.2-q24,
approximately 16 cM centromeric to HOX2B (142961). For this purpose,
they used a highly polymorphic dinucleotide repeat found close to the
gene in linkage analysis. At the same time, they excluded the CACNLB1
gene as the site of the mutation in malignant hyperthermia families that
do not show linkage to chromosome 19q13.1 markers.

To determine the role of the beta-1 subunit in channel activity and
excitation-contraction coupling, Gregg et al. (1996) used gene targeting
to inactivate the beta-1 subunit in mice. Homozygous mutant fetuses had
a phenotype very similar to that seen in mice with mutations in either
the alpha-1S subunit ('muscular dysgenic') or in the ryanodine
receptor-1 (180901), 'skrr.' All 3 mutants lacked excitation-contraction
coupling. Beta-1-null mice died at birth from asphyxia. Electrical
stimulation of beta-1-muscle failed to induce twitches; however,
contractures were induced by caffeine. In isolated beta-1-null myotubes,
action potentials were normal but failed to elicit calcium ion
transient. Immunohistochemistry of cultured myotubes showed that not
only was the beta-1 subunit absent, but the amount of alpha-1S in the
membrane was also undetectable. In contrast, the beta-1 subunit was
appropriately localized in alpha-1S-null cells. Therefore, Gregg et al.
(1996) concluded that the beta-1 subunit may not only play an important
role in the transport/insertion of the alpha-1S subunit into the
membrane, but may also be vital for the targeting of the muscle
dihydropyridine receptor complex to the transverse tubule/sarcoplasmic
reticulum junction.

*FIELD* RF
1. Gregg, R. G.; Messing, A.; Strube, C.; Beurg, M.; Moss, R.; Behan,
M.; Sukhareva, M.; Haynes, S.; Powell, J. A.; Coronado, R.; Powers,
P. A.: Absence of the beta subunit (cchb1) of the skeletal muscle
dihydropyridine receptor alters expression of the alpha-1 subunit
and eliminates excitation-contraction coupling. Proc. Nat. Acad.
Sci. 93: 13961-13966, 1996.

2. Iles, D. E.; Segers, B.; Sengers, R. C. A.; Monsieurs, K.; Heytens,
L.; Halsall, P. J.; Hopkins, P. M.; Ellis, F. R.; Hall-Curran, J.
L.; Stewart, A. D.; Wieringa, B.: Genetic mapping of the beta-1-
and gamma-subunits of the human skeletal muscle L-type voltage-dependent
calcium channel on chromosome 17q and exclusion as candidate genes
for malignant hyperthermia susceptibility. Hum. Molec. Genet. 2:
863-868, 1993.

3. Powers, P. A.; Liu, S.; Hogan, K.; Gregg, R. G.: Skeletal muscle
and brain isoforms of a beta-subunit of human voltage-dependent calcium
channels are encoded by a single gene. J. Biol. Chem. 267: 22967-22972,
1992.

4. Pragnell, M.; Sakamoto, J.; Jay, S. D.; Campbell, K. P.: Cloning
and tissue-specific expression of the brain calcium channel beta-subunit. FEBS
Lett. 291: 253-258, 1991.

*FIELD* CD
Victor A. McKusick: 2/7/1992

*FIELD* ED
terry: 01/22/1997
terry: 1/10/1997
mark: 1/23/1996
carol: 6/24/1994
mimadm: 5/18/1994
carol: 8/17/1993
carol: 1/5/1993
carol: 6/22/1992
carol: 3/23/1992

*RECORD*
*FIELD* NO
114208
*FIELD* TI
*114208 CALCIUM CHANNEL, L TYPE, ALPHA-1 POLYPEPTIDE, ISOFORM 3, SKELETAL
MUSCLE; CACNL1A3
CALCIUM CHANNEL, SKELETAL MUSCLE DIHYDROPYRIDINE-SENSITIVE, ALPHA-1;;
SUBUNIT;;
CCHL1A3
*FIELD* TX
The major type of voltage-sensitive Ca(2+) channels in skeletal muscle
is the slowly inactivating L-type that is sensitive to calcium channel
blockers such as 1,4-dihydropyridines (DHP), phenylalkylamines, and
benzothiazepines. These skeletal muscle Ca(2+) channels play a key role
in excitation-contraction coupling, a process whereby electrical signals
generated by action potentials at the muscle cell surface are transduced
into intracellular release of calcium and ultimately muscle fiber
contraction. The DHP-sensitive L-type Ca(2+) channel from skeletal
muscle is an oligomeric protein composed of 2 high-molecular-weight
polypeptide subunits (alpha-1 and alpha-2) and 3 smaller units (beta,
gamma, and delta). The alpha-1 subunit confers the structural features
needed for Ca(2+) channel function and also contains the binding sites
for the Ca(2+) channel blockers. In the mouse, the gene for the alpha-1
subunit, symbolized Cchl1a3, is mutant in 'muscular dysgenesis' (mdg), a
lethal autosomal recessive disorder in which there is total lack of
excitation-contraction coupling in homozygotes (Gluecksohn-Waelsch,
1963; Pai, 1965). In the affected muscle, the reduction of the level of
slow Ca(2+) channel/dihydropyridine receptor and the lack of L type
Ca(2+) current indicate that this channel may be implicated in the
mutation. The alpha-1 subunit of the channel, which contains the DHP
binding site and the voltage sensor element, is missing in mdg/mdg
animals. In mice, Tanabe et al. (1988) found that microinjection of
alpha-1 cDNA into mdg/mdg myotubes can restore a normal
excitation-contraction coupling. Chaudhari (1992) reported that the mdg
mutation is characterized by deletion of nucleotide 4010 in the cDNA
transcribed from the gene encoding the alpha-1 subunit, resulting in a
shift of the translational reading frame.

Using a rat brain cDNA probe for Cchl1a3 for hybridization to Southern
blots of DNAs from a panel of Chinese hamster/mouse somatic cell
hybrids, Chin et al. (1992) showed that the gene mapped to mouse
chromosome 1. Analysis of interspecific crosses positioned the Cchl1a3
gene 1.3 cM proximal to the Pep-3 locus. Thus the corresponding gene in
humans is probably located on distal 1q, since Pep-3 corresponds to
PEPC, which is located on human 1q42.

Gregg et al. (1993) used all of the nucleotides based on a partial
sequence of the CACNL1A3 gene to PCR amplify specifically the human gene
in human/rodent somatic cell hybrids, thus allowing the assignment of
the gene to chromosome 1. A polymorphic dinucleotide repeat was
identified in the human clone and by PCR was typed on CEPH families to
position the CACNL1A3 gene between D1S52 and D1S70 on 1q31-q32. Drouet
et al. (1993) mapped this gene to mouse chromosome 1 and human 1q32 by
in situ hybridization. They confirmed the localization in the mouse by
linkage studies in a C57BL/6 x Mus spretus interspecific backcross.
Drouet et al. (1993) localized the mdg mutation to mouse chromosome 1 by
analyzing the offspring of an interspecific backcross segregating the
mutant allele and showed that it is very closely linked to the myogenin
(Myog) locus. Iles et al. (1994) also used in situ hybridization to map
the CACNL1A3 gene to 1q32.

Using an intragenic microsatellite as a marker, Fontaine et al. (1994)
demonstrated that the CACNL1A3 gene maps to 1q31-q32 and shares a 5-cM
interval with the gene for hypokalemic periodic paralysis (HOKPP;
170400). By isolation of overlapping genomic DNA clones from human
cosmid, phage, and P1 libraries, Hogan et al. (1996) defined the
sequences of the exons and flanking introns of the CACNL1A3 gene. The
gene spans 90 kb and consists of 44 exons.

In 2 informative families, Fontaine et al. (1994) showed that CACNL1A3
cosegregated with hypokalemic periodic paralysis without recombinants,
making it a strong candidate for the HOKPP gene. Ptacek et al. (1994)
proved that CACNL1A3 indeed was the site of mutations in hypokalemic
periodic paralysis. Among 11 unrelated probands, they found mutations in
1 of 2 adjacent nucleotides within the same codon that predicted
substitution of a highly conserved arginine in the S4 segment of domain
4 by either histidine (114208.0001) or glycine (114208.0002). In 1
kindred, the mutation arose de novo.

In a Dutch hypokalemic periodic paralysis kindred with 55 affected
members in the last 5 generations, Boerman et al. (1995) used
microsatellite markers to demonstrate linkage to 1q31-q32. A G-to-A
transition causing the arg528-to-his substitution (114208.0003) was
demonstrated as the causative mutation.

Elbaz et al. (1995) found the arg1239-to-his mutation (114208.0001) in 8
of 16 families with hypokalemic periodic paralysis of Caucasian origin;
arg528-to-his (114208.0003) was the mutation in the other 8 families.
Using dinucleotide repeats contained within or close to the CACNL1A3
gene, in conjunction with demonstration of a de novo arg1239-to-his
mutation, Elbaz et al. (1995) showed that a founder effect is unlikely
to account for the 2 predominant mutations.

*FIELD* AV
.0001
HYPOKALEMIC PERIODIC PARALYSIS
CACNL1A3, ARG1239HIS
In patients with hypokalemic periodic paralysis, Ptacek et al. (1994)
demonstrated a G-to-A transition at a position analogous to basepair
3716 in rabbit cDNA (Tanabe et al., 1987). The change from CGT to CAT
predicted substitution of an arginine residue by a histidine at a
position corresponding to amino acid 1239 in the rabbit DHP receptor.
This arginine is completely conserved among genes encoding DHP receptors
from rabbit, carp, ray, and human skeletal muscle. Elbaz et al. (1995)
demonstrated a de novo arg1239-to-his mutation.

.0002
HYPOKALEMIC PERIODIC PARALYSIS
CACNL1A3, ARG1239GLY
In affected family members with HOKPP, Ptacek et al. (1994) demonstrated
a C-to-G transversion at a position analogous to basepair 3715 in rabbit
cDNA. The change from CGT to GGT predicted a substitution of an arginine
residue with a glycine residue at a position corresponding to amino acid
1239 in the rabbit DHP receptor (Tanabe et al., 1987).

.0003
HYPOKALEMIC PERIODIC PARALYSIS
CACNL1A3, ARG528HIS
By sequencing of cDNA of the CACNL1A3 gene in 2 patients with
hypokalemic periodic paralysis, Jurkat-Rott et al. (1994) demonstrated a
G-to-A transition in nucleotide 1583 predicting a substitution of
histidine for arginine-528. The mutation affected the outermost positive
charge in the transmembrane segment IIS4 that was considered to
participate in voltage sensing. By restriction fragment analysis, the
mutation was detected in the affected members of 9 out of 25 hypokalemic
periodic paralysis families. An altered excitation-contraction coupling
may explain the occurrence of muscle weakness. Elbaz et al. (1995), who
found the arg528-to-his mutation in 8 of 16 families of Caucasian
origin, demonstrated that incomplete penetrance is a distinctive feature
of this mutation. Boerman et al. (1995) found this mutation in 55
affected members of a Dutch kindred.

*FIELD* RF
1. Boerman, R. H.; Ophoff, R. A.; Links, T. P.; van Eijk, R.; Sandkuijl,
L. A.; Elbaz, A.; Vale-Santos, J. E.; Wintzen, A. R.; van Deutekom,
J. C.; Isles, D. E.; Fontaine, B.; Padberg, G. W.; Frants, R. R.:
Mutation in DHP receptor alpha-1 subunit (CACLN1A3) gene in a Dutch
family with hypokalaemic periodic paralysis. J. Med. Genet. 32:
44-47, 1995.

2. Chaudhari, N.: A single nucleotide deletion in the skeletal muscle-specific
calcium channel transcript of muscular dysgenesis (mdg) mice. J.
Biol. Chem. 267: 25636-25639, 1992.

3. Chin, H.; Krall, M.; Kim, H.-L.; Kozak, C. A.; Mock, B.: The gene
for the alpha-1 subunit of the skeletal muscle dihydropyridine-sensitive
calcium channel (Cchl1a3) maps to mouse chromosome 1. Genomics 14:
1089-1091, 1992.

4. Drouet, B.; Garcia, L.; Simon-Chazottes, D.; Mattei, M. G.; Guenet,
J.-L.; Schwartz, A.; Varadi, G.; Pincon-Raymond, M.: The gene coding
for the alpha-1 subunit of the skeletal dihydropyridine receptor (Cchl1a3
= mdg) maps to mouse chromosome 1 and human 1q32. Mammalian Genome 4:
499-503, 1993.

5. Elbaz, A.; Vale-Santos, J.; Jurkat-Rott, K.; Lapie, P.; Ophoff,
R. A.; Bady, B.; Links, T. P.; Piussan, C.; Vila, A.; Monnier, N.;
Padberg, G. W.; Abe, K.; Feingold, N.; Guimaraes, J.; Wintzen, A.
R.; van der Hoeven, J. H.; Saudubray, J. M.; Grunfeld, J. P.; Lenoir,
G.; Nivet, H.; Echenne, B.; Frants, R. R.; Fardeau, M.; Lehmann-Horn,
F.; Fontaine, B.: Hypokalemic periodic paralysis and the dihydropyridine
receptor (CACNL1A3): genotype/phenotype correlations for two predominant
mutations and evidence for the absence of a founder effect in 16 Caucasian
families. Am. J. Hum. Genet. 56: 374-380, 1995.

6. Fontaine, B.; Vale-Santos, J.; Jurkat-Rott, K.; Reboul, J.; Plassart,
E.; Rime, C.-S.; Elbaz, A.; Heine, R.; Guimaraes, J.; Weissenbach,
J.; Baumann, N.; Fardeau, M.; Lehmann-Horn, F.: Mapping of the hypokalaemic
periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European
families. Nature Genet. 6: 267-272, 1994.

7. Gluecksohn-Waelsch, S.: Lethal genes and analysis of differentiation.
Science 142: 1269-1276, 1963.

8. Gregg, R. G.; Couch, F.; Hogan, K.; Powers, P. A.: Assignment
of the human gene for the alpha-1 subunit of the skeletal muscle DHP-sensitive
Ca(2+) channel (CACNL1A3) to chromosome 1q31-q32. Genomics 15:
107-112, 1993.

9. Hogan, K.; Gregg, R. G.; Powers, P. A.: The structure of the gene
encoding the human skeletal muscle alpha-1 subunit of the dihydropyridine-sensitive
L-type calcium channel (CACNL1A3). Genomics 31: 392-394, 1996.

10. Iles, D. E.; Segers, B.; Weghuis, D. O.; Suijkerbuijk, R.; Mikala,
G.; Schwartz, A.; Wieringa, B.: Refined localization of the alpha-1-subunit
of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3)
to human chromosome 1q32 by in situ hybridization. Genomics 19:
561-563, 1994.

11. Jurkat-Rott, K.; Lehmann-Horn, F.; Elbaz, A.; Heine, R.; Gregg,
R. G.; Hogan, K.; Powers, P. A.; Lapie, P.; Vale-Santos, J. E.; Weissenbach,
J.; Fontaine, B.: A calcium channel mutation causing hypokalemic
periodic paralysis. Hum. Molec. Genet. 3: 1415-1419, 1994.

12. Pai, A. C.: Developmental genetics of a lethal mutation, muscular
dysgenesis (mdg), in the mouse. I. Genetic analysis and gross morphology.
Dev. Biol. 11: 82-92, 1965.

13. Ptacek, L. J.; Tawil, R.; Griggs, R. C.; Engel, A. G.; Layzer,
R. B.; Kwiecinski, H.; McManis, P. G.; Santiago, L.; Moore, M.; Fouad,
G.; Bradley, P.; Leppert, M. F.: Dihydropyridine receptor mutations
cause hypokalemic periodic paralysis. Cell 77: 863-868, 1994.

14. Tanabe, T.; Beam, K. G.; Powell, J. A.; Numa, S.: Restoration
of excitation-contraction coupling and slow calcium current in dysgenic
muscle by dihydropyridine receptor complementary DNA. Nature 336:
134-139, 1988.

15. Tanabe, T.; Takeshima, H.; Mikami, A.; Flockerzi, V.; Takahashi,
H.; Kangawa, K.; Kojima, M.; Matsuo, H.; Hirose, T.; Numa, S.: Primary
structure of the receptor for calcium channel blockers from skeletal
muscle. Nature 328: 313-318, 1987.

*FIELD* CD
Victor A. McKusick: 1/14/1993

*FIELD* ED
mark: 03/21/1996
terry: 3/11/1996
mark: 3/17/1995
carol: 2/27/1995
terry: 10/17/1994
jason: 7/12/1994
carol: 10/21/1993
carol: 10/11/1993

*RECORD*
*FIELD* NO
114209
*FIELD* TI
*114209 CALCIUM CHANNEL, L TYPE, GAMMA POLYPEPTIDE; CACNLG
CALCIUM CHANNEL, NEURONAL DIHYDROPYRIDINE-SENSITIVE, GAMMA SUBUNIT
*FIELD* TX
Powers et al. (1993) demonstrated that the gamma subunit of the skeletal
muscle and neuronal dihydropyridine-sensitive calcium channel is encoded
by a gene located on 17q11.2-q24 in the same region as the gene for the
beta-1 subunit (CACNLB1; 114207).

Iles et al. (1993) excluded this gene as the site of the mutation in a
considerable number of families with malignant hyperthermia
susceptibility in which there was no linkage to chromosome 19. They
estimated that the CACNLG locus is about 19 cM distal to the SCN4A
(170500) and GH1 (139250) loci, which in turn are about 32 cM telomeric
of the HOX2B locus (142961), on chromosome 17. Iles et al. (1993) mapped
the CACNLG gene to 17q24 by in situ hybridization. They also identified
a polymorphic repetitive DNA sequence in the gene locus and proposed its
use in investigating whether the gene plays a role in malignant
hyperthermia and other disorders mapping to 17q.

*FIELD* SA
Iles et al. (1993)
*FIELD* RF
1. Iles, D. E.; Segers, B.; Sengers, R. C. A.; Monsieurs, K.; Heytens,
L.; Halsall, P. J.; Hopkins, P. M.; Ellis, F. R.; Hall-Curran, J.
L.; Stewart, A. D.; Wieringa, B.: Genetic mapping of the beta-1-
and gamma-subunits of the human skeletal muscle L-type voltage-dependent
calcium channel on chromosome 17q and exclusion as candidate genes
for malignant hyperthermia susceptibility. Hum. Molec. Genet. 2:
863-868, 1993.

2. Iles, D. E.; Segers, B.; Weghuis, D. O.; Suikerbuijk, R.; Wieringa,
B.: Localization of the gamma-subunit of the skeletal muscle L-type
voltage-dependent calcium channel gene (CACNLG) to human chromosome
band 17q24 by in situ hybridization and identification of a polymorphic
repetitive DNA sequence at the gene locus. Cytogenet. Cell Genet. 64:
227-230, 1993.

3. Powers, P. A.; Liu, S.; Hogan, K.; Gregg, R. G.: Molecular characterization
of the gene encoding the gamma subunit of the human skeletal muscle
1,4-dihydropyridine-sensitive Ca(2+) channel (CACNLG), cDNA sequence,
gene structure, and chromosomal location. J. Biol. Chem. 268: 9275-9279,
1993.

*FIELD* CD
Victor A. McKusick: 8/17/1993

*FIELD* ED
mark: 01/23/1996
carol: 11/3/1993
carol: 9/23/1993
carol: 8/27/1993
carol: 8/17/1993

*RECORD*
*FIELD* NO
114210
*FIELD* TI
*114210 S100 CALCIUM-BINDING PROTEIN A4; S100A4
CALCIUM PLACENTAL PROTEIN; CAPL
*FIELD* TX
Jackson-Grusby et al. (1987) isolated a probe for the mouse placental
protein for which the human equivalent was symbolized CAPL by van
Heyningen et al. (1989). By Southern blot analysis of DNAs from somatic
cell hybrids, van Heyningen et al. (1989) and Dorin et al. (1990) showed
that the CAPL gene in man cosegregates with CAGA (123885), CAGB
(123886), and calcyclin (114110). In the hands of van Heyningen et al.
(1989), Southern blot analysis of DNA from BxD recombinant inbred strain
mice showed a TaqI polymorphism for CAPL probe 18A2 to distinguish the
parental strains. CAPL cosegregated in the BxD mice with a fifth member
of this gene family, the p11 protein (mouse symbol Cal11) which had been
mapped to chromosome 3 by Saris et al. (1987). In the mouse Capl is
within 8 kb of Cacy; thus, by homology, the CAPL gene in man is probably
in region 1q21-q25 where the CACY gene has been mapped.

Schafer et al. (1995) isolated a YAC clone from the 1q21 region on which
9 different genes coding for S100 calcium-binding proteins could be
localized. The clustered organization of S100 genes allowed introduction
of a new logical nomenclature based on their physical arrangement on the
chromosome, with S100A1 (176940) being closest to the telomere and
S100A9 being closest to the centromere. In this revised nomenclature,
CAPL became S100A4.

Ambartsumian et al. (1995) showed that the gene consists of 4 exons and
described 2 alternative splice variants that differ in their 5-prime
untranslated regions.

*FIELD* RF
1. Ambartsumian, N.; Tarabykina, S.; Grigorian, M.; Tulchinsky, E.;
Hulgaard, E.; Georgiev, G.; Lukanidin, E.: Characterization of two
splice variants of metastasis-associated human mts1 gene. Gene 159:
125-130, 1995.

2. Dorin, J. R.; Emslie, E.; van Heyningen, V.: Related calcium-binding
proteins map to the same subregion of chromosome 1q and to an extended
region of synteny on mouse chromosome 3. Genomics 8: 420-426, 1990.

3. Jackson-Grusby, L. L.; Swiergiel, J.; Linzer, D. I.: A growth-related
mRNA in cultured mouse cells encodes a placental calcium binding protein.
Nucleic Acids Res. 15: 6677-6690, 1987.

4. Saris, C. J.; Kristensen, T.; D'Eustachio, P.; Hicks, L. J.; Noonan,
D. J.; Hunter, T.; Tack, B. F.: cDNA sequence and tissue distribution
of the mRNA for bovine and murine p11, the S100-related light chain
of the protein-tyrosine kinase substrate p36 (calpactin I). J. Biol.
Chem. 262: 10663-10671, 1987.

5. Schafer, B. W.; Wicki, R.; Engelkamp, D.; Mattei, M.-G.; Heizmann,
C. W.: Isolation of a YAC clone covering a cluster of nine S100 genes
on human chromosome 1q21: rationale for a new nomenclature of the
S100 calcium-binding protein family. Genomics 25: 638-643, 1995.

6. van Heyningen, V.; Emslie, E.; Dorin, J. R.: Related calcium binding
proteins map to the same sub-region of chromosome 1q and to an extended
region of synteny on mouse chromosome 3.   (Abstract) Cytogenet.
Cell Genet. 51: 1095, 1989.

*FIELD* CN
Alan F. Scott - updated: 12/7/1995

*FIELD* CD
Victor A. McKusick: 6/2/1989

*FIELD* ED
mark: 04/22/1996
mark: 6/15/1995
carol: 1/23/1995
supermim: 3/16/1992
carol: 12/4/1990
carol: 12/3/1990
carol: 11/28/1990

*RECORD*
*FIELD* NO
114212
*FIELD* TI
*114212 CALCYPHOSINE; CAPS
*FIELD* TX
Calcyphosine was first described as a potentially important regulatory
protein in the dog thyroid (Lefort et al., 1989). Lefort et al. (1990)
isolated a genomic clone for human calcyphosine form the Maniatis
library using a probe corresponding to the coding region of the dog
calcyphosine cDNA. They used this clone to assign the human gene to
19p13.3 by in situ hybridization.

*FIELD* RF
1. Lefort, A.; Lecocq, R.; Libert, F.; Lamy, F.; Swillens, S.; Vassart,
G.; Dumont, J. E.: Cloning and sequencing of a calcium-binding protein
regulated by cyclic AMP in the thyroid. EMBO J. 8: 111-116, 1989.

2. Lefort, A.; Passage, E.; Libert, F.; Szpirer, J.; Vassart, G.;
Mattei, M.-G.: Localization of human calcyphosine gene (CAPS) to
the p13.3 region of chromosome 19 by in situ hybridization. Cytogenet.
Cell Genet. 54: 154-155, 1990.

*FIELD* CD
Victor A. McKusick: 2/26/1991

*FIELD* ED
supermim: 3/16/1992
carol: 2/27/1991
carol: 2/26/1991

*RECORD*
*FIELD* NO
114213
*FIELD* TI
*114213 CALDESMON-1; CALD1
CDM
*FIELD* TX
Caldesmon is a potential actomyosin regulatory protein found in smooth
muscle and nonmuscle cells. Domain mapping and physical studies
suggested that CDM is an elongated molecule with an N-terminal
myosin/calmodulin-binding domain and a C-terminal
tropomyosin/actin/calmodulin-binding domain separated by a 40-nm-long
central helix. Humphrey et al. (1992) used a probe encoding part of
avian caldesmon to screen a human aorta library and clone smooth-muscle
and nonmuscle CDM-encoding cDNAs. The predicted smooth-muscle
polypeptide is 793 amino acids long. As in the case of chicken CDM,
nonmuscle CDM was missing the central helical domain of 256 amino acids.
The nonmuscle form appeared to be generated by exon skipping. Humphrey
et al. (1992) suggested that the CDMs are a small family of highly
conserved proteins which are probably derived from a single gene.

The high-molecular-weight caldesmon is predominantly expressed in smooth
muscles, whereas the low-molecular-weight caldesmon is widely
distributed in nonmuscle tissues and cells. Hayashi et al. (1992)
demonstrated that the human CDM gene is composed of 14 exons. By
fluorescence in situ hybridization, they showed that it is encoded by a
single gene located at 7q33-q34. The regulation of high-molecular-weight
and low-molecular-weight caldesmon expression was thought to depend on
selection of the 2 5-prime splice sites within exon 3.

*FIELD* RF
1. Hayashi, K.; Yano, H.; Hashida, T.; Takeuchi, R.; Takeda, O.; Asada,
K.; Takahashi, E.; Kato, I.; Sobue, K.: Genomic structure of the
human caldesmon gene. Proc. Nat. Acad. Sci. 89: 12122-12126, 1992.

2. Humphrey, M. B.; Herrera-Sosa, H.; Gonzalez, G.; Lee, R.; Bryan,
J.: Cloning of cDNAs encoding human caldesmons. Gene 112: 197-204,
1992.

*FIELD* CD
Victor A. McKusick: 6/15/1992

*FIELD* ED
randy: 08/31/1996
carol: 1/12/1993
carol: 6/15/1992

*RECORD*
*FIELD* NO
114217
*FIELD* TI
*114217 CALNEXIN; CANX
*FIELD* TX
Calnexin is a 90-kilodalton integral membrane protein of the endoplasmic
reticulum (ER). It exhibits high affinity for the binding of calcium
ions, which was the means by which it was first identified. Calcium ions
are known to play a central role in the regulation of cellular
metabolism, including signal transduction events and the transport of
proteins through the ER. Calnexin has been shown to be associated with
several cell surface proteins during translocation through the ER and
has been isolated as a complex with other ER proteins involved in
calcium ion-dependent retention of proteins. It may function as a
chaperone to regulate the transit of proteins through the ER. Gray et
al. (1993) hybridized a CANX cDNA probe to Southern blots of a panel of
31 EcoRI-digested somatic cell human-mouse hybrid DNAs. The CANX probe
segregated concordantly with chromosome 5. In situ hybridization with a
tritium-labeled calnexin cDNA probe regionally localized the CANX gene
to 5q35. Tjoelker et al. (1994) isolated cDNA clones of the human,
mouse, and rat calnexins. Comparisons of the sequences demonstrated a
high level of conservation of sequence identity, suggesting that
calnexin performs important cellular functions. Tjoelker et al. (1994)
reported the details of the mapping of the human CANX gene to 5q35 as
reported in abstract by Gray et al. (1993).

*FIELD* RF
1. Gray, P. W.; Byers, M. G.; Eddy, R. L.; Shows, T. B.: The assignment
of the calnexin gene to the q35 region of chromosome 5.  (Abstract) Human
Genome Mapping Workshop 93 9 only, 1993.

2. Tjoelker, L. W.; Seyfried, C. E.; Eddy, R. L., Jr.; Byers, M. G.;
Shows, T. B.; Calderon, J.; Schreiber, R. B.; Gray, P. W.: Human,
mouse, and rat calnexin cDNA cloning: identification of potential
calcium binding motifs and gene localization to human chromosome 5.
Biochemistry 33: 3229-3236, 1994.

*FIELD* CD
Victor A. McKusick: 12/6/1993

*FIELD* ED
carol: 5/20/1994
carol: 12/6/1993

*RECORD*
*FIELD* NO
114220
*FIELD* TI
*114220 CALPAIN I, LARGE SUBUNIT; CANPL1; CAPN1
*FIELD* TX
Calpain (calcium-dependent protease; CANP; EC 3.4.22.17) is an
intracellular protease that requires calcium for its catalytic activity.
Two isozymes (CANP1 and CANP2), with different calcium requirements,
have been identified. Both are heterodimers composed of L (large,
catalytic, 80 kD) and S (small, regulatory, 30 kD) subunits. The
isozymes share an identical S subunit (114170); differences arise from
the L subunits (L1 and L2). Using cDNA clones as probes, Ohno et al.
(1989) mapped the CANPL1 and CANPL2 genes as well as the CANPS gene and
a gene for another protein, L3, that is homologous to the other 2 L
subunits; they used a combination of spot blot hybridization with sorted
chromosomes and Southern hybridization with human-mouse cell hybrid
DNAs. In this way they were able to assign CANPL1 to chromosome 11;
CANPL2 to chromosome 1; CANPL3 to chromosome 15; and CANPS to chromosome
19.

*FIELD* SA
Ohno et al. (1990)
*FIELD* RF
1. Ohno, S.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Ohmi-Imajoh,
S.; Suzuki, K.; Shimizu, Y.; Shimizu, N.: Four genes for the calpain
family locate on four distinct human chromosomes.  (Abstract) Cytogenet.
Cell Genet. 51: 1054-1055, 1989.

2. Ohno, S.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Shimizu, Y.;
Ohmi-Imajoh, S.; Shimizu, N.; Suzuki, K.: Four genes for the calpain
family locate on four distinct human chromosomes. Cytogenet. Cell
Genet. 53: 225-229, 1990.

*FIELD* CD
Victor A. McKusick: 6/5/1989

*FIELD* ED
supermim: 3/16/1992
carol: 4/29/1991
supermim: 3/20/1990
carol: 12/19/1989
ddp: 10/27/1989

*RECORD*
*FIELD* NO
114230
*FIELD* TI
*114230 CALPAIN II, LARGE SUBUNIT; CANPL2; CAPN2
*FIELD* TX
See 114220.

*FIELD* CD
Victor A. McKusick: 6/5/1989
*FIELD* ED
carol: 4/7/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 9/23/1989
root: 6/5/1989
*RECORD*
*FIELD* NO
114240
*FIELD* TI
*114240 CALPAIN, LARGE POLYPEPTIDE L3; CAPN3
CALPAIN III, LARGE SUBUNIT; CANPL3;;
CALCIUM-ACTIVATED NEUTRAL PROTEASE 3, MUSCLE-SPECIFIC, LARGE SUBUNIT;
CANP3
*FIELD* TX
See 114220. The calpains, or calcium-activated neutral proteases
(calpains; EC 3.4.22.17) are nonlysosomal intracellular cysteine
proteases. The mammalian calpains include 2 ubiquitous proteins, CAPN1
(114220) and CAPN2 (114230), as well as 2 stomach-specific proteins, and
CAPN3, which is muscle-specific. The ubiquitous enzymes consist of
heterodimers with distinct large subunits associated with a common small
subunit, all of which are encoded by different genes. The association of
tissue-specific large subunits with a small subunit has not yet been
demonstrated. The large subunits of calpains can be subdivided into 4
domains: domains I and III, whose functions remain unknown, show no
homology with known proteins. The former, however, may be important for
the regulation of the proteolytic activity. Domain II shows similarity
with other cysteine proteases, which share histidine, cysteine, and
asparagine residues at their active sites. Domain IV comprises 4 EF hand
structures that are potential calcium-binding sites. In addition, 3
unique regions with no known homology are present in the muscle-specific
CAPN protein, namely NS, IS1, and IS2, the latter containing a nuclear
translocation signal (Sorimachi et al., 1989). These regions may be
important for the muscle-specific function of CAPN3.

Richard et al. (1995) demonstrated that the CAPN3 gene (symbolized CANP3
by them) consists of 24 exons and extends over 40 kb. Ohno et al. (1989)
mapped the CAPN3 gene to chromosome 15. In the course of detailed
genetic and physical mapping of the region of chromosome 15 containing
the gene for limb-girdle muscular dystrophy type 2A (LGMD2A; 253600),
candidate genes for LGMD2A were isolated. One of these, previously
cloned by Sorimachi et al. (1989), the CAPN3 gene, was a particularly
attractive candidate because of its functional role in muscle. By a
mutation screen in LGMD2A families, Richard et al. (1995) identified 15
nonsense, splice site, frameshift, or missense CAPN3 mutations
cosegregating with the disease (see 114240.0001, 114240.0002, and
114240.0003). Six of these were found within an inbred population of La
Reunion islanders, and haplotype analysis suggested the existence of at
least 1 more mutation in the group. The occurrence of multiple
independent events in other small populations had been reported for the
Hurler syndrome (MPS1; 252800) by Bach et al. (1993) and for
metachromatic leukodystrophy (MLD; 250100) by Heinisch et al. (1995).
Richard et al. (1995) suggested that the problem, which they referred to
as the Reunion paradox, could be due to the fact that this condition,
which had been considered a monogenic disorder, has a more complex
inheritance pattern in which expression of the calpain mutations is
dependent on genetic background, either nuclear or mitochondrial.
Consider, for instance, a digenic model: only in the presence of
specific alleles at a permissive second unlinked locus (e.g., a
compensatory, partially redundant, regulatory, or modifier gene) would
there be expression of calpain mutations. Since one would need mutations
at both loci to be affected, the disease prevalence would remain low.
Under this model, members of the La Reunion island community would, as a
result of genetic drift, have a disease-associated allele at the
hypothesized second locus at high frequency (or even fixed in this small
population), conditions that would explain the apparent complete
penetrance of the calpain mutations. Complete penetrance of this disease
in the Amish and in the other described LGMD2A pedigrees would also be
under control of the second locus. If this model is true, there may be
fewer selected pressures against the appearance of CAPN3 mutations, as a
result of the conditional penetrance. In other words, the frequency of
the calpain variants in the overall population may be much higher than
initially deduced, based on the estimates of the prevalence of the
disease under a simple monogenic model. Under this model, some of the
families in which the LGMD2A locus was previously excluded based on
linkage analyses (assuming simple monogenic inheritance) might be
authentic LGMD2A families, reflecting differential segregation of the 2
unlinked genes. The digenic inheritance model would predict that in a
number of kindreds, there will be healthy individuals with 2 mutant
calpain genes. Digenic inheritance of retinitis pigmentosa has been
reported (see 180721 and 179605).

Zlotogora et al. (1996) suggested that the occurrence of multiple
mutations in the calpain gene among Reunion Island patients may be an
example of a high mutation rate in the gene coupled with selective
advantage to carriers. Beckmann (1996) offered rebuttal to this
explanation of the 'Reunion paradox' and defended their previously
reported digenic model. He stated that to that time a total of 7
distinct calpain mutations had been identified among Reunion Island
patients with limb girdle muscular dystrophy.

Previous to the identification of CAPN3 as the defective gene in LGMD2A,
all identified molecular mechanisms in muscular dystrophies had involved
structural components of muscle. CAPN3 appears to have a very rapid
turnover mediated by autocatalysis, possibly reflecting the need for
precise regulation of its activity. Furthermore, CPN3 shows a nuclear
localization, possibly mediated by the nuclear translocation signal in
the IS2 region. Richard et al. (1995) favored the idea that the CAPN3
protein is involved in the control of gene expression by regulating the
turnover or activity of transcription factors or of their inhibitors.

Richard and Beckmann (1996) found that the mouse Canp3 gene encodes an
mRNA of a size similar to the human CANP3 mRNA. The mouse gene directs
the synthesis of an 821-amino acid protein. Results obtained from a
somatic cell hybrid panel indicated the localization on mouse chromosome
2 or chromosome 4 but did not allow distinction between these 2
chromosomes, since all hybrids carrying mouse chromosome 2 also carried
chromosome 4. The fact that isolated murine YACs amplified a
sequence-tagged site (STS) for the TYRO3 gene (600341), which maps to
human chromosome 15, suggested to Richard and Beckmann (1996) that the 2
genes are adjacent in the mouse. Homology between mouse chromosome 2 and
human chromosome 15 is well established by a number of examples of
synteny; no homology of synteny has been demonstrated between human 15
and mouse 4.

*FIELD* AV
.0001
LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2A, AMISH
CAPN3, ARG769GLN
In patients with LGMD2A from the northern Indiana Amish group, Richard
et al. (1995) identified a G-to-A missense mutation at nucleotide 2306
within exon 22 of the CAPN3 gene, transforming arg769 to glutamine in
the protein product. The arg769 residue, which is conserved throughout
all members of the calpain family in all species, is located in domain
IV of the protein within the third EF hand of the helix-loop junction.
This mutation was encountered in a homozygous state in all patients from
10 chromosome 15-linked Amish families. This nucleotide change was not
present in patients from the 6 southern Indiana Amish LGMD families for
which the chromosome 15 locus was excluded by linkage analysis, thus
confirming the genetic heterogeneity of this disease in the Amish. The
same mutation was found by Richard et al. (1995) in a Brazilian family
where it was imbedded, however, in a completely different haplotype.

.0002
LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2A, AMISH
CAPN3, ARG572GLN
In affected individuals in family R12 in La Reunion island, Richard et
al. (1995) found homozygosity for a G-to-A transition at base 1,715 of
exon 13, resulting in a substitution of glutamine for arg572 inside
domain III. This residue is highly conserved throughout all known
calpains. The mutation, detectable by loss of an MspI restriction site,
was present only in this family and in no other examined LGMD2A families
or unrelated controls. It was one of 6 different CAPN3 mutations found
in La Reunion island patients, and at least one more mutation was
predicted from haplotype analysis.

.0003
LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2A, AMISH
CAPN3, ARG110TER
In a Brazilian family, Richard et al. (1995) found a C-to-T transition
at nucleotide 328 in exon 2 in homozygous state, replacing arg110 with a
TGA stop codon, thus presumably leading to a much truncated and inactive
protein. The parents were consanguineous.

*FIELD* RF
1. Bach, G.; Moskowitz, S. M.; Tieu, P. T.; Matynia, A.; Neufeld,
E. F.: Molecular analysis of Hurler syndrome in Druze and Muslim
Arab patients in Israel: multiple allelic mutations of the IDUA gene
in a small geographic area. Am. J. Hum. Genet. 53: 330-338, 1993.

2. Beckmann, J. S.: The Reunion paradox and the digenic model. (Letter) Am.
J. Hum. Genet. 59: 1400-1402, 1996.

3. Heinisch, U.; Zlotogora, J.; Kafert, S.; Gieselmann, V.: Multiple
mutations are responsible for the high frequency of metachromatic
leukodystrophy in a small geographic area. Am. J. Hum. Genet. 56:
51-57, 1995.

4. Ohno, S.; Minoshima, S.; Kudoh, J.; Fukuyama, R.; Ohmi-Imajoh,
S.; Suzuki, K.; Shimizu, Y.; Shimizu, N.: Four genes for the calpain
family locate on four distinct human chromosomes. Cytogenet. Cell
Genet. 51: 1054-1055, 1989.

5. Richard, I.; Beckmann, J. S.: Molecular cloning of mouse canp3,
the gene associated with limb-girdle muscular dystrophy 2A in human. Mammalian
Genome 7: 377-379, 1996.

6. Richard, I.; Broux, O.; Allamand, V.; Fougerousse, F.; Chiannilkulchai,
N.; Bourg, N.; Brenguier, L.; Devaud, C.; Pasturaud, P.; Roudaut,
C.; Hillaire, D.; Passos-Bueno, M.-R.; Zatz, M.; Tischfield, J. A.;
Fardeau, M.; Jackson, C. E.; Cohen, D.; Beckmann, J. S.: Mutations
in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy
type 2A. Cell 81: 27-40, 1995.

7. Sorimachi, H.; Imajoh-Ohmi, S.; Emori, Y.; Kawasaki, H.; Ohno,
S.; Minami, Y.; Suzuki, K.: Molecular cloning of a novel mammalian
calcium-dependent protease distinct from both m- and mu-types: specific
expression of the mRNA in skeletal muscle. J. Biol. Chem. 264: 20106-20111,
1989.

8. Zlotogora, J.; Gieselmann, V.; Bach, G.: Multiple mutations in
a specific gene in a small geographic area: a common phenomenon? (Letter) Am.
J. Hum. Genet. 58: 241-243, 1996.

*FIELD* CD
Victor A. McKusick: 6/5/1989

*FIELD* ED
jamie: 01/15/1997
terry: 1/8/1997
mark: 6/14/1996
terry: 6/14/1996
terry: 6/11/1996
mark: 11/17/1995
terry: 6/3/1995
supermim: 3/16/1992
supermim: 3/20/1990
carol: 12/19/1989
ddp: 10/26/1989

*RECORD*
*FIELD* NO
114250
*FIELD* TI
*114250 CALSEQUESTRIN, FAST-TWITCH, SKELETAL MUSCLE 1; CASQ1; CASQ
CALMITINE;;
CALSEQUESTRIN, CELL
*FIELD* TX
Calsequestrin, an acid glycoprotein located in the luminal space of the
terminal cisternae of the sarcoplasmic reticulum, binds calcium ion and
is believed to function as a storage protein for calcium. Comparison of
the complete amino acid sequences of rabbit fast-twitch muscle
calsequestrin and dog cardiac muscle calsequestrin, as derived from
sequence cDNAs, indicate that these isoforms are clearly the products of
different genes. The rabbit fast-twitch muscle calsequestrin has, in the
mature protein, 367 amino acid residues. It is synthesized with a
28-residue NH(2)-terminal signal sequence that is cleaved off during
synthesis. The gene in the rabbit has 11 exons and spans approximately
14 kb of genomic DNA. Fujii et al. (1990) isolated a genomic clone for
human fast-twitch skeletal muscle calsequestrin and deduced the amino
acid sequence of the protein and the exon-intron boundaries of the gene
from its sequence. They assigned the gene to human chromosome 1 through
the use of a human-mouse somatic cell hybrid mapping panel. Like the
rabbit gene, the human gene has 11 exons, but 5 amino acids near the
COOH terminus of the rabbit sequence are lacking in the human protein.
By fluorescence in situ hybridization, Otsu et al. (1993) mapped the
CASQ1 gene to 1q21.

Calmitine is a mitochondrial calcium-binding protein specific for
fast-twitch muscle fibers. It is absent in patients with Duchenne and
Becker types of muscular dystrophy and in dystrophic dy/dy mice.
Bataille et al. (1994) cloned the human cDNA of calmitine. Sequence
analysis demonstrated that it was identical to the low affinity but high
capacity calcium-binding protein from the sarcoplasmic reticulum,
calsequestrin. Calmitine represents the Ca(2+) reservoir of
mitochondria; calsequestrin may play a similar role in the sarcoplasmic
reticulum.

*FIELD* RF
1. Bataille, N.; Schmitt, N.; Aumercier-Maes, P.; Ollivier, B.; Lucas-Heron,
B.; Lestienne, P.: Molecular cloning of human calmitine, a mitochondrial
calcium binding protein, reveals identity with calsequestrine. Biochem.
Biophys. Res. Commun. 203: 1477-1482, 1994.

2. Fujii, J.; Willard, H. F.; MacLennan, D. H.: Characterization
and localization to human chromosome 1 of human fast-twitch skeletal
muscle calsequestrin gene. Somat. Cell Molec. Genet. 16: 185-189,
1990.

3. Otsu, K.; Fujii, J.; Periasamy, M.; Difilippantonio, M.; Uppender,
M.; Ward, D. C.; MacLennan, D. H.: Chromosome mapping of five human
cardiac and skeletal muscle sarcoplasmic reticulum protein genes.
Genomics 17: 507-509, 1993.

*FIELD* CD
Victor A. McKusick: 7/10/1990

*FIELD* ED
terry: 1/27/1995
carol: 8/23/1993
carol: 11/25/1992
supermim: 3/16/1992
carol: 8/23/1990
carol: 7/10/1990

*RECORD*
*FIELD* NO
114251
*FIELD* TI
*114251 CALSEQUESTRIN, FAST-TWITCH, CARDIAC MUSCLE; CASQ2
*FIELD* TX
Cardiac muscle sarcoplasmic reticulum contains a cardiac isoform of
calsequestrin (see 114250 for the isoform in skeletal muscle). By
fluorescence in situ hybridization, Otsu et al. (1993) mapped the CASQ2
gene to 1p13.3-p11; the skeletal isoform is encoded by 1q21.

*FIELD* RF
1. Otsu, K.; Fujii, J.; Periasamy, M.; Difilippantonio, M.; Uppender,
M.; Ward, D. C.; MacLennan, D. H.: Chromosome mapping of five human
cardiac and skeletal muscle sarcoplasmic reticulum protein genes.
Genomics 17: 507-509, 1993.

*FIELD* CD
Victor A. McKusick: 8/25/1993

*FIELD* ED
carol: 8/25/1993

*RECORD*
*FIELD* NO
^114260
*FIELD* TI
^114260 MOVED TO 300006
*FIELD* TX
This entry was incorporated into entry 300006 on 30 January 1996.

*FIELD* CD
Victor A. McKusick: 12/14/1993
*FIELD* ED
joanna: 01/30/1996
mark: 1/15/1996
carol: 2/20/1995
carol: 12/14/1993
*RECORD*
*FIELD* NO
114280
*FIELD* TI
*114280 CAMPATH-1 ANTIGEN; CDW52
*FIELD* TX
The CAMPATH-1 family of monoclonal antibodies recognize an antigen
expressed on human lymphocytes and monocytes. The antigen is an
unusually good target for complement-mediated attack and, for this
reason, the IgM antibody, CAMPATH-1M, has been widely used for removal
of T lymphocytes from donor bone marrow to prevent graft-vs-host
disease. Because the target antigen is expressed in most cases of
lymphoid malignancy, serotherapy of lymphoma and leukemia with CAMPATH-1
antibodies has also been attempted. A human IgG1 antibody (CAMPATH-1H)
was constructed by genetic engineering. It could be administered for
longer periods than the rat antibody and produced better clinical
results. Xia et al. (1991) purified the CAMPATH-1 antigen from human
spleen. Experiments with phosphatidylinositol-specific phospholipase C
indicated that the antigen is anchored by a glycosylphosphatidylinositol
(GPI) anchor. Xia et al. (1991) isolated cDNA clones and deduced the
full amino acid sequence: 37 amino acid residues plus a 24-residue
signal peptide. Why the antigen is such a good target for cell lysis in
vitro and in vivo was not clear.

*FIELD* RF
1. Xia, M.-Q.; Tone, M.; Packman, L.; Hale, G.; Waldmann, H.: Characterization
of the CAMPATH1 (CDw52) antigen: biochemical analysis and cDNA cloning
reveal an unusually small peptide backbone. Europ. J. Immun. 21:
1677-1684, 1991.

*FIELD* CD
Victor A. McKusick: 10/23/1992

*FIELD* ED
carol: 10/23/1992

*RECORD*
*FIELD* NO
114290
*FIELD* TI
114290 CAMPOMELIC DYSPLASIA
*FIELD* TX
Lynch et al. (1993) reported a mother and daughter with clinical and
radiologic findings consistent with the diagnosis of campomelic
dysplasia. This disorder has usually been thought to be autosomal
recessive (211970) because of recurrence in sib pairs and also the
presence of consanguinity in some families. Milder tibial bowing and
significant shortening of the phalanges in both the hands and the feet
were suggested as distinguishing features from the classic form of the
disease. Lynch et al. (1993) pointed to the report by Thurmon et al.
(1973) of campomelic dysplasia in half-sibs, the mother of whom had mild
tibial bowing. They suggested that this could be an example of autosomal
dominant inheritance with reduced penetrance or maternal gonadal
mosaicism.

Molecular evidence appears to indicate that campomelic dysplasia with
sex reversal is, in fact, an autosomal dominant disorder. Foster et al.
(1994) cloned the chromosome 17 translocation breakpoint from such a
patient and identified a nearby gene, SOX9 (211970), which is mutant in
1 allele in affected patients and normally appears to be involved in
both bone formation and control of testis development.

Mansour et al. (1995) collected information on 36 patients with
campomelic dysplasia from genetic centers, radiologists, and
pathologists in the United Kingdom. The chromosomal sex ratio was
approximately 1:1. There was a predominance of phenotypic females owing
to sex reversal. Sex reversal or ambiguous genitalia was found in
three-quarters of the chromosomal males. Three patients were still
alive, 2 with chromosomal rearrangements involving 17q. Most of the
patients died in the neonatal period. The 36 index cases had 41 sibs of
whom only 2 were affected. Formal segregation analysis gave a
segregation ratio of 0.05; 95% CI = approximately 0.00 to 0.11. This was
considered to exclude autosomal recessive inheritance and to suggest
that this disorder is a sporadic, autosomal dominant. Patients with a
chromosomal rearrangement involving 17q23.3-q25.1 showed a milder
phenotype. The molecular mechanism for the difference was unknown. As in
the case of other neonatal lethal autosomal dominant disorders that have
been thought to be autosomal recessive (e.g., osteogenesis imperfecta
congenita; see 259400), parents of infants with campomelic dysplasia
have probably often been dissuaded from having further children in the
past. Mansour et al. (1995) provided diagnostic criteria.

*FIELD* RF
1. Foster, J. W.; Dominguez-Steglich, M. A.; Guioli, S.; Kwok, C.;
Weller, P. A.; Stevanovic, M.; Weissenbach, J.; Mansour, S.; Young,
I. D.; Goodfellow, P. N.; Brook, J. D.; Schafer, A. J.: Campomelic
dysplasia and autosomal sex reversal caused by mutations in an SRY-related
gene. Nature 372: 525-530, 1994.

2. Lynch, S. A.; Gaunt, M. L.; Minford, A. M. B.: Campomelic dysplasia:
evidence of autosomal dominant inheritance. J. Med. Genet. 30:
683-686, 1993.

3. Mansour, S.; Hall, C. M.; Pembrey, M. E.; Young, I. D.: A clinical
and genetic study of campomelic dysplasia. J. Med. Genet. 32: 415-420,
1995.

4. Thurmon, T. F.; De Fraites, E. B.; Anderson, E. E.: Familial campomelic
dwarfism. J. Pediat. 83: 841-843, 1973.

*FIELD* CS

Growth:
   Short-limb dwarfism;
   Neonatal death usual

Cranium:
   Chondrocranium small;
   Neurocranium large;
   Occasional platybasia

Facies:
   Small;
   Flat

Eyes:
   Hypertelorism

Nose:
   Nasal root depressed

Mandible:
   Micrognathia

Mouth:
   Cleft-palate;
   Retroglossia

Lung:
   Hypoplasia

Resp:
   Tracheobronchial hypoplasia

Skel:
   Pelvis high and narrow;
   Hips dislocated

Spine:
   Platyspondyly;
   Kyphoscoliosis

Neuro:
   Hypotonia;
   Olfactory nerves absent

Thorax:
   Small;
   Hypoplastic scapulae;
   Eleven pairs of ribs

Limbs:
   Short phalanges both hands and feet;
   Mild bowed femur;
   Milder bowed tibia than in recessive form;
   Short tibia;
   Equinovarus deformities

Skin:
   Cutaneous dimpling

GU:
   Sex reversal in some karyotypic males

Inheritance:
   Autosomal dominant form;
   Autosomal recessive more common

*FIELD* CD
Victor A. McKusick: 10/7/1993

*FIELD* ED
mark: 7/21/1995
carol: 1/3/1995
mimadm: 4/9/1994
carol: 10/7/1993

*RECORD*
*FIELD* NO
114300
*FIELD* TI
*114300 CAMPTODACTYLY, CLEFT PALATE, AND CLUBFOOT
GORDON SYNDROME;;
ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE IIA
*FIELD* TX
Gordon et al. (1969) described 6 affected persons (3 males, 3 females)
in 3 generations. All 3 anomalies were present in 2 persons, whereas the
other 4 persons had 1 or 2 of the 3 anomalies. Among the 6 affected,
clubfoot occurred in 5, camptodactyly in 4, and cleft palate in 3. No
similar family was found in the literature. A useful list of
camptodactyly syndromes was provided. Higgins et al. (1972) studied a
father and 2 children with the same syndrome. The oldest affected son
had several holes in the palate, camptodactyly, and minor foot
deformity, while the youngest child had a bifid uvula, camptodactyly and
foot anomaly, but no cleft palate; the father had camptodactyly and foot
anomaly without cleft palate. The syndrome was validated by the report
of a 5-generation kindred by Halal and Fraser (1979). Penetrance was
reduced more in females than in males, and cleft palate was the least
frequently manifested trait. Say et al. (1980) described a sporadic
case. Robinow and Johnson (1981) reported affected mother and daughter.
Hall et al. (1982) called this 'distal arthrogryposis, type IIA'; they
suggested that the first report was that of Moldenhauer (1964) and that
the same disorder was present in the case of Krieger and Espiritu
(1972). Moldenhauer (1964) described 4 females of 3 generations of a
family with a condition he called Nielson syndrome. The features were
short stature, ptosis, cleft palate, camptodactyly, pterygium colli, and
vertebral anomalies. Fertility was normal. Ioan et al. (1993) reported a
kindred with affected members in 5 generations. They pointed to reduced
penetrance and carrier females as a cardinal feature of the Gordon
syndrome.

*FIELD* RF
1. Gordon, H.; Davies, D.; Berman, M. M.: Camptodactyly, cleft palate
and club foot: syndrome showing the autosomal-dominant pattern of
inheritance. J. Med. Genet. 6: 266-274, 1969.

2. Halal, F.; Fraser, F. C.: Camptodacytly, cleft palate, and club
foot (the Gordon syndrome): a report of a large pedigree. J. Med.
Genet. 16: 149-150, 1979.

3. Hall, J. G.; Reed, S. D.; Greene, G.: The distal arthrogryposes:
delineation of new entities--review and nosologic discussion. Am.
J. Med. Genet. 11: 185-239, 1982.

4. Higgins, J. V.; Hackel, E.; Kapur, S.: A second family with cleft
palate, club feet and camptodactyly.  (Abstract) Am. J. Hum. Genet. 24:
58A only, 1972.

5. Ioan, D. M.; Belengeanu, V.; Maximilian, C.; Fryns, J. P.: Distal
arthrogryposis with autosomal dominant inheritance and reduced penetrance
in females: the Gordon syndrome. Clin. Genet. 43: 300-302, 1993.

6. Krieger, I.; Espiritu, C. E.: Arthrogryposis multiplex congenita
and the Turner phenotype. Am. J. Dis. Child. 123: 141-144, 1972.

7. Moldenhauer, E.: Zur Klinik des Nielson-Syndromes. Derm. Wschr. 150:
594-601, 1964.

8. Robinow, M.; Johnson, G. F.: The Gordon syndrome: autosomal dominant
cleft palate, camptodactyly, and club feet. Am. J. Med. Genet. 9:
139-146, 1981.

9. Say, B.; Barber, D. H.; Thompson, R. C.; Leichtman, L. G.: The
Gordon syndrome.  (Letter) J. Med. Genet. 17: 405 only, 1980.

*FIELD* CS

Limbs:
   Clubfoot;
   Camptodactyly;
   Distal arthrogryposis

Mouth:
   Cleft palate;
   Multiple palate defects;
   Bifid uvula

Growth:
   Short stature

Eyes:
   Ptosis

Neck:
   Pterygium colli

Spine:
   Vertebral anomalies

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
carol: 11/9/1993
supermim: 3/16/1992
carol: 2/27/1992
carol: 8/24/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
114350
*FIELD* TI
*114350 CAIN GENE; CAN
NUCLEOPORIN, 214-KD; NUP214;;
D9S46E
*FIELD* TX
The CAN gene on human 9q34 forms a fusion gene with the DEK (125264)
gene at 6p23 in a subset of acute myeloid leukemia (acute nonlymphocytic
leukemia) carrying a t(6;9)(p23;q34) translocation. Von Lindern et al.
(1990) estimated that the CAN gene lies 360 kb distal to ABL (189980).
The breakpoints in the translocations were clustered in an 8-kb intron
of a gene encoding a 7.5-kb transcript. The gene was called Cain
(symbol, CAN), presumably for 'cancer intron on nine.' The gene measured
more than 65 kb and was transcribed 5-prime centromeric-to-3-prime
telomeric on the chromosome . It is the 3-prime portion of the CAN gene
that participates in the fusion gene in the leukemogenic translocation
t(6;9).

Von Lindern et al. (1990) reported the complete cDNA-derived primary
structure of the human CAN protein. Kraemer et al. (1994) found that the
partial amino acid sequence of a putative nuclear pore complex protein
(nucleoporin) of rat showed a high degree of similarity with the
sequence of the human CAN protein. To confirm its homology and to
determine its subcellular localization, Kraemer et al. (1994) expressed
a 39-kD internal segment of the 213,790-Da CAN protein in Escherichia
coli and raised monospecific antibodies that reacted with the putative
rat nucleoporin. Immunofluorescence microscopy of HeLa cells gave a
punctate nuclear surface staining pattern characteristic of
nucleoporins, and immunoelectron microscopy yielded specific decoration
of the cytoplasmic side of the nuclear pore complex. This suggested that
the protein is part of the short fibers that emanate from the
cytoplasmic aspect of the nuclear pore complex. In agreement with
previously proposed nomenclature for nucleoporins, they proposed the
alternative term NUP214 (nucleoporin of 214 kD) for the CAN protein.

By interspecific backcross linkage analysis, Pilz et al. (1995) mapped
the Cain gene to mouse chromosome 2.

*FIELD* RF
1. Kraemer, D.; Wozniak, R. W.; Blobel, G.; Radu, A.: The human CAN
protein, a putative oncogene product associated with myeloid leukemogenesis,
is a nuclear pore complex protein that faces the cytoplasm. Proc.
Nat. Acad. Sci. 91: 1519-1523, 1994.

2. Pilz, A.; Woodward, K.; Povey, S.; Abbott, C.: Comparative mapping
of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25:
139-149, 1995.

3. von Lindern, M.; Poustka, A.; Lehrach, H.; Grosveld, G.: The (6;9)
chromosome translocation, associated with a specific subtype of acute
nonlymphocytic leukemia, leads to aberrant transcription of a target
gene on 9q34. Molec. Cell. Biol. 10: 4016-4026, 1990.

*FIELD* CD
Victor A. McKusick: 12/23/1993

*FIELD* ED
mark: 01/12/1996
carol: 2/7/1995
carol: 12/23/1993

*RECORD*
*FIELD* NO
114400
*FIELD* TI
#114400 CANCER
CANCER FAMILY SYNDROME, INCLUDED;;
LYNCH CANCER FAMILY SYNDROME II, INCLUDED; LCFS2
*FIELD* TX
A number sign (#) is used with this entry because it is likely that
germinal mutations in any one of several different genes can be
responsible for familial cancer and because the Lynch cancer family
syndrome II appears to be due to mutation in a gene on chromosome 2
(MSH2; 120435) and perhaps to mutation in other genes, including one on
chromosome 18 (see later).

Using the fourth edition (1975) of these catalogs, Mulvihill et al.
(1977) counted 200 entries in which neoplasia was a regular or
occasional feature. Some, such as von Recklinghausen neurofibromatosis
(162200), tylosis (148500), the several types of intestinal polyposis
(e.g., 175100), von Hippel-Lindau syndrome (193300), and the basal cell
nevus syndrome (109400), are listed in the dominant catalog. Xeroderma
pigmentosum (e.g., 278700), a recessive, is complicated by skin
malignancy unless exposure to ultraviolet light is stringently avoided.
In addition, notable instances of 'cancer families' are on record. For
example, Lynch et al. (1966) reported 2 large 'cancer families.' In 1
family, 9 of 11 sibs had histologically confirmed cancers, with 4 of
these showing multiple primary tumors. In the second family, 7 of 13
sibs showed histologically proven cancers, with multiple primary
malignant neoplasm in 4. The 2 families contained 6 instances of the
ordinarily rare combination of primary colonic and endometrial
carcinoma. The 'cancer family' of Warthin is another notable example
(Hauser and Weller, 1936).

Lynch et al. (1966) and Lynch and Krush (1967) suggested the existence
of a syndrome, which they called the cancer-family syndrome, that is
characterized by (1) increased occurrence of endometrial carcinoma and
adenocarcinoma of the colon as well as multiple primary malignant
neoplasms, and (2) autosomal dominant inheritance. Lynch and Lynch
(1979) pointed out that cancer of the right colon is particularly
characteristic of the cancer-family syndrome. Familial aggregation alone
may be chance inasmuch as about 1 in 4 Americans develops cancer in a
lifetime. Features of cancers with a genetic origin include early age of
onset, bilaterality or multifocality, multiplicity of primary cancers,
and, of course, familiality. Biochemical insight into familial
susceptibility to cancer is beginning. Lynch et al. (1973) suggested
that among families with breast cancer some have an excess of ovarian
cancer, others are prone to sarcoma, brain tumors and leukemia, whereas
yet others have associated gastrointestinal cancer. Genetic differences
in inducibility of aryl hydrocarbon hydroxylase (see 108340) may
underlie susceptibility to lung cancer and colon cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is subdivided into (1)
Lynch syndrome I (site-specific colonic cancer; see 114500) and (2)
Lynch syndrome II (colonic cancer in association with other forms of
cancer, particularly carcinoma of the endometrium and ovary, but also
cancer of the pancreas) (Lynch et al., 1985). Both HNPCC disorders show
a proclivity to early onset, predominant proximal location of colon
cancer, a dominant pattern of inheritance, an excess of multiple primary
cancers, and significantly improved survival when compared stage for
stage with the American College of Surgeons Audit Series. Use of these
features in surveillance and management programs mandates periodic
colonoscopy or double air-contrast barium enema, because of the proximal
location, and a lifelong watchfulness with attention to other tumors
integral to the syndrome.

Warthin's original description of 'Family G' (Warthin, 1913) showed an
excess of gastric cancer. The decline in incidence of gastric carcinoma
and increase in colonic cancer in recent years was found to have its
parallel in Family G on update by Lynch and Krush (1971). Cristofaro et
al. (1987) and Guanti et al. (1990) described an extensively affected
Italian family with the characteristic features of the Lynch cancer
family syndrome II: early age of onset of tumors, increased frequency of
adenocarcinomas of the colon, mainly with proximal location, and high
occurrence of gastric, endometrial, and multiple primary malignancies.
Unique pathologic findings included chronic atrophic gastritis and an
excess of macrophages in association with atrophy of crypts in the
colonic mucosa. Abusamra et al. (1987) described a family in which 8
cancers (6 colonic and 2 endometrial) occurred in 7 members of 3
generations. The colonic cancer was diagnosed in 5 of the 6 affected
patients at an unusually young age, had a predilection for the proximal
colon, and was of the mucinous type in 4 patients. No polyposis was
found.

Lynch et al. (1991) estimated that hereditary nonpolyposis colorectal
cancer accounts for about 4 to 6% of colorectal cancer.

Lynch et al. (1985) described linkage of the cancer family syndrome
(Lynch syndrome II) to Kidd blood group (111000); a lod score of 3.19
was obtained. The Kidd blood group locus has been assigned to 18q11-q12;
colorectal cancer-related sequences have been identified in the region
18q23.3-qter (120470).

*FIELD* SA
Blattner et al. (1979); Brisman et al. (1967); Dubosson  (1977); Dunstone
and Knaggs (1972); Fielding  (1969); Lynch  (1967); Lynch et al. (1985);
Maack and Rudiger (1983)
*FIELD* RF
1. Abusamra, H.; Maximova, S.; Bar-Meir, S.; Krispin, M.; Rotmensch,
H. H.: Cancer family syndrome of Lynch. Am. J. Med. 83: 981-983,
1987.

2. Blattner, W. A.; McGuire, D. B.; Mulvihill, J. J.; Lampkin, B.
C.; Hananian, J.; Fraumeni, J. F., Jr.: Genealogy of cancer in a
family. J.A.M.A. 241: 259-261, 1979.

3. Brisman, R.; Baker, R. R.; Elkins, R.; Hartmann, W. H.: Carcinoma
of lung in four siblings. Cancer 20: 2048-2053, 1967.

4. Cristofaro, G.; Lynch, H. T.; Caruso, M. L.; Attolini, A.; DiMatteo,
G.; Giorgio, P.; Senatore, S.; Argentieri, A.; Sbano, E.; Guanti,
G.; Fusaro, R.; Giorgio, I.: New phenotypic aspects in a family with
Lynch syndrome II. Cancer 60: 51-58, 1987.

5. Dubosson, J.-D.: Adenocarcinomatose hereditaire dans quatre generations
d'une famille Valaissanne. J. Genet. Hum. 25: 233-278, 1977.

6. Dunstone, G. H.; Knaggs, T. W. L.: Familial cancer of the colon
and rectum. J. Med. Genet. 9: 451-456, 1972.

7. Fielding, J. F.: Familial non-polypotic carcinoma of the colon.
Brit. Med. J. 1: 512-513, 1969.

8. Guanti, G.; Susca, F.; Cristofaro, G.; Caruso, M. L.; Massari,
S.; Porsia, R.; Stella, A.; Giorgio, I.: Cancer family syndrome:
cytogenetic investigations, in vitro tetraploidy, and biomarker studies
in a large family. J. Med. Genet. 27: 441-445, 1990.

9. Hauser, I. J.; Weller, C. V.: A further report on the cancer family
of Warthin. Am. J. Cancer 27: 434-449, 1936.

10. Lynch, H. T.: Hereditary Factors in Carcinoma.  Berlin and
New York: Springer (pub.)  1967.

11. Lynch, H. T.; Krush, A. J.: Heredity and adenocarcinoma of the
colon. Gastroenterology 53: 517-527, 1967.

12. Lynch, H. T.; Krush, A. J.: Cancer family 'G' revisited: 1895-1970.
Cancer 27: 1505-1511, 1971.

13. Lynch, H. T.; Krush, A. J.; Guirgis, H.: Genetic factors in families
with combined gastrointestinal and breast cancer. Am. J. Gastroent. 59:
31-40, 1973.

14. Lynch, H. T.; Lanspa, S.; Smyrk, T.; Boman, B.; Watson, P.; Lynch,
J.: Hereditary nonpolyposis colorectal cancer (Lynch syndromes I
& II): genetics, pathology, natural history, and cancer control. Part
I. Cancer Genet. Cytogenet. 53: 143-160, 1991.

15. Lynch, H. T.; Lynch, P.: The cancer-family syndrome: a pragmatic
basis for syndrome identification. Dis. Colon Rectum 22: 106-110,
1979.

16. Lynch, H. T.; Schuelke, G. S.; Kimberling, W. J.; Albano, W. A.;
Lynch, J. F.; Biscone, K. A.; Lipkin, M. L.; Deschner, E. E.; Mikol,
Y. B.; Sandberg, A. A.; Elston, R. C.; Bailey-Wilson, J. E.; Danes,
B. S.: Hereditary nonpolyposis colorectal cancer (Lynch syndromes
I and II). II. Biomarker studies. Cancer 56: 939-951, 1985.

17. Lynch, H. T.; Shaw, M. W.; Magnuson, C. W.; Larsen, A. L.; Krush,
A. J.: Hereditary factors in cancer: study of two large midwestern
kindreds. Arch. Intern. Med. 117: 206-212, 1966.

18. Lynch, H. T.; Voorhees, G. J.; Lanspa, S. J.; McGreevy, P. S.;
Lynch, J. F.: Pancreatic carcinoma and hereditary nonpolyposis colorectal
cancer: a family study. Brit. J. Cancer 52: 271-273, 1985.

19. Maack, P.; Rudiger, H. W.: Familial cancer or cancer family syndrome:
report on a cancer family and consideration of genetic mechanisms.
Clin. Genet. 24: 36-40, 1983.

20. Mulvihill, J. J.; Miller, R. W.; Fraumeni, J. F.: Genetics of
Human Cancer.  New York: Raven Press (pub.)  1977.

21. Warthin, A. S.: Heredity with reference to carcinoma. Arch.
Intern. Med. 12: 546-555, 1913.

*FIELD* CS

Oncology:
   Multiple primary malignant neoplasms;
   Primary colon (esp. right colon) and endometrial carcinoma;
   Breast cancer with ovarian cancer, sarcoma, brain tumors, leukemia,
   or gastrointestinal cancer;
   Increased gastric cancer

Misc:
   Early age of onset;
   Bilateral or multifocal

Inheritance:
   Autosomal dominant (multiple loci, chrom 2 and 18)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 5/17/1994
terry: 5/13/1994
carol: 4/9/1994
pfoster: 3/25/1994
warfield: 3/21/1994
carol: 10/21/1993

*RECORD*
*FIELD* NO
114450
*FIELD* TI
114450 CANCER, FAMILIAL, WITH IN VITRO RADIORESISTANCE
*FIELD* TX
Bech-Hansen et al. (1981) studied a family in which members had had a
diversity of neoplasms over 6 generations (originally reported by
Blattner et al., 1979). Two members had neoplasms of possible radiogenic
origin. Gamma-irradiation survival studies of cultured skin fibroblasts
in these 2 patients and in 3 other relatives, but not their spouses,
over 3 generations demonstrated resistance to cell killing.
Radioresistance, as well as radiosensitivity (e.g., in
ataxia-telangiectasia and xeroderma pigmentosum to gamma- and
UV-irradiation, respectively), measured in vitro may be a marker for
increased cancer risk. Thus, one subset of 'cancer families,' such as
that described by Li and Fraumeni (1969), may represent this category.

*FIELD* RF
1. Bech-Hansen, N. T.; Blattner, W. A.; Sell, B. M.; McKeen, E. A.;
Lampkin, B. C.; Fraumeni, J. F., Jr.; Paterson, M. C.: Transmission
of in-vitro radioresistance in a cancer-prone family. Lancet I:
1335-1337, 1981.

2. Blattner, W. A.; McGuire, D. B.; Mulvihill, J. J.; Lampkin, B.
C.; Hananian, J.; Fraumeni, J. F., Jr.: Genealogy of cancer in a
family. J.A.M.A. 241: 259-261, 1979.

3. Li, F. P.; Fraumeni, J. F., Jr.: Rhabdomyosarcoma in children:
epidemiologic study and identification of a familial cancer syndrome.
J. Nat. Cancer Inst. 43: 1365-1373, 1969.

*FIELD* CS

Oncology:
   Familial cancer;
   Possible radiogenic tumor origin

Lab:
   In vitro resistance to cell killing by gamma-irradiation

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
114480
*FIELD* TI
#114480 CANCER OF THE BREAST, FAMILIAL; BCS
BREAST CANCER, FAMILIAL
BREAST CANCER, FAMILIAL MALE, INCLUDED
*FIELD* TX

DESCRIPTION

A number sign (#) is used with this entry because of evidence that
mutation at more than one locus can be involved in different families or
even in the same case. These loci include BRCA1 (113705) on 17q and TP53
(191170) on 17p.

Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is
histopathologically and almost certainly etiologically and genetically
heterogeneous. Important genetic factors have been indicated by familial
occurrence and bilateral involvement. At least one causative mutant gene
(BRCA1) has been identified on chromosome 17q by linkage analysis.

CLINICAL FEATURES

Cady (1970) described a family in which 3 sisters had bilateral breast
cancer. Together with reports in the literature, this suggested to him
the existence of families with a particular tendency to early-onset,
bilateral breast cancer. The genetic basis might, of course, be
multifactorial.

Anderson (1974) concluded that the sisters of women with breast cancer
whose mothers also had breast cancer have a risk 47 to 51 times that in
control women; a revised estimate was 39 times (Anderson, 1976). The
disease in these women usually developed before menopause, was often
bilateral, and seemed to be associated with ovarian function. About 30%
of daughters with early-onset, bilateral breast cancer inherited the
susceptibility. The risk of breast cancer to women with affected
relatives is higher when the diagnosis is made at an early age and when
the disease is bilateral. Ottman et al. (1983) provided tables that give
the cumulative risk of breast cancer to mothers and sisters at various
ages. The highest risk group is sisters of premenstrual probands with
bilateral disease. Among the sisters of women with breast cancer,
Anderson and Badzioch (1985) found the highest lifetime risks when the
proband had bilateral disease, an affected mother (25 +/- 7.2%), or an
affected sister (28 +/- 11%). The risks were reduced to 18 +/- 3.3% and
14 +/- 2.6%, respectively, with unilateral disease. An early example of
familial breast cancer was provided by Broca (1866). According to the
pedigree drawn by Lynch (1976), 10 women in 4 generations of the family
of Broca's wife died of breast cancer.

Two families with an extraordinary incidence of male breast cancer and
father-to-son transmission of same was reported by Everson et al.
(1976). They found a suggestion of elevated urinary estrogen in 3 of the
affected males. Teasdale et al. (1976) described breast cancer in 2
brothers and in a daughter of 1 brother. Kozak et al. (1986) reported
breast cancer in 2 related males, an uncle and nephew. In this family
and in several reported families with male breast cancer, Kozak et al.
(1986) found women in the same family with breast cancer.

Soft tissue sarcomas are associated with breast cancer in the
Li-Fraumeni syndrome (151623). Mulvihill (1982) used the term cancer
family syndrome of Lynch (114400) for the association of colon and
endometrial carcinoma and other neoplasms including breast cancer.

Seltzer et al. (1990) concluded that dermatoglyphics can help in the
identification of women either with or at risk for breast cancer. They
found that the presence of 6 or more whorls is associated in a
statistically significant manner with breast cancer.

Marger et al. (1975) presented the cases of 2 brothers with breast
cancer and reviewed the courses of 28 other previously unreported male
patients. In one of the brothers, breast cancer was preceded by
prostatic cancer and estrogen administration, raising the possibility
that the breast cancer was a metastatic deposit. The possibility of
prostatic metastases was raised in 2 other patients. Demeter et al.
(1990) reported breast cancer in a 64-year-old man who had had bilateral
gynecomastia since childhood. His maternal grandfather had been found to
have adenocarcinoma of the breast at the age of 65. His maternal
grandmother had radical mastectomy for breast cancer at the age of 66
and 2 years later underwent radiation therapy for rib metastases. The
proband's sister developed breast cancer at the age of 31 years and
despite aggressive therapy died 1 year later with extensive metastases.

Hauser et al. (1992) reported a family in which 2 females and 2 males in
2 generations had breast cancer. Two females in the family had
prophylactic bilateral mastectomy at a young age. One male developed a
left breast mass and axillary node at age 59 and died of metastatic
disease at age 62. His paternal uncle presented at age 57 years with
bleeding from his right breast. Biopsy suggested Paget disease of the
breast and he underwent mastectomy. He subsequently died at age 75 years
of prostatic carcinoma. He had a daughter who developed breast cancer at
age 27 years and died at age 30 with disseminated disease, and a son who
developed infiltrating grade 4 adenocarcinoma of the breast at age 54.

OTHER FEATURES

Chang et al. (1987) showed that the noncancerous skin fibroblasts of
members of a family with Li-Fraumeni syndrome (which show resistance to
the killing effect of ionizing radiation) have a 3- to 8-fold elevation
in expression of the MYC oncogene (190080) and an apparent activation of
the RAF1 gene (164760). Normal fetal and adult skin fibroblasts show
distinctive migratory behavior when plated on 3-dimensional collagen
gels.

Haggie et al. (1987) found that skin fibroblasts from 13 of 15 patients
with hereditary breast cancer showed fetal-like behavior compared with
only 1 of 12 age-matched healthy controls. In addition, 10 of 15
first-degree relatives of patients with hereditary breast cancer showed
a fetal-like fibroblast phenotype, compared with none of 7 surgical
controls.

INHERITANCE

Petrakis (1977) listed the evidence for a genetic role in breast cancer
as follows: 1) family history of breast cancer, especially bilateral
breast cancer; 2) marked differences in rates between certain racial
groups (lower in Orientals); 3) lack of major change in incidence over
many years despite dramatic decline in other cancers; 4) concordance in
monozygotic twins; and 5) concordance of laterality in closely related
persons. Lynch et al. (1984) found evidence consistent with a hereditary
breast cancer syndrome in 5% of 225 consecutively ascertained patients
with verified breast cancer. From a maximum-likelihood mendelian model,
the frequency of the susceptibility allele was 0.0006 in the general
population, and the lifetime risk of breast cancer was 0.82 among
susceptible women and 0.08 among women without the susceptibility
allele. They concluded that inherited susceptibility affected only 4% of
the families in the sample; multiple cases of this relatively common
disease occurred in other families by chance. They pictured an extended
pedigree with 14 cases of breast cancer, 3 of them in men.

The Danish twin registry (Holm et al., 1980) had 5 out of 45 MZ twins
and 4 out of 77 DZ twins concordant for breast cancer; heritability was
calculated at 0.3-0.4.

From complex segregation analysis of 200 Danish breast cancer pedigrees,
Williams and Anderson (1984) concluded that the distribution of cases
was compatible with transmission of an autosomal dominant gene. Newman
et al. (1988) used complex segregation analysis to investigate patterns
of breast cancer occurrence in 1,579 nuclear families. They concluded
that an autosomal dominant model with a highly penetrant susceptibility
allele fully explains disease clustering.

Iselius et al. (1992) reanalyzed the Danish breast cancer data collected
by Jacobsen (1946), using morbid risks that incorporate mortality due to
breast cancer. They interpreted the results to favor a dominant gene for
familial breast cancer. No evidence of heterogeneity was found. Cases
with bilateral breast cancer and males with breast cancer all belonged
to families favoring a major gene. Of the cancer sites frequently
reported to be associated with familial breast cancer, only ovarian
breast cancer was significant in this study.

Houlston et al. (1992) showed that the risk of breast cancer increased
progressively in inverse relationship to the age of the index patient.
First-degree relatives of patients with bilateral breast cancer had a
6.43-fold increase in risk. Houlston et al. (1992) estimated that the
genetic contribution to overall lifetime liability to breast cancer in
relatives declined with increasing age of onset of breast cancer in the
index case from 37% at 20 years to 8% by 45 years. In Iceland, Tulinius
et al. (1992) likewise found that early onset and bilaterality of breast
cancer increased the risk to relatives. In an analysis of a prospective
cohort study, Sellers et al. (1992) found that the increase in the risk
of breast cancer associated with a high waist-to-hip ratio (the
circumference of the waist divided by that of the hips), low parity, or
greater age at first pregnancy was more pronounced among women with a
family history of breast cancer. They concluded that there are etiologic
differences between familial breast cancer and the sporadic form.

MAPPING

For linkage between glutamate-pyruvate transaminase (138200) and breast
cancer, King et al. (1980) found a lod score of 1.84 for 6 families
showing linkage and 1.43 for all 11 breast cancer families studied. In
Mormon breast cancer pedigrees, however, McLellan et al. (1984) obtained
a cumulative lod score of -3.86 for breast cancer and GPT, thus
eliminating this possible linkage.

Pathak and Goodacre (1986) found reciprocal translocations involving
1q21 and chromosomes 3, 5, 10, 11, and 12. Chen et al. (1989)
demonstrated loss of heterozygosity (LOH) in the region 1q23-q32.

Because of the possibility that inherited rare alleles at the HRAS locus
(190020) might be associated with susceptibility to breast cancer, Hall
et al. (1990) studied linkage to markers on 11p in 12 high-risk
families. Linkage could be excluded within 17 cM of HRAS; the lod score
for close linkage to HRAS was -19.9.

Goldstein et al. (1989) found a suggestion of linkage to acid
phosphatase (ACP1; 171500); maximum lod score = 1.01 at theta = 0.001.
Very close linkage was excluded between breast cancer and ABO, GC, GPT,
MNS, and PGM1. By linkage studies, Bowcock et al. (1990) excluded the
retinoblastoma gene (180200) and 13q in general as the site of the
primary lesion. Abnormality there was sought because of observation of
LOH of alleles on 13q in some ductal breast tumors and because 2 breast
cancer lines had been found to have an alteration in the retinoblastoma
gene. Narod and Amos (1990) analyzed the effects of phenocopies and
genetic heterogeneity on the demonstration of linkage between a putative
cancer susceptibility gene and polymorphic DNA markers.

See 113705 for a review of the extensive linkage studies that
demonstrate the existence of a gene for susceptibility to early-onset
breast cancer (BRCA1) on 17q.

MOLECULAR GENETICS

A previously reported loss of alleles at the HRAS locus, located at
11p14, in about 20% of tumors was confirmed by Mackay et al. (1988).
Comparing tumor and blood leukocyte DNA from a consecutive series of
patients with primary breast cancer, Mackay et al. (1988) found that 61%
of the tumors had allele loss demonstrated with a probe located at
17p13.3.

Coles et al. (1990) mapped regions of LOH on chromosome 17 by comparing
DNA of paired tumor and blood leukocyte samples. They confirmed a high
frequency of LOH on 17p, where 2 distinct regions of LOH were identified
in bands p13.3 and p13.1. The latter probably involves the structural
gene TP53. The frequency of LOH was higher, however, at 17p13.3, and
there was no correlation between allele loss at the 2 sites. Since LOH
at 17p13.3 was associated with overexpression of p53 mRNA, Coles et al.
(1990) suggested the existence of a gene some 20 megabases telomeric of
TP53 that regulates its expression; see 113721. They concluded that
lesions of this regulatory gene are involved in the majority of breast
cancers. Devilee et al. (1991) reported LOH data.

Davidoff et al. (1991) found that in 11 (22%) of 49 primary invasive
human breast cancers, widespread overexpression of p53 was indicated by
immunohistochemical staining. The p53 gene was directly sequenced in 7
of the tumors with elevated levels of protein, and in each case a
mutation that altered the coding sequence for p53 was found in a highly
conserved region of the gene. Whereas 4 of these tumors contained only a
mutant p53 allele, the other 3 exhibited coding sequences from both a
mutant and a wildtype allele. Six tumors that were deleted at or near
the p53 locus but did not express high levels of the protein were
sequenced and all retained a wildtype p53 allele. This was interpreted
as indicating that overexpression of the p53 protein, not allelic loss,
was associated with mutation of the p53 gene.

ANIMAL MODEL

Parallels may exist with breast cancer in mice, which has long been
studied from the viewpoint of genetic-viral etiology and pathogenesis.
This story begins with Bittner's 'milk agent,' originally discovered by
Bittner (1936); using reciprocal matings between high tumor and low
tumor strains, the Jackson Laboratory staff showed in 1933 that the
tumor incidence in F1 females was a function of the strain of the
mother. Virologists demonstrated that the mouse mammary tumor virus
(MMTV, also called MuMTV) is indeed transmitted through the milk and is
an RNA virus seen in its mature form as the B particle. This was the
first virus universally accepted in this country as a cancer-causing
virus. Some mouse strains have been shown to carry a potent MMTV
transmitted in milk and also in the egg and sperm (see review by Heston
and Parks, 1977). Strains of mice purged of the MMTV by foster-nursing
the young on a clean strain still show a low incidence of breast cancer
developing at a late age. By introducing the cancer-enhancing gene
A(vy), the incidence could be raised to 90%; however, the agent was not
transmitted through the milk but by both eggs and sperm.

In one strain developed by Muhlbock (1965), Bentvelzen (1972)
demonstrated that the high incidence of mammary tumors was caused by an
MMTV transmitted in milk, eggs, and sperm. Particles resembling B-type
retroviruses have been identified in human milk (Moore et al., 1971);
MMTV-related RNA has been found in some breast cancers (Axel et al.,
1972) and a breast cancer cell line that releases retrovirus-like
particles has been established (McGrath et al., 1974). Callahan et al.
(1982) and Westley and May (1984) demonstrated sequences in normal human
DNA that appear to be homologous to endogenous retroviral sequences. By
transfection of NIH 3T3 mouse cells, Lane et al. (1981) demonstrated a
transforming gene in a human mammary tumor cell line (MCF-7). See 164820
for information on the human homolog of the putative mammary tumor
oncogene.

*FIELD* SA
Anderson  (1972); Armstrong and Davies (1978); Lynch  (1981); Lynch
et al. (1985); Miyagi et al. (1992)
*FIELD* RF
1. Anderson, D. E.: A genetic study of human breast cancer. J.
Nat. Cancer Inst. 48: 1029-1034, 1972.

2. Anderson, D. E.: Genetic study of breast cancer: identification
of a high risk group. Cancer 34: 1090-1097, 1974.

3. Anderson, D. E.: Genetic predisposition to breast cancer. Recent
Results Cancer Res. 57: 10-20, 1976.

4. Anderson, D. E.; Badzioch, M. D.: Risk of familial breast cancer.
Cancer 56: 383-387, 1985.

5. Armstrong, A. E.; Davies, J. M.: Familial breast cancer: report
of a family pedigree. Brit. J. Cancer 37: 294-307, 1978.

6. Axel, R.; Schlom, J.; Spiegelman, S.: Presence in human breast
cancer of RNA homologous to mouse mammary tumour virus RNA. Nature 235:
32-36, 1972.

7. Bentvelzen, P.: Hereditary infection with mammary tumor viruses
in mice. In: Emmelot, P.; Bentvelzen, P.: RNA Viruses and Host Genome
in Oncogenesis.  Amsterdam: North Holland (pub.)  1972.

8. Bittner, J. J.: Some possible effects of nursing on the mammary
gland tumor incidence in mice. Science 84: 162 only, 1936.

9. Bowcock, A. M.; Hall, J. M.; Hebert, J. M.; King, M.-C.: Exclusion
of the retinoblastoma gene and chromosome 13q as the site of a primary
lesion for human breast cancer. Am. J. Hum. Genet. 46: 12-17, 1990.

10. Broca, P. P.: Traite des Tumeurs.  Paris: P. Asselin (pub.)
1: 1866. Pp. 80 only.

11. Cady, B.: Familial bilateral cancer of the breast. Ann. Surg. 172:
264-272, 1970.

12. Callahan, R.; Drohan, W.; Tronick, S.; Schlom, J.: Detection
and cloning of human DNA sequences related to the mouse mammary tumor
virus genome. Proc. Nat. Acad. Sci. 79: 5503-5507, 1982.

13. Chang, E. H.; Pirollo, K. F.; Zou, Z. Q.; Cheung, H.-Y.; Lawler,
E. L.; Garner, R.; White, E.; Bernstein, W. B.; Fraumeni, J. W., Jr.;
Blattner, W. A.: Oncogenes in radioresistant, noncancerous skin fibroblasts
from a cancer-prone family. Science 237: 1036-1039, 1987.

14. Chen, L.-C.; Dollbaum, C.; Smith, H. S.: Loss of heterozygosity
on chromosome 1q in human breast cancer. Proc. Nat. Acad. Sci. 86:
7204-7207, 1989.

15. Coles, C.; Thompson, A. M.; Elder, P. A.; Cohen, B. B.; Mackenzie,
I. M.; Cranston, G.; Chetty, U.; Mackay, J.; Macdonald, M.; Nakamura,
Y.; Hoyheim, B.; Steel, C. M.: Evidence implicating at least two
genes on chromosome 17p in breast carcinogenesis. Lancet 336: 761-763,
1990.

16. Davidoff, A. M.; Humphrey, P. A.; Iglehart, J. D.; Marks, J. R.
: Genetic basis for p53 overexpression in human breast cancer. Proc.
Nat. Acad. Sci. 88: 5006-5010, 1991.

17. Demeter, J. G.; Waterman, N. G.; Verdi, G. D.: Familial male
breast carcinoma. Cancer 65: 2342-2343, 1990.

18. Devilee, P.; van Vliet, M.; van Sloun, P.; Kuipers Dijkshoorn,
N.; Hermans, J.; Pearson, P. L.; Cornelisse, C. J.: Allelotype of
human breast carcinoma: a second major site for loss of heterozygosity
is on chromosome 6q. Oncogene 6: 1705-1711, 1991.

19. Everson, R. B.; Li, F. P.; Fraumeni, J. F., Jr.; Fishman, J.;
Wilson, R. E.; Stout, D.; Norris, H. J.: Familial male breast cancer.
Lancet I: 9-12, 1976.

20. Goldstein, A. M.; Haile, R. W.; Spence, M. A.; Sparkes, R. S.;
Paganini-Hill, A.: A genetic epidemiologic investigation of breast
cancer in families with bilateral breast cancer. II. Linkage analysis.
Clin. Genet. 36: 100-106, 1989.

21. Haggie, J. A.; Sellwood, R. A.; Howell, A.; Birch, J. M.; Schor,
S. L.: Fibroblasts from relatives of patients with hereditary breast
cancer show fetal-like behaviour in vitro. Lancet I: 1455-1457,
1987.

22. Hall, J. M.; Huey, B.; Morrow, J.; Newman, B.; Lee, M.; Jones,
E.; Carter, C.; Buehring, G. C.; King, M.-C.: Rare HRAS alleles and
susceptibility to human breast cancer. Genomics 6: 188-191, 1990.

23. Hauser, A. R.; Lerner, I. J.; King, R. A.: Familial breast cancer.
(Letter) Am. J. Med. Genet. 44: 839-840, 1992.

24. Heston, W. E.; Parks, W. P.: Mammary tumors and mammary tumor
virus expression in hybrid mice of strains C57BL and GR. J. Exp.
Med. 146: 1206-1220, 1977.

25. Holm, N. V.; Hauge, M.; Harvald, B.: Etiologic factors of breast
cancer elucidated in a study of unselected twins. J. Nat. Cancer
Inst. 65: 285-298, 1980.

26. Houlston, R. S.; McCarter, E.; Parbhoo, S.; Scurr, J. H.; Slack,
J.: Family history and risk of breast cancer. J. Med. Genet. 29:
154-157, 1992.

27. Iselius, L.; Littler, M.; Morton, N.: Transmission of breast
cancer--a controversy resolved. Clin. Genet. 41: 211-217, 1992.

28. Jacobsen, O.: Heredity and Breast Cancer.  London: H. K. Lewis
(pub.)  1946.

29. King, M.-C.; Go, R. C. P.; Elston, R. C.; Lynch, H. T.; Petrakis,
N. L.: Allele increasing susceptibility to human breast cancer may
be linked to the glutamate-pyruvate transaminase locus. Science 208:
406-408, 1980.

30. Kozak, F. K.; Hall, J. G.; Baird, P. A.: Familial breast cancer
in males: a case report and review of the literature. Cancer 58:
2736-2739, 1986.

31. Lane, M.-A.; Sainten, A.; Cooper, G. M.: Activation of related
transforming genes in mouse and human mammary carcinomas. Proc.
Nat. Acad. Sci. 78: 5185-5189, 1981.

32. Lynch, H. T.: Introduction to cancer genetics. In: Lynch, H.
T.: Cancer Genetics.  Springfield, Ill.: Charles C Thomas (pub.)
1976. Pp. 3-31.

33. Lynch, H. T.: Genetics and Breast Cancer.  New York: Van Nostrand-Reinhold
(pub.)  1981.

34. Lynch, H. T.; Albano, W. A.; Danes, B. S.; Layton, M. A.; Kimberling,
W. J.; Lynch, J. F.; Cheng, S. C.; Costello, K. A.; Mulcahy, G. M.;
Wagner, C. A.; Tindall, S. L.: Genetic predisposition to breast cancer.
Cancer 53: 612-622, 1984.

35. Lynch, H. T.; Katz, D. A.; Bogard, P. J.; Lynch, J. F.: The sarcoma,
breast cancer, lung cancer, and adrenocortical carcinoma syndrome
revisited. Am. J. Dis. Child. 139: 134-136, 1985.

36. Mackay, J.; Steel, C. M.; Elder, P. A.; Forrest, A. P. M.; Evans,
H. J.: Allele loss on short arm of chromosome 17 in breast cancers.
Lancet II: 1384-1385, 1988.

37. Marger, D.; Urdaneta, N.; Fischer, J. J.: Breast cancer in brothers:
case reports and a review of 30 cases of male breast cancer. Cancer 36:
458-461, 1975.

38. McGrath, C. M.; Grant, P. M.; Soule, H. D.; Glancy, T.; Rich,
M. A.: Replication of oncornavirus-like particle in human breast
carcinoma cell line, MCF-7. Nature 252: 247-250, 1974.

39. McLellan, T.; Cannon, L. A.; Bishop, D. T.; Skolnick, M. H.:
The cumulative lod score between a breast cancer susceptibility locus
and GPT is -3.86.  (Abstract) Cytogenet. Cell Genet. 37: 536-537,
1984.

40. Miyagi, M.; Inazawa, J.; Takita, K.; Nakamura, Y.: Cloning and
characterization of an interstitial deletion at chromosome 11p15 in
a sporadic breast cancer. Hum. Molec. Genet. 1: 705-708, 1992.

41. Moore, D. H.; Charney, J.; Kramarsky, B.; Lasfargues, E. Y.; Sarkar,
N. H.; Brennan, M. J.; Burrows, J. H.; Sirsat, S. M.; Paymaster, J.
C.; Vaidya, A. B.: Search for a human breast cancer virus. Nature 229:
611-615, 1971.

42. Muhlbock, O.: Note of a new inbred mouse strain GR/A. Europ.
J. Cancer 1: 123-124, 1965.

43. Mulvihill, J. J.: Personal Communication. Bethesda, Md.  6/11/1982.

44. Narod, S. A.; Amos, C.: Estimating the power of linkage analysis
in hereditary breast cancer. Am. J. Hum. Genet. 46: 266-272, 1990.

45. Newman, B.; Austin, M. A.; Lee, M.; King, M.-C.: Inheritance
of human breast cancer: evidence for autosomal dominant transmission
in high-risk families. Proc. Nat. Acad. Sci. 85: 3044-3048, 1988.

46. Ottman, R.; Pike, M. C.; King, M.-C.; Henderson, B. E.: Practical
guide for estimating risk for familial breast cancer. Lancet II:
556-558, 1983.

47. Pathak, S.; Goodacre, A.: Specific chromosome anomalies and predisposition
to human breast, renal cell, and colorectal carcinoma. Cancer Genet.
Cytogenet. 19: 29-36, 1986.

48. Petrakis, N. L.: Genetic factors in the etiology of breast cancer.
Cancer 39: 2709-2715, 1977.

49. Sellers, T. A.; Kushi, L. H.; Potter, J. D.; Kaye, S. A.; Nelson,
C. L.; McGovern, P. G.; Folsom, A. R.: Effect of family history,
body-fat distribution, and reproductive factors on the risk of postmenopausal
breast cancer. New Eng. J. Med. 326: 1323-1329, 1992.

50. Seltzer, M. H.; Plato, C. C.; Fox, K. M.: Dermatoglyphics in
the identification of women either with or at risk for breast cancer.
Am. J. Med. Genet. 37: 482-488, 1990.

51. Teasdale, C.; Forbes, J. F.; Baum, M.: Familial male breast cancer.
(Letter) Lancet I: 360-361, 1976.

52. Tulinius, H.; Sigvaldason, H.; Olafsdottir, G.; Tryggvadottir,
L.: Epidemiology of breast cancer in families in Iceland. J. Med.
Genet. 29: 158-164, 1992.

53. Westley, B.; May, F. E. B.: The human genome contains multiple
sequences of varying homology to mouse mammary tumour virus DNA. Gene 28:
221-227, 1984.

54. Williams, W. R.; Anderson, D. E.: Genetic epidemiology of breast
cancer: segregation analysis of 200 Danish pedigrees. Genet. Epidemiol. 1:
7-20, 1984.

*FIELD* CS

Oncology:
   Breast cancer

Misc:
   High risk for women with early-onset bilateral breast cancer in relatives;
   Risk associated with high waist-to-hip ratio,low parity, or greater
   age at first pregnancy;
   Increased risk for males

Inheritance:
   Autosomal dominant vs. multifactorial

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 6/11/1995
davew: 7/18/1994
mimadm: 4/18/1994
warfield: 4/6/1994
pfoster: 3/24/1994
carol: 3/16/1994

*RECORD*
*FIELD* NO
114500
*FIELD* TI
#114500 CANCER OF COLON
COLORECTAL CANCER; CRC
LYNCH CANCER FAMILY SYNDROME I, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because it is clear that more
than one gene locus can be involved alone or in combination in the
production of the phenotype. Kinzler and Vogelstein (1996) gave a review
of hereditary colorectal cancer (HCC) and the multistep process of
carcinogenesis which typically develops over decades and appears to
require at least 7 genetic events for completion. Inheritance of a
single altered gene can result in a marked predisposition to colorectal
cancer in 2 distinct syndromes, familial adenomatous polyposis (FAP;
175100) and hereditary nonpolyposis colorectal cancer. The genetic
defect in FAP involves the rate of tumor initiation by targeting the
gatekeeper function of the APC gene (175100). In contrast, the defect in
HNPCC largely affects tumor aggression by targeting the genome guardian
function of DNA repair. Studies of these syndromes have provided unique
insights into both inherited and sporadic forms of human tumors.

Colon cancer is a well-known feature of familial polyposis coli (APC;
175100). Cancer of the colon occurred in 7 members of 4 successive
generations of the family reported by Kluge (1964), leading him to
suggest a simple genetic basis for colonic cancer independent of
polyposis. Morson (1973) studied a similar family. The combination of
colonic and endometrial cancer has been observed in many families (e.g.,
Williams, 1978). Sivak et al. (1981) studied a kindred with the familial
cancer syndrome in which every confirmed affected member had at least 1
primary carcinoma of the colon. The average age at which cancer appeared
was 38 years. Multiple primary neoplasms occurred in 23% of cancer
patients. Linkage studies with HLA showed 3 crossovers out of 17
opportunities. The lod score was 1.06 at a recombination fraction of
0.20. Budd and Fink (1981) reported a family with a high frequency of
mucoid colonic carcinoma. Since endometrial carcinoma, atypical
endometrial hyperplasia, uterine leiomyosarcoma, bladder transitional
carcinoma, and renal cell carcinoma also occurred in the family, this
may be the same disorder as the cancer family syndrome of Lynch, type II
(114400). Lynch and Lynch (1979) pointed out that cancer of the right
colon is particularly characteristic of the cancer-family syndrome. In
the DNA from 1 colon and 2 lung carcinoma cell lines, Perucho et al.
(1981) demonstrated the same or closely related transforming elements.
By DNA-mediated gene transfer, mouse fibroblasts could be
morphologically transformed and rendered tumorigenic in nude mice.
Bamezai et al. (1984) reported an Indian Sikh kindred in which 8 persons
suffered from cancer of the cecum, not associated with polyposis. Burt
et al. (1985) studied a large Utah kindred called to attention because
of occurrence of colorectal cancer in a brother, a sister, and a nephew.
No clear inheritance pattern was discernible until systematic screening
was undertaken for colonic polyps using flexible proctosigmoidoscopy.
One or more adenomatous polyps were found in 41 of 191 family members
(21%) and 12 of 132 controls (9%)--p less than 0.005. Pedigree analysis
showed best fit with autosomal dominant inheritance. Cannon-Albright et
al. (1988) extended the studies with investigations of 33 additional
kindreds. The kindreds were selected through either a single person with
an adenomatous polyp or a cluster of relatives with colonic cancer. The
kindreds all had common colorectal cancers, not the rare inherited
condition of familial polyposis coli or nonpolyposis inherited
colorectal cancer. Likelihood analysis strongly supported dominant
inheritance of a susceptibility to colorectal adenomas and cancers, with
a gene frequency of 19%. According to the most likely genetic model,
adenomatous polyps and colorectal cancers occur only in genetically
susceptible persons; however, the 95% confidence interval for this
proportion was 53 to 100%. Ponz de Leon et al. (1992) analyzed data on
605 families of probands with colorectal cancer in the province of
Modena in Italy. Among the 577 presumed nonpolyposis cases, both parents
had colorectal cancer in 11, one parent in 130, and neither parent in
436. Segregation was compatible with dominant transmission of
susceptibility to cancer. In preliminary observations, Pathak and
Goodacre (1986) found deletion of 12p in colorectal cancer specimens.

Fearon et al. (1987) studied the clonal composition of human colorectal
tumors. Using X-linked RFLPs, they showed that all 50 tumors from
females showed a monoclonal pattern of X-chromosome inactivation; these
tumors included 20 carcinomas and 30 adenomas of either familial or
spontaneous type. In over 75% of carcinomas examined, somatic loss of
chromosome 17p sequences was found; such loss was rare in adenomas.
Fearon et al. (1987) suggested that a gene on the short arm of
chromosome 17 may be associated with progression from the benign to the
malignant state. Mecklin (1987) investigated the frequency of hereditary
colorectal cancer among all colorectal cancer patients diagnosed in 1
Finnish county during the 1970s. The cancer family syndrome type of
hereditary nonpolyposis colorectal carcinoma emerged as the most common
verifiable risk factor, involving between 3.8 and 5.5% of all colorectal
cancer patients. The frequencies of familial adenomatosis and ulcerative
colitis were 0.2% and 0.6%, respectively. The observed frequency is
probably an underestimate. The patients with cancer family syndrome were
young, accounting for 29 to 39% of the patients under 50 years of age,
and their tumors were located predominantly (65%) in the right
hemicolon. By a combination of DNA hybridization analyses and tissue
sectioning techniques, Bos et al. (1987) demonstrated that RAS gene
mutations occur in over a third of colorectal cancers, that most of the
mutations are at codon 12 of the KRAS gene (190070), and that the
mutations usually precede the development of malignancy. In 38 tumors
from 25 patients with familial polyposis coli, and in 20 sporadic colon
carcinomas, Okamoto et al. (1988) found frequent occurrence of allele
loss on chromosome 22, with some additional losses on chromosomes 5, 6,
12q, and 15. The DNA probe C11p11, which has been found to be linked to
familial polyposis coli, also detected frequent allele loss in both
familial and sporadic colon carcinomas but not in benign adenomas. In a
more extensive study, Vogelstein et al. (1988) studied the
interrelationships of the 4 alterations demonstrated in colorectal
cancer (RAS gene mutations and deletions of chromosome 5, 17 and 18
sequences) and determined their occurrence with respect to different
stages of colorectal tumorigenesis. They found RAS gene mutations
frequently in adenomas, this being the first demonstration of such in
benign human tumors. In adenomas greater than 1 cm in size, the
prevalence was similar to that observed in carcinomas (58% and 47%,
respectively). Sequences on chromosome 5 that are linked to familial
adenomatous polyposis were seldom lost in adenomas from such patients.
Therefore, the Knudson model is unlikely to be applicable to the
adenoma/carcinoma sequence in this disorder. Chromosome 18 sequences
were lost frequently in colon carcinomas (73%) and in advanced adenomas
(47%), but only occasionally in earlier stage adenomas (11-13%); see
120470. Chromosome 17 sequences were usually lost only in carcinomas
(75%). The results suggested a model wherein the steps required for
malignancy involve the activation of a dominantly acting oncogene
coupled with the loss of several genes that normally suppress
tumorigenesis; see 120460.

Wildrick and Boman (1988) found deletion of the glucocorticoid receptor
locus (138040), located on 5q, in colorectal cancers. Law et al. (1988)
examined the question of whether the gene for familial polyposis coli on
chromosome 5 may be the site of changes leading to colorectal cancer in
the general population, analogous to recessive tumor genes in
retinoblastoma and Wilms tumor. To avoid error in interpretation of
allelic loss from a study of nonhomogeneous samples, tumor cell
populations were first microdissected from 24 colorectal carcinomas, an
additional 9 cancers were engrafted in nude mice, and nuclei were
flow-sorted in an additional 2. Of 31 cancers informative for chromosome
5 markers, only 6 (19%) showed loss of heterozygosity of chromosome 5
alleles, compared to 19 of 34 (56%) on chromosome 17, and 17 of 33 (52%)
on chromosome 18. Law et al. (1988) concluded that FPC is a true
dominant for adenomatosis but not a common recessive gene for colon
cancer, and that simple mendelian models involving loss of alleles at a
single locus may be inappropriate for understanding common human solid
tumors. Vogelstein et al. (1989) examined the extent and variation of
allelic loss for polymorphic DNA markers in every nonacrocentric
autosomal arm in 56 paired colorectal carcinoma and adjacent normal
colonic mucosa specimens. They referred to the analysis as an
allelotype, in analogy with a karyotype. Three major conclusions were
drawn from the study: (1) Allelic deletions are remarkably common; 1 of
the alleles of each polymorphic marker tested was lost in at least some
tumors, and some tumors lost more than half of their parental alleles.
(2) In addition to allelic deletions, new DNA fragments not present in
normal tissue were identified in 5 carcinomas; these new fragments
contained repeated sequences (of the variable-number-of-tandem-repeat
type). (3) Patients with more than the median percentage of allelic
deletions had a considerably worse prognosis than did the other
patients, although the stage and size of the primary tumors were very
similar in the 2 groups.

Delattre et al. (1989) reviewed the 3 general types of genetic
alterations in colorectal cancer: (1) change in DNA content of the
malignant cells as monitored by flow cytometry; (2) specific loss of
genetic material, i.e., a complete loss of chromosome 18 and a
structural rearrangement of chromosome 17 leading most often to the loss
of 1 short arm, and loss of part of 5q as demonstrated by loss of
heterozygosity; and (3) in nearly 40% of tumors, activation by point
mutation of RAS oncogenes (never HRAS, rarely NRAS, and most frequently
KRAS). In KRAS, with 1 exception, the activation has always occurred by
a change in the coding properties of the 12th or 13th codon. In studies
of the multiple genetic alterations in colorectal cancer, Delattre et
al. (1989) found that deletions and mitotic abnormalities occurred more
frequently in distal than in proximal tumors. The frequency of KRAS
mutations did not differ between proximal and distal cancers. In studies
of 15 colorectal tumors, Konstantinova et al. (1991) found
rearrangements of the short arm of chromosome 17, leading to deletion of
this arm or part of it in 12; in 2 others, one of the homologs of pair
17 was lost. One chromosome 18 was lost in 12 out of 13 cases with fully
identified numerical abnormalities; chromosome 5, in 6 tumors; and other
chromosomes in lesser numbers of cases. See 120470 for a discussion of a
gene on chromosome 18 called DCC ('deleted in colorectal cancer') that
shows mutations, including point mutations, in colorectal tumor tissue;
also see 164790 for a discussion of a mutation in the NRAS oncogene in
colorectal cancer. Kikuchi-Yanoshita et al. (1992) presented evidence
that genetic changes in both alleles of the TP53 gene through mutation
and LOH, which result in abnormal protein accumulation, are involved in
the conversion of adenoma to early carcinoma in both familial
adenomatous polyposis and in nonfamilial polyposis cases. On the basis
of complex segregation analysis of a published series of consecutive
pedigrees ascertained through patients undergoing treatment for
colorectal cancer, Houlston et al. (1992) concluded that a dominant gene
(or genes) with a frequency of 0.006 with a lifetime penetrance of 0.63
is likely. The gene was thought to account for 81% of colorectal cancer
in patients under 35 years of age; however, by age 65, about 85%
appeared to be phenocopies.

Fearon and Vogelstein (1990) reviewed the evidence supporting their
multistep genetic model for colorectal tumorigenesis. They suggested
that multiple mutations lead to a progression from normal epithelium to
metastatic carcinoma through hyperplastic epithelium--early
adenoma--intermediate adenoma--late adenoma--and carcinoma. The genes in
which mutations occur at steps in this process include APC on chromosome
5, KRAS on chromosome 12, TP53 (191170) on 17p, and DCC on chromosome
18. Hereditary nonpolyposis colorectal carcinoma (HNPCC) comprises about
5% of all colorectal carcinomas (Lynch, 1986; Mecklin, 1987). The
minimum criterion of HNPCC is that colorectal carcinoma is diagnosed and
histologically verified in at least 3 relatives belonging to 2 or more
successive generations. Moreover, the age of onset should be less than
50 years in at least 1 patient. In addition to the colon (most often the
right side), organs commonly affected with cancer include the
endometrium, stomach, biliary and pancreatic system, and urinary tract
(Mecklin and Jarvinen, 1991). Peltomaki et al. (1992) performed linkage
studies in 9 Finnish families, demonstrating that HNPCC is not linked to
the MCC (mutated in colon cancer; 159350)/APC region on 5q21; combined
maximum lod score = -22.57 at a recombination fraction of 0.00. The
report demonstrated the feasibility of studying DNA not only from blood
samples from living family members but also from formaldehyde-fixed
archival pathology specimens from deceased individuals.

Other genes that have been demonstrated or suspected of involvement in
colorectal cancer include MSH2 (120435) on chromosome 2 and the DRA
candidate colon tumor-suppressor gene (126650) on chromosome 7.

In addition, the state of DNA methylation appears to play a role in
genetic instability in colorectal cancer cells. Lengauer et al. (1997)
noted that DNA methylation is essential in prokaryotes, dispensable in
lower eukaryotes (such as Saccharomyces cerevisiae) yet present and
presumably important in mammals. Many cancers have been shown to have a
global hypomethylation of DNA compared with normal tissues. Treatment of
cells or animals with 5-azacytidine (5-aza-C), a demethylating agent
that irreversibly inactivates methyltransferase (see 156569), is
oncogenic in vitro and in vivo. Conversely, other studies showed that
hypermethylation of specific sequences found in some tumors can be
associated with the inactivation of tumor suppressor gene expression.
Mice genetically deficient in methyltransferase are resistant to
colorectal tumorigenesis initiated by mutation of the APC tumor
suppressor gene, and treatment of these mice with 5-aza-C enhances the
resistance (Laird et al., 1995).

Lengauer et al. (1997) reported a striking difference in the expression
of exogenously introduced retroviral genes in various colorectal cancer
cell lines. Extinguished expression was associated with DNA methylation
and could be reversed by treatment with the demethylating agent 5-aza-C.
A striking correlation between genetic instability and methylation
capacity suggested that methylation abnormalities may play a role in the
chromosome segregation processes in cancer cells. It has been speculated
that genetic instability is necessary for a tumor to accumulate the
numerous genetic alterations that accompany carcinogenesis. There
appeared to exist 2 pathways of genetic instability in colorectal
cancer. The first is found in about 15% of tumors and involves point
mutations, microdeletions, and microinsertions associated with
deficiency of mismatch repair (MMR). The second is found in
MMR-proficient cells and involves gains and losses of whole chromosomes.
Lengauer et al. (1997) suggested that methylation abnormalities are
intrinsically and directly involved in the generation of the second type
of instability, thus allowing for the selection of methylation-negative
cells during the clonal evolution of tumors. The hypothesis was
supported by the observation that demethylation is associated with
chromosomal aberrations, including mitotic dysfunction and
translocation, and was consistent with the hypothesis relating
methylation and aneuploidy put forward by Thomas (1995). Jones and
Gonzalgo (1997) commented on altered DNA methylation and genome
instability as a new pathway to cancer.

In a second report, Lengauer et al. (1997) showed that tumors without
microsatellite instability exhibit a striking defect in chromosome
segregation, resulting in gains or losses in excess of 10(-2) per
chromosome per generation. This form of chromosomal instability
reflected a continuing cellular defect that persisted throughout the
lifetime of the tumor cell and was not simply related to chromosome
number. While microsatellite instability is a recessive trait,
chromosomal instability appeared to be dominant. The data indicated that
persistent genetic instability may be critical for the development of
all colorectal cancers, and that this instability can arise through 2
distinct pathways.

*FIELD* SA
Lovett  (1976); Lovett  (1976); Mathis  (1962)
*FIELD* RF
1. Bamezai, R.; Singh, G.; Khanna, N. N.; Singh, S.: Genetics of
site specific colon cancer: a family study. Clin. Genet. 26: 129-132,
1984.

2. Bos, J. L.; Fearon, E. R.; Hamilton, S. R.; Verlaan-de Vries, M.;
van Boom, J. H.; van der Eb, A. J.; Vogelstein, B.: Prevalence of
ras gene mutations in human colorectal cancers. Nature 327: 293-297,
1987.

3. Budd, D. C.; Fink, D. L.: Mucoid colonic carcinoma as an autosomal-dominant
inherited syndrome. Arch. Surg. 116: 901-905, 1981.

4. Burt, R. W.; Bishop, D. T.; Cannon, L. A.; Dowdle, M. A.; Lee,
R. G.; Skolnick, M. H.: Dominant inheritance of adenomatous colonic
polyps and colorectal cancer. New Eng. J. Med. 312: 1540-1544, 1985.

5. Cannon-Albright, L. A.; Skolnick, M. H.; Bishop, T.; Lee, R. G.;
Burt, R. W.: Common inheritance of susceptibility to colonic adenomatous
polyps and associated colorectal cancers. New Eng. J. Med. 319:
533-537, 1988.

6. Delattre, O.; Olschwang, S.; Law, D. J.; Melot, T.; Remvikos, Y.;
Salmon, R. J.; Sastre, X.; Validire, P.; Feinberg, A. P.; Thomas,
G.: Multiple genetic alterations in distal and proximal colorectal
cancer. Lancet II: 353-356, 1989.

7. Fearon, E. R.; Hamilton, S. R.; Vogelstein, B.: Clonal analysis
of human colorectal tumors. Science 238: 193-197, 1987.

8. Fearon, E. R.; Vogelstein, B.: A genetic model for colorectal
tumorigenesis. Cell 61: 759-767, 1990.

9. Houlston, R. S.; Collins, A.; Slack, J.; Morton, N. E.: Dominant
genes for colorectal cancer are not rare. Ann. Hum. Genet. 56: 99-103,
1992.

10. Jones, P. A.; Gonzalgo, M. L.: Altered DNA methylation and genome
instability: a new pathway to cancer? Proc. Nat. Acad. Sci. 94:
2103-2105, 1997.

11. Kikuchi-Yanoshita, R.; Konishi, M.; Ito, S.; Seki, M.; Tanaka,
K.; Maeda, Y.; Iino, H.; Fukayama, M.; Koike, M.; Mori, T.; Sakuraba,
H.; Fukunari, H.; Iwama, T.; Miyaki, M.: Genetic changes of both
p53 alleles associated with the conversion from colorectal adenoma
to early carcinoma in familial adenomatous polyposis and non-familial
adenomatous polyposis patients. Cancer Res. 52: 3965-3971, 1992.

12. Kinzler, K. W.; Vogelstein, B.: Lessons from hereditary colorectal
cancer. Cell 87: 159-170, 1996.

13. Kluge, T.: Familial cancer of the colon. Acta Chir. Scand. 127:
392-398, 1964.

14. Konstantinova, L. N.; Fleischman, E. W.; Knisch, V. I.; Perevozchikov,
A. G.; Kopnin, B. P.: Karyotype pecularities (sic) of human colorectal
adenocarcinomas. Hum. Genet. 86: 491-496, 1991.

15. Laird, P. W.; Jackson-Grusby, L.; Fazeli, A.; Dickinson, S. L.;
Jung, W. E.; Li, E.; Weinberg, R. A.; Jaenisch, R.: Suppression of
intestinal neoplasia by DNA hypomethylation. Cell 81: 197-205, 1995.

16. Law, D. J.; Olschwang, S.; Monpezat, J. P.; Lefrancois, D.; Jagelman,
D.; Petrelli, N. J.; Thomas, G.; Feinberg, A. P.: Concerted nonsyntenic
allelic loss in human colorectal carcinoma. Science 241: 961-965,
1988.

17. Lengauer, C.; Kinzler, K. W.; Vogelstein, B.: Genetic instability
in colorectal cancers. Nature 386: 623-627, 1997.

18. Lengauer, C.; Kinzler, K. W.; Vogelstein, B.: DNA methylation
and genetic instability in colorectal cancer cells. Proc. Nat. Acad.
Sci. 94: 2545-2550, 1997.

19. Lovett, E.: Familial cancer of the gastro-intestinal tract. Brit.
J. Surg. 63: 19-22, 1976.

20. Lovett, E.: Family studies in cancer of the colon and rectum. Brit.
J. Surg. 63: 13-18, 1976.

21. Lynch, H. T.: Frequency of hereditary nonpolyposis colorectal
carcinoma (Lynch syndromes I and II). Gastroenterology 90: 486-492,
1986.

22. Lynch, H. T.; Lynch, P.: The cancer-family syndrome: a pragmatic
basis for syndrome identification. Dis. Colon Rectum 22: 106-110,
1979.

23. Mathis, V. M.: Familiaeres Colon Karzinom. Ein Stammbaum aus
dem Kanton Aargau. Schweiz. Med. Wschr. 92: 1673-1678, 1962.

24. Mecklin, J.-P.: Frequency of hereditary colorectal carcinoma. Gastroenterology 93:
1021-1025, 1987.

25. Mecklin, J.-P.; Jarvinen, H. J.: Tumor spectrum in cancer family
syndrome (hereditary nonpolyposis colorectal cancer). Cancer 68:
1109-1112, 1991.

26. Morson, B. C.: Personal Communication. London  1973.

27. Okamoto, M.; Sasaki, M.; Sugio, K.; Sato, C.; Iwama, T.; Ikeuchi,
T.; Tonomura, A.; Sasazuki, T.; Miyaki, M.: Loss of constitutional
heterozygosity in colon carcinoma from patients with familial polyposis
coli. Nature 331: 273-277, 1988.

28. Pathak, S.; Goodacre, A.: Specific chromosome anomalies and predisposition
to human breast, renal cell, and colorectal carcinoma. Cancer Genet.
Cytogenet. 19: 29-36, 1986.

29. Peltomaki, P.; Sistonen, P.; Mecklin, J.-P.; Pylkkanen, L.; Aaltonen,
L.; Nordling, S.; Kere, J.; Jarvinen, H.; Hamilton, S. R.; Petersen,
G.; Kinzler, K. W.; Vogelstein, B.; de la Chapelle, A.: Evidence
that the MCC-APC gene region in 5q21 is not the site for susceptibility
to hereditary nonpolyposis colorectal carcinoma. Cancer Res. 52:
4530-4533, 1992.

30. Perucho, M.; Goldfarb, M.; Shimizu, K.; Lama, C.; Fogh, J.; Wigler,
M.: Human-tumor-derived cell lines contain common and different transforming
genes. Cell 27: 467-476, 1981.

31. Ponz de Leon, M.; Scapoli, C.; Zanghieri, G.; Sassatelli, R.;
Sacchetti, C.; Barrai, I.: Genetic transmission of colorectal cancer:
exploratory data analysis from a population based registry. J. Med.
Genet. 29: 531-538, 1992.

32. Sivak, M. V., Jr.; Sivak, D. S.; Braun, W. A.; Sullivan, B. H.,
Jr.: A linkage study of HLA and inherited adenocarcinoma of the colon. Cancer 48:
76-81, 1981.

33. Thomas, J. H. :Proc. Nat. Acad. Sci. 92: 480-482, 1995.

34. Vogelstein, B.; Fearon, E. R.; Hamilton, S. R.; Kern, S. E.; Preisinger,
A. C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A. M. M.; Bos,
J. L.: Genetic alterations during colorectal-tumor development. New
Eng. J. Med. 319: 525-532, 1988.

35. Vogelstein, B.; Fearon, E. R.; Kern, S. E.; Hamilton, S. R.; Preisinger,
A. C.; Nakamura, Y.; White, R.: Allelotype of colorectal carcinomas. Science 244:
207-211, 1989.

36. Wildrick, D. M.; Boman, B. M.: Chromosome 5 allele loss at the
glucocorticoid receptor locus in human colorectal carcinomas. Biochem.
Biophys. Res. Commun. 150: 591-598, 1988.

37. Williams, C.: Management of malignancy in 'cancer families.'. Lancet I:
198-199, 1978.

*FIELD* CS

Oncology:
   Hereditary nonpolyposis colorectal carcinoma;
   Associated endometrial carcinoma, atypical endometrial hyperplasia,
   uterine leiomyosarcoma, bladder transitional carcinoma, gastric, biliary
   and renal cell carcinoma;
   APC, RAS, DCC or KRAS gene mutations;
   Allele loss on chromosomes 5, 6, 12q, 15, 17, 18, or 22

Inheritance:
   Autosomal dominantly acting oncogene plus loss of suppressor gene(s)

*FIELD* CN
Victor A. McKusick - updated: 04/21/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jenny: 04/21/1997
terry: 4/14/1997
terry: 12/10/1996
terry: 12/9/1996
carol: 5/31/1994
terry: 5/13/1994
mimadm: 4/9/1994
warfield: 4/6/1994
carol: 2/24/1993
carol: 10/12/1992

*RECORD*
*FIELD* NO
114550
*FIELD* TI
*114550 CANCER, HEPATOCELLULAR
LIVER CANCER;;
LIVER CELL CARCINOMA; LCC;;
HEPATOCELLULAR CARCINOMA; HCC;;
HEPATOMA
HEPATITIS B VIRUS INTEGRATION SITE, INCLUDED;;
HVBS1, INCLUDED;;
HBVS1, INCLUDED
*FIELD* TX
Primary cancer of the liver in 3 brothers was described by Kaplan and
Cole (1965) and by Hagstrom and Baker (1968). In these patients there
was no recognized preexisting liver disease. Denison et al. (1971)
described 2 adult brothers who died of primary hepatocellular carcinoma.
Both had micronodular cirrhosis with features of subacute progressive
viral hepatitis. Australia antigen was demonstrated in the brother in
whom it was sought. Their father had died much earlier of hepatocellular
carcinoma. See 231100 for description of liver cancer as a complication
of giant cell hepatitis of infancy. Familial LCC might also have its
explanation in alpha-1-antitrypsin deficiency (107400), hemochromatosis
(235200), and tyrosinemia (276700). Integration of the hepatitis B virus
(HBV) into cellular DNA occurs during longterm persistent infection in
man. Hepatocellular carcinomas isolated from carriers of virus often
contain clonally propagated viral DNA. Shen et al. (1991) presented
evidence for the interaction of inherited susceptibility and hepatitis B
viral infection in cases of primary hepatocellular carcinoma in eastern
China. Complex segregation analysis of 490 extended families supported
the existence of a recessive allele with population frequency
approximately 0.25, which results in a lifetime risk of HCC in the
presence of both HBV infection and genetic susceptibility, of 0.84 for
males and 0.46 for females. The model further predicted that, in the
absence of genetic susceptibility, lifetime risk of HCC is 0.09 for
HBV-infected males and 0.01 for HBV-infected females and that regardless
of genotype the risk is virtually zero for uninfected persons.

The finding of small deletions in retinoblastoma and Wilms tumor
prompted Rogler et al. (1985) to look for the same in association with
HBV integration in hepatocellular carcinoma. They demonstrated a
deletion of at least 13.5 kb of cellular sequences in a liver cancer.
The HBV integration and the deletion occurred on the short arm of
chromosome 11 at location 11p14-p13. The deleted sequences were lost in
tumor cells leaving only a single copy. Clones of the DNA flanking the
deleted segment were used for the mapping of the deletion in somatic
cell hybrids and by in situ hybridization. Cellular sequences homologous
to the deleted region were cloned and used to exclude the possibility
that this DNA had been moved to other positions in the genome. Fisher et
al. (1987) extended the observations of Rogler et al. (1985). Using
somatic cell hybrids that contained defined 11p deletions, 2 cloned DNA
sequences that flank the deletion generated by a hepatocellular
carcinoma (as a consequence of hepatitis B virus integration) were
mapped to 11p13. Wilms tumor (194070) and the tumors of
Beckwith-Wiedemann syndrome (130650) are also determined by changes on
11p. See 142330 for familial hepatic adenoma, sometimes associated with
hepatocellular carcinoma.

Henderson et al. (1988) found that unique cellular DNA to the left of an
HBV DNA integration site cloned from a primary tumor mapped to
chromosome 18q (18q11.1-q11.2), whereas right-hand flanking DNA mapped
to chromosome 17 at a subterminal region of the long arm. In a hepatoma
specimen from Shanghai, Zhou et al. (1988) identified integration of
hepatitis B virus into 17p12-p11.2, which is near the human
protooncogene p53 (191170). Furthermore, the sequence of flanking
cellular DNA showed highly significant homology with a conserved region
of a number of functional mammalian DNAs, including the human
autonomously replicated sequence-1 (ARS1; 109110). ARS1 is a sequence of
human DNA that allows replication of Saccharomyces cerevisiae
integrative plasmids as autonomously replicating elements in S.
cerevisiae cells. Since integration of viral DNA is not a required step
in the replicative cycle of the hepatitis virus, the presence of
integrated HBV sequences in many human hepatocellular carcinomas
suggests a causal relationship. Since any 1 of several integration sites
may lead to the same result, the crucial cellular targets involved in
triggering liver cell malignant transformation may differ from tumor to
tumor. Smith et al. (1989) gave evidence for microdeletions of
chromosome 4q involving the alcohol dehydrogenase isoenzyme gene ADH3
and hepatomas from 3 of 5 individuals heterozygous for an XbaI RFLP
detectable by the ADH probe. Two of 7 individuals heterozygous for an
epidermal growth factor RFLP had lost 1 EGF allele in their hepatoma
tissue.

Primary hepatocellular carcinoma occurs at high frequencies in east Asia
and sub-Saharan Africa. In these areas of the world, chronic infection
with the hepatitis B virus (HBV) is the best documented risk factor;
however, only 20-25% of HBV carriers develop HCC. Exposure to the fungal
toxin aflatoxin B1 (AFB1) has been suggested to increase HCC risk, in
part because in vitro experiments demonstrated that AFB1 mutagenic
metabolites bind to DNA and are capable of inducing G-to-T
transversions. In certain areas of the HCC endemic regions, a mutational
hot spot has been reported in the p53 tumor suppressor gene (TP53;
191170): an AGG-to-AGT transversion (arginine to serine) of codon 249 in
exon 7 (191170.0006). Microsomal epoxide hydrolase (EPHX; 132810) and
glutathione-S-transferase M1 (GSTM1; 138350) are both involved in AFB1
detoxification in hepatocytes. Polymorphism of both genes has been
identified. In Ghana and China, McGlynn et al. (1995) conducted studies
to determine whether mutant alleles at one or both of these loci are
associated with increased levels of serum AFB1-albumin adducts, with
HCC, and with mutations at codon 249 of p53. In a cross-sectional study,
they found that mutant alleles at both loci were significantly
overrepresented in individuals with serum AFB1 albumin adducts.
Additionally, in a case-control study, mutant alleles of EPHX were
significantly overrepresented in persons with HCC. The relationship of
EPHX to HCC varied by hepatitis B surface antigen status, indicating
that a synergistic effect may exist. Mutations at codon 249 of p53 were
observed only among HCC patients with one or both high-risk genotypes.
These findings by McGlynn et al. (1995) supported the existence of
genetic susceptibility in humans to the environmental carcinogen AFB1
and indicated that there is a synergistic increase in risk of HCC with
the combination of hepatitis B virus infection and susceptible genotype.

*FIELD* SA
Chang et al. (1984); Lynch et al. (1984)
*FIELD* RF
1. Chang, M.-H.; Hsu, H.-C.; Lee, C.-Y.; Chen, D.-S.; Lee, C.-H.;
Lin, K.-S.: Fraternal hepatocellular carcinoma in young children
in two families. Cancer 53: 1807-1810, 1984.

2. Denison, E. K.; Peters, R. L.; Reynolds, T. B.: Familial hepatoma
with hepatitis-associated antigen. Ann. Intern. Med. 74: 391-394,
1971.

3. Fisher, J. H.; Scoggin, C. H.; Rogler, C. E.: Sequences which
flank an 11p deletion observed in an hepatocellular carcinoma map
to 11p13. Hum. Genet. 75: 66-69, 1987.

4. Hagstrom, R. M.; Baker, T. D.: Primary hepatocellular carcinoma
in three male siblings. Cancer 22: 142-150, 1968.

5. Henderson, A. S.; Ripley, S.; Hino, O.; Rogler, C. E.: Identification
of a chromosomal aberration associated with a hepatitis B DNA integration
site in human cells. Cancer Genet. Cytogenet. 30: 269-275, 1988.

6. Kaplan, L.; Cole, L.: Fraternal primary hepatocellular carcinoma
in three male, adult siblings. Am. J. Med. 39: 305-311, 1965.

7. Lynch, H. T.; Srivatanskul, P.; Phornthutkul, K.; Lynch, J. F.
: Familial hepatocellular carcinoma in an endemic area of Thailand.
Cancer Genet. Cytogenet. 11: 11-18, 1984.

8. McGlynn, K. A.; Rosvold, E. A.; Lustbader, E. D.; Hu, Y.; Clapper,
M. L.; Zhou, T.; Wild, C. P.; Xia, X.-L.; Baffoe-Bonnie, A.; Ofori-Adjei,
D.; Chen, G.-C.; London, W. T.; Shen, F.-M.; Buetow, K. H.: Susceptibility
to hepatocellular carcinoma is associated with genetic variation in
the enzymatic detoxification of aflatoxin B1. Proc. Nat. Acad. Sci. 92:
2384-2387, 1995.

9. Rogler, C. E.; Sherman, M.; Su, C. Y.; Shafritz, D. A.; Summers,
J.; Shows, T. B.; Henderson, A.; Kew, M.: Deletion in chromosome
11p associated with a hepatitis B integration site in hepatocellular
carcinoma. Science 230: 319-322, 1985.

10. Shen, F.-M.; Lee, M. K.; Gong, H.-M.; Cai, X.-Q.; King, M.-C.
: Complex segregation analysis of primary hepatocellular carcinoma
in Chinese families: interaction of inherited susceptibility and hepatitis
B viral infection. Am. J. Hum. Genet. 49: 88-93, 1991.

11. Smith, M.; Yoshiyama, K.; Kew, M.: Evidence for chromosome 4q
deletions in human hepatomas.  (Abstract) Cytogenet. Cell Genet. 51:
1081 only, 1989.

12. Zhou, Y.-Z.; Slagle, B. L.; Donehower, L. A.; vanTuinen, P.; Ledbetter,
D. H.; Butel, J. S.: Structural analysis of a hepatitis B virus genome
integrated into chromosome 17p of a human hepatocellular carcinoma.
J. Virol. 62: 4224-4231, 1988.

*FIELD* CS

Oncology:
   Primary liver cancer

GI:
   Micronodular cirrhosis;
   Subacute progressive viral hepatitis

Lab:
   Often integrated HBV sequences in hepatocellular carcinomas

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 6/3/1995
mark: 5/12/1995
mimadm: 4/9/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 2/28/1992

*RECORD*
*FIELD* NO
114580
*FIELD* TI
114580 CANDIDIASIS, FAMILIAL CHRONIC MUCOCUTANEOUS, DOMINANT TYPE
*FIELD* TX
Sams et al. (1979) described a 'dominant family' with this disorder.
Nine persons in 3 generations were affected. Dermatophytosis, alopecia,
loss of teeth, and recurrent viral infections were present in some.
Tests of cell-mediated immunity showed total cutaneous anergy in 3 of 8
affected persons. Four of the other 5 had negative lymphocyte
transformation and skin tests to candida. The authors made the
significant observation that candida skin tests were positive and
lymphocyte transformation normal under age 2 years in 2 children with
chronic mucocutaneous candidiasis present clinically since the age of 6
months. After age 2, however, these tests became negative. The authors
referred to other reports of affected parent and child. This form of
familial candidiasis is distinguished from other forms (e.g., 212050,
240300) by dominant inheritance and lack of associated endocrinopathy.

*FIELD* RF
1. Sams, W. M., Jr.; Jorizzo, J. L.; Snyderman, R.; Jegasothy, B.
V.; Ward, F. E.; Weiner, M.; Wilson, J. G.; Yount, W. J.; Dillard,
S. B.: Chronic mucocutaneous candidiasis: immunologic studies of
three generations of a single family. Am. J. Med. 67: 948-959,
1979.

*FIELD* CS

Immunology:
   Chronic mucocutaneous candidiasis;
   Recurrent viral infections;
   Cutaneous anergy

Skin:
   Dermatophytosis

Hair:
   Alopecia

Teeth:
   Teeth loss

Endocrine:
   No associated endocrinopathy

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
carol: 3/6/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
114600
*FIELD* TI
*114600 CANINE TEETH, ABSENCE OF UPPER PERMANENT
*FIELD* TX
Dolamore (1925) described a case of persistent deciduous canines with
absence of permanent successors in father and son. Gruneberg (1936)
described the same in 7 members of 3 generations of a German Jewish
family.

*FIELD* RF
1. Dolamore, W. H.: Absent canines. Brit. Dent. J. 46: 5-8, 1925.

2. Gruneberg, H.: Two independent inherited tooth anomalies in one
family. J. Hered. 27: 225-228, 1936.

*FIELD* CS

Teeth:
   Absent permanent canines;
   Persistent deciduous canines

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
114610
*FIELD* TI
*114610 CANNABINOID RECEPTOR; CNR
*FIELD* TX
The cannabinoids are psychoactive ingredients of marijuana, principally
delta-9-tetrahydrocannabinol, as well as the synthetic analogs. Matsuda
et al. (1990) cloned a cannabinoid receptor from a rat brain. Using a
cosmid clone of the entire coding sequence of the human gene, Modi and
Bonner (1991) mapped the human CNR locus to 6q14-q15 by in situ
hybridization. Gerard et al. (1991) isolated a cDNA encoding a
cannabinoid receptor from a human brainstem cDNA library. The deduced
amino acid sequence encoded a protein of 472 residues which shared 97.3%
identity with the rat cannabinoid receptor cloned by Matsuda et al.
(1990). They provided evidence for the existence of an identical
cannabinoid receptor expressed in human testis. Hoehe et al. (1991)
determined the genomic localization of the CNR gene by combination of
genetic linkage mapping and chromosomal in situ hybridization. Close
linkage was suggested with CGA (118850), which is located at 6q21.1-q23;
maximum lod = 2.71 at theta = 0.0. Moreover, CNR was linked to markers
that define locus D6Z1, a sequence localized exclusively to centromeres
of all chromosomes and enriched on chromosome 6.

*FIELD* RF
1. Gerard, C. M.; Mollereau, C.; Vassart, G.; Parmentier, M.: Molecular
cloning of a human cannabinoid receptor which is also expressed in
testis. Biochem. J. 279: 129-134, 1991.

2. Hoehe, M. R.; Caenazzo, L.; Martinez, M. M.; Hsieh, W.-T.; Modi,
W. S.; Gershon, E. S.; Bonner, T. I.: Genetic and physical mapping
of the human cannabinoid receptor gene to chromosome 6q14-q15. New
Biologist 3: 880-885, 1991.

3. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.;
Bonner, T. I.: Structure of a cannabinoid receptor and functional
expression of the cloned cDNA. Nature 346: 561-564, 1990.

4. Modi, W. S.; Bonner, T. I.: Localization of the cannabanoid (sic)
receptor locus using non-isotopic in situ hybridization.  (Abstract) Cytogenet.
Cell Genet. 58: 1915 only, 1991.

*FIELD* CD
Victor A. McKusick: 8/6/1991

*FIELD* ED
supermim: 3/16/1992
carol: 2/21/1992
carol: 12/11/1991
carol: 11/27/1991
carol: 8/6/1991

*RECORD*
*FIELD* NO
114620
*FIELD* TI
114620 CANTU SYNDROME
*FIELD* TX
Cantu et al. (1982) reported 4 unrelated girls with an apparently
identical syndrome consisting of mild mental retardation, short stature,
macrocranium, prominent forehead, hypertelorism, exophthalmos, cardiac
anomalies, cutis laxa, wrinkled palms and soles, joint
hyperextensibility, wide ribs, and small vertebral bodies. The cases
were all sporadic. The parents were nonconsanguineous. The father's age
in each case was advanced: 45, 55, 46, and 51. The authors suggested
that these patients were the result of de novo autosomal dominant
mutation. (Possibly X-linked dominant mutation is equally plausible.)

*FIELD* RF
1. Cantu, J. M.; Sanchez-Corona, J.; Hernandes, A.; Nazara, Z.; Garcia-Cruz,
D.: Individualization of a syndrome with mental deficiency, macrocranium,
peculiar facies, and cardiac and skeletal anomalies. Clin. Genet. 22:
172-179, 1982.

*FIELD* CS

Neuro:
   Mild mental retardation

Growth:
   Short stature

Head:
   Macrocranium;
   Prominent forehead

Eyes:
   Hypertelorism;
   Exophthalmos

Cardiac:
   Cardiac anomalies

Skin:
   Cutis laxa;
   Wrinkled palms and soles

Joints:
   Joint hyperextensibility

Skel:
   Wide ribs;
   Small vertebral bodies

Misc:
   All cases sporadic

Inheritance:
   De novo autosomal dominant (vs. X-linked) mutation

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
114650
*FIELD* TI
114650 CAR FACTOR DEFICIENCY
*FIELD* TX
A mother and 2 sons (with different fathers) had a bleeding disorder and
a serum defect in thromboplastin generation (Komp, 1975). The defect was
not corrected by serum from 3 members of the Italian family whose name
(in abbreviated form) was used by Chirico and McElfresh (1957) to
designate a clotting factor in which they were deficient, the Car
factor.

*FIELD* RF
1. Chirico, A. M.; McElfresh, A. E.: A possible new thromboplastin
deficiency occurring in five siblings. Blood 12: 933-941, 1957.

2. Komp, D. M.: 'Car factor' deficiency revisited. Pediat. Res. 9:
184-189, 1975.

*FIELD* CS

Heme:
   Bleeding disorder

Lab:
   Defect in thromboplastin generation;
   Car factor deficiency

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
114700
*FIELD* TI
114700 CARABELLI ANOMALY OF MAXILLARY MOLAR TEETH
*FIELD* TX
Kraus (1951) was of the opinion that homozygosity of a gene is
responsible for a pronounced tubercle, whereas the heterozygote shows
slight grooves, pits, tubercles or bulge. He provided good pictures of
the anomaly. Lee and Goose (1972) studied the inheritance of this and
four other common dental traits, namely, shovel incisors (147400),
maxillary molar cusp number, mandibular molar cusp number, and fissure
patterns. They concluded that all are probably multifactorial.

*FIELD* SA
Dietz  (1944)
*FIELD* RF
1. Dietz, V. H.: A common dental morphotropic factor: the Carabelli
cusp. J. Am. Dent. Assoc. 31: 784-789, 1944.

2. Kraus, B. S.: Carabelli's anomaly of the maxillary molar teeth:
observations on Mexicans and Papago Indians and an interpretation
of the inheritance. Am. J. Hum. Genet. 3: 348-355, 1951.

3. Lee, G. T. R.; Goose, D. H.: The inheritance of dental traits
in a Chinese population in the United Kingdom. J. Med. Genet. 9:
336-339, 1972.

*FIELD* CS

Teeth:
   Grooves, pits, tubercles or bulges of maxillary molars

Inheritance:
   Autosomal dominant vs. multifactorial

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 4/9/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
114750
*FIELD* TI
*114750 CARBONIC ANHYDRASE III; CA III
CARBONIC ANHYDRASE C; CA3;;
CARBONIC ANHYDRASE, MUSCLE-SPECIFIC
*FIELD* TX
Carbonic anhydrase III is found in high concentration in muscle. It
shows relatively poor hydratase and esterase activities compared to the
red cell isozymes CA I and CA II, but is similar in subunit structure
(monomer) and molecular size (28,000). Heath et al. (1985) explored use
of CA III in conjunction with creatine kinase detection of the carrier
state for Duchenne muscular dystrophy. Using a cDNA clone of the CA3
gene in the study of human-rodent hybrids, Edwards et al. (1985, 1986)
mapped the gene to chromosome 8 which carries a cluster of CA genes.
This was the first assignment of the CA3 locus in any species. Wade et
al. (1986) identified a CA3 mRNA transcript from an adult human muscle
cDNA library and presented the complete nucleotide sequence of the cDNA
clone. Using a panel of human-mouse cell hybrids, they localized the CA3
gene to chromosome 8, thus confirming the work of Edwards et al. (1986).
Beechey et al. (1990) mapped the mouse equivalent, Car-3, to chromosome
3 in that species and showed, by analysis of an interspecific backcross,
that Car-3 is 2.4 map units from both Car-1 and Car-2. No recombinants
were found between Car-1 and Car-2 in 100 backcross offspring.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Carter et al. (1979); Lloyd et al. (1987); Lloyd et al. (1986); Lloyd
et al. (1985)
*FIELD* RF
1. Beechey, C.; Tweedie, S.; Spurr, N.; Ball, S.; Peters, J.; Edwards,
Y.: Mapping of mouse carbonic anhydrase-3, Car-3: another locus in
the homologous region of mouse chromosome 3 and human chromosome 8.
Genomics 6: 692-696, 1990.

2. Carter, N.; Jeffery, S.; Shiels, A.; Edwards, Y.; Tipler, T.; Hopkinson,
D. A.: Characterization of human carbonic anhydrase III from skeletal
muscle. Biochem. Genet. 17: 837-854, 1979.

3. Edwards, Y. H.; Lloyd, J.; Parkar, M.; Povey, S.: Human muscle
specific carbonic anhydrase, CA3, is on chromosome 8.  (Abstract) Cytogenet.
Cell Genet. 40: 621 only, 1985.

4. Edwards, Y. H.; Lloyd, J. C.; Parkar, M.; Povey, S.: The gene
for human muscle specific carbonic anhydrase (CAIII) is assigned to
chromosome 8. Ann. Hum. Genet. 50: 41-47, 1986.

5. Heath, R.; Carter, N. D.; Jeffery, S.; Edwards, R. J.; Watts, D.
C.; Watts, R. L.: Evaluation of carrier detection of Duchenne muscular
dystrophy using carbonic anhydrase III and creatine kinase. Am.
J. Med. Genet. 21: 291-296, 1985.

6. Lloyd, J.; Brownson, C.; Tweedie, S.; Charlton, J.; Edwards, Y.
H.: Human muscle carbonic anhydrase: gene structure and DNA methylation
patterns in fetal and adult tissues. Genes Dev. 1: 594-602, 1987.

7. Lloyd, J.; McMillan, S.; Hopkinson, D.; Edwards, Y. H.: Nucleotide
sequence and derived amino acid sequence of a cDNA encoding human
muscle carbonic anhydrase. Gene 41: 233-239, 1986.

8. Lloyd, J. C.; Isenberg, H.; Hopkinson, D. A.; Edwards, Y. H.:
Isolation of a cDNA clone for the human muscle specific carbonic anhydrase,
CA III. Ann. Hum. Genet. 49: 241-251, 1985.

9. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.)  1988.

10. Wade, R.; Gunning, P.; Eddy, R.; Shows, T.; Kedes, L.: Nucleotide
sequence, tissue-specific expression, and chromosome location of human
carbonic anhydrase III: the human CAIII gene is located on the same
chromosome as the closely linked CAI and CAII genes. Proc. Nat.
Acad. Sci. 83: 9571-9575, 1986.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 12/13/1990
carol: 8/24/1990
carol: 6/13/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
114760
*FIELD* TI
*114760 CARBONIC ANHYDRASE IV; CA IV; CA4
*FIELD* TX
CA IV is a glycosylphosphatidylinositol-anchored membrane isozyme
expressed on the luminal surfaces of pulmonary (and certain other)
capillaries and on the luminal surface of proximal renal tubules. CA IV
has ancient evolutionary status among CA isozymes. It is functionally
important in CO2 and bicarbonate transport and has a possible role in
inherited renal abnormalities of bicarbonate transport. Okuyama et al.
(1992) isolated a full-length cDNA for human CA IV that contained a
47-bp 5-prime untranslated region, a 936-bp open reading frame, and a
122-bp 3-prime untranslated region. Okuyama et al. (1993) isolated a
full-length genomic clone. They found that the 9.5-kb gene contains 8
exons and 7 introns. The first exon (exon 1a) encodes the signal
sequence. Exon 7 encodes the C-terminus of the enzyme precursor, the
C-terminus of the mature protein and the 120-bp sequence corresponding
to the 3-prime untranslated region of the cDNA. Patients with renal
abnormalities that selectively disturb bicarbonate transport, such as
those with pure proximal renal tubular acidosis, are candidates for
deficiency of carbonic anhydrase IV.

By the use of PCR on DNA from human/rodent somatic cell hybrids, Okuyama
et al. (1993) assigned the CA4 gene to chromosome 17. They confirmed and
regionalized the assignment to 17q23 by in situ hybridization. A
different gene called CA4 that was earlier assigned to chromosome 16 was
in fact CA7 (114770), which indeed is on 16q.

CA IV was originally purified from bovine lung as a 52-kD protein by
Whitney and Briggle (1982). The human enzyme is smaller (35 kD) and
contains no detectable N-linked or O-linked glycosylation (Zhu and Sly,
1990). CA IV is expressed on the apical surfaces of some segments of the
nephron (Brown et al., 1990), the apical plasma membrane of the colon,
and the plasma membrane of specialized capillary beds, including the
cortical capillaries in brain (Ghandour et al., 1992), the
choriocapillaris of the eye (Hageman et al., 1991), the pulmonary
microvasculature (Fleming et al., 1993), and microcapillaries of
skeletal and cardiac muscle (Sender et al., 1994).

Fleming et al. (1995) presented Northern blot data that characterized
the regional distribution of CA IV in rat gastrintestinal tract in
comparison with other CA isozymes known to be expressed in the gut. They
demonstrated that CA IV is an abundant brush border enzyme in the lower
GI tract of both rat and human. They stated that the findings are
consistent with participation of CA IV in the extensive iron and fluid
transport in the distal small and large intestine.

*FIELD* RF
1. Brown, D.; Zhu, X. L.; Sly, W. S.: Localization of membrane-associated
carbonic anhydrase type IV in kidney epithelial cells. Proc. Nat.
Acad. Sci. 87: 7457-7461, 1990.

2. Fleming, R. E.; Crouch, E. C.; Ruzicka, C. A.; Sly, W. S.: Pulmonary
carbonic anhydrase IV: developmental regulation and cell-specific
expression in the capillary endothelium. Am. J. Physiol. 265: L627-L635,
1993.

3. Fleming, R. E.; Parkkila, S.; Parkkila, A.-K.; Rajaniemi, H.; Waheed,
A.; Sly, W. S.: Carbonic anhydrase IV expression in rat and human
gastrointestinal tract regional, cellular, and subcellular localization. J.
Clin. Invest. 96: 2907-2913, 1995.

4. Ghandour, M. S.; Langley, O. K.; Zhu, X. L.; Waheed, A.; Sly, W.
S.: Carbonic anhydrase IV on brain capillary endothelial cells: a
marker associated with the blood-brain barrier. Proc. Nat. Acad.
Sci. 89: 6823-6827, 1992.

5. Hageman, G. S.; Zhu, X. L.; Waheed, A.; Sly, W. S.: Localization
of carbonic anhydrase IV in a specific capillary bed of the human
eye. Proc. Nat. Acad. Sci. 88: 2716-2720, 1991.

6. Okuyama, T.; Batanian, J. R.; Sly, W. S.: Genomic organization
and localization of gene for human carbonic anhydrase IV to chromosome
17q. Genomics 16: 678-684, 1993.

7. Okuyama, T.; Sato, S.; Zhu, X. L.; Waheed, A.; Sly, W. S.: Human
carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression
in COS cell membranes. Proc. Nat. Acad. Sci. 89: 1315-1319, 1992.

8. Sender, S.; Gros, G.; Wahleed, A.; Hageman, G. S.; Sly, W. S.:
Immunohistochemical localization of carbonic anhydrase IV in capillaries
of rat and human skeletal muscle. J. Histochem. Cytochem. 42: 1229-1236,
1994.

9. Whitney, P. L.; Briggle, T. V.: Membrane-associated carbonic anhydrase
purified from bovine lung. J. Biol. Chem. 257: 12056-12059, 1982.

10. Zhu, X. L.; Sly, W. S.: Carbonic anhydrase IV from human lung:
purification, characterization, and comparison with membrane carbonic
anhydrase from human kidney. J. Biol. Chem. 265: 8795-8801, 1990.

*FIELD* CD
Victor A. McKusick: 10/23/1987

*FIELD* ED
mark: 01/27/1996
terry: 1/19/1996
mark: 11/16/1995
carol: 6/18/1993
carol: 4/29/1992
supermim: 3/16/1992
supermim: 3/20/1990
carol: 3/6/1990

*RECORD*
*FIELD* NO
114761
*FIELD* TI
*114761 CARBONIC ANHYDRASE V MITOCHONDRIAL; CA5
CA V
*FIELD* TX
The 7 carbonic anhydrases identified in mammals differ in their
physical, chemical, and enzymatic properties and in their subcellular
localizations (Tashian, 1992). CA I (114800), CA II (259730), CA III
(114750), and CA VII (114700) are cytosolic. CA IV (114760) is anchored
to the extracellular surface of the plasma membranes in certain
differentiated cells, CA V is mitochondrial, and CA VI (114780) is
secreted in saliva. Using a mouse cDNA that presumably encoded a
mitochondrial carbonic anhydrase, Nagao et al. (1993) isolated a
full-length cDNA clone encoding human CA V from a human liver cDNA
library. The N-terminal sequence was determined directly on the 30-kD
soluble CA V purified from COS cells transfected with the cDNA. These
sequence data indicated that processing of the precursor polypeptide to
mature human CA V involves removal of a 38-amino acid mitochondrial
leader sequence. Nagao et al. (1993) found that the 267-amino acid
sequence deduced for mature human CA V is 30 to 49% homologous to amino
acid sequences of previously characterized human CAs and 76% homologous
to the amino acid sequence deduced from the mouse cDNA for CA5. PCR
analysis of DNAs from human/rodent somatic cell hybrids localized the
CA5 gene to human chromosome 16, the same chromosome to which CA7 had
previously been mapped.

Nagao et al. (1994) demonstrated that the homologous murine and rat
cDNAs both expressed the CA activity in transfected COS cells. They
identified the N-terminal processing sites that are cleaved to produce
the mature 31- and 30-kD forms found in mouse and rat liver. Heck et al.
(1994) characterized the kinetic properties of the enzyme expressed in
bacteria from murine cDNA.

Nagao et al. (1995) showed that the human CA5 gene contains 7 exons in
approximately 50 kb of genomic DNA. The exon/intron boundaries are at
positions identical to those of the other CA genes. The authors mapped
the gene to 16q24.3 by fluorescence in situ hybridization. They also
noted an unprocessed pseudogene containing exons 3-7 and mapped it to
16p12-p11.2.

Lakkis et al. (1997) demonstrated that the murine homolog maps to mouse
chromosome 8. The symbol used for the mouse gene was Car5.

*FIELD* RF
1. Heck, R. W.; Tanhauser, S. M.; Manda, R.; Tu, C.; Laipis, P. J.;
Silverman, D. N.: Catalytic properties of mouse carbonic anhydrase
V. J. Biol. Chem. 269: 24742-24746, 1994.

2. Lakkis, M. M.; Venta, P. J.; Tashian, R. E.: Localization of the
mitochondrial carbonic anhydrase V gene, Car5, on mouse chromosome
8. Mammalian Genome 8: 225-226, 1997.

3. Nagao, Y.; Batanian, J. R.; Clemente, M. F.; Sly, W. S.: Genomic
organization of the human gene (CA5) and pseudogene for mitochondrial
carbonic anhydrase V and their localization to chromosomes 16q and
16p. Genomics 28: 477-484, 1995.

4. Nagao, Y.; Platero, J. S.; Waheed, A.; Sly, W. S.: Human mitochondrial
carbonic anhydrase: cDNA cloning, expression, subcellular localization,
and mapping to chromosome 16. Proc. Nat. Acad. Sci. 90: 7623-7627,
1993.

5. Nagao, Y.; Srinivasan, M.; Platero, J. S.; Svendrowski, M.; Waheed,
A.; Sly, W. S.: Mitochondrial carbonic anhydrase (isozyme V) in mouse
and rat: cDNA cloning, expression, subcellular localization, processing,
and tissue distribution. Proc. Nat. Acad. Sci. 91: 10330-10334,
1994.

6. Tashian, R. E.: Genetics of the mammalian carbonic anhydrases. Adv.
Genet. 30: 321-356, 1992.

*FIELD* CN
Victor A. McKusick - updated: 04/15/1997
Alan F. Scott - updated: 9/26/1995

*FIELD* CD
Victor A. McKusick: 12/30/1989

*FIELD* ED
jenny: 04/15/1997
terry: 4/10/1997
terry: 4/17/1996
mark: 3/7/1996
mark: 4/10/1995
carol: 9/15/1993
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/7/1990

*RECORD*
*FIELD* NO
114770
*FIELD* TI
*114770 CARBONIC ANHYDRASE VII; CA7; CA VII
*FIELD* TX
Carbonic anhydrases I (114800), II (259730), and III (114750) are
soluble cytoplasmic isozymes; CA IV (114760) is the membrane-bound form,
CA V (114761) is a mitochondrial matrix enzyme, and CA VI (114780) is
the secreted isozyme. A gene coding for a seventh carbonic anhydrase,
possibly another cytoplasmic isozyme, was described by Venta et al.
(1987). Montgomery et al. (1987, 1991) mapped the partially
characterized CA7 isozyme to chromosome 16q21-q23 by analysis of somatic
cell hybrids and by in situ hybridization. The mRNA for CA VII was
detected only in salivary glands. The genetic organization and
evolutionary relationships of the carbonic anhydrase genes were reviewed
by Tashian (1992).

*FIELD* RF
1. Montgomery, J. C.; Shows, T. B.; Venta, P. J.; Tashian, R. E.:
Gene for novel human carbonic anhydrase (CA) isozyme on chromosome
16 is unlinked to the CA1/CA2/CA3 gene cluster.  (Abstract) Am. J.
Hum. Genet. 41: A229 only, 1987.

2. Montgomery, J. C.; Venta, P. J.; Eddy, R. L.; Fukushima, Y.-S.;
Shows, T. B.; Tashian, R. E.: Characterization of the human gene
for a newly discovered carbonic anhydrase, CA VII, and its localization
to chromosome 16. Genomics 11: 835-848, 1991.

3. Tashian, R. E.: Genetics of mammalian carbonic anhydrases. Adv.
Genet. 30: 321-356, 1992.

4. Venta, P. J.; Montgomery, J. C.; Tashian, R. E.: Molecular genetics
of carbonic anhydrase isozymes. Isozymes: Curr. Top. Biol. Med.
Res. 14: 59-72, 1987.

*FIELD* CD
Victor A. McKusick: 10/17/1989

*FIELD* ED
mark: 4/7/1995
supermim: 3/16/1992
carol: 12/5/1991
carol: 3/1/1991
carol: 2/26/1991
carol: 2/25/1991

*RECORD*
*FIELD* NO
114780
*FIELD* TI
*114780 CARBONIC ANHYDRASE VI; CA VI; CA6
CARBONIC ANHYDRASE, SECRETED
*FIELD* TX
Seven isozymes of the enzyme carbonic anhydrase (carbonate dehydratase;
EC 4.2.1.1) have been identified. In humans, the 3 cytoplasmic isozymes,
CA I (114800), CA II (259730), and CA III (114750), are encoded by genes
on chromosome 8. CA VI is a 42-kD secreted isozyme found only in
salivary glands and saliva (Murakami and Sly, 1987). It has diverged
significantly in its structure from the cytoplasmic isozymes which are
closely related to one another. By means of Southern analysis of a
somatic cell hybrid panel and by in situ hybridization, Sutherland et
al. (1989) mapped the CA6 gene to 1p36.33-p36.22. Aldred et al. (1991)
isolated and sequenced cDNA clones coding for CA6. The clones identified
a 1.45-kb mRNA that was present in high levels in parotid submandibular
salivary glands but absent in other tissues such as sublingual gland,
kidney, liver, and prostate. The cDNA encoded a protein of 308 amino
acids that included a 17-amino acid leader sequence typical of secreted
proteins. The mature CA VI protein has 291 amino acids, compared to the
259 or 260 residues of the cytoplasmic isozymes (CA I, CA II, and CA
III); most of the extra amino acids present are in the carboxyl terminal
region. The CA VI protein has 35% sequence identity with human CA II,
while residues involved in the active site of the enzymes have been
conserved. Southern analysis of human DNA indicated that there is only 1
gene coding for CA VI.

*FIELD* RF
1. Aldred, P.; Fu, P.; Barrett, G.; Penschow, J. D.; Wright, R. D.;
Coghlan, J. P.; Fernley, R. T.: Human secreted carbonic anhydrase:
cDNA cloning, nucleotide sequence, and hybridization histochemistry.
Biochemistry 30: 569-575, 1991.

2. Murakami, H.; Sly, W. S.: Purification and characterization of
human salivary carbonic anhydrase. J. Biol. Chem. 262: 1382-1388,
1987.

3. Sutherland, G. R.; Baker, E.; Fernandez, K. E. W.; Callen, D. F.;
Aldred, P.; Coghlan, J. P.; Wright, R. D.; Fernley, R. T.: The gene
for human carbonic anhydrase VI (CA6) is on the tip of the short arm
of chromosome 1. Cytogenet. Cell Genet. 50: 149-150, 1989.

*FIELD* CD
Victor A. McKusick: 10/17/1989

*FIELD* ED
mark: 4/10/1995
supermim: 3/16/1992
carol: 2/25/1991
supermim: 4/13/1990
supermim: 3/20/1990
supermim: 2/2/1990

*RECORD*
*FIELD* NO
114800
*FIELD* TI
*114800 CARBONIC ANHYDRASE I, ERYTHROCYTE, ELECTROPHORETIC VARIANTS OF; CA
I; CA1
CARBONIC ANHYDRASE A
*FIELD* TX
By starch gel electrophoresis, Tashian et al. (1963) detected a
genetically determined variant of erythrocyte carbonic anhydrase.
Erythrocyte carbonic anhydrase has 2 isoenzymes with different amino
acid sequences and specific activities. B and C were the original
designations for these 2 major forms which later were called CA I (or A)
and CA II (or B; 259730), respectively. Tashian (1969) reviewed the
biochemical genetics of the 2 forms of red cell carbonic anhydrase.
These are under the control of separate autosomal loci. The amino acid
change in several CA I mutants was determined by Carter et al. (1972).
Moore et al. (1973) demonstrated the autosomal dominant inheritance of
CA I and CA II variants. CA I and CA II are linked in the rodent genus
Cavia (Carter, 1972), closely linked in an Old World monkey, Macaca
nemestrina (DeSimone et al., 1973), and tightly linked in the mouse
(Eicher et al., 1976). Using a cDNA clone of the CA1 gene in the study
of human-rodent hybrids, Butterworth et al. (1985) and Edwards et al.
(1986) assigned the CA1 gene to chromosome 8, which carries a cluster of
CA genes. By somatic cell genetic techniques and in situ hybridization,
Davis et al. (1986, 1987) mapped the CA1 and CA3 (114750) genes to
8q13-q22. By pulsed field gel electrophoresis, Lowe et al. (1991)
determined that the order of the genes is CA2, CA3, CA1. CA2 and CA3 are
separated by 20 kb and are transcribed in the same direction, away from
CA1. CA1 is separated from CA3 by over 80 kb and is transcribed in the
opposite direction to CA2 and CA3. Lowe et al. (1991) concluded that the
arrangement of the genes is consistent with proposals that the
duplication event that gave rise to CA1 predated the duplication that
gave rise to CA2 and CA3. The order of the 3 genes differs from that
suggested for the mouse based on recombination frequency. Four other CA
genes--CA4 (114760), CA5 (114761), CA6 (114780) and CA7 (114770)--have
been described. Their gene organization and evolutionary relationships
were reviewed by Tashian (1992).

CA II is deficient in the syndrome of osteopetrosis with renal tubular
acidosis (259730). In a family on the Greek island of Icaria, Kendall
and Tashian (1977) found virtually complete absence of erythrocyte
carbonic anhydrase I in 3 persons and reduced levels thought to
represent the heterozygous state in 2 others. No obvious hematologic or
renal consequences were found in any of them. Venta et al. (1987)
reported preliminary observations involving restriction analysis of DNA
from white cells of CA-I-deficient members of this family, which showed
that the deficiency is not caused by a major deletion in at least 1 part
of the gene. Wagner et al. (1991) and Tashian (1992) reported that CA
I-deficient members of this family have a missense mutation in exon 7 of
their CA1 gene (arg246-to-his). Replacement of the highly conserved
arg246 is the probable cause of the CA I deficiency.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
CARBONIC ANHYDRASE I, GUAM
CA-1(GUAM)
CA-1(3N)
CA1, GLY253ARG
Carbonic anhydrase Guam has substitution of arginine for glycine
(Tashian and Carter, 1976). Omoto et al. (1981) established identity of
a CA-1 variant in Philippine Negritos, CA-1(3N), to CA-1(Guam); both
have substitution of arginine for glycine at amino acid 253.

.0002
CARBONIC ANHYDRASE I, ICARIA
CA1, ARG246HIS
In healthy members with almost complete absence of red cell CA I in the
Icaria family reported by Kendall and Tashian (1977), Wagner et al.
(1991) found an arg246-to-his missense mutation in the CA1 gene.

*FIELD* SA
Blake  (1978); Blake and Kirk (1978); Carter  (1972); Goriki et al.
(1979); Hopkinson et al. (1974); Kageoka et al. (1981); Lindskog et
al. (1971); Marriq et al. (1970); Omoto  (1979); Shapira et al. (1974);
Tashian et al. (1971)
*FIELD* RF
1. Blake, N. M.: Genetic variants of carbonic anhydrase in the Asian-Pacific
area. Ann. Hum. Biol. 5: 557-568, 1978.

2. Blake, N. M.; Kirk, R. L.: Widespread distribution of variant
forms of carbonic anhydrase in Australian aboriginals. Med. J. Aust. 1:
183-185, 1978.

3. Butterworth, P.; Barlow, J.; Konialis, C.; Povey, S.; Edwards,
Y. H.: The assignment of human erythrocyte carbonic anhydrase CA1
to chromosome 8.  (Abstract) Cytogenet. Cell Genet. 40: 597 only,
1985.

4. Carter, N. D.: Carbonic anhydrase II polymorphism in Africa. Hum.
Hered. 22: 539-541, 1972.

5. Carter, N. D.: Carbonic anhydrase isozymes in Cavia porcellus,
Cavia aperea and their hybrids. Comp. Biochem. Physiol. B 43: 743-747,
1972.

6. Carter, N. D.; Tashian, R. E.; Huntsman, R. G.; Sacker, L.: Characterization
of two new variants of red cell carbonic anhydrase in the British
population: Ca Ie Portsmouth and Ca Ie Hull. Am. J. Hum. Genet. 24:
330-338, 1972.

7. Davis, M. B.; West, L. F.; Barlow, J. H.; Butterworth, P. H. W.;
Lloyd, J. C.; Edwards, Y. H.: Regional localization of carbonic anhydrase
genes CA1 and CA3 on human chromosome 8. Somat. Cell Molec. Genet. 13:
173-178, 1987.

8. Davis, M. B.; West, L. F.; Butterworth, P.; Edwards, Y. H.: The
assignment of human carbonic anhydrases CA1 and CA3 to chromosome
8q13-22.  (Abstract) 7th Int. Cong. Hum. Genet., Berlin 616 only,
1986.

9. DeSimone, J.; Linde, M.; Tashian, R. E.: Evidence for linkage
of carbonic anhydrase isozyme genes in the pig-tailed macaque, Macaca
nemestrina. Nature N.B. 242: 55-56, 1973.

10. Edwards, Y. H.; Barlow, J. H.; Konialis, C. P.; Povey, S.; Butterworth,
P. H. W.: Assignment of the gene determining human carbonic anhydrase,
CAI, to chromosome 8. Ann. Hum. Genet. 50: 123-129, 1986.

11. Eicher, E. M.; Stern, R. H.; Womack, J. E.; Davisson, M. T.; Roderick,
T. H.; Reynolds, S. C.: Evolution of mammalian carbonic anhydrase
loci by tandem duplication: close linkage of Car-1 and Car-2 to the
centromere region of chromosome 3 of the mouse. Biochem. Genet. 14:
651-660, 1976.

12. Goriki, K.; Tashian, R. E.; Stroup, S. K.; Yu, Y.-S. L.; Henriksson,
D. M.: Chemical characterization of a new Japanese variant of carbonic
anhydrase I, Ca 2 (Nagasaki 1) (76 arg-to-gln). Biochem. Genet. 17:
449-460, 1979.

13. Hopkinson, D. A.; Coppock, J. S.; Muhlemann, M. F.; Edwards, Y.
H.: The detection and differentiation of the products of the human
carbonic anhydrase loci, Ca I and Ca II, using fluorogenic substrates.
Ann. Hum. Genet. 38: 155-162, 1974.

14. Kageoka, T.; Hewett-Emmett, D.; Stroup, S. K.; Yu, Y.-S. L.; Tashian,
R. E.: Amino acid substitution and chemical characterization of a
Japanese variant of carbonic anhydrase I: CA I Hiroshima-1 (86 asp-to-gly).
Biochem. Genet. 19: 535-549, 1981.

15. Kendall, A. G.; Tashian, R. E.: Erythrocyte carbonic anhydrase
I: inherited deficiency in humans. Science 197: 471-472, 1977.

16. Lindskog, S.; Henderson, L. E.; Kannan, K. K.; Liljas, A.; Nyman,
P. O.; Strandberg, B.: Carbonic anhydrase. In: Boyer, P. D.: The
Enzymes.  New York: Academic Press (pub.)  5: 1971. Pp. 587-665.

17. Lowe, N.; Edwards, Y. H.; Edwards, M.; Butterworth, P. H. W.:
Physical mapping of the human carbonic anhydrase gene cluster on chromosome
8. Genomics 10: 882-888, 1991.

18. Marriq, C.; Gulian, J. M.; Laurent, G.: Cleavage by cyanogen
bromide of carbonic anhydrase from human erythrocyte B. Biochim.
Biophys. Acta 221: 662-664, 1970.

19. Moore, M. J.; Deutsch, H. F.; Ellis, F. R.: Human carbonic anhydrase.
IX. Inheritance of variant erythrocyte forms. Am. J. Hum. Genet. 25:
29-35, 1973.

20. Omoto, K.: Carbonic anhydrase-I polymorphism in a Philippine
aboriginal population. Am. J. Hum. Genet. 31: 747-750, 1979.

21. Omoto, K.; Ueda, S.; Goriki, K.; Takahashi, N.; Misawa, S.; Pagaran,
I. G.: Population genetic studies of the Philippine Negritos. III.
Identification of the carbonic anhydrase-1 variant with CA(1) Guam.
Am. J. Hum. Genet. 33: 105-111, 1981.

22. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

23. Shapira, E.; Ben-Yoseph, Y.; Eyal, G.; Russell, A.: Enzymatically
inactive red cell carbonic anhydrase B in a family with renal tubular
acidosis. J. Clin. Invest. 53: 59-63, 1974.

24. Tashian, R. E.: The esterases and carbonic anhydrases of human
erythrocytes. In: Yunis, J. J.: Biochemical Methods in Red Cell Genetics.
New York: Academic Press (pub.)  1969. Pp. 307-336.

25. Tashian, R. E.: Genetics of the mammalian carbonic anhydrases.
Adv. Genet. 30: 321-356, 1992.

26. Tashian, R. E.; Carter, N. D.: Biochemical genetics of carbonic
anhydrase. Adv. Hum. Genet. 7: 1-56, 1976.

27. Tashian, R. E.; Goodman, M.; Headings, V. E.; Desimone, J.; Ward,
R. H.: Genetic variation and evolution in the red cell carbonic anhydrase
isozymes of Macaque monkeys. Biochem. Genet. 5: 183-200, 1971.

28. Tashian, R. E.; Plato, C. C.; Shows, T. B.: Inherited variant
of erythrocyte carbonic anhydrase in Micronesians from Guam and Saipan.
Science 140: 53-54, 1963.

29. Venta, P. J.; Montgomery, J. C.; Tashian, R. E.: Molecular genetics
of carbonic anhydrase isozymes. Isozymes: Curr. Top. Biol. Med.
Res. 14: 59-72, 1987.

30. Wagner, L. E.; Venta, P. J.; Tashian, R. E.: A human carbonic
anhydrase I deficiency appears to be caused by a destabilizing amino
acid substitution (246arg-to-his). Isozyme Bull. 24: 35 only, 1991.

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mark: 5/18/1995
carol: 5/11/1994
mimadm: 4/18/1994
carol: 10/26/1993
carol: 10/21/1993
supermim: 3/20/1992

*RECORD*
*FIELD* NO
114815
*FIELD* TI
*114815 CARBONIC ANHYDRASE VIII; CA8
CARBONIC ANHYDRASE-RELATED POLYPEPTIDE; CARP;;
CARBONIC ANHYDRASE-LIKE SEQUENCE; CALS
*FIELD* TX
Kato (1990) discovered a new member of the carbonic anhydrase gene
family in a mouse brain cDNA library and demonstrated that it is
expressed in the Purkinje cells of the cerebellum. The gene product was
referred to as CA-related protein, or polypeptide (CARP). To determine
whether a similar protein exists in humans, Skaggs et al. (1993) used
PCR to amplify the human CARP gene from several cDNA libraries. They
found a cDNA with a sequence that was 89.3% identical to mouse CARP at
the nucleotide level and 97.9% at the amino acid level. Bergenhem et al.
(1993) found that CARP cosegregated with chromosome 8. CARP was so named
when it was first described in mouse brain cDNA because seemingly the
gene product was without carbonic anhydrase activity (i.e., the
reversible hydration of carbon dioxide). Nonetheless, the gene product
was designated carbonic anhydrase VIII by several workers because it
showed a clear sequence identity to other members of the carbonic
anhydrase gene family from many sources. This apparently acatalytic CA
form may have an important function. Kelly et al. (1994) reported
absence of CA VIII mRNA in the cerebellum of the 'lurcher' mutant mouse
with a neurologic defect. Using human/mouse hybrid mapping and
fluorescence in situ hybridization, Bergenhem et al. (1995) demonstrated
that the CA8 gene is located on human chromosome 8q11-q12 between the
centromere and the CA1/CA2/CA3 cluster at 8q22-q23. Kelly et al. (1994)
mapped the mouse gene (Car8) to chromosome 4 in a region syntenic to
human chromosome 8.

*FIELD* RF
1. Bergenhem, N. C. H.; Eddy, R. L.; Shows, T. B.; Tashian, R. E.
: Assignment of the gene for human carbonic anhydrase-related protein
to chromosome 8.    (Abstract) Human Genome Meeting, Kobe, Japan 15-17
November 1993: 1993.

2. Bergenhem, N. C. H.; Sait, S. S. J.; Eddy, R. L.; Shows, T. B.;
Tashian, R. E.: Assignment of the gene for human carbonic anhydrase
VIII (CA8) to chromosome 8q11-q12. Cytogenet. Cell Genet. 71: 299-300,
1995.

3. Kato, K.: Sequence of a novel carbonic anhydrase-related polypeptide
and its exclusive presence in Purkinje cells. FEBS Lett. 271: 137-140,
1990.

4. Kelly, C.; Nogradi, A.; Walker, R.; Caddy, K.; Peters, J.; Carter,
N.: Lurching, reeling, waddling and staggering in mice: is carbonic
anhydrase (CA) VIII a candidate gene? Biochem. Soc. Trans. 22: 359S,
1994.

5. Skaggs, L. A.; Bergenhem, N. C. H.; Venta, P. J.; Tashian, R. E.
: The deduced amino acid sequence of human carbonic anhydrase-related
protein (CARP) is 98% identical to the mouse homologue. Gene 126:
291-292, 1993.

*FIELD* CD
Victor A. McKusick: 6/29/1993

*FIELD* ED
mark: 01/28/1996
terry: 1/23/1996
mark: 5/10/1995
carol: 12/16/1993
carol: 6/29/1993

*RECORD*
*FIELD* NO
114830
*FIELD* TI
*114830 CARBONYL REDUCTASE; CBR
*FIELD* TX
Carbonyl reductase (EC 1.1.1.184) is 1 of several monomeric,
NADPH-dependent oxidoreductases having wide specificity for carbonyl
compounds that are generally referred to as aldoketoreductases. Others
include aldehyde reductase (EC 1.1.1.2; 103830) and aldose reductase (EC
1.1.1.21; 103880). Wermuth et al. (1988) isolated and characterized a
cDNA complementary to carbonyl reductase mRNA from a human placenta cDNA
library. The cDNA contained an open reading frame encoding a protein
comprised of 277 amino acids with a molecular weight of 30,375.
Comparison of the predicted protein sequence with the primary structures
of other aldoketoreductases showed no significant homologies. A possible
homology, on the other hand, was found between carbonyl reductase and
'short' subunit alcohol/polyol dehydrogenases. Carbonyl reductase
catalyzes the reduction of a great variety of carbonyl compounds, e.g.,
quinones derived from polycyclic aromatic hydrocarbons,
9-ketoprostaglandins, and the antitumor anthracycline antibiotics
daunorubicin and doxorubicin. The enzyme is widely distributed in human
tissues and also occurs in other mammalian and nonmammalian species.

In a carbonyl reductase cDNA cloned from a breast cancer cell line,
Forrest et al. (1990) demonstrated 1,219 basepairs. Southern analysis of
genomic DNA digested with several restriction enzymes and analyzed by
hybridization with a labeled cDNA probe indicated that carbonyl
reductase is probably coded by a single gene and does not belong to a
family of structurally similar enzymes. Southern analysis of 17
mouse/human somatic cell hybrids showed that carbonyl reductase is
located on chromosome 21. Carbonyl reductase mRNA was induced 3- or
4-fold in 24 hours with BHA, beta-naphthoflavone, or Sudan 1.
Avramopoulos et al. (1992) confirmed assignment to chromosome 21 by
genetic linkage mapping using a DNA polymorphism from the 3-prime
untranslated region of the CBR gene. They demonstrated, furthermore,
that the gene lies between that for interferon-alpha receptor (107450)
and D21S55, being about 3.4 and 7.2 cM, respectively, from the 2
flanking loci. The findings placed CBR in the telomeric band 21q22.3. By
high-resolution fluorescence in situ hybridization, Lemieux et al.
(1993) mapped the CBR gene to 21q22.12, very close to the SOD1 locus at
position 21q22.11. CBR displayed gene dosage effects in trisomy 21 human
lymphoblasts at both the DNA and the mRNA levels. With increasing
chromosome 21 ploidy, lymphoblasts also showed increased aldo-keto
reductase activity and increased quinone reductase activity. Both of
these activities have been shown to be associated with carbonyl
reductase. The location of CBR near SOD1 and the increased enzyme
activity and potential for free radical modulation in trisomy 21 cells
implicate CBR as a candidate for contributing to the pathology of Down
syndrome.

Wei et al. (1996) mapped the mouse Cbr1 gene to distal mouse chromosome
16, as had others. They identified a second carbonyl reductase gene,
Cbr2, and found that it mapped to distal mouse chromosome 11.

*FIELD* RF
1. Avramopoulos, D.; Cox, T.; Forrest, G. L.; Chakravarti, A.; Antonarakis,
S. E.: Linkage mapping of the carbonyl reductase (CBR) gene on human
chromosome 21 using a DNA polymorphism in the 3-prime untranslated
region. Genomics 13: 447-448, 1992.

2. Forrest, G. L.; Akman, S.; Krutzik, S.; Paxton, R. J.; Sparkes,
R. S.; Doroshow, J.; Felsted, R. L.; Glover, C. J.; Mohandas, T.;
Bachur, N. R.: Induction of a human carbonyl reductase gene located
on chromosome 21. Biochim. Biophys. Acta 1048: 149-155, 1990.

3. Lemieux, N.; Malfoy, B.; Forrest, G. L.: Human carbonyl reductase
(CBR) localized to band 21q22.1 by high-resolution fluorescence in
situ hybridization displays gene dosage effects in trisomy 21 cells.
Genomics 15: 169-172, 1993.

4. Wei, J.; Dlouhy, S. R.; Hara, A.; Ghetti, B.; Hodes, M. E.: Cloning
a cDNA for carbonyl reductase (Cbr) from mouse cerebellum: murine
genes that express Cbr map to chromosomes 16 and 11. Genomics 34:
147-148, 1996.

5. Wermuth, B.; Bohren, K. M.; Heinemann, G.; von Wartburg, J.-P.;
Gabbay, K. H.: Human carbonyl reductase: nucleotide sequence analysis
of a cDNA and amino acid sequence of the encoded protein. J. Biol.
Chem. 263: 16185-16188, 1988.

*FIELD* CD
Victor A. McKusick: 12/20/1988

*FIELD* ED
terry: 06/05/1996
terry: 6/3/1996
carol: 2/11/1993
carol: 6/26/1992
carol: 6/24/1992
supermim: 3/16/1992
carol: 2/20/1991
carol: 10/10/1990

*RECORD*
*FIELD* NO
114835
*FIELD* TI
*114835 CARBOXYLESTERASE 1; CES1
SERINE ESTERASE-1; SES1
MONOCYTE ESTERASE DEFICIENCY, INCLUDED;;
MONOCYTE CARBOXYLESTERASE DEFICIENCY, INCLUDED
*FIELD* TX
Monocyte/macrophage serine esterase (EC 3.1.1.1), commonly known as
alpha-naphthylacetate esterase, comprises a group of 5 enzyme variants
distinguished by their isoelectric points from esterase variants of the
other blood cell populations. Becker-Follmann et al. (1991) cloned one
of the monocyte serine esterase variants, which they designated SES1 but
which was later designated CES1 by HGM11. The deduced amino acid
sequence of 503 residues showed up to 78% identity with other serine
esterases of different species. By Southern blot analysis of DNA from
mouse/human somatic cell hybrids representing various breakpoints on
human chromosome 16, Becker-Follmann et al. (1991) assigned the CES1
gene to 16q13-q22.1. Leukocyte esterase B3 (ESB3; 133290) had previously
been mapped to chromosome 16. Both CES1 and ESB3 accept
alpha-naphthylbutyrate or acetate as substrates; however, it was not
clear whether these were identical esterases. The homologous gene was
mapped to mouse chromosome 8.

In 3 generations of a family, Markey et al. (1986) found a cytochemical
staining abnormality of monocytes. Alpha-naphthylacetate and
alpha-naphthylbutyrate esterase staining reactions were consistently
negative in 95% of the monocytes of the proposita and her son and in 60
to 70% of the monocytes in 2 of 4 grandchildren. A daughter who had an
equivocal test had 2 affected children, a son and a daughter. The
affected son had a daughter with an equivocal test and a son who was
normal. Thus, X-linked dominant inheritance is possible. The family
reported by Markey et al. (1986) was ascertained through a patient (the
grandmother) with non-Hodgkin lymphoma. Markey et al. (1987) studied
monocyte esterase activity in 1,000 doctor-attending patients with
normal hematologic indices and in 56 patients with non-Hodgkin lymphoma
(NHL) or B-cell chronic lymphocytic leukemia (CLL). The incidence of
esterase deficiency was significantly greater in the NHL-CLL patients
(7.1%) than in the population group (1.7%). Study of the families in the
NHL-CLL group showed that the esterase deficiency was a familial
characteristic. There were 2 instances of apparent male-to-male
transmission: a man with NHL and the deficiency had a sister and brother
with the deficiency and their father also had the deficiency. Bell et
al. (1992) described familial monocyte esterase deficiency in 4 patients
with rheumatoid arthritis.

*FIELD* RF
1. Becker-Follmann, J.; Zschunke, F.; Parwaresch, M. R.; Radzun, H.
J.; Scherer, G.: Assignment of human monocyte/macrophage serine esterase
1 (HMSE1) to human chromosome 16q13-q22.1 and of its homologue to
the proximal esterase cluster on mouse chromosome 8.  (Abstract) Cytogenet.
Cell Genet. 58: 1997 only, 1991.

2. Bell, A. L.; Markey, G. M.; McCaigue, M. D.; Middleton, D.; McCormick,
J. A.; Wilson, A. G.; Morris, T. C. M.: Heredofamilial deficiency
of monocyte esterase in patients with rheumatoid arthritis. Ann.
Rheum. Dis. 51: 668-670, 1992.

3. Markey, G. M.; Alexander, H. D.; McConnell, R.; Kyle, A.; Morris,
T. C. M.; Robertson, J. H.: Hereditary monocyte esterase deficiency.
Brit. J. Haemat. 63: 359-362, 1986.

4. Markey, G. M.; Morris, T. C. M.; Alexander, H. D.; Kyle, A.; Middleton,
D.; Turner, A.; Burnside, P.; Drexler, H. G.; Gaedicke, G.; Hartmen,
W.; Robertson, J. H.: Monocyte esterase? A factor involved in the
pathogenesis of lymphoproliferative neoplasia. Leukemia 1: 236-239,
1987.

*FIELD* CD
Victor A. McKusick: 10/11/1991

*FIELD* ED
carol: 5/11/1994
carol: 2/19/1993
supermim: 3/16/1992
carol: 2/21/1992
carol: 2/13/1992
carol: 10/11/1991

*RECORD*
*FIELD* NO
114836
*FIELD* TI
*114836 CARBOXYLESTERASE, LIVER
*FIELD* TX
The carboxylesterases (CE; EC 3.1.1.1) are a group of serine-dependent
esterases that are found in a wide range of tissues and organisms.
Whereas the biological role of some of these enzymes, e.g.,
acetylcholinesterase (100740), is clearly known, the function of the
remaining enzymes is not so evident. Hepatic microsomal carboxylesterase
appears to be involved in the detoxification of foreign compounds.
Ketterman et al. (1989) presented evidence for 2 CEs from human liver by
kinetic analysis of purified enzyme. Riddles et al. (1991) cloned a
human liver carboxylesterase-encoding cDNA using synthetic
oligodeoxyribonucleotides based on the known amino acid sequences of
rabbit and rat liver CEs. Shibata et al. (1993) isolated a cDNA encoding
a human liver carboxylesterase and its corresponding gene. The
organization of the gene supported the conclusion that the multiple
carboxylesterases evolved from a common ancestral gene.

*FIELD* RF
1. Ketterman, A. J.; Bowles, M. R.; Pond, S. M.: Purification and
characterization of two human liver carboxylesterases. Int. J. Biochem. 21:
1303-1312, 1989.

2. Riddles, P. W.; Richards, L. J.; Bowles, M. R.; Pond, S. M.: Cloning
and analysis of a cDNA encoding a human liver carboxylesterase. Gene 108:
289-292, 1991.

3. Shibata, F.; Takagi, Y.; Kitajima, M.; Kuroda, T.; Omura, T.:
Molecular cloning and characterization of a human carboxylesterase
gene. Genomics 17: 76-82, 1993.

*FIELD* CD
Victor A. McKusick: 2/13/1992

*FIELD* ED
carol: 7/13/1993
supermim: 3/16/1992
carol: 2/13/1992

*RECORD*
*FIELD* NO
114840
*FIELD* TI
*114840 CARBOXYL-ESTER LIPASE; CEL
CARBOXYL-ESTER HYDROLASE;;
CHOLESTEROL ESTERASE;;
LYSOPHOSPHOLIPASE;;
BILE-SALT STIMULATED LIPASE; BSSL
*FIELD* TX
Carboxyl-ester lipase is a major component of pancreatic juice and is
responsible for the hydrolysis of cholesterol esters as well as a
variety of other dietary esters. Using Southern analysis of mouse-human
somatic cell hybrids and in situ hybridization, Taylor et al. (1991)
mapped the CEL gene to the most distal part of 9q, namely, 9q34.3. A
chromosome 9 translocation was used to confirm that CEL is distal to a
breakpoint at 9q31-q32. Taylor et al. (1991) found that the CEL locus
has a high degree of polymorphism because of a hypervariable region of
the insertion/deletion type. Lidberg et al. (1992) confirmed the
chromosomal assignment by analysis of somatic cell hybrids. They
demonstrated, furthermore, that the gene spans 9,832 bp and contains 11
exons interrupted by 10 introns. The exons range in size from 88 to 204
bp, except for the last exon, which is 841 bp. They found a major and a
minor transcription initiation site 13 and 7 bp, respectively, upstream
of the initiator methionine. Lidberg et al. (1992) also found a
previously unknown gene with a striking homology to the CEL gene, which
they referred to as CEL-like (CELL). They concluded that CELL most
likely is a pseudogene in light of the absence of a 4.8-kb segment which
includes exons 2-7; the gene was transcribed, however. They found that
the CELL gene also maps to the terminal region of 9q. Kumar et al.
(1992) also presented data on the structure of the human pancreatic
cholesterol esterase gene and the CELL gene. They pointed to the fact
that heterogeneity in intestinal absorption of cholesterol has been
described and may be under polygenic control (Kesaniemi and Miettinen,
1986; Kesaniemi et al., 1987; Miettinen and Kesaniemi, 1989). Small
structural changes in the catalytic regions of pancreatic cholesterol
esterase, such as the consensus heparin binding site of the charge-relay
system, could produce profound changes in intestinal cholesterol uptake.

*FIELD* SA
Taylor et al. (1991)
*FIELD* RF
1. Kesaniemi, Y. A.; Ehnholm, C.; Miettinen, T. A.: Intestinal cholesterol
absorption efficiency in man is related to apoprotein E phenotype.
J. Clin. Invest. 80: 578-581, 1987.

2. Kesaniemi, Y. A.; Miettinen, T. A.: Cholesterol absorption, serum
sitosterol and cholesterol synthesis in subjects with low vs high
low density lipoprotein levels.  (Abstract) Circulation 74: 158
only, 1986.

3. Kumar, B. V.; Aleman-Gomez, J. A.; Colwell, N.; Lopez-Candales,
A.; Bosner, M. S.; Spilburg, C. A.; Lowe, M.; Lange, L. G.: Structure
of the human pancreatic cholesterol esterase gene. Biochemistry 31:
6077-6081, 1992.

4. Lidberg, U.; Nilsson, J.; Stromberg, K.; Stenman, G.; Sahlin, P.;
Enerback, S.; Bjursell, G.: Genomic organization, sequence analysis,
and chromosomal localization of the human carboxyl ester lipase (CEL)
gene and a CEL-like (CELL) gene. Genomics 13: 630-640, 1992.

5. Miettinen, T. A.; Kesaniemi, Y. A.: Cholesterol absorption: regulation
of cholesterol synthesis and elimination and within-population variations
of serum cholesterol levels. Am. J. Clin. Nutr. 49: 629-635, 1989.

6. Taylor, A. K.; Zambaux, J. L.; Klisak, I.; Mohandas, T.; Sparkes,
R. S.; Schotz, M. C.; Lusis, A. J.: Carboxyl-ester lipase: a highly
polymorphic locus on human chromosome 9qter. Genomics 10: 425-431,
1991.

7. Taylor, A. K.; Zambaux, J. L.; Klisak, I.; Mohandas, T.; Sparkes,
R. S.; Schotz, M. C.; Lusis, A. J.: Carboxyl ester lipase: a highly
polymorphic locus on human chromosome 9q34.3.  (Abstract) Cytogenet.
Cell Genet. 58: 1945 only, 1991.

*FIELD* CD
Victor A. McKusick: 2/26/1991

*FIELD* ED
carol: 9/4/1992
carol: 6/29/1992
supermim: 3/16/1992
carol: 2/21/1992
carol: 1/29/1992
carol: 8/8/1991

*RECORD*
*FIELD* NO
114841
*FIELD* TI
*114841 CARBOXYL-ESTER LIPASE-LIKE; CELL
*FIELD* TX
The human lactating mammary gland and pancreas produce a lipolytic
enzyme, carboxyl ester lipase (CEL; 114840), earlier called bile
salt-stimulated lipase. The enzyme exerts its function in duodenal
juice, is activated when mixed with bile salts, and plays an important
role in the digestion of milk fat in newborn infants. Lidberg et al.
(1992) described the genomic organization of the CEL gene and proposed
the presence of a transcribed pseudogene, designated carboxyl ester
lipase-like gene (CELL). The existence of the CELL gene was confirmed by
Kumar et al. (1992). The main difference between CEL and CELL is that
the latter lacks a 4.8-kb fragment, including exons 2-7. Furthermore, in
the coding sequence, several differences are found in exons 10 and 11.
The remaining coding regions are identical in the 2 genes. The intron
sequences of the genes show a 97.5% homology. The CELL gene does not
include exon 5, in which the active serine is located, indicating that
the product of this gene cannot be a lipase. Nilsson et al. (1993) found
that in contrast to the CEL gene, CELL is expressed in low amounts in
all tissues analyzed. They found that the average length of the cDNA for
CELL is 1,214 bases. This sequence includes several termination codons
in all 3 reading frames. The longest open reading frame with the same
start of translation as that of the CEL transcript could encode a
59-amino acid-long peptide, presumably without any function. The CELL
gene may have arisen as a result of gene duplication of the CEL gene
followed by deletions and point mutations. A hypervariable region was
characterized in the last exon of the CELL gene. Nilsson et al. (1993)
suggested that this polymorphism would be useful for linkage analysis.
Taylor et al. (1991) suggested that the CEL gene contains a
hypervariable region, according to results obtained by Southern
blotting. Most processed pseudogenes (Vanin, 1985) are transcriptionally
silent; transcribed pseudogenes are rare because once the coding
information of a particular gene is inactivated by a mutational event,
further mutation of promoter sequences would not be selected against.
Two known pseudogenes that retained their ability to be transcribed are
the high-affinity dopamine receptor pseudogene (Weinshank et al., 1991)
and the murine glyceraldhyde-3-phosphate dehydrogenase pseudogene
(Galland et al., 1990). These genes may have arisen through gene
duplication followed by several mutations. Thus, even though these genes
are expressed, they will not give rise to functional protein. Nilsson et
al. (1993) stated that 'the CEL gene and the CELL gene were mapped to
the same region of chromosome 9,' namely, 9q34.3.

Lidmer et al. (1995) used DNA hybridization to isolate a 2.04-kb cDNA
encoding carboxyl ester lipase from a mouse lactating mammary gland,
lambda-gt10 cDNA library.

*FIELD* RF
1. Galland, F.; Stefanova, M.; Pirisi, V.; Birnbaum, D.: Characterization
of a murine glyceraldehyde-3-phosphate dehydrogenase pseudogene. Biochimie 72:
759-762, 1990.

2. Kumar, B. V.; Aleman-Gomez, J. A.; Colwell, N.; Lopez-Candales,
A.; Bosner, M. S.; Spilburg, C. A.; Lowe, M.; Lange, L. G.: Structure
of the human pancreatic cholesterol esterase gene. Biochemistry 31:
6077-6081, 1992.

3. Lidberg, U.; Nilsson, J.; Stromberg, K.; Stenman, G.; Sahlin, P.;
Enerback, S.; Bjursell, G.: Genomic organization, sequence analysis,
and chromosomal localization of the human carboxyl ester lipase (CEL)
gene and a CEL-like (CELL) gene. Genomics 13: 630-640, 1992.

4. Lidmer, A.-S.; Kannius, M.; Lundberg, L.; Bjursell, G.; Nilsson,
J.: Molecular cloning and characterization of the mouse carboxyl
ester lipase gene and evidence for expression in the lactating mammary
gland. Genomics 29: 115-122, 1995.

5. Nilsson, J.; Hellquist, M.; Bjursell, G.: The human carboxyl ester
lipase-like (CELL) gene is ubiquitously expressed and contains a hypervariable
region. Genomics 17: 416-422, 1993.

6. Taylor, A. K.; Zambaux, J. L.; Klisak, I.; Mohandas, T.; Sparkes,
R. S.; Schotz, M. C.; Lusis, A. J.: Carboxyl-ester lipase: a highly
polymorphic locus on chromosome 9qter. Genomics 10: 425-431, 1991.

7. Vanin, E. F.: Processed pseudogenes: characteristics and evolution.
Annu. Rev. Genet. 19: 253-272, 1985.

8. Weinshank, R. L.; Adham, N.; Macchi, M.; Olsen, M. A.; Branchek,
T. A.; Hartig, P. R.: Molecular cloning and characterization of a
high affinity dopamine receptor (D-1-beta) and its pseudogene. J.
Biol. Chem. 266: 22427-22435, 1991.

*FIELD* CD
Victor A. McKusick: 8/23/1993

*FIELD* ED
mark: 10/2/1995
carol: 5/11/1994
carol: 8/31/1993
carol: 8/30/1993
carol: 8/23/1993

*RECORD*
*FIELD* NO
114850
*FIELD* TI
*114850 CARBOXYPEPTIDASE A1; CPA1
CPA;;
PROCARBOXYPEPTIDASE A1, PANCREATIC
*FIELD* TX
Carboxypeptidase A (EC 3.4.2.1) is a pancreatic exopeptidase. Three
different forms of human pancreatic procarboxypeptidase A have been
isolated. The A1 and A2 (600688) forms are monomeric proteins with
different biochemical properties. Honey et al. (1984, 1986) found that
an 8.6-kb human DNA fragment (detected by means of a rat cDNA probe for
CPA) cosegregated with chromosome 7. The assignment was narrowed by
demonstration of absence of the human DNA fragment in cells with a
deletion of 7q22-qter. By studying mouse-hamster hybrid cells, Honey et
al. (1986) assigned the CPA gene to mouse chromosome 6. Trypsin (276000)
is also on human 7q22-qter and on mouse 6. Stewart et al. (1990)
concluded from multipoint linkage analysis with established chromosome 7
markers that the most likely location of carboxypeptidase is 7q31-qter.
It lies distal to cystic fibrosis at a distance of approximately 12 cM.

Catasus et al. (1992) cloned the A1 form using antibodies to screen an
expression library of human pancreatic cDNA. The cDNA contains a reading
frame encoding 419 amino acids and is very similar to the A1 forms from
rat and bovine pancreatic glands.

See also pancreatic carboxypeptidase B (114852).

Carboxypeptidase A1 is one of the genes whose expression in the pancreas
was demonstrated by Velculescu et al. (1995) with a novel method for
serial analysis of gene expression (SAGE). The method allowed the
quantitative and simultaneous analysis of a large number of transcripts.
To demonstrate the strategy, short diagnostic sequence tags (SSTs) were
isolated from pancreas, concatenated, and cloned. Manual sequencing of
1,000 tags revealed a gene expression pattern characteristic of
pancreas. New pancreatic transcripts corresponding to novel tags were
also identified. SAGE is based on 2 principles: first, that a short
nucleotide sequence tag (9 to 10 bp) contained sufficient information to
uniquely identify a transcript; and second, that concatenation of SSTs
allows the efficient analysis of transcripts in a serial manner by the
sequencing of multiple tags within a single clone. Using SAGE,
Velculescu et al. (1995) found that procarboxypeptidase A1 was the gene
represented by the tag found most frequently in the pancreatic
transcripts (7.6%). The authors suggested that SAGE should allow a
direct readout of expression in any given cell type or tissue. They
envisioned a major application to be the comparison of gene expression
patterns in various developmental and disease states. Any laboratory
with the capability to perform PCR and manual sequencing could perform
SAGE for this purpose. Adaptation of this technique to an automated
sequencer would allow the analysis of over 1,000 transcripts in a single
3-hour run.

(Velculescu et al. (1997) used SAGE to analyze a set of genes expressed
from the yeast genome (referred to by them as the transcriptome).
Analysis of 60,633 transcripts revealed 4,665 genes, with expression
levels ranging from 0.3 to over 200 transcripts per cell. Of these
genes, 1,981 had known functions, while 2,684 were previously
uncharacterized. The integration of positional information with gene
expression data allowed the generation of chromosomal expression maps
identifying physical regions of transcriptional activity and identified
genes that had not been predicted by sequence information alone. The
studies of Velculescu et al. (1997) provided insight into global
patterns of gene expression in yeast and demonstrated the feasibility of
genome-wide expression studies in eukaryotes.)

*FIELD* RF
1. Catasus, L.; Villegas, V.; Pascual, R.; Aviles, F. X.; Wicker-Planquart,
C.; Puigserver, A.: cDNA cloning and sequence analysis of human pancreatic
procarboxypeptidase A1. Biochem. J. 287: 299-303, 1992.

2. Honey, N. K.; Sakaguchi, A. Y.; Lalley, P. A.; Quinto, C.; Rutter,
W. J.; Naylor, S. L.: Assignment of the gene for carboxypeptidase
A to human chromosome 7q22-qter and to mouse chromosome 6. Hum. Genet. 72:
27-31, 1986.

3. Honey, N. K.; Sakaguchi, A. Y.; Quinto, C.; MacDonald, R. J.; Rutter,
W. J.; Naylor, S. L.: Assignment of the human genes for elastase
to chromosome 12, and for trypsin and carboxypeptidase A to chromosome
7 (Abstract) Cytogenet. Cell Genet. 37: 492, 1984.

4. Stewart, E. A.; Craik, C. S.; Hake, L.; Bowcock, A. M.: Human
carboxypeptidase A identifies a BglII RFLP and maps to 7q31-qter. Am.
J. Hum. Genet. 46: 795-800, 1990.

5. Velculescu, V. E.; Zhang, L.; Vogelstein, B.; Kinzler, K. W.:
Serial analysis of gene expression. Science 270: 484-487, 1995.

6. Velculescu, V. E.; Zhang, L.; Zhou, W.; Vogelstein, J.; Basrai,
M. A.; Bassett, D. E., Jr.; Hieter, P.; Vogelstein, B.; Kinzler, K.
W.: Characterization of the yeast transcriptome. Cell 88: 1-20,
1997.

*FIELD* CN
Alan F. Scott - updated: 8/7/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/22/1997
terry: 1/22/1997
mark: 9/30/1996
terry: 9/26/1996
terry: 4/17/1996
mark: 3/7/1996
mark: 12/5/1995
terry: 12/5/1995
supermim: 3/16/1992
carol: 7/2/1991
carol: 5/29/1990
supermim: 5/19/1990

*RECORD*
*FIELD* NO
114851
*FIELD* TI
*114851 CARBOXYPEPTIDASE A3, MAST CELL; CPA3
*FIELD* TX
Mast cell carboxypeptidase A is a secretory granule metalloexopeptidase
that has a pH optimum in the neutral to basic range. It resembles
pancreatic carboxypeptidase A (114850) in cleaving COOH-terminal
aromatic and aliphatic amino acid residues. The amino acid sequence
deduced from mRNA has 317 amino acids in the preproenzyme. Reynolds et
al. (1992) isolated the 32-kb human MC-CPA gene (CPA3), which was found
to contain 11 exons. The gene was assigned to chromosome 3 by PCR
analysis of DNAs from 18 human/hamster somatic cell hybrid cell lines.
Reynolds et al. (1992) provided an analysis of the evolutionary tree of
the carboxypeptidase gene family.

(The gene for mast cell carboxypeptidase A is tentatively symbolized
CPA3. CPA2 has been used for a separate carboxypeptidase identified in
the rat (Gardell et al., 1988).)

*FIELD* RF
1. Gardell, S. J.; Craik, C. S.; Clauser, E.; Goldsmith, E. J.; Stewart,
C. B.; Graf, M.; Rutter, W. J.: A novel rat carboxypeptidase, CPA2:
characterization, molecular cloning, and evolutionary implications
on substrate specificity in the carboxypeptidase gene family. J.
Biol. Chem. 263: 17828-17836, 1988.

2. Reynolds, D. S.; Gurley, D. S.; Austen, K. F.: Cloning and characterization
of the novel gene for mast cell carboxypeptidase A. J. Clin. Invest. 89:
273-282, 1992.

*FIELD* CD
Victor A. McKusick: 2/17/1992

*FIELD* ED
mark: 12/29/1996
supermim: 3/16/1992
carol: 2/24/1992
carol: 2/17/1992

*RECORD*
*FIELD* NO
114852
*FIELD* TI
*114852 CARBOXYPEPTIDASE B1, TISSUE; CPB1
CARBOXYPEPTIDASE B, PANCREATIC;;
PROCARBOXYPEPTIDASE B, PANCREATIC; PCPB;;
PANCREAS-SPECIFIC PROTEIN; PASP
*FIELD* TX
Carboxypeptidase B1 is a highly tissue-specific protein and is a useful
serum marker for acute pancreatitis and dysfunction of pancreatic
transplants. It is not elevated in pancreatic carcinoma. The protein,
referred to as pancreas-specific protein (PSAP) by Yamamoto et al.
(1992), has a molecular mass of 44,500 Da and constitutes about 2% of
total pancreatic cytosolic proteins. A computer search of protein
sequence data using the first 25 amino acids from the N-terminal end
suggested that PASP is pancreatic procarboxypeptidase B. Yamamoto et al.
(1992) isolated a cDNA for PASP/PCPB and demonstrated that the deduced
amino acid sequence represented a 416-amino acid preproenzyme with a
15-amino acid signal/leader peptide and a 95-amino acid activation
peptide. RNA blot analyses indicated that the human PCPB mRNA, with
1,400 nucleotides, is transcribed from a single locus in the human
genome in a tissue-specific fashion.

*FIELD* RF
1. Yamamoto, K. K.; Pousette, A.; Chow, P.; Wilson, H.; El Shami,
S.; French, C. K.: Isolation of a cDNA encoding a human serum marker
for acute pancreatitis: identification of pancreas-specific protein
as pancreatic procarboxypeptidase B. J. Biol. Chem. 267: 2575-2581,
1992.

*FIELD* CD
Victor A. McKusick: 9/9/1992

*FIELD* ED
mark: 12/06/1995
carol: 10/27/1992
carol: 9/9/1992

*RECORD*
*FIELD* NO
114855
*FIELD* TI
*114855 CARBOXYPEPTIDASE E; CPE
CARBOXYPEPTIDASE H
*FIELD* TX
Manser et al. (1990) characterized a human and a rat brain cDNA that
encodes carboxypeptidase E (CPE; EC 3.4.17.10). Hall et al. (1993)
assigned the CPE gene to chromosome 4 by Southern analysis of a panel of
somatic cell hybrid DNAs.

Naggert et al. (1995) stated that mice homozygous for the 'fat' mutation
develop obesity and hyperglycemia that can be suppressed by treatment
with exogenous insulin. The 'fat' mutation maps to mouse chromosome 8,
very close to the gene for carboxypeptidase E (Cpe), which encodes an
enzyme (CPE) that processes prohormone intermediates such as proinsulin.
Naggert et al. (1995) demonstrated a defect in proinsulin processing
associated with the virtual absence of CPE activity in extracts of
fat/fat pancreatic islets and pituitaries. A single ser202-to-pro
mutation distinguished the mutant Cpe allele and abolished enzymatic
activity in vitro. Thus, the 'fat' mutation represents the first
demonstration of an obesity-diabetes syndrome elicited by a genetic
defect in a prohormone processing pathway.

Cool et al. (1997) noted that secretory proteins in general are released
from cells via a nonregulated constitutive pathway; however, in
neuroendocrine cells of the nervous and endocrine systems, there is also
a regulated secretory pathway (RSP) from which hormones, neuropeptides,
and the granins are secreted in a calcium-dependent manner. The larger
inactive proforms of these peptide hormones and neuropeptides are
packaged into the granules of the RSP and are processed to active
peptides intragranularly, although early processing steps may occur at
the trans-Golgi network. The specific sorting of RSP proteins away from
those destined for the plasma membrane or other compartments, e.g.,
lysosomes, is an active and selective process requiring a sorting
signal. A proposed mechanism for sorting secretory proteins into
granules for release via the regulated secretory pathway involved
binding the proteins to a sorting receptor at the trans-Golgi network,
followed by binding and granule formation. Cool et al. (1997) identified
such a sorting receptor as membrane-associated CPE in pituitary
Golgi-enriched and secretory granule membranes. CPE specifically bound
regulated secretory pathway proteins, including prohormones, but not
constitutively secreted proteins. Cool et al. (1997) showed that in the
Cpe(fat) mutant mouse lacking CPE, the pituitary prohormone,
proopiomelanocortin (POMC; 176830), was missorted to the constitutive
pathway and secreted in an unregulated manner. Thus, obliteration of
CPE, the sorting receptor, led to multiple endocrine disorders of these
genetically defective mice, including hyperproinsulinemia and
infertility.

*FIELD* RF
1. Cool, D. R.; Normant, E.; Shen, F.; Chen, H.-C.; Pannell, L.; Zhang,
Y.; Loh, Y. P.: Carboxypeptidase E is a regulated secretory pathway
sorting receptor: genetic obliteration leads to endocrine disorders
in Cpe(fat) mice. Cell 88: 73-83, 1997.

2. Hall, C.; Manser, E.; Spurr, N. K.; Lim, L.: Assignment of the
human carboxypeptidase E (CPE) gene to chromosome 4. Genomics 15:
461-463, 1993.

3. Manser, E.; Fernandez, D.; Loo, L.; Goh, P. Y.; Monfries, C.; Hall,
C.; Lim, L.: Human carboxypeptidase E: isolation and characterization
of the cDNA, sequence conservation, expression and processing in vitro. Biochem.
J. 267: 517-525, 1990.

4. Naggert, J. K.; Fricker, L. D.; Varlamov, O.; Nishina, P. M.; Rouille,
Y.; Steiner, D. F.; Carroll, R. J.; Paigen, B. J.; Leiter, E. H.:
Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase
E mutation which reduces enzyme activity. Nature Genet. 10: 135-142,
1995.

*FIELD* CN
Victor A. McKusick - updated: 02/11/1997

*FIELD* CD
Victor A. McKusick: 3/17/1993

*FIELD* ED
terry: 02/11/1997
terry: 2/4/1997
mark: 7/25/1995
carol: 4/7/1993
carol: 3/25/1993
carol: 3/17/1993

*RECORD*
*FIELD* NO
114860
*FIELD* TI
*114860 CARBOXYPEPTIDASE M; CPM
*FIELD* TX
Carboxypeptidases specifically remove COOH-terminal basic amino acids
(arginine or lysine). They have important functions in many biologic
processes, including activation, inactivation, or modulation of peptide
hormone activity and alteration of physical properties of proteins and
enzymes. Carboxypeptidase M is a membrane-bound arginine/lysine
carboxypeptidase found in many tissues and cultured cells. Rehli et al.
(1995) found that its expression associated with monocyte to macrophage
differentiation.

Tan et al. (1989) described the molecular cloning and sequencing of the
cDNA for human carboxypeptidase M from a human placental cDNA library.
The 2-kb cDNA contained an open reading frame of 1,317 base pairs,
encoding a 439-amino acid protein. Sequence analysis revealed
hydrophobic regions at the NH(2) and carboxy termini. There are 6
potential asparagine-linked glycosylation sites. Observed sequence
homologies with other carboxypeptidases were as follows: human plasma
carboxypeptidase N, 41%; bovine carboxypeptidase H, 41%; and bovine
pancreatic carboxypeptidases A and B, 15%. The active site residues of
carboxypeptidases A and B are conserved in carboxypeptidase M.

In constructing a YAC contig from the region of the high-mobility group
protein gene (600698) on chromosome 12, Kas et al. (1995) found an STS
with a stretch of 135 nucleotides that matched perfectly with known cDNA
sequences of the CPM gene, which had not been previously localized. They
initially mapped the CPM gene to 12q31-qter by chromosome assignment
using somatic cell hybrids analysis (CASH). The YAC clone containing the
sequence was also shown to map to 12q15 by fluorescence in situ
hybridization analysis.

*FIELD* RF
1. Kas, K.; Schoenmakers, E. F. P. M.; Van de Ven, W. J. M.: Physical
map location of the human carboxypeptidase M gene (CPM) distal to
D12S375 and proximal to D12S8 at chromosome 12q15. Genomics 30:
403-405, 1995.

2. Rehli, M.; Krause, S. W.; Kreutz, M.; Andreesen, R.: Carboxypeptidase
M is identical to the MAX.1 antigen and its expression is associated
with monocyte to macrophage differentiation. J. Biol. Chem. 270:
15644-15649, 1995.

3. Tan, F.; Chan, S. J.; Steiner, D. F.; Schilling, J. W.; Skidgel,
R. A.: Molecular cloning and sequencing of the cDNA for human membrane-bound
carboxypeptidase M: comparison with carboxypeptidases A, B, H, and
N. J. Biol. Chem. 264: 13165-13170, 1989.

*FIELD* CD
Victor A. McKusick: 10/6/1989

*FIELD* ED
terry: 02/06/1996
mark: 1/14/1996
supermim: 3/16/1992
supermim: 3/20/1990
carol: 3/10/1990
ddp: 10/26/1989
root: 10/6/1989

*RECORD*
*FIELD* NO
114890
*FIELD* TI
*114890 CARCINOEMBRYONIC ANTIGEN; CEA
*FIELD* TX
Carcinoembryonic antigen, first described by Gold and Freedman (1965),
is a complex immunoreactive glycoprotein with a molecular weight of
180,000 comprising 60% carbohydrate. It is found in adenocarcinomas of
endodermally derived digestive system epithelia and in fetal colon. CEA
immunoassay is useful in the diagnosis and serial monitoring of cancer
patients for recurrent disease or response to therapy, particularly in
the case of colonic cancer. Oikawa et al. (1987) cloned cDNAs
corresponding to the mRNA encoding a polypeptide that is immunoreactive
with the antisera specific to CEA. The amino acid sequence deduced from
the nucleotide sequence of the cDNA showed that CEA is synthesized as a
precursor with a signal peptide followed by 668 amino acids of the
putative mature CEA peptide. Zimmermann et al. (1987) isolated and
characterized cDNA clones for human CEA. They found no CEA mRNA in HeLa
cells or in normal human fibroblasts. Thompson et al. (1987) suggested
that the CEA gene family, which includes CEA-related antigens such as
nonspecific crossreacting antigen (NCA) and biliary glycoprotein,
evolved from a common ancestor shared with neural cell adhesion molecule
(116930) and alpha-1-B-glycoprotein (138670) and is perhaps a subfamily
of the immunoglobulin superfamily. A subfamily of about 10 genes appears
to exist (Thompson et al., 1987; Oikawa et al., 1987). Kamarck et al.
(1987) prepared a cDNA for CEA from an adenocarcinoma cell line. They
confirmed its identity by specific hybridization to DNA transfected into
L cells, which then expressed CEA. Hybridization of the cDNA insert to
genomic DNA from colon carcinoma cells showed no rearrangement in the
tumors. By analysis of somatic cell hybrids, the sequence was mapped to
chromosome 19.

By genomic clones used in somatic cell hybrids and by in situ
hybridization, Willcocks et al. (1987, 1989) assigned the CEA locus to
19q13.1-q13.3. Zimmermann et al. (1988) used a DNA fragment from the NCA
gene to localize the gene(s) by in situ hybridization to chromosome 19.
Two specific hybridization sites were found, 1 on the long arm,
19q31-q32, and a minor accumulation on the short arm, 19p13.2-p13.3.
Zimmermann et al. (1988) also used a fragment from the repeat region of
the CEA cDNA clone to map the gene to 19q31-q32 by in situ
hybridization. No accumulation of grains was observed over the short
arm. Nishi et al. (1991) assigned the CEA gene to 19q13.2 by in situ
hybridization. Thompson and Zimmermann (1988) stated that the CEA gene
family, consisting of approximately 10 genes, is localized in 2 clusters
on chromosome 19. By the time of their report, mRNA species for 5 of the
genes had been identified and found to show tissue variability in their
transcriptional activity. Willcocks and Craig (1990) found that the CEA
gene comprises 9 exons encoding amino acids and 1 encoding a 3-prime
untranslated fragment. Thompson et al. (1992) stated that various
methods, including hybridization analysis of large DNA fragments
separated by pulsed field gel electrophoresis, yielded similar results,
indicating that the entire CEA gene family is contained in a region
located at 19q13.1-q13.2 between the CYP2A (123960) and D19S15/D19S8
markers. They found that the CEA subgroup has 9 members, including CEA,
nonspecific crossreacting antigen (NCA; 163980), biliary glycoprotein
(BGP1; 109770), and 6 genes referred to as CEA gene family members:
CGM1, CGM2, CGM6, CGM7, CGM8, and CGM9. From large groups of ordered
cosmid clones, Thompson et al. (1992) confirmed the identity of all
known CEA subgroup genes, either by hybridization using gene-specific
probes or by DNA sequencing. These studies identified a new member of
the CEA subgroup, CGM8, which they concluded probably represents a
pseudogene due to the existence of 2 stop codons, one in the leader exon
and one in the N-terminal domain exon. The gene order and orientation,
which were determined with hybridization with probes from the 5-prime
and 3-prime regions of the genes, were determined to be as follows:
cen/3-prime CGM7/3-prime CGM2/5-prime CEA/5-prime NCA/5-prime
CGM1/3-prime BGP/3-prime CGM9/3-prime CGM6/5-prime CGM8///PSG
cluster/qter. By fluorescence in situ hybridization, Brandriff et al.
(1992) concluded that the gene order is
cen--CGM7--CEA--NCA--CGM1--BGP--CGM9--CGM8--PSG--tel. The order agreed
completely with that obtained by Thompson et al. (1992).

*FIELD* RF
1. Brandriff, B. F.; Gordon, L. A.; Tynan, K. T.; Olsen, A. S.; Mohrenweiser,
H. W.; Fertitta, A.; Carrano, A. V.; Trask, B. J.: Order and genomic
distances among members of the carcinoembryonic antigen (CEA) gene
family determined by fluorescence in situ hybridization. Genomics 12:
773-779, 1992.

2. Gold, P.; Freedman, S. O.: Demonstration of tumor-specific antigens
in human colonic carcinomata by immunological tolerance and absorption
techniques. J. Exp. Med. 121: 439-462, 1965.

3. Kamarck, M. E.; Elting, J. J.; Hart, J. T.; Goebel, S. J.; Rae,
P. M. M.; Nothdurft, M. A.; Nedwin, J. J.; Barnett, T. R.: Carcinoembryonic
antigen family: expression in a mouse L-cell transfectant and characterization
of a partial cDNA in bacteriophage lambda-gt11. Proc. Nat. Acad.
Sci. 84: 5350-5354, 1987.

4. Nishi, M.; Inazawa, J.; Inoue, K.; Nakagawa, H.; Taniwaki, M.;
Misawa, S.; Oikawa, S.; Nakazato, H.; Abe, T.: Regional chromosomal
assignment of carcinoembryonic antigen gene (CEA) to chromosome 19
at band q13.2. Cancer Genet. Cytogenet. 54: 77-81, 1991.

5. Oikawa, S.; Nakazato, H.; Kosaki, G.: Primary structure of human
carcinoembryonic antigen (CEA) deduced from cDNA sequence. Biochem.
Biophys. Res. Commun. 142: 511-528, 1987.

6. Thompson, J.; Zimmermann, W.: The carcinoembryonic antigen gene
family: structure, expression and evolution. Tumor Biol. 9: 63-83,
1988.

7. Thompson, J.; Zimmermann, W.; Osthus-Bugat, P.; Schleussner, C.;
Eades-Perner, A.-M.; Barnert, S.; Von Kleist, S.; Willcocks, T.; Craig,
I.; Tynan, K.; Olsen, A.; Mohrenweiser, H.: Long-range chromosomal
mapping of the carcinoembryonic antigen (CEA) gene family cluster.
Genomics 12: 761-772, 1992.

8. Thompson, J. A.; Pande, H.; Paxton, R. J.; Shively, L.; Padma,
A.; Simmer, R. L.; Todd, C. W.; Riggs, A. D.; Shively, J. E.: Molecular
cloning of a gene belonging to the carcinoembryonic antigen gene family
and discussion of a domain model. Proc. Nat. Acad. Sci. 84: 2965-2969,
1987.

9. Willcocks, T. C.; Craig, I. W.: Characterization of the genomic
organization of human carcinoembryonic antigen (CEA): comparison with
other family members and sequence analysis of 5-prime controlling
region. Genomics 8: 492-500, 1990.

10. Willcocks, T. C.; Craig, S. P.; Coates, D.; Craig, I. W.: Coding
sequences for carcinoembryonic antigen (CEA) assigned to human chromosome
19q13.  (Abstract) Cytogenet. Cell Genet. 46: 716 only, 1987.

11. Willcocks, T. C.; Craig, S. P.; Craig, I. W.: Assignment of the
coding sequence for carcinoembryonic antigen (CEA) and normal cross-reacting
antigen (NCA) to human chromosome 19q13. Ann. Hum. Genet. 53: 141-148,
1989.

12. Zimmermann, W.; Ortlieb, B.; Friedrich, R.; von Kleist, S.: Isolation
and characterization of cDNA clones encoding the human carcinoembryonic
antigen reveal a highly conserved repeating structure. Proc. Nat.
Acad. Sci. 84: 2960-2964, 1987.

13. Zimmermann, W.; Weber, B.; Ortlieb, B.; Rudert, F.; Schempp, W.;
Fiebig, H.-H.; Shively, J. E.; von Kleist, S.; Thompson, J. A.: Chromosomal
localization of the carcinoembryonic antigen gene family and differential
expression in various tumors. Cancer Res. 48: 2550-2554, 1988.

*FIELD* CS

Oncology:
   CEA immunoassay useful in diagnosis and serial monitoring of cancer
   patients for recurrent disease or response to therapy, esp. in colonic
   cancer

Lab:
   Increased carcinoembryonic antigen in adenocarcinomas of endodermally
   derived digestive system epithelia

Inheritance:
   Autosomal dominant (Multigene family in 2 clusters on chromosome 19)

*FIELD* CD
Victor A. McKusick: 4/14/1987

*FIELD* ED
terry: 5/13/1994
mimadm: 4/9/1994
carol: 4/5/1993
carol: 6/9/1992
carol: 6/2/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
114900
*FIELD* TI
114900 CARCINOID, INTESTINAL
*FIELD* TX
Anderson (1966) observed appendiceal carcinoid in father and daughter.
Eschbach and Rinaldo (1962) reported fatal malignant carcinoid of the
ileum in brother and sister. Duodenal carcinoid is described with
multiple endocrine neoplasia (131100, 162300, 171400).

*FIELD* SA
Moertel and Dockerty (1973)
*FIELD* RF
1. Anderson, R. E.: A familial instance of appendiceal carcinoid.
Am. J. Surg. 111: 738-740, 1966.

2. Eschbach, J. W.; Rinaldo, J. A., Jr.: Metastatic carcinoid: a
familial occurrence. Ann. Intern. Med. 57: 647-650, 1962.

3. Moertel, C. G.; Dockerty, M. B.: Familial occurrence of metastasizing
carcinoid tumors. Ann. Intern. Med. 78: 389-390, 1973.

*FIELD* CS

Oncology:
   Intestinal carcinoid;
   Appendiceal carcinoid;
   Malignant carcinoid of ileum

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
115000
*FIELD* TI
115000 CARDIAC ARRHYTHMIA
EXTRASYSTOLES
*FIELD* TX
Kuhn et al. (1964) described 2 sisters with polymorphic and polytopic
ventricular extrasystoles. One had syncopal attacks. A brother died
suddenly at age 10 and the mother at age 40, under circumstances
suggesting the presence of the same disorder.

*FIELD* SA
Berg  (1960); Gault et al. (1972); Sacks et al. (1974); Waynberger
et al. (1974)
*FIELD* RF
1. Berg, K. J.: Multifocal ventricular extrasystoles with Adams-Stokes
syndrome in siblings. Am. Heart J. 60: 965-970, 1960.

2. Gault, J. H.; Cantwell, J.; Lev, M.; Braunwald, E.: Fatal familial
cardiac arrhythmias. Am. J. Cardiol. 29: 548-553, 1972.

3. Kuhn, E.; Wolf, D.; Stieler, M.: Familial polytopic and polymorphic
extrasystoles. Jpn. Heart J. 5: 81-84, 1964.

4. Sacks, H. S.; Matisonn, R.; Kennelly, B. M.: Familial paroxysmal
ventricular tachycardia in two sisters. Am. Heart J. 87: 217-222,
1974.

5. Waynberger, M.; Courtadon, M.; Peltier, J.-M.; Ducloux, G.; Jallut,
H.; Slama, R.: Tachycardies ventriculaires familiales: a propos de
7 observations. Presse Med. 14: 1857-1860, 1974.

*FIELD* CS

Cardiac:
   Arrhythmia;
   Polymorphic and polytopic ventricular extrasystoles

Neuro:
   Syncopal attacks

Misc:
   Sudden death

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
115080
*FIELD* TI
*115080 CARDIAC CONDUCTION DEFECT
FAMILIAL SUDDEN DEATH, INCLUDED
*FIELD* TX
Green et al. (1969) described a family in which sudden death occurred in
at least 10 persons in 3 generations at an average age of 21 years
(range 4-44). No clinical abnormalities were detectable in members of
the family, including one who died suddenly. An abnormality of the
conduction system was postulated but not definitely demonstrated. See
heart block (140400) and bundle branch block (113900, 211550). Gault et
al. (1972) described a 10-year-old girl with 'alternating bidirection
tachycardia.' Autopsy showed fatty and mononuclear cell infiltration in
the atrioventricular conduction system and the main left bundle branch.
A similar arrhythmia was documented in an 18-year-old sister. Autopsy
showed no gross cardiac abnormality but the conduction system was not
studied. A brother, aged 21 years, and the mother, aged 45, also had
ventricular bigeminal rhythm and the maternal grandmother and a maternal
uncle had died suddenly. Cardiac irregularity was known to have been
present in the grandmother. Lynch et al. (1973) described a kindred in
which many persons in several generations had a progressive
atrioventricular conduction defect. Prolonged AV conduction had its
onset usually in the 30s with loss of R waves in the right precordial
leads. Arrhythmia occurred only as a late manifestation. Syncopal
attacks were the main symptom. Progression from first- to third-degree
block was usually slow, but in a few persons a relatively fulminant
course with death in 2 or 3 years was observed. Since the disorder
appears to be limited to the conduction system, prognosis with
artificial pacemaker should be excellent. The authors found several
reports that may concern the same disorder.

Brookfield et al. (1988) described a family rather similar to that of
Green et al. (1969). A 15.5-year-old boy died suddenly after completing
a 100-yard swim. He had had 4 syncopal episodes over a 3-year period,
all occurring after strenuous exercise; extensive studies, including
cardiac catheterization and electrophysiologic studies, revealed no
abnormality. The patient's 12-year-old brother had died suddenly while
swimming about 16 months before the proband's death. A maternal uncle
had died at age 18, and 2 brothers of the maternal grandfather had died
at ages 17 and 15. The great grandmother had died at age 35. All of
these were sudden deaths. The mother and the maternal grandfather,
presumed carriers, were normal by physical examination,
electrocardiogram, and 2D echocardiogram, except for induction of
ventricular ectopic beats and polymorphic nonsustained (325 beats)
ventricular tachycardia with some procedures. The patient had been
placed on 40 mg of nadolol, a beta-adrenergic blocker, 1 year before
death. Also, the patient developed right bundle branch block after
infusion of isoproterenol. Autopsy showed right ventricular septal
hypertrophy with displacement of the conduction bundle. Thus, this
family may fall in the category of asymmetric septal hypertrophy
(192600). Strasberg et al. (1983) described a mother and daughter with
paroxysmal torsade de pointes. Both had structurally normal hearts and a
normal QT interval. Both were successfully treated with propranolol
during their limited follow-up.

Chambers et al. (1995) described familial sudden death syndrome with an
abnormal signal-averaged electrocardiogram (Simson, 1981) as a potential
marker. No structural heart disease or 12-lead electrocardiographic
abnormalities were found in the individuals studied. The proposita was a
50-year-old white woman who developed ventricular fibrillation without a
history of previous medical problems. The heart was unremarkable at
autopsy. The 16-year-old daughter of her brother died suddenly while
swimming and no anatomic cause of death was found. Her paternal
grandmother died suddenly at age 40 while working in her kitchen. Her
53-year-old brother, the father of the 16-year-old niece, had a history
of palpitations and 2 episodes of syncope resulting in injury. Another
of his daughters had 2 cardiac arrests at ages 13 and 19, both while
swimming, and was successfully resuscitated each time. A brother of
these 2 girls and a nephew of the proposita drowned at age 3 years in
what was thought to be an accidental drowning. The 2 surviving family
members with a clinical history of arrhythmic events had abnormal
signal-averaged electrocardiograms and inducible ventricular arrhythmias
during electrophysiologic studies. Chambers et al. (1995) raised the
question of whether an abnormal signal-averaged electrocardiogram may be
a marker for the sudden death trait.

*FIELD* SA
Rosen et al. (1978); Stephan  (1974)
*FIELD* RF
1. Brookfield, L.; Bharati, S.; Denes, P.; Halstead, R. D.; Lev, M.
: Familial sudden death: report of a case and review of the literature.
Chest 94: 989-993, 1988.

2. Chambers, J. W.; Denes, P.; Dahl, W.; Olson, D. A.; Galita, D.;
Osborn, M. J.; Titus, J. L.: Familial sudden death syndrome with
an abnormal signal-averaged electrocardiogram as a potential marker.
Am. Heart J. 130: 318-323, 1995.

3. Gault, J. H.; Cantwell, J.; Lev, M.; Braunwald, E.: Fatal familial
cardiac arrhythmias: histologic observations on the cardiac conduction
system. Am. J. Cardiol. 29: 548-553, 1972.

4. Green, J. R., Jr.; Krovetz, M. J.; Shanklin, D. R.; DeVito, J.
J.; Taylor, W. J.: Sudden unexpected death in three generations.
Arch. Intern. Med. 124: 359-363, 1969.

5. Lynch, H. T.; Mohiuddin, S.; Sketch, M. H.; Krush, A. J.; Carter,
S.; Runco, V.: Hereditary progressive atrioventricular conduction
defect: a new syndrome?. J.A.M.A. 225: 1465-1470, 1973.

6. Rosen, K.; Bharati, S.; Bauernfeind, R.; Scheinman, M.; Cheitlin,
M.; Denes, P.; Wu, D.; Lev, M.: Congenital abnormalities of the conduction
system in two patients with recurrent tachyarrhythmia.  (Abstract) Clin.
Res. 26: 485A only, 1978.

7. Simson, M. B.: Use of signals in the terminal QRS complex to identify
patients with ventricular tachycardia after myocardial infarction.
Circulation 64: 235-242, 1981.

8. Stephan, E.: Familial atrioventricular block.  (Letter) J.A.M.A. 228:
697 only, 1974.

9. Strasberg, B.; Welch, W.; Palileo, E.; Swiryn, S.; Bauernfeind,
R.; Rosen, K. M.: Familial inducible torsade de pointes with normal
QT interval. Europ. Heart J. 4: 383-390, 1983.

*FIELD* CS

Cardiac:
   Progressive atrial conduction defect;
   Arrhythmia

Neuro:
   Syncope

Misc:
   Sudden death

Lab:
   Fatty and mononuclear cell infiltration in the atrioventricular conduction
   system and the main left bundle branch

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/16/1995
mimadm: 6/25/1994
terry: 5/13/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
115150
*FIELD* TI
115150 CARDIOFACIOCUTANEOUS SYNDROME
CFC SYNDROME
*FIELD* TX
Reynolds et al. (1986) described 4 males and 4 females, each from a
different family, with a previously undefined multiple congenital
anomalies/mental retardation syndrome that they designated the
cardiofaciocutaneous syndrome. The manifestations included congenital
heart defects, characteristic facial appearance, ectodermal
abnormalities, and growth failure. The most common cardiac defects were
pulmonic stenosis and atrial septal defect. Typical facial
characteristics were high forehead with bitemporal constriction,
hypoplasia of the supraorbital ridges, antimongoloid slant of palpebral
fissures, depressed bridge of nose, and posteriorly angulated ears with
prominent helices. The hair was usually sparse and friable. Skin changes
varied from patchy hyperkeratosis to a severe generalized
ichthyosis-like condition. There was no history of consanguinity. Neri
et al. (1987) reported 2 cases; again, no parental consanguinity was
observed. Verloes et al. (1988) reported 2 cases and pointed out the
similarity to Noonan syndrome (163950). They also suggested that the
Noonan-like short stature syndrome with sparse hair described by
Baraitser and Patton (1986) is the same disorder. The first of their
patients had the habitus of Noonan syndrome associated with keratosis
plantaris and nystagmus; the second had a somewhat Noonan-like face,
macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy.
Chrzanowska et al. (1989) described an affected girl whose twin brother
died shortly after birth and may have had the same malformation
syndrome. The father and mother, aged 35 and 36 years, respectively,
were healthy and nonconsanguineous. Mucklow (1989) described 1 case, and
Sorge et al. (1989) described 3 cases. In addition to high cranial
vault, bitemporal frontal constriction was noted. Gross-Tsur et al.
(1990) described what they alleged to be the 16th reported case.

Fryer et al. (1991) also emphasized the phenotypic overlap between the
CFC syndrome and the Noonan syndrome. They presented findings in the
patient reported by Navaratnam and Hodgson (1973), published photographs
spanning from infancy to age 21 years, and showed the appearance of the
pectus carinatum/excavatum and the keratotic skin lesions. Matsuda et
al. (1991) described 2 Japanese boys with the CFC syndrome but without
hyperkeratosis of the skin. Neri et al. (1991) concluded that the Noonan
and CFC syndromes are indeed distinct and separate conditions, both
falling within the broad and causally heterogeneous spectrum of the
Noonan/congenital lymphedema phenotype; other members of the cluster
were listed. Bottani et al. (1991) reported a patient and reviewed the
cases, all sporadic, reported to date. In 20 cases for which information
was available, the average age of fathers at the birth of the child was
39 years. This evidence of paternal age effect significantly supports
autosomal dominant inheritance. Corsello and Giuffre (1991) reported 2
unrelated boys with CFC syndrome. The parents were nonconsanguineous but
the fathers were 45 and 50 years old. Turnpenny et al. (1992) described
a 7-year-old girl whose features were thought to satisfy the diagnosis
of CFC syndrome. The ectodermal features consisted of fine and sparse
hair, thin and opalescent nails, finger tip pads, generalized cutaneous
pigmentation, but no hyperkeratosis.

Although CFC syndrome is distinguished from Noonan syndrome by the
presence of abnormal hair and hyperkeratotic lesions and by its usual
sporadic occurrence, Ward et al. (1994) supported the suggestion of
Fryer et al. (1991) that it falls 'within the clinical spectrum of the
Noonan phenotype.' They described mother and daughter who had features
consistent with the CFC syndrome but had other features which have been
reported in the Noonan syndrome but not in the CFC syndrome, namely,
hemorrhagic diathesis and ocular abnormalities. They were described as
having ulerythema ophryogenes (keratosis pilaris affecting the follicles
of the eyebrow hairs, associated with erythema, scarring, and atrophy).
Krajewska-Walasek et al. (1996) reported 2 unrelated children (a boy and
a girl) with CFC syndrome who had 'Noonan-like' face, sparse, thin,
curly hair, and severe mental retardation. The girl also had altered
sensation of the distal part of the limbs, which has been described in
patients with Noonan syndrome but not in patients with CFC syndrome.
Leichtman (1996) described a family suggesting that CFC syndrome is a
variable expression of Noonan syndrome. He reported a 4-year-old girl
with features sufficient to meet the criteria for CFC, including
developmental delay, hypotrichosis, eczematic eruption, and
characteristic facial and cardiac anomalies, whose mother demonstrated
typical manifestations of Noonan syndrome.

Manoukian et al. (1996) reported the case of a 25-year-old woman with
typical features of CFC syndrome but without mental retardation. She had
valvular and infundibular pulmonic stenosis, brittle and woolly hair
with patchy alopecia, scant body hair, dry and hypohydrotic skin, and
characteristic facial traits. At the age of 3 years the patient had
shown fullness of periorbital tissues, ectropion of the lower palpebral
fissures, malar hypoplasia, bulbous nose, hyperplasia of the helix and
earlobes. At the age of 25 she showed downslanting palpebral fissures
with scant eyebrows and absent eyelashes on the nasal side, edematous
eyelids, and ectropion of the lower eyelids, posteriorly angulated ears
with hyperplastic helix and lobes, and webbed neck.

*FIELD* RF
1. Baraitser, M.; Patton, M. A.: A Noonan-like short stature syndrome
with sparse hair. J. Med. Genet. 24: 9-13, 1986.

2. Bottani, A.; Hammerer, I.; Schinzel, A.: The cardio-facio-cutaneous
syndrome: report of a patient and review of the literature. Europ.
J. Pediat. 150: 486-488, 1991.

3. Chrzanowska, K.; Fryns, J. P.; Van den Berghe, H.: Cardio-facio-cutaneous
(CFC) syndrome: report of a new patient. Am. J. Med. Genet. 33:
471-473, 1989.

4. Corsello, G.; Giuffre, L.: Cardiofaciocutaneous syndrome: notes
on clinical variability and natural history. (Letter) Am. J. Med.
Genet. 41: 265-266, 1991.

5. Fryer, A. E.; Holt, P. J.; Hughes, H. E.: The cardio-facio-cutaneous
(CFC) syndrome and Noonan syndrome: are they the same? Am. J. Med.
Genet. 38: 548-551, 1991.

6. Gross-Tsur, V.; Gross-Kieselstein, E.; Amir, N.: Cardio-facio
cutaneous syndrome: neurological manifestations. Clin. Genet. 38:
382-386, 1990.

7. Krajewska-Walasek, M.; Chrzanowska, K.; Jastrzbska, M.: The cardio-facio-cutaneous
(CFC) syndrome: two possible new cases and review of the literature. Clin.
Dysmorph.. 5: 65-72, 1996.

8. Leichtman, L. G.: Are cardio-facio-cutaneous syndrome and Noonan
syndrome distinct? A case of CFC offspring of a mother with Noonan
syndrome. Clin. Dysmorph. 5: 61-64, 1996.

9. Manoukian, S.; Lalatta, F.; Selicorni, A.; Tadini, G.; Cavalli,
R.; Neri, G.: Cardio-facio-cutaneous (CFC) syndrome: report of an
adult without mental retardation. Am. J. Med. Genet. 63: 382-385,
1996.

10. Matsuda, Y.; Murano, I.; Kondoh, O.; Matsuo, K.; Kajii, T.: Cardio-facio-cutaneous
(CFC) syndrome: report of two patients without hyperkeratotic skin
lesions. Am. J. Med. Genet. 39: 144-147, 1991.

11. Mucklow, E. S.: A case of cardio-facio-cutaneous syndrome. Am.
J. Med. Genet. 33: 474-475, 1989.

12. Navaratnam, A. E. D.; Hodgson, G. A.: Ulerythema ophryogenes
with mental retardation. Proc. Roy. Soc. Med. 66: 233-234, 1973.

13. Neri, G.; Sabatino, G.; Bertini, E.; Genuardi, M.: The CFC syndrome--report
of the first two cases outside the United States. Am. J. Med. Genet. 27:
767-771, 1987.

14. Neri, G.; Zollino, M.; Reynolds, J. F.: The Noonan-CFC controversy.
(Editorial) Am. J. Med. Genet. 39: 367-370, 1991.

15. Reynolds, J. F.; Neri, G.; Herrmann, J. P.; Blumberg, B.; Coldwell,
J. G.; Miles, P. V.; Opitz, J. M.: New multiple congenital anomalies/mental
retardation syndrome with cardio-facio-cutaneous involvement--the
CFC syndrome. Am. J. Med. Genet. 25: 413-427, 1986.

16. Sorge, G.; DiForti, F.; Scarano, G.; Ventruto, V.; Zelante, L.;
Dallapiccola, B.: CFC syndrome: report on three additional cases.
Am. J. Med. Genet. 33: 476-478, 1989.

17. Turnpenny, P. D.; Dean, J. C. S.; Auchterlonie, I. A.; Johnston,
A. W.: Cardiofaciocutaneous syndrome with new ectodermal manifestations.
J. Med. Genet. 29: 428-429, 1992.

18. Verloes, A.; Le Merrer, M.; Soyeur, D.; Kaplan, J.; Pangalos,
C.; Rigo, J.; Briard, M.-L.: CFC syndrome: a syndrome distinct from
Noonan syndrome. Ann. Genet. 31: 230-234, 1988.

19. Ward, K. A.; Moss, C.; McKeown, C.: The cardio-facio-cutaneous
syndrome: a manifestation of the Noonan syndrome? Brit. J. Derm. 131:
270-274, 1994.

*FIELD* CS

Neuro:
   Mental retardation

Cardiac:
   Congenital heart defect;
   Pulmonic stenosis;
   Atrial septal defect;
   Hypertrophic cardiomyopathy

Growth:
   Growth failure

Head:
   Macrocephaly;
   High forehead;
   Bitemporal constriction;
   Hypoplastic supraorbital ridges

Eyes:
   Nystagmus;
   Antimongoloid slant of palpebral fissures

Nose:
   Depressed nasal bridge

Ears:
   Posteriorly angulated ears;
   Prominent ear helices

Skin:
   Patchy hyperkeratosis;
   Generalized ichthyosis-like dermatosis;
   Keratosis plantaris;
   Generalized cutaneous pigmentation;
   Keratosis pilaris

Hair:
   Sparse friable hair

Nails:
   Thin opalescent nails

Limbs:
   Finger tip pads

Thorax:
   Pectus carinatum/excavatum

Misc:
   All reported cases sporadic;
   Paternal age effect

Inheritance:
   Autosomal dominant

*FIELD* CN
Iosif W. Lurie - updated: 07/26/1996

*FIELD* CD
Victor A. McKusick: 11/13/1987

*FIELD* ED
carol: 07/26/1996
terry: 7/2/1996
terry: 6/20/1996
carol: 1/30/1995
mimadm: 6/25/1994
terry: 5/13/1994
carol: 10/21/1993
carol: 7/1/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
115195
*FIELD* TI
#115195 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2; CMH2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
type of familial hypertrophic cardiomyopathy linked to 1q is caused by
mutations in the cardiac troponin-T gene (TNNT2; 191045).

By linkage studies in a large family with familial hypertrophic
cardiomyopathy not linked to the beta cardiac myosin heavy chain gene,
Watkins et al. (1993) demonstrated that the disease gene was located on
1q3; the maximum multipoint lod score = 8.47. This locus was designated
CMH2, CMH1 (192600) being the locus on chromosome 14 and CMH3 (115196)
being the locus on chromosome 15. At least one other locus determining
familial hypertrophic myopathy exists because some families are not
linked to markers on any of these 3 chromosomes. Three sarcomeric
contractile proteins--troponin I (191042), tropomyosin (191030), and
actin (102610)--are located in a region on chromosome 1 making them
strong candidate genes.

*FIELD* RF
1. Watkins, H.; MacRae, C.; Thierfelder, L.; Chou, Y.-H.; Frenneaux,
M.; McKenna, W.; Seidman, J. G.; Seidman, C. E.: A disease locus
for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nature
Genet. 3: 333-337, 1993.

*FIELD* CS

Cardiac:
   Hypertrophic cardiomyopathy

Inheritance:
   Autosomal dominant (1q3);
   other forms at loci on chromosomes 11, 14, 15 and at least one other
   locus

*FIELD* CD
Victor A. McKusick: 3/10/1993

*FIELD* ED
pfoster: 11/10/1995
mimadm: 6/25/1994
jason: 6/17/1994
carol: 4/29/1993
carol: 3/10/1993

*RECORD*
*FIELD* NO
115196
*FIELD* TI
#115196 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3; CMH3
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
form of familial hypertrophic cardiomyopathy linked to 15q2 is caused by
mutation in the alpha-tropomyosin gene (TPM1; 191010).

By linkage analysis, Thierfelder et al. (1993) identified a form of
familial hypertrophic cardiomyopathy that maps to 15q2. This was
designated CMH3, CMH1 (192600) being the locus on chromosome 14 and CMH2
(115195) being the locus on chromosome 1. At least one more form of
familial CMH is thought to exist because there are families that do not
show linkage to any of these 3 locations. Although the gene for cardiac
actin (ACTC; 102540) maps to 15q, it was excluded as a candidate gene on
the basis of recombination with the CMH3 clinical phenotype (Thierfelder
et al., 1993).

Schleef et al. (1993) mapped the murine alpha-tropomyosin (TPM1; 191010)
gene to a region that is syntenic to human chromosome 15. Because
alpha-tropomyosin is an important component of muscle thin filaments, it
became a candidate gene for CMH3.

Thierfelder et al. (1994) found that missense mutations (asp175-to-asn;
glu180-to-gly) in the TPM1 gene cause CMH3.

*FIELD* RF
1. Schleef, M.; Werner, K.; Satzger, U.; Kaupmann, K.; Jokusch, H.
: Chromosomal location and genomic cloning of the mouse alpha-tropomyosin
gene Tpm-1. Genomics 17: 519-521, 1993.

2. Thierfelder, L.; MacRae, C.; Watkins, H.; Tomfohrde, J.; Williams,
M.; McKenna, W.; Bohm, K.; Noeske, G.; Schlepper, M.; Bowcock, A.;
Vosberg, H.-P.; Seidman, J. G.; Seidman, C.: A familial hypertrophic
cardiomyopathy locus maps to chromosome 15q2. Proc. Nat. Acad. Sci. 90:
6270-6274, 1993.

3. Thierfelder, L.; Watkins, H.; MacRae, C.; Lamas, R.; McKenna, W.;
Vosberg, H.-P.; Seidman, J. G.; Seidman, C. E.: Alpha-tropomyosin
and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy:
a disease of the sarcomere. Cell 77: 701-712, 1994.

*FIELD* CS

Cardiac:
   Hypertrophic cardiomyopathy

Inheritance:
   Autosomal dominant (15);
   other forms at loci on chromosomes 1, 11, 14, and at least one other
   locus

*FIELD* CD
Victor A. McKusick: 3/10/1993

*FIELD* ED
pfoster: 11/10/1995
mimadm: 9/24/1994
jason: 7/29/1994
carol: 7/9/1993
carol: 5/21/1993
carol: 3/10/1993

*RECORD*
*FIELD* NO
115197
*FIELD* TI
#115197 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4; CMH4
*FIELD* TX
A number sign (#) is used with this entry because of the demonstration
that it is caused by mutations in the gene encoding cardiac myosin
binding protein-C (600958).

Carrier et al. (1993) found evidence of a locus on chromosome 11
responsible for familial hypertrophic cardiomyopathy. In a French
pedigree in which the disease was not linked to the MYH7 gene (160760),
they found linkage to several microsatellite (CA)n repeats located on
chromosome 11. They concluded that the gene could be localized to a
17-cM region in 11p13-q13. Kullmann et al. (1993) reported the case of a
patient with Holt-Oram syndrome (142900) who had atrial septal defect
and developed hypertrophic cardiomyopathy during the first year of life.
A reciprocal translocation was found in this patient between 1p13 and
11q13. The cardiac transcription factor-1 gene (600502) is a possible
candidate gene for this disorder.

Bonne et al. (1995) concluded that the COX8 gene (123870) that encodes
cytochrome c oxidase subunit XIII is probably not the site of the
mutation in CMH4, since in affected members of a family with chromosome
11-linked CMH, no deletions or insertions were found in COX8 cDNA or
mRNA and no abnormality was detected in the COX8 sequence.

Both Watkins et al. (1995) and Bonne et al. (1995) demonstrated
mutations in the MYBPC gene which cause CMH4 (600958.0001, 600958.0002,
600958.0003).

Ko et al. (1996) reported results of linkage analysis in a Chinese
family with apical hypertrophic cardiomyopathy. Apical hypertrophic
cardiomyopathy (Japanese type) appears to be a distinct subtype of
hypertrophic cardiomyopathy. It is characterized by giant negative T
waves on EKG and left ventricular hypertrophy localized to the apex. The
authors reported a maximal lod score of 3.38 at theta = 0.00 between the
disease gene and the microsatellite markers D11S905, D11S987 and D11S913
which have been assigned to 11p13-q13.

*FIELD* RF
1. Bonne, G.; Carrier, L.; Bercovici, J.; Cruaud, C.; Richard, P.;
Hainque, B.; Gautel, M.; Labeit, S.; James, M.; Beckmann, J.; Weissenbach,
J.; Vosberg, H.-P.; Fiszman, M.; Komajda, M.; Schwartz, K.: Cardiac
myosin binding protein-C gene splice acceptor site mutation is associated
with familial hypertrophic cardiomyopathy. Nature Genet. 11: 438-440,
1995.

2. Bonne, G.; Carrier, L.; Schwartz, K.; Komajda, M.: The COX8 gene
is not the disease gene of the CMH4 locus in familial hypertrophic
cardiomyopathy.     (Letter) J. Med. Genet. 32: 670-671, 1995.

3. Carrier, L.; Hengstenberg, C.; Beckmann, J. S.; Guicheney, P.;
Dufour, C.; Bercovici, J.; Dausse, E.; Berebbi-Bertrand, I.; Wisnewsky,
C.; Pulvenis, D.; Fetler, L.; Vignal, A.; Weissenbach, J.; Hillaire,
D.; Feingold, J.; Bouhour, J.-B.; Hagege, A.; Desnos, M.; Isnard,
R.; Dubourg, O.; Komajda, M.; Schwartz, K.: Mapping of a novel gene
for familial hypertrophic cardiomyopathy to chromosome 11. Nature
Genet. 4: 311-313, 1993.

4. Ko, Y.-L.; Chen, J.-J.; Tang, T.-K.; Teng, M.-S.; Lin, S.-Y.; Kuan,
P.; Wu, C.-W.; Lien, W.-P.; Liew, C.-C.: Mapping the locus for familial
hypertrophic cardiomyopathy to chromosome 11 in a family with a case
of apical hypertrophic cardiomyopathy of the Japanese type. Hum.
Genet. 97: 457-461, 1996.

5. Kullmann, F.; Koch, R.; Feichtinger, W.; Giesen, H.; Schmid, M.;
Grimm, T.: Holt-Oram syndrom in kombination mit reziproker translokation,
lungenhypoplasie und kardiomyopathie. Klin. Padiat. 205: 185-189,
1993.

6. Watkins, H.; Conner, D.; Thierfelder, L.; Jarcho, J. A.; MacRae,
C.; McKenna, W. J.; Maron, B. J.; Seidman, J. G.; Seidman, C. E.:
Mutations in the cardiac myosin binding protein-C gene on chromosome
11 cause familial hypertrophic cardiomyopathy. Nature Genet. 11:
434-437, 1995.

*FIELD* CS

Cardiac:
   Hypertrophic cardiomyopathy

Inheritance:
   Autosomal dominant (11p13-q13);
   other forms at loci on chromosomes 1, 14, 15 and at least one other
   locus

*FIELD* CN
Moyra Smith - updated: 3/13/1996

*FIELD* CD
Victor A. McKusick: 5/21/1993

*FIELD* ED
mark: 03/21/1996
mark: 3/13/1996
terry: 3/13/1996
mark: 3/13/1996
mark: 12/13/1995
terry: 12/5/1995
terry: 12/4/1995
mark: 9/22/1995
mimadm: 6/25/1994
carol: 9/23/1993
carol: 5/21/1993

*RECORD*
*FIELD* NO
115198
*FIELD* TI
115198 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 5; CMH5
*FIELD* TX
Hengstenberg et al. (1993) studied a family with familial hypertrophic
cardiomyopathy in which linkage to chromosomes 14q1, 1q3, 11p13-q13, and
15q2 could be excluded. The findings implied the existence of a fifth
locus causing this disorder.

MacRae et al. (1995) described a locus on 7q3 to which familial
hypertrophic cardiomyopathy associated with Wolff-Parkinson-White
syndrome mapped. The location of this form, designated here CMH6
(600858), was excluded as the site of the mutation in 2 additional
families, with typical FHC (without WPW), which did not map to any of
the 4 known FHC loci. Linkage to 7q3 was excluded, as well as linkage to
the other 4 loci.

*FIELD* RF
1. Hengstenberg, C.; Charron, P.; Beckmann, J. S.; Weissenbach, J.;
Isnard, R.; Komajda, M.; Schwartz, K.: Evidence for the existence
of a fifth gene causing familial hypertrophic cardiomyopathy.  (Abstract) Am.
J. Hum. Genet. 53 (suppl.): A1013 only, 1993.

2. MacRae, C. A.; Ghaisas, N.; Kass, S.; Donnelly, S.; Basson, C.
T.; Watkins, H. C.; Anan, R.; Thierfelder, L. H.; McGarry, K.; Rowland,
E.; McKenna, W. J.; Seidman, J. G.; Seidman, C. E.: Familial hypertrophic
cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus
on chromosome 7q3. J. Clin. Invest. 96: 1216-1220, 1995.

*FIELD* CS

Cardiac:
   Hypertrophic cardiomyopathy

Inheritance:
   Autosomal dominant;
   other forms at loci on chromosomes 1, 11, 14, and 15

*FIELD* CD
Victor A. McKusick: 9/28/1993

*FIELD* ED
mark: 10/13/1995
mimadm: 6/25/1994
carol: 9/28/1993

*RECORD*
*FIELD* NO
115200
*FIELD* TI
*115200 CARDIOMYOPATHY, DILATED 1A; CMD1A
CARDIOMYOPATHY, DILATED, WITH CONDUCTION DEFECT-1; CDCD1;;
CARDIOMYOPATHY, FAMILIAL IDIOPATHIC
CARDIOMYOPATHY, CONGESTIVE, INCLUDED
*FIELD* TX
See also CDCD2 (601154), which maps to chromosome 3p25-p22. Whitfield
(1961) described a family in which 10 members were suffering or had died
from cardiomyopathy and 6 others were probably affected. Although both
males and females were affected, transmission seemingly occurred only
through the female. Schrader et al. (1961) described 2 sisters with
familial idiopathic cardiomegaly. Almost certainly the mother, who died
at age 34, and probably 1 brother, who died at age 16, had the same
condition. In the family reported by Battersby and Glenner (1961),
affected persons were limited to 1 sibship and deposits of a
nonmetachromatic, diastase-resistant, PAS-positive polysaccharide were
described in the myocardium. Undoubtedly heterogeneity exists in the
group of cardiomyopathies. Boyd et al. (1965) suggested that there may
be 3 types: (1) form with predominant fibrosis, (2) form with
predominant hypertrophy (see ventricular hypertrophy, hereditary;
192600), and (3) form with deposits described above. See amyloidosis III
(176300.0007) for another familial myocardopathy. Kariv et al. (1966)
observed 6 affected persons in 3 generations. In 2 of these persons,
Adams-Stokes attacks required an artificial pacemaker. The affected
males showed significant increase in the serum levels of multiple
muscle-derived enzymes. Heterogeneity was suggested by the finding of
normal serum enzyme levels in affected members of a second family.
Rywlin et al. (1969) favored the view that obstructive and
nonobstructive forms of familial cardiopathy are different expressions
of a single entity. Classification into 'hypertrophic' and 'congestive'
clinical types by Goodwin (1970) implies the same. Sommer et al. (1972)
took an opposite view, i.e., that there is a separate nonobstructive
familial cardiomyopathy. They described an Amish family with affected
persons in 3 generations. Severity varied widely. The most severely
affected pursued a rapidly fatal course whereas others manifested mainly
conduction defects compatible with long survival. Machida et al. (1971)
described a Japanese family with affected persons in 2 and perhaps 3
generations with male-to-male transmission. Emanuel et al. (1971)
suggested that both dominant and recessive forms may exist. The
possibility of an autosomal recessive form of congestive cardiomyopathy
was raised by Yamaguchi et al. (1977), who found an astoundingly high
rate of parental consanguinity (about 64%) and a segregation ratio of
0.196 consistent with autosomal recessive inheritance.

Fragola et al. (1988) studied 44 first-degree relatives of 12 probands
with idiopathic dilated cardiomyopathy. Affected relatives were
identified in 4 of 12 families. In each case, the affected relatives
were sibs. This may be due to a late age of onset for expression of
genetic factors involved in the etiology of this condition. An asterisk
seems justified with this entry since there appears to be at least one
autosomal dominant form of cardiomyopathy separate from other entries.
We studied a kindred in which bizarre ventricular arrhythmia dominated
the clinical picture in some, congestive cardiomyopathy in others, in 3
generations (P15207). Buchner et al. (1978) reviewed studies of the
hereditary cardiomyopathy, a recessive in the golden hamster, discovered
by Hamburger (1962). The genetic defect is thought to concern
actomyosin. Moller et al. (1979) described an autosomal dominant form of
congestive cardiomyopathy. The earliest sign of the disease was
arrhythmia and/or conduction defects. Symptoms of pump failure had their
onset in adulthood. Three members of the extensively affected kindred
had died suddenly. Septal hypertrophy was found in 2 affected persons.
O'Connell et al. (1984) used endomyocardial biopsy and gallium-67 scans
in patients with dilated cardiomyopathy to demonstrate a subset of
patients with myocardial inflammation. Histologic confirmation was found
at autopsy. A defect in suppressor lymphocyte function was found in 1
patient, who showed improvement with immunosuppressive therapy. In 1
family, 5 persons in 3 generations were affected; in another, a father
and 2 brothers were affected. A puzzling feature of a family with
cardiomyopathy I once saw was striking pericardial effusion (Battersby
and Glenner, 1961). Other early reports (e.g., Evans, 1949) have
commented on inflammatory changes found at necropsy. Pericardial
effusion occurs episodically with the iron-overload cardiomyopathy of
multitransfused thalassemia and occurs also in the cardiomyopathy of
Friedreich ataxia (229300).

Ozick et al. (1984) reported identical twin sisters with congestive
cardiomyopathy and autoimmune thyroid disease. Both had antithyroid
microsomal antibodies and cytolytic antiheart myolemmal antibodies. The
postpartum state may have been a factor in one of the twins; both
cardiomyopathy and autoimmune thyroid disease may become clinically
apparent in the postpartum period. Gardner et al. (1985) evaluated a
kindred in which 12 persons had cardiomegaly with poor ventricular
function and/or dysrhythmia. The disorder was evident by echocardiogram
in a 6-month-old infant. Skeletal muscle biopsies showed subtle
myopathic alterations. The pedigree, spanning 5 generations, was
consistent with autosomal dominant inheritance. Gardner et al. (1987)
described a family in which multiple members in 3 and probably 4
generations had dilated cardiomyopathy with overt clinical onset between
the fourth and seventh decades. Dysrhythmia was frequent. They concluded
that there might be an associated skeletal myopathy manifested by very
mild proximal weakness or detectable only on biopsy. MacLennan et al.
(1987) described 8 affected individuals, 4 of whom were males in 3
generations. Average age at presentation was 39.5 years. Average time to
death from onset of symptoms suggestive of cardiomyopathy in 6 affected
members was 16 months. One member died suddenly after being
asymptomatic. The myocardium showed variation in muscle fiber size and
interstitial fibrosis.

Graber et al. (1986) described a large kindred with an autosomal
dominant form of disease of the cardiac conduction system and of the
myocardium. Stage I occurred in the second and third decades and was
characterized by absence of symptoms, normal heart size, sinus
bradycardia, and premature atrial contractions. Stage II was marked by
first-degree AV block in the third and fourth decades. Stage III
occurred in the fourth and fifth decades and was accompanied by chest
pain, fatigue, lightheadedness, and advanced AV block, followed by the
development of atrial fibrillation or flutter. Stage IV, in the fifth
and sixth decades of life, was characterized by congestive heart failure
and recurrent ventricular arrhythmias. Right ventricular endomyocardial
biopsy specimens showed progressive changes. At autopsy in the proband,
the atrial changes were more severe than the ventricular ones. This
suggested that the disorder discussed in entry 108770 is the same as
this condition. While there was a range in the phenotypic expression of
the inherited gene defect in this kindred, the dilated cardiomyopathy
was less impressive than the dysrhythmia. Arrhythmias were the earliest
manifestation of the disease (in the second to third decade). By linkage
studies, Kass et al. (1994) demonstrated linkage of the disease locus to
polymorphic loci near the centromere of chromosome 1; maximum multipoint
lod score = 13.2 in the interval between D1S305 and D1S176. Based on the
disease phenotype and the map location, Kass et al. (1994) speculated
that the gap junction protein connexin 40 (121013) is a candidate for
the site of mutations that result in conduction system disease and
dilated cardiomyopathy.

Koike et al. (1987) described 2 families with dilated cardiomyopathy. In
1 of these families, the mode of inheritance was autosomal dominant; in
the other, it appeared to be autosomal recessive. In both families, the
pattern of inheritance was consistent with linkage to the HLA locus;
however, because the families were small, the lod scores were low.

Schmidt et al. (1988) studied familial dilated cardiomyopathy in 6
families. The familial nature of the disorder was not readily apparent
in 3 of these families until thorough family investigations were
performed. The authors suggested that the family history should be
reviewed in all patients with dilated cardiomyopathy and that further
investigation of relatives should be performed if there are cases of
unexplained heart disease, sudden unexpected death, or syncopal
episodes. Echocardiography is a convenient noninvasive tool for these
investigations. Early diagnosis is indicated for 2 reasons: treatment of
significant arrhythmias may prevent sudden unexpected death, and genetic
counseling can be provided. In studies of the first-degree relatives of
59 index cases with idiopathic dilated cardiomyopathy, Michels et al.
(1992) found that 18 relatives from 12 families had dilated
cardiomyopathy. Thus, 12 of the 59 index patients (20.3%) had familial
disease. No differences in age, sex, severity of disease, exposure to
selected environmental factors, or electrocardiographic or
echocardiographic features were detected between the index patients with
familial disease and those with nonfamilial disease. A noteworthy
finding was that 22 of 240 healthy relatives (9.2%) with normal ejection
fractions had increased left ventricular diameters during systole or
diastole (or both), as compared with 2 of 112 healthy control subjects
(1.8%) who were studied separately. In a case-control study of
idiopathic dilated cardiomyopathy in Baltimore, a roughly 3-fold
increase in risk was observed among blacks after adjustment for
potential confounding variables (Coughlin et al., 1990). The increased
frequency of dilated cardiomyopathy in black males was the basis in the
past of the designation 'Osler-2 myocarditis'; Osler-2 was the black
male ward at The Johns Hopkins Hospital.

Michels et al. (1993) performed PCR-based assays and Southern blot
analysis of the dystrophin gene (DMD; 310200) in 27 males with
idiopathic dilated cardiomyopathy. Five families had familial disease,
without male-to-male transmission in 4 families. In the fifth family,
there was no evidence of male-to-male transmission when the family was
entered into the study, but on follow-up the index patient's son was
found to have developed the disease. None of the patients had clinical
evidence of skeletal muscle disease or any systemic illness that could
cause heart disease. The mean age of the patients was 50.2 years; the
range of age was 5 to 72 years. No dystrophin gene defects were found.

From linkage studies in 12 families, Olson et al. (1995) excluded
genetic linkage between the disease phenotype and a 21-cM region
spanning the HLA cluster in at least 60% of the families.

Csanady et al. (1995) compared 31 familial and 209 nonfamilial cases of
dilated cardiomyopathy. They concluded that the familial form is more
malignant: it occurs at an earlier age and progresses more rapidly than
the nonfamilial form.

*FIELD* SA
Barry and Hall (1962); Biorck and Orinius (1964); Bishop et al. (1962);
Michels et al. (1989)
*FIELD* RF
1. Barry, M.; Hall, M.: Familial cardiomyopathy. Brit. Heart J. 24:
613-624, 1962.

2. Battersby, E. J.; Glenner, G. G.: Familial cardiomyopathy. Am.
J. Med. 30: 382-391, 1961.

3. Biorck, G.; Orinius, E.: Familial cardiomyopathies. Acta Med.
Scand. 176: 407-424, 1964.

4. Bishop, J. M.; Campbell, M.; Jones, E. W.: Cardiomyopathy in four
members of a family. Brit. Heart J. 24: 715-728, 1962.

5. Boyd, D. L.; Mishkin, M. E.; Feigenbaum, H.; Genovese, P. D.:
Three families with familial cardiomyopathy. Ann. Intern. Med. 63:
386-401, 1965.

6. Buchner, F.; Onishi, S.; Wada, A.: Cardiomyopathy Associated with
Systemic Myopathy: Genetic Defect of Actomyocin Influencing Muscular
Structure and Function.  Baltimore and Munich: Urban and Schwarzenberg
(pub.)  1978.

7. Coughlin, S. S.; Szklo, M.; Baughman, K.; Pearson, T. A.: The
epidemiology of idiopathic dilated cardiomyopathy in a biracial community. Am.
J. Epidemiol. 131: 48-56, 1990.

8. Csanady, M.; Hogye, M.; Kallai, A.; Forster, T.; Szarazajtai, T.
: Familial dilated cardiomyopathy: a worse prognosis compared with
sporadic forms. Brit. Heart J. 74: 171-173, 1995.

9. Emanuel, R.; Withers, R.; O'Brien, K.: Dominant and recessive
modes of inheritance in idiopathic cardiomyopathy. Lancet II: 1065-1067,
1971.

10. Evans, W.: Familial cardiomegaly. Brit. Heart J. 11: 68-82,
1949.

11. Fragola, P. V.; Autore, C.; Picelli, A.; Sommariva, L.; Cannata,
D.; Sangiorgi, M.: Familial idiopathic dilated cardiomyopathy. Am.
Heart J. 115: 912-914, 1988.

12. Gardner, R. J. M.; Ardinger, H. H.; Florentine, M. S.; Hanson,
J. W.; Hart, M. N.; Hinrichs, R. L.; Ionasescu, V. V.; Mahoney, L.
T.; Rose, E. E.; Skorton, D. J.: Dominantly inherited dilated cardiomyopathy
with skeletal myopathy. (Abstract) Am. J. Hum. Genet. 37: A54, 1985.

13. Gardner, R. J. M.; Hanson, J. W.; Ionasescu, V. V.; Ardinger,
H. H.; Skorton, D. J.; Mahoney, L. T.; Hart, M. N.; Rose, E. F.; Smith,
W. L.; Florentine, M. S.; Hinrichs, R. L.: Dominantly inherited dilated
cardiomyopathy. Am. J. Med. Genet. 27: 61-73, 1987.

14. Goodwin, J. F.: Congestive and hypertrophic cardiomyopathies. Lancet I:
731-739, 1970.

15. Graber, H. L.; Unverferth, D. V.; Baker, P. B.; Ryan, J. M.; Baba,
N.; Wooley, C. F.: Evolution of a hereditary cardiac conduction and
muscle disorder: a study involving a family with six generations affected. Circulation 74:
21-35, 1986.

16. Kariv, I.; Szeinberg, A.; Fabian, I.; Sherf, L.; Kreisler, B.;
Zeltzer, M.: A family with cardiomyopathy. Am. J. Med. 40: 140-148,
1966.

17. Kass, S.; MacRae, C.; Graber, H. L.; Sparks, E. A.; McNamara,
D.; Boudoulas, H.; Basson, C. T.; Baker, P. B., III; Cody, R. J.;
Fishman, M. C.; Cox, N.; Kong, A.; Wooley, C. F.; Seidman, J. G.;
Seidman, C. E.: A gene defect that causes conduction system disease
and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nature Genet. 7:
546-551, 1994.

18. Koike, S.; Kawa, S.; Yabu, K.; Endo, R.; Sasaki, Y.; Furuta, S.;
Ota, M.: Familial dilated cardiomyopathy and human leucocyte antigen:
a report of two family cases. Jpn. Heart J. 28: 941-945, 1987.

19. Machida, K.; Iguchi, K.; Yoshimi, S.; Saito, Y.; Sugishita, Y.;
Murayama, M.; Mori, M.; Yamaguchi, H.; Ito, I.; Uede, H.: Familial
cardiomyopathy: immunological studies and review of literatures on
autopsied cases in Japan. Jpn. Heart J. 12: 40-49, 1971.

20. MacLennan, B. A.; Tsoi, E. Y.; Maguire, C.; Adgey, A. A. J.:
Familial idiopathic congestive cardiomyopathy in three generations:
a family study with eight affected members. Quart. J. Med. 63: 335-347,
1987.

21. Michels, V. V.; Moll, P. P.; Miller, F. A.; Tajik, A. J.; Chu,
J. S.; Driscoll, D. J.; Burnett, J. C.; Rodeheffer, R. J.; Chesebro,
J. H.; Tazelaar, H. D.: The frequency of familial dilated cardiomyopathy
in a series of patients with idiopathic dilated cardiomyopathy. New
Eng. J. Med. 326: 77-82, 1992.

22. Michels, V. V.; Moll, P. P.; Miller, F. A.; Tajik, A. J.; Driscoll,
D. J.; Chu, J. S.; Burnett, J. C.; Chesebro, J. H.; Rodeheffer, R.
J.: Frequency of familial dilated cardiomyopathy in an unselected
series of patients with idiopathic dilated cardiomyopathy. (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A55, 1989.

23. Michels, V. V.; Pastores, G. M.; Moll, P. P.; Driscoll, D. J.;
Miller, F. A.; Burnett, J. C.; Rodeheffer, R. J.; Tajik, J. A.; Beggs,
A. H.; Kunkel, L. M.; Thibodeau, S. N.: Dystrophin analysis in idiopathic
dilated cardiomyopathy. J. Med. Genet. 30: 955-957, 1993.

24. Moller, P.; Lunde, P.; Hovig, T.; Nitter-Hauge, S.: Familial
cardiomyopathy: autosomally, dominantly inherited congestive cardiomyopathy
with two cases of septal hypertrophy in one family. Clin. Genet. 16:
233-243, 1979.

25. O'Connell, J. B.; Fowles, R. E.; Robinson, J. A.; Subramanian,
R.; Henkin, R. E.; Gunnar, R. M.: Clinical and pathologic findings
of myocarditis in two families with dilated cardiomyopathy. Am. Heart
J. 107: 127-135, 1984.

26. Olson, T. M.; Thibodeau, S. N.; Lundquist, P. A.; Schaid, D. J.;
Michels, V. V.: Exclusion of a primary defect at the HLA locus in
familial idiopathic dilated cardiomyopathy. J. Med. Genet. 32: 876-880,
1995.

27. Ozick, H.; Hollander, G.; Greengart, A.; Shani, J.; Lichstein,
E.: Dilated cardiomyopathy in identical twins. Chest 86: 878-880,
1984.

28. Rywlin, A. M.; Barold, S. S.; Linhart, J. W.; Kramer, H. C.; Meitus,
M. L.; Samet, P.: Idiopathic familial cardiopathy: a study of two
families. J. Genet. Hum. 17: 453-470, 1969.

29. Schmidt, M. A.; Michels, V. V.; Edwards, W. D.; Miller, F. A.
: Familial dilated cardiomyopathy. Am. J. Med. Genet. 31: 135-143,
1988.

30. Schrader, W. H.; Pankey, G. A.; Davis, R. B.; Theologides, A.
: Familial idiopathic cardiomegaly. Circulation 24: 599-606, 1961.

31. Sommer, A.; Sanz, G.; Craenen, J. M.; Newton, W. A., Jr.: Familial
cardiomyopathy. Birth Defects Orig. Art. Ser. VIII(5): 178-181,
1972.

32. Whitfield, A. G. W.: Familial cardiomyopathy. Quart. J. Med. 30:
119-134, 1961.

33. Yamaguchi, M.; Toshima, H.; Yanase, T.; Ikeda, H.; Koga, Y.; Yoshioka,
H.; Ito, M.; Fujino, T.; Yasuda, H.: A family study of idiopathic
cardiomyopathy. Proc. Jpn. Acad. 53 (ser. B): 209-214, 1977.

*FIELD* CS

Cardiac:
   Congestive cardiomyopathy;
   Conduction defects;
   Atrial fibrillation or flutter;
   Ventricular arrhythmia;
   Congestive heart failure;
   Pericardial effusion

Neuro:
   Normal neurologic examination;
   Adams-Stokes attacks

Lab:
   Myocardial deposits of a nonmetachromatic, diastase-resistant, PAS-positive
   polysaccharide;
   Defect in suppressor lymphocyte function

Inheritance:
   Autosomal dominant;
   ? a recessive form also

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
mark: 01/06/1997
mark: 11/11/1996
mark: 3/22/1996
terry: 3/18/1996
mark: 1/31/1996
terry: 1/30/1996
terry: 1/24/1996
carol: 11/8/1994
davew: 6/27/1994
mimadm: 6/25/1994
terry: 5/13/1994
pfoster: 3/31/1994
carol: 12/20/1993

*RECORD*
*FIELD* NO
115210
*FIELD* TI
*115210 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE
*FIELD* TX
In contrast to the hypertrophic and some congestive forms of
cardiomyopathy, idiopathic restrictive cardiomyopathy has generally not
been recognized as familial. Aroney et al. (1988) described father and
daughter with idiopathic restrictive cardiomyopathy. The hemodynamic
profile was characteristic and there was echocardiographic evidence of
diastolic dysfunction and atrial enlargement without ventricular
dilatation.

Kushwaha et al. (1997) reviewed the evidence for a familial basis of
idiopathic restrictive cardiomyopathy. Fitzpatrick et al. (1990)
reported an Italian family in which autosomal dominant restrictive
cardiomyopathy with atrial ventricular block and skeletal myopathy
occurred in members of 5 generations. Symptoms developed in the third to
fourth decade of life, with the eventual appearance of atrial
ventricular block and skeletal muscle weakness. Katritsis et al. (1991)
and Ishiwata et al. (1993) likewise described familial restrictive
cardiomyopathy associated with distal skeletal myopathy. Feld and Caspi
(1992) described familial cardiomyopathy with variable hypertrophic and
restrictive features. A familial, nonhypertrophic restrictive
cardiomyopathy with autosomal dominant inheritance and variable
penetrance was described by Cooke et al. (1994) in association with
Noonan syndrome (163950).

*FIELD* RF
1. Aroney, C.; Bett, N.; Radford, D.: Familial restrictive cardiomyopathy. Aust.
New Zeal. J. Med. 18: 877-878, 1988.

2. Cooke, R. A.; Chambers, J. B.; Curry, P. V.: Noonan's cardiomyopathy:
a non-hypertrophic variant. Brit. Heart J. 71: 561-565, 1994.

3. Feld, S.; Caspi, A.: Familial cardiomyopathy with variable hypertrophic
and restrictive features and common HLA haplotype. Israel J. Med.
Sci. 28: 277-280, 1992.

4. Fitzpatrick, A. P.; Shapiro, L. M.; Rickards, A. F.; Poole-Wilson,
P. A.: Familial restrictive cardiomyopathy with atrioventricular
block and skeletal myopathy. Brit. Heart J. 63: 114-118, 1990.

5. Ishiwata, S.; Nishiyama, S.; Seki, A.; Kojima, S.: Restrictive
cardiomyopathy with complete atrioventricular block and distal myopathy
with rimmed vacuoles. Jpn. Circ. J. 57: 928-933, 1993.

6. Katritsis, D.; Wilmshurst, P. T.; Wendon, J. A.; Davies, M. J.;
Webb-Peploe, M. M.: Primary restrictive cardiomyopathy: clinical
and pathologic characteristics. J. Am. Coll. Cardiol. 18: 1230-1235,
1991.

7. Kushwaha, S. S.; Fallon, J. T.; Fuster, V.: Restrictive cardiomyopathy. New
Eng. J. Med. 336: 267-276, 1997.

*FIELD* CS

Cardiac:
   Restrictive cardiomyopathy

Lab:
   Diastolic dysfunction and atrial enlargement without ventricular dilatation
   by echocardiography

Inheritance:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 03/04/1997

*FIELD* CD
Victor A. McKusick: 6/8/1989

*FIELD* ED
mark: 03/04/1997
jamie: 3/4/1997
terry: 3/3/1997
mimadm: 6/25/1994
carol: 4/7/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 6/8/1989

*RECORD*
*FIELD* NO
115250
*FIELD* TI
115250 CARDIOMYOPATHY-HYPOGONADISM-COLLAGENOMA SYNDROME
COLLAGENOMA, FAMILIAL CUTANEOUS, INCLUDED;;
CONNECTIVE TISSUE NEVUS, INCLUDED
*FIELD* TX
Sacks et al. (1980) described a 48-year-old man with tricuspid
regurgitation and, at autopsy, a cardiomyopathy involving both
ventricles but with predominant involvement of the right ventricle. He
also had primary testicular failure and a distinctive type of cutaneous
collagenoma. The patient's 2 brothers were found to have similar
collagenomas and testicular failure, as well as signs of a mild to
moderate degree of cardiomyopathy. The father was 68 years old at death.
For several years he had cardiomegaly with atrial fibrillation and
chronic congestive heart failure. From birth he had a posterior
occipital scalp lesion devoid of hair (this also being the description
of the lesion in his 3 sons). Henderson et al. (1968) described 3
brothers with numerous skin nodules on the back. These consisted of
thickened dermis due to increased collagenous tissue. One brother had
idiopathic myocardiopathy, a second had atrophy of the left iris and
severe high frequency sensorineural hearing loss, and the third had
recurrent vasculitis. Thus, the cutaneous abnormality may be merely part
of a systemic disorder. Uitto et al. (1979) reported an American black
family with 7 affected in 3 generations, including 1 instance of
male-to-male transmission. The asymptomatic skin nodules were mainly on
the back and chest. Individual lesions varied from a few millimeters to
several centimeters in size, were indurated, and showed minimal
epidermal changes. Histologically, they were characterized by excessive
accumulations of dense, coarse collagen fibers in the dermis. Onset was
in the teens and the number of lesions increased during pregnancy.
Hormonal influence is suggested.

*FIELD* RF
1. Henderson, R. R.; Wheeler, C. E., Jr.; Abele, D. C.: Familial
cutaneous collagenoma. Arch. Derm. 98: 23-27, 1968.

2. Sacks, H. N.; Crawley, I. S.; Ward, J. A.; Fine, R. M.: Familial
cardiomyopathy, hypogonadism, and collagenoma. Ann. Intern. Med. 93:
813-817, 1980.

3. Uitto, J.; Santa-Cruz, D. J.; Eisen, A. Z.: Familial cutaneous
collagenoma: genetic studies on a family. Brit. J. Derm. 101: 185-195,
1979.

*FIELD* CS

Cardiac:
   Tricuspid regurgitation;
   Cardiomyopathy, esp. right ventricular;
   Atrial fibrillation;
   Chronic congestive heart failure

GU:
   Primary testicular failure

Skin:
   Cutaneous collagenomas;
   Congenital posterior occipital alopecia

Eyes:
   Iris atrophy

Ears:
   Sensorineural hearing loss

Vascular:
   Recurrent vasculitis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/24/1986

*RECORD*
*FIELD* NO
115300
*FIELD* TI
115300 CAROTENEMIA, FAMILIAL
*FIELD* TX
Sharvill (1970) described very high levels of blood carotene in a woman,
her mother, a sib and her son. Low levels of vitamin A were found at
times. A defect in conversion of carotene to vitamin A was considered
one possibility. Frenk (1966) described 3 patients with yellow-colored
keratodermia associated with a lowered level of serum vitamin A and a
raised level of carotenes. Carotenoids are converted into vitamin A by
beta-carotene 15,15-prime-oxygenase, and deficiency of this enzyme is a
possible cause of carotenemia. Attard-Montalto et al. (1992) described
the case of a 5-year-old girl with intermittent orange discoloration of
her palms, soles, and face. There were persistently low levels of both
vitamin A and serum-specific retinol-binding protein (RBP4; 180250).
Attard-Montalto et al. (1992) postulated that the low serum RBP
concentration resulted in slow uptake and release of vitamin A by the
liver. The conversion of carotene to vitamin A was consequently
inhibited, resulting in hypercarotenemia. Vitamin A supplements were
unable to raise the serum vitamin A concentration and did not relieve
the carotenemia.

*FIELD* RF
1. Attard-Montalto, S.; Evans, N.; Sherwood, R. A.: Carotenaemia
with low vitamin A levels and low retinol-binding protein. J. Inherit.
Metab. Dis. 15: 929-930, 1992.

2. Frenk, P. E.: Etat keratodermique avec taux serique abaisse de
la vitamine A et hypercarotinemie. Dermatologica 132: 96-98, 1966.

3. Sharvill, D. E.: Familial hypercarotinaemia and hypovitaminosis
A. Proc. Roy. Soc. Med. 63: 605-606, 1970.

*FIELD* CS

Skin:
   Yellow-colored keratodermia

Lab:
   Very high blood carotene levels;
   Variable low vitamin A levels;
   Deficient conversion of carotene to vitamin A by beta-carotene 15,15-prime-oxygenase

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 2/10/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
115310
*FIELD* TI
115310 CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS
*FIELD* TX
Possibly distinct from familial carotid body tumors (paragangliomata;
168000) is the syndrome of familial carotid body tumors and multiple
extraadrenal pheochromocytomas as reported by Pritchett (1982) and
Jensen et al. (1991). The occurrence of pheochromocytoma and multiple
paragangliomas in neurofibromatosis (162200) was described by DeAngelis
et al. (1987).

*FIELD* RF
1. DeAngelis, L. M.; Kelleher, M. B.; Post, K. D.; Fetell, M. R.:
Multiple paragangliomas in neurofibromatosis: a new neuroendocrine
neoplasia. Neurology 37: 129-133, 1987.

2. Jensen, J. C.; Choyke, P. L.; Rosenfeld, M.; Pass, H. I.; Keiser,
H.; White, B.; Travis, W.; Linehan, W. M.: A report of familial carotid
body tumors and multiple extra-adrenal pheochromocytomas. J. Urol. 145:
1040-1042, 1991.

3. Pritchett, J. W.: Familial concurrence of carotid body tumor and
pheochromocytoma. Cancer 49: 2578-2579, 1982.

*FIELD* CS

Oncology:
   Carotid body tumors;
   Multiple extraadrenal pheochromocytomas

Inheritance:
   Autosomal dominant;
   ? same as Paragangliomata (168000)

*FIELD* CD
Victor A. McKusick: 6/25/1991

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 6/26/1991
carol: 6/25/1991

*RECORD*
*FIELD* NO
115400
*FIELD* TI
115400 CARPAL DISPLACEMENT
CARPAL BOSSING
*FIELD* TX
Ellsworth (1927) found displacement of the carpal bone group on the
radius and ulna. The distal epiphyses of these bones were misshapen.
Five females in 4 generations were affected in a pattern equally
consistent with either autosomal or X-linked inheritance. Carpal bossing
appears to be the same trait as Ellsworth described. A prominence is
produced by a double beak between the third metacarpal and the capitate
bone of the wrist. Photographs and x-rays were presented by Larson et
al. (1958), who estimated that it is present in about 26% of adults but
only 1 of 50 children under 15 years of age. The genetics has not been
worked out. Both genetic and environmental (e.g., occupational) factors
may be involved. Surana (1973) described carpal bossing (which is
probably a better term than carpal displacement) in several members of 3
generations, with male-to-male transmission. Clinically, they showed a
small bony prominence on the third metacarpal-carpal joint.
Roentgenograms of the wrist in marked palmar flexion showed a bony
overgrowth of the dorsal aspect of both the capitate and the third
metacarpal at the joint margin producing a characteristic double beak.
All affected persons were asymptomatic. Surana (1973) stated that this
trait was first described by Fiolle (1931) as 'carpe bossu.'

*FIELD* RF
1. Ellsworth, H. A.: Inheritance of carpal displacement. J. Hered. 18:
133 only, 1927.

2. Larson, R. L.; Lazcano, M. A.; Janes, J. M.: Carpal bossing, a
common clinical entity. Mayo Clin. Proc. 33: 337-343, 1958.

3. Surana, R. B.: Inheritance of carpal bossing.  (Abstract) Am.
J. Hum. Genet. 25: 77A only, 1973.

*FIELD* CS

Limbs:
   Carpal bossing

Radiology:
   Misshapen distal carpal epiphyses

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 6/27/1994
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
115430
*FIELD* TI
*115430 CARPAL TUNNEL SYNDROME; CTS; CTS1
THENAR AMYOTROPHY OF CARPAL ORIGIN
*FIELD* TX
Danta (1975) reported carpal tunnel syndrome (constrictive median
neuropathy) in 4 persons in 3 generations with male-to-male
transmission. Symptoms began in the first decade in father and son, and
in both the median nerve at operation was found to be constricted under
a thickened transverse carpal ligament. Carpal tunnel syndrome has been
described in amyloid neuropathy (see 176300) and in
mucopolysaccharidoses (e.g., 253200) and mucolipidoses (252600). Gray et
al. (1979) described bilateral carpal tunnel syndrome in 19 of 43 living
members of a nonconsanguineous family, with male-to-male transmission.
Sixty-three percent of the affected persons also had symptomatic digital
flexor and tenosynovitis, often polytendinous, and requiring surgery in
4. Age of onset was most often in the 20s but was at age 10 in 1
patient. Vallat and Dunoyer (1979) reported carpal tunnel syndrome in
father and daughter. Kishi et al. (1975) and Kishi and Folkers (1976)
used the level of erythrocyte glutamic oxaloacetic transaminase (EGOT)
as a measure of vitamin B6 deficiency. Ellis et al. (1977) demonstrated
severe deficiency of B6 in CTS. Administration of pyridoxine corrected
the B6 deficiency and alleviated the neurologic disorder (Ellis et al.,
1979). Further documentation of the improvement, which may obviate
surgery, was presented by Ellis et al. (1982). They concluded that,
since K(m) values of EGOT were identical in patients with and without
CTS but with identical specific activities, CTS is a primary deficiency
of B6, not a dependency state. Sparkes et al. (1985) found no linkage
between idiopathic carpal tunnel syndrome and 20 informative markers.
For 8 of these, linkage was excluded by a lod score less than 2.0.
Serratrice et al. (1985) described familial occurrence and onset at an
early age (before 12 years) especially in the right hand (see also
Lettin, 1965). McDonnell et al. (1987) described 5 definite and 3
possible cases of carpal-tunnel syndrome in 3 generations of a family. A
remarkable feature was the development of symptoms as early as age 4
years.

*FIELD* SA
Hess and Baumann (1969); MacArthur et al. (1969); Mochizuki et al.
(1981)
*FIELD* RF
1. Danta, G.: Familial carpal tunnel syndrome with onset in childhood.
J. Neurol. Neurosurg. Psychiat. 38: 350-355, 1975.

2. Ellis, J. M.; Azuma, J.; Watanabe, T.; Folkers, K.; Lowell, J.
R.; Hurst, G. A.; Ahn, C. H.; Shuford, E. H., Jr.; Ulrich, R. F.:
Survey and new data on treatment with pyridoxine of patients having
a clinical syndrome including the carpal tunnel and other defects.
Res. Commun. Chem. Path. Pharm. 17: 165-177, 1977.

3. Ellis, J. M.; Folkers, K.; Levy, M.; Shizukuishi, S.; Lewandowski,
J.; Nishii, S.; Schubert, H. A.; Ulrich, R.: Response of vitamin
B-6 deficiency and the carpal tunnel syndrome to pyridoxine. Proc.
Nat. Acad. Sci. 79: 7494-7498, 1982.

4. Ellis, J. M.; Folkers, K.; Watanabe, T.; Kaji, M.; Saji, S.; Caldwell,
J. W.; Temple, C. A.; Wood, F. S.: Clinical results of a cross-over
treatment with pyridoxine and placebo of the carpal tunnel syndrome.
Am. J. Clin. Nutr. 32: 2040-2046, 1979.

5. Gray, R. G.; Poppo, M. J.; Gottlieb, N. L.: Primary familial bilateral
carpal tunnel syndrome. Ann. Intern. Med. 91: 37-40, 1979.

6. Hess, H.; Baumann, F.: Ueber das familiaere Vorkommen eines Karpaltunnelsyndroms.
Ztschr. Orthop. Grenzgebiete 106: 565-569, 1969.

7. Kishi, H.; Folkers, K.: Improved and effective assays of the glutamic
oxaloacetic transaminase by the coenzyme-apoenzyme system (CAS) principle.
J. Nutr. Sci. Vitaminol. 22: 225-234, 1976.

8. Kishi, H.; Kishi, T.; Williams, R. H.; Folkers, K.: Human deficiencies
of vitamin B6. I. Studies on parameters of the assay of the glutamic
oxaloacetic transaminase by the CAS principle. Res. Commun. Chem.
Path. Pharm. 12: 557-569, 1975.

9. Lettin, A. W. F.: Carpal tunnel syndrome in childhood: report
of a case. J. Bone Joint Surg. 47B: 556-559, 1965.

10. MacArthur, R. G.; Hayles, A. B.; Gomez, M. R.; Bianco, A. J.,
Jr.: Carpal tunnel syndrome and trigger finger in childhood. Am.
J. Dis. Child. 117: 463-469, 1969.

11. McDonnell, J. M.; Makley, J. T.; Horwitz, S. J.: Familial carpal-tunnel
syndrome presenting in childhood: report of two cases. J. Bone Joint
Surg. 69A: 928-930, 1987.

12. Mochizuki, Y.; Ohkubo, H.; Motomura, T.: Familial bilateral carpal
tunnel syndrome.  (Letter) J. Neurol. Neurosurg. Psychiat. 44: 367
only, 1981.

13. Serratrice, G.; Roger, J.; Guastalla, B.; Saint-Jean, J. C.:
Amyotrophies thenariennes familiales d'origine carpienne. Rev. Neurol. 141:
746-749, 1985.

14. Sparkes, R. S.; Spence, M. A.; Gottlieb, N. L.; Gray, R. G.; Crist,
M.; Sparkes, M. C.; Marazita, M.: Genetic linkage analysis of the
carpal tunnel syndrome. Hum. Hered. 35: 288-291, 1985.

15. Vallat, J. M.; Dunoyer, J.: Familial occurrence of entrapment
neuropathies.  (Letter) Arch. Neurol. 36: 323 only, 1979.

*FIELD* CS

Neuro:
   Constrictive median neuropathy;
   Tunnel sign

Limbs:
   Thickened transverse carpal ligament;
   Digital flexor tenosynovitis

Misc:
   Responsive to pyridoxine administration;
   Early onset age

Lab:
   Vitamin B6 deficiency

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 4/14/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
115435
*FIELD* TI
*115435 CARTILAGE LINK PROTEIN; CRTL1
*FIELD* TX
Using a cDNA for the chicken protein, Osborne-Lawrence et al. (1990)
isolated 2 overlapping clones that encode the entire human cartilage
link protein. The deduced amino acid sequence is 354 residues long and
shows a striking degree of similarity to porcine, rat, and chicken link
protein sequences. By in situ hybridization, they mapped the gene to
5q13-q14.1. Dudhia et al. (1994) found that the CRTL1 gene comprises 5
exons and is spread over more than 60 kb. Primer extension and S1
nuclease protection analysis revealed transcription initiation to be 315
bases upstream from the translation initiation codon.

Loughlin et al. (1994) excluded the CRTL1 gene as the site of the
causative mutation in 1 pedigree of autosomal dominant
hypochondroplasia, 2 pedigrees of autosomal recessive SED tarda, 1
pedigree of autosomal dominant SED tarda, 1 pedigree of autosomal
dominant achondroplasia, and 1 pedigree of autosomal dominant multiple
epiphyseal dysplasia. In all these pedigrees, the CRTL1 gene segregated
independently of the disorder.

*FIELD* RF
1. Dudhia, J.; Bayliss, M. T.; Hardingham, T. E.: Human link protein
gene: structure and transcription pattern in chondrocytes. Biochem.
J. 303: 329-333, 1994.

2. Loughlin, J.; Irven, C.; Sykes, B.: Exclusion of the cartilage
link protein and the cartilage matrix protein genes as the mutant
loci in several heritable chondrodysplasias. Hum. Genet. 94: 698-700,
1994.

3. Osborne-Lawrence, S. L.; Sinclair, A. K.; Hicks, R. C.; Lacey,
S. W.; Eddy, R. L., Jr.; Byers, M. G.; Shows, T. B.; Duby, A. D.:
Complete amino acid sequence of human cartilage link protein (CRTL1)
deduced from cDNA clones and chromosomal assignment of the gene. Genomics 8:
562-567, 1990.

*FIELD* CD
Victor A. McKusick: 9/7/1990

*FIELD* ED
carol: 1/12/1995
terry: 12/22/1994
supermim: 3/16/1992
carol: 8/7/1991
carol: 9/7/1990

*RECORD*
*FIELD* NO
115437
*FIELD* TI
*115437 CARTILAGE MATRIX PROTEIN; CRTM; CMP
*FIELD* TX
Cartilage matrix protein is a major component of the extracellular
matrix of nonarticular cartilage. Jenkins et al. (1990) used a partial
chicken CMP cDNA probe to isolate 3 overlapping human genomic clones.
From one of these clones, a probe containing 2 human CMP exons was
isolated and used to map the gene to 1p35, by a combination of Southern
blot analysis of somatic cell hybrids and in situ chromosomal
hybridization. The genomic probe was also used to screen a human retina
cDNA library. The protein sequence predicted by the cDNA clones had 496
amino acids, including a 22-residue signal peptide. The structure of the
CMP gene and polypeptide were strikingly similar in the chicken and in
the human. The human gene spans 12 kb and has 8 exons and 7 introns.

By linkage studies, Loughlin et al. (1994) demonstrated that the CRTM
gene segregated independently of several heritable chondrodysplasias:
hypochondrodysplasia, achondroplasia, autosomal dominant SED tarda, and
multiple epiphyseal dysplasia.

*FIELD* RF
1. Jenkins, R. N.; Osborne-Lawrence, S. L.; Sinclair, A. K.; Eddy,
R. L., Jr.; Byers, M. G.; Shows, T. B.; Duby, A. D.: Structure and
chromosomal location of the human gene encoding cartilage matrix protein.
J. Biol. Chem. 265: 19624-19631, 1990.

2. Loughlin, J.; Irven, C.; Sykes, B.: Exclusion of the cartilage
link protein and the cartilage matrix protein genes as the mutant
loci in several heritable chondrodysplasias. Hum. Genet. 94: 698-700,
1994.

*FIELD* CD
Victor A. McKusick: 1/2/1991

*FIELD* ED
carol: 1/12/1995
supermim: 3/16/1992
carol: 3/19/1991
carol: 1/10/1991
carol: 1/2/1991

*RECORD*
*FIELD* NO
115440
*FIELD* TI
*115440 CASEIN KINASE 2, ALPHA 1 POLYPEPTIDE; CSNK2A1
CASEIN KINASE II, ALPHA SUBUNIT; CK2A1
*FIELD* TX
Casein kinase II is a serine/threonine kinase that phosphorylates acidic
protein such as casein. It has a tetrameric a(2)/b(2) structure. The
alpha subunit of molecular weight 40,000 possesses catalytic activity,
whereas the beta subunit (115441), molecular weight 25,000, is
autophosphorylated in vitro. Meisner et al. (1989) reported the
identification and nucleotide sequencing of a complete human cDNA for
the alpha subunit. Using the full-length cDNA probe, Meisner et al.
(1989) found 2 bands with restriction enzymes that have no recognition
sites within the cDNA and 3 to 6 bands with enzymes having single
internal sites. These results were considered consistent with the
existence of 2 genes encoding alpha subunits. See 115442. By segregation
analysis of rodent-human somatic cell hybrids and chromosomal in situ
hybridization, Yang-Feng et al. (1991) identified 2 loci for the alpha
subunit of casein kinase II: 11p15.5-p.15.4 and 20p13. Whether one of
these is a pseudogene remained to be determined. Boldyreff et al. (1992)
likewise found 2 assignments by in situ hybridization: 11pter-p15.1 and
20p13. Only the locus on chromosome 11 was confirmed by somatic cell
hybrid analysis, based on the presence of a CK2A1-specific 20-kb
fragment. However, Wirkner et al. (1992) demonstrated that the sequence
that maps to 11p15 by in situ hybridization has the characteristics of a
processed pseudogene. Wirkner et al. (1994) demonstrated that the
CSNK2A1 gene contains 8 exons whose sequences comprise bases 102 to 824
of the coding region of the human casein kinase II alpha subunit. The
exon/intron splice junctions conformed to the gt/ag rule. Three of the 9
introns are located at positions corresponding to those of the
homologous gene in the nematode Caenorhabditis elegans. The introns
contain 8 complete and 8 incomplete Alu repeats. By fluorescence in situ
hybridization using an 18.9-kb genomic clone representing the central
portion of the gene, Wirkner et al. (1994) mapped CSNK2A1 to 20p13.
Using the genomic clone, no hybridization signal was obtained in 11p15
as had previously been the case when the cDNA was used as probe
(Yang-Feng et al., 1991).

*FIELD* RF
1. Boldyreff, B.; Klett, C.; Gottert, E.; Geurts van Kessel, A.; Hameister,
H.; Issinger, O.-G.: Assignment of casein kinase 2 alpha sequences
to two different human chromosomes. Hum. Genet. 89: 79-82, 1992.

2. Meisner, H.; Heller-Harrison, R.; Buxton, J.; Czech, M. P.: Molecular
cloning of the human casein kinase II alpha subunit. Biochemistry 28:
4072-4076, 1989.

3. Wirkner, U.; Voss, H.; Lichter, P.; Ansorge, W.; Pyerin, W.: The
human gene (CSNK2A1) coding for the casein kinase II subunit alpha
is located on chromosome 20 and contains tandemly arranged Alu repeats. Genomics 19:
257-265, 1994.

4. Wirkner, U.; Voss, H.; Lichter, P.; Weitz, S.; Ansorge, W.; Pyerin,
W.: Human casein kinase II subunit alpha: sequence of a processed
(pseudo)gene and its localization on chromosome 11. Biochim. Biophys.
Acta 1131: 220-222, 1992.

5. Yang-Feng, T. L.; Zheng, K.; Kopatz, I.; Naiman, T.; Canaani, D.
: Mapping of the human casein kinase II catalytic subunit genes: two
loci carrying the homologous sequences for the alpha subunit. Nucleic
Acids Res. 19: 7125-7129, 1991.

*FIELD* CD
Victor A. McKusick: 6/12/1989

*FIELD* ED
mark: 10/16/1996
carol: 4/12/1994
carol: 10/8/1992
carol: 6/11/1992
carol: 3/25/1992
supermim: 3/16/1992
carol: 1/2/1991

*RECORD*
*FIELD* NO
115441
*FIELD* TI
*115441 CASEIN KINASE 2, BETA POLYPEPTIDE; CSNK2B
CASEIN KINASE II, BETA SUBUNIT; CK2B;;
PHOSVITIN
*FIELD* TX
Phosvitin/casein kinase type II is a ubiquitous, highly conserved enzyme
consisting of subunits alpha (115440), alpha-prime (115442), and beta.
It is a ubiquitous messenger-independent serine/threonine kinase,
localized in both the cytoplasm and the nucleus. Jakobi et al. (1989)
prepared subunit beta from human placenta and determined the amino acid
sequence of a protease digestion peptide. The deduced nucleotide
sequence was used for the synthesis of a mixture of 20-mers as a
hybridization probe to screen a lambda-gt10 HeLa cell cDNA library for
clones encoding the beta subunit. The beta subunit presumably serves
regulatory functions. Heller-Harrison et al. (1989) found evidence of a
single gene. They described a cDNA of 2.57 kb containing 96 bp of
5-prime untranslated sequence, 645 bp of open reading frame, and 1,832
bp of 3-prime untranslated sequence. By hybridization to spot-blotting
filters of flow-sorted human chromosomes followed by in situ
hybridization, Yang-Feng et al. (1990) mapped the CSNK2B gene to 6p21.1.

Voss et al. (1991) analyzed the structure of the gene encoding human
casein kinase II subunit beta and Boldyreff and Issinger (1995)
determined the structure of the mouse counterpart. The latter is
composed of 7 exons contained within 7,874 bp. The lengths of the mouse
coding exons correspond exactly to the lengths of the exons in the human
CK2B gene. Both genes contain a first untranslated exon. Despite common
features, a striking difference concerned the human CK2A subunit binding
domain at position -170 to -239 of the human gene. This domain has no
counterpart in the mouse gene.

Albertella et al. (1996) characterized the genes in the central 1,100-kb
class III region of the major histocompatibility complex. One of the
genes found in this region was identified as CSNK2B. This would suggest
that CSNK2B is located in the 6p21.3 region rather than the 6p21.1
region.

*FIELD* RF
1. Albertella, M. R.; Jones, H.; Thomson, W.; Olavesen, M. G.; Campbell,
R. D.: Localization of eight additional genes in the human major
histocompatibility complex, including the gene encoding the casein
kinase II beta subunit (CSNK2B). Genomics 36: 240-251, 1996.

2. Boldyreff, B.; Issinger, O.-G.: Structure of the gene encoding
the murine protein kinase CK2-beta subunit. Genomics 29: 253-256,
1995.

3. Heller-Harrison, R. A.; Meisner, H.; Czech, M. P.: Cloning and
characterization of a cDNA encoding the beta subunit of human casein
kinase II. Biochemistry 28: 9053-9058, 1989.

4. Jakobi, R.; Voss, H.; Pyerin, W.: Human phosvitin/casein kinase
type II: molecular cloning and sequencing of full-length cDNA encoding
subunit beta. Europ. J. Biochem. 183: 227-233, 1989.

5. Voss, H.; Wirkner, U.; Jacoki, R.; Hewitt, N. A.; Schwager, C.;
Zimmermann, J.; Ansorge, W.; Pyerin, W.: Structure of the gene encoding
human casein kinase II subunit beta. J. Biol. Chem. 266: 13706-13711,
1991.

6. Yang-Feng, T. L.; Teitz, T.; Cheung, M. C.; Kan, Y. W.; Canaani,
D.: Assignment of the human casein kinase II beta-subunit gene to
6p12-p21. Genomics 8: 741-742, 1990.

*FIELD* CD
Victor A. McKusick: 11/22/1989

*FIELD* ED
mark: 10/09/1996
terry: 10/9/1996
terry: 10/30/1995
mark: 10/2/1995
supermim: 3/16/1992
carol: 1/2/1991
carol: 12/14/1990
carol: 10/26/1990

*RECORD*
*FIELD* NO
115442
*FIELD* TI
*115442 CASEIN KINASE 2, ALPHA-PRIME SUBUNIT; CSNK2A2
CASEIN KINASE II, ALPHA-PRIME SUBUNIT; CK2A2
*FIELD* TX
Casein kinase II catalyzes the phosphorylation of serine or threonine
residues in proteins; i.e., it is a protein serine/threonine kinase. The
enzyme is probably present in all eukaryotic cells, implying that it has
fundamental cellular functions. The holoenzyme is a tetramer containing
2 alpha or alpha-prime subunits (or one of each) and 2 beta subunits.
The function of the beta subunit is unknown but presumably it fills a
regulatory role in the holoenzyme. The alpha subunit is the catalytic
subunit. Lozeman et al. (1990) reported studies indicating that the 2
catalytic subunits, alpha and alpha-prime, have distinct sequences and
that these sequences are largely conserved between the bovine and the
human. By somatic cell hybrid analysis, Yang-Feng et al. (1991)
demonstrated that the CK2A2 gene maps to chromosome 16. By in situ
hybridization, Yang-Feng et al. (1994) mapped the CSNK2A2 gene to
16p13.3-p13.2. (In the title and body of the article, Yang-Feng et al.
(1994) incorrectly referred to the gene in question as CSNK2A1; CSNK2A1
(115440) is located on 20p13.)

*FIELD* RF
1. Lozeman, F. J.; Litchfield, D. W.; Piening, C.; Takio, K.; Walsh,
K. A.; Krebs, E. G.: Isolation and characterization of human cDNA
clones encoding the alpha and the alpha-prime subunits of casein kinase
II. Biochemistry 29: 8436-8447, 1990.

2. Yang-Feng, T. L.; Naiman, T.; Kopatz, I.; Eli, D.; Dafni, N.; Canaani,
D.: Assignment of the human casein kinase II alpha-prime subunit
gene (CSNK2A1) to chromosome 16p13.2-p13.3. Genomics 19: 173 only,
1994.

3. Yang-Feng, T. L.; Zheng, K.; Kopatz, I.; Naiman, T.; Canaani, D.
: Mapping of the human casein kinase II catalytic subunit genes: two
loci carrying the homologous sequences for the alpha subunit. Nucleic
Acids Res. 19: 7125-7129, 1991.

*FIELD* CD
Victor A. McKusick: 10/26/1990

*FIELD* ED
mark: 10/18/1996
carol: 2/8/1994
carol: 3/25/1992
supermim: 3/16/1992
carol: 1/2/1991
carol: 10/26/1990

*RECORD*
*FIELD* NO
115450
*FIELD* TI
*115450 CASEIN, ALPHA; CSN1
CASA;;
CASEIN, ALPHA-S1, INCLUDED
*FIELD* TX
Milk casein can apparently be separated by urea starch electrophoresis
into 3 regions, alpha, beta (115460), and kappa (601695) casein. Alpha
and beta variants are present in the human population. Voglino and
Ponzone (1972) postulated 2 biallelic systems. In Italy the frequency of
the 2 alpha alleles was 0.908 and 0.092; 2 beta alleles had a frequency
of 0.678 and 0.322.

Fujiwara et al. (1997) found that the human alpha-S1, beta-, and
kappa-casein genes are closely linked and arranged in that order. By
fluorescence in situ hybridization, they demonstrated that the casein
gene family is localized to 4q21.1.

*FIELD* RF
1. Fujiwara, Y.; Miwa, M.; Nogami, M.; Okumura, K.; Nobori, T.; Suzuki,
T.; Ueda, M.: Genomic organization and chromosomal localization of
the human casein gene family. Hum. Genet. 99: 368-373, 1997.

2. Voglino, G. F.; Ponzone, A.: Polymorphism in human casein. Nature
N.B. 238: 149 only, 1972.

*FIELD* CN
Victor A. McKusick - updated: 03/04/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/04/1997
terry: 3/3/1997
supermim: 3/16/1992
carol: 11/6/1991
carol: 8/7/1991
supermim: 3/20/1990
ddp: 10/26/1989
root: 2/9/1989

*RECORD*
*FIELD* NO
115460
*FIELD* TI
*115460 CASEIN, BETA; CSN2
CASB
*FIELD* TX
See 115450. The caseins have been shown to be members of a multigene
family in at least 2 species, cow and man. They are among the most
rapidly diverging groups of proteins. Bovine milk contains 4 caseins, 2
alpha, 1 beta, and 1 kappa. Human milk, on the other hand, contains only
2 caseins, beta and kappa. Beta-casein is the major casein in human
milk, accounting for as much as 30% of its total protein mass. In
addition to being the primary source of essential amino acids,
beta-casein in concert with kappa-casein forms micelles that transport
calcium and phosphorus to the developing infant. Menon and Ham (1989)
and Lonnerdal et al. (1990) cloned cDNAs for human beta-casein.
Comparison with other species indicates that the caseins are among the
most rapidly evolving proteins (Dayhoff, 1976). Nevertheless, a number
of well-conserved residues are distributed along its entire length.
These residues are thought to play an important role in conserving the
3-dimensional structure of the protein. Menon et al. (1992) showed that
in relation to the beta-casein of other species the mature protein in
the human shows a deletion of amino acids encoded by exon 3. They
concluded that an interruption of the polypyrimidine tract adjacent to
the 5-prime end of the exon 3 sequence may account for the omission of
the exon from human beta-casein mRNA. They stated that a broader
sampling would be required for a firm conclusion that exon 3 is never
expressed in human beta-casein. Nevertheless, the lack of expression of
exon 3 is at the very least a frequent occurrence in humans and may well
be species-specific. Exon 3 encodes 9 residues, including 2 additional
phosphorylation sites, serine residues 7 and 8. The N-terminal
phosphoserine/phosphothreonine amino acids of beta-casein are crucial to
the biologic function of the molecule, and variations in their number
could affect the overall quality of milk.

Using PCR on genomic DNA from somatic cell hybrids, Menon et al. (1992)
localized the CSN2 gene to 4pter-q21. All members of the casein
multigene family are located in a 200-kb region on bovine chromosome 6.
Mouse caseins alpha, beta, and gamma have been localized to chromosome
5.

McConkey et al. (1996) used fluorescence in situ hybridization (FISH)
and beta-casein phage clones to assign the human CSN2 gene to 4q13-q21.
They reported that CSN2 maps to 3p13-p12 in chimpanzees; chimpanzee
chromosome 3 is homologous to human chromosome 4. This finding confirmed
the presence of the pericentric inversion that distinguishes the 2
species.

The human caseins include alpha-S1-casein and beta-casein, which are the
substrates for protein kinase and precipitate in the presence of calcium
(so called calcium-sensitive caseins), and kappa-casein (601695), which
prevents the precipitation of the other caseins by calcium through
micelle formation in cattle (Ferretti et al., 1990; Threadgill and
Womack, 1990). Fujiwara et al. (1997) demonstrated that in the human the
alpha-S1 kappa forms of casein are closely linked and arranged in that
order. By FISH, they demonstrated that the casein gene family is located
on 4q21.1.

*FIELD* SA
Menon et al. (1992)
*FIELD* RF
1. Dayhoff, M. O.: Atlas of Protein Sequence and Structure.  Silver
Spring, Md.: National Biomedical Research Foundation (pub.)  1976.

2. Ferretti, L.; Leone, P.; Sgaramella, V.: Long range restriction
analysis of the bovine casein genes. Nucleic Acids Res. 18: 6829-6833,
1990.

3. Fujiwara, Y.; Miwa, M.; Nogami, M.; Okumura, K.; Nobori, T.; Suzuki,
T.; Ueda, M.: Genomic organization and chromosomal localization of
the human casein gene family. Hum. Genet. 99: 368-373, 1997.

4. Lonnerdal, B.; Bergstrom, S.; Andersson, Y.; Hjalmarsson, K.; Sundqvist,
A. K.; Hernell, O.: Cloning and sequencing of a cDNA encoding human
milk beta-casein. FEBS Lett. 269: 153-156, 1990.

5. McConkey, E. H.; Menon, R.; Williams, G.; Baker, E.; Sutherland,
G. R.: Assignment of the gene for beta-casein (CSN2) to 4q13-q21
in humans and 3p13-p12 in chimpanzees. Cytogenet. Cell Genet. 72:
60-62, 1996.

6. Menon, R. S.; Chang, Y.-F.; Jeffers, K. F.; Ham, R. G.: Exon skipping
in human beta-casein. Genomics 12: 13-17, 1992.

7. Menon, R. S.; Chang, Y.-F.; Jeffers, K. F.; Jones, C.; Ham, R.
G.: Regional localization of human beta-casein gene (CSN2) to 4pter-q21. Genomics 13:
225-226, 1992.

8. Menon, R. S.; Ham, R. G.: Human beta-casein: partial cDNA sequence
and apparent polymorphism. Nucleic Acids Res. 17: 2869, 1989.

9. Threadgill, D. W.; Womack, J. E.: Genomic analysis of the major
bovine milk protein genes. Nucleic Acids Res. 18: 6935-6942, 1990.

*FIELD* CN
Victor A. McKusick - updated: 03/04/1997
Moyra Smith - updated: 4/15/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/04/1997
terry: 3/3/1997
terry: 4/15/1996
mark: 4/15/1996
carol: 11/20/1992
carol: 5/22/1992
supermim: 3/16/1992
carol: 2/16/1992
carol: 1/6/1992
carol: 11/18/1991

*RECORD*
*FIELD* NO
115470
*FIELD* TI
#115470 CAT EYE SYNDROME; CES
SCHMID-FRACCARO SYNDROME;;
CHROMOSOME 22 PARTIAL TETRASOMY;;
ADDITIONAL INV DUP(22)(Q11)
*FIELD* MN

The characteristic cat eye syndrome (CES) is a combination of coloboma
of the iris and anal atresia with fistula, downslanting palpebral
fissures, preauricular tags and/or pits, frequent occurrence of heart
and renal malformations, and near-normal mental development. A small,
supernumerary chromosome (smaller than chromosome 21) is present, has 2
centromeres, is bisatellited, and represents an inv dup(22)(q11) (Mears
et al., 1994). In many cases the abnormality is in only a portion of the
patients' cells; the mosaicism is sometimes transmitted through several
generations. Within a single family, a wide spectrum of features can
occur, ranging from marginally affected individuals to those with the
full pattern of malformations and lethal outcome (Schinzel, 1994).
Minimal features include downslanting palpebral fissures and misshapen
ears with a preauricular pit or tag or both, hypertelorism, strabismus,
inner epicanthic folds, flat nasal bridge, and small mandible. Major
malformations, listed in order of decreasing frequency, are: anal
atresia with a fistula from the rectum into the bladder, vagina, or
vulva in females, and the bladder, urethra, or perineum in males; uni-
or bilateral coloboma of the iris, choroid and/or optic nerve,
microphthalmia (almost always unilateral); cleft palate; congenital
heart malformations, particularly total anomalous pulmonary venous
return and tetralogy of Fallot; renal malformations, e.g., absence,
hydronephrosis, supernumerary kidneys or renal hypoplasia; hernias;
reduction of the auricles to several tags, mostly with atresia of the
external auditory canal and often unilateral. Rarer malformations
include: aniridia, corneal clouding, coloboma of eyelids, cataract, and
the Duane anomaly; craniofacial malformations, e.g., choanal atresia,
skin tags on the cheeks; hypothalamic growth hormone deficiency; cleft
lip and palate; limb malformations, e.g., radial aplasia, duplication of
the hallux, absent toes, and sirenomelia; thoracic and abdominal
malformations, e.g., absence or synostosis of ribs, vertebral fusions,
Eisenmenger complex, pulmonary segmentation defects, malrotation of the
gut, Meckel diverticulum, Hirschsprung disease, biliary atresia; neural
tube defects; hypoplastic uterus and vaginal atresia; hypospadias
(Schinzel et al., 1981).

A few patients die from multiple malformations during early infancy; of
the remainder, life expectancy is not significantly reduced. Growth
retardation is a variable feature as is mental retardation. The majority
of patients function in the borderline normal to mildly retarded range,
a few are normal, and a few are moderately to severely retarded.

There are no data on the recurrence risk for sibs of a CES patient.The
additional chromosome 22 generally arises de novo from one of the
parents. Because mosaicism for an extra inv dup(22)(q11) chromosome may
produce a normal phenotype, chromosome examination of both parents is
indicated after the birth of an affected child. Even if a lymphocyte
chromosome study indicates a nonmosaic diploid karyotype, a hidden
(including germline) mosaicism cannot fully be excluded, and a small
recurrence risk will remain. For offspring the risk will be close to 50%
(Luleci et al., 1989).

Differential staining by FISH (Liehr et al., 1992) shows that the marker
chromosome is composed of material from the 2 different maternal
chromosome 22s. Variation in the number of probes from the region
present in 4 or 3 copies points toward both asymmetry of the extra
chromosome and the variability of the duplicated/triplicated segment in
different patients (Mears et al., 1994).

*FIELD* TX

DESCRIPTION

A number sign (#) is used with this entry because a chromosomal
abnormality is known in this syndrome. However, because in many of the
reported cases the abnormality is in only a portion of the patients'
cells, and because the mosaicism is sometimes transmitted through
several generations, mendelian factors may be important in its
causation.

Cat eye syndrome (CES) is characterized clinically by the combination of
coloboma of the iris and anal atresia with fistula, downslanting
palpebral fissures, preauricular tags and/or pits, frequent occurrence
of heart and renal malformations, and normal or near-normal mental
development. A small supernumerary chromosome (smaller than chromosome
21) is present, frequently has 2 centromeres, is bisatellited, and
represents an inv dup(22)(q11).

CLINICAL FEATURES

The variability of clinical features, particularly congenital
malformations, is enormous (see Schachenmann et al., 1965, Schinzel et
al., 1981, and Schinzel, 1994). Within a single family, a wide spectrum
of features can be observed, ranging from marginally affected
individuals in whom, unless other members are affected, no chromosome
examination would be performed, to those with the full pattern of
malformations and lethal outcome. Only mild prenatal growth retardation
occurs. Minimal features include downslanting palpebral fissures and
misshapen ears with a preauricular pit or tag or both. Other frequently
encountered minor anomalies include hypertelorism, strabismus, inner
epicanthic folds, flat nasal bridge, and small mandible.

The following major malformations may occur and are listed in order of
decreasing frequency: anal atresia with a fistula from the rectum into
the bladder, vagina, or vulva in females, and the bladder, urethra, or
perineum in males; coloboma of the iris, either uni- or bilateral and
total or (rarely) partial and coloboma of the choroid and/or optic
nerve, microphthalmia (almost always unilateral); cleft palate;
congenital heart malformations, particularly totally anomalous pulmonary
venous return (TAPVR) and tetralogy of Fallot (TOF); various renal
malformations, e.g., absence of 1 or both kidneys, hydronephrosis,
supernumerary kidneys or renal hypoplasia; hernias; reduction of the
auricles to several tags, mostly in combination with atresia of the
external auditory canal and often unilateral.

Rarer malformations may affect almost every organ; the eyes are
preferentially affected: aniridia (Weber et al., 1970), corneal clouding
(Giraud et al., 1975), coloboma of eyelids (Carmi et al., 1980),
cataract (Schinzel et al., 1981), and the Duane anomaly (Cullen et al.,
1993). Craniofacial malformations include: choanal atresia (Ginsberg et
al., 1968), skin tags on the cheeks (Fryns et al., 1972); hypothalamic
growth hormone deficiency (Pierson et al., 1975); cleft lip and palate
(Loevy et al., 1977). Limb malformations include: radial aplasia (Balci
et al., 1974,; Guanti, 1981); duplication of the hallux (Carmi et al.,
1980) absent toes and sirenomelia (Jensen and Hansen, 1981). Thoracic
and abdominal malformations include: absence or synostosis of ribs
(Ginsberg et al., 1968; Balci et al., 1974; Pierson et al., 1975),
vertebral fusions (Toomey et al., 1977; Schinzel et al., 1981),
Eisenmenger complex (Schinzel et al., 1981), pulmonary segmentation
defects; malrotation of the gut (Ginsberg et al., 1968; Hoo et al.,
1986), Meckel diverticulum, Hirschsprung disease (Guanti, 1981; Mahboubi
and Templeton, 1984; Ward et al., 1989), biliary atresia (Gerald et al.,
1972; Johnson et al., 1974); spina bifida (Cory and Jamison, 1974) and
MMC (Carmi et al., 1980), hypoplastic uterus and vaginal atresia
(Schinzel et al., 1981), hypospadias (Guanti, 1981; Schinzel et al.,
1981).

A few patients die from multiple malformations during early infancy; of
the remainder, life expectancy is not significantly reduced. Growth
retardation is a variable feature as is mental retardation. The majority
of patients function in the borderline normal to mildly retarded range,
a few are normal, and some are moderately to severely retarded, although
the latter condition is rare. Behavioral problems have been reported in
individual cases, but are not characteristic of the disorder (Schinzel
et al., 1981).

INHERITANCE

The additional chromosome 22 generally arises de novo from one of the
parents. Since CES is a rare chromosome disorder in which transmission
is possible through both sexes, chromosome examination should be
performed if one of the parents displays characteristic features such as
a preauricular pit or downslanting palpebral fissures. Even in
nonsymptomatic parents, mosaicism for an extra chromosome is possible.
Direct transmission was reported by Schachenmann et al. (1965); Gerald
et al. (1972); Darby and Hughes (1971); Krmpotic et al. (1971); Noel et
al. (1976); Schinzel et al. (1981); and Luleci et al. (1989).

- Recurrence Risk

There are no data available on the recurrence risk for sibs of a CES
patient. However, because mosaicism for an extra inv dup(22)(q11)
chromosome may produce a normal phenotype, chromosome examination of
both parents is indicated after the birth of an affected child. Even if
a lymphocyte chromosome study indicates a nonmosaic diploid karyotype, a
hidden (including germline) mosaicism cannot fully be excluded, and a
small recurrence risk will remain. For offspring of an affected who does
not appear to have reduced fertility, the risk will be close to 50%
(Noel et al., 1976; Schinzel et al., 1981; Luleci et al., 1989).

CYTOGENETICS

The additional marker is always dicentric, which can be demonstrated by
centromere staining. By different stainings of heterochromatin and NORs
it can be shown in most cases that the marker contains short arm
material from acrocentrics on both arms (Schinzel et al., 1981; Petit et
al., 1980). Differential staining can show that the chromosome is
composed, thus far without exception, of material from the 2 different
maternal chromosome 22 (Magenis et al., 1988). Secondary rearrangements
can occur in the dicentric and hence unstable marker resulting in extra
chromosomes of different appearance in a mother and daughter (Ing et
al., 1987). The easiest and most elegant way to demonstrate the origin
of the chromosome 22 marker is by FISH examination with a chromosome 22
library (Liehr et al., 1992).

A particular feature of familial CES is the frequent occurrence of
mosaicism resulting from early loss of the marker during postzygotic
divisions (Gerald et al., 1972; Luleci et al., 1989).

Wenger et al. (1994) evaluated the marker chromosome in a proband and
his mother by cytogenetic banding techniques to verify the dicentric
chromosomal rearrangement and by fluorescence in situ hybridization to
confirm the involvement of chromosome 22. The mother also had an
offspring with an unrelated aneuploidy, trisomy 21. At birth the proband
showed coloboma of the iris, preauricular pits, and anal stenosis.
Developmentally, he had short stature and was moderately mentally
retarded. Diagnosis of biliary atresia was made in infancy. The mother
was moderately mentally retarded and had stigmata of the cat eye
syndrome which had been cytogenetically confirmed in the neonatal
period. Anal atresia had been surgically corrected during childhood. She
was 19 years old at the time of the birth of her son with CES.

MAPPING

Among others, Zhang et al. (1990), Delattre et al. (1991), and Budarf et
al. (1991) constructed restriction maps of chromosome 22, the latter
authors with special attention to the critical cat eye region. Mears et
al. (1994) investigated patients with cat eye syndrome and with DiGeorge
syndrome with probes from proximal 22q and could show that the distal
boundary of the critical cat eye segment (represented by probe D22S36)
is proximal to the critical DiGeorge region.

McDermid et al. (1996) constructed a long-range restriction map of the
region of 22q which is duplicated in the typical CES marker chromosome,
the region extending from the centromere to locus D22S36. The map
covered approximately 3.6 Mb. They also used 15 loci to construct a YAC
contig that encompassed about half of the region critical to the
production of the CES phenotype (from the centromere to D22S57).

MOLECULAR GENETICS

McDermid et al. (1986) isolated a single copy DNA probe, D22S29, from a
chromosome 22 library and localized it by in situ hybridization to the
critical cat eye region. By dosage, this probe was present in 4 copies
in all examined cat eye patients while patients with familial partial
trisomy of the proximal 22q region contained 3 copies, and normal
individuals, 2 copies of the critical region.

Mears et al. (1994) demonstrated 4 copies of the following probes in all
10 cat eye patients examined: D22S9, D22S43, D22S57; more distal
sequences (D22S36 and D22S75) were duplicated only in a proportion of
the patients. The observation that D22S36 was present in 3 copies in a
few patients, the most distal marker, D22S75, was usually present in
only 2 copies, and in a minority of patients in 3 copies, points toward
both asymmetry of the extra chromosome and the variability of the
duplicated/triplicated segment in different patients. Interestingly, no
correlation between the length of the duplicated/triplicated segment and
the severity of clinical features and the extent of mental handicap
could be demonstrated.

Mears et al. (1995) described an individual who inherited a minute
supernumerary double ring chromosome 22, resulting in expression of all
the cardinal features of CES. The ATP6E gene (108746) and 2 anonymous
probes were found to be present in 4 copies, whereas 2 other anonymous
probes were present in 2 copies. This finding further delineated the
distal boundary of the critical region of CES, with ATP6E being the most
distal duplicated locus identified. The phenotypically normal father and
grandfather of the patient each had a small supernumerary ring
chromosome and demonstrated 3 copies of the 3 loci which were present in
quadruplicate in the proband. Mears et al. (1995) hypothesized that,
although 3 copies of this region had been reported in other cases with
CES features, it is possible that the presence of 4 copies leads to
greater susceptibility.

Hough et al. (1995) demonstrated that the supernumerary chromosome in
CES contains none of the lambda immunoglobulin gene sequences (146770)
as indicated by the fact that no increased copy number was found in the
DNA from 10 CES individuals tested.

HETEROGENEITY

Cases with the characteristic clinical pattern occur in which
examination of different tissue fails to detect a marker chromosome.
Since these patients have thus far not been investigated molecularly, it
is not possible to exclude tetrasomy of the small critical region on
22q11 which presumably causes all or most of the clinical findings of
CES (Franklin and Parslow, 1972).

DIAGNOSIS

Although CES was initially defined as the combination of an additional
chromosome, with coloboma and anal atresia as primary features, it
became evident from the patients reported by Schachenmann et al. (1965)
that neither coloboma nor anal atresia were obligatory findings. In
addition to the above features, the following are helpful for the
diagnosis: heart malformations, renal malformations, downslanting
palpebral fissures, preauricular pits and/or tags, and reduction of the
auricles with atresia of the external auditory canal. The diagnosis
nowadays, however, is based on the presence of an extra marker
chromosome which, by FISH examination, is derived from chromosome 22 and
contains 2 copies of the critical CES region in proximal 22q11.

CLINICAL MANAGEMENT

Surgery is required for anal atresia and complex cardiac malformations.
With intestinal problems, malrotation, Meckel diverticulum, and biliary
atresia have to be considered. Patients with very short stature might
have additional hypothalamic growth hormone deficiency and thus be
candidates for growth hormone therapy (Pierson et al., 1975).

POPULATION GENETICS

There are no estimates on the incidence of the marker. An incidence
between 1:50,000 and 1:150,000 seems a reasonable estimate from patients
observed in Northeastern Switzerland during the last 20 years.

HISTORY

The association between iridal coloboma and anal atresia was probably
first noticed by Haab (1879). The first report on the association of
coloboma and anal atresia with a small extra chromosome came from Schmid
in Zurich and Fraccaro in Pavia (Schachenmann et al., 1965). These
authors proposed the term cat eye syndrome, in analogy with the cat cry
or cri-du-chat syndrome (123450). However, more than half of the
patients with the chromosome aberration lack any coloboma.

*FIELD* SA
Ferrandez and Schmid (1971); Noel et al. (1976); Verma et al. (1985)
*FIELD* RF
1. Balci, S.; Halicioglu, C.; Say, B.; Taysi, K.: The cat-eye syndrome
with unusual skeletal malformations. Acta Paediatr. Scand. 63: 623-626,
1974.

2. Budarf, M. L.; McDermid, H. E.; Sellinger, B.; Emanuel, B.S.:
Isolation and regional localization of 35 unique anonymous DNA markers
for human chromosome 22. Genomics 10: 996-1002, 1991.

3. Carmi, R.; Abeliovic, D.; Bar-Ziv, J.; Karplus, M.; Cohen, M. M.
: Malformation syndrome associated with small extra chromosome. Am.
J. Med. Genet. 5: 101-107, 1980.

4. Cory, C. C.; Jamison, D. L.: The cat eye syndrome. Arch. Ophthalmol. 92:
259-262, 1974.

5. Cullen, P.; Rodgers, C. M.; Callen, D. F.; Connolly, V. M.; Eyre,
H.; Fells, P.; Gordon, H.; Winter, R. M.; Thakker, R. V.: Association
of familial Duane anomaly and urogenital abnormalities with a bisatellited
marker derived from chromosome 22. Am. J. Med. Genet. 47: 925-930,
1993.

6. Darby, C. W.; Hughes, D. T.: Dermatoglyphics and chromosomes in
cat-eye syndrome. Brit. Med. J. 262: 47-48, 1971.

7. Delattre, O.; Azambuja, C. J.; Aurias, A,; Zuchman, J.; Peter,
M.; Zhang, F.; Hors-Cayla, M. C.; Rouleau, G.; Thomas, G.: Mapping
of human chromosome 22 with a panel of somatic cell hybrids. Genomics 9:
721-727, 1991.

8. Ferrandez, A.; Schmid, W.: Potter-Syndrom (Nierenagenesie) mit
chromosomaler Aberration beim Patient und Mosaik beim Vater. Helv.
Paediatr. Acta 26: 210-214, 1971.

9. Franklin, R. C.; Parslow, M. I.: The cat eye syndrome. Review
and two further cases occurring in female siblings with normal chromosomes.. Acta
Paediatr. Scand. 61: 581-586, 1972.

10. Fryns, J. P.; Eggermont, E.; Verresen, H.; van den Berghe, H.
: A newborn with the cat-eye syndrome. Humangenetik 15: 242-248,
1972.

11. Gerald, P. S.; Davis, C.; Say, B.; Wilkins, J.: Syndromal association
of imperforate anus: the Cat Eye syndrome. Birth Defects Orig. Art.
Ser. VIII(2): 79-84, 1972.

12. Ginsberg, J.; Dignan, P.; Soukup, S.: Ocular abnormality associated
with extra small autosome. Am. J. Ophthalmol. 65: 740-746, 1968.

13. Giraud, F.; Mattei, J. F.; Hartung, M.; Mattei, M. G.: Petit
chromosome submetacentrique surnumeraire et syndrome des yeux de chat. Ann.
Pediatr. (Paris) 22: 449-452, 1975.

14. Guanti, G.: The aetiology of the cat eye syndrome reconsidered. J.
Med. Genet. 18: 108-118, 1981.

15. Haab, O.: . Albrecht v Graefes Arch. Ophthalmol. 24: 257 only,
1879.

16. Hoo, J. J.; Robertson, A.; Fowlow, S. B.; Bowen, P.; Lin, C. C.
: Inverted duplication of 22pter;q11.22 in cat-eye syndrome. (Letter) Am.
J. Med. Genet. 24: 543-545, 1986.

17. Hough, C. A.; White, B. N.; Holden, J. J. A.: Absence of lambda
immunoglobulin sequences on the supernumerary chromosome of the 'cat
eye' syndrome. Am. J. Med. Genet. 58: 277-281, 1995.

18. Ing, P. S.; Lubinsky, M. S.; Smith, S. D.; Golden, E.; Sanger,
W. G.; Duncan, A. M. V.: Cat-eye syndrome with different marker chromosomes
in a mother and daughter. Am. J. Med. Genet. 26: 621-628, 1987.

19. Jensen, P. K. A.; Hansen, P.: A bisatellited marker chromosome
in an infant with the caudal regression anomalad. Clin. Genet. 19:
126-129, 1981.

20. Johnson, L. D.; Harris, R. C.; Henderson, A. S.: Ribosomal DNA
sites in a metacentric chromosome fragment. Humangenetik 21: 217-219,
1974.

21. Krmpotic, E.; Rosnick, M. R.; Zollar, L. M.: Genetic counseling.
Secondary nondisjunction in partial trisomy 13. Obstet. Gynecol. 37:
381-390, 1971.

22. Liehr, T.; Pfeiffer, R. A.; Trautmann, U.: Typical and partial
cat eye syndrome: identification of the marker chromosome by FISH. Clin.
Genet. 42: 91-96, 1992.

23. Loevy, H. T.; Jayaram, B. N.; Rosenthal, I. M.; Pildes, R.: Partial
trisomy 13 associated with cleft lip and cleft palate. Cleft Palate
J. 14: 239-243, 1977.

24. Luleci, G.; Bagci, G.; Kivran, M.; Luleci, E.; Bektas, S.; Basaran,
S.: A hereditary bisatellite-dicentric supernumerary chromosome in
a case of cat eye syndrome. Hereditas 111: 7-10, 1989.

25. Magenis, R. E.; Sheehy, R. R.; Brown, M. G.; McDermid, H. E.;
White, B. N.; Zonana, J.; Weleber, R.: Parental origin of the extra
chromosome in the cat eye syndrome: evidence from heteromorphism and
in situ hybridization analysis. Am. J. Med. Genet. 29: 9-19, 1988.

26. Mahboubi, S.; Templeton, J. M.: Association of Hirschsprung's
disease and imperforate anus in a patient with 'cat eye' syndrome. Pediatr.
Radiol. 14: 441-442, 1984.

27. McDermid, H. E.; Duncan, A. M. V.; Brasch, K. R.; Holden, J. J.
A.; Magenis, E.; Sheehy, R.; Burn, J.; Kardon, N.; Noel, B.; Schinzel,
A.; Teshima, I.; White, B. N.: Characterization of the supernumerary
chromosome in cat eye syndrome. Science 232: 646-648, 1986.

28. McDermid, H. E.; McTaggart, K. E.; Ali Riazi, M.; Hudson, T. J.;
Budarf, M. L.; Emanuel, B. S.; Bell, C. J.: Long-range mapping and
construction of a YAC contig within the cat eye syndrome critical
region. Genome Res. 6: 1149-1159, 1996.

29. Mears, A. J.; Duncan, A. M. V.; Biegel, J. A.; Budarf, M. L.;
Emanuel, B. S.; Siegel-Bartelt, J.; Greenberg, C. R.; McDermid, H.
E.: Molecular characterization of the marker chromosome associated
with cat eye syndrome. Am. J. Hum. Genet. 55: 134-142, 1994.

30. Mears, A. J.; El-Shanti, H.; Murray, J. C.; McDermid, H. E.; Patil,
S. R.: Minute supernumerary ring chromosome 22 associated with cat
eye syndrome: further delineation of the critical region. Am. J.
Hum. Genet. 57: 667-673, 1995.

31. Noel, B.; Ayraud, N.; Levy, M.; Cau, D.: Le syndrome des yeux
de chat. Etude chromosomique et conseil genetique. J. Genet. Hum. 24:
279-291, 1976.

32. Noel, B.; Quack, B.; Rethore, M. O.: Partial deletions and trisomies
of chromosome 13; mapping of bands associated with particular malformations. Clin.
Genet. 9: 593-602, 1976.

33. Petit, P.; Godart, S.; Fryns, J. P.: Silver staining of the supernumerary
chromosome in the cat-eye syndrome. Ann. Genet. (Paris) 23: 114-116,
1980.

34. Pierson, M.; Gilgenkrantz, S.; Saborio, M.: Syndrome dit de l'oeil
de chat avec nanisme hypophysaire et developpement mental normal. Arch.
Franc. Pediatr. 32: 835-848, 1975.

35. Schachenmann, G.; Schmid, W.; Fraccaro, M.; Mannini, A.; Tiepolo,
L.; Perona, G. P.; Sartori, E.: Chromosomes in coloboma and anal
atresia. (Letter) Lancet II: 290 only, 1965.

36. Schinzel, A.:    Human Cytogenetics Database.    (Series) (Series)
Oxford Medical Databases Series.  Oxford: Oxford University Press,
Electronic Publishing (pub.)  1994.

37. Schinzel, A.; Schmid, W.; Fraccaro, M.; Tiepolo, L.; Zuffardi,
O.; Opitz, J. M.; Lindsten, J.; Zetterqvist, P.; Enell, H.; Baccichetti,
C.; Tenconi, R.; Pagon, R. A.: The 'cat eye syndrome': Decentric
small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11)
associated with a characteristic phenotype. Report of 11 patients
and delineation of the clinical picture. Hum. Genet. 57: 148-158,
1981.

38. Toomey, K. E.; Mohandas, T.; Leisti, J.; Szalay, G.; Kaback, M.
M.: Further delineation of the supernumerary chromosome in the cat
eye syndrome. Clin. Genet. 12: 275-284, 1977.

39. Verma, R. S.; Babu, K. A.; Rosenfeld, W.; Jhaveri, R. C.: Marker
chromosome in cat eye syndrome. (Letter) Clin. Genet. 27: 526-528,
1985.

40. Ward, J.; Sierra, I. A.; D'Croz, E.: Cat eye syndrome associated
with aganglionosis of the small and large intestine. J. Med. Genet. 26:
647-648, 1989.

41. Weber, F. M.; Dooley, R. R.; Sparkes, R. S.: Anal atresia, eye
anomalies, and an additional small abnormal acrocentric chromosome
(47,XX,mar+): report of a case. J. Pediatr. 76: 594-597, 1970.

42. Wenger, S. L.; Surti, U.; Nwokoro, N. A.; Steele, M. W.: Cytogenetic
characterization of cat eye syndrome marker chromosome. Ann. Genet. 37:
33-36, 1994.

43. Zhang, F. R.; Aurias, A.; Delattre, O.; Stern, M. H.; Benitez,
J; Rouleau, G.; Thomas, G.: Mapping of human chromosome 22 by in
situ hybridization. Genomics 7: 319-324, 1990.

*FIELD* CS

Growth:
   Mostly normal

Ear:
   Preauricular malformations, ear reduction;

Eye:
   coloboma, microphthalmia, rarely other malformations

Heart:
   CHD, especially TAPVR and TOF

GI:
   anal atresia with fistula;
   rarely malrotation, Meckel diverticulum, biliary atresia

GU:
   renal malformations

Skel:
   rarely syndactyly or radial aplasia

Neuro:
   Normal to mild/moderate mental retardation

Genetics:
   Additional inv dup(22)(q11) chromosome

*FIELD* CN
Victor A. McKusick - updated: 3/4/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jamie: 03/04/1997
jenny: 3/4/1997
terry: 2/24/1997
pfoster: 11/10/1995
mark: 9/14/1995
terry: 9/16/1994
mimadm: 6/25/1994
warfield: 4/7/1994
schinzel: 4/4/1994

*RECORD*
*FIELD* NO
115500
*FIELD* TI
*115500 CATALASE; CAT
ACATALASEMIA, INCLUDED;;
ACATALASIA, INCLUDED;;
CATALASE DEFICIENCY, INCLUDED
*FIELD* TX
Several rare electrophoretic variants of red cell catalase were
identified by Baur (1963). Nance et al. (1968) also described
electrophoretic variants. Data on gene frequencies of allelic variants
were tabulated by Roychoudhury and Nei (1988).

Wieacker et al. (1980) assigned a gene for catalase to 11p by study of
man-mouse cell hybrid clones. In the hybrid cells, detection of human
catalase was precluded by the complexity of the electrophoretic patterns
resulting from interference by a catalase-modifying enzyme activity.
Therefore, a specific antihuman antibody was used in conjunction with
electrophoresis. In mouse, catalase is not syntenic to the beta-globin
cluster or to LDH-A. Junien et al. (1980) investigated catalase gene
dosage effects in a case of 11p13 deletion, a case of trisomy of all of
11p except 11p13, and a case of trisomy 11p13. The results were
consistent with assignment of the catalase locus to 11p13 and its
linkage with the WAGR complex (194070). Assay of catalase activity
should be useful in identifying those cases of presumed new mutation
aniridia that have a risk of Wilms tumor or gonadoblastoma, even in the
absence of visible chromosomal deletion. In karyotypically normal
patients with aniridia, Wilms tumor, or the combination of the two,
Ferrell and Riccardi (1981) found normal catalase levels. Niikawa et al.
(1982) confirmed the close linkage of catalase to the gene of the WAGR
complex by demonstrating low levels of catalase activity in the
erythrocytes of 2 unrelated patients with the WAGR syndrome and small
deletions in 11p. From the study of dosage in 2 unrelated patients with
an interstitial deletion involving 11p13, Narahara et al. (1984)
concluded that both the catalase locus and the WAGR locus are situated
in the chromosome segment 11p1306-p1305, with catalase distal to WAGR.
Boyd et al. (1986) described a catalase RFLP with 2 different enzymes
and used these polymorphisms to exclude deletion of the catalase gene in
patients with sporadic aniridia, including one who was known to have a
deletion and another suspected of having a deletion. Mannens et al.
(1987) found deletion of the catalase locus in 6 of 9 patients with
aniridia (AN2; 106210). One of these catalase-deficient aniridia
patients had a normal karyotype. No catalase deletion could be
demonstrated in 7 Wilms tumors. By classic linkage studies using RFLPs
of the several genes as markers, Kittur et al. (1985) derived the
following sequence of loci: cen--CAT--16 cM--CALC--8 cM--PTH--pter, with
the interval between CAT and PTH estimated at 26 cM.

Differences in molecular weight of enzymes in different tissues is not
proof that the enzymes are coded by different genes because
tissue-specific variations in transcription or in posttranslational
processing may occur. For example, catalase of red cells and that of
liver are of different molecular weight, but from other evidence both
are coded by the single gene located on 11p. Quan et al. (1986) found
that the CAT gene is 34 kb long and split into 13 exons. Bell et al.
(1986) gave the cDNA sequence for human kidney catalase. The coding
region had 1,581 basepairs.

Acatalasia was first discovered in Japan by Takahara, an
otolaryngologist who found that in cases of progressive oral gangrene,
hydrogen peroxide applied to the ulcerated areas did not froth in the
usual manner (Takahara and Miyamoto, 1948). Heterozygotes have an
intermediate level of catalase in the blood. The frequency of the gene,
although relatively high in Japan, is variable. The frequency of
heterozygotes is 0.09% in Hiroshima and Nagasaki but is of the order of
1.4% in other parts of Japan (Hamilton et al., 1961). Acatalasia has
been detected in Switzerland (Aebi et al., 1962) and in Israel
(Szeinberg et al., 1963). In the Swiss and the Israelis, the homozygotes
showed some residual catalase activity suggesting that this may be a
different mutation from that responsible for the Japanese disease in
which catalase activity is zero and no cross-reacting material has been
identified. Hamilton and Neel (1963) presented evidence that at least 2
forms of acatalasia exist in Japan. In an extensive kindred with
acatalasia in 2 sibships, heterozygotes showed catalase values
overlapping with the normal. Ogata (1991) compared the properties of
residual catalase in the Japanese and Swiss forms of the disease and in
the mutant mouse. Hypocatalasia has also been found in the guinea pig,
dog, and domestic fowl (see review by Lush, 1966). Shibata et al. (1967)
found that an immunologically reactive but enzymatically inactive
protein about one-sixth the size of active catalase is present in red
cells of acatalasemics. In the acatalasemic mouse, Shaffer and Preston
(1990) demonstrated that a CAG (glutamine)-to-CAT (histidine)
transversion in the third position of codon 11 was responsible for the
deficiency.

*FIELD* AV
.0001
ACATALASEMIA, JAPANESE TYPE
CAT, IVS4, G-A, +5
By sequencing the CAT gene for all exons, exon/intron junctions, and
5-prime and 3-prime flanking regions in a case of the Japanese type of
acatalasemia, Wen et al. (1990) concluded that the genetic disorder
resulted from a splicing mutation, namely, a G-to-A substitution at the
fifth position of intron 4. In studies using chimeric genes constructed
from the normal or mutant CAT gene and a part of the alpha-globin gene,
Wen et al. (1990) showed that when the mutant gene construct was
introduced into COS-7 cells, abnormal splicing occurred. The same splice
site mutation was found in the genomic DNA of another unrelated
acatalasemic person. Kishimoto et al. (1992) found the same mutation in
2 other unrelated Japanese patients and suggested that only a single
mutated allele had spread in the Japanese population.

*FIELD* SA
Aebi et al. (1964); Aebi and Suter (1972); Agar et al. (1986); Feinstein
et al. (1966); Kidd et al. (1987); Matsubara et al. (1967); Matsunaga
et al. (1985); Quan et al. (1985); Schroeder and Saunders (1987)
*FIELD* RF
1. Aebi, H.; Baggiolini, M.; Dewald, B.; Lauber, E.; Sutter, H.; Micheli,
A.; Frei, J.: Observations in two Swiss families with acatalasia.
Enzym. Biol. Clin. 4: 121-151, 1964.

2. Aebi, H.; Jeunet, F.; Richterich, R.; Suter, H.; Butler, R.; Frei,
J.; Marti, H. R.: Observations in two Swiss families with acatalasia.
Enzym. Biol. Clin. 2: 1-22, 1962.

3. Aebi, H.; Suter, H.: Acatalasia. In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.: The Metabolic Basis of Inherited Disease.
New York: McGraw-Hill (pub.)  (3rd ed.): 1972. Pp. 1710-1729.

4. Agar, N. S.; Sadrzadeh, S. M. H.; Hallaway, P. E.; Eaton, J. W.
: Erythrocyte catalase: a somatic oxidant defense?. J. Clin. Invest. 77:
319-321, 1986.

5. Baur, E. W.: Catalase abnormality in a Caucasian family in the
United States. Science 140: 816-817, 1963.

6. Bell, G. I.; Najarian, R. C.; Mullenbach, G. T.; Hallewell, R.
A.: cDNA sequence coding for human kidney catalase. Nucleic Acids
Res. 14: 5561-5562, 1986.

7. Boyd, P.; van Heyningen, V.; Seawright, A.; Fekete, G.; Hastie,
N.: Use of catalase polymorphisms in the study of sporadic aniridia.
Hum. Genet. 73: 171-174, 1986.

8. Feinstein, R. N.; Howard, J. B.; Braun, J. T.; Seaholm, J. E.:
Acatalasemic and hypocatalasemic mouse mutants. Genetics 53: 923-933,
1966.

9. Ferrell, R. E.; Riccardi, V. M.: Catalase levels in patients with
aniridia and-or Wilms' tumor: utility and limitations. Cytogenet.
Cell Genet. 31: 120-123, 1981.

10. Hamilton, H. B.; Neel, J. V.: Genetic heterogeneity in human
acatalasia. Am. J. Hum. Genet. 15: 408-419, 1963.

11. Hamilton, H. B.; Neel, J. V.; Kobara, T. Y.; Ozaki, K.: The frequency
in Japan of carriers of the rare 'recessive' gene causing acatalasemia.
J. Clin. Invest. 40: 2199-2208, 1961.

12. Junien, C.; Turleau, C.; de Grouchy, J.; Said, R.; Rethore, M.-O.;
Tenconi, R.; Dufier, J. L.: Regional assignment of catalase (CAT)
gene to band 11p13: association with the aniridia-Wilms' tumor-gonadoblastoma
(WAGR) complex. Ann. Genet. 23: 165-168, 1980.

13. Kidd, J. R.; Castiglione, C. M.; Pakstis, A. J.; Kidd, K. K.:
The anonymous RFLP locus D11S16 is tightly linked to catalase on 11p.
Cytogenet. Cell Genet. 45: 63-64, 1987.

14. Kishimoto, Y.; Murakami, Y.; Hayashi, K.; Takahara, S.; Sugimura,
T.; Sekiya, T.: Detection of a common mutation of the catalase gene
in Japanese acatalasemic patients. Hum. Genet. 88: 487-490, 1992.

15. Kittur, S. D.; Hoppener, J. W. M.; Antonarakis, S. E.; Daniels,
J. D. J.; Meyers, D. A.; Maestri, N. E.; Jansen, M.; Korneluk, R.
G.; Nelkin, B. D.; Kazazian, H. H., Jr.: Linkage map of the short
arm of human chromosome 11: location of the genes for catalase calcitonin,
and insulin-like growth factor II. Proc. Nat. Acad. Sci. 82: 5064-5067,
1985.

16. Lush, I. E.: The Biochemical Genetics of Vertebrates Except Man.
Philadelphia: W. B. Saunders (pub.)  1966.

17. Mannens, M.; Slater, R. M.; Heyting, C.; Bliek, J.; Hoovers, J.;
Bleeker-Wagemakers, E. M.; Voute, P. A.; Coad, N.; Frants, R. R.;
Pearson, P. L.: Chromosome 11, Wilms' tumour and associated congenital
diseases.  (Abstract) Cytogenet. Cell Genet. 46: 655 only, 1987.

18. Matsubara, S.; Suter, H.; Aebi, H.: Fractionation of erythrocyte
catalase from normal, hypocatalatic and acatalatic humans. Humangenetik 4:
29-41, 1967.

19. Matsunaga, T.; Seger, R.; Hoger, P.; Tiefenauer, L.; Hitzig, W.
H.: Congenital acatalasemia: a study of neutrophil functions after
provocation with hydrogen peroxide. Pediat. Res. 19: 1187-1190,
1985.

20. Nance, W. E.; Empson, J. E.; Bennett, T. W.; Larson, L.: Haptoglobin
and catalase loci in man: possible genetic linkage. Science 160:
1230-1231, 1968.

21. Narahara, K.; Kikkawa, K.; Kimira, S.; Kimoto, H.; Ogata, M.;
Kasai, R.; Hamawaki, M.; Matsuoka, K.: Regional mapping of catalase
and Wilms tumor--aniridia, genitourinary abnormalities, and mental
retardation triad loci to the chromosome segment 11p1305-p1306. Hum.
Genet. 66: 181-185, 1984.

22. Niikawa, N.; Fukushima, Y.; Taniguchi, N.; Iizuka, S.; Kajii,
T.: Chromosome abnormalities involving 11p13 and low erythrocyte
catalase activity. Hum. Genet. 60: 373-375, 1982.

23. Ogata, M.: Acatalasemia. Hum. Genet. 86: 331-340, 1991.

24. Quan, F.; Korneluk, R. G.; MacLeod, H. L.; Tsui, L. C.; Gravel,
R. A.: An RFLP associated with the human catalase gene. Nucleic
Acids Res. 13: 8288 only, 1985.

25. Quan, F.; Korneluk, R. G.; Tropak, M. B.; Gravel, R. A.: Isolation
and characterization of the human catalase gene. Nucleic Acids Res. 14:
5321-5335, 1986.

26. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

27. Schroeder, W. T.; Saunders, G. F.: Localization of the human
catalase and apolipoprotein A-I genes to chromosome 11. Cytogenet.
Cell Genet. 44: 231-233, 1987.

28. Shaffer, J. B.; Preston, K. E.: Molecular analysis of an acatalasemic
mouse mutant. Biochem. Biophys. Res. Commun. 173: 1043-1050, 1990.

29. Shibata, Y.; Higashi, T.; Hirai, H.; Hamilton, H. B.: Immunochemical
studies on catalase. II. An anticatalase reacting component in normal
hypocatalasic, and acatalasic human erythrocytes. Arch. Biochem. 118:
200-209, 1967.

30. Szeinberg, A.; De Vries, A.; Pinkhas, J.; Djaldetti, M.; Ezra,
R.: A dual hereditary red blood cell defect in one family: hypocatalasemia
and glucose-6-phosphate dehydrogenase deficiency. Acta Genet. Med.
Gemellol. 12: 247-255, 1963.

31. Takahara, S.; Miyamoto, H.: Three cases of progressive oral gangrene
due to lack of catalase in the blood. Nippon Jibi-Inkoka Gakkai
Kaiho 51: 163 only, 1948.

32. Wen, J. K.; Osumi, T.; Hashimoto, T.; Ogata, M.: Molecular analysis
of human acatalasemia: identification of a splicing mutation. J.
Molec. Biol. 211: 383-393, 1990.

33. Wieacker, P.; Mueller, C. R.; Mayerova, A.; Grzeschik, K. H.;
Ropers, H. H.: Assignment of the gene coding for human catalase to
the short arm of chromosome 11. Ann. Genet. 23: 73-77, 1980.

*FIELD* CS

Misc:
   Failure of tissue to cause hydrogen peroxide frothing

Lab:
   Catalase deficiency

Inheritance:
   Autosomal dominant (11p13);
   polymorphism

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
davew: 8/1/1994
mimadm: 6/25/1994
carol: 10/21/1993
carol: 6/3/1992
carol: 4/28/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
115501
*FIELD* TI
*115501 TYROSINASE-RELATED PROTEIN 1; TYRP1
TYRP; TRP;;
CATALASE B; CATB; CAS2;;
GLYCOPROTEIN-75; GP75;;
b-PROTEIN
*FIELD* TX
Two melanocyte-specific cDNAs were isolated by Kwon et al. (1989) and
both were ascribed to tyrosinase. Based on deduced amino acid sequence,
both code for glycoproteins of similar size, with a membrane-spanning
domain and conserved positions of cysteine and histidine. One of the
clones was assigned to the c locus on mouse chromosome 7 and to human
chromosome 11 (see 203100); the other was assigned to the brown (b)
locus on mouse chromosome 4 (Jackson, 1988). The mutant b allele confers
brown coat color and the B(lt) allele confers an almost white color to
normally black mice. Transfected wildtype c locus cDNA induced
tyrosinase activity and melanin synthesis in fibroblasts, amelanotic
melanoma cells, albino melanocytes, and albino transgenic mice, whereas
wildtype b locus cDNA did not. Halaban and Moellmann (1990) showed that
the b locus protein is a catalase and is identical to a known human
melanosomal protein, gp75. Only the protein encoded by the c locus has
tyrosinase activity. They referred to the protein as catalase B. The b
mutation is in a heme-associated domain. The B(lt) mutation renders the
protein susceptible to rapid proteolytic degradation. During melanin
synthesis, hydroperoxides are produced during autooxidation of melanin
precursor indoles by oxygen, and addition of catalase to tyrosinase
reaction mixtures in vitro increases the yield of melanin. Absence of
catalase B in b mutant melanocytes and concomitant brown instead of
black coat color are indirect evidence that melanogenesis is regulated
through peroxide levels in melanosomes, the subcellular organelles to
which the 2 proteins, tyrosinase and catalase B, have been localized by
ultrastructural immunocytochemistry. Cohen et al. (1990) reported the
nucleotide and deduced amino acid sequence of the cDNA coding for the
human homolog of the mouse b locus gene product. They referred to the
protein as tyrosinase-related protein (TRP). In the mouse the protein
encoded by chromosome 4 is referred to as tyrosinase-related protein-1
because a second such protein, Trp-2, encoded by mouse chromosome 14 has
been demonstrated (Jackson et al., 1992). The locus on chromosome 14 is
the site of the 'slaty' mutation. Human TRP is shorter than the mouse
Trp-1 by 10 amino acids at the carboxy terminus and the degree of
sequence homology is about 93%.

Johnson and Jackson (1992) characterized 'light,' a dominant mutant
allele at the mouse 'brown' locus. The mutation results in hairs
pigmented only at their tips. They showed that the phenotype is due to
premature melanocyte death and, by sequencing the tyrosinase-related
protein-1 cDNA from light mice, demonstrated a single base alteration
causing an arg-to-cys change in the protein. Premature melanocyte death
occurred only in pigmented mice, indicating that the cell death is
mediated through the inherent cytotoxicity of pigment production. They
suggested that this gene should be studied as a candidate gene in
premature graying in humans (139100). Shibahara et al. (1992)
demonstrated that the b gene in the mouse is about 18 kb long and
organized into 8 exons and 7 introns. Two missense mutations, resulting
in a cys-to-tyr substitution at position 86 (codon 110) and an
arg-to-cys substitution at position 302 (codon 326), were found in 2
b-mutant strains.

Ramsay et al. (1991) referred to the human gene as CAS2 since its
product is thought to have catalase activity. By Southern blot analysis
with 2 somatic cell hybrid lines, one with chromosome 9 as its only
human component and another with 9q as its only human component, Ramsay
et al. (1991) and Chintamaneni et al. (1991) demonstrated that CAS2 maps
to 9p. This was confirmed by in situ hybridization, which demonstrated
location of the gene in the region 9pter-p22. They were prompted to seek
mapping on chromosome 9 because of the considerable homology between
human chromosome 9 and mouse chromosome 4. By species-specific PCR in
connection with human/rodent somatic cell hybrids, Abbott et al. (1991)
also mapped the TYRP gene to human 9p. Murty et al. (1992) refined the
assignment to 9p23. They pointed out that the 9p region has been
reported to be altered nonrandomly in human melanoma, suggesting a role
for the region near the TYRP locus in melanocyte transformation.
However, the work of Fountain et al. (1992) excluded the TYRP locus from
involvement in cutaneous malignant melanoma (155600).

Sturm et al. (1995) showed that the TYRP1 protein is encoded in 7 exons
spread over 24 kb of genomic DNA. By contrast, the TYRP2 protein is
encoded by 8 exons. TYRP1, TYRP2, and the tyrosinase gene share a common
C-terminal membrane spanning exon. The position of intron junctions
suggested that TYRP1 was derived from a TYR duplication and then was
itself duplicated to give rise to the TYRP2 gene. The comparisons also
suggested that at least some of the introns within the TYR, TYRP1, and
TYRP2 coding regions were gained after duplication and that intron
slippage was unlikely to have occurred.

Evidence indicated that the 'brown albinism' mutation (203290) is
homologous to 'brown' in the mouse (King, 1992).

Boissy et al. (1996) described a set of African-American fraternal
twins, one of whom had light brown skin and hair and blue-gray irides
with a red reflex consistent with brown oculocutaneous albinism. The
unaffected twin had dark hair and skin pigment. Melanocytes from the
affected twin showed an absence of immune-reactive TYRP1. Analysis of
mRNA revealed that transcription of TYRP1 was completely absent in the
affected twin. Through the amplification of exons by PCR for SSCP
analysis, the affected twin was found to be homozygous for a single
basepair deletion in exon 6. The deletion of an A in codon 368 led to a
premature stop at codon 384. Boissy et al. (1996) proposed that the
association of this mutation with the absence of a transcript is due to
decreased stability of the truncated transcript.

*FIELD* AV
.0001
ALBINISM, OCULOCUTANEOUS, TYPE III
BROWN OCULOCUTANEOUS ALBINISM
TYRP1, 1-BP DEL, 384TER
In an African-American fraternal twin, Boissy et al. (1996) found a
single basepair deletion in exon 6. The deletion of an A in codon 368
led to a premature stop at codon 384.

*FIELD* SA
Muller et al. (1988)
*FIELD* RF
1. Abbott, C.; Jackson, I. J.; Carritt, B.; Povey, S.: The human
homolog of the mouse brown gene maps to the short arm of chromosome
9 and extends the known region of homology with mouse chromosome 4. Genomics 11:
471-473, 1991.

2. Boissy, R. E.; Zhao, H.; Oetting, W. S.; Austin, L. M.; Wildenberg,
S. C.; Boissy, Y. L.; Zhao, Y.; Sturm, R. A.; Hearing, V. J.; King,
R. A.; Nordlund, J. J.: Mutation in and lack of expression of tyrosinase-related
protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous
albinism: a new subtype of albinism classified as 'OCA3.' Am. J.
Hum. Genet. 58: 1145-1156, 1996.

3. Chintamaneni, C. D.; Ramsay, M.; Colman, M.-A.; Fox, M. F.; Pickard,
R. T.; Kwon, B. S.: Mapping the human CAS2 gene, the homologue of
the mouse brown (b) locus, to human chromosome 9p22-pter. Biochem.
Biophys. Res. Commun. 178: 227-235, 1991.

4. Cohen, T.; Muller, R. M.; Tomita, Y.; Shibahara, S.: Nucleotide
sequence of the cDNA encoding human tyrosinase-related protein. Nucleic
Acids Res. 18: 2807-2808, 1990.

5. Fountain, J. W.; Karayiorgou, M.; Ernstoff, M. S.; Kirkwood, J.
M.; Vlock, D. R.; Titus-Ernstoff, L.; Bouchard, B.; Vijayasaradhi,
S.; Houghton, A. N.; Lahti, J.; Kidd, V. J.; Housman, D. E.; Dracopoli,
N. C.: Homozygous deletions within human chromosome band 9p21 in
melanoma. Proc. Nat. Acad. Sci. 89: 10557-10561, 1992.

6. Halaban, R.; Moellmann, G.: Murine and human b locus pigmentation
genes encode a glycoprotein (gp75) with catalase activity. Proc.
Nat. Acad. Sci. 87: 4809-4813, 1990.

7. Jackson, I. J.: A cDNA encoding tyrosinase-related protein maps
to the brown locus in mouse. Proc. Nat. Acad. Sci. 85: 4392-4396,
1988. Note: Erratum: Proc. Nat. Acad. Sci. 86: 997 only, 1989.

8. Jackson, I. J.; Chambers, D. M.; Tsukamoto, K.; Copeland, N. G.;
Gilbert, D. J.; Jenkins, N. A.; Hearing, V.: A second tyrosinase-related
protein, TRP-2, maps to and is mutated at the mouse slaty locus. EMBO
J. 11: 527-535, 1992.

9. Johnson, R.; Jackson, I. J.: Light is a dominant mouse mutation
resulting in premature cell death. Nature Genet. 1: 226-229, 1992.

10. King, R. A.: Personal Communication. Minneapolis, Minn.  12/31/1992.

11. Kwon, B. S.; Halaban, R.; Chintamaneni, C.: Molecular basis of
mouse Himalayan mutation. Biochem. Biophys. Res. Commun. 161: 252-260,
1989.

12. Muller, G.; Ruppert, S.; Schmid, E.; Schutz, G.: Functional analysis
of alternatively spliced tyrosinase gene transcripts. EMBO J. 7:
2723-2730, 1988.

13. Murty, V. V. V. S.; Bouchard, B.; Mathew, S.; Vijayasaradhi, S.;
Houghton, A. N.: Assignment of the human TYRP (brown) locus to chromosome
region 9p23 by nonradioactive in situ hybridization. Genomics 13:
227-229, 1992.

14. Ramsay, M.; Colman, M. A.; Jenkins, T.; Fox, M.; Chintamaneni,
C.; Pickard, R.; Kwon, B.: The human CAS2 locus (homologous to the
mouse b locus) maps to 9p22-pter. (Abstract) Cytogenet. Cell Genet. 58:
1943 only, 1991.

15. Shibahara, S.; Tomita, Y.; Yoshizawa, M.; Shibata, K.; Tagami,
H.: Identification of mutation in the pigment cell-specific gene
located at the brown locus in mouse. Pigment Cell Res. Suppl. 2:
90-95, 1992.

16. Sturm, R. A.; O'Sullivan B. J.; Box, N. F.; Smith, A. G.; Smit,
S. E.; Puttick, E. R. J.; Parsons, P. G.; Dunn, I. S.: Chromosomal
structure of the human TYRP1 and TYRP2 loci and comparison of the
tyrosinase-related protein gene family. Genomics 29: 24-34, 1995.

*FIELD* CN
Moyra Smith - updated: 6/18/1996

*FIELD* CD
Victor A. McKusick: 8/24/1990

*FIELD* ED
mark: 11/27/1996
carol: 6/18/1996
mark: 10/4/1995
terry: 1/27/1995
jason: 6/7/1994
warfield: 4/7/1994
pfoster: 3/25/1994
mimadm: 2/11/1994

*RECORD*
*FIELD* NO
115645
*FIELD* TI
115645 CATARACT, ABERRANT ORAL FRENULA, AND GROWTH RETARDATION
*FIELD* TX
Wellesley et al. (1991) described a mother and 2 children, a boy and a
girl, with short stature, cataracts, and aberrant oral frenula. The
mother was 150 cm tall (less than the third centile) and had had
cataracts removed in early adulthood. The boy had left ptosis with
hypermetropia, and bilateral posterior polar cataracts were removed at
the age of 3 years. His facial changes consisted of epicanthal folds.
There were numerous aberrant frenula of the upper alveolar margin. He
had a small umbilical hernia and had had bilateral inguinal
herniorrhaphies. The girl had a cavernous hemangioma at the right corner
of her mouth but at 19 months had not yet developed cataracts which
occurred later in her brother.

*FIELD* RF
1. Wellesley, D.; Carman, P.; French, N.; Goldblatt, J.: Cataracts,
aberrant oral frenula, and growth retardation: a new autosomal dominant
syndrome. Am. J. Med. Genet. 40: 341-342, 1991.

*FIELD* CS

Growth:
   Short stature

Eyes:
   Cataracts

Mouth:
   Aberrant oral frenula;
   Ptosis;
   Hypermetropia;
   Epicanthus

Abdomen:
   Umbilical hernia;
   Inguinal hernia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/25/1991

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 10/25/1991

*RECORD*
*FIELD* NO
115650
*FIELD* TI
*115650 CATARACT, ANTERIOR POLAR 1; CTAA1
CATARACT, ANTERIOR POLAR; CAP
*FIELD* TX
Anterior polar cataracts, small opacities on the anterior surface of the
lens, usually do not interfere with vision. They are said (Merin, 1974)
to occur as either an autosomal dominant, autosomal recessive, or
X-linked trait. (See 156850 for the association of anterior polar
cataracts with microphthalmia and other features.) Three mechanisms are
postulated for their formation: imperfect separation of the lens from
the surface ectoderm during the fifth week of embryologic development;
secondary changes in the epithelial cells with formation of an abnormal
mass in the region of the anterior pole; and incomplete resorption of
blood vessels and mesoderm at the anterior pole of the embryonic lens.
One of these mechanisms may have occurred in the 4 persons in 3
generations of a family reported by Moross et al. (1984) with an
apparently balanced translocation t(2;14)(p25;q24) and anterior polar
cataract. Miller et al. (1992) described an infant girl with multiple
congenital anomalies associated with a rare terminal deletion of
chromosome 14; the karyotype was that of mos46,XX/46,XX,del(14)(q32.3).
There was unilateral nuclear cataract of the left eye. Miller et al.
(1992) suggested that the finding, together with the report of Moross et
al. (1984), indicates the localization of a cataract-producing mutation
on chromosome 14. It should be noted, however, that the abnormality in
the case of Miller et al. (1992) was situated more distal.

Mutations causing congenital cataracts have been mapped to 1q2 (116200),
2q33-q35 (123660), 16q22.1 (116800), and Xp (302200) or Xp22.3-p21.1
(302350), the last 2 possibly representing the same entity.

*FIELD* RF
1. Merin, S.: Congenital cataracts.In: Goldberg, M. F.: Genetic
and Metabolic Eye Disease.  Boston: Little, Brown (pub.)  1974.
Pp. 337-355.

2. Miller, B. A.; Jaafar, M. S.; Capo, H.: Chromosome 14--terminal
deletion and cataracts. Arch. Ophthal. 110: 1053 only, 1992.

3. Moross, T.; Vaithilingam, S. S.; Styles, S.; Gardner, H. A.: Autosomal
dominant anterior polar cataracts associated with a familial 2;14
translocation. J. Med. Genet. 21: 52-53, 1984.

*FIELD* CS

Eyes:
   Small anterior lens surface opacities;
   Vision usually normal

Inheritance:
   Autosomal dominant;
   also autosomal recessive, or X-linked

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/12/1997
carol: 12/20/1994
mimadm: 6/25/1994
carol: 12/15/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
115660
*FIELD* TI
*115660 CATARACT, CONGENITAL, CERULEAN TYPE 1; CCA1
*FIELD* TX
Cerulean cataract, first described by Vogt (1922), is characterized by
predominantly peripheral bluish and white opacifications organized in
concentric layers with occasional central lesions arranged radially. The
opacities are observed in the superficial layers of the fetal nucleus as
well as the adult nucleus of the lens. Involvement is usually bilateral.
Visual acuity is only mildly reduced in childhood. In adulthood, the
opacifications may progress, making lens extraction necessary.
Histologically the lesions are described as fusiform cavities between
lens fibers which contain a deeply staining granular material. Although
the lesions may take on various colors, a dull blue is the most common
appearance and is responsible for the designation 'cerulean cataract.'
Bodker et al. (1990) reported a kindred in which autosomal dominant
cataract (also 'autosomal dominant congenital cataract,' or ADCC) is
known to have occurred in at least 6 generations. Of a total of 159
relatives, 17 affected persons were evaluated. Visual acuity was normal
to mildly decreased until adult life except in 1 female, the product of
affected first cousins, who was born with bilateral microphthalmos and
dense congenital cataracts. Bodker et al. (1990) suggested that this
represented the homozygous state. There were no extraocular
abnormalities; specifically, the patient was of normal intelligence.
Linkage at short distances could be excluded for all 18 markers that
were informative.

Armitage et al. (1995) performed linkage analysis in a large
4-generation pedigree in which cerulean cataract segregated. A
genome-wide search led to the disorder being mapped to 17q24 through
linkage to DNA markers. They described the disorder as early in onset
and progressive rather than congenital. Affected newborns appeared
asymptomatic until the age of 18 to 24 months, at which time they could
be clinically diagnosed by slit-lamp examination through the appearance
of tiny blue or white opacities that formed first in the superficial
layers of the fetal lens nucleus. Armitage et al. (1995) suggested that
cerulean cataracts should be classified as a developmental cataract
rather than a congenital cataract. The opacities progressed throughout
the adult lens nucleus and the cortex, forming concentric layers, with
central lesions oriented radially. The galactokinase gene (230200) maps
to the same region and was investigated as a possible site of the
mutation in cerulean cataract. See also 601547, a locus for
cerulean-type cataract linked to the beta-crystallin region (600929) of
chromosome 22.

*FIELD* SA
Vogt  (1922)
*FIELD* RF
1. Armitage, M. M.; Kivlin, J. D.; Ferrell, R. E.: A progressive
early onset cataract gene maps to human chromosome 17q24. Nature
Genet. 9: 37-40, 1995.

2. Bodker, F. S.; Lavery, M. A.; Mitchell, T. N.; Lovrien, E. W.;
Maumenee, I. H.: Microphthalmos in the presumed homozygous offspring
of a first cousin marriage and linkage analysis of a locus in a family
with autosomal dominant cerulean congenital cataracts. Am. J. Med.
Genet. 37: 54-59, 1990.

3. Vogt, A.: Die Spezifitat angeborener und erworbener Starformen
fur die einzelnen Linsenzonen. Graefe Arch. Klin. Exp. Ophthal. 108:
219-228, 1922.

4. Vogt, A.: Weitere Ergebnisse der Spaltlampenmikroskopie des vorderen
Bulbusabschnittes. III. (Abschnitt-Fortsetzung). Angeborene und fruh
aufgetretene Linsenveranderungen. Graefe Arch. Klin. Exp. Ophthal. 108:
182-191, 1922.

*FIELD* CS

Eyes:
   Peripheral bluish and white concentric layered opacities with occasional
   central lesions arranged radially;
   Mild visual loss

Inheritance:
   Autosomal dominant

*FIELD* CN
Moyra Smith - updated: 12/18/1996

*FIELD* CD
Victor A. McKusick: 10/23/1990

*FIELD* ED
mark: 12/18/1996
terry: 12/17/1996
carol: 1/20/1995
mimadm: 6/25/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 10/23/1990

*RECORD*
*FIELD* NO
115665
*FIELD* TI
*115665 CATARACT, CONGENITAL, VOLKMANN TYPE; CCV
*FIELD* TX
In a large Danish kindred by the name of Volkmann, Lund et al. (1992)
observed autosomal dominant congenital cataract with variable
expressivity. All affected persons eventually required surgery, most of
them in the first or second decade of life. Linkage studies revealed no
linkage to CRYG (123660) or to Fy (110700), on chromosome 2 and
chromosome 1, respectively, to which linkage of congenital cataract has
been demonstrated. Location on chromosome 16, which is the site of the
Marner cataract mutation in another large Danish kindred (116800), was
also excluded. The findings confirm heterogeneity of congenital
cataract. Eiberg et al. (1995) established close linkage to a short
tandem repeat polymorphism at locus D1S243; maximum lod = 14.04 at theta
in males in 0.025, theta in females = 0.00, at a penetrance of 0.90.
This disorder is characterized by a progressive, central and zonular
cataract, with opacities both in the embryonic, fetal, and juvenile
nucleus and around the anterior and posterior Y-suture. Expression is
highly variable, ranging from hardly recognizable opacities in the lens
to dense cataracts. Affected members may thus be unaware of having the
disease. Comparison with other markers indicated that CCV is located in
the telomeric portion of 1p distal to GDH (138090), which is located in
1pter-p36.13. The gene of enolase-1 (ENO1; 172430) is in the same
region. This was considered a candidate gene because ENO1 encodes
tau-crystallin; however, the 1 family described with hereditary red cell
enolase partial deficiency (Lachant et al., 1986) showed no evidence of
cataract.

In a 3-generation family ascertained through the East of Scotland Blood
Transfusion Service in Dundee, Scotland, Huang et al. (1996) found that
a cataract-causing mutation was cosegregating with an autosomal dominant
anomaly of RH type known as the Evans phenotype. The geography and the
genetic linkage suggested that the form of cataract may be the same as
that in the Danish family. The red cell Evans phenotype is produced by a
hybrid RH gene in which exons 2-6 from the RHD gene (111680) is
transferred to the RHCE gene (111700). Warburg (1996) reported that her
colleague, Hans Eiberg, found no evidence of linkage with Rh in this
family.

*FIELD* RF
1. Eiberg, H.; Lund, A. M.; Warburg, M.; Rosenberg, T.: Assignment
of congenital cataract Volkmann type (CCV) to chromosome 1p36. Hum.
Genet. 96: 33-38, 1995.

2. Huang, C.-H.; Chen, Y.; Reid, M.; Ghosh, S.: Genetic recombination
at the human RH locus: a family study of the red-cell Evans phenotype
reveals a transfer of exons 2-6 from the RHD to the RHCE gene. Am.
J. Hum. Genet. 59: 825-833, 1996.

3. Lachant, N. A.; Jennings, M. A.; Tanaka, K. R.: Partial erythrocyte
enolase deficiency: a hereditary disorder with variable clinical expression.
(Abstract) Blood 68: 55a only, 1986.

4. Lund, A. M.; Eiberg, H.; Rosenberg, T.; Warburg, M.: Autosomal
dominant cataract; linkage relations; clinical and genetic heterogeneity. Clin.
Genet. 41: 65-69, 1992.

5. Warburg, M.: Personal Communication. Tureby, Denmark  11/24/1996.

*FIELD* CS

Eyes:
   Congenital cataract;
   Progressive visual loss

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 5/1/1992

*FIELD* ED
mark: 12/26/1996
terry: 12/17/1996
mark: 10/25/1996
terry: 10/16/1996
joanna: 11/29/1995
mark: 7/19/1995
mimadm: 6/25/1994
carol: 5/1/1992

*RECORD*
*FIELD* NO
115700
*FIELD* TI
*115700 CATARACT, CRYSTALLINE ACULEIFORM OR FROSTED
*FIELD* TX
Although recessive inheritance is suggested by some reports, dominant
inheritance is clear from studies such as those of Romer (1926) and of
Gifford and Puntenney (1937).

*FIELD* RF
1. Gifford, S. R.; Puntenney, I.: Coralliform cataract and a new
form of congenital cataract with crystals in the lens. Arch. Ophthal. 17:
885-892, 1937.

2. Romer, A.: Untersuchung ueber die Erblichkeit der Spiesskatarakt
(Vogt). Arch. Klaus Stift. Vererbungsforsch. 2: 207-220, 1926.

*FIELD* CS

Eyes:
   Crystalline cataract;
   Congenital cataract

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
115800
*FIELD* TI
*115800 CATARACT, CRYSTALLINE CORALLIFORM
*FIELD* TX
Both types of crystalline cataract (coralliform and aculeiform) are
characterized by fine crystals in the axial region of the lens. Both are
usually inherited as dominants, although in rare instances recessive
inheritance is suspected. Dominant pedigrees of coralliform crystalline
cataract were reported by Nettleship (1909), Riad (1938) and Jordan
(1955).

*FIELD* RF
1. Jordan, M.: Stammbaumuntersuchungen bei Cataracta stellata coralliformis.
Klin. Mbl. Augenheilk. 126: 469-475, 1955.

2. Nettleship, E.: Seven new pedigrees of hereditary cataract. Trans.
Ophthal. Soc. U.K. 29: 188-211, 1909.

3. Riad, M.: Congenital familial cataract with cholesterin deposits.
Brit. J. Ophthal. 22: 745-749, 1938.

*FIELD* CS

Eyes:
   Crystalline coralliform cataract;
   Fine crystals in axial lens region

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
115900
*FIELD* TI
*115900 CATARACT, FLORIFORM
*FIELD* TX
Transmission of floriform cataract was recorded through 4 generations by
Doggart (1957) and through 5 generations by Tosch (1958).

*FIELD* RF
1. Doggart, J. H.: Congenital cataract. Trans. Ophthal. Soc. U.K. 77:
31-37, 1957.

2. Tosch, C.: Beitrag zur Stammbaumforschung der Cataracta floriformis.
Klin. Mbl. Augenheilk. 133: 60-66, 1958.

*FIELD* CS

Eyes:
   Floriform cataract;
   Congenital cataract

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 10/21/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
116100
*FIELD* TI
116100 CATARACT, MEMBRANOUS
*FIELD* TX
Gruber (1945) described 6 cases in 4 generations. This should be
considered a total cataract that has undergone regression or resorption.

*FIELD* SA
Sellars and Beighton (1978)
*FIELD* RF
1. Gruber, M.: Ueber primaere familiaere Linsendysplasie. Ophthalmologica 110:
60-73, 1945.

2. Sellars, S. L.; Beighton, P. H.: Deafness in osteodysplasty of
Melnick and Needles. Arch. Otolaryng. 104: 225-227, 1978.

*FIELD* CS

Eyes:
   Membranous cataract

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
116150
*FIELD* TI
*116150 CATARACT-MICROCORNEA SYNDROME
MICROCORNEA-CATARACT SYNDROME
*FIELD* TX
Mollica et al. (1985) studied a Sicilian family in which many persons
had cataract with microcornea and myopia. Although cataracts started
early, they were apparently not congenital. The axial length of the
globe was normal. Myopia was thought by the authors to distinguish this
disorder from the cataract-microcornea syndromes reported by Friedmann
and Wright (1952) and by Polomeno and Cummings (1979). It is possible
that these 3 families all had the same disorder. Indeed, Salmon et al.
(1988) were of that opinion and pointed to the family of Green and
Johnson (1986) as another example. Salmon et al. (1988) documented the
syndrome in a 7-generation family. Microcornea and cataract were present
in 18 members, and an additional 6 had sclerocornea or Peters anomaly.
Most persons with microcornea had a corneal diameter of less than 11 mm
in both meridians, with moderately steep corneal curvatures. The
inherited cataracts progressed to form a total cataract after visual
maturity had been achieved. In the 4 affected children who had not
undergone cataract extraction, the common abnormality was a posterior
polar lens opacity.

Stefaniak et al. (1995) reported a family in which 14 members were
affected. Transmission was probably autosomal dominant, although the
proportion of affected members was so high that Stefaniak et al. (1995)
were tempted to suspect preferential transmission of the chromosome
carrying the mutant gene. In this 4-generation family, all 7 members of
the third generation were affected and almost all members of the fourth
generation as well.

*FIELD* RF
1. Friedmann, M. W.; Wright, E. S.: Hereditary microcornea and cataract
in 5 generations. Am. J. Ophthal. 35: 1017-1021, 1952.

2. Green, J. S.; Johnson, G. J.: Congenital cataract with microcornea
and Peters' anomaly as expressions of one autosomal dominant gene.
Ophthal. Paediat. Genet. 7: 187-194, 1986.

3. Mollica, F.; Li Volti, S.; Tomarchio, S.; Gangi, A.; Risiglione,
V.; Gorgone, G.: Autosomal dominant cataract and microcornea associated
with myopia in a Sicilian family. Clin. Genet. 28: 42-46, 1985.

4. Polomeno, R. C.; Cummings, C.: Autosomal dominant cataracts and
microcornea. Canad. J. Ophthal. 14: 227-229, 1979.

5. Salmon, J. F.; Wallis, C. E.; Murray, A. D. N.: Variable expressivity
of autosomal dominant microcornea with cataract. Arch. Ophthal. 106:
505-510, 1988.

6. Stefaniak, E.; Zaremba, J.; Cieslinska, I.; Kropinska, E.: An
unusual pedigree with microcornea-cataract syndrome. J. Med. Genet. 32:
813-815, 1995.

*FIELD* CS

Eyes:
   Cataract;
   Microcornea;
   Iris coloboma;
   Myopia;
   Sclerocornea;
   Peters anomaly

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/6/1995
mimadm: 6/25/1994
carol: 3/31/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
116200
*FIELD* TI
*116200 CATARACT, LAMELLAR
CATARACT, ZONULAR PULVERULENT 1; CAE1; CAE;;
PULVERULENT ZONULAR CATARACT;;
CATARACT, NUCLEAR;;
CATARACT, DUFFY-LINKED
*FIELD* TX
Nettleship and Ogilvie (1906) described 18 cases in 4 generations.
Harman (1909) reported 19 cases in 5 generations, Smith (1910) 26 in 4
generations, Lee and Benedict (1950) 63 in 6 generations, etc. Zonular
pulverulent cataract was present in the family in which linkage with
Duffy blood group was demonstrated by Renwick and Lawler (1963). The
kindred, by the name of Coppock, had been described earlier by
Nettleship (1909). Renwick and Lawler (1963) referred to the disorder as
congenital zonular cataract. Renwick (1970) referred to it as total
nuclear cataract. In the latter publication the possibility that some
other forms of dominant cataract might be linked with Duffy was
discussed. A morphologically identical cataract was described by
Hammerstein and Scholt (1973) who in their kindred found no linkage with
Duffy. Conneally et al. (1978) found linkage to 1qh in one family (lod
of 2.7 at a recombination fraction of 0.0) and no linkage to chromosome
1 markers in several other families. In the family showing linkage, the
lenticular opacities were located in the fetal nucleus with scattered,
fine, diffuse cortical opacities and incomplete cortical 'riders'
similar to those described by Nettleship (1909). Phillips and Cook
(1979) suggested that the Coppock cataract is specifically central
pulverulent cataract with only mild visual disability that never seems
to require operation. They found it not linked to Duffy. The
Duffy-linked type is zonular or lamellar with a pulverulent center. The
CAE cataract affects both the embryonic nucleus and the fetal nucleus,
i.e., is 'total nuclear.' It is larger (about 4 mm) than the
Coppock-like cataract (about 2 mm), which is limited to the embryonic
nucleus (Renwick, 1987) and is apparently caused by mutation in
gamma-crystallin (123660).

Scott et al. (1994) described a family in which 28 of 53 examined
individuals had congenital cataracts. Of these 28 individuals, 19 had
unilateral cataracts (8 on the right and 11 on the left) and 9 had
bilateral cataracts. The clinically unaffected eye in patients with
unilateral cataracts showed no evidence of lenticular opacity under
detailed slit-lamp examination. Severity of the cataracts included a
subtle unilateral zonular cataract with 20/20 visual acuity, bilateral
inner fetal nuclear pulverulent opacities with 20/16 visual acuity in
both eyes, and dense unilateral and bilateral nuclear cataracts
requiring early surgical removal. Incorporating the historic data on
patients who were not examined, Scott et al. (1994) found 48 affected
members, including 3 obligate carriers who were not examined. In all, 28
members of the family had unilateral cataracts. Linkage studies were
necessary to determine whether the gene was linked to previously defined
cataract loci on chromosomes 1, 2, or 16 or unlinked to any of these.

*FIELD* SA
Lubsen et al. (1987)
*FIELD* RF
1. Conneally, P. M.; Wilson, A. F.; Merritt, A. D.; Helveston, E.
M.; Palmer, C. G.; Wang, L. V.: Confirmation of genetic heterogeneity
in autosomal dominant forms of congenital cataracts from linkage studies.
Cytogenet. Cell Genet. 22: 295-297, 1978.

2. Hammerstein, W.; Scholt, W.: Familiaere Form einer 'Cataracta
centralis': klinisch-genetische Studie mit Koppelungsdaten. Graefe
Arch. Klin. Exp. Ophthal. 189: 9-19, 1973.

3. Harman, N. B.: Congenital cataract, a pedigree of five generations.
Trans. Ophthal. Soc. U.K. 29: 101-108, 1909.

4. Lee, J. B.; Benedict, W. L.: Hereditary nuclear cataract. Arch.
Ophthal. 44: 643-650, 1950.

5. Lubsen, N. H.; Renwick, J. H.; Tsui, L.-C.; Breitman, M. L.; Schoenmakers,
J. G. G.: A locus for a human hereditary cataract is closely linked
to the gamma-crystallin gene family. Proc. Nat. Acad. Sci. 84:
489-492, 1987.

6. Nettleship, E.: Seven new pedigrees of hereditary cataract. Trans.
Ophthal. Soc. U.K. 29: 188-211, 1909.

7. Nettleship, E.; Ogilvie, F. M.: A peculiar form of hereditary
congenital cataract. Trans. Ophthal. Soc. U.K. 26: 191-206, 1906.

8. Phillips, C. I.; Cook, P. J. L.: Personal Communication. Edinburgh,
Scotland and London, England, respectively  6/24/1979.

9. Renwick, J. H.: Eyes on chromosomes. J. Med. Genet. 7: 239-243,
1970.

10. Renwick, J. H.: Personal Communication. London, England  3/16/1987.

11. Renwick, J. H.; Lawler, S. D.: Probable linkage between a congenital
cataract locus and the Duffy blood group locus. Ann. Hum. Genet. 27:
67-84, 1963.

12. Scott, M. H.; Hejtmancik, J. F.; Wozencraft, L. A.; Reuter, L.
M.; Parks, M. M.; Kaiser-Kupfer, M. I.: Autosomal dominant congenital
cataract: interocular phenotypic variability. Ophthalmology 101:
866-871, 1994.

13. Smith, P.: A pedigree of Doyne's discoid cataract. Trans. Ophthal.
Soc. U.K. 30: 37-42, 1910.

*FIELD* CS

Eyes:
   Nuclear cataract;
   Pulverulent zonular cataract;
   Congenital cataract

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 8/24/1994
davew: 6/27/1994
mimadm: 6/25/1994
warfield: 4/7/1994
carol: 10/21/1993
carol: 1/8/1993

*RECORD*
*FIELD* NO
116300
*FIELD* TI
*116300 CATARACT, NUCLEAR DIFFUSE NONPROGRESSIVE
*FIELD* TX
Opacity is limited to the fetal nucleus, resembles that of senile
nuclear sclerosis, and is nonprogressive. Vogt (1931) and Weber (1940)
documented dominant inheritance.

*FIELD* RF
1. Vogt, A.: Lehrbuch und Atlas der Spaltlampenmikroskopie des lebenden
Auges. Linse und Zonula.  Berlin: J. Springer (pub.)  1931.

2. Weber, E.: Weitere Untersuchungen ueber den kongenitalen, vererbten
Kernstar (Cataracta nuclearis diffusa congenita hereditaria Vogt).
Schweiz. Med. Wschr. 70: 295-297, 1940.

*FIELD* CS

Eyes:
   Cataract, nuclear diffuse nonprogressive

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
116400
*FIELD* TI
*116400 CATARACT, NUCLEAR TOTAL
*FIELD* TX
This is one of the most frequent types of severe congenital cataract
that interferes seriously with vision. Dominant pedigrees were reported
by Brown (1924), Parrow (1955), and others.

*FIELD* RF
1. Brown, A. L.: Hereditary cataract. Am. J. Ophthal. 7: 36-38,
1924.

2. Parrow, R. D.: Hereditary cataract in two families. Acta Paediat. 44:
460-464, 1955.

*FIELD* CS

Eyes:
   Nuclear cataract;
   Congenital cataract;
   Vision seriously impaired

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
116600
*FIELD* TI
*116600 CATARACT, POSTERIOR POLAR
CTPA
*FIELD* TX
In Nettleship's family (Nettleship, 1909, 1912), congenital posterior
polar opacities were present and scattered cortical opacities appeared
in childhood and progressed to total cataract. Tulloh (1955) described
15 affected in 5 generations. Valk and Binkhorst (1956) described
associated choroideremia and myopia in 2 generations.

Ionides et al. (1997) mapped autosomal dominant posterior polar cataract
(symbolized CPP by them) to 1p on the basis of studies in a single
family. In the 10 affected members of the family, the opacity, which was
bilateral in all cases, consisted of a single well-defined plaque
confined to the posterior pole of the lens and varied from 0.5 to 3 mm
in diameter. Hospital records indicated that the opacity was usually
present at birth or developed within the first few months of life but
did not progress with age to other regions of the lens. There was no
evidence of posterior lenticonus or high myopia and no family history of
other ocular or systemic abnormalities. Significantly positive lod
scores were obtained for markers D1S508 and D1S468; multipoint analysis
gave a maximum lod score of 3.48 (theta = 0.07) between markers D1S508
and D1S468. From haplotype data, however, Ionides et al. (1997)
concluded that the CPP locus probably lies in the telomeric interval
1pter-D1S2845, which includes the locus for the clinically distinct
Volkman congenital cataract (CCV; 115665).

*FIELD* RF
1. Ionides, A. C. W.; Berry, V.; Mackay, D. S.; Moore, A. T.; Bhattacharya,
S. S.; Shiels, A.: A locus for autosomal dominant posterior polar
cataract on chromosome 1p. Hum. Molec. Genet. 6: 47-51, 1997.

2. Nettleship, E.: Seven new pedigrees of hereditary cataract. Trans.
Ophthal. Soc. U.K. 29: 188-211, 1909.

3. Nettleship, E.: A pedigree of presenile or juvenile cataract. Trans.
Ophthal. Soc. U.K. 32: 337-352, 1912.

4. Tulloh, C. G.: Heredity of posterior polar cataract with report
of a pedigree. Brit. J. Ophthal. 39: 374-379, 1955.

5. Valk, L. E. M.; Binkhorst, P. G.: A case of familial dwarfism,
with choroideremia, myopia, posterior polar cataract and zonular cataract. Ophthalmologica 132:
299 only, 1956.

*FIELD* CS

Eyes:
   Posterior polar cataract;
   Congenital cataract;
   Total cataract;
   Choroideremia;
   Myopia

Inheritance:
   Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 2/12/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/14/1997
terry: 2/12/1997
terry: 2/7/1997
davew: 6/27/1994
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
116700
*FIELD* TI
116700 CATARACT, TOTAL CONGENITAL; CC
*FIELD* TX
Meissner (1933) reported 22 cases in 6 generations of 1 family and 13
cases in 5 generations in a second. Three generations were affected in
the family reported by Jahns (1938). Richards et al. (1984) studied
linkage in a kindred with autosomal dominant congenital cataract. No
linkage was found with Duffy (110700), thus indicating that this is a
form of cataract distinct from that symbolized CAE (116200). A peak lod
score of 2.109 at theta = 0.10 was obtained for linkage of CC with HP
(140100), which is on chromosome 16. Reese et al. (1987) described
congenital cataract in father and infant son, both of whom had
translocation t(3;4)(p26.2;p15). In the child, the cataracts were not
found by an examining physician at age 4 weeks, but 'milky' pupils were
noted by the mother at 7 weeks, and at 9 weeks both lenses showed fully
mature cataracts with no retinal reflex. The father had dense bilateral
cataracts diagnosed at birth and underwent uneventful lens aspirations
at 3 and 8 months of age; thus, it is possible that the cause of this
cataract is a genetic change at or near one of the breakpoints, 3p26.2
or 4p15.

*FIELD* RF
1. Jahns, H.: Angeborener Star in drei Generationen. Klin. Mbl.
Augenheilk. 100: 481-482, 1938.

2. Meissner, M.: Augenaerztliches aus dem Blindeninstitut. Z. Augenheilk. 80:
48-58, 1933.

3. Reese, P. D.; Tuck-Muller, C. M.; Maumenee, I. H.: Autosomal dominant
congenital cataract associated with chromosomal translocation [t(3;4)(p26.2;p15)].
Arch. Ophthal. 105: 1382-1384, 1987.

4. Richards, J.; Maumenee, I. H.; Rowe, S.; Lovrien, E. W.: Congenital
cataract possibly linked to haptoglobin.  (Abstract) Cytogenet. Cell
Genet. 37: 570 only, 1984.

*FIELD* CS

Eyes:
   Congenital cataract;
   Total cataract

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 3/4/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 5/9/1989

*RECORD*
*FIELD* NO
116790
*FIELD* TI
*116790 CATECHOL-O-METHYLTRANSFERASE; COMT
CATECHOL-O-METHYLTRANSFERASE ACTIVITY, LOW, IN RED CELL, INCLUDED
*FIELD* TX
Catechol-O-methyltransferase (COMT; EC 2.1.1.6) catalyzes the transfer
of a methyl group from S-adenosylmethionine to catecholamines, including
the neurotransmitters dopamine, epinephrine, and norepinephrine. This
O-methylation results in one of the major degradative pathways of the
catecholamine transmitters. In addition to its role in the metabolism of
endogenous substance, COMT is important in the metabolism of catechol
drugs used in the treatment of hypertension, asthma and Parkinson's
disease. In blood COMT is found in erythrocytes, while in leukocytes it
exhibits low activity. Weinshilboum and Raymond (1977) found bimodality
for red cell catechol-O-methyltransferase activity. Of a randomly
selected population, 23% had low activity. Segregation analysis of
family data suggested that low activity is recessive. Scanlon et al.
(1979) found that homozygotes have a thermolabile enzyme. Thus, the site
of the low COMT mutation is presumably the structural locus. Levitt and
Baron (1981) confirmed the bimodality of human erythrocyte COMT. They
further showed thermolability of the enzyme in 'low COMT' samples,
suggesting a structural alteration in the enzyme. Autosomal codominant
inheritance of the gene coding for erythrocyte COMT activity was adduced
by Floderus and Wetterberg (1981) and by Weinshilboum and Dunnette
(1981). Gershon and Goldin (1981) concluded that codominant inheritance
was consistent with the family data. Spielman and Weinshilboum (1981)
suggested that the inheritance of red cell COMT is intermediate, or
codominant, there being 3 phenotypes corresponding to the 3 genotypes in
a 2-allele system. The COMT of persons with low enzyme activity is more
thermolabile than that of persons with high activity.

Wilson et al. (1984) excluded tight and close linkage with 21 and 15
loci, respectively. A lod score of 1.27 at theta = 0.1 was found between
COMT and phosphogluconate dehydrogenase (PGD; 172200), which is on
chromosome 1. Gustavson et al. (1973, 1982) reported that COMT activity
was about 40% higher in Down syndrome children than in normal controls.
They attributed this to dosage effect owing to the location of the COMT
gene on chromosome 21. Brahe et al. (1986) studied the expression of
human COMT in interspecies somatic cell hybrids and found 27%
discordance between human chromosome 21 and human COMT. In further
studies of mouse-human cell hybrids with a method permitting direct
detection of COMT isozymes in autoradiozymograms, Brahe et al. (1986)
located the COMT gene on human chromosome 22. By study of DNAs from a
panel of human-hamster somatic cell hybrid lines, Grossman et al. (1991,
1992) mapped COMT to 22q11.1-q11.2. Winqvist et al. (1991) assigned COMT
to 22q11.2 by means of Southern blot analysis of somatic cell hybrids
and chromosomal in situ hybridization. They concluded that COMT is
located proximal to the BCR region involved in chronic myeloid leukemia
(151410). Bucan et al. (1993) mapped the homologous murine gene to
chromosome 16, where, as in the human, it is closely linked to the
lambda light chain genes.

During experiments aimed at building a contiguous group of YACs spanning
22q11, Dunham et al. (1992) found that the HP500 sequence often deleted
in the velocardiofacial syndrome (VCFS; 192430) was located within the
same 450-kb YAC as the COMT gene. They raised the question of whether
low COMT might be responsible for psychotic illness, which is a feature
of the VCF syndrome in adolescents or adults (Shprintzen et al., 1992).

Lundstrom et al. (1991) isolated cDNA clones for COMT from a human
placental cDNA library using synthetic oligonucleotides as probes. The
clones contained an open reading frame that potentially coded for a
24.4-kD polypeptide, presumably corresponding to the cytoplasmic form of
COMT. DNA analysis suggested that the human, as well as the rat, dog,
and monkey, has 1 gene for COMT.

*FIELD* SA
Brahe et al. (1986); Floderus et al. (1982); Goldin et al. (1982);
Siervogel et al. (1984); Weinshilboum  (1979)
*FIELD* RF
1. Brahe, C.; Bannetta, P.; Meera Khan, P.; Arwert, F.; Serra, A.
: Assignment of the catechol-O-methyltransferase gene to human chromosome
22 in somatic cell hybrids. Hum. Genet. 74: 230-234, 1986.

2. Brahe, C.; Bannetta, P.; Serra, A.; Arwert, F.: The increased
COMT activity in Down syndrome patients is not a consequence of dosage
effect owing to location of the gene on chromosome 21: further evidence.
(Letter) Am. J. Med. Genet. 24: 203-204, 1986.

3. Bucan, M.; Gatalica, B.; Nolan, P.; Chung, A.; Leroux, A.; Grossman,
M. H.; Nadeau, J. H.; Emanuel, B. S.; Budarf, M.: Comparative mapping
of 9 human chromosome 22q loci in the laboratory mouse. Hum. Molec.
Genet. 2: 1245-1252, 1993.

4. Dunham, I.; Collins, J.; Wadey, R.; Scambler, P.: Possible role
for COMT in psychosis associated with velo-cardio-facial syndrome.
(Letter) Lancet 340: 1361-1362, 1992.

5. Floderus, Y.; Iselius, L.; Lindsten, J.; Wetterberg, L.: Evidence
for a major locus as well as a multifactorial component in the regulation
of human red blood cell catechol-O-methyl-transferase activity. Hum.
Hered. 32: 76-79, 1982.

6. Floderus, Y.; Wetterberg, L.: The inheritance of human erythrocyte
catechol-O-methyltransferase activity. Clin. Genet. 19: 392-395,
1981.

7. Gershon, E. S.; Goldin, L. R.: Segregation and linkage studies
of plasma dopamine-beta-hydroxylase (DBH), erythrocyte catechol-O-methyltransferase
(COMT) and platelet monoamine oxidase (MAO): possible linkage between
the ABO locus and a gene controlling DBH activity.  (Abstract) Am.
J. Hum. Genet. 33: 136A only, 1981.

8. Goldin, L. R.; Gershon, E. S.; Lake, C. R.; Murphy, D. L.; McGinniss,
M.; Sparkes, R. S.: Segregation and linkage studies of plasma dopamine-beta-hydroxylase
(DBH), erythrocyte catechol-O-methyltransferase (COMT), and platelet
monoamine oxidase (MAO): possible linkage between the ABO locus and
a gene controlling DBH activity. Am. J. Hum. Genet. 34: 250-262,
1982.

9. Grossman, M. H.; Emanuel, B. S.; Budarf, M. L.: Chromosomal mapping
of the human catechol-O-methyltransferase gene to 22q11.1-q11.2. Genomics 12:
822-825, 1992.

10. Grossman, M. H.; Littrell, J.; Weinstein, R.; Punnett, H. H.;
Emanuel, B. S.; Budarf, M.: The gene for human catechol-O-methyltransferase
(COMT) maps to 22pter-22q11.1.  (Abstract) Cytogenet. Cell Genet. 58:
2048 only, 1991.

11. Gustavson, K. H.; Floderus, Y.; Jagell, S.; Wetterberg, L.; Ross,
S. B.: Catechol-O-methyltransferase activity in erythrocytes in Down's
syndrome: family studies. Clin. Genet. 22: 22-24, 1982.

12. Gustavson, K. H.; Wetterberg, L.; Backstrom, M.; Ross, S. B.:
Catechol-O-methyltransferase activity in erythrocytes in Down's syndrome.
Clin. Genet. 4: 279-280, 1973.

13. Levitt, M.; Baron, M.: Human erythrocyte catechol-O-transferase:
variation in thermal lability.  (Abstract) Sixth Int. Cong. Hum.
Genet., Jerusalem 21 only, 1981.

14. Lundstrom, K.; Salminen, M.; Jalanko, A.; Savolainen, R.; Ulmanen,
I.: Cloning and characterization of human placental catechol-O-methyltransferase
cDNA. DNA Cell Biol. 10: 181-189, 1991.

15. Scanlon, P. D.; Raymond, F. A.; Weinshilboum, R. M.: Catechol-O-methyltransferase:
thermolabile enzyme in erythrocytes of subjects homozygous for allele
for low activity. Science 203: 63-65, 1979.

16. Shprintzen, R. J.; Goldberg, R.; Golding-Kushner, K. J.; Marion,
R.: Late-onset psychosis in the velo-cardio-facial syndrome. Am.
J. Med. Genet. 42: 141-142, 1992.

17. Siervogel, R. M.; Weinshilboum, R.; Wilson, A. F.; Elston, R.
C.: Major gene model for the inheritance of catechol-O-methyltransferase
activity in five large families. Am. J. Med. Genet. 19: 315-323,
1984.

18. Spielman, R. S.; Weinshilboum, R. M.: Genetics of red cell COMT
activity: analysis of thermal stability and family data. Am. J.
Med. Genet. 10: 279-290, 1981.

19. Weinshilboum, R.; Dunnette, J.: Thermal stability and the biochemical
genetics of erythrocyte catechol-O-methyltransferase and plasma dopamine-beta-hydroxylase.
Clin. Genet. 19: 426-437, 1981.

20. Weinshilboum, R. M.: Catecholamine biochemical genetics in human
populations. In: Breakefield, X. O.: Neurogenetics: Genetic Approaches
to the Nervous System.  New York: Elsevier/North Holland (pub.)
1979. Pp. 257-282.

21. Weinshilboum, R. M.; Raymond, F. A.: Inheritance of low erythrocyte
catechol-O-methyltransferase activity in man. Am. J. Hum. Genet. 29:
125-135, 1977.

22. Wilson, A. F.; Elston, R. C.; Siervogel, R. M.; Weinshilboum,
R.; Ward, L. J.: Linkage relationships between a major gene for catechol-O-methyltransferase
activity and 25 polymorphic marker systems. Am. J. Med. Genet. 19:
525-532, 1984.

23. Winqvist, R.; Lundstrom, K.; Salminen, M.; Laatikainen, M.; Ulmanen,
I.: Mapping of human catechol-O-methyltransferase gene to 22q11.2
and detection of a frequent RFLP with BglI.  (Abstract) Cytogenet.
Cell Genet. 58: 2051 only, 1991.

*FIELD* CS

Metabolic:
   Catecholamine transmitter degradation

Lab:
   Catechol-O-methyltransferase deficiency

Inheritance:
   Autosomal recessive (22q11.2)

*FIELD* CD
Victor A. McKusick: 1/7/1987

*FIELD* ED
mimadm: 6/25/1994
carol: 10/21/1993
carol: 9/20/1993
carol: 3/25/1993
carol: 12/7/1992
carol: 6/9/1992

*RECORD*
*FIELD* NO
116800
*FIELD* TI
*116800 CATARACT, ZONULAR
PERINUCLEAR CATARACT;;
LAMELLAR CATARACT
MARNER CATARACT, INCLUDED;;
CAM, INCLUDED;;
CTM, INCLUDED
*FIELD* TX
Striking pedigrees were presented by Cridland (1918), Hilbert (1912),
Jankiewicz and Freeberg (1956), Keizer (1952), Knapp (1926), and Marner
(1949), among others. In Marner's family, 132 in 8 generations were
affected, mainly by zonular cataract but some by nuclear, anterior
polar, or stellate cataract. The opacities were progressive, and
'anticipation' (progressively earlier onset in successive generations)
was suggested. In Harman's family (Harman, 1910), malformation of the
fingers was associated. Eiberg et al. (1988) studied the very large
family originally reported by Marner (1949) and found strong evidence of
linkage to haptoglobin: lod score = 8.33 at theta = 0.05 for males and
females combined. See also Marner et al. (1989). The observation by
Richards et al. (1984) of probable linkage of a form of congenital
cataract, described by Maumenee (1979) as posterior polar cataract, to
the haptoglobin locus raises a question as to whether CAM may represent
the same locus as that in the Richards family; see 116700. Possibly
these represent different pathologic alleles. Detailed morphologic
studies of the cataract in as many affected members of each family as
possible and further linkage studies will be worthwhile.

*FIELD* RF
1. Cridland, A. B.: Three cases of hereditary cortical cataract,
with a chart showing the pedigree of a family in which they occurred.
Trans. Ophthal. Soc. U.K. 38: 375-376, 1918.

2. Eiberg, H.; Marner, E.; Rosenberg, T.; Mohr, J.: Marner's cataract
(CAM) assigned to chromosome 16: linkage to haptoglobin. Clin. Genet. 34:
272-275, 1988.

3. Harman, N. B.: Congenital cataract. In: Treasury of Human Inheritance.
London: Cambridge Univ. Press (pub.)  1, Part 4: 1910. Pp. 126-169.

4. Hilbert, R.: Schichtstarbildung durch vier Generationen einer
Familie. Muench. Med. Wschr. 59: 1272-1273, 1912.

5. Jankiewicz, H.; Freeberg, D. D.: A six generation pedigree of
congenital zonular cataract. Am. J. Optom. 33: 555-557, 1956.

6. Keizer, D. P. R.: Congenitale cataract. Nederl. T. Geneesk. 96:
763-765, 1952.

7. Knapp, F. N.: Familial cataract: a study through five generations.
Am. J. Ophthal. 9: 683-684, 1926.

8. Marner, E.: A family with eight generations of hereditary cataract.
Acta Ophthal. 27: 537-551, 1949.

9. Marner, E.; Rosenberg, T.; Eiberg, H.: Autosomal dominant congenital
cataract: morphology and genetic mapping. Acta Ophthal. 67: 151-158,
1989.

10. Maumenee, I. H.: Classification of hereditary cataracts in children
by linkage analysis. Ophthalmology 86: 1554-1558, 1979.

11. Richards, J.; Maumenee, I. H.; Rowe, S.; Lovrien, E. W.: Congenital
cataract possibly linked to haptoglobin. Cytogenet. Cell Genet. 37:
570 only, 1984.

*FIELD* CS

Eyes:
   Zonular cataract;
   Stellate cataract;
   Nuclear cataract;
   Anterior polar cataract;
   Perinuclear cataract;
   Lamellar cataract

Limbs:
   Finger malformation in some kindreds

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 6/27/1994
mimadm: 6/25/1994
pfoster: 3/31/1994
supermim: 3/16/1992
carol: 2/27/1992
carol: 9/6/1990

*RECORD*
*FIELD* NO
116805
*FIELD* TI
*116805 CATENIN, ALPHA 1; CTNNA1
CADHERIN-ASSOCIATED PROTEIN
*FIELD* TX
E-cadherin is a transmembrane glycoprotein responsible for physical
connection of epithelial cells through Ca(2+)-binding regions in its
extracellular domain. E-cadherin-mediated cell-cell adhesion is effected
by 3 cytoplasmic proteins known as catenins alpha, beta, and gamma.
These catenins are thought to work as connectors that anchor the
E-cadherin to the cytoskeletal actin bundle through the cadherin
cytoplasmic domain. Dysfunction of this adhesion complex causes
dissociation of cancer cells from primary tumor nodules, thus possibly
contributing to cancer invasion and metastasis. Herrenknecht et al.
(1991) and Nagafuchi et al. (1991) isolated a murine cDNA encoding the
102-kD alpha-catenin (CAP102). Oda et al. (1993) cloned and sequenced
human alpha-catenin. They found that it shows extensive homology with
that of the mouse. Hirano et al. (1992) and Shimoyama et al. (1992)
showed that a human lung cancer cell line, PC9, which expresses
E-cadherin but only a small quantity of abnormal-sized alpha-catenin,
grew initially as isolated cells and then regained its cell-cell
adhesion potential when transfected with alpha-catenin. Oda et al.
(1993) found 2 abnormal mRNA sequences of alpha-catenin in PC9; one was
a 957-bp deletion resulting in a 319-amino-acid deletion and another was
a 761-bp deletion resulting in a frameshift. The deletions were thought
to be responsible for the loss of alpha-catenin expression.

Furukawa et al. (1994) showed that the CTNNA1 transcript is 3.4 kb long
and consists of 16 coding exons encoding 906 amino acids and at least 1
5-prime noncoding exon. The 102-kD predicted protein is the same size as
the murine homolog, and the amino acid sequences of the 2 proteins are
99.2% homologous. Analysis by reverse transcription-PCR demonstrated
that the gene is expressed ubiquitously in normal tissues. By
fluorescence in situ hybridization, Furukawa et al. (1994) mapped the
CTNNA1 gene to 5q31. McPherson et al. (1994) sequenced partial
alpha-catenin cDNAs from a human prostate cDNA library and used these
data to map the CTNNA1 gene by PCR analysis of a panel of somatic cell
hybrids carrying various deletions. They concluded that the gene was
located in the segment between mid 5q21 and distal 5q22. The discrepancy
was resolved by Nollet et al. (1995), who characterized a catenin
processed pseudogene (CTNNAP1) which shows 90% nucleotide sequence
identity to the catenin functional gene (CTNNA1). The authors mapped the
pseudogene to 5q22 and the functional gene to 5q31 by fluorescence in
situ hybridization. The corresponding gene (symbolized Catna1) was
mapped to mouse chromosome 18 by analysis of the segregation pattern of
informative DNA polymorphisms among the progeny of 2 interspecific
backcrosses.

*FIELD* SA
Guenet et al. (1995)
*FIELD* RF
1. Furukawa, Y.; Nakatsuru, S.; Nagafuchi, A.; Tsukita, S.; Muto,
T.; Nakamura, Y.; Horii, A.: Structure, expression and chromosome
assignment of the human catenin (cadherin-associated protein) alpha
1 gene (CTNNA1). Cytogenet. Cell Genet. 65: 74-78, 1994.

2. Guenet, J.-L.; Simon-Chazottes, D.; Ringwald, M.; Kemler, R.:
The genes coding for alpha and beta catenin (Catna1 and Catnb) and
plakoglobin (Jup) map to mouse chromosomes 18, 9, and 11, respectively.
Mammalian Genome 6: 363-366, 1995.

3. Herrenknecht, K.; Ozawa, M.; Eckerskorn, C.; Lottspeich, F.; Lenter,
M.; Kemler, R.: The uvomorulin-anchorage protein alpha-catenin is
a vinculin homologue. Proc. Nat. Acad. Sci. 88: 9156-9160, 1991.

4. Hirano, S.; Kimoto, N.; Shimoyama, Y.; Hirohashi, S.; Takeichi,
M.: Identification of a neural alpha-catenin as a key regulator of
cadherin function and multicellular organization. Cell 70: 293-301,
1992.

5. McPherson, J. D.; Morton, R. A.; Ewing, C. M.; Wasmuth, J. J.;
Overhauser, J.; Nagafuchi, A.; Tsukita, S.; Isaacs, W. B.: Assignment
of the human alpha-catenin gene (CTNNA1) to chromosome 5q21-q22. Genomics 19:
188-190, 1994.

6. Nagafuchi, A.; Takeichi, M.; Tsukita, S.: The 102 kd cadherin-associated
protein: similarity to vinculin and posttranscriptional regulation
of expression. Cell 65: 849-857, 1991.

7. Nollet, F.; van Hengel, J.; Berx, G.; Molemans, F.; van Roy, F.
: Isolation and characterization of a human pseudogene (CTNNAP1) for
alpha-E-catenin (CTNNA1): assignment of the pseudogene to 5q22 and
the alpha-E-catenin gene to 5q31. Genomics 26: 410-413, 1995.

8. Oda, T.; Kanai, Y.; Shimoyama, Y.; Nagafuchi, A.; Tsukita, S.;
Hirohashi, S.: Cloning of the human alpha-catenin cDNA and its aberrant
mRNA in a human cancer cell line. Biochem. Biophys. Res. Commun. 193:
897-904, 1993.

9. Shimoyama, Y.; Nagafuchi, A.; Fujita, S.; Gotoh, M.; Takeichi,
M.; Tsukita, S.; Hirohashi, S.: Cadherin dysfunction in a human cancer
cell line: possible involvement of loss of alpha-catenin expression
in reduced cell-cell adhesiveness. Cancer Res. 52: 5770-5774, 1992.

*FIELD* CN
Alan F. Scott - updated: 10/11/1995

*FIELD* CD
Victor A. McKusick: 9/2/1993

*FIELD* ED
terry: 04/17/1996
mark: 3/7/1996
mark: 6/15/1995
carol: 2/9/1994
carol: 12/16/1993
carol: 10/26/1993
carol: 9/15/1993

*RECORD*
*FIELD* NO
116806
*FIELD* TI
*116806 CATENIN, BETA 1; CTNNB1
CADHERIN-ASSOCIATED PROTEIN, BETA; CTNNB
*FIELD* TX
Beta-catenin is an adherens junction protein. Adherens junctions (AJs;
also called the zonula adherens) are critical for the establishment and
maintenance of epithelial layers, such as those lining organ surfaces.
AJs mediate adhesion between cells, communicate a signal that
neighboring cells are present, and anchor the actin cytoskeleton. In
serving these roles, AJs regulate normal cell growth and behavior. At
several stages of embryogenesis, wound healing, and tumor cell
metastasis, cells form and leave epithelia. This process, which involves
the disruption and reestablishment of epithelial cell-cell contacts, may
be regulated by the disassembly and assembly of AJs. AJs may also
function in the transmission of the 'contact inhibition' signal, which
instructs cells to stop dividing once an epithelial sheet is complete.

As reviewed by Peifer (1993), the AJ is a multiprotein complex assembled
around calcium-regulated cell adhesion molecules called cadherins (e.g.,
114020 and 114021). Cadherins are transmembrane proteins: the
extracellular domain mediates homotypic adhesion with cadherins on
neighboring cells, and the intracellular domain interacts with
cytoplasmic proteins that transmit the adhesion signal and anchor the AJ
to the actin cytoskeleton. These cytoplasmic proteins include the
alpha-, beta-, and gamma-catenins. The beta-catenin gene, which was
cloned by McCrea et al. (1991), shows no similarity in sequence to the
genes for the alpha-catenins. The beta-catenin protein shares 70% amino
acid identity with both plakoglobin (173325), which is found in
desmosomes (another type of intracellular junction), and the product of
the Drosophila segment polarity gene 'armadillo.' 'Armadillo' is part of
a multiprotein AJ complex in Drosophila that also includes some homologs
of alpha-catenin and cadherin, and genetic studies indicate that it is
required for cell adhesion and cytoskeletal integrity. The 'armadillo'
gene was originally identified as one of a group of segment polarity
genes that regulate pattern formation of the Drosophila embryonic
cuticle.

By fluorescence in situ hybridization (FISH), Kraus et al. (1994) mapped
the CTNNB1 gene to 3p21, a region frequently affected by somatic
alterations in a variety of tumors. Using PCR primers for the genomic
amplification of beta-catenin sequences on the basis of homology to exon
4 of the Drosophila armadillo gene, they analyzed a panel of somatic
cell hybrids to confirm the localization of the gene to human chromosome
3. Exclusion mapping of 3 hybrids carrying defined fragments of 3p
allowed them to determine that the CTNNB1 locus is close to marker D3S2.
Guenet et al. (1995) mapped the homologous gene, symbolized Catnb by
them, to mouse chromosome 9 by analysis of interspecific backcrosses.
Bailey et al. (1995) used FISH and PCR analysis of somatic cell hybrid
DNAs to show that the CTNNB1 gene is located in the 3p22-p21 region. By
FISH, van Hengel et al. (1995) assigned CTNNB1 to 3p22-p21.3. Trent et
al. (1995) likewise localized the CTNNB1 gene to 3p22 by FISH. They
stated that because APC-binding proteins (like beta-catenin) represent a
'downstream' modulator of APC activity, the chromosomal locus of such a
protein might be expected to be a site involved in chromosome
rearrangements in malignancy.

Nollet et al. (1996) showed that CTNNB1 has 16 exons and spans 23.2 kb.
Alternative splicing within exon 16 produced a splice variant that is
159-bp shorter in the 3-prime untranslated region. The promoter region
was shown to be GC-rich and contains a TATA box. The authors
demonstrated promoter activity in mouse epithelial cells for the 5-prime
flanking region when it was linked to the reporter gene alkaline
phosphatase.

Work by Korinek et al. (1997) and by Morin et al. (1997) established
that the APC gene (175100), which is mutant in adenomatous polyposis of
the colon, is a negative regulator of beta-catenin signaling. The APC
protein normally binds to beta-catenin, which interacts with Tcf and Lef
transcription factors. Korinek et al. (1997) cloned a gene they called
hTcf-4, a Tcf family member that is expressed in colonic epithelium. The
protein product (Tcf-4) transactivates transcription only when
associated with beta-catenin. Nuclei of APC(-/-) colon carcinoma cells
were found to contain a stable beta-catenin/Tcf-4 complex that was
constitutively active, as measured by transcription of a Tcf reporter
gene. Reintroduction of APC removed beta-catenin from Tcf-4 and
abrogated the transcriptional activation. Korinek et al. (1997)
concluded that constitutive transcription of Tcf target genes, caused by
loss of APC function, may be a crucial event in the early transformation
of colonic epithelium. Morin et al. (1997) likewise found that the
protein products of mutant APC genes present in colorectal tumors were
defective in downregulating transcriptional activation mediated by
beta-catenin and T-cell transcription factor 4. Furthermore, colorectal
tumors with intact APC genes were found to contain activating mutations
of beta-catenin that altered functionally significant phosphorylation
sites. These results indicated that regulation of beta-catenin is
critical to APC's tumor suppressive effect and that this regulation can
be circumvented by mutations in either APC or beta-catenin. Morin et al.
(1997) found a total of 3 tumors that contained CTNNB1 mutations that
altered potential phosphorylation sites. Each mutation was somatic and
appeared to affect only 1 of the 2 CTNNB1 alleles. Causative mutations
were heterozygous. They hypothesized that the mutations might exert a
dominant effect, rendering a fraction of cellular beta-catenin
insensitive to APC-mediated downregulation. Thus, disruption of
APC-mediated regulation of CRT is critical for colorectal tumorigenesis.
This is most commonly achieved by recessive inactivating mutations of
both APC alleles, but can also be achieved by dominant mutations of
CTNNB1 that render CRT insensitive to the effects of wildtype APC.

Rubinfeld et al. (1997) detected abnormally high amounts of beta-catenin
in 7 of 26 human melanoma cell lines. Unusual messenger RNA splicing and
missense mutations in the CTNNB1 gene that result in stabilization of
the protein were identified in 6 of the 7 lines, and the APC gene was
altered or missing in 2 others. In the APC-deficient cells, ectopic
expression of wildtype APC eliminated the excess beta-catenin. Cells
with stabilized beta-catenin contained a constitutive beta-catenin/Lef-1
complex. Thus, Rubinfeld et al. (1997) concluded that genetic defects
that result in upregulation of beta-catenin may play a role in melanoma
progression.

*FIELD* AV
.0001
COLORECTAL CANCER
CTNNB1, 3-BP DEL, SER45 DEL
In 2 colorectal tumor cell lines that expressed full-length APC, yet had
escaped inhibition of transcriptional activation mediated by
beta-catenin and T cell transcription factor 4, Morin et al. (1997)
found a mutation in a downstream component of the APC tumor suppressor
pathway, namely in the CTNNB1 gene. Each tumor line had a different
mutation: a 3-bp deletion that removed an amino acid (ser45) in one and
a C-to-A missense mutation that changed ser33 to tyr (116806.0002) in
the other. Analysis of paraffin-imbedded archival tissue from the first
patient confirmed the somatic nature of this mutation and its presence
in the primary tumor before culture. Both mutations affected serines
that have been implicated in the downregulation of beta-catenin through
phosphorylation.

.0002
COLORECTAL CANCER
CTNNB1, SER33TYR
See 116806.0001 and Morin et al. (1997).

*FIELD* RF
1. Bailey, A.; Norris, A. L.; Leek, J. P.; Clissold, P. M.; Carr,
I. M.; Ogilvie, D. J.; Morrison, J. F. J.; Meredith, D. M.; Markham,
A. F.: Yeast artificial chromosome cloning of the beta-catenin locus
on human chromosome 3p21-22. Chromosome Res. 3: 201-203, 1995.

2. Guenet, J.-L.; Simon-Chazottes, D.; Ringwald, M.; Kemler, R.:
The genes coding for alpha and beta catenin (Catna1 and Catnb) and
plakoglobin (Jup) map to mouse chromosomes 18, 9, and 11, respectively. Mammalian
Genome 6: 363-366, 1995.

3. Korinek, V.; Barker, N.; Morin, P. J.; van Wichen, D.; de Weger,
R.; Kinzler, K. W.; Vogelstein, B.; Clevers, H.: Constitutive transcriptional
activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275:
1784-1787, 1997.

4. Kraus, C.; Liehr, T.; Hulsken, J.; Behrens, J.; Birchmeier, W.;
Grzeschik, K.-H.; Ballhausen, W. G.: Localization of the human beta-catenin
gene (CTNNB1) to 3p21: a region implicated in tumor development. Genomics 23:
272-274, 1994.

5. McCrea, P. D.; Turck, C. W.; Gumbiner, B.: A homolog of the armadillo
protein in Drosophila (plakoglobin) associated with E-cadherin. Science 254:
1359-1361, 1991.

6. Morin, P. J.; Sparks, A. B.; Korinek, V.; Barker, N.; Clevers,
H.; Vogelstein, B.; Kinzler, K. W.: Activation of beta-catenin-Tcf
signaling in colon cancer by mutations in beta-catenin or APC. Science 275:
1787-1790, 1997.

7. Nollet, F.; Berx, G.; Molemans, F.; van Roy, F.: Genomic organization
of the human beta-catenin gene (CTNNB1). Genomics 32: 413-424, 1996.

8. Peifer, M.: Cancer, catenins, and cuticle pattern: a complex connection. Science 262:
1667-1668, 1993.

9. Rubinfeld, B.; Robbins, P.; El-Gamil, M.; Albert, I.; Porfiri,
E.; Polakis, P.: Stabilization of beta-catenin by genetic defects
in melanoma cell lines. Science 275: 1790-1792, 1997.

10. Trent, J. M.; Wiltshire, R.; Su, L.-K.; Nicolaides, N. C.; Vogelstein,
B.; Kinzler, K. W.: The gene for the APC-binding protein beta-catenin
(CTNNB1) maps to chromosome 3p22, a region frequently altered in human
malignancies. Cytogenet. Cell Genet. 71: 343-344, 1995.

11. van Hengel, J.; Nollet, F.; Berx, G.; van Roy, N.; Speleman, F.;
van Roy, F.: Assignment of the human beta-catenin gene (CTNNB1) to
3p22-p21.3 by fluorescence in situ hybridization. Cytogenet. Cell
Genet. 70: 68-70, 1995.

*FIELD* CN
Victor A. McKusick - updated: 4/29/1997
Alan F. Scott - updated: 4/18/1996

*FIELD* CD
Victor A. McKusick: 6/16/1994

*FIELD* ED
mark: 04/30/1997
alopez: 4/29/1997
terry: 4/21/1997
terry: 5/14/1996
terry: 5/10/1996
terry: 4/18/1996
mark: 4/18/1996
mark: 7/11/1995
carol: 11/7/1994
jason: 6/16/1994

*RECORD*
*FIELD* NO
116810
*FIELD* TI
*116810 CATHEPSIN B; CTSB
AMYLOID PRECURSOR PROTEIN SECRETASE, INCLUDED;;
AAP SECRETASE, INCLUDED;;
APPS, INCLUDED
*FIELD* TX
Murnane (1985) pointed out amino acid sequence homology between HRAS p21
(190020) and cathepsin B. Chan et al. (1986) determined the complete
coding sequence for human preprocathepsin B by use of cDNA clones. Wang
et al. (1987) assigned the CTSB gene to 8p22 by means of a cDNA probe
used in Southern blot analysis of somatic cell hybrids and in situ
hybridization.

Esch et al. (1990) demonstrated cleavage of the amyloid beta peptide
during constitutive processing of its precursor (104760). Cleavage
occurs in the interior of the amyloid peptide sequence, thereby
precluding formation and deposition of the APP protein. Esch et al.
(1990) suggested that a genetic defect in this processing mechanism
might be a basis of Alzheimer disease (104300). Tagawa et al. (1991)
demonstrated that APP secretase is identical to cathepsin B. Fong et al.
(1992) mapped CTSB to 8p23.1-p22 by 3 independent methods: analysis of
human-hamster somatic cell hybrid DNA by polymerase chain reaction
(PCR), comparison of hybridization signals to cathepsin B in interphase
nuclei of normal fibroblasts and fibroblasts with a chromosome 8
deletion, and fluorescence in situ hybridization.

*FIELD* RF
1. Chan, S. J.; San Segundo, B.; McCormick, M. B.; Steiner, D. F.
: Nucleotide and predicted amino acid sequences of cloned human and
mouse preprocathepsin B cDNAs. Proc. Nat. Acad. Sci. 83: 7721-7725,
1986.

2. Esch, F. S.; Keim, P. S.; Beattie, E. C.; Blacher, R. W.; Culwell,
A. R.; Oltersdorf, T.; McClure, D.; Ward, P. J.: Cleavage of amyloid
beta peptide during constitutive processing of its precursor. Science 248:
1122-1124, 1990.

3. Fong, D.; Chan, M. M.-Y.; Hsieh, W.-T.; Menninger, J. C.; Ward,
D. C.: Confirmation of the human cathepsin B gene (CTSB) assignment
to chromosome 8. Hum. Genet. 89: 10-12, 1992.

4. Murnane, M. J.: Cathepsin B-like thiol proteases: distant amino
acid sequence homology to H-RAS p21.  (Abstract) Am. J. Hum. Genet. 37:
A33 only, 1985.

5. Tagawa, K.; Kunishita, T.; Maruyama, K.; Yoshikawa, K.; Kominami,
E.; Tsuchiya, T.; Suzuki, K.; Tabira, T.; Sugita, H.; Ishiura, S.
: Alzheimer's disease amyloid beta-clipping enzyme (APP secretase):
identification, purification, and characterization of the enzyme.
Biochem. Biophys. Res. Commun. 177: 377-387, 1991.

6. Wang, X.; Chan, S. J.; Eddy, R. L.; Byers, M. G.; Fukushima, Y.;
Henry, W. M.; Haley, L. L.; Steiner, D. F.; Shows, T. B.: Chromosome
assignment of cathepsin B (CTSB) to 8p22 and cathepsin H (CTSH) to
15q24-q25.  (Abstract) Cytogenet. Cell Genet. 46: 710-711, 1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 4/7/1993
carol: 6/11/1992
carol: 4/7/1992
supermim: 3/16/1992
carol: 7/12/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
116820
*FIELD* TI
*116820 CATHEPSIN H; CTSH
*FIELD* TX
The cathepsins comprise a group of intracellular preteases which have
been found in vertebrate and invertebrate tissues. The major cathepsin
activities include a group of cysteine-dependent proteases, cathepsins
B, H and L, which are structurally related to papain. The mature active
forms of cathepsins are located predominantly in lysosomes where they
play an important role in regulating intracellular protein degradation
and turnover. The cathepsin genes have been cloned (Chan et al., 1986).
Using these cDNAs as hybridization probes, Wang et al. (1987) mapped
CTSH to 15q24-q25. One form of Batten disease (204200), representing
perhaps about one-fourth of all cases, has been found to show deficiency
of cathepsin H. The Batten disease phenotype maps to chromosome 16,
however.

*FIELD* RF
1. Chan, S. J.; San Segundo, B.; McCormick, M. B.; Steiner, D. F.
: Nucleotide and predicted amino acid sequences of cloned human and
mouse preprocathepsin B cDNAs. Proc. Nat. Acad. Sci. 83: 7721-7725,
1986.

2. Wang, X.; Chan, S. J.; Eddy, R. L.; Byers, M. G.; Fukushima, Y.;
Henry, W. M.; Haley, L. L.; Steiner, D. F.; Shows, T. B.: Chromosome
assignment of cathepsin B (CTSB) to 8p22 and cathepsin H (CTSH) to
15q24-q25.  (Abstract) Cytogenet. Cell Genet. 46: 710-711, 1987.

*FIELD* CD
Victor A. McKusick: 9/23/1987

*FIELD* ED
supermim: 3/16/1992
carol: 5/2/1991
supermim: 3/20/1990
ddp: 10/26/1989
root: 7/11/1989
root: 6/9/1988

*RECORD*
*FIELD* NO
116830
*FIELD* TI
*116830 CATHEPSIN G; CTSG
*FIELD* TX
Neutrophilic polymorphonuclear leukocytes contain specialized azurophil
granules whose contents, including the serine proteases cathepsin G and
elastase, may participate in the killing and digestion of engulfed
pathogens, and in connective tissue remodeling at sites of inflammation.
Cathepsin G is a 26,000-Da protease. Using mRNA from a leukemic cell
line, Salvesen et al. (1987) isolated and determined the sequence of a
cDNA clone encoding CTSG. Hohn et al. (1989) found that the CTSG gene
spans 2.7 kb of genomic DNA and consists of 5 exons and 4 introns. The
genomic organization is similar to that of neutrophil elastase. Using in
situ hybridization, they localized the gene to 14q11.2. Using human CTSG
cDNA as a probe, Heusel et al. (1993) cloned and characterized a novel
related murine hematopoietic serine protease gene which was highly
homologous to the human gene at nucleotide and amino acid levels. They
assigned the gene to mouse chromosome 14, tightly linked to the Ctla-1
gene. Since one form of Alzheimer disease, AD3, maps to 14q24.3, the
lysosomal serine protease cathepsin G, which also maps to 14q, is a
candidate for the site of the mutation. A defect in the cellular
processing of amyloid precursor protein in familial Alzheimer disease
has been postulated. Wong et al. (1993) analyzed the nucleotide sequence
of the entire open reading frame of the CTSG gene and found no
abnormality in 1 clinically affected member from each of 5 large FAD
pedigrees that showed significant or nearly significant lod scores with
one or more markers on chromosome 14. The sequence was compared with
that of his/her unaffected living parent in each case and no differences
were found.

In transgenic mice, Grisolano et al. (1994) found that the human CTSG
gene was expressed in early myeloid precursors in a manner coordinate
with the expression of the endogenous murine gene in the bone marrow and
spleen.

*FIELD* RF
1. Grisolano, J. L.; Sclar, G. M.; Ley, T. J.: Early myeloid cell-specific
expression of the human cathepsin G gene in transgenic mice. Proc.
Nat. Acad. Sci. 91: 8989-8993, 1994.

2. Heusel, J. W.; Scarpati, E. M.; Jenkins, N. A.; Gilbert, D. J.;
Copeland, N. G.; Shapiro, S. D.; Ley, T. J.: Molecular cloning, chromosomal
location, and tissue-specific expression of the murine cathepsin G
gene. Blood 81: 1614-1623, 1993.

3. Hohn, P. A.; Popescu, N. C.; Hanson, R. D.; Salvesen, G.; Ley,
T. J.: Genomic organization and chromosomal localization of the human
cathepsin G gene. J. Biol. Chem. 264: 13412-13419, 1989.

4. Salvesen, G.; Farley, D.; Shuman, J.; Przybyla, A.; Reilly, C.;
Travis, J.: Molecular cloning of human cathepsin G: structural similarity
to mast cell and cytotoxic T lymphocyte proteinases. Biochemistry 26:
2289-2293, 1987.

5. Wong, L.; Liang, Y.; Jiang, L.; Tsuda, T.; Fong, Q.; Galway, G.;
Alexandrova, N.; Rogaeva, E.; Lukiw, W.; Smith, J.; Rogaev, E.; Crapper
McLachlan, D.; St. George-Hyslop, P.: Mutation of the gene for the
human lysosomal serine protease cathepsin G is not the cause of aberrant
APP processing in familial Alzheimer disease. Neurosci. Lett. 152:
96-98, 1993.

*FIELD* CD
Victor A. McKusick: 5/26/1987

*FIELD* ED
carol: 11/14/1994
warfield: 3/31/1994
carol: 6/3/1993
carol: 5/14/1993
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
116831
*FIELD* TI
*116831 CATHEPSIN G-LIKE 2; CTSGL2
CGL2;;
GRANZYME H
*FIELD* TX
This gene is located in a cluster on 14q11.2 (Hanson et al., 1990) with
cathepsin G (116830) and CTSGL1 (123910). A similar cluster of genes in
the mouse is located on chromosome 14 near the TCRA locus (186880)
(Crosby et al., 1990).

*FIELD* RF
1. Crosby, J. L.; Bleackley, R. C.; Nadeau, J. H.: A complex of serine
protease genes expressed preferentially in cytotoxic T-lymphocytes
is closely linked to the T-cell receptor alpha- and delta-chain genes
on mouse chromosome 14. Genomics 6: 252-259, 1990.

2. Hanson, R. D.; Hohn, P. A.; Popescu, N. C.; Ley, T. J.: A cluster
of hematopoietic serine protease genes is found on the same chromosomal
band as the human alpha/delta T-cell receptor locus. Proc. Nat. Acad.
Sci. 87: 960-963, 1990.

*FIELD* CD
Victor A. McKusick: 3/1/1990

*FIELD* ED
mark: 10/04/1996
carol: 9/29/1992
supermim: 3/16/1992
carol: 1/29/1991
supermim: 3/20/1990
supermim: 3/1/1990

*RECORD*
*FIELD* NO
116840
*FIELD* TI
*116840 CATHEPSIN D; CTSD
*FIELD* TX
By study of somatic cell hybrids, Hasilik et al. (1982) assigned the
structural gene for cathepsin D to chromosome 11 and specifically to the
region 11pter-11q12. Cathepsin D is one of the lysosomal proteinases (EC
3.4.23.5). By somatic cell hybrid deletion mapping and in situ
hybridization, Qin et al. (1987) mapped CTSD to 11p15. Henry et al.
(1989) likewise mapped CTSD to 11p15 using somatic cell hybrids with
specific deletions. CTSD mapped distal to a breakpoint at 11p15.4.

*FIELD* SA
Faust et al. (1985)
*FIELD* RF
1. Faust, P. L.; Kornfeld, S.; Chirgwin, J. M.: Cloning and sequence
analysis of cDNA for human cathepsin D. Proc. Nat. Acad. Sci. 82:
4910-4914, 1985.

2. Hasilik, A.; von Figura, K.; Grzeschik, K.-H.: Assignment of a
gene for human cathepsin D to chromosome 11.  (Abstract) Cytogenet.
Cell Genet. 32: 284 only, 1982.

3. Henry, I.; Puech, A.; Antignac, C.; Couillin, P.; Jeanpierre, M.;
Ahnine, L.; Barichard, F.; Boehm, T.; Augereau, P.; Scrable, H.; Rabbitts,
T. H.; Rochefort, H.; Cavenee, W.; Junien, C.: Subregional mapping
of BWS, CTSD, MYOD1, and a T-ALL breakpoint in 11p15.  (Abstract) Cytogenet.
Cell Genet. 51: 1013 only, 1989.

4. Qin, S.; Nakai, H.; Byers, M. G.; Eddy, R. L.; Haley, L. L.; Henry,
W. M.; Wang, X.; Watkins, P. C.; Chirgwin, J. M.; Shows, T. B.: Mapping
FSHB, CAT, and CTSD to specific sites on 11p.  (Abstract) Cytogenet.
Cell Genet. 46: 678 only, 1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 3/9/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 2/26/1988

*RECORD*
*FIELD* NO
116845
*FIELD* TI
*116845 CATHEPSIN S; CTSS
*FIELD* TX
Alveolar macrophages express an elastase activity of acidic pH optimum
inhibitable by cysteine protease inhibitors. It had been shown that the
only previously known eukaryotic elastinolytic cysteine protease,
cathepsin L (116880), could not completely account for this activity. In
a search for additional cysteine proteases with elastinolytic activity,
Shi et al. (1992) used low degeneracy oligonucleotide primers based on
regions of strong amino acid homology among the known cysteine proteases
to screen reverse-transcribed human alveolar macrophage RNA for cysteine
proteases by the polymerase chain reaction (PCR). The screening turned
up a cDNA sequence highly homologous to bovine cathepsin S. The
recombinant enzyme was found to be elastinolytic. The relatively broad
pH range of human cathepsin S activity suggested that it plays a
significant role in the contact-dependent elastase activity of alveolar
macrophages.

Shi et al. (1994) found that the structure of the gene is similar to
that of cathepsin L through the first 5 exons, except that cathepsin S
introns are substantially larger. In contrast to cathepsin B (116810),
cathepsin S was found to contain only 2 SP1 and at least 18 AP1 binding
sites that potentially may be involved in regulation of the gene. The
5-prime flanking region also contained CA microsatellites. The presence
of AP1 sites and CA microsatellites suggested that cathepsin S may be
specifically regulated. This hypothesis was supported by the results of
Northern blotting which showed that only cathepsin S shows a restricted
tissue distribution, with highest levels in spleen, heart, and lung.
Immunostaining of lung tissue demonstrated detectable cathepsin S only
in lung macrophages. The high level of expression in the spleen and in
phagocytes suggested that cathepsin S may have a specific function in
immunity, perhaps related to antigen processing.

By fluorescence in situ hybridization, Shi et al. (1994) mapped the CTSS
gene to 1q21.

*FIELD* RF
1. Shi, G.-P.; Munger, J. S.; Meara, J. P.; Rich, D. H.; Chapman,
H. A.: Molecular cloning and expression of human alveolar macrophage
cathepsin S, an elastinolytic cysteine protease. J. Biol. Chem. 267:
7258-7262, 1992.

2. Shi, G.-P.; Webb, A. C.; Foster, K. E.; Knoll, J. H. M.; Lemere,
C. A.; Munger, J. S.; Chapman, H. A.: Human cathepsin S: chromosomal
localization, gene structure, and tissue distribution. J. Biol.
Chem. 269: 11530-11536, 1994.

*FIELD* CD
Victor A. McKusick: 6/15/1992

*FIELD* ED
carol: 5/24/1994
carol: 6/15/1992

*RECORD*
*FIELD* NO
116850
*FIELD* TI
116850 CATATRICHY
FORELOCK
*FIELD* TX
In this trait a forelock 4 to 6 inches long is present. The hair is
usually finer than that of the rest of the head and may be more wavy
than the rest. Stoddard (1939) described a family with affected persons
in 4 generations. At least 1 skipped generation involved a male.
Catatrichy is less evident in men than in women.

*FIELD* RF
1. Stoddard, S. E.: Inheritance of 'natural bangs': catatrichy, new
character dependent upon dominant autosomal gene. J. Hered. 30:
543-545, 1939.

*FIELD* CS

Hair:
   Fine wavy forelock

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
116860
*FIELD* TI
*116860 CEREBRAL CAVERNOUS MALFORMATIONS 1; CCM1
CAVERNOUS ANGIOMA, FAMILIAL;;
HEMANGIOMA, CAVERNOUS, OF BRAIN
CAVERNOUS MALFORMATIONS OF CNS AND RETINA, INCLUDED;;
CAVERNOUS ANGIOMATOUS MALFORMATIONS; CAM
*FIELD* TX
Cavernous angiomas are relatively rare vascular malformations that may
involve any part of the central nervous system. Some are clinically
silent, whereas others cause seizures, hemorrhage, or focal neurologic
deficit. Identification of these lesions is important because surgical
removal of many is relatively easy. Magnetic resonance imaging (MRI) is
replacing computerized axial tomography as the diagnostic modality of
choice. Bicknell et al. (1978) found 3 reports of familial incidence and
added 2 from their own experience. In 1 family a woman, 2 of her sons,
and 1 of her son's sons were affected; in the second family a woman and
her daughter were affected. Successive generations were affected in
families reported by Michael and Levin (1936), Kidd and Cumings (1947),
and Clark (1970). Michael and Levin (1936) described a Swedish family in
which a mother, her 2 brothers, and 3 daughters had multiple
telangiectases of the brain. Convulsions and migraine attacks were
observed. Autopsy in one case demonstrated calcification in the vascular
lesions of the brain. (The lesions in the Michael-Levin cases seem more
appropriately called cavernous angiomata.) Clark (1970) described
cavernous angioma of the brain in a man who died in 1945 at age 27 and
in his daughter who died in 1969 at age 28. Hayman et al. (1982)
examined 43 relatives in 1 kindred by cranial computed tomography (CCT)
and found 15 affected with cerebral vascular angiomas. Angiography
failed to detect lesions in 5 patients who had positive CCT. Expression
was variable and in 2 individuals, each the parent of an affected
offspring, the CCT was normal. Familial cavernous angioma should be
included in the differential diagnosis of any young person with
cerebrovascular impairment, seizures, intracranial calcifications or
hemorrhage. Gorlin (1985) told me of an extensively affected
3-generation family.

Mason et al. (1988) described cavernous angiomas in 10 of 22 members of
a large Hispanic family. The authors commented that 2 families
previously reported by them (Bicknell et al., 1978), the family reported
by Hayman et al. (1982), and 5 of the 6 families reported in abstract by
Rigamonti et al. (1987) were Hispanic as well. Dobyns et al. (1987)
described a family in which 4 persons from 3 generations had multiple
cavernous malformations ('angiomas') of the CNS and/or retina. They
found reports of 16 other families containing a total of 50 cases.
Excluding the probands, 68% of the patients were symptomatic. Cutaneous
vascular lesions were an inconsistent manifestation. They recommended
that any patient with a vascular malformation, especially a cavernous
one of the brain, spinal cord, or retina, be evaluated for the
possibility of this syndrome which they referred to as FCMCR. All
first-degree relatives should undergo a full evaluation if multiple
vascular malformations are detected in the index patient or if the
family history is suggestive because of seizures, cutaneous vascular
lesions, recognized intracranial hemorrhage, or sudden unexplained
death. Presymptomatic diagnosis in affected relatives will permit
genetic counseling and close monitoring to allow prompt treatment if
symptoms occur. Dobyns et al. (1987) concluded that there is a second
group of patients with multiple cutaneous lesions and inconsistent CNS
lesions referred to as hereditary neurocutaneous angioma (106070). The
vascular lesions in this group were always arteriovenous malformations
and were often located in the spinal cord.

Rigamonti et al. (1988) reviewed familial occurrence, presenting signs
and symptoms, and radiographic features of the disorder in 24 patients
with histologically verified cerebral cavernous malformations. Eleven
patients had no evidence of a heritable trait and had negative family
histories. The other 13 patients were members of 6 unrelated
Mexican-American families. Among 64 first-degree and second-degree
relatives, 11% had seizures. MRI was performed in 16 relatives (5 of
whom were asymptomatic); 14 studies showed cavernous malformations and
11 studies identified multiple lesions. MRI was far more accurate in
detecting these lesions than computerized tomography or angiography.
Rigamonti et al. (1988) concluded that a familial form of this disorder
is particularly frequent among Mexican-Americans. Bicknell (1989)
described cavernous angioma of the brain stem in a 23-year-old Hispanic
woman whose mother had died of brain hemorrhage. After moving to
Baltimore from the southwestern part of the United States, Rigamonti
(1993) concluded that there is not an unusual frequency of the disorder
among Mexican-Americans. He emphasized that cavernous angiomas are not
arteriovenous malformations; they represent a honeycomb of veins. They
are not demonstrated by arteriography and therefore have been referred
to as angiographically silent. Epilepsy is the most frequent symptom;
bleeds occur in some cases. Dellemijn and Vanneste (1993) investigated
20 relatives of a 23-year-old woman with cavernous angiomatosis of the
central nervous system. Studies revealed 4 additional patients with
symptomatic cavernous angioma and 1 with asymptomatic cavernous angioma.
The basis of the neurologic symptoms had not previously been identified
in the symptomatic patients. The pedigree pattern was consistent with
autosomal dominant inheritance.

Steichen-Gersdorf et al. (1992) reported a family in which cavernous
angiomas of the brain were documented in 6 individuals in 5 sibships of
4 generations of a family. Two brothers in the third generation were
asymptomatic but showed changes on MRI. Filling-Katz et al. (1989, 1992)
described a family with cavernous angiomatosis in which 2 members had
terminal transverse defects at the midforearm. Multiple family members
had had episodic bleeding from cavernous angiomas of the central nervous
system. Two had had retinal cavernous angiomas, one hepatic angioma, and
2 cavernous angiomas of soft tissue; skin angiomas were frequent.
Studies of the forearm in 1 of the affected individuals showed abrupt
termination distal to the normal radius and ulnar heads and apparently
normal blood vessels. Filling-Katz et al. (1989, 1992) suggested that
acute vascular disruption is the cause and that this is related to the
fundamental defect in familial cavernous angiomatosis. Corboy and
Galetta (1989) described a family in which the proband had suffered for
9 years from recurrent 'acute chiasmal syndrome,' diagnosed at first as
retrobulbar neuritis.

Angiomatous malformations, arteriovenous malformations, hemangiomata,
nevus flammeus (port-wine stain), etc., occur in many syndromes, some of
them mendelian, and may occur as isolated mendelian traits. In some,
intracranial vascular malformations are associated with hemangiomas of
the skin. Pasyk et al. (1984) described a remarkable family in which
multiple vascular malformations, including cavernous hemangiomas,
arteriovenous malformations, and capillary hemangiomas, occurred in 25
persons in 5 generations. Slightly reduced penetrance was suggested by
the fact that a clinically unaffected woman had a child with a
hemangioma on the foot and that in the part of the pedigree with the
most complete documentation, the ratio of affected to unaffected was
15:20. Norwood and Everett (1964) reported the case of a 21-year-old
black female who during pregnancy developed large hemangiomas at many
sites, such as earlobe and axilla, and heart failure as a result. After
delivery, the hemangiomas rapidly subsided. The patient's mother and
6-year-old son had macular hemangiomas of the face and trunk and her
brother had classical Klippel-Trenaunay-Weber syndrome of the right
lower extremity. Beers and Clark (1942) described a family with
cutaneous hemangiomas ranging in size from a millimeter to many
centimeters in diameter, in 12 persons in 3 generations. Metatarsus
atavicus (second toe longer than the first toe) was an independent
dominant trait in this family. (See toes, relative length of 1st and
2nd; 189200.) Michels et al. (1985) stated that 19 families with 77
persons with cavernous angiomas of the central nervous system and retina
have been described. They described a 3-generation family ascertained
through an 8-year-old boy with seizures and 2 unexplained lesions on CT
and MRI. His mother presented a year later with a seizure and similar
brain lesions. Angiography and eye examination were normal. The
asymptomatic grandfather had 5 intracranial lesions on MRI scan. Keret
et al. (1990) described an 18-year-old male with left scrotal cavernous
hemangioma. Cutaneous hemangiomata were found in 34 relatives (21 males
and 13 females). Only the proband had a genital lesion. The
differentiation of scrotal hemangioma from varicocele was discussed.

Computed tomography and MRI led to reassessment of the incidence of
cavernous angioma of the brain including its familial occurrence. Drigo
et al. (1994) described an Italian family with multiple cavernous
angiomas of the brain, sometimes in association with liver angiomas, in
10 members of 4 generations. No neurologic symptoms were detected in
subjects from the first 2 generations but symptoms were found in adult
age in members of the third generation; 2 fourth-generation members came
under medical observation at 2.5 years of age. Symptoms included partial
epileptic fits which sometimes became generalized later and were
generally controlled adequately by therapy. None of the patients was
mentally retarded or restricted in daily life. Because of symptomatic
hepatomegaly and postmortem finding of multiple liver and brain
cavernomas in a member of the first generation, liver ultrasonography
was performed in all members of the family with detection of liver
angiomas in members of the second and third generation. Retinal angioma
was detected in 1 patient.

Using linkage analysis and a set of short tandem repeat polymorphisms,
Dubovsky et al. (1995) mapped the gene responsible for cavernous
malformations in a large Hispanic kindred to 7q11-q22. The maximum
pairwise lod score of 4.2 was obtained at zero recombination with a
marker at locus D7S804. Lod scores in excess of 3.0 were obtained with 4
additional markers closely linked to D7S804. A chromosome 7q haplotype
of 33 cM on the sex-averaged ED map was shared by all affected
individuals, indicating that the gene lies between D7S502 and D7S479.
Using a linkage approach in 2 extended cavernous malformation kindreds,
Gunel et al. (1995) also linked CAM to 7q, specifically 7q11.2-q21.
Multipoint linkage analysis yielded a maximum lod score of 6.88 with
zero recombination with D7S669 and localized the gene to a 7-cM region
in the interval between ELN (130160) and D7S802. The preferred symbol
for this gene CCM1 for cerebral cavernous malformations 1.

Marchuk et al. (1995) likewise mapped the gene in this disorder to
proximal 7q by linkage methods. In 2 families, 1 of Italian-American
origin and 1 of Mexican-American origin, they found a combined maximum
lod score of 3.92 at theta = 0.0 for marker D7S479. Haplotype analysis
placed the locus between D7S502 proximally and D7S515 distally, an
interval of approximately 41 cM. The chromosomal location distinguishes
this disorder from the autosomal dominant vascular malformation syndrome
(VMCM; 600195) in which lesions are primarily cutaneous; VMCM is due to
a gene that maps to 9p21.

Gunel et al. (1996) found that 47 affected members of 14 Hispanic
American kindreds shared identical alleles for up to 15 markers linked
to the cavernous-malformation gene in a short segment of proximal 7q.
Ten patients with sporadic cases also shared these same alleles,
indicating that they too had inherited the same mutation. Thirty-three
asymptomatic carriers of the disease gene were identified, demonstrating
the variability and age dependence of the development of symptoms and
explaining the appearance of apparently sporadic cases. Gunel et al.
(1996) concluded that virtually all cases of familial and sporadic
cavernous malformation among Hispanic Americans of Mexican descent are
due to the inheritance of the same mutation from a common ancestor.

*FIELD* RF
1. Beers, C. V.; Clark, L. A.: Tumors and short-toe--a dihybrid pedigree:
a family history showing the inheritance of hemangioma and metatarsus
atavicus. J. Hered. 33: 366-368, 1942.

2. Bicknell, J. M.: Familial cavernous angioma of the brain stem
dominantly inherited in Hispanics. Neurosurgery 24: 102-105, 1989.

3. Bicknell, J. M.; Carlow, T. J.; Kornfeld, M.; Stovring, J.; Turner,
P.: Familial cavernous angiomas. Arch. Neurol. 35: 746-749, 1978.

4. Clark, J. V.: Familial occurrence of cavernous angiomata of the
brain. J. Neurol. Neurosurg. Psychiat. 33: 871-876, 1970.

5. Corboy, J. R.; Galetta, S. L.: Familial cavernous angiomas manifesting
with an acute chiasmal syndrome. Am. J. Ophthal. 108: 245-250, 1989.

6. Dellemijn, P. L. I.; Vanneste, J. A. L.: Cavernous angiomatosis
of the central nervous system: usefulness of screening the family. Acta
Neurol. Scand. 88: 259-263, 1993.

7. Dobyns, W. B.; Michels, V. V.; Groover, R. V.; Mokri, B.; Trautmann,
J. C.; Forbes, G. S.; Laws, E. R., Jr.: Familial cavernous malformations
of the central nervous system and retina. Ann. Neurol. 21: 578-583,
1987.

8. Drigo, P.; Mammi, I.; Battistella, P. A.; Riccheri, G.; Carollo,
C.: Familial cerebral, hepatic, and retinal cavernous angiomas: a
new syndrome. Child's Nerv. Syst. 10: 205-209, 1994.

9. Dubovsky, J.; Zabramski, J. M.; Kurth, J.; Spetzler, R. F.; Rich,
S. S.; Orr, H. T.; Weber, J. L.: A gene responsible for cavernous
malformations of the brain maps to chromosome 7q. Hum. Molec. Genet. 4:
453-458, 1995.

10. Filling-Katz, M. R.; Levin, S. W.; Patronas, N. J.; Katz, N. N.
K.: Terminal transverse limb defects associated with familial cavernous
angiomatosis. Am. J. Med. Genet. 42: 346-351, 1992.

11. Filling-Katz, M. R.; Levin, S. W.; Patronas, N. J.; Katz, N. N.
K.: Terminal transverse defects are associated with familial cavernous
angiomatosis. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A45, 1989.

12. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.
3/12/1985.

13. Gunel, M.; Awad, I. A.; Anson, J.; Lifton, R. P.: Mapping a gene
causing cerebral cavernous malformation to 7q11.2-q21. Proc. Nat.
Acad. Sci. 92: 6620-6624, 1995.

14. Gunel, M.; Awad, I. A.; Finberg, K.; Anson, J. A.; Steinberg,
G. K.; Batjer, H. H.; Kopitnik, T. A.; Morrison, L.; Giannotta, S.
L.; Nelson-Williams, C.; Lifton, R. P.: A founder mutation as a cause
of cerebral cavernous malformation in Hispanic Americans. New Eng.
J. Med. 334: 946-951, 1996.

15. Hayman, L. A.; Evans, R. A.; Ferrell, R. E.; Fahr, L. M.; Ostrow,
P.; Riccardi, V. M.: Familial cavernous angiomas: natural history
and genetic study over a 5-year period. Am. J. Med. Genet. 11: 147-160,
1982.

16. Keret, D.; Kam, I.; Ben-Arieh, Y.; Hashmonai, M.: Scrotal cavernous
haemangioma with a family history of cutaneous angiomata. J. Roy.
Soc. Med. 83: 402-403, 1990.

17. Kidd, H. A.; Cumings, J. N.: Cerebral angiomata in an Icelandic
family. Lancet I: 747-748, 1947.

18. Marchuk, D. A.; Gallione, C. J.; Morrison, L. A.; Clericuzio,
C. L.; Hart, B. L.; Kosofsky, B. E.; Louis, D. N.; Gusella, J. F.;
Davis, L. E.; Prenger, V. L.: A locus for cerebral cavernous malformations
maps to chromosome 7q in two families. Genomics 28: 311-314, 1995.

19. Mason, I.; Aase, J. M.; Orrison, W. W.; Wicks, J. D.; Seigel,
R. S.; Bicknell, J. M.: Familial cavernous angiomas of the brain
in an Hispanic family. Neurology 38: 324-326, 1988.

20. Michael, J. C.; Levin, P. M.: Multiple telangiectases of brain:
a discussion of hereditary factors in their development. Arch. Neurol.
Psychiat. 36: 514-536, 1936.

21. Michels, V. V.; Dobyns, W. B.; Groover, R. V.; Mokri, B.; Forbes,
G. S.; Laws, E. R.: Familial cavernous angiomas of the central nervous
system and retina. (Abstract) Am. J. Hum. Genet. 37: A69, 1985.

22. Norwood, O. T.; Everett, M. A.: Cardiac failure due to endocrine
dependent hemangiomas. Arch. Derm. 89: 759-760, 1964.

23. Pasyk, K. A.; Argenta, L. C.; Erickson, R. P.: Familial vascular
malformations: report of 25 members of one family. Clin. Genet. 26:
221-227, 1984.

24. Rigamonti, D.: Personal Communication. Baltimore, Md.  9/15/1993.

25. Rigamonti, D.; Drayer, B.; Johnsen, S.; Johnson, P.; Sidell, A.;
Tarby, T.; Spetzler, R.: Cavernous malformations, MRI, and epilepsy.
(Abstract) Neurology 37: 322, 1987.

26. Rigamonti, D.; Hadley, M. N.; Drayer, B. P.; Johnson, P. C.; Hoenig-Rigamonti,
K.; Knight, J. T.; Spetzler, R. F.: Cerebral cavernous malformations:
incidence and familial occurrence. New Eng. J. Med. 319: 343-347,
1988.

27. Steichen-Gersdorf, E.; Felber, S.; Fuchs, W.; Russeger, L.; Twerdy,
K.: Familial cavernous angiomas of the brain: observations in a four
generation family. Europ. J. Pediat. 151: 861-863, 1992.

*FIELD* CS

Neuro:
   Cavernous angioma of brain;
   Seizures;
   Intracranial hemorrhage;
   Focal neurologic deficit;
   Migraine;
   Acute chiasmal syndrome

Eyes:
   Retinal angiomas

Skin:
   Cutaneous angiomas

Limbs:
   Terminal transverse midforearm defect

GI:
   Hepatic angioma

Misc:
   Sudden death;
   Cavernous soft tissue angiomas

Radiology:
   Cavernous malformations on MRI;
   Intracranial calcifications

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 01/18/1997
mark: 4/30/1996
terry: 4/29/1996
mark: 10/30/1995
terry: 4/24/1995
carol: 9/15/1994
mimadm: 6/25/1994
warfield: 4/7/1994
carol: 12/16/1993

*RECORD*
*FIELD* NO
116870
*FIELD* TI
116870 CELIAC ARTERY STENOSIS FROM COMPRESSION BY MEDIAN ARCUATE LIGAMENT
OF DIAPHRAGM
*FIELD* TX
Dodinval and Dreze (1972) described a mother and daughter with this
finding. The celiac artery was malpositioned congenitally. Both suffered
from abdominal pains which were relieved by appropriate surgery.

*FIELD* RF
1. Dodinval, P.; Dreze, C.: Stenose du tronc ceoliaque chez une mere
et sa fille par compression due au ligament arque median du diaphragme
(1-ere observation familiale). J. Genet. Hum. 20: 49-67, 1972.

*FIELD* CS

Vascular:
   Celiac artery compression;
   Aberrant celiac artery

Abdomen:
   Abdominal pain

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
116880
*FIELD* TI
*116880 CATHEPSIN L; CTSL
MAJOR EXCRETED PROTEIN; MEP
*FIELD* TX
Cathepsin L is a lysosomal cysteine proteinase with a major role in
intracellular protein catabolism. It also shows the most potent
collagenolytic and elastinolytic activity in vitro of any of the
cathepsins. It has been shown to proteolytically inactivate alpha-1
protease inhibitor, a major controlling element of human neutrophil
elastase activity in vivo. Cathepsin L has been implicated in pathologic
processes including myofibril necrosis in myopathies and in myocardial
ischemia, and in the renal tubular response to proteinuria. Joseph et
al. (1988) presented the complete nucleotide and predicted amino acid
sequence for human preprocathepsin L, demonstrated cathepsin L mRNA in a
human tumor, and showed evidence for a higher molecular weight human
kidney transcript. The human and murine sequences were compared. Mouse
fibroblasts that are malignantly transformed are stimulated by growth
factors or tumor promoters to synthesize and secrete increased amounts
of a 39-kD glycoprotein with acid-proteinase activity. This protein,
termed MEP for major excreted protein, is a precursor for 2 lysosomal
proteins of lower molecular weight and contains the lysosomal
recognition marker mannose 6-phosphate. By cross-hybridization with a
mouse MEP cDNA clone, Gal and Gottesman (1988) isolated and
characterized a full-length MEP cDNA clone. A 1.6-kb cDNA showed 70%
deduced amino acid sequence identity with mouse MEP. The deduced amino
acid sequence of the cloned human MEP was the same, except for 2 amino
acids, as the N-terminal sequence of mature human cathepsin L, thereby
establishing that human MEP is human pro-cathepsin L. Using the clones
prepared by Joseph et al. (1988) for in situ hybridization and Southern
analysis of human-mouse cell hybrids, Fan et al. (1989) assigned the
CTSL gene to 9q21-q22. Because of hybridizing bands that cosegregated
with human chromosome 10, they concluded that there is a similar
sequence, perhaps a cathepsin L-like gene (CTSLL), located on chromosome
10. Chauhan et al. (1993) demonstrated the concurrent expression of 2
distinct human CTSL mRNAs in adenocarcinoma, hepatoma, and renal cancer
cell lines. Cloning and subsequent sequencing of genomic DNA
demonstrated that the 2 mRNAs are encoded by a single gene. The 3-prime
end of the first intron contains the 5-prime portion of the second mRNA
and is contiguous to the second exon of the gene. The data suggested
either the possibility of alternative splicing or the presence of a
second promoter within the first intron of the CTSL gene. Chauhan et al.
(1993) mapped the gene to 9q21-q22 by radioisotopic in situ
hybridization and also located the gene on chromosome 9 by PCR
amplification of rodent/human somatic cell hybrid DNAs. By in situ
hybridization, they also found a second signal at 10q23-q24 and pointed
out that this might be related to the fact that chromosomes 9 and 10
show evolutionary homeology.

By interspecific backcross linkage analysis, Pilz et al. (1995) mapped
the Ctsl gene to mouse chromosome 13.

*FIELD* RF
1. Chauhan, S. S.; Popescu, N. C.; Ray, D.; Fleischmann, R.; Gottesman,
M. M.; Troen, B. R.: Cloning, genomic organization, and chromosomal
localization of human cathepsin L. J. Biol. Chem. 268: 1039-1045,
1993.

2. Fan, Y.-S.; Byers, M. G.; Eddy, R. L.; Joseph, L.; Sukhatme, V.;
Chan, S.-J.; Shows, T. B.: Cathepsin L (CTSL) is located in the chromosome
9q21-q22 region: a related sequence is located on chromosome 10.
(Abstract) Cytogenet. Cell Genet. 51: 996 only, 1989.

3. Gal, S.; Gottesman, M. M.: Isolation and sequence of a cDNA for
human pro-(cathepsin L). Biochem. J. 253: 303-306, 1988.

4. Joseph, L. J.; Chang, L. C.; Stamenkovich, D.; Sukhatme, V. P.
: Complete nucleotide and deduced amino acid sequences of human and
murine preprocathepsin L: an abundant transcript induced by transformation
of fibroblasts. J. Clin. Invest. 81: 1621-1629, 1988.

5. Pilz, A.; Woodward, K.; Povey, S.; Abbott, C.: Comparative mapping
of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25:
139-149, 1995.

*FIELD* CD
Victor A. McKusick: 5/25/1988

*FIELD* ED
terry: 2/7/1995
carol: 2/24/1993
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/2/1990
ddp: 10/27/1989

*RECORD*
*FIELD* NO
116890
*FIELD* TI
*116890 CATHEPSIN E; CTSE
*FIELD* TX
Cathepsin E is an immunologically discrete aspartic protease found in
the gastrointestinal tract. Other enzymes in this class include
pepsinogen A (PGA; 169700), pepsinogen C (PGC; 169740), cathepsin D
(CTSD; 116840), and renin (REN; 179820). Unlike pepsinogens PGA and PGC,
CTSE is an intracellular proteinase that does not appear to be involved
in the digestion of dietary protein. It is found in highest
concentration in the surface of epithelial mucus-producing cells of the
stomach. It is the first aspartic proteinase expressed in the fetal
stomach and is found in more than half of gastric cancers. It appears,
therefore, to be an 'oncofetal' antigen. Taggart et al. (1989) used sets
of complementary oligonucleotide probes specific for the highly
conserved active site region of aspartic proteinases (AGS) to isolate
cDNA clones encoding previously unidentified enzymes of this class.
Taggart et al. (1989) identified 6 classes of cDNA clones in a gastric
adenocarcinoma cDNA library using a set of 18-mer probes and mapped the
corresponding genes to specific human chromosomes by analysis of a panel
of human x mouse somatic cell hybrids. One of the cDNAs, designated
AGS402, was shown by DNA analysis to correspond to the predicted coding
sequence of cathepsin E. They demonstrated that the CTSE gene is located
on chromosome 1 in the human. (The other 4 cDNAs that were mapped were
as follows: AGS7 to chromosome 13; AGS8 to chromosome 8; AGS422 to
chromosome 7; and AGS405 to chromosome 19.) Couvreur et al. (1989, 1990)
isolated a full-length cDNA clone from a gastric adenocarcinoma cDNA
library and used it to localize the gene to 1q23-qter by analysis of
human/rodent hybrid cell lines containing different X;1 translocations.
CTSE was further localized to 1q31 by in situ hybridization. Azuma et
al. (1989) also assigned the CTSE gene to chromosome 1. In addition,
they reported the amino acid sequence of CTSE predicted on the basis of
the cDNA sequence and compared the sequence with that of other aspartic
proteinases.

Azuma et al. (1992) demonstrated that multiple transcripts result from
alternative polyadenylation of the primary transcripts of the single
CTSE gene. They found that the size and placement of the 9 exons found
in the 17.5-kb CTSE gene are highly conserved relative to other aspartic
proteinases.

*FIELD* SA
Azuma et al. (1989)
*FIELD* RF
1. Azuma, T.; Liu, W. G.; Vander Laan, D. J.; Bowcock, A. M.; Taggart,
R. T.: Human gastric cathepsin E gene: multiple transcripts result
from alternative polyadenylation of the primary transcripts of a single
gene locus at 1q31-q32. J. Biol. Chem. 267: 1609-1614, 1992.

2. Azuma, T.; Pals, G.; Mohandas, T. K.; Couvreur, J. M.; Taggart,
R. T.: Cathepsin E: molecular cloning and characterization using
aspartyl proteinase active site probes.  (Abstract) Am. J. Hum. Genet. 45
(suppl.): A171 only, 1989.

3. Azuma, T.; Pals, G.; Mohandas, T. K.; Couvreur, J. M.; Taggart,
R. T.: Human gastric cathepsin E: predicted sequence, localization
to chromosome 1, and sequence homology with other aspartic proteinases.
J. Biol. Chem. 264: 16748-16753, 1989.

4. Couvreur, J. M.; Azuma, T.; Miller, D. A.; Rocchi, M.; Mohandas,
T. K.; Boudi, F. A.; Taggart, R. T.: Assignment of cathepsin E (CTSE)
to human chromosome region 1q31 by in situ hybridization and analysis
of somatic cell hybrids. Cytogenet. Cell Genet. 53: 137-139, 1990.

5. Couvreur, J. M.; Johnson, M. P.; Azuma, T.; Boudi, F. A.; Rocchi,
M.; Mohandas, T. K.; Miller, D. A.; Taggart, R. T.: Cathepsin E:
localization of a single gene locus to 1q31 by restriction analysis
of X;1 translocation somatic cell hybrids, and in situ hybridization.
(Abstract) Am. J. Hum. Genet. 45 (suppl.): A135 only, 1989.

6. Taggart, R. T.; Azuma, T.; Couvreur, J. M.; Mohandas, T. K.: Isolation
and mapping genes identified with probes specific for the conserved
active site of aspartic proteinases.  (Abstract) Cytogenet. Cell
Genet. 51: 1088 only, 1989.

*FIELD* CD
Victor A. McKusick: 6/2/1989

*FIELD* ED
carol: 1/13/1993
supermim: 3/16/1992
supermim: 9/28/1990
supermim: 3/20/1990
carol: 12/1/1989
carol: 11/10/1989

*RECORD*
*FIELD* NO
116896
*FIELD* TI
*116896 CCAAT DISPLACEMENT PROTEIN; CDP
CUT (DROSOPHILA)-LIKE, 1; CUTL1
*FIELD* TX
The activity of CDP, CCAAT displacement protein, was first identified in
sea urchin as a possible repressor of a sperm-specific histone H2b gene.
As implied by its name, CDP is thought to act by preventing binding of
positively-acting CCAAT factors to promoters, although there is little
experimental evidence for this (Neufeld, 1995). The wide distribution of
CDP in mammalian cell lines and its postulated mechanism of action made
it a potential candidate for a general repressor of developmentally
regulated genes. Neufeld et al. (1992) purified CDP from HeLa cells by
DNA binding-site affinity chromatography. The cDNA encoding CDP was
obtained by immunoscreening a lambda-gt11 library with antibody raised
against purified protein. The deduced primary amino acid sequence of CDP
showed remarkable homology to the Drosophila homeoprotein cut with
respect to the presence of a unique homeodomain and 'cut repeats.' As
cut participates in determination of cell fate in several tissues in
Drosophila, the similarity predicts a broad role for CDP in mammalian
development. Neufeld et al. (1992) studied CDP because of its likely
role in regulation of the gene encoding the protein deficient in
X-linked chronic granulomatous disease (306400). By analysis of a panel
of rodent/human somatic cell hybrids containing various portions of
chromosome 7, Scherer et al. (1993) determined that the gene for CCAAT
displacement protein, symbolized CUTL1, maps to the distal boundary of
7q22. Kere et al. (1989) described deletions in this region in patients
with leukemia.

*FIELD* RF
1. Kere, J.; Ruutu, T.; Davies, K. A.; Roninson, I. B.; Watkins, P.
C.; Winqvist, R.; de la Chapelle, A.: Chromosome 7 long arm deletion
in myeloid disorders: a narrow breakpoint region in 7q22 defined by
molecular mapping. Blood 73: 230-234, 1989.

2. Neufeld, E. J.: Personal Communication. Boston, Mass.  2/21/1995.

3. Neufeld, E. J.; Skalnik, D. G.; Lievens, P. M.-J.; Orkin, S. H.
: Human CCAAT displacement protein is homologous to the Drosophila
homeoprotein, cut. Nature Genet. 1: 50-55, 1992.

4. Scherer, S. W.; Neufeld, E. J.; Lievens, P. M.-J.; Orkin, S. H.;
Kim, J.; Tsui, L.-C.: Regional localization of the CCAAT displacement
protein gene (CUTL1) to 7q22 by analysis of somatic cell hybrids.
Genomics 15: 695-696, 1993.

*FIELD* CD
Victor A. McKusick: 6/10/1992

*FIELD* ED
carol: 3/2/1995
carol: 4/7/1993
carol: 3/22/1993
carol: 6/10/1992

*RECORD*
*FIELD* NO
116897
*FIELD* TI
*116897 CCAAT/ENHANCER BINDING PROTEIN (C/EBP), ALPHA; CEBPA
C/EBP-ALPHA;;
CEBP
*FIELD* TX
The CCAAT/enhancer-binding protein bears sequence homology and
functional similarities to LAP (189965) (Descombes et al., 1990). See
Landschulz et al. (1989). By means of somatic cell hybrids segregating
either human or rat chromosomes, Szpirer et al. (1992) mapped the CEBP
gene to human chromosome 19 and rat chromosome 1. These results provided
further evidence for conservation of synteny on these 1 chromosomes (and
on mouse chromosome 7). Using human/hamster somatic cell hybrids
containing restricted fragments of human chromosome 19, Hendricks-Taylor
et al. (1992) mapped the CEBPA gene to 19q13.1 between the loci GPI and
TGFB. This position was confirmed by fluorescence in situ hybridization.
Birkenmeier et al. (1989) mapped the Cebpa gene to mouse chromosome 7.

According to the nomenclature proposed by Cao et al. (1991), the
CCAAT/enhancer binding protein is C/ERB-alpha and NF-IL6 is C/EBP-beta
(189965), with the corresponding genes being CEBPA and CEBPB. CEBPB was
formerly symbolized TCF5.

Wang et al. (1995) found that mice homozygous for the targeted deletion
of the Cepba gene did not store hepatic glycogen and died from
hypoglycemia within 8 hours after birth. In these mutant mice, the
amounts of glycogen synthase (138571) mRNA were 50 to 70% of normal and
the transcriptional induction of the genes for 2 gluconeogenic enzymes,
phosphoenolpyruvate carboxykinase (261680) and glucose-6-phosphatase
(232200), was delayed. The hepatocytes and adipocytes of the mutant mice
failed to accumulate lipid and the expression of the gene for uncoupling
protein (113730), the defining marker of brown adipose tissue was
reduced. The findings demonstrated that C/EBP-alpha is critical for the
establishment and maintenance of energy homeostasis in neonates.

Flodby et al. (1996) made transgenic knockout mice in which the CEBPA
gene was selectively disrupted. The homozygous mutant Cebpa -/- mice
died, usually within the first 20 hours after birth and had defects in
the control of hepatic growth and lung development. Histologic analysis
revealed that these animals had severely disturbed liver architecture,
with acinar formation, in a pattern suggestive of either regenerating
liver or hepatocellular carcinoma. Pulmonary histology showed
hyperproliferation of type II pneumocytes and disturbed alveolar
architecture. Molecular analysis showed that accumulation of glycogen
and lipids in the liver and adipose tissue is impaired and that the
mutant animals are severely hypoglycemic. The authors found by Northern
blot analysis that levels of c-myc and c-jun RNAs are specifically
induced by several fold in the livers of these animals indicating an
active proliferative state. They found by immunohistology that
cyclin-stained cells are present in the liver of Cebpa -/- mice at a 5
to 10 times higher frequency than normal, also indicating abnormally
active proliferation. Flodby et al. (1996) suggested that CEBPA may have
an important role in the acquisition and maintenance of terminal
differentiation in hepatocytes.

Miller et al. (1996) characterized the promoter of the human gene
encoding leptin (164160), a signaling factor expressed in adipose tissue
with an important role in body weight homeostasis. They found that CEBPA
modulates leptin expression and suggested a function for CEBPA in
treatment of human obesity.

*FIELD* RF
1. Birkenmeier, E. H.; Gwynn, B.; Howard, S.; Jerry, J.; Gordon, J.
I.; Landschulz, W. H.; McKnight, S. L.: Tissue-specific expression,
developmental regulation, and genetic mapping of the gene encoding
CCAAT/enhancer binding protein. Genes Dev. 3: 1146-1156, 1989.

2. Cao, Z.; Umek, R. M.; McKnight, S. L.: Regulated expression of
three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes
Dev. 5: 1538-1552, 1991.

3. Descombes, P.; Chojkier, M.; Lichtsteiner, S.; Falvey, E.; Schibler,
U.: LAP, a novel member of the C/EBP gene family, encodes a liver-enriched
transcriptional activator protein. Genes Dev. 4: 1541-1551, 1990.

4. Flodby, P.; Barlow, C.; Kylefjord, H.; Ahrlund-Richter, L.; Xanthopoulos,
K. G.: Increased hepatic cell proliferation and lung abnormalities
in mice deficient in CCAAT/enhancer binding protein alpha. J. Biol.
Chem. 271: 24753-24760, 1996.

5. Hendricks-Taylor, L. R.; Bachinski, L. L.; Siciliano, M. J.; Fertitta,
A.; Trask, B.; de Jong, P. J.; Ledbetter, D. H.; Darlington, G. J.
: The CCAAT/enhancer binding protein (C/EBP-alpha) gene (CEBPA) maps
to human chromosome 19q13.1 and the related nuclear factor NF-IL6
(C/EBP-beta) gene (CEBPB) maps to human chromosome 20q13.1. Genomics 14:
12-17, 1992.

6. Landschulz, W. H.; Johnson, P. F.; McKnight, S. L.: The DNA binding
domain of the rat liver nuclear protein C/EBP is bipartite. Science 243:
1681-1688, 1989.

7. Miller, S. G.; De Vos, P.; Guerre-Millo, M.; Wong, K.; Hermann,
T.; Staels, B.; Briggs, M. R.; Auwerx, J.: The adipocyte specific
transcription factor C/EBP-alpha modulates human ob gene expression. Proc.
Nat. Acad. Sci. 93: 5507-5511, 1996.

8. Szpirer, C.; Riviere, M.; Cortese, R.; Nakamura, T.; Islam, M.
Q.; Levan, G.; Szpirer, J.: Chromosomal localization in man and rat
of the genes encoding the liver-enriched transcription factors C/EBP,
DBP, and HNF1/LFB-1 (CEBP, DBP, and transcription factor 1, TCF1,
respectively) and of the hepatocyte growth factor/scatter factor gene
(HGF). Genomics 13: 293-300, 1992.

9. Wang, N-d.; Finegold, M. J.; Bradley, A.; Ou, C. N.; Abdelsayed,
S. V.; Wilde, M. D.; Taylor, L. R.; Wilson, D. R.; Darlington, G.
J.: Impaired energy homeostasis in C/EBP-alpha knockout mice. Science 269:
1108-1112, 1995.

*FIELD* CN
Jennifer P. Macke - updated: 11/20/1996
Alan F. Scott - updated: 9/17/1996
Mark H. Paalman - updated: 7/11/1996

*FIELD* CD
Victor A. McKusick: 10/26/1990

*FIELD* ED
jamie: 02/04/1997
terry: 1/17/1997
jamie: 11/20/1996
mark: 9/17/1996
mark: 7/11/1996
terry: 6/28/1996
mark: 10/12/1995
terry: 9/11/1995
carol: 5/26/1993
carol: 4/7/1993
carol: 10/13/1992
carol: 9/25/1992

*RECORD*
*FIELD* NO
116898
*FIELD* TI
*116898 CCAAT/ENHANCER-BINDING PROTEIN (C/EBP), DELTA; CEBPD
C/EBP-DELTA;;
CRP3
*FIELD* TX
In an attempt to identify C/EBP-like transcription factors expressed in
the prostate, Cleutjens et al. (1993) isolated a cDNA homologous to the
mouse C/EBP-delta (CRP3) and the rat Celf gene. A genomic clone
containing the entire human CEBPD gene was isolated using a cDNA
fragment as a probe. By fluorescence in situ hybridization, Cleutjens et
al. (1993) assigned the CEBPD gene to 8q11. The chromosomal localization
was confirmed by analysis of a panel of human/hamster somatic cell
hybrid DNA samples containing various portions of chromosome 8 with a
CEBPD-specific STS. They positioned the CEBPD gene between the gene for
tissue plasminogen activator (173370) and the MOS oncogene (190060). The
murine gene is located on mouse chromosome 16 (cited by Williams et al.,
1991).

Kirchgessner et al. (1995) established a synteny group between human
8q11, containing the gene for the p350 subunit of DNA-activated protein
kinase (202500) and the CEBPD gene, and the centromeric region of mouse
chromosome 16.

Jenkins et al. (1995) demonstrated that the Cebpb gene maps to mouse
chromosome 16. Interspecific backcross analysis was used for the
mapping. The assignment to mouse chromosome 16 defines a new region of
homology with human chromosome 8. By cell hybrid and fluorescence in
situ hybridization mapping, Wood et al. (1995) placed both CEBPD and
FGFR1 (136350) within the chromosome region 8p11.2-p11.1.

*FIELD* RF
1. Cleutjens, C. B. J. M.; van Eekelen, C. C. E. M.; van Dekken, H.;
Smit, E. M. E.; Hagemeijer, A.; Wagner, M. J.; Wells, D. E.; Trapman,
J.: The human C/EBP-delta (CRP3/CELF) gene: structure and chromosomal
localization. Genomics 16: 520-523, 1993.

2. Jenkins, N. A.; Gilbert, D. J.; Cho, B. C.; Strobel, M. C.; Williams,
S. C.; Copeland, N. G.; Johnson, P. F.: Mouse chromosomal location
of the CCAAT/enhancer binding proteins C/EBP-beta (Cebpb), C/EBP-delta
(Cebpd), and CRP1 (Cebpe). Genomics 28: 333-336, 1995.

3. Kirchgessner, C. U.; Patil, C. K.; Evans, J. W.; Cuomo, C. A.;
Fried, L. M.; Carter, T.; Oettinger, M. A.; Brown, J. M.: DNA-dependent
kinase (p350) as a candidate gene for the murine SCID defect. Science 267:
1178-1183, 1995.

4. Williams, S. C.; Cantwell, C. A.; Johnson, P. F.: A family of
C/EBP-related proteins capable of forming covalently linked leucine
zipper dimers in vitro. Genes Dev. 5: 1553-1567, 1991.

5. Wood, S.; Schertzer, M.; Yaremko, M. L.: Sequence identity locates
CEBPD and FGFR1 to mapped human loci within proximal 8p. Cytogenet.
Cell Genet. 70: 188-191, 1995.

*FIELD* CN
Alan F. Scott - updated: 09/17/1996

*FIELD* CD
Victor A. McKusick: 5/26/1993

*FIELD* ED
mark: 09/17/1996
mark: 10/20/1995
carol: 6/7/1993
carol: 5/26/1993

*RECORD*
*FIELD* NO
116899
*FIELD* TI
*116899 CYCLIN-DEPENDENT INHIBITOR 1A; CDKN1A
CDK-INTERACTING PROTEIN 1; CIP1;;
WILDTYPE p53-ACTIVATED FRAGMENT 1; WAF1;;
p21; P21
*FIELD* TX
The cyclin-dependent kinase CDK2 (116953) associates with cyclins A
(123835), D (168461), and E (123837) and has been implicated in the
control of the G1 to S phase transition in mammals. To identify
potential CDK2 regulators, Harper et al. (1993) used an improved
2-hybrid system to isolate human genes encoding CDK-interacting proteins
(CIPs) which they called CIP1. CIP1 was found to encode a novel 21-kd
protein that is found in immunoprecipitates of cyclin A, cyclin D1,
cyclin E, and CDK2. It is a potent, tight-binding inhibitor of CDKs and
can inhibit the phosphorylation of the retinoblastoma protein by several
of these complexes. Cotransfection experiments indicated that CIP1 and
SV40T antigen function in a mutually antagonistic manner to control cell
cycle progression.

The ability of p53 (191170) to activate transcription from specific
sequences suggests that genes induced by p53 may mediate its biologic
role as a tumor suppressor. Using a subtractive hybridization approach,
El-Deiry et al. (1993) identified a gene they called WAF1 (for wildtype
p53-activated fragment 1), whose induction was associated with wildtype
but not mutant p53 gene expression in a human brain tumor cell line.
They mapped the WAF1 gene to 6p21.2 by fluorescence in situ
hybridization. They found that the sequence, structure, and activation
by p53 was conserved in rodents. Introduction of WAF1 cDNA suppressed
the growth of human brain, lung, and colon tumor cells in culture. Using
a yeast enhancer trap, they identified a p53-binding site 2.4 kb
upstream of WAF1 coding sequences. The WAF1 promoter, including this
p53-binding site, conferred p53-dependent inducibility upon a
heterologous reporter gene. After acceptance of their paper for
publication, El-Deiry et al. (1993) learned that Harper et al. (1993)
had identified a gene, called CIP1, whose product binds to cyclin
complexes and inhibits the function of cyclin-dependent kinases. They
found that the sequence of CIP1, described by Harper et al. (1993) in
the same issue of Cell, was identical to that of WAF1. The results
provided a dramatic example of the interplay between tumor suppressor
genes and the cell cycle.

Chedid et al. (1994) identified a polymorphism at codon 31 where a
single point mutation changed AGC (ser) to AGA (arg) (116899.0001). The
change resulted in the loss of a restriction site and gain of another,
allowing for rapid screening of the polymorphism. Analysis of genomic
DNAs from 50 randomly selected individuals revealed that the basepair
substitution occurred with an allelic frequency of 0.14. Transfection
studies demonstrated that expression of the arg allele was not
associated with loss of tumor suppressor activity. Moreover, screening
of 22 tumor DNA samples revealed no association between tumor phenotype
and the arg allele.

Huppi et al. (1994) cloned and sequenced a mouse p21 cDNA and
established that the gene locus, Waf1, lies proximal to H-2 on
chromosome 17.

The preferred symbol for this gene is cyclin-dependent kinase inhibitor
1A (CDKN1A). Also referred to as p21 and as CDKN1, this protein inhibits
cyclin-kinase activity, is tightly regulated at the transcriptional
level by p53, and probably serves as the effector of p53 cell cycle
control. By fluorescence in situ hybridization, Demetrick et al. (1995)
also mapped the gene to 6p21.2.

The WAF1-encoded protein, p21, mediates p53 suppression of tumor cell
growth. Overexpression of p21 in a tumor cell line suppresses colony
formation similar to that resulting from p53 overexpression. To localize
the tumor suppression function within the structure of p21, Zakut and
Givol (1995) used vectors constructed with systematic truncations of p21
and tested their efficiency in suppressing tumor cell growth. They
demonstrated that the N-terminal half of the p21 molecule shows better
tumor cell growth suppression than the entire p21 molecule, whereas the
C-terminal half of p21 did not show this effect.

*FIELD* AV
.0001
CIP1/WAF1 TUMOR-ASSOCIATED POLYMORPHISM 1
CDKN1A, SER31ARG
Since CDKN1A probably mediated the growth suppression effects of p53 by
arresting the cell cycle at the G1/S checkpoint and inducing apoptosis,
Mousses et al. (1995) sought mutations in the gene in primary human
tumors. Unique or acquired somatic mutations were not observed in
primary breast and carcinoma specimens; however, 2 common variants were
identified. The variants were not unique to tumors, as 10.7% of normal
individuals exhibited the variants. Nonetheless, the frequency of the
variants in tumors with wildtype p53 (20.4%) was significantly greater
(P = 0.05) than in normal DNAs. In contrast, the frequency of the
variants (4.1%) was found to be significantly lower in tumors with p53
mutations (p = 0.006). These data suggested to the authors that
occurrence of the variants may have a direct effect on tumor development
and may, in some cases, be incompatible with p53 mutations. One of the
variants found by Mousses et al. (1995) was an AGC-to-AGA substitution
in codon 31 (ser31-to-arg), which had been observed previously by Chedid
et al. (1994). The other was a C-to-T change in the 3-prime untranslated
region of the CDKN1A gene 20 bp following the stop codon. Sjalander et
al. (1996) found an increased frequency of the p21 codon 31ARG allele in
lung cancer patients, especially in comparison with patients with
chronic obstructive pulmonary disease (COPD); p = 0.004. Thus allelic
variants of both p53 and its effector protein p21 may have an influence
on lung cancer.

*FIELD* RF
1. Chedid, M.; Michieli, P.; Lengel, C.; Huppi, K.; Givol, D.: A
single nucleotide substitution at codon 31 (ser/arg) defines a polymorphism
in a highly conserved region of the p53-inducible gene WAF1/CIP1. Oncogene 9:
3021-3024, 1994.

2. Demetrick, D. J.; Matsumoto, S.; Hannon, G. J.; Okamoto, K.; Xiong,
Y.; Zhang, H.; Beach, D. H.: Chromosomal mapping of the genes for
the human cell cycle proteins cyclin C (CCNC), cyclin E (CCNE), p21
(CDKN1) and KAP (CDKN3). Cytogenet. Cell Genet. 69: 190-192, 1995.

3. El-Deiry, W. S.; Tokino, T.; Velculescu, V. E.; Levy, D. B.; Parsons,
R.; Trent, J. M.; Lin, D.; Mercer, E.; Kinzler, K. W.; Vogelstein,
B.: WAF1, a potential mediator of p53 tumor suppression. Cell 75:
817-825, 1993.

4. Harper, J. W.; Adami, G. R.; Wei, N.; Keyomarsi, K.; Elledge, S.
J.: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of
G1 cyclin-dependent kinases. Cell 75: 805-816, 1993.

5. Huppi, K.; Siwarski, D.; Dosik, J.; Michieli, P.; Chedid, M.; Reed,
S.; Mock, B.; Givol, D.; Mushinski, J. F.: Molecular cloning, sequencing,
chromosomal localization and expression of mouse p21 (Waf1). Oncogene 9:
3017-3020, 1994.

6. Mousses, S.; Ozcelik, H.; Lee, P. D.; Malkin, D.; Bull, S. B.;
Andrulis, I. L.: Two variants of the CIP1/WAF1 gene occur together
and are associated with human cancer. Hum. Molec. Genet. 4: 1089-1092,
1995.

7. Sjalander, A.; Birgander, R.; Rannug, A.; Alexandrie, A.-K.; Tornling,
G.; Beckman, G.: Association between the p21 codon 31A1 (arg) allele
and lung cancer. Hum. Hered. 46: 221-225, 1996.

8. Zakut, R.; Givol, D.: The tumor suppression function of p21(Waf)
is contained in its N-terminal half ('half-WAF'). Oncogene 11: 393-395,
1995.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
mark: 01/18/1997
mark: 12/9/1996
terry: 11/7/1996
mark: 9/22/1996
mark: 12/20/1995
terry: 10/27/1995
mark: 7/21/1995
carol: 2/17/1995
jason: 6/17/1994

*RECORD*
*FIELD* NO
116900
*FIELD* TI
*116900 CDC2-ASSOCIATED PROTEIN CKS1; CKS1
*FIELD* TX
The Cks1 protein is a component of the Cdc28 protein kinase in the
budding yeast Saccharomyces cerevisiae. Richardson et al. (1990) cloned
2 human homologs of the Cks1 gene of yeast. Designated CKS1 and CKS2,
both encode proteins of 79 amino acids that share considerable homology
at the amino acid level with the products of the corresponding gene in
S. cerevisiae and another gene in the fission yeast Schizosaccharomyces
pombe. Both human homologs were capable of rescuing a null mutation of
the S. cerevisiae Cks1 gene when expressed from the S. cerevisiae GAL1
promoter. Linked to Sepharose beads, the CKS1 and CKS2 proteins could
bind the CDC28/CDC2 protein kinase from both S. cerevisiae and human
cells (CDC2; 116940). The CKS1 and CKS2 mRNAs are found to be expressed
in different patterns through the cell cycle in HeLa cells, which
reflects specialized roles for the encoded proteins.

Bourne et al. (1996) analyzed the crystal structure of the CDK-CKS1
complex and defined the critical protein domains involved in the
interaction of the 2 molecules. They tested the biologic importance of
the structure-based model by constructing mutant alleles of CKS1 that
led to decreased interaction with CDK2. Bourne et al. (1996) concluded
that the structural analysis revealed the mode of CDK2 binding to CKS1,
suggested a possible mechanism of cooperativity and self regulation of
CKS proteins during the cell cycle, and implicated CKS as a targeting or
matchmaking protein for CDK and at least 1 other phosphoprotein.

By fluorescence in situ hybridization, Demetrick et al. (1996) mapped
the CKS1 gene to 8q21.

*FIELD* RF
1. Bourne, Y.; Watson, M. H.; Hickey, M. J.; Holmes, W.; Rocque, W.;
Reed, S. I.; Turner, J. A.: Crystal structure and mutational analysis
of the human CDK2 kinase complex with cell cycle-regulatory protein
CksHs1. Cell 84: 863-874, 1996.

2. Demetrick, D. J.; Zhang, H.; Beach, D. H.: Chromosomal mapping
of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenet. Cell
Genet. 73: 250-254, 1996.

3. Richardson, H. E.; Stueland, C. S.; Thomas, J.; Russell, P.; Reed,
S. I.: Human cDNAs encoding homologs of the small p34-Cdc28/Cdc2-associated
protein of Saccharomyces cerevisiae and Schizosaccharomyces pombe. Genes
Dev. 4: 1332-1344, 1990.

*FIELD* CN
Moyra Smith - updated: 4/15/1996

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
terry: 01/17/1997
terry: 11/11/1996
mark: 4/17/1996
carol: 4/16/1996
carol: 4/15/1996
jason: 6/17/1994

*RECORD*
*FIELD* NO
116901
*FIELD* TI
*116901 CDC2-ASSOCIATED PROTEIN CKS2; CKS2
*FIELD* TX
See CDC2-associated protein CKS1 (116900).

By fluorescence in situ hybridization, Demetrick et al. (1996) mapped
CKS2 to 9q22.

*FIELD* RF
1. Demetrick, D. J.; Zhang, H.; Beach, D. H.: Chromosomal mapping
of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenet. Cell
Genet. 73: 250-254, 1996.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
terry: 11/11/1996
jason: 6/17/1994

*RECORD*
*FIELD* NO
116920
*FIELD* TI
#116920 LEUKOCYTE ADHESION DEFICIENCY, TYPE 1; LAD
LAD1
*FIELD* MN

A number sign (#) is used with this entry because the phenotype is
caused by mutations in the integrin beta-2 chain of the leukocyte cell
adhesion molecule (ITGB2; 600065).

Leukocyte adhesion deficiency is an autosomal recessive disorder
characterized by recurrent bacterial infections, impaired pus formation
and wound healing, and abnormalities of a wide variety of
adhesion-dependent functions of granulocytes, monocytes, and
lymphocytes. These include defects in initiation of the neutrophil
respiratory burst to particulate but not soluble stimuli, defects in
neutrophil chemotaxis and phagocytosis, or both (Anderson and Springer,
1987). There is considerable variation in severity. The primary defect
is in the beta subunit of a family of glycoproteins, CD18/CD11, in the
leukocyte membrane.

Before the elucidation by Springer et al. (1986) and Barclay et al.
(1993), extraordinary confusion surrounded the group of patients with
leukocyte dysfunction and deficiency of cell surface antigens. In part,
the confusion was created by the bewildering nomenclature; in part it
was due to the fact that different investigators looked at different
ones of the 3 glycoprotein adhesion molecules that share a common beta
subunit.

Often the first manifestation is infection of the umbilical cord stump,
occasionally progressing to omphalitis (Abramson et al., 1981).
Gingivitis (periodontosis) may be noted with eruption of the primary
teeth. Systemic bacterial infections such as pneumonia, peritonitis, and
deep abscesses are more frequent during infancy and with complete
deficiency (Ross, 1986).

The review by Todd and Freyer (1988) reports 41 patients in whom the
clinical picture fitted that of CD18/CD11 glycoprotein deficiency. At
least 4 patients with a moderately severe variant (10% expression of
CD18/CD11 glycoprotein) have survived to adulthood.

The property of leukocyte adhesion necessary for a wide variety of
adhesion-dependent interactions in the immune system depends on a family
of glycoproteins in the leukocyte plasma membrane. These have a common
beta subunit, CD18, and 1 of 3 alpha subunits, CD11A, -B, or -C. These 3
cell adhesion molecules are LFA-1 (CD18/CD11A) on all leukocytes; Mo1 or
Mac1 or CR3A (CD18/CD11B) on monocytes, neutrophils, and killer cells;
and p150,95 (CD18/CD11C) on monocytes and neutrophils. LAD results from
deficient or abnormal CD18, causing a deficiency in all 3 heterodimers
(Springer et al., 1984).

Kishimoto et al. (1987) identified 5 distinct beta-subunit phenotypes
among LAD patients: an undetectable beta-subunit mRNA and protein
precursor; low levels of beta-subunit mRNA and precursor; an aberrantly
large beta-subunit precursor, probably due to an extra glycosylation
site; an aberrantly small precursor; and a grossly normal precursor,
with abnormal posttranslational processing (Dana et al., 1987).

Autosomal recessive inheritance is suggested by occurrence in sibs with
normal parents. The neutrophils from parents and sibs of patients often
show half-normal amounts of CR3/LFA1/p150,95 antigens (Arnaout et al.,
1984; Springer et al., 1984). In other cases, both parents have normal
amounts of antigen or only 1 parent has half-normal amounts (Ross et
al., 1985).

The CD18 gene has been mapped to 21q22.3 (Petersen et al., 1991) and
cloned (Kishimoto et al., 1987). Various mutations have been identified
including base substitutions, deletions, and insertions, leading to
defects in translation, association with the alpha subunit, or splicing
(Nelson et al., 1992; Matsuura et al., 1992).

Diagnosis is facilitated by the use of commercially available monoclonal
antibodies specific for the alpha chains of CR3 and p150,95.

Bone marrow transplantation may be successful with complete restoration
of leukocyte function and the absence of need for any further treatment
in some patients (Fischer et al., 1986). Human CD18 cDNA has been
introduced into the bone marrow progenitor cells of patients with LAD,
demonstrating the potential for gene therapy (Yorifuji et al., 1993).

*FIELD* TX

DESCRIPTION

Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder
of neutrophil function resulting from a deficiency of the beta-2
integrin subunit of the leukocyte cell adhesion molecule. The leukocyte
cell adhesion molecule is present on the surface of peripheral blood
mononuclear leukocytes and granulocytes and mediates cell-cell and
cell-extracellular matrix adhesion. LAD is characterized by recurrent
bacterial infections; impaired pus formation and wound healing;
abnormalities of a wide variety of adhesion-dependent functions of
granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L,
beta-2/alpha-M, and beta-2/alpha-X expression.

NOMENCLATURE

The beta-2 integrin chain gene is designated ITGB2 and the leukocyte
antigen has been designated CD18. The 3 alpha integrin chains associated
individually with the beta-2 chain as a heterodimer have gene
designations of ITGAL, ITGAM, and ITGAX (and leukocyte antigen
designations of CD11A, CD11B, and CD11C, respectively).

The 3 integrin molecules associated with LAD have leukocyte antigen
designations of (1) CD18/CD11A: also referred to as LFA-1, Leu CAMa; and
integrin beta-2/alpha-L; (2) CD18/CD11B: also referred to as CR3, Leu
CAMb, Mac-1, Mo1, OKM-1 and integrin beta-2/alpha M; (3) CD18/CD11C:
also referred to as p150 (p150, 95) Leu CAMc and integrin beta-2/alpha-X
(Barclay et al., 1993).

CLINICAL FEATURES

Beginning in the 1970s, patients were recognized who had recurrent
bacterial infections, defective neutrophil mobility, and delayed
separation of the umbilical cord (e.g., Hayward et al., 1979). Before
the elucidation by Springer et al. (1984, 1986) and Barclay et al.
(1993), extraordinary confusion surrounded the group of patients with
leukocyte dysfunction and deficiency of cell surface antigens (see, for
example, Arnaout et al., 1982; Bowen et al., 1982; Dana et al., 1984).
In the seventh edition of these catalogs (1986), one entry related to
the ITGB2 locus (which is mutant in these patients), but 3 others
described neutrophil dysfunction syndromes now known to be leukocyte
adhesion deficiency. Confusion was created by different investigators
looking at the different alpha subunits which share a common beta
subunit.

Van der Meer et al. (1975) described a 'new' defect in the intracellular
killing of ingested microorganisms. A sister and probably 2 brothers
were affected. During infections, the white blood count was as high as
55,000 per cu mm, mostly neutrophils, with a slight shift to the left.
Other patients with recurring bacterial infections were reported who had
defects in initiation of the neutrophil respiratory burst to particulate
but not soluble stimuli (e.g., Weening et al., 1976; Harvath and
Andersen, 1979), defects in neutrophil chemotaxis and phagocytosis
(e.g., Niethammer et al., 1975), or both (Harvath and Andersen, 1979).
Crowley et al. (1980) were the first to propose that the defects in
neutrophil chemotaxis and phagocytosis were secondary to an abnormality
in cell adhesion.

Using specific monoclonal antibodies, Dana et al. (1984), Beatty et al.
(1984), and others demonstrated deficiency of both the alpha and the
beta subunits of Mac-1 (also designated Mo1, and as beta-2/alpha M in
integrin terminology) in the neutrophils of patients of this type.
Arnaout et al. (1984) and others demonstrated that the LFA-1 alpha-beta
complex (beta-2/alpha X) is also deficient on patients' neutrophils and
lymphocytes. Springer et al. (1984, 1986) found that a third type of
alpha-beta complex is also deficient on patients' neutrophils and
lymphocytes. Springer et al. (1984, 1986) proposed that the primary
defect in these patients resides in the beta subunit (which is shared by
all 3 deficient proteins) and that the beta subunit is necessary for
cell surface expression on the alpha subunit. Such neutrophils have a
reduced phagocytic and respiratory burst response to bacteria and yeast
as well as a reduced ability to adhere to various substances and migrate
into sites of infection. Most of the clinical features are probably the
result of neutrophil and monocyte deficiency of CR3 (beta-2/alpha M).

There have been reports of about 30 patients with recurrent bacterial
infections due to deficiency of this family of cell membrane
glycoproteins. Ross (1986) tabulated the findings in reported cases.
Often the first manifestation is infection of the umbilical cord stump,
occasionally progressing to omphalitis (Abramson et al., 1981; Bissenden
et al., 1981). Gingivitis (periodontosis) may be noted with eruption of
the primary teeth. Systemic bacterial infections such as pneumonia,
peritonitis, and deep abscesses are more frequent during infancy and
with complete deficiency.

See review by Todd and Freyer (1988), who found reports of 41 patients
in whom the clinical picture fitted that of CD18/CD11 (beta-2/alpha)
glycoprotein deficiency. At least 4 patients suspected or documented to
have a moderately severe variant (10% expression of CD18/CD11
glycoprotein) have survived to adulthood (Anderson et al., 1985; van der
Meer et al., 1975; Weening et al., 1976) and 3 homozygous persons are
known to have parented affected or presumably heterozygous offspring.

Kobayashi et al. (1984) described a 3-month-old Japanese female infant
with persistent navel infection due to Pseudomonas aeruginosa since
birth and recurrent bacterial skin infections. They found a severe
abnormality of neutrophil adhesion on a surface, leading to a lack of
chemotaxis and mild impairment of phagocytosis. Neutrophil bactericidal
activity and nitroblue tetrazolium reduction were unimpaired. By sodium
dodecyl sulfate polyacrylamide gel electrophoresis of neutrophil
membrane proteins, 2 glycoproteins were shown to be lacking. In both
parents, both glycoproteins were reduced. Fujita et al. (1985) reported
the subsequent birth of a male sib with the same defect. Fujita et al.
(1988) described juvenile rheumatoid arthritis of systemic onset in
these sibs, then aged 5 and 3 years, respectively, who had a severe form
of congenital leukocyte adhesion deficiency.

BIOCHEMICAL FEATURES

Kishimoto et al. (1987) identified 5 distinct beta-subunit phenotypes
among LAD patients: an undetectable beta-subunit mRNA and protein
precursor; low levels of beta-subunit mRNA and precursor; an aberrantly
large beta-subunit precursor, probably due to an extra glycosylation
site; an aberrantly small precursor; and a grossly normal precursor.
Mutant beta-subunit precursors from LAD patients failed to associate
with the LFA-1 alpha subunit (alpha-L). Family studies with aberrant
precursors correlated with recessive inheritance of leukocyte adhesion
deficiency.

Marlin et al. (1986) showed that the genetic defect in leukocyte
adhesion deficiency (also known as LFA-1 immunodeficiency and by several
other designations) resides in the beta subunit that is common to 3 cell
adhesion molecules. (Boucheix (1987) indicated that a tentative
designation for the beta chain of these 3 proteins is CD18.) The 3, each
with a unique alpha chain, are CR3A (also known as CD11B, Mac-1; Mo1;
120980; beta-2/alpha-M), LFA-1 (CD11A; 153370; beta-2/alpha-L), and
p150,90 (CD11C; 151510; beta-2/alpha-X).

INHERITANCE

The neutrophils from parents and sibs of patients often show half-normal
amounts of CR3/LFA1/p150,95 antigens (CD18/CD11B, CD18/CD11A and
CD18/CD11C, respectively) (Arnaout et al., 1984; Springer et al., 1984).
In other cases, both parents have normal amounts of antigen or only 1
parent has half-normal amounts (Ross et al., 1985; Arnaout et al.,
1984). The only suggestion of a mode of inheritance other than autosomal
recessive came from Crowley et al. (1980), who first proposed that an
adhesion defect exists in this condition. X-linked recessive inheritance
was suggested because only the mother and sister of the affected male
showed evidence of the carrier state; the cells of the father and
brother were functionally normal and had a normal content of the
relevant glycoprotein.

MAPPING

Suomalainen et al. (1985, 1986) showed that the integrin beta-2 gene is
located on chromosome 21.

MOLECULAR GENETICS

Kishimoto et al. (1987) cloned the beta subunit and demonstrated
homology to integrin. The cloning of the gene opens up the possibility
of exploration of gene therapy for LAD.

Dana et al. (1987) studied 4 unrelated patients with the family of 3
leukocyte adhesion molecules, which they called Leu-CAM. They called the
3 antigens, Mo1, LFA-1, and Leu M5. In all 4 patients, they found that B
cells synthesized a normal-sized, beta-subunit precursor that either
failed to 'mature' or matured only partially to the membrane-expressed
form. Furthermore, B cells from all 4 patients had a single
normal-sized, beta-subunit mRNA of about 3.4 kb. Thus, leukocyte
adhesion deficiency in these 4 patients was not due to the absence of
the beta chain gene or to aberrant splicing of its mRNA. The findings
were consistent with a defective beta-subunit gene (ITGB2) resulting in
abnormal posttranslational processing of the synthesized beta molecule.

DIAGNOSIS

Diagnosis of hereditary deficiency of CR3 is facilitated by commercial
availability of monoclonal antibodies specific for the alpha integrin
chains of CR3 and p150,95.

CLINICAL MANAGEMENT

In a retrospective survey of 162 patients in whom bone marrow
transplantation was performed in 14 European centers between 1969 and
1985, Fischer et al. (1986) found 4 patients with leukocyte adhesion
deficiency. Bone marrow transplantation was successful; engraftment of
donor cells resulted in complete restoration of leukocyte function and
the absence of need for any further treatment in some of these patients.

Wilson et al. (1990) corrected the genetic and functional abnormalities
in a lymphocyte cell line from a patient with LAD by retrovirus-mediated
transduction of a functional ITGB2 (CD18) gene. Yorifuji et al. (1993)
extended this work by reporting the introduction of human CD18 cDNA into
the bone marrow progenitor cells of patients with LAD.

EVOLUTION

This glycoprotein family is conserved in mouse and human.

ANIMAL MODEL

Vedder et al. (1988) showed that use of a monoclonal antibody against
CD18 reduced organ injury and improved survival from hemorrhagic shock
in rabbits. Krauss et al. (1991) developed an in vivo model for gene
therapy of LAD. Recombinant retroviruses were used to transduce a
functional human ITGB2 (CD18) gene into murine bone marrow cells which
were then transplanted into lethally irradiated syngeneic recipients.
Since they had human-specific CD18 monoclonal antibodies and since human
CD18 can form chimeric heterodimers with murine CD11A on the cell
surface, Krauss et al. (1991) were able to do a reliable flow cytometric
assay for human CD18 in transplant recipients. Human CD18 was detected
in leukocytes in a substantial number of transplant recipients for at
least 6 months, suggesting that the gene had been transduced into stem
cells. There were no apparent untoward effects. Expression was
consistently highest and most frequent in granulocytes. Murine
granulocytes demonstrated appropriate posttranscriptional regulation of
human CD18 in response to activation of protein kinase C with PMA.

Kehrli et al. (1992) described beta-2 integrin deficiency in Holstein
cattle. The disorder was characterized by recurrent pneumonia,
ulcerative and granulomatous stomatitis, enteritis with bacterial
overgrowth, periodontitis, delayed wound healing, persistent
neutrophilia, and death at an early age. The underlying genetic defect
was identified as a D128G (asp128-to-gly) amino acid substitution in the
26-amino acid sequence that is completely homologous with human and
murine CD18 protein sequences. In a Holstein calf afflicted with
leukocyte adhesion deficiency, Shuster et al. (1992) found 2 point
mutations: one caused a D128G substitution in a highly conserved
extracellular region where several mutations have been found to cause
human LAD, and the other mutation was silent. All 20 calves tested were
homozygous for the D128G allele. The carrier frequency among Holstein
cattle in the United States was approximately 15% among bulls and 6%
among cows. All cattle with a mutant allele are related to 1 bull, who
through the use of artificial insemination sired many calves in the
1950s and 1960s. It was suggested that the organization of the dairy
industry and the diagnostic test described by Shuster et al. (1992)
would enable nearly complete eradication of bovine LAD within 1 year.

*FIELD* SA
Akao et al. (1987); Anderson and Springer (1987); Arnaout et al. (1990);
Back et al. (1993); Back et al. (1992); Bairoch  (1994); Hibbs et
al. (1990); Hynes  (1992); Kishimoto et al. (1987); Matsuura et al.
(1992); Nelson et al. (1992); Petersen et al. (1991); Pierce et al.
(1986); Sligh et al. (1989); Solomon et al. (1988); Springer et al.
(1985); Taylor et al. (1988); Wardlaw et al. (1990); Weitzman et al.
(1991)
*FIELD* RF
1. Abramson, J. S.; Mills, E. L.; Sawyer, M. K.; Regelman, W. R.;
Nelson, J. D.; Quie, P. G.: Recurrent infections and delayed separation
of the umbilical cord in an infant with abnormal phagocytic cell locomotion
and oxidative response during particle phagocytosis. J. Pediat. 99:
887-894, 1981.

2. Akao, Y.; Utsumi, K. R.; Naito, K.; Ueda, R.; Takahashi, T.; Yamada,
K.: Chromosomal assignments of genes coding for human leukocyte common
antigen, T-200, and lymphocyte function-associated antigen 1, LFA-1
beta subunit. Somat. Cell Molec. Genet. 13: 273-278, 1987.

3. Anderson, D. C.; Schmalstieg, F. C.; Finegold, M. J.; Hughes, B.
J.; Rothlein, R.; Miller, L. J.; Kohl, S.; Tosi, M. F.; Jacobs, R.
L.; Waldrop, T. C.; Goldman, A. S.; Shearer, W. T.; Springer, T. A.
: The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency:
their quantitative definition and relation to leukocyte dysfunction
and clinical features. J. Infect. Dis. 152: 668-689, 1985.

4. Anderson, D. C.; Springer, T. A.: Leukocyte adhesion deficiency:
an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins.
Annu. Rev. Med. 38: 175-194, 1987.

5. Arnaout, M. A.; Dana, N.; Gupta, S. K.; Tenen, D. G.; Fathallah,
D. M.: Point mutations impairing cell surface expression of the common
beta subunit (CD18) in a patient with leukocyte adhesion molecule
(Leu-CAM) deficiency. J. Clin. Invest. 85: 977-981, 1990.

6. Arnaout, M. A.; Pitt, J.; Cohen, H. J.; Melamed, J.; Rosen, F.
S.; Colten, H. R.: Deficiency of a granulocyte-membrane glycoprotein
(gp150) in a boy with recurrent bacterial infections. New Eng. J.
Med. 306: 693-699, 1982.

7. Arnaout, M. A.; Spits, H.; Terhorst, C.; Pitt, J.; Todd, R. F.,
III: Deficiency of a leukocyte surface glycoprotein (LFA-1) in two
patients with Mo1 deficiency: effects of cell activation on Mo1/LFA-1
surface expression in normal and deficient leukocytes. J. Clin.
Invest. 74: 1291-1300, 1984.

8. Back, A. L.; Kerkering, M.; Baker, D.; Bauer, T. R.; Embree, L.
J.; Hickstein, D. D.: A point mutation associated with leukocyte
adhesion deficiency type 1 of moderate severity. Biochem. Biophys.
Res. Commun. 193: 912-918, 1993.

9. Back, A. L.; Kwok, W. W.; Hickstein, D. D.: Identification of
two molecular defects in a child with leukocyte adherence deficiency.
J. Biol. Chem. 267: 5482-5487, 1992.

10. Bairoch, A.: Personal Communication. Geneva, Switzerland  5/13/1994.

11. Barclay, A. N.; Birkeland, M. L.; Brown, M. H.; Beyers, A. D.;
Davis, S. J.; Somoza, C.; Williams, A. F.: The Leukocyte Antigen
Facts Book.  New York: Academic Press (pub.)  1993. Pp. 124-127
and 140-141.

12. Beatty, P. G.; Ochs, H. D.; Harlan, J. M.; Price, T. H.; Rosen,
H.; Taylor, R. F.; Hansen, J. A.; Klebanoff, S. J.: Absence of monoclonal-antibody-defined
protein complex in a boy with abnormal leucocyte function. Lancet I:
535-537, 1984.

13. Bissenden, J. G.; Haeney, M. R.; Tarlow, M. J.; Thompson, R. A.
: Delayed separation of the umbilical cord, severe widespread infections
and immunodeficiency. Arch. Dis. Child. 56: 397-399, 1981.

14. Boucheix, C.: Personal Communication. Villejuif, France  1/31/1987.

15. Bowen, T. J.; Ochs, H. D.; Altman, L. C.; Price, T. H.; Van Epps,
D. E.; Brautigan, D. L.; Rosin, R. E.; Perkins, W. D.; Babior, B.
M.; Klebanoff, S. J.; Wedgwood, R. J.: Severe recurrent bacterial
infections associated with defective adherence and chemotaxis in two
patients with neutrophils deficient in a cell-associated glycoprotein.
J. Pediat. 101: 932-940, 1982.

16. Crowley, C. A.; Curnutte, J. T.; Rosin, R. E.; Andre-Schwartz,
J.; Gallin, J. I.; Klempner, M.; Snyderman, R.; Southwick, F. S.;
Stossel, T. P.; Babior, B. M.: An inherited abnormality of neutrophil
adhesion: its genetic transmission and its association with a missing
protein. New Eng. J. Med. 302: 1163-1168, 1980.

17. Dana, N.; Clayton, L. K.; Tennen, D. G.; Pierce, M. W.; Lachmann,
P. J.; Law, S. A.; Arnaout, M. A.: Leukocytes from four patients
with complete or partial Leu-CAM deficiency contain the common beta-subunit
precursor and beta-subunit messenger RNA. J. Clin. Invest. 79:
1010-1015, 1987.

18. Dana, N.; Todd, R. F., III; Pitt, J.; Springer, T. A.; Arnaout,
M. A.: Deficiency of a surface membrane glycoprotein (Mo1) in man.
J. Clin. Invest. 73: 153-159, 1984.

19. Fischer, A.; Friedrich, W.; Levinsky, R.; Vossen, J.; Griscelli,
C.; Kubanek, B.; Morgan, G.; Wagemaker, G.; Landais, P.: Bone-marrow
transplantation for immunodeficiencies and osteopetrosis: European
survey, 1968-1985. Lancet II: 1080-1084, 1986.

20. Fujita, K.; Kobayashi, K.; Kajii, T.: Impaired neutrophil adhesion:
a new patient in a previously reported family. Acta Paediat. Jpn. 27:
527-534, 1985.

21. Fujita, K.; Kobayashi, K.; Okino, F.: Juvenile rheumatoid arthritis
in two siblings with congenital leucocyte adhesion deficiency. Europ.
J. Pediat. 148: 118-119, 1988.

22. Harvath, L.; Andersen, B. R.: Defective initiation of oxidative
metabolism in polymorphonuclear leukocytes. New Eng. J. Med. 300:
1130-1135, 1979.

23. Hayward, A. R.; Leonard, J.; Harvey, B. A. M.; Greenwood, M. C.;
Wood, C. B. S.; Soothill, J. F.: Delayed separation of the umbilical
cord, widespread infections and defective neutrophil mobility. Lancet I:
1099-1101, 1979.

24. Hibbs, M. L.; Wardlaw, A. J.; Stacker, S. A.; Anderson, D. C.;
Lee, A.; Roberts, T. M.; Springer, T. A.: Transfection of cells from
patients with leukocyte adhesion deficiency with an integrin beta
subunit (CD18) restores lymphocyte function-associated antigen-1 expression
and function. J. Clin. Invest. 85: 674-681, 1990.

25. Hynes, R. O.: Integrins: versatility, modulation and signaling
in cell adhesion. Cell 69: 11-25, 1992.

26. Kehrli, M. E., Jr.; Ackermann, M. R.; Shuster, D. E.; van der
Maaten, M. J.; Schmalstieg, F. C.; Anderson, D. C.; Hughes, B. J.
: Bovine leukocyte adhesion deficiency: beta(2) integrin deficiency
in young Holstein cattle. Am. J. Path. 140: 1489-1492, 1992.

27. Kishimoto, T. K.; Hollander, N.; Roberts, T. M.; Anderson, D.
C.; Springer, T. A.: Heterogeneous mutations in the beta subunit
common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte
adhesion deficiency. Cell 50: 193-202, 1987.

28. Kishimoto, T. K.; O'Connor, K.; Lee, A.; Roberts, T. M.; Springer,
T. A.: Cloning of the beta subunit of the leukocyte adhesion proteins:
homology to an extracellular matrix receptor defines a novel supergene
family. Cell 48: 681-690, 1987.

29. Kobayashi, K.; Fujita, K.; Okino, F.; Kajii, T.: An abnormality
of neutrophil adhesion: autosomal recessive inheritance associated
with missing neutrophil glycoproteins. Pediatrics 73: 606-610,
1984.

30. Krauss, J. C.; Mayo-Bond, L. A.; Rogers, C. E.; Weber, K. L.;
Todd, R. F., III; Wilson, J. M.: An in vivo animal model of gene
therapy for leukocyte adhesion deficiency. J. Clin. Invest. 88:
1412-1417, 1991.

31. Marlin, S. D.; Morton, C. C.; Anderson, D. C.; Springer, T. A.
: LFA-1 immunodeficiency disease: definition of the genetic defect
and chromosomal mapping of alpha and beta subunits of the lymphocyte
function-associated antigen 1 (LFA-1) by complementation in hybrid
cells. J. Exp. Med. 164: 855-867, 1986.

32. Matsuura, S.; Kishi, F.; Tsukahara, M.; Nunoi, H.; Matsuda, I.;
Kobayashi, K.; Kajii, T.: Leukocyte adhesion deficiency: identification
of novel mutations in two Japanese patients with a severe form. Biochem.
Biophys. Res. Commun. 184: 1460-1467, 1992.

33. Nelson, C.; Rabb, H.; Arnaout, M. A.: Genetic cause of leukocyte
adhesion molecule deficiency: abnormal splicing and a missense mutation
in a conserved region of CD18 impair cell surface expression of beta-2
integrins. J. Biol. Chem. 267: 3351-3357, 1992.

34. Niethammer, D.; Dieterle, U.; Kleihauer, E.; Wildfeuer, A.; Haferkamp,
O.; Hitzig, W. H.: An inherited defect in granulocyte function: impaired
chemotaxis, phagocytosis and intracellular killing of microorganisms.
Helv. Paediat. Acta 30: 537-541, 1975.

35. Petersen, M. B.; Slaugenhaupt, S. A.; Lewis, J. G.; Warren, A.
C.; Chakravarti, A.; Antonarakis, S. E.: A genetic linkage map of
27 markers on human chromosome 21. Genomics 9: 407-419, 1991.

36. Pierce, M. W.; Remold-O'Donnell, E.; Todd, R. F., III; Arnaout,
M. A.: N-terminal sequence of human leukocyte glycoprotein Mo1: conservation
across species and homology to platelet IIb/IIIa. Biochim. Biophys.
Acta 874: 368-371, 1986.

37. Ross, G. D.: Clinical and laboratory features of patients with
an inherited deficiency of neutrophil membrane complement receptor
type 3 (CR3) and the related membrane antigens LFA-1 and p150,95.
J. Clin. Immun. 6: 107-113, 1986.

38. Ross, G. D.; Thompson, R. A.; Walport, M. J.; Springer, T. A.;
Watson, J. V.; Ward, R. H. R.; Lida, J.; Newman, S. L.; Harrison,
R. A.; Lachmann, P. J.: Characterization of patients with an increased
susceptibility to bacterial infections and a genetic deficiency of
leukocyte membrane complement receptor type three (CR3) and the related
membrane antigen LFA-1. Blood 66: 882-890, 1985.

39. Shuster, D. E.; Kehrli, M. E., Jr.; Ackermann, M. R.; Gilbert,
R. O.: Identification and prevalence of a genetic defect that causes
leukocyte adhesion deficiency in Holstein cattle. Proc. Nat. Acad.
Sci. 89: 9225-9229, 1992.

40. Sligh, J. E., Jr.; Anderson, D. C.; Beaudet, A. L.: A mutation
in the initiation codon of the CD18 gene in a patient with the moderate
phenotype of leukocyte adhesion deficiency.  (Abstract) Am. J. Hum.
Genet. 45 (suppl.): A219 only, 1989.

41. Solomon, E.; Palmer, R. W.; Hing, S.; Law, S. K. A.: Regional
localization of CD18, the beta-subunit of the cell surface adhesion
molecule LFA-1, on human chromosome 21 by in situ hybridization. Ann.
Hum. Genet. 52: 123-128, 1988.

42. Springer, T. A.; Miller, L. J.; Anderson, D. C.: p150,95, the
third member of the Mac-1, LFA-1 human leukocyte adhesion glycoprotein
family. J. Immun. 136: 240-245, 1986.

43. Springer, T. A.; Teplow, D. B.; Dreyer, W. J.: Sequence homology
of the LFA-1 and Mac-1 leukocyte adhesion glycoproteins and unexpected
relation to leukocyte interferon. Nature 314: 540-542, 1985.

44. Springer, T. A.; Thompson, W. S.; Miller, L. J.; Schmalstieg,
F. C.; Anderson, D. C.: Inherited deficiency of the Mac-1, LFA-1,
p150,95 glycoprotein family and its molecular basis. J. Exp. Med. 160:
1901-1918, 1984.

45. Suomalainen, H. A.; Gahmberg, C. G.; Patarroyo, M.; Beatty, P.
G.; Schroder, J.: Genetic assignment of GP90, leukocyte adhesion
glycoprotein to human chromosome 21. Somat. Cell Molec. Genet. 12:
297-302, 1986.

46. Suomalainen, H. A.; Gahmberg, C. G.; Patarroyo, M.; Schroder,
J.: GP90 (Leu-CAM antigen) is coded for by genes on chromosome 21.
(Abstract) Cytogenet. Cell Genet. 40: 755 only, 1985.

47. Taylor, G. M.; Williams, A.; D'Souza, S. W.; Fergusson, W. D.;
Donnai, D.; Fennell, J.; Harris, R.: The expression of CD18 is increased
on trisomy 21 (Down syndrome) lymphoblastoid cells. Clin. Exp. Immun. 71:
324-328, 1988.

48. Todd, R. F., III; Freyer, D. R.: The CD11/CD18 leukocyte glycoprotein
deficiency. Hemat. Oncol. Clin. North Am. 2: 13-31, 1988.

49. van der Meer, J. W. M.; van Zwet, T. L.; van Furth, R.; Weemaes,
C. M. R.: New familial defect in microbicidal function of polymorphonuclear
leucocytes. Lancet II: 630-632, 1975.

50. Vedder, N. B.; Winn, R. K.; Rice, C. L.; Chi, E. Y.; Arfors, K.-E.;
Harlan, J. M.: A monoclonal antibody to the adherence-promoting leukocyte
glycoprotein, CD18, reduces organ injury and improves survival from
hemorrhagic shock and resuscitation in rabbits. J. Clin. Invest. 81:
939-944, 1988.

51. Wardlaw, A. J.; Hibbs, M. L.; Stacker, S. A.; Springer, T. A.
: Distinct mutations in two patients with leukocyte adhesion deficiency
and their functional correlates. J. Exp. Med. 172: 335-345, 1990.

52. Weening, R. S.; Roos, D.; Weemaes, C. M. R.; Homan-Muller, J.
W. T.; van Schaik, M. L. J.: Defective initiation of the metabolic
stimulation in phagocytizing granulocytes: a new congenital defect.
J. Lab. Clin. Med. 88: 757-768, 1976.

53. Weitzman, J. B.; Wells, C. E.; Wright, A. H.; Clark, P. A.; Law,
S. K. A.: The gene organisation of the human beta-2 integrin subunit
(CD18). FEBS Lett. 294: 97-103, 1991.

54. Wilson, J. M.; Ping, A. J.; Krauss, J. C.; Mayo-Bond, L.; Rogers,
C. E.; Anderson, D. C.; Todd, R. F., III: Correction of CD18-deficient
lymphocytes by retrovirus-mediated gene transfer. Science 248:
1413-1416, 1990.

55. Yorifuji, T.; Wilson, R. W.; Beaudet, A. L.: Retroviral mediated
expression of CD18 in normal and deficient human bone marrow progenitor
cells. Hum. Molec. Genet. 2: 1443-1448, 1993.

*FIELD* CS

Heme:
   Leukocyte adhesion deficiency

Immunology:
   Recurrent bacterial infections;
   Impaired pus formation and wound healing;
   Abnormal adhesion-dependent functions of granulocytes, monocytes,
   and lymphocytes;
   Infection of umbilical cord stump;
   Omphalitis;
   Gingivitis (periodontosis)

Misc:
   Corrected by bone marrow transplantation;
   Associated systemic onset juvenile rheumatoid arthritis

Lab:
   Leukocyte cell adhesion molecule defect;
   Reduced neutrophil phagocytic and respiratory burst response to bacteria
   and yeast, reduced adherance to various substances and reduced migration
   into infection sites

Inheritance:
   Autosomal recessive disorder (21q22.3)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 6/11/1995
terry: 3/7/1995
pfoster: 2/14/1995
show: 7/11/1994
carol: 5/16/1994
mimadm: 4/18/1994

*RECORD*
*FIELD* NO
116930
*FIELD* TI
*116930 CELL ADHESION MOLECULE, NEURAL; NCAM
*FIELD* TX
Because of evidence indicating close homology of neural cell adhesion
molecule (NCAM) in man and mouse, a murine cDNA probe for NCAM could be
used directly for in situ hybridization to human metaphase chromosomes
(Nguyen et al., 1985). This procedure indicated that the NCAM gene is
located at 11q22-q23. Mietus-Snyder et al. (1989) corroborated the
location of the NCAM gene to the 11q23 region by finding linkage to the
apolipoprotein gene cluster, APOA1--APOC3--APOA4 (107680, 107720,
107690); a maximum lod score of 3.65 at theta = 0.10 was observed.
Further studies by Mietus-Snyder et al. (1990) showed a maximum lod
score of 15.9 at a recombination fraction of 0.028. D'Eustachio et al.
(1985) mapped the NCAM gene to mouse chromosome 9 by means of a genomic
probe in somatic cell hybrids. The gene is close to two others on mouse
9 whose expression is related to the nervous system, namely Thy-1 (see
188230 for the human counterpart) and the cerebellar connectional mutant
staggerer (sg); NCAM-associated DNA polymorphisms were used in
recombinant inbred strains of mice to show these linkages as well as
close linkage to Sep-1 (apolipoprotein 1) and Lap-1 (leucine
aminopeptidase 1). Great structural diversity in NCAM is due to
transcriptional variations of a single gene and posttranslational
mechanisms which are under exquisite developmental control (Rutishauser
and Goridis, 1986). The neural cell adhesion molecule appears on early
embryonic cells and is important in the formation of cell collectives
and their boundaries at sites of morphogenesis. Later in development it
is found on various differentiated tissues and is a major CAM mediating
adhesion among neurons and between neurons and muscle.

NCAM shares many features with immunoglobulins and is considered a
member of the immunoglobulin superfamily. Cunningham et al. (1987)
determined the structure of the 3 polypeptides of chicken NCAM; the
chains are called ld, sd, and ssd. Bello et al. (1989) sublocalized NCAM
to 11q23.1 by in situ hybridization to pachytene bivalents. Because of
the close mapping of the 'staggerer' mutation with the Ncam locus in the
mouse, it was earlier thought that the sg mutation might involve the
Ncam locus. By demonstrating recombination between the 2 loci,
D'Eustachio and Davisson (1993) proved that the murine neurologic
disease is not due to mutation in the NCAM protein. By linkage analysis
and pulsed field gel electrophoresis, Telatar et al. (1995) mapped the
NCAM gene to 11q23, proximal to the locus for dopamine receptor D2
(DRD2; 126450).

Lin et al. (1994) stated that there are cell adhesion molecules in
invertebrates related to NCAM. Fasciclin II has been cloned in
grasshoppers and Drosophila; apCAM has been identified in Aplysia. In
these species, the NCAM analogs are members of the immunoglobulin
superfamily both in structure (5 C2-type immunoglobulin domains followed
by 2 fibronectin type 3 domains) and sequence. All of these molecules
can mediate homophilic cell aggregation in vitro. Lin et al. (1994) used
loss-of-function and gain-of-function mutants of fasciclin II in
Drosophila to study the protein's function during growth cone guidance.
The fasciclin II mutants had impaired fasciculation, but other aspects
of outgrowth and directional guidance were intact, and thus genetically
separate.

NCAM is a membrane-bound glycoprotein that plays a role in cell-cell and
cell-matrix adhesion through both its homophilic and heterophilic
binding activity. To investigate the significance of this binding,
Rabinowitz et al. (1996) used a gene targeting strategy in embryonic
stem (ES) cells to replace the membrane-associated form of NCAM with a
soluble, secreted form of its extracellular domain. Although the
heterozygous mutant ES cells were able to generate low coat color
chimeric mice, only the wildtype allele was transmitted, suggesting the
possibility of dominant lethality. Analysis of chimeric embryos with a
high level of ES cell contribution revealed severe growth retardation
and morphologic defects by embryonic days 8.5-9.5. The second allele was
also targeted and embryos derived almost entirely from the homozygous
mutant ES cells exhibited the same lethal phenotype as observed with
heterozygous chimeras.

*FIELD* SA
Nguyen et al. (1986); Rutishauser et al. (1988)
*FIELD* RF
1. Bello, M. J.; Salagnon, N.; Rey, J. A.; Guichaoua, M. R.; Berge-Lefranc,
J. L.; Jordan, B. R.; Luciani, J. M.: Precise in situ localization
of NCAM, ETS1, and D11S29 on human meiotic chromosomes. Cytogenet.
Cell Genet. 52: 7-10, 1989.

2. Cunningham, B. A.; Hemperly, J. J.; Murray, B. A.; Prediger, E.
A.; Brackenbury, R.; Edelman, G. M.: Neural cell adhesion molecule:
structure, immunoglobulin-like domains, cell surface modulation, and
alternative RNA splicing. Science 236: 799-806, 1987.

3. D'Eustachio, P.; Davisson, M. T.: Resolution of the staggerer
(sg) mutation from the neural cell adhesion molecule locus (Ncam)
on mouse chromosome 9. Mammalian Genome 4: 278-280, 1993.

4. D'Eustachio, P.; Owens, G. C.; Edelman, G. M.; Cunningham, B. A.
: Chromosomal location of the gene encoding the neural cell adhesion
molecule (N-CAM) in the mouse. Proc. Nat. Acad. Sci. 82: 7631-7635,
1985.

5. Lin, D. M.; Fetter, R. D.; Kopczynski, C.; Grenningloh, G.; Goodman,
C. S.: Genetic analysis of fasciclin II in Drosophila: defasciculation,
refasciculation, and altered fasciculation. Neuron 13: 1055-1069,
1994.

6. Mietus-Snyder, M.; Charmley, P.; Korf, B.; Ladias, J. A. A.: Gatti,
R. A. and Karathanasis, S. K.: Genetic linkage of the human apolipoprotein
AI-CIII-AIV gene cluster and the neural cell adhesion molecule (NCAM)
gene. Genomics 7: 633-637, 1990.

7. Mietus-Snyder, M.; Korf, B.; Ladias, J. A.; Karathanasis, S. K.
: Linkage of the human apolipoproteins A1, C3, A4 and the neural cell
adhesion molecule (NCAM) genes. (Abstract) Cytogenet. Cell Genet. 51:
1044 only, 1989.

8. Nguyen, C.; Mattei, M. G.; Goridis, C.; Mattei, J. F.; Jordan,
B. R.: Localization of the human N-CAM gene to chromosome 11 by in
situ hybridization with a murine N-CAM cDNA probe. (Abstract) Cytogenet.
Cell Genet. 40: 713 only, 1985.

9. Nguyen, C.; Mattei, M. G.; Mattei, J.-F.; Santoni, M.-J.; Goridis,
C.; Jordan, B. R.: Localization of the human NCAM gene to band q23
of chromosome 11: the third gene coding for a cell interaction molecule
mapped to the distal portion of the long arm of chromosome 11. J.
Cell Biol. 102: 711-715, 1986.

10. Rabinowitz, J. E.; Rutishauser, U.; Magnuson, T.: Targeted mutation
of Ncam to produce a secreted molecule results in a dominant embryonic
lethality. Proc. Nat. Acad. Sci. 93: 6421-6424, 1996.

11. Rutishauser, U.; Acheson, A.; Hall, A. K.; Mann, D. M.; Sunshine,
J.: The neural cell adhesion molecule (NCAM) as a regulator of cell-cell
interactions. Science 240: 53-57, 1988.

12. Rutishauser, U.; Goridis, C.: NCAM: the molecule and its genetics. Trends
Genet. 2: 72-76, 1986.

13. Telatar, M.; Lange, E.; Uhrhammer, N.; Gatti, R. A.: New localization
of NCAM, proximal to DRD2 at chromosome 11q23. Mammalian Genome 6:
59-60, 1995.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/24/1996
terry: 11/7/1996
O.: 9/24/1995
terry: 4/18/1995
carol: 1/21/1994
supermim: 3/16/1992
carol: 9/8/1990
carol: 8/22/1990

*RECORD*
*FIELD* NO
116935
*FIELD* TI
*116935 CELL ADHESION REGULATOR; CAR
CELL MATRIX ADHESION REGULATOR; CMAR
*FIELD* TX
Molecules of the cadherin (e.g., 114020) and integrin (e.g., 116920)
families involved in cell-cell and cell-matrix adhesion have been
implicated in epithelial differentiation, carcinogenesis, and
metastasis. Having observed that a colon cancer cell line bound avidly
to collagen type I, inducing integrin-triggered glandular
differentiation, Pullman and Bodmer (1992) investigated the regulation
of integrin function in these cells. Using attachment to collagen type I
to select for adhesive phenotype in a mammalian expression cloning
system, they isolated a cDNA clone that increased cell adhesion to
components of the extracellular matrix. The corresponding gene, called
cell adhesion regulator (CAR), was located on 16q by Southern blot
analysis of a panel of human/rodent hybrid DNAs. The gene was found to
encode a 142-amino acid protein, which had an N-terminal myristoylation
motif and a consensus tyrosine-kinase phosphorylation site at the C
terminus. Removal of the tyrosine residue abolished enhancement of
cell-matrix adhesion. Pullman and Bodmer (1992) suggested that CAR may
encode an adhesion signal transduction molecule that functions in the
suppression of tumor invasion. By genetic linkage analysis using a TaqI
polymorphism in CEPH families, Koyama et al. (1993) demonstrated that
CAR is close to D16S7 and D16S154, which are located in the
'peritelomeric' region of 16q. They also showed a second type of
variation, an insertion/deletion polymorphism, in the coding region; the
variant was detected in 9 chromosomes among 30 unrelated Japanese
individuals. Durbin et al. (1994) detected a 4-bp insertion (CACA) at
nucleotide 241 of the CMAR gene.

*FIELD* RF
1. Durbin, H.; Novelli, M.; Bodmer, W.: Detection of a 4-bp insertion
(CACA) functional polymorphism at nucleotide 241 of the cellular adhesion
regulatory molecule CMAR (formerly CAR). Genomics 19: 181-182,
1994.

2. Koyama, K.; Emi, M.; Nakamura, Y.: The cell adhesion regulator
(CAR) gene, TaqI and insertion/deletion polymorphisms, and regional
assignment to the peritelomeric region of 16q by linkage analysis.
Genomics 16: 264-265, 1993.

3. Pullman, W. E.; Bodmer, W. F.: Cloning and characterization of
a gene that regulates cell adhesion. Nature 356: 529-532, 1992.

*FIELD* CD
Victor A. McKusick: 7/13/1992

*FIELD* ED
carol: 2/9/1994
carol: 5/4/1993
carol: 9/3/1992
carol: 7/13/1992

*RECORD*
*FIELD* NO
116940
*FIELD* TI
*116940 CELL DIVISION CYCLE 2, G1 TO S AND G2 TO M; CDC2
CELL CYCLE CONTROLLER CDC2;;
p34(CDC2)
*FIELD* TX
CDC2 is a catalytic subunit of a protein kinase complex, called the
M-phase promoting factor, that induces entry into mitosis and is
universal among eukaryotes. In the fission yeast Schizosaccharomyces
pombe, the gene CDC2 is responsible for controlling the transition from
G1 phase to the S phase and from the G2 phase to the M phase of the cell
cycle. Lee and Nurse (1987) rescued the human homolog of this gene by
complementation of a yeast temperature-sensitive mutant deleted for the
CDC2 function. The human sequences were cloned and found to contain an
open reading frame of about 800 bp. Using a probe from this region,
Spurr et al. (1987, 1988) studied a panel of somatic cell hybrids and
determined that the human homolog of the CDC2 gene is located on
chromosome 10. By in situ hybridization, Nazarenko et al. (1991)
regionalized the CDC2 gene to 10q21. Using the human CDC2 gene as a DNA
probe, Spurr et al. (1990) isolated cDNA clones corresponding to the
mouse cdc2 gene. The deduced amino acid sequence of the mouse protein
showed 96% identity to its human homolog.

Lee et al. (1988) described the regulated expression and phosphorylation
of the CDC2 homolog in human and murine in vitro systems. While the
yeast CDC2 expression does not appear to be transcriptionally regulated,
serum stimulation of human and mouse fibroblasts results in a marked
increase in CDC2 transcription. Both the yeast and mammalian systems
seem to be regulated by phosphorylation of the CDC2 gene product, a
protein kinase of molecular weight 34,000--designated p34(cdc2). Draetta
et al. (1988) showed that, in HeLa cells, cdc2 is the most abundant
phosphotyrosine-containing protein and its phosphotyrosine content is
subject to cell-cycle regulation. One site of CDC2 tyrosine
phosphorylation in vivo is selectively phosphorylated in vitro by a
product of the SRC gene (190090).

*FIELD* RF
1. Draetta, G.; Piwnica-Worms, H.; Morrison, D.; Druker, B.; Roberts,
T.; Beach, D.: Human CDC2 protein kinase is a major cell-cycle regulated
tyrosine kinase substrate. Nature 336: 738-744, 1988.

2. Lee, M. G.; Norbury, C. J.; Spurr, N. K.; Nurse, P.: Regulated
expression and phosphorylation of a possible mammalian cell-cycle
control protein.   (Letter) Nature 333: 676-679, 1988.

3. Lee, M. G.; Nurse, P.: Complementation used to clone a human homologue
of the fission yeast cell cycle control gene cdc2. Nature 327:
31-35, 1987.

4. Nazarenko, S. A.; Ostroverhova, N. V.; Spurr, N. K.: Regional
assignment of the human cell cycle control gene CDC2 to chromosome
10q21 by in situ hybridization. Hum. Genet. 87: 621-622, 1991.

5. Spurr, N. K.; Goodfellow, P. N.; Nurse, P.; Lee, M.: Assignment
of the human homologue of the yeast cell cycle control gene CDC2 to
chromosome 10.   (Abstract) Cytogenet. Cell Genet. 46: 698, 1987.

6. Spurr, N. K.; Gough, A.; Goodfellow, P. J.; Goodfellow, P. N.;
Lee, M. G.; Nurse, P.: Evolutionary conservation of the human homologue
of the yeast cell cycle control gene cdc2 and assignment of CD2 to
chromosome 10. Hum. Genet. 78: 333-337, 1988.

7. Spurr, N. K.; Gough, A. C.; Lee, M. G.: Cloning of the mouse homologue
of the yeast cell cycle control gene cdc2. DNA Sequence 1: 49-54,
1990.

*FIELD* CD
Victor A. McKusick: 8/31/1987

*FIELD* ED
mark: 04/01/1996
carol: 5/6/1994
supermim: 3/16/1992
carol: 2/18/1992
carol: 11/4/1991
carol: 10/24/1991
carol: 10/23/1991

*RECORD*
*FIELD* NO
116945
*FIELD* TI
*116945 CELL DIVISION CYCLE-LIKE 1
CDC-LIKE 1; CDCL1;;
NUCLEAR PROTEIN BM28
*FIELD* TX
BM28 is a human nuclear protein that may play an important role in 2
crucial steps of the cell cycle, namely, onset of DNA replication and
cell division. It is similar to members of the family of early S-phase
proteins. Using plasmid DNA containing the complete coding sequence of
the CDCL1 gene as a probe for fluorescence in situ hybridization,
Mincheva et al. (1994) mapped the gene to 3q21. From its localization,
CDCL1 became a candidate for an oncogene affected by chromosomal breaks
in acute myeloid leukemia (AML).

*FIELD* RF
1. Mincheva, A.; Todorov, I.; Werner, D.; Fink, T. M.; Lichter, P.
: The human gene for nuclear protein BM28 (CDCL1), a new member of
the early S-phase family of proteins, maps to chromosome band 3q21.
Cytogenet. Cell Genet. 65: 276-277, 1994.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
jason: 6/17/1994

*RECORD*
*FIELD* NO
116946
*FIELD* TI
*116946 CELL DIVISION CYCLE 27; CDC27
*FIELD* TX
Tugendreich et al. (1993) described a strategy for quickly identifying
and positionally mapping human homologs of yeast genes in order to
cross-reference the rich biologic and genetic information concerning
yeast genes to mammalian species. Optimized computer search methods were
developed to scan the rapidly expanding expressed sequence tag (EST)
database of Venter and colleagues (Adams et al., 1992) to find human
open reading frames related to yeast protein sequences. The
corresponding human cDNA was then used to obtain a high-resolution map
position on human and mouse chromosomes, providing the links between
yeast genetic analysis and mapped mammalian loci. In this way,
Tugendreich et al. (1993) identified a human homolog of CDC27 of
Saccharomyces cerevisiae and mapped it to human chromosome 17 and mouse
chromosome 11 between the PKCA gene (176960) at 17q22-q23.2 and the
ERBB2 gene (164870) at 17q12-q21. The assignment to human chromosome 17
was achieved by PCR analysis of a panel of somatic cell hybrids; the
mapping to chromosome 11 between the murine homologs of the PKCA and
ERBB2 genes was done by linkage analysis. That CDC27 is located between
these genes in the human was inferred from the strong homology of
synteny. Human CDC27 encodes an 823-amino acid protein with global
similarity to its fungal homologs.

*FIELD* RF
1. Adams, M. D.; Dubnick, M.; Kerlavage, A. R.; Moreno, R.; Kelley,
J. M.; Utterback, T. R.; Nagle, J. W.; Fields, C.; Venter, J. C.:
Sequence identification of 2,375 human brain genes. Nature 355:
632-634, 1992.

2. Tugendreich, S.; Boguski, M. S.; Seldin, M. S.; Hieter, P.: Linking
yeast genetics to mammalian genomes: identification and mapping of
the human homolog of CDC27 via the expressed sequence tag (EST) data
base. Proc. Nat. Acad. Sci. 90: 10031-10035, 1993.

*FIELD* CD
Victor A. McKusick: 4/6/1994

*FIELD* ED
carol: 4/6/1994

*RECORD*
*FIELD* NO
116947
*FIELD* TI
*116947 CELL DIVISION CYCLE 25A; CDC25A
*FIELD* TX
The human CDC25 tyrosine phosphatases trigger activation of CDC2 by
removing inhibitory phosphate from tyrosine and threonine residues of
the cyclin-dependent kinases. Thus, the genes encoding these
phosphatases are suspected of being potential oncogenes because of their
role in promoting cell division. Three human CDC25 genes have been
identified: CDC25A, CDC25B (116949), and CDC25C (157680). Demetrick and
Beach (1993) mapped CDC25A to 3p21 by fluorescence in situ hybridization
with confirmation by PCR analysis of hamster/human somatic cell hybrid
DNAs. An area near 3p21 is frequently involved in karyotypic
abnormalities in renal carcinomas, small cell carcinomas of the lung,
and benign tumors of the salivary gland.

Galaktionov et al. (1995) showed that in rodent cells, human CDC25A or
CDC25B but not CDC25C phosphatases cooperate with either the
gly12-to-val mutation of the HRAS gene (190020.0001) or loss of RB1
(180200) in oncogenic focus formation. The transformants were highly
aneuploid, grew in soft agar, and formed high-grade tumors in nude mice.
Overexpression of CDC25B was detected in 32% of human primary breast
cancers tested.

*FIELD* RF
1. Demetrick, D. J.; Beach, D. H.: Chromosome mapping of human CDC25A
and CDC25B phosphatases. Genomics 18: 144-147, 1993.

2. Galaktionov, K.; Lee, A. K.; Eckstein, J.; Draetta, G.; Meckler,
J.; Loda, M.; Beach, D.: CDC25 phosphatases as potential human oncogenes.
Science 269: 1575-1577, 1995.

*FIELD* CD
Victor A. McKusick: 10/14/1993

*FIELD* ED
mark: 9/22/1995
carol: 10/14/1993

*RECORD*
*FIELD* NO
116948
*FIELD* TI
*116948 CELL DIVISION CYCLE 34; CDC34
*FIELD* TX
Genomic instability with aneuploidy and chromosomal rearrangement is a
hallmark of human malignancies. Normal eukaryotes from yeasts to humans
have a conserved checkpoint mechanism in cell division for maintenance
of genomic stability. After DNA strand breaks, checkpoint genes induce
rest in the G1 and G2 phases of the cell cycle until the damage is
repaired. The tumor suppressor gene p53 (191170) is a checkpoint gene
required for the G1 arrest after DNA damage. Plon et al. (1993) isolated
a putative human G2 checkpoint gene, a homolog of the CDC34 gene of
Saccharomyces cerevisiae. Human CDC34 could substitute efficiently for
yeast CDC34. Plon et al. (1993) demonstrated by in situ hybridization
that the CDC34 gene is located in the far telomeric region of 19p13.3,
in a region of homology between human 19p and mouse 11.

*FIELD* RF
1. Plon, S. E.; Leppig, K. A.; Do, H.-N.; Groudine, M.: Cloning of
the human homolog of the CDC34 cell cycle gene by complementation
in yeast. Proc. Nat. Acad. Sci. 90: 10484-10488, 1993.

*FIELD* CD
Victor A. McKusick: 9/28/1993

*FIELD* ED
carol: 4/1/1994
carol: 12/9/1993
carol: 10/13/1993
carol: 9/28/1993

*RECORD*
*FIELD* NO
116949
*FIELD* TI
*116949 CELL DIVISION CYCLE 25B; CDC25B
*FIELD* TX
Central to the onset of mitosis in all eukaryotic cells is the CDC2
protein kinase (116940), the activity of which is negatively regulated
by phosphorylation and positively activated by dephosphorylation. The
latter function is carried out by a specific phosphatase, CDC25. At
least 3 human CDC25 genes code for the A, B, and C forms of CDC25.
CDC25C (157680) maps to chromosome 5. Lane et al. (1993) demonstrated by
fluorescence in situ hybridization that CDC25B maps to 20p13. PCR
analysis of a monochromosomal hybrid cell panel yielded results
supporting this chromosome assignment. Demetrick and Beach (1993) also
mapped CDC25B to 20p13 by fluorescence in situ hybridization with
confirmation by the polymerase chain reaction of hamster/human somatic
cell hybrid DNA.

*FIELD* RF
1. Demetrick, D. J.; Beach, D. H.: Chromosome mapping of human CDC25A
and CDC25B phosphatases. Genomics 18: 144-147, 1993.

2. Lane, S. A.; Baker, E.; Sutherland, G. R.; Tonks, I.; Hayward,
N.; Ellem, K.: The human cell cycle gene CDC25B is located at 20p13.
Genomics 15: 693-694, 1993.

*FIELD* CD
Victor A. McKusick: 3/22/1993

*FIELD* ED
carol: 10/14/1993
carol: 3/22/1993

*RECORD*
*FIELD* NO
116950
*FIELD* TI
*116950 CELL CYCLE CONTROLLER G1
TEMPERATURE-SENSITIVE AF8 COMPLEMENT; AF8T
*FIELD* TX
Ming et al. (1976) demonstrated that a factor essential to the normal
mammalian cell cycle is located on human chromosome 3. AF8 Syrian
hamster cells have a temperature-sensitive mutation; they grow normally
at 33.5 degrees F, but at 39 degrees are blocked in mid-G1. When these
cells are fused with Lesch-Nyhan fibroblasts transformed by simian virus
40, the hybrid cells grow at 39 degrees. Ming et al. (1976) observed
preferential retention of human chromosome 3 in all hybrid clones that
would grow at 39 degrees and often only that chromosome was retained.
This indicates that a factor (or factors) concerned with the mammalian
cell cycle at the G1 stage is carried by chromosome 3. Other temperature
sensitivity complementation loci, all cell cycle specific, are located
on chromosomes 9 (187290), 14 (187310), 4 (187320), and 6 (187330). See
313650 for description of an X-linked temperature-sensitive mutation of
mouse and hamster (complemented by the human X-chromosome). Ashihara et
al. (1978) showed that the tsAF8 cells are blocked, at the nonpermissive
temperature, at a specific point in the mid-G1 phase of the cell cycle.
Rossini and Baserga (1978) showed that the temperature-sensitive defect
in AF8 cells is associated with loss of RNA polymerase II activity. One
subunit of RNA polymerase II (180660) is coded by chromosome 17p.

*FIELD* SA
Simchen  (1978)
*FIELD* RF
1. Ashihara, T.; Chang, S. D.; Baserga, R.: Constancy of the shift-up
point in two temperature-sensitive mammalian cell lines that assert
in G(1). J. Cell. Physiol. 96: 15-21, 1978.

2. Ming, P.-M. L.; Chang, H. L.; Baserga, R.: Release by human chromosome
3 of the block at G1 of the cell cycle, in hybrids between tsAF8 hamster
and human cells. Proc. Nat. Acad. Sci. 73: 2052-2055, 1976.

3. Rossini, M.; Baserga, R.: RNA synthesis in cell cycle-specific
temperature sensitive mutant from hamster cell line. Biochemistry 17:
858-863, 1978.

4. Simchen, G.: Cell cycle mutants. Ann. Rev. Genet. 12: 161-191,
1978.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/3/1990
carol: 12/4/1989
ddp: 10/26/1989
carol: 4/3/1989

*RECORD*
*FIELD* NO
116951
*FIELD* TI
*116951 CELL DIVISION CYCLE 2-LIKE 2; CDC2L2
*FIELD* TX
Protein kinase p58 (176873) is a human cell division control
(CDC)-related molecule that is structurally and functionally related to
p34 (CDC2; 116940). Whereas the p58 gene is located on 1p36, Eipers et
al. (1991) found by mouse-human somatic cell hybrid studies that a
highly related p58 sequence maps to chromosome 15. Its function is
unknown.

*FIELD* RF
1. Eipers, P. G.; Barnoski, B. L.; Han, J.; Carroll, A. J.; Kidd,
V. J.: Localization of the expressed human p58 protein kinase chromosomal
gene to chromosome 1p36 and a highly related sequence to chromosome
15. Genomics 11: 621-629, 1991.

*FIELD* CD
Victor A. McKusick: 1/2/1992

*FIELD* ED
supermim: 3/16/1992
carol: 1/2/1992

*RECORD*
*FIELD* NO
116952
*FIELD* TI
*116952 CELL DIVISION CYCLE 42; CDC42
*FIELD* TX
From a human placental library, Shinjo et al. (1990) isolated cDNA
clones that code for cdc42, a low-molecular-weight GTP-binding protein
originally designated G(p) and also called G25K. The predicted amino
acid sequence of the protein was very similar to those of various
members of the RAS superfamily of low-molecular-weight GTP-binding
proteins, including NRAS, KRAS, HRAS, and the RHO proteins. The highest
degree of sequence identity (80%) was found with the Saccharomyces
cerevisiae cell division cycle protein CDC42. The human placental gene
complemented a cdc42 mutation in S. cerevisiae. Munemitsu et al. (1990)
presented further evidence that G25K is the human homolog of the CDC42
gene product.

Moats-Staats and Stiles (1995) showed that the 5-prime end of another
gene, called BB1 by them (601106), overlaps with the 3-prime end of
G25K.

Marks and Kwiatkowski (1996) identified 2 isoforms of CDC42. They
demonstrated that the 2 murine isoforms arise from a single gene by
alternative splicing. Although one is expressed in a wide variety of
tissues, the second isoform appeared to be expressed exclusively in
brain. Using SSCP analysis of a mouse backcross panel, they demonstrated
that the gene encoding cdc42 is localized to the distal portion of mouse
chromosome 4 between Erk (176946) proximally and Cappb (601572)
distally. The human homologs of both of the 2 flanking genes were mapped
to human chromosome 1p36.1 by Barron-Casella et al. (1995), thus
indicating this is the likely site of the human CDC42 gene.

*FIELD* RF
1. Barron-Casella, E. A.; Torres, M. A.; Scherer, S. W.; Heng, H.
H.; Tsui, L. C.; Casella, J. F.: Sequence analysis and chromosomal
localization of human Cap Z: conserved residues within the actin-binding
domain may link Cap Z to gelsolin/severin and profilin protein families. J.
Biol.Chem. 270: 21472-21479, 1995.

2. Marks, P. W.; Kwiatkowski, D. J.: Genomic organization and chromosomal
location of murine Cdc42. Genomics 38: 13-18, 1996.

3. Moats-Staats, B. M.; Stiles, A. D.: Southern hybridization analyses
of somatic cell hybrids reveal that human BB1 is a member of a multigene
family dispersed throughout the human genome and appears to be linked
to the human G25K genes. DNA Cell Biol. 14: 465-474, 1995.

4. Munemitsu, S.; Innis, M. A.; Clark, R.; McCormick, F.; Ullrich,
A.; Polakis, P.: Molecular cloning and expression of a G25K cDNA,
the human homolog of the yeast cell cycle gene CDC42. Molec. Cell.
Biol. 10: 5977-5982, 1990.

5. Shinjo, K.; Koland, J. G.; Hart, M. J.; Narasimhan, V.; Johnson,
D. I.; Evans, T.; Cerione, R. A.: Molecular cloning of the gene for
the human placental GTP-binding protein G(p) (G25K): identification
of this GTP-binding protein as the human homolog of the yeast cell-division-cycle
protein CDC42. Proc. Nat. Acad. Sci. 87: 9853-9857, 1990.

*FIELD* CN
Alan F. Scott - updated: 3/6/1996

*FIELD* CD
Victor A. McKusick: 1/17/1991

*FIELD* ED
mark: 12/16/1996
terry: 12/10/1996
terry: 4/17/1996
mark: 3/6/1996
carol: 4/1/1994
supermim: 3/16/1992
carol: 1/2/1992
carol: 3/4/1991
carol: 1/17/1991

*RECORD*
*FIELD* NO
116953
*FIELD* TI
*116953 CELL DIVISION KINASE-2
CYCLIN-DEPENDENT KINASE 2; CDK2;;
p33(CDK2)
*FIELD* TX
Ninomiya-Tsuji et al. (1991) cloned 2 different cDNAs that can
complement cdc28 mutations of budding yeast Saccharomyces cerevisiae.
One corresponded to a gene encoding human p34(CDC2) kinase (116940), and
the other to a gene that had not been characterized previously, CDK2
(cell division kinase-2). The CDK2 protein was highly homologous to
p34(CDC2) kinase and more significantly homologous to Xenopus Eg1
kinase, suggesting that CDK2 is the human homolog of Eg1. The human CDC2
and CDK2 genes were both able to complement the inviability of a null
allele of S. cerevisiae, CDC28. However, CDK2 was unable to complement
cdc2 mutants in fission yeast Schizosaccharomyces pombe under the
condition where the human CDC2 gene could complement them. CDK2 mRNA
appeared late in G1 or in early S phase, slightly before CDC2 mRNA,
after growth stimulation in the normal human fibroblast cells. Thus, 2
different CDC2-like kinases appear to regulate the human cell cycle at
different stages.

The complex formed of p34(cdc2) (116940) and cyclin B (176740) is
required for the G2-to-M transition in cell division. Human cyclin A
(123835) binds independently to 2 kinases, p34(cdc2) or p33. In
adenovirus-transformed cells, the viral E1A oncoprotein seems to
associate with p33/cyclin A but not with p34(cdc2)/cyclin A. Tsai et al.
(1991) isolated the gene for p33, which shares 65% sequence identity
with p34(cdc2). They suggested that p33(cdk2) plays a unique role in
cell-cycle regulation of vertebrate cells.

De Bondt et al. (1993) reported the crystal structure of CDK2. Bourne et
al. (1996) analyzed the crystal structure of the CDK-CKS1 complex and
defined the critical protein domains involved in the interaction of the
2 molecules. They tested the biologic importance of the structure-based
model by constructing mutant alleles of CKS1 that led to decreased
interaction with CDK2. Bourne et al. (1996) concluded that the
structural analysis revealed the mode of CDK2 binding to CKS1, suggested
a possible mechanism of cooperativity and self regulation of CKS
proteins during the cell cycle, and implicated CKS as a targeting or
matchmaking protein for CDK and at least one other phosphoprotein.

By fluorescence in situ hybridization, Demetrick et al. (1994) mapped
the CDK2 gene to 12q13, the same region to which the CDK4 gene (123829)
maps.

Shiffman et al. (1996) described the cloning of an approximately 2.4-kb
genomic DNA fragment from the upstream region of the CDK2 gene. This
fragment was found to contain 5 transcription initiation sites within a
72-nucleotide stretch. A 200-bp subfragment that confers 70% of maximal
basal promoter activity was shown to contain 2 synergistically acting
Sp1 sites. The intron-exon boundaries of 7 exons in this gene were also
identified.

*FIELD* RF
1. Bourne, Y.; Watson, M. H.; Hickey, M. J.; Holmes, W.; Rocque, W.;
Reed, S. I.; Turner, J. A.: Crystal structure and mutational analysis
of the human CDK2 kinase complex with cell cycle-regulatory protein
CksHs1. Cell 84: 863-874, 1996.

2. De Bondt, H. L.; Rosenblatt, J.; Jancarik, J.; Jones, H. D.; Morgan,
D. O.; Kim, S.-H.: Crystal structure of cyclin-dependent kinase 2.
Nature 363: 595-602, 1993.

3. Demetrick, D. J.; Zhang, H.; Beach, D. H.: Chromosomal mapping
of human CDK2, CDK4, and CDK5 cell cycle kinase genes. Cytogenet.
Cell Genet. 66: 72-74, 1994.

4. Ninomiya-Tsuji, J.; Nomoto, S.; Yasuda, H.; Reed, S. I.; Matsumoto,
K.: Cloning of a human cDNA encoding a CDC2-related kinase by complementation
of a budding yeast cdc28 mutation. Proc. Nat. Acad. Sci. 88: 9006-9010,
1991.

5. Shiffman, D.; Brooks, E. E.; Brooks, A. R.; Chan, C. S.; Milner,
P. G.: Characterization of the human cyclin-dependent kinase 2 gene:
promoter analysis and gene structure. J. Biol. Chem. 271: 12199-12204,
1996.

6. Tsai, L.-H.; Harlow, E.; Meyerson, M.: Isolation of the human
cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated
p33 kinase. Nature 353: 174-177, 1991.

*FIELD* CN
Jon B. Obray - updated: 07/13/1996
Moyra Smith - updated: 4/15/1996

*FIELD* CD
Victor A. McKusick: 8/21/1991

*FIELD* ED
carol: 07/13/1996
carol: 4/19/1996
carol: 4/15/1996
carol: 4/29/1994
carol: 6/28/1993
supermim: 3/16/1992
carol: 3/2/1992
carol: 2/13/1992
carol: 11/4/1991

*RECORD*
*FIELD* NO
116954
*FIELD* TI
*116954 CELL SURFACE ANTIGEN DEFINED BY MONOCLONAL ANTIBODY TRA-2-10; MIC10
*FIELD* TX
Andrews et al. (1985) studied an antigen expressed by most human cells,
but not erythrocytes, and defined by monoclonal antibody TRA-2-10. The
antigen was expressed on the surface of human-mouse somatic cell
hybrids; segregation analysis showed that the antigen is determined by a
gene on human chromosome 1.

*FIELD* RF
1. Andrews, P. W.; Knowles, B. B.; Parkar, M.; Pym, B.; Stanley, K.;
Goodfellow, P. N.: A human cell-surface antigen defined by a monoclonal
antibody and controlled by a gene on human chromosome 1. Ann. Hum.
Genet. 49: 31-39, 1985.

*FIELD* CD
Victor A. McKusick: 6/7/1991

*FIELD* ED
supermim: 3/16/1992
carol: 6/7/1991

*RECORD*
*FIELD* NO
116955
*FIELD* TI
*116955 CELLULAR RETROVIRAL NUCLEIC ACID BINDING PROTEIN-1; CNBP1
ZINC FINGER PROTEIN-9; ZNF9
*FIELD* TX
Cholesterol homeostasis is maintained in part by negative feedback
regulation of the genes for proteins involved in cholesterol synthesis
and the cellular uptake of cholesterol. The apparent coordinate
regulation of several such genes, including HMG-CoA reductase (142910),
HMG-CoA synthase (142940), farnesylpyrophosphate synthetase (134631),
and the LDL receptor (143890) suggest that these genes may be regulated
by a common trans-acting factor that is able to 'sense' the levels of
cellular sterols. In a search for such a trans-acting factor,
Rajavashisth et al. (1989) identified a cDNA that encodes a 19-kD
protein containing 7 highly conserved zinc finger repeats with
remarkable sequence similarity to the finger domains of the family of
retroviral nucleic acid binding proteins (NBPs). They designated the
protein cellular NBP (CNBP). In common with the viral NBPs, CNBP
appeared to have a strong preference for single-stranded DNA. Lusis et
al. (1990) assigned the CNBP gene to chromosome 3 by Southern analysis
of DNAs from mouse/human somatic cell hybrids and regionalized the gene
to 3q13.3-q24 by in situ hybridization.

*FIELD* RF
1. Lusis, A. J.; Rajavashisth, T. B.; Klisak, I.; Heinzmann, C.; Mohandas,
T.; Sparkes, R. S.: Mapping of the gene for CNBP, a finger protein,
to human chromosome 3q13.3-q24. Genomics 8: 411-414, 1990. Note:
Erratum: Genomics 9: 564 only, 1991.

2. Rajavashisth, T. B.; Taylor, A. K.; Andalibi, A.; Svenson, K. L.;
Lusis, A. J.: Identification of a zinc finger protein that binds
to the sterol regulatory element. Science 245: 640-643, 1989.

*FIELD* CD
Victor A. McKusick: 10/11/1990

*FIELD* ED
pfoster: 3/25/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 3/2/1992
carol: 3/7/1991
carol: 10/11/1990

*RECORD*
*FIELD* NO
116957
*FIELD* TI
*116957 RETINOBLASTOMA-LIKE 1; RBL1
CELLULAR PROTEIN p107; CP107
*FIELD* TX
The cellular protein p107, like the retinoblastoma gene product
(180200), has been shown to form a specific complex with adenovirus E1A
and SV40 large T antigen (T). The binding characteristics implied that
RB1 and p107 share a common biochemical function. Ewen et al. (1991)
used a partial cDNA for human p107 to map the gene to 20q11.2 by
fluorescence in situ hybridization. The cDNA encoded a 936-residue
protein. Comparison with RB1 showed a major region of homology extending
over 564 residues. This region in RB1 is essential to its
growth-controlling function. Sequences outside of this region are
largely unique to each protein.

Cellular protein p107 is also known as retinoblastoma-like 1 (RBL1). The
retinoblastoma-like gene on chromosome 16 (180203) is designated as
RBL2. Thus, p107, like RB1, may have a function in cell cycle
regulation.

Kim et al. (1995) showed that the 4.9- and 2.4-kb Rbl1 transcripts of
the fetal mouse are a consequence of alternative splicing. The larger
message encodes a 119-kD protein and the smaller a 68-kD protein. Huppi
et al. (1996) cloned the mouse Rbl1 gene and compared its sequence with
its human counterpart. The extreme N-terminal and C-terminal regions are
the most conserved between the 2 sequences. They found that the Rbl1
gene maps to the distal end of mouse chromosome 2, as does also the E2f1
gene (189971).

*FIELD* RF
1. Ewen, M. E.; Xing, Y.; Lawrence, J. B.; Livingston, D. M.: Molecular
cloning, chromosomal mapping, and expression of the cDNA for p107,
a retinoblastoma gene product-related protein. Cell 66: 1155-1164,
1991.

2. Huppi, K.; Siwarski, D.; Mock, B. A.; Dosik, J.; Hamel, P. A.:
Molecular cloning, chromosomal mapping, and expression of the mouse
p107 gene. Mammalian Genome 7: 353-355, 1996.

3. Kim, K. K.; Soonpaa, M. H.; Wang, H.; Field, L. J.: Developmental
expression of p107 mRNA and evidence for alternative splicing of the
p107 (RBL1) gene product. Genomics 28: 520-529, 1995.

*FIELD* CN
Alan F. Scott - updated: 9/27/1995

*FIELD* CD
Victor A. McKusick: 10/4/1991

*FIELD* ED
terry: 06/13/1996
terry: 6/11/1996
terry: 4/17/1996
mark: 3/7/1996
carol: 4/19/1994
supermim: 3/16/1992
carol: 10/4/1991

*RECORD*
*FIELD* NO
116960
*FIELD* TI
*116960 CELLULAR SENESCENCE
SENESCENCE-RELATED (CELLULAR) 1; SEN;;
CELL SENESCENCE-RELATED GENE, COMPLEMENTATION GROUP B; CSR
CELLULAR IMMORTALITY, INCLUDED;;
INDEFINITE CELLULAR DIVISION, INCLUDED
*FIELD* TX
Fusion of normal with immortal human cells yields hybrids having limited
potential for division (Pereira-Smith and Smith, 1983). This indicates
that the phenotype of limited proliferation, or cellular senescence, is
dominant and that immortal cells result from recessive changes in normal
growth regulatory genes. The limited division potential of normal human
cells in culture has been accepted as a model for cellular senescence
and is called the Hayflick phenomenon (Hayflick, 1965; Goldstein, 1990).
By fusing immortal human cell lines with each other, Pereira-Smith and
Smith (1988) assigned 21 cell lines to a minimum of 4 complementation
groups for the phenotype of immortality. Cell type, embryonal layer of
origin, and tumor type did not affect group assignment. However, all
cell lines transformed by simian virus 40 were assigned to the same
group. Using the technique of microcell fusion for introducing single
human chromosomes into immortal human cell lines, Ning et al. (1991)
found that a normal human chromosome 4 resulted in loss of proliferation
and reversal of the immortal phenotype when introduced into 3 immortal
cell lines of complementation group B: HeLa, J82, and T98G. No effect on
the proliferation potential of cell lines representing other
complementation groups was observed.

*FIELD* RF
1. Goldstein, S.: Replicative senescence: the human fibroblast comes
of age. Science 249: 1129-1133, 1990.

2. Hayflick, L.: The limited in vitro lifetime of human diploid cell
strains. Exp. Cell Res. 37: 614-636, 1965.

3. Ning, Y.; Weber, J. L.; Killary, A. M.; Ledbetter, D. H.; Smith,
J. R.; Pereira-Smith, O. M.: Genetic analysis of indefinite division
in human cells: evidence for a cell senescence-related gene(s) on
human chromosome 4. Proc. Nat. Acad. Sci. 88: 5635-5639, 1991.

4. Pereira-Smith, O. M.; Smith, J. R.: Evidence for the recessive
nature of cellular immortality. Science 221: 964-966, 1983.

5. Pereira-Smith, O. M.; Smith, J. R.: Genetic analysis of indefinite
division in human cells: identification of four complementation groups.
Proc. Nat. Acad. Sci. 85: 6042-6046, 1988.

*FIELD* CD
Victor A. McKusick: 11/14/1988

*FIELD* ED
supermim: 3/16/1992
carol: 9/4/1991
supermim: 3/20/1990
ddp: 10/26/1989
root: 11/14/1988

*RECORD*
*FIELD* NO
117000
*FIELD* TI
#117000 CENTRAL CORE DISEASE OF MUSCLE; CCD; CCO
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
phenotype is in most, perhaps all, instances caused by mutations in the
ryanodine receptor-1 gene (RYR1; 180901).

Central core disease was the first described (Shy and Magee, 1956)
example of a stationary muscle disorder, although the name was not given
the entity until later. Five persons in 5 different sibships in 3
generations of the original family were affected. In the family studied
by Engel et al. (1961), only the proband had clinical manifestations but
his father had the same biochemical abnormality of muscle, namely, one
involving the liberation of phosphate from glucose-6-phosphate. Central
core disease is one of the conditions that produces the 'floppy infant'
(see amyotonia congenita of Oppenheim, 205000). Nemaline myopathy
(161800, 256030) and central core disease have been described in the
same family and indeed in the same patient (Afifi et al., 1965). It is
possible that the 'central core' morphologic change is nonspecific,
i.e., may occur with other types of myopathy in addition to the specific
entity to which the name can be applied. Bethlem et al. (1966) described
a nonprogressive myopathy in 3 females of 3 successive generations. The
father of the earliest patient may have been affected. Histologic
findings of central core disease were found. Muscle cramps followed
exercise and no hypotonia was present in infancy--features different
from previously reported cases of central core disease. Creatine
excretion in the urine was greatly increased. Creatine kinase and
oxidative phosphorylation in the muscles were normal. Dubowitz and Roy
(1970) described 4 cases in 3 generations. The disorder consisted of
slowly progressive weakness after the age of 5 years, resembling limb
girdle muscular dystrophy. Only type 1 muscle fibers showed central
cores. Isaacs et al. (1975) studied a South African kindred with
affected members spanning 5 successive generations. Eng et al. (1978)
observed autosomal dominant transmission through 5 generations with two
skips in a kindred ascertained through a child with malignant
hyperthermia (MHS; 145600). Gamstorp (1982) stated that this disorder is
rare in Scandinavia. She described the case of a girl who at age 2 was
found to be clumsy and to have weak hip muscles. Her facial expression
was normal. The father 'had never been able to carry a heavy burden
upstairs' and he was unable to sit up on a chair without the help of his
hands. Muscle biopsy showed central core disease in the father as well
as in the daughter, whose disorder had remained stationary to age 8
years. Byrne described a kindred in which at least 37 members in 5
generations had suffered from CCD.

Haan et al. (1990) mapped the CCO gene to 19q12-q13.2 by family linkage
studies. Kausch et al. (1991) also mapped the CCD gene to proximal
19q13.1 by linkage to markers. Frank et al. (1978) noted that 4 families
with central core disease and malignant hyperthermia had been described
and added another familial instance of the combination. Creatine kinase
blood levels were increased. In vitro muscle contraction studies with
caffeine and halothane identified those susceptible to malignant
hyperthermia. See Frank et al. (1980) for the full report. The work of
Mulley et al. (1993) supported the possibility that the CCO gene is an
allele at the RYR1 locus, which maps to the same region of chromosome
19. In a large kindred in which the gene for CCO was segregating,
2-point linkage analysis gave a maximum lod score, between CCO and the
RYR1 locus, of 11.8, with no recombination. Recombination was observed
between CCO and the markers flanking RYR1. Zhang et al. (1993) and Quane
et al. (1993) identified mutations in the ryanodine receptor-1 gene in
patients with central core disease. The involvement of RYR1 mutations in
a congenital myopathy are supported by the findings of Takeshima et al.
(1994). Mice homozygous for a targeted mutation in the skeletal muscle
ryanodine receptor gene died perinatally with gross abnormalities of
skeletal muscle. The contractile response to electrical stimulation
under physiologic conditions was totally abolished in the mutant muscle,
although ryanodine receptors other than the skeletal-muscle type seemed
to exist because the response to caffeine was retained. Takeshima et al.
(1994) interpreted the results as indicating that the skeletal muscle
ryanodine receptor is essential for both muscular maturation and
excitation-contraction (E-C) coupling, and that the function of the
skeletal muscle receptor during EC coupling cannot be substituted by
other subtypes of the receptor.

Fananapazir et al. (1993) demonstrated that many patients with
hypertrophic cardiomyopathy due to mutation in the beta-myosin heavy
chain gene (MYH7; 160760) have histologic changes on soleus muscle
biopsy consistent with central core disease. A few of the patients had
'significant muscle weakness' and 2 adults and 3 children from a family
with the leu908-to-val mutation of the MYH7 gene were observed to have
CCD changes in the soleus muscle with no cardiac hypertrophy as defined
by echocardiogram. The histologic hallmark of CCD was the absence of
mitochondria in the center of many type I fibers as revealed by light
microscopic examination of NADH-stained fresh-frozen skeletal muscle
sections. McKenna (1993), who stated that he had never seen clinical
evidence of skeletal myopathy in CMH1, doubted the significance of the
findings.

*FIELD* SA
Byrne et al. (1982); Gadoth et al. (1978); Patterson et al. (1979);
Shy et al. (1962)
*FIELD* RF
1. Afifi, A. K.; Smith, J. W.; Zellweger, H.: Congenital nonprogressive
myopathy. Central core disease and nemaline myopathy in one family.
Neurology 15: 371-381, 1965.

2. Bethlem, J.; Van Gool, J.; Hulsmann, W. C.; Meijer, A. E. F. H.
: Familial nonprogressive myopathy with muscle cramps after exercise:
a new disease associated with cores in the muscle fibres. Brain 89:
569-588, 1966.

3. Byrne, E.; Blumbergs, P. C.; Hallpike, J. F.: Central core disease:
study of a family with five affected generations. J. Neurol. Sci. 53:
77-83, 1982.

4. Dubowitz, V.; Roy, S.: Central core disease of muscle: clinical,
histochemical and electron microscopic studies of an affected mother
and child. Brain 93: 133-146, 1970.

5. Eng, G. D.; Epstein, B. S.; Engel, W. K.; McKay, D. W.; McKay,
R.: Malignant hyperthermia and central core disease in a child with
congenital dislocating hips: case presentation and review. Arch.
Neurol. 35: 189-197, 1978.

6. Engel, W. K.; Foster, J. B.; Hughes, B. P.; Huxley, H. E.; Mahler,
R.: Central core disease--an investigation of a rare muscle cell
abnormality. Brain 84: 167-185, 1961.

7. Fananapazir, L.; Dalakas, M. C.; Cyran, F.; Cohn, G.; Epstein,
N. D.: Missense mutations in the beta-myosin heavy-chain gene cause
central core disease in hypertrophic cardiomyopathy. Proc. Nat.
Acad. Sci. 90: 3993-3997, 1993.

8. Frank, J. P.; Harati, Y.; Butler, I. J.; Nelson, T. E.; Scott,
C. I.: Central core disease and malignant hyperthermia syndrome.
Ann. Neurol. 7: 11-17, 1980.

9. Frank, J. P.; Harati, Y.; Butler, I. J.; Scott, C. I., Jr.: Central
core disease (CCD) and the malignant hyperthermia syndrome (MHS).
(Abstract) Am. J. Hum. Genet. 30: 51A only, 1978.

10. Gadoth, N.; Margalit, D.; Shapira, Y.: Myopathy with multiple
central cores: a case with hypersensitivity to pyrexia. Neuropaediatrie 9:
239-244, 1978.

11. Gamstorp, I.: Non-dystrophic, myogenic myopathies with onset
in infancy or childhood: a review of some characteristic syndromes.
Acta Paediat. Scand. 71: 881-886, 1982.

12. Haan, E. A.; Freemantle, C. J.; McCure, J. A.; Friend, K. L.;
Mulley, J. C.: Assignment of the gene for central core disease to
chromosome 19. Hum. Genet. 86: 187-190, 1990.

13. Isaacs, H.; Heffron, J. J. A.; Badenhorst, M.: Central core disease:
a correlated genetic, physiochemical, ultramicroscopic, and biochemical
study. J. Neurol. Neurosurg. Psychiat. 38: 1177-1186, 1975.

14. Kausch, K.; Lehmann-Horn, F.; Janka, M.; Wieringa, B.; Grimm,
T.; Muller, C. R.: Evidence for linkage of the central core disease
locus to the proximal long arm of human chromosome 19. Genomics 10:
765-769, 1991.

15. McKenna, W. J.: Personal Communication. London, England  5/30/1993.

16. Mulley, J. C.; Kozman, H. M.; Phillips, H. A.; Gedeon, A. K.;
McCure, J. A.; Iles, D. E.; Gregg, R. G.; Hogan, K.; Couch, F. J.;
MacLennan, D. H.; Haan, E. A.: Refined genetic localization for central
core disease. Am. J. Hum. Genet. 52: 398-405, 1993.

17. Patterson, V. H.; Hill, T. R. G.; Fletcher, P. J. H.; Heron, J.
R.: Central core disease: clinical and pathological evidence of progression
within a family. Brain 102: 581-594, 1979.

18. Quane, K. A.; Healy, J. M. S.; Keating, K. E.; Manning, B. M.;
Couch, F. J.; Palmucci, L. M.; Doriguzzi, C.; Fagerlund, T. H.; Berg,
K.; Ording, H.; Bendixen, D.; Mortier, W.; Linz, U.; Muller, C. R.;
McCarthy, T. V.: Mutations in the ryanodine receptor gene in central
core disease and malignant hyperthermia. Nature Genet. 5: 51-55,
1993.

19. Shy, G. M.; Engel, W. K.; Wanko, T.: Central core disease: a
myofibrillary and mitochondrial abnormality of muscle. Ann. Intern.
Med. 56: 511-520, 1962.

20. Shy, G. M.; Magee, K. R.: A new congenital non-progressive myopathy.
Brain 79: 610-621, 1956.

21. Takeshima, H.; Iino, M.; Takekura, H.; Nishi, M.; Kuno, J.; Minowa,
O.; Takano, H.; Noda, T.: Excitation-contraction uncoupling and muscular
degeneration in mice lacking functional skeletal muscle ryanodine-receptor
gene. Nature 369: 556-559, 1994.

22. Zhang, Y.; Chen, H. S.; Khanna, V. K.; De Leon, S.; Phillips,
M. S.; Schappert, K.; Britt, B. A.; Brownell, A. K. W.; MacLennan,
D. H.: A mutation in the human ryanodine receptor gene associated
with central core disease. Nature Genet. 5: 46-50, 1993.

*FIELD* CS

Muscle:
   Slowly progressive muscle weakness;
   Muscle cramps after exercise;
   Myopathy

Neuro:
   Neonatal hypotonia

Lab:
   Absent mitochondria in the center of many type I muscle fibers;
   Increased urinary creatine

Inheritance:
   Autosomal dominant (19q12-q13.2), mostly ryanodine receptor-1 gene
   mutations (RYR1;
   180901)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jason: 7/19/1994
mimadm: 6/25/1994
warfield: 4/7/1994
carol: 10/21/1993
carol: 9/27/1993
carol: 6/4/1993

*RECORD*
*FIELD* NO
117100
*FIELD* TI
*117100 CENTRALOPATHIC EPILEPSY
CENTROTEMPORAL EPILEPSY; ECT;;
TEMPORAL-CENTRAL FOCAL EPILEPSY;;
BENIGN ROLANDIC EPILEPSY
*FIELD* TX
Benign centrotemporal epilepsy has a mean age of onset of 10 years and
includes brief, hemifacial seizures that tend to become generalized when
they occur nocturnally. The EEG findings include slow, diphasic, high
voltage, centrotemporal spikes, activated by sleep. The prognosis is
excellent; recovery is the rule. Metrakos and Metrakos (1961) concluded
that the centrencephalic type of electroencephalogram (associated with
'centralopathic epilepsy') is an expression of an autosomal dominant
gene, with the unusual characteristics of a very low penetrance at
birth, a rapid rise to nearly complete penetrance for ages 4.5 to 16.5
years, and a gradual decline to almost no penetrance after the age of
40.5 years. In this form of epilepsy seizures of varying clinical
appearance are associated with paroxysmal, diffuse, bilateral
synchronous spike-wave EEG abnormalities. Although their studies did not
lead them to a definite dominant hypothesis, Bray and Wiser (1964, 1965)
presented evidence for a genetic basis of one form of temporal lobe
epilepsy. Heijbel et al. (1975) studied 19 probands. Of 34 sibs, 15% had
seizures and rolandic discharges and 19% had rolandic discharges in
isolation. Of the 38 parents, 11% had a history of seizures in childhood
and 3% had rolandic discharges on EEG. Heijbel et al. (1975) concluded
that an autosomal dominant gene with age dependent penetrance is
responsible for the EEG trait.

Janjua et al. (1989) documented elevated plasma levels of glutamic acid
in EL mice, an inbred strain with a genetic predisposition to
tonic-clonic seizures in response to vestibular stimulation. The
epilepsy in EL mice is similar to that of human temporal lobe epilepsy
and is considered an excellent model of the latter.

In a study of the neurologic mutant mouse strain El, a model for complex
partial seizures in humans, Rise et al. (1991) identified a major gene
for this epileptic phenotype (El-1) on mouse chromosome 9. At least one
other gene, linked to markers on mouse chromosome 2, influences the
seizure phenotype.

*FIELD* SA
Gardiner  (1990)
*FIELD* RF
1. Bray, P. F.; Wiser, W. C.: Evidence for a genetic etiology of
temporal-central abnormalities in focal epilepsy. New Eng. J. Med. 271:
926-933, 1964.

2. Bray, P. F.; Wiser, W. C.: Hereditary characteristics of familial
temporal-central focal epilepsy. Pediatrics 36: 207-211, 1965.

3. Gardiner, R. M.: Genes and epilepsy. J. Med. Genet. 27: 537-544,
1990.

4. Heijbel, J.; Blom, S.; Rasmuson, M.: Benign epilepsy of childhood
with centro-temporal EEG foci: a genetic study. Epilepsia 16: 285-293,
1975.

5. Janjua, N. A.; Mori, A.; Kabuto, H.; Andermann, E.: Elevated plasma
glutamic acid levels in a genetic model of epilepsy.    (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A6, 1989.

6. Metrakos, K.; Metrakos, J. D.: Genetics of convulsive disorders.
II. Genetic and electroencephalographic studies in centrencephalic
epilepsy. Neurology 11: 474-483, 1961.

7. Rise, M. L.; Frankel, W. N.; Coffin, J. M.; Seyfried, T. N.: Genes
for epilepsy mapped in the mouse. Science 253: 669-673, 1991.

*FIELD* CS

Neuro:
   Benign centrotemporal epilepsy;
   Brief, hemifacial seizures;
   Generalized nocturnal seizures

Misc:
   Mean onset age 10 years

Lab:
   EEG shows slow, diphasic, high voltage, centrotemporal spikes, activated
   by sleep

Inheritance:
   Autosomal dominant

*FIELD* CN
Orest Hurko - updated: 2/22/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/15/1996
mark: 2/22/1996
terry: 2/9/1996
mimadm: 6/25/1994
carol: 3/26/1992
supermim: 3/16/1992
carol: 2/17/1992
carol: 10/10/1991
carol: 10/3/1991

*RECORD*
*FIELD* NO
117139
*FIELD* TI
*117139 CENTROMERIC PROTEIN A; CENPA
*FIELD* TX
See 117140. Earnshaw (1991) discussed the distinction between centromere
and kinetochore.

*FIELD* RF
1. Earnshaw, W. C.: When is a centromere not a kinetochore?. J.
Cell Sci. 99: 1-4, 1991.

*FIELD* CD
Victor A. McKusick: 6/18/1991

*FIELD* ED
supermim: 3/16/1992
carol: 7/23/1991
carol: 6/19/1991
carol: 6/18/1991

*RECORD*
*FIELD* NO
117140
*FIELD* TI
*117140 CENTROMERIC PROTEIN B; CENPB
*FIELD* TX
The structure and function of the centromere regions of mitotic
chromosomes have been of interest to cell biologists, geneticists and
rheumatologists. Cell biologists focus on the centromere as both the
site of sister chromatid pairing and the site of mitotic spindle
attachment. The latter site, the kinetochore, is a trilaminar plaque
structure embedded in the chromatin at the surface of the chromosome, as
visualized by electron microscopy. Geneticists have been interested in
centromeric sequences involved in the control of chromosomal
segregation. Rheumatologists became interested in centromere structure
when it was observed that centromere compounds are the target of
autoimmune responses. Earnshaw et al. (1987) isolated a series of
overlapping DNA clones for about 95% of the mRNA that encodes the B
centromeric protein. Anticentromere antibodies recognize 3 antigens:
CENPA (17 kD; 117139), CENPB (80 kD), and CENPC (140 kD; 117141). CENPB
is considered the major centromere antigen since antibody to it is
consistently present at high titer in serum positive for anticentromere
antibodies. The B protein is the product of a 2.9-kb mRNA that is
encoded by a single locus.

By optimizing the primer-annealing temperature in a rapid air cycling
procedure, Sugimoto et al. (1993) specifically amplified human DNA
sequences encoding CENPB and CENPC, without any detectable amplification
of highly homologous rodent DNA sequences. Using a panel of rodent/human
hybrid DNAs, the human CENPB and CENPC genes were mapped to chromosomes
20 and 12, respectively. By fluorescence in situ hybridization, Seki et
al. (1994) assigned the CENPB gene to 20p13.

*FIELD* RF
1. Earnshaw, W. C.; Sullivan, K. F.; Machlin, P. S.; Cooke, C. A.;
Kaiser, D. A.; Pollard, T. D.; Rothfield, N. F.; Cleveland, D. W.
: Molecular cloning of cDNA for CENP-B, the major human centromere
autoantigen. J. Cell Biol. 104: 817-829, 1987.

2. Seki, N.; Saito, T.; Kitagawa, K.; Masumoto, H.; Okazaki, T.; Hori,
T.-A.: Mapping of the human centromere protein B gene (CENPB) to
chromosome 20p13 by fluorescence in situ hybridization. Genomics 24:
187-188, 1994.

3. Sugimoto, K.; Yata, H.; Himeno, M.: Mapping of the human CENP-B
gene to chromosome 20 and the CENP-C gene to chromosome 12 by a rapid
cycle DNA amplification procedure. Genomics 17: 240-242, 1993.

*FIELD* CD
Victor A. McKusick: 10/16/1987

*FIELD* ED
terry: 12/5/1994
carol: 7/19/1993
supermim: 3/16/1992
carol: 7/23/1991
carol: 6/18/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
117141
*FIELD* TI
*117141 CENTROMERIC PROTEIN C; CENPC
*FIELD* TX
See 117140. Using anticentromere antibodies from 39 individuals with
Raynaud syndrome or disease, Earnshaw et al. (1986) recognized 3
antigens: centromere protein B (CENPB; 117140) with molecular weight
80,000, recognized by all sera; CENPA (117139) with molecular weight
17,000, recognized by 38 of 39 sera; and CENPC with molecular weight
140,000, recognized by 37 of 39 sera. None of these antigens was
recognized by any of 123 control sera. By study of rodent/human somatic
cell hybrid DNAs, Sugimoto et al. (1993) mapped the CENPC gene to
chromosome 12. Jones et al. (1993) also mapped the CENPC gene to
chromosome 12 by study of a panel of human/hamster somatic cell hybrids.
By in situ hybridization, however, McKay et al. (1994) mapped these
genes to human 4q12-q13.3 and mouse 5E2-E5. They found additional
secondary sites in man on chromosome 12q21.2-q21.33 and in mouse on
chromosome 2B. Because DNA sequence analysis of the mouse Cenpc gene
indicated several stop codons in the coding sequence, these secondary
sites are likely to be pseudogenes (McKay et al., 1994). Although the
primary map locations are in a region of linkage group conservation
between the two species, the secondary sites are not syntenic.

The stability of dicentric chromosomes in humans seems to result from
inactivation of one centromere, yielding a functionally monocentric
chromosome. Such chromosomes display a single primary constriction,
assumed to be the active centromere. When monospecific antibodies were
used to analyze an isodicentric chromosome 13, Earnshaw et al. (1989)
found that although CENPB was present at both centromeres, CENPC was
detectable only at the primary constriction. The inactive centromere,
lacking a constriction, also lacked CENPC. CENPC therefore seemed to be
necessary for active centromeres, and the absence of CENPC appeared to
be a marker of centromere inactivation. That this was the case was
demonstrated by Page et al. (1995), who studied a dicentric (X;15)
translocation using simultaneous indirect immunofluorescence, for
detection of CENPC, and and fluorescence in situ hybridization, to
localize chromosome-specific alpha-satellite DNA. In both fibroblast and
lymphoblast cell lines containing the translocation, the X chromosome
centromere consistently had both a primary constriction and CENPC
immunofluorescence, and was, therefore, the active centromere. CENPC was
never detected at the chromosome 15 centromere, which appeared to be
inactive. The inactivation pattern was apparently stable and was
observed in all cells with the translocation. Immunofluorescence with
CREST serum revealed staining at both centromeres of the translocation,
and thus was not specific to the active centromere.

By fluorescence in situ hybridization, Xie and Heng (1996) mapped CENPC
to 4q13-q21.

*FIELD* SA
Earnshaw and Rothfield (1985)
*FIELD* RF
1. Earnshaw, W.; Bordwell, B.; Marino, C.; Rothfield, N.: Three human
chromosomal autoantigens are recognized by sera from patients with
anti-centromere antibodies. J. Clin. Invest. 77: 426-430, 1986.

2. Earnshaw, W. C.; Ratrie, H., III; Stetten, G.: Visualization of
centromere proteins CENP-B and CENP-C on a stable dicentric chromosome
in cytological spreads. Chromosoma 98: 1-12, 1989.

3. Earnshaw, W. C.; Rothfield, N.: Identification of a family of
human centromere proteins using autoimmune sera from patients with
scleroderma. Chromosoma 91: 313-321, 1985.

4. Jones, C.; Nguyen, L.; Burkin, D.; McGrew, J.; Tomkiel, J.; Earnshaw,
W.: Localization of centromere autoantigen C (CENPC) to human chromosome
12. (Abstract) Human Genome Mapping Workshop 93 25 only, 1993.

5. McKay, S.; Thomson, E.; Cooke, H.: Sequence homologies and linkage
group conservation of the human and mouse Cenpc genes. Genomics 22:
36-40, 1994.

6. Page, S. L.; Earnshaw, W. C.; Choo, K. H. A.; Shaffer, L. G.:
Further evidence that CENP-C is a necessary component of active centromeres:
studies of a dic(X;15) with simultaneous immunofluorescence and FISH. Hum.
Molec. Genet. 4: 289-294, 1995.

7. Sugimoto, K.; Yata, H.; Himeno, M.: Mapping of the human CENP-B
gene to chromosome 20 and the CENP-C gene to chromosome 12 by a rapid
cycle DNA amplification procedure. Genomics 17: 240-242, 1993.

8. Xie, Y.; Heng, H. H. Q.: FISH mapping of centromere protein C
(CENPC) on human chromosome 4q13-q21. Cytogenet. Cell Genet. 74:
192-193, 1996.

*FIELD* CD
Victor A. McKusick: 6/18/1991

*FIELD* ED
terry: 01/13/1997
mark: 3/31/1995
jason: 7/15/1994
carol: 12/2/1993
carol: 7/19/1993
supermim: 3/16/1992
carol: 7/23/1991

*RECORD*
*FIELD* NO
117142
*FIELD* TI
*117142 CENTROMERIC PROTEIN D; CENPD
*FIELD* TX
See 117140. By indirect immunofluorescence and immunoblotting using
serum from a patient with the CREST variant of scleroderma (181750),
Kingwell and Rattner (1987) identified a 50-kD antigen located at the
surface of the primary constrictions (kinetochore region) of both human
and Indian muntjac chromosomes.

*FIELD* RF
1. Kingwell, B.; Rattner, J. B.: Mammalian kinetochore/centromere
composition: a 50 kDa antigen is present in the mammalian kinetochore/centromere.
Chromosoma 95: 403-407, 1987.

*FIELD* CD
Victor A. McKusick: 6/18/1991

*FIELD* ED
supermim: 3/16/1992
carol: 7/23/1991
carol: 6/19/1991
carol: 6/18/1991

*RECORD*
*FIELD* NO
117143
*FIELD* TI
*117143 CENTROMERIC PROTEIN E; CENPE
*FIELD* TX
Yen et al. (1991) identified a 250-300 kD human centromere-associated
protein, CENPE, by preparing monoclonal antibodies against a fraction of
HeLa chromosome scaffold proteins enriched for centromere/kinetochore
components. In cells progressing through different parts of the cell
cycle, the localization of CENPE differs markedly from that observed for
the previously identified centromere proteins CENPA (117139), CENPB
(117140), CENPC (117141), and CENPD (117142). In contrast to these
antigens, no monoclonal antibody staining was detected during
interphase, and staining first appeared at the centromere region of
chromosomes during prometaphase. Microinjection of the monoclonal
antibody 177, which demonstrated CENPE, into metaphase cells blocked or
significantly delayed progression into anaphase, although the morphology
of the spindle and the configuration of the metaphase chromosomes
appeared normal in these metaphase-arrested cells. Thus, CENPE function
is required for the transition from metaphase to anaphase. Yen et al.
(1992) identified CENPE as a kinesin-like motor protein (Mr 312,000)
that accumulates in the G2 phase of the cell cycle. CENPE associates
with kinetochores during congression, relocates to the spindle midzone
at anaphase, and is quantitatively discarded at the end of the cell
division. CENPE is probably one of the motors responsible for mammalian
chromosome movement and/or spindle elongation.

Testa et al. (1994) used CENPE cDNA to map the gene to 4q24-q25 by
fluorescence in situ hybridization.

*FIELD* RF
1. Testa, J. R.; Zhou, J.; Bell, D. W.; Yen, T. J.: Chromosomal localization
of the genes encoding the kinetochore proteins CENPE and CENPF to
human chromosomes 4q24-q25 and 1q32-q41, respectively, by fluorescence
in situ hybridization. Genomics 23: 691-693, 1994.

2. Yen, T. J.; Compton, D. A.; Wise, D.; Zinkowski, R. P.; Brinkley,
B. R.; Earnshaw, W. C.; Cleveland, D. W.: CENP-E, a novel human centromere-associated
protein required for progression from metaphase to anaphase. EMBO
J. 10: 1245-1254, 1991.

3. Yen, T. J.; Li, G.; Schaar, B. T.; Szilak, I.; Cleveland, D. W.
: CENP-E is a putative kinetochore motor that accumulates just before
mitosis. Nature 359: 536-539, 1992.

*FIELD* CD
Victor A. McKusick: 6/18/1991

*FIELD* ED
carol: 12/13/1994
carol: 11/2/1992
supermim: 3/16/1992
carol: 7/23/1991
carol: 6/18/1991

*RECORD*
*FIELD* NO
117200
*FIELD* TI
#117200 CEREBELLAR ATAXIA
*FIELD* TX
A number sign (#) is used with this entry because it is clear that a
single locus is not represented.

The spinocerebellar ataxias represent a nosologically confused category.
Friedreich ataxia is clearly a recessive disorder. So-called Marie
ataxia is characterized by late onset and dominant inheritance. It
probably is a heterogeneous category encompassing several of the
conditions listed here as separate disorders under the general heading
of either olivopontocerebellar atrophy (q.v.) or cerebellar parenchymal
disorder (q.v.). Nosologic and genetic studies of the ataxias include
those of Sjogren (1943). Nosologic studies based on pathologic findings
were done by Greenfield (1954). In their extensive nosologic studies,
Konigsmark and Weiner (1970) also insisted on histopathologic studies
before they attempted to categorize a given family, either reported or
in their own experience. A form of cerebellar ataxia possibly distinct
from the other forms discussed here was described by Becker et al.
(1971). Pathologic findings included cerebellar cortical atrophy with
Purkinje cell loss, pontine atrophy, spinocerebellar fiber loss and
vestibular neuronal loss. In the mouse, Richard L. Sidman and his
colleagues have been able to analyze the cerebellar ataxias in a manner
not yet possible in the human counterparts. They have, for example,
divided the 'cerebellar mutants' into those involving primarily Purkinje
cells ('nervous,' 'lurcher,' 'Purkinje cell degeneration') and those
involving granular cell degeneration ('staggerer,' 'weaver,' 'reeler').
Within each of these two groups, different disturbances in cerebellar
development can be shown. For example, Zanjani et al. (1994) noted that
the primary defect in the staggerer mutation is in the Purkinje cell
population, which has a cascade effect on afferent populations with
target-related cell death of virtually all the cerebellar granule cells
and the majority of neurons in the inferior olive. Only one class, the
type II or complex dendritic type of inferior olivary neurons, survive
in the mutant.

Hirayama et al. (1994) conducted a nationwide survey of Japanese
patients with various forms of spinocerebellar degeneration and
estimated that there were 5,050 such patients with an approximate
prevalence of 4.53 per 100,000. They subdivided the spinocerebellar
degenerations into 4 general categories: 1) nonhereditary multisystemic
types (olivopontocerebellar atrophy, Shy-Drager syndrome, and
striatonigral degeneration); 2) hereditary multisystemic types (Menzel
hereditary cerebellar ataxia, dentatorubropallidoluysian atrophy, and
Machado-Joseph disease); 3) spinal types (Friedreich ataxia and
hereditary spastic paraplegia); and 4) cerebellar types (Holmes
hereditary cerebellar ataxia and late-onset cortical cerebellar
atrophy). The percentages that they found belonging to each subtype,
according to their definitions, were olivopontocerebellar atrophy,
34.4%; late-onset cortical cerebellar atrophy, 15.2%; Menzel hereditary
cerebellar ataxia, 12.6%; Holmes hereditary cerebellar ataxia, 7.5%;
Shy-Drager syndrome, 7.0%; hereditary spastic paraplegia, 3.9%;
dentatorubropallidoluysian atrophy, 2.5%; Friedreich ataxia, 2.4%;
Machado-Joseph disease, 2.0%; and striatonigral degeneration, 1.5%.
Although the authors described their criteria for making these
diagnoses, they are considerably at variance with the classification
scheme used elsewhere. For example, in most classification systems,
including the one adhered to in MIM, OPCA is a descriptor of a number of
hereditary syndromes, mostly autosomal dominant but including X-linked
and recessive types, whereas Hirayama et al. (1994) used it to refer to
a sporadic disorder.

*FIELD* SA
Skre  (1974)
*FIELD* RF
1. Becker, P. E.; Sabuncu, N.; Hopf, H. C.: Dominant erblicher Typ
von 'cerebellarer Ataxie.'. Z. Neurol. 199: 116-139, 1971.

2. Greenfield, J. G.: The Spino-cerebellar Degenerations.  Oxford:
Blackwell (pub.)  1954.

3. Hirayama, K.; Takayanagi, T.; Nakamura, R.; Yanagisawa, N.; Hattori,
T.; Kita, K.; Yanagimoto, S.; Fujita, M.; Nagaoka, M.; Satomura, Y.;
Sobue, I.; Iizuka, R.; Toyokura, Y.; Satoyoshi, E.: Spinocerebellar
degenerations in Japan: a nationwide epidemiological and clinical
study. Acta Neurol. Scand. 89 (suppl. 153): 1-22, 1994.

4. Konigsmark, B. W.; Weiner, L. P.: The olivo-ponto-cerebellar atrophies:
a review. Medicine 49: 227-242, 1970.

5. Sjogren, T.: Klinische und erbbiologische Untersuchungen ueber
die Heredoataxien. Acta Psychiat. Neurol. Scand. 27 (suppl.): 1-200,
1943.

6. Skre, H.: Spino-cerebellar ataxia in Western Norway. Clin. Genet. 6:
265-288, 1974.

7. Zanjani, H. S.; Herrup, K.; Guastavino, J.-M.; Delhaye-Bouchaud,
N.; Mariani, J.: Developmental studies of the inferior olivary nucleus
in staggerer mutant mice. Develop. Brain Res. 82: 18-28, 1994.

*FIELD* CS

Neuro:
   Ataxia

Inheritance:
   Autosomal dominant;
   also autosomal recessive forms

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 2/17/1995
terry: 10/26/1994
mimadm: 6/25/1994
carol: 10/21/1993
supermim: 3/16/1992
carol: 2/6/1992

*RECORD*
*FIELD* NO
117210
*FIELD* TI
*117210 CEREBELLAR ATAXIA, AUTOSOMAL DOMINANT PURE
CEREBELLAR ATAXIA, HOLMES TYPE
*FIELD* TX
In her classification of dominantly inherited ataxias based on clinical
criteria, Harding (1982) separated a pure cerebellar ataxia from ataxia
associated with additional noncerebellar signs. According to her, the
pure form is very rare having been described at that time in only 2
families, that of Hoffman et al. (1971) and her own family (Harding,
1982). Frontali et al. (1992) studied a family with late-onset
cerebellar ataxia in which neuroimaging and electrophysiologic studies
were in agreement with the clinical evidence that the disorder involved
only the cerebellum, even many years after onset. No atrophy of the
inferior olives was observed by magnetic resonance imaging, while
cerebellar atrophy was extremely marked. The disease was very slowly
progressive in all the patients. Clinically the disorder could be
differentiated from the form of spinocerebellar ataxia that maps to 6p
(SCA1; 164400), which shows an early multisystem involvement and a more
rapid progression toward incapacitation. Frontali et al. (1992) excluded
close linkage with the 6p DNA marker D6S89, thus supporting the
distinction from SCA1. Pure cerebellar ataxia is sometimes referred to
as the Holmes type (Frontali et al., 1991).

In a nationwide survey of Japanese patients, Hirayama et al. (1994)
estimated the prevalence of all forms of spinocerebellar degeneration to
be 4.53 per 100,000. Of these, 7.5% were estimated to have cerebellar
ataxia of the Holmes type, defined by the authors as a progressive
disorder with onset of ataxia after young adulthood. Cerebellar atrophy,
but not brain stem atrophy, was appreciable on CT or MRI scanning.
Hirayama et al. (1994) did not consider endocrine disturbance or
hypergonadism to be an essential part of the diagnosis.

*FIELD* RF
1. Frontali, M.; Spadaro, M.; Giunti, P.; Bianco, F.; Jodice, C.;
Persichetti, F.; Colazza, G. B.; Lulli, P.; Terrenato, L.; Morocutti,
C.: Autosomal dominant pure cerebellar ataxia: neurological and genetic
study. Brain 115: 1647-1654, 1992.

2. Frontali, M.; Spadaro, M.; Giunti, P.; Jodice, C.; Persichetti,
F.; Malaspina, P.; Novelletto, A.; Lulli, P.; Morocutti, C.; Terrenato,
L.: Pure cerebellar ataxia (Holmes type) is not mapping at SCA1 locus
on 6p.  (Abstract) Cytogenet. Cell Genet. 58: 1910 only, 1991.

3. Harding, A. E.: The clinical features and classification of the
late onset autosomal dominant cerebellar ataxias: a study of 11 families,
including descendants of 'the Drew family of Walworth.'. Brain 105:
1-28, 1982.

4. Hirayama, K.; Takayanagi, T.; Nakamura, R.; Yanagisawa, N.; Hattori,
T.; Kita, K.; Yanagimoto, S.; Fujita, M.; Nagaoka, M.; Satomura, Y.;
Sobue, I.; Iizuka, R.; Toyokura, Y.; Satoyoshi, E.: Spinocerebellar
degenerations in Japan: a nationwide epidemiological and clinical
study. Acta Neurol. Scand. 89 (suppl. 153): 1-22, 1994.

5. Hoffman, P. M.; Stuart, W. H.; Earle, K. M.; Brody, J. A.: Hereditary
late-onset cerebellar degeneration. Neurology 21: 771-777, 1971.

*FIELD* CS

Neuro:
   Pure cerebellar ataxia;
   No additional noncerebellar signs

Radiology:
   Neuroimaging shows only cerebellar involvement

Misc:
   Very slowly progressive

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 3/11/1993

*FIELD* ED
carol: 10/26/1994
mimadm: 6/25/1994
carol: 10/21/1993
carol: 3/20/1993
carol: 3/11/1993

*RECORD*
*FIELD* NO
117300
*FIELD* TI
117300 CEREBELLAR ATAXIA, CATARACT, DEAFNESS, AND DEMENTIA OR PSYCHOSIS
HEREDOPATHIA OPHTHALMOOTOENCEPHALICA; HOOE
*FIELD* TX
Stromgren et al. (1970) described this syndrome in 9 persons in 5
generations. Intention tremor was present. Paranoid psychosis or
increasing dementia occurred in late life. Posterior polar cataracts
appeared between ages 20 and 30, and deafness which appeared about the
same time became severe by age 45. In a follow-up, Stromgren (1981)
presented a pedigree with affected persons in 5 sibships of 4
generations but no male-to-male transmission. The brain was examined in
1 case; 'the dominating pathological feature was an accumulation of
large quantities of cholesterol and cholesterol compounds freely in the
tissue and, to a lesser degree, in glial cells, walls and lumina of
vessels.' Stromgren (1982) reported that further cases had appeared in
the family in the 2.5 years since he prepared the follow-up.

*FIELD* RF
1. Stromgren, E.: Heredopathia ophthalmo-oto-encephalica. In: Myrianthopoulos,
N. C.: Handbook of Clinical Neurology. Neurogenetic Directory.
New York: Elsevier/North Holland (pub.)  42, Part I: 1981. Pp. 150-152.

2. Stromgren, E.: Personal Communication. Risskov, Denmark  6/16/1982.

3. Stromgren, E.; Dalby, A.; Dalby, M. A.; Ranheim, B.: Cataracts,
deafness, cerebellar ataxia, psychosis, and dementia--a new syndrome.
Acta Neurol. Scand. 43 (suppl.): 261-262, 1970.

*FIELD* CS

Neuro:
   Ataxia;
   Intention tremor;
   Psychosis;
   Dementia

Eyes:
   Posterior polar cataracts

Ears:
   Hearing loss

Lab:
   Large quantities of cholesterol and cholesterol compounds in tissue
   and in glial cells, walls and lumina of vessels

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
davew: 7/26/1994
mimadm: 6/25/1994
pfoster: 3/31/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
117340
*FIELD* TI
*117340 CEREBELLAR DEGENERATION-RELATED AUTOANTIGEN-2; CDR2; CDR62
*FIELD* TX
Paraneoplastic cerebellar degeneration is an autoimmune disorder
associated with neoplasms of lung, ovary, breast, or Hodgkin disease.
Patients with paraneoplastic cerebellar degeneration carry a
characteristic antibody called anti-Yo. On Western blot analysis of
Purkinje cells and tumor tissue, the anti-Yo sera react with at least 2
antigens, a major species of 62 kD called CDR62 and a minor species of
34 kD called CDR34, where CDR means cerebellar degeneration-related.
CDR34 is encoded by a gene on the X chromosome (CDR1; 302650). Furneaux
et al. (1990) cloned and characterized the gene encoding CDR62, a
leucine-zipper DNA-binding protein; see Fathallah-Shaykh et al. (1991).
By a combination of study of rodent/human somatic cell hybrids and in
situ hybridization, Gress et al. (1991, 1992) assigned the CDR2 gene to
16p13.1-p12. The gene is positioned in an interval that contains 2 rare
heritable fragile sites.

*FIELD* SA
Furneaux et al. (1990)
*FIELD* RF
1. Fathallah-Shaykh, H.; Wolf, S.; Wong, E.; Posner, J. B.: Cloning
of a leucine-zipper protein recognized by the sera of patients with
antibody-associated paraneoplastic cerebellar degeneration. Proc.
Nat. Acad. Sci. 88: 3451-3454, 1991.

2. Furneaux, H. M.; Rosenblum, M. K.; Dalmau, J.; Wong, E.; Woodruff,
P.; Graus, F.; Posner, J. B.: Selective expression of Purkinje-cell
antigens in tumor tissue from patients with paraneoplastic cerebellar
degeneration. New Eng. J. Med. 322: 1844-1851, 1990.

3. Furneaux, H. M.; Wong, E.; Posner, J. B.: Isolation of cDNA clones
encoding the major Yo paraneoplastic antigen.  (Abstract) Neurology 40
(suppl. 1): 166 only, 1990.

4. Gress, T.; Baldini, A.; Rocchi, M.; Furneaux, H.; Posner, J. B.;
Siniscalco, M.: In situ mapping of the gene coding for a leucine
zipper DNA binding protein (CDR 2) to the region between two rare
fragile sites of autosome 16 (16p12-p13.1).  (Abstract) Cytogenet.
Cell Genet. 58: 1999-2000, 1991.

5. Gress, T.; Baldini, A.; Rocchi, M.; Furneaux, H.; Posner, J. B.;
Siniscalco, M.: In situ mapping of the gene coding for a leucine
zipper DNA binding protein (CDR62) to 16p12-16p13.1. Genomics 13:
1340-1342, 1992.

*FIELD* CD
Victor A. McKusick: 8/21/1991

*FIELD* ED
carol: 10/19/1994
carol: 10/13/1992
carol: 8/17/1992
supermim: 3/16/1992
carol: 2/21/1992
carol: 9/4/1991

*RECORD*
*FIELD* NO
117350
*FIELD* TI
*117350 CEREBELLAR DEGENERATION WITH SLOW EYE MOVEMENTS
WADIA-SWAMI SYNDROME;;
SPINOCEREBELLAR DEGENERATION WITH SLOW EYE MOVEMENTS; SDSEM
*FIELD* TX
Wadia and Swami (1971) reported the association of spinocerebellar
degeneration and abnormal eye movements, specifically, absent rapid
saccades (scanning) and abnormally slow pursuit (tracking). They
described 37 patients in 12 families in India. Some of the patients were
'mentally backward.' Starkman et al. (1972) described the syndrome in a
U.S. family. Whyte and Dekaban (1976) described a family. Their proband
had nevus of Ota which they concluded was unrelated. Progressive mental
deterioration was a feature. They suggested that the eye signs are due
to a brain-stem lesion of the paramedian pontine reticular formation. No
histopathologic studies are available. This may be the most frequent
form of spinocerebellar degeneration in India. The disorder has a
rapidly progressive course with fatality in less than 10 years after
onset. See 271322 for a possible recessive form of the Wadia-Swami
syndrome.

*FIELD* RF
1. Starkman, S.; Kaul, S.; Fried, J.; Behrens, M.: Unusual abnormal
eye movements in a family with hereditary spino-cerebellar degeneration.
(Abstract) Neurology 22: 402 only, 1972.

2. Wadia, N. H.; Swami, R. K.: A new form of heredo-familial spino-cerebellar
degeneration with slow eye movements (nine families). Brain 94:
359-374, 1971.

3. Whyte, M. P.; Dekaban, A. S.: Familial cerebellar degeneration
with slow eye-movements, mental deterioration and incidental nevus
of Ota (oculo-dermal melanocytosis). Dev. Med. Child. Neurol. 18:
373-380, 1976.

*FIELD* CS

Eyes:
   Absent rapid saccades;
   Slow pursuit

Neuro:
   Ataxia;
   Progressive mental deterioration

Misc:
   Death within 10 years of onset

Inheritance:
   Autosomal dominant;
   also possibly a recessive form

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/17/1994
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 10/16/1990
carol: 10/9/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
117360
*FIELD* TI
117360 CEREBELLAR VERMIS APLASIA
APLASIA OF CEREBELLAR VERMIS; ACV;;
CEREBELLAR ATAXIA, EARLY-ONSET NONPROGRESSIVE
*FIELD* TX
Fenichel and Phillips (1989) described a family in which 4 persons in 3
generations had nonprogressive ataxia from birth. Magnetic resonance
imaging in 1 child showed hypoplasia or partial aplasia of the
cerebellar vermis. Furman et al. (1985) described a possibly identical
situation in a mother and 2 daughters. The mother presented because of
oscillopsia and visual blurring at the age of 32 years. She had been
clumsy all her life, without progression of symptoms. She had normal
intelligence, truncal ataxia, mild limb dysmetria, upbeating nystagmus,
and gaze-provoked horizontal nystagmus. All 3 affected members had
changes in the cerebellar vermis by magnetic resonance imaging. Tomiwa
et al. (1987) described affected mother and daughter. Kattah et al.
(1983) described a similar syndrome, which presented with primary
position vertical nystagmus, in 5 family members. Fenichel and Phillips
(1989) were impressed with the fact that 12 of 14 reported persons were
female and that 2 affected males were more severely affected than were
their female relatives. This led them to suggest both X-linked dominant
and autosomal dominant inheritance as possibilities. Rivier and Echenne
(1992) described a mother and her 2 daughters with this disorder. Slowly
progressive improvement of motor abilities in all 3 patients was an
unusual feature. Imamura et al. (1993) described a mother and daughter
with early-onset nonprogressive cerebellar ataxia. The mother had a
broad-based unsteady gait with frequent falling dating from the first
years of life. She had cerebellar signs, including bilateral horizontal
nystagmus. MRI at the age of 29 demonstrated increased sulcation of the
cerebellar hemispheres and atrophic vermian lobules and hemispheric
folia, especially in the anterior part. The basal cistern was enlarged.
One of her 2 children, a daughter, was floppy from birth and at 8 months
also demonstrated delayed development and truncal ataxia. Cerebellar
atrophy, which could not be detected by CT at the age of 12 months, was
clearly discernible by MRI at the age of 3. Male-to-male transmission
was reported by Kornberg and Shield (1991). A preponderance of female
patients seems to have been observed.

*FIELD* RF
1. Fenichel, G. M.; Phillips, J. A.: Familial aplasia of the cerebellar
vermis: possible X-linked dominant inheritance. Arch. Neurol. 46:
582-583, 1989.

2. Furman, J. M.; Baloh, R. W.; Chugani, H.; Waluch, V.; Bradley,
W. G.: Infantile cerebellar atrophy. Ann. Neurol. 17: 399-402,
1985.

3. Imamura, S.; Tachi, N.; Oya, K.: Dominantly inherited early-onset
non-progressive cerebellar ataxia syndrome. Brain Dev. 15: 372-376,
1993.

4. Kattah, J. C.; Kolsky, M. P.; Guy, J.; O'Doherty, D.: Primary
position vertical nystagmus and cerebellar ataxia. Arch. Neurol. 40:
310-314, 1983.

5. Kornberg, A. J.; Shield, L. K.: An extended phenotype of an early-onset
inherited nonprogressive cerebellar ataxia syndrome. J. Child Neurol. 6:
20-23, 1991.

6. Rivier, F.; Echenne, B.: Dominantly inherited hypoplasia of the
vermis. Neuropediatrics 23: 206-208, 1992.

7. Tomiwa, K.; Baraitser, M.; Wilson, J.: Dominantly inherited congenital
cerebellar ataxia with atrophy of the vermis. Pediat. Neurol. 3:
360-362, 1987.

*FIELD* CS

Neuro:
   Congenital nonprogressive ataxia;
   Neonatal hypotonia;
   Clumsiness;
   Dysmetria

Eyes:
   Oscillopsia;
   Visual blurring;
   Upbeating nystagmus;
   Gaze-provoked horizontal nystagmus

Misc:
   Preponderance of affected females

Radiology:
   MRI shows hypoplasia or partial aplasia of cerebellar vermis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 7/7/1989

*FIELD* ED
mimadm: 6/25/1994
carol: 12/20/1993
carol: 12/13/1993
carol: 11/9/1992
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
117400
*FIELD* TI
*117400 CEREBELLOPARENCHYMAL DISORDER I; CPD I
CEREBELLOOLIVARY ATROPHY
*FIELD* TX
The disorders involving primarily the cerebellar parenchyma have been
classed into six forms by Weiner and Konigsmark (1971). It is their
classification which is followed here. CPD I is characterized by late
onset (fifth or sixth decade), with unsteadiness of gait and speech
difficulties and progressive dementia. Pathologically there is marked
loss of Purkinje cells, especially in the superior cerebellum.
Preservation of the pontine nuclei and fibers distinguish it from the
olivopontocerebellar atrophies of which five types are described
elsewhere. Affected families have been described by Hall et al. (1941),
Richter (1950), Weber and Greenfield (1942), and others.

Subramony et al. (1996) described a family segregating late-onset
progressive cerebellar ataxia with onset of gait difficulties at age 50.
There was no pontine atrophy at autopsy nor was there evidence of
hypogonadism. The segregation appeared to be autosomal dominant with
multiple instances of male-to-male transmission. Direct DNA analysis
excluded expansions at the SCA1 (164400), Machado-Joseph (109150), and
DRPLA (125370) loci.

*FIELD* SA
Hoffman et al. (1971)
*FIELD* RF
1. Hall, B.; Noad, K. B.; Latham, O.: Familial cortical cerebellar
atrophy. Brain 64: 178-194, 1941.

2. Hoffman, P. M.; Stuart, W. H.; Earle, K. M.; Brody, J. A.: Hereditary
late-onset cerebellar degeneration. Neurology 21: 771-777, 1971.

3. Richter, R. B.: Late cortical cerebellar atrophy: a form of hereditary
cerebellar ataxia. Am. J. Hum. Genet. 2: 1-29, 1950.

4. Subramony, S. H.; Fratkin, J. D.; Manyam, B. V.; Currier, R. D.
: Dominantly inherited cerebello-olivary atrophy is not due to a mutation
at the spinocerebellar ataxia-I, Machado-Joseph disease, or dentato-rubro-pallido-luysian
atrophy locus. Movement Disorders 11: 174-180, 1996.

5. Weber, F. P.; Greenfield, J. G.: Cerebello-olivary degeneration:
an example of heredo-familial incidence. Brain 65: 220-231, 1942.

6. Weiner, L. P.; Konigsmark, B. W.: Hereditary disease of the cerebellar
parenchyma. Birth Defects Orig. Art. Ser. VII(1): 192-196, 1971.

*FIELD* CS

Neuro:
   Ataxia;
   Unsteady gait;
   Dysarthria;
   Dementia

Misc:
   Late onset (fifth or sixth decade)

Lab:
   Marked loss of Purkinje cells, esp. in superior cerebellum;
   Preservation of the pontine nuclei and fibers

Inheritance:
   Autosomal Dominant

*FIELD* CN
Orest Hurko - updated: 05/08/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 05/08/1996
terry: 5/3/1996
mimadm: 6/25/1994
carol: 3/11/1993
supermim: 3/16/1992
carol: 2/21/1992
carol: 8/8/1991
carol: 8/24/1990

*RECORD*
*FIELD* NO
117550
*FIELD* TI
*117550 CEREBRAL GIGANTISM
SOTOS SYNDROME
*FIELD* TX
Sotos et al. (1964) described 5 children with a disorder characterized
by excessively rapid growth, acromegalic features, and a nonprogressive
cerebral disorder with mental retardation. High-arched palate and
prominent jaw were noted in several of them. Birth length was between
the 90th and 97th centiles in all. Bone age was advanced in most of
them.

Except for a concordant set of identical twins (Hook and Reynolds,
1967), most cases have been sporadic. (I observed the case of an
affected boy whose father, not available for study, was described as
having similar features.) The reported cases may represent new dominant
mutations. Large hands and feet are present from birth. Growth is rapid
in the first years of life but final height may not be excessive. Bone
age is advanced. The skull is large with moderate prognathism. Mild
dilation of the cerebral ventricles, nonspecific EEG changes, and
seizures have been observed. Poor coordination and mental retardation
are features. The differential diagnosis should include the XYY
syndrome. In 2 patients, Bejar et al. (1970) found abnormal
dermatoglyphics, normal growth hormone levels, and high levels of
valine, isoleucine and leucine in the blood. The glycine-to-valine ratio
seemed particularly useful in distinguishing patients from controls.
Hooft et al. (1968) described cerebral gigantism in 2 first cousins.
Nevo et al. (1974) described affected brother and sister and their
affected double first cousin, in an inbred Arab family in Israel. Two of
the 3 showed generalized edema and flexion contractures of the feet at
birth. This may represent a distinct disorder; see Nevo syndrome
(601451).

Hansen and Friis (1976) described affected mother and child. Zonana et
al. (1976) described affected mother and 2 children (male and female).
The mother's father may have been affected. Rosenbaum (1977) showed me
mother and infant daughter with cerebral gigantism. The mother had a
master's degree in education, exostoses of the alveolar ridges, and size
11 shoes. Both mother and daughter showed early eruption of teeth.
Zonana et al. (1977) reported 3 families showing vertical transmission
and equal severity in males and females; no male-to-male transmission
was observed. As an addendum, they commented on a fourth instance of
affected mother and son.

Ruvalcaba et al. (1980) found hamartomatous polyps of the intestine and
melanin spots of the penis in 2 males with the Sotos syndrome. Smith et
al. (1981) observed affected mother and daughter--the presumed fifth
instance of dominant inheritance. The mother had primary hypothyroidism
due to Hashimoto disease. Halal (1982) reported a family in which the
father and 2 of his sons were affected. She knew of no other instance of
documented male-to-male transmission. Halal (1983) reported that the
older of the boys she reported with cerebral gigantism had pigmented
spots on the genitalia and that the father had been found to have a
rectal polyp--findings like those in 2 unrelated adult males reported by
Ruvalcaba et al. (1980). Presumed Sotos syndrome was described in a
mother and 2 daughters by Bale et al. (1985). They suggested that
instances of seemingly autosomal recessive inheritance may be examples
of incomplete penetrance, gonadal mosaicism, or genetic heterogeneity.

In a study of the metacarpophalangeal pattern profile in Sotos syndrome,
Butler et al. (1985) found no evidence of heterogeneity and developed a
diagnostic tool they suggested may be useful. Winship (1985) described a
'Cape Coloured' family with affected father and 4 children by 2
different, unrelated wives. Kaneko et al. (1987) found congenital heart
defects in 5 of 10 patients with typical Sotos syndrome. Goldstein et
al. (1988) described 2 unrelated children with macrocephaly, excessive
growth, strabismus, hypotonia and developmental delay, and improvement
with age. Minor changes in the mother of each infant suggested dominant
inheritance of a Sotos sequence. Fryns (1988) referred to cases of the
fragile X syndrome (309550) in which Sotos syndrome had been diagnosed;
he therefore suggested that this disorder be designated the Sotos
sequence or the mental retardation-overgrowth sequence. Nance et al.
(1990) described a 15-month-old child with Sotos syndrome and a
paraspinal neuroblastoma. From this and other evidence, they concluded
that children with this disorder may be at an increased risk for
developing tumors.

In a review, Cole and Hughes (1990) emphasized that the handicaps in
Sotos syndrome are fewer than previously believed and tend to improve
with age. The latter feature makes identification of affected adults
difficult. Cole and Hughes (1994) clinically assessed 79 patients with a
provisional diagnosis of Sotos syndrome and evaluated their photographs
between ages 1 and 6 years. These photographs, together with photographs
of first-degree relatives, also at ages 1 to 6 years, were reviewed by 4
clinical geneticists. In 41 probands, but no first-degree relatives, the
facial gestalt was thought to be characteristic of Sotos syndrome.
Comparison of anthropometric measurements, bone age, and developmental
delay in these 41 probands showed marked differences between them and
the remaining 38 probands. Length was identified as the most
significantly increased prenatal parameter. In childhood,
occipitofrontal head circumference (OFC), height, and weight were all
increased. OFC remained above the 97th percentile in all but one case
throughout childhood and adulthood, whereas height and weight had a
tendency to return toward the mean. This 'normalization' was more
pronounced in females and was probably related to their early puberty.
Early developmental delay and an advanced bone age were seen in 100% and
84% of cases, respectively. Cole and Hughes (1994) suggested that facial
gestalt, growth pattern, bone age, and developmental delay are the major
diagnostic criteria. Using these criteria, no affected first-degree
relatives were identified.

Scarpa et al. (1994) described a sister and brother with macrocrania and
coarse face (frontal bossing, highly arched palate, prognathism, pointed
chin, large ears). Psychomotor development of the sister, who also had
advanced osseous maturation, improved significantly at the age of 7
years. Accelerated growth with normal bone age, optic atrophy, renal
agenesis with contralateral double kidney, and significant mental
retardation (IQ, 45) were shown in the brother at 3.5 years of age. The
father of these children was tall, with macrocrania and large hands and
feet. He had had learning difficulties in school and was a manual
laborer. Scarpa et al. (1994) suggested that these children and their
father showed different manifestations of Sotos syndrome.

Schrander-Stumpel et al. (1990) described a 6-year-old boy with Sotos
syndrome who also had a de novo, apparently balanced translocation,
t(3;6)(p21;p21). They suggested that the autosomal dominant gene for the
Sotos syndrome may be located either at 3p21 or 6p21. Tsukahara and
Kajii (1991) could find no abnormality in high resolution-banded
chromosomes from 5 patients. Involvement of genes at 3p21 was also
suggested by the case reported by Cole et al. (1992); a 22-year-old
female with Sotos syndrome, a nonsmoker, died of small cell lung
carcinoma (182280) for which genetic determinants in the 3p21 region are
suggested by loss-of-heterozygosity studies. Maroun et al. (1994)
reported the case of a 4-year-old girl with Sotos phenotype and a de
novo balanced translocation between 5q and 15q: 46,XX,t(5,15)(q35;q22).
They thus suggested 5q35 or 15q22 as the site of an autosomal dominant
gene determining Sotos syndrome.

Allanson and Cole (1996) presented anthropometric evaluation of the head
in 45 patients with Sotos syndrome between age 1 and 25 years. With
increasing age, the face lengthens and the chin becomes more striking.

The possibility of uniparental disomy in Sotos syndrome was investigated
by Smith et al. (1997). Using 112 dinucleotide repeat DNA polymorphisms,
they examined parental inheritance of all autosomal pairs, except
chromosome 15, in 29 patients with Sotos syndrome. All informative cases
showed biparental inheritance and no cases of UPD were found.

*FIELD* SA
Boman and Nilsson (1980); Dodge et al. (1983); Stephenson et al. (1968)
*FIELD* RF
1. Allanson, J. E.; Cole, T. R. P.: Sotos syndrome: evolution of
facial phenotype subjective and objective assessment. Am. J. Med.
Genet. 65: 13-20, 1996.

2. Bale, A. E.; Drum, M. A.; Parry, D. M.; Mulvihill, J. J.: Familial
Sotos syndrome (cerebral gigantism): craniofacial and psychological
characteristics. Am. J. Med. Genet. 20: 613-624, 1985.

3. Bejar, R. L.; Smith, G. F.; Park, S.; Spellacy, W. N.; Wolfson,
S. L.; Nyhan, W. L.: Cerebral gigantism: concentrations of amino
acids in plasma and muscle. J. Pediat. 76: 105-111, 1970.

4. Boman, H.; Nilsson, D.: Sotos syndrome in two brothers. Clin.
Genet. 18: 421-427, 1980.

5. Butler, M. G.; Meaney, F. J.; Kittur, S.; Hersh, J. H.; Hornstein,
L.: Metacarpophalangeal pattern profile analysis in Sotos syndrome. Am.
J. Med. Genet. 20: 625-629, 1985.

6. Cole, T. R. P.; Hughes, H. E.: Sotos syndrome: a study of the
diagnostic criteria and natural history. J. Med. Genet. 31: 20-32,
1994.

7. Cole, T. R. P.; Hughes, H. E.: Sotos syndrome. J. Med. Genet. 27:
571-576, 1990.

8. Cole, T. R. P.; Hughes, H. E.; Jeffreys, M. J.; Williams, G. T.;
Arnold, M. M.: Small cell lung carcinoma in a patient with Sotos
syndrome: are genes at 3p21 involved in both conditions?. J. Med.
Genet. 29: 338-341, 1992.

9. Dodge, P. R.; Homes, S. J.; Sotos, J. F.: Cerebral gigantism. Dev.
Med. Child Neurol. 25: 248-252, 1983.

10. Fryns, J. P.: The Prader-Willi syndrome and the Sotos syndrome:
syndromes or sequences? (Letter) Clin. Genet. 33: 457-458, 1988.

11. Goldstein, D. J.; Ward, R. E.; Moore, E.; Fremion, A. S.; Wappner,
R. S.: Overgrowth, congenital hypotonia, nystagmus, strabismus, and
mental retardation: variant of dominantly inherited Sotos sequence?. Am.
J. Med. Genet. 29: 783-792, 1988.

12. Halal, F.: Cerebral gigantism, intestinal polyposis, and pigmentary
spotting of the genitalia. (Letter) Am. J. Med. Genet. 15: 161,
1983.

13. Halal, F.: Male to male transmission of cerebral gigantism. Am.
J. Med. Genet. 12: 411-419, 1982.

14. Hansen, F. J.; Friis, B.: Familial occurrence of cerebral gigantism,
Sotos' syndrome. Acta Paediat. Scand. 65: 387-389, 1976.

15. Hooft, C.; Schotte, H.; Van Hooren, G.: Familial cerebral gigantism. Acta
Paediat. Belg. 22: 173-186, 1968.

16. Hook, E. B.; Reynolds, J. W.: Cerebral gigantism: endocrinological
and clinical observations of six patients including a congenital giant,
concordant monozygotic twins, and a child who achieved adult gigantic
size. J. Pediat. 70: 900-914, 1967.

17. Kaneko, H.; Tsukahara, M.; Tachibana, H.; Kurashige, H.; Kuwano,
A.; Kajii, T.: Congenital heart defects in Sotos sequence. Am. J.
Med. Genet. 26: 569-576, 1987.

18. Maroun, C.; Schmerler, S.; Hutcheon, R. G.: Child with Sotos
phenotype and a 5:15 translocation. Am. J. Med. Genet. 50: 291-293,
1994.

19. Nance, M. A.; Neglia, J. P.; Talwar, D.; Berry, S. A.: Neuroblastoma
in a patient with Sotos' syndrome. J. Med. Genet. 27: 130-132, 1990.

20. Nevo, S.; Zeltzer, M.; Benderly, A.; Levy, J.: Evidence for autosomal
recessive inheritance in cerebral gigantism. J. Med. Genet. 11:
158-165, 1974.

21. Rosenbaum, K. N.: Personal Communication. Baltimore, Md.  1977.

22. Ruvalcaba, R. H. A.; Myhre, S.; Smith, D. W.: Sotos syndrome
with intestinal polyposis and pigmentary changes of the genitalia. Clin.
Genet. 18: 413-416, 1980.

23. Scarpa, P.; Faggioli, R.; Voghenzi, A.: Familial Sotos syndrome:
longitudinal study of two additional cases. Genet. Counsel. 5: 155-159,
1994.

24. Schrander-Stumpel, C. T. R. M.; Fryns, J. P.; Hamers, G. G.:
Sotos syndrome and de novo balanced autosomal translocation (t(3;6)(p21;p21)). Clin.
Genet. 37: 226-229, 1990.

25. Smith, A.; Farrar, J. R.; Silink, M.; Judzewitsch, R.: Investigations
in dominant Sotos syndrome. Ann. Genet. 24: 226-228, 1981.

26. Smith, M.; Fullwood, P.; Qi, Y.; Palmer, S.; Upadhyaya, M.; Cole,
T.: No evidence for uniparental disomy as a common cause of Sotos
syndrome. J. Med. Genet. 34: 10-12, 1997.

27. Sotos, J. F.; Dodge, P. R.; Muirhead, D.; Crawford, J. D.; Talbot,
N. B.: Cerebral gigantism in childhood: a syndrome of excessively
rapid growth with acromegalic features and a nonprogressive neurologic
disorder. New Eng. J. Med. 271: 109-116, 1964.

28. Stephenson, J. N.; Mellinger, R. C.; Manson, G.: Cerebral gigantism. Pediatrics 41:
130-138, 1968.

29. Tsukahara, M.; Kajii, T.: High resolution-banded chromosomes
from patients with Sotos syndrome. (Letter) Clin. Genet. 39: 313-314,
1991.

30. Winship, I. M.: Sotos syndrome--autosomal dominant inheritance
substantiated. Clin. Genet. 28: 243-246, 1985.

31. Zonana, J.; Rimoin, D. L.; Fisher, D. A.: Cerebral gigantism--apparent
dominant inheritance. Birth Defects Orig. Art. Ser. XII(6): 63-69,
1976.

32. Zonana, J.; Sotos, J. F.; Romshe, C. A.; Fisher, D. A.; Elders,
M. J.; Rimoin, D. L.: Dominant inheritance of cerebral gigantism. J.
Pediat. 91: 251-256, 1977.

*FIELD* CS

Growth:
   Large hands and feet at birth;
   Rapid early growth;
   Excessive growth;
   Arm span greater than height

Head:
   Macrocephaly;
   Dolichocephaly

Facies:
   Moderate prognathism;
   Prominent forehead

Eyes:
   Strabismus;
   Hypertelorism;
   Downslanting palpebral fissures

Mouth:
   Alveolar ridge exostoses;
   High arched palate

Teeth:
   Early eruption of teeth

Neuro:
   Seizures;
   Poor coordination;
   Mental retardation;
   Neonatal hypotonia;
   Developmental delay

Skin:
   Abnormal dermatoglyphics;
   Neonatal generalized edema

Limbs:
   Congenital foot flexion contractures

Cardiac:
   Congenital heart defect

Oncology:
   Increased risk for tumors

Endocrine:
   Hyperthyroidism;
   Hypothyroidism

Misc:
   Most cases sporadic

Radiology:
   Advanced bone age;
   Mild dilation of the cerebral ventricles

Lab:
   Nonspecific EEG changes;
   Normal growth hormone levels;
   High blood valine, isoleucine and leucine

Inheritance:
   Autosomal Dominant

*FIELD* CN
Victor A. McKusick: 04/01/1997
Iosif W. Lurie - updated: 7/15/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/01/1997
terry: 3/20/1997
jamie: 1/7/1997
jamie: 1/6/1997
carol: 9/27/1996
carol: 8/22/1996
marlene: 8/2/1996
terry: 8/1/1996
carol: 7/15/1996
mark: 3/14/1996
terry: 2/29/1996
davew: 8/17/1994
mimadm: 6/25/1994
carol: 5/31/1994
warfield: 4/7/1994
carol: 6/23/1992
carol: 3/31/1992

*RECORD*
*FIELD* NO
117600
*FIELD* TI
117600 CEREBRAL SARCOMA
*FIELD* TX
In 2 families Gainer et al. (1975) observed 4 cases of cerebral
fibrosarcoma (father and daughter; 2 sisters).

*FIELD* RF
1. Gainer, J. V., Jr.; Chou, S. M.; Chadduck, W. M.: Familial cerebral
sarcomas. Arch. Neurol. 32: 665-669, 1975.

*FIELD* CS

Oncology:
   Cerebral fibrosarcoma

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
117650
*FIELD* TI
117650 CEREBROCOSTOMANDIBULAR SYNDROME
CCM SYNDROME; CCMS;;
RIB GAP DEFECTS WITH MICROGNATHIA
*FIELD* TX
In a female and 2 male sibs, McNicholl et al. (1970) described a
syndrome of mental retardation, palatal defects (short hard palate with
central hole, absent soft palate, absent uvula), micrognathia,
glossoptosis, and severe costovertebral abnormalities. A barking cough
in one suggested tracheal cartilage abnormality as in the case of Smith
et al. (1966) which bore other similarities. In the family reported by
McNicholl et al. (1970), the normal father and mother were 40 and 33,
respectively, at the birth of the first affected child. The condition
has also been designated 'rib gap defects with micrognathia' (Miller et
al., 1972). The 'gaps' occur in the posterior portion of the ribs and
may lead to 'flail chest.' Silverman et al. (1980) gave an extensive
review of 22 cases. They pointed out that familial cases are seemingly
unusual and stated that 'the possibility exists that some teratogenic
agent has played a role in the clustering of cases since 1963...' Cleft
palate and glossoptosis often contribute to the presenting sign,
neonatal respiratory distress. Intrauterine and postnatal growth
retardation are common. Deficiency in the posterior portion of affected
ribs by roentgenography is a sine qua non for diagnosis. Leroy et al.
(1981) provided the first evidence of dominant inheritance; a mother and
her son and daughter (by different fathers) were affected. The 3
patients were intellectually normal, but indistinct speech was commented
on. The authors suggested that mental defect may not be inherent to CCMS
but rather a frequent consequence of neonatal respiratory distress.
Schroer and Meyer (1985) reported an isolated case in a 15-year-old
girl. Hennekam et al. (1985) reported 2 affected brothers who also had
spina bifida. Trautman et al. (1985) reported CCMS in the sib of a
patient reported by Silverman et al. (1980). This observation lends
support to autosomal recessive inheritance. Drossou-Agakidou et al.
(1991) described a sibship with 2 sets of dizygotic twins with CCMS. All
4 had Pierre-Robin anomalad and rib dysplasia. Cerebral involvement was
evident in 2 who had had perinatal asphyxia.

Plotz et al. (1996) described 2 more sporadic cases of this syndrome in
males, one of whom died at 12 hours and the another at 10 months. A
detailed review of 48 previously reported cases showed that respiratory
distress, gaps of posterior ribs, and micrognathia are virtually
constant manifestations. Males were affected in 28 of 47 cases.
Approximately two-thirds of patients had cleft palate and glossoptosis.
Microcephaly was found in 11 of 28 cases. Defects of the heart and
kidneys were uncommon.

Merlob et al. (1987) described affected father and daughter. Prenatal
diagnosis was made by ultrasonography in the case of the daughter. The
most prominent ultrasonographic sign was the unusual shape of the ribs,
which were very short and defective. The diagnosis can be confirmed in
utero by ultrasound examination of the fetal mandible and head.

*FIELD* SA
Faure et al. (1978); Kuhn et al. (1975); Tachibana et al. (1980)
*FIELD* RF
1. Drossou-Agakidou, V.; Andreou, A.; Soubassi-Griva, V.; Pandouraki,
M.: Cerebrocostomandibular syndrome in four sibs, two pairs of twins.
J. Med. Genet. 28: 704-707, 1991.

2. Faure, C.; Valleur, D.; Vital, J.-L.: Le syndrome cerebro-costo-mandibulaire:
trois nouvelles observations. Nouv. Presse Med. 7: 445-448, 1978.

3. Hennekam, R. C. M.; Beemer, F. A.; Huijbers, W. A. R.; Hustinx,
P. A.; van Sprang, F. J.: The cerebro-costo-mandibular syndrome:
third report of familial occurrence. Clin. Genet. 28: 118-121,
1985.

4. Kuhn, J. P.; Lee, S. B.; Jockin, H.; Wieder, W.: Cerebro-costo-mandibular
syndrome--case with cardiac anomaly. J. Pediat. 86: 243-244, 1975.

5. Leroy, J. G.; Devos, E. A.; Vanden Bulcke, L. J.; Robbe, N. S.
: Cerebro-costo-mandibular syndrome with autosomal dominant inheritance.
J. Pediat. 99: 441-443, 1981.

6. McNicholl, B.; Egan-Mitchell, B.; Murray, J. P.; Doyle, J. F.;
Kennedy, J. D.; Crome, L.: Cerebro-costo-mandibular syndrome: a new
familial developmental disorder. Arch. Dis. Child. 45: 421-424,
1970.

7. Merlob, P.; Schonfeld, A.; Grunebaum, A.; Mor, N.; Reisner, S.
H.: Autosomal dominant cerebro-costo-mandibular syndrome: ultrasonographic
and clinical findings. Am. J. Med. Genet. 26: 195-202, 1987.

8. Miller, K. E.; Allen, R. P.; Davis, W. S.: Rib gap defects with
micrognathia. Am. J. Roentgen. 114: 253-256, 1972.

9. Plotz, F. B.; van Essen, A. J.; Bosschaart, A. N.; Bos, A. P.:
Cerebro-costo-mandibular syndrome. Am. J. Med. Genet. 62: 286-292,
1996.

10. Schroer, R. J.; Meyer, L. C.: Cerebro-costo-mandibular syndrome.
Proc. Greenwood Genet. Center 4: 55-59, 1985.

11. Silverman, F. N.; Strefling, A. M.; Stevenson, D. K.; Lazarus,
J.: Cerebro-costo-mandibular syndrome. J. Pediat. 97: 406-416,
1980.

12. Smith, D. W.; Theiler, K.; Schachenmann, G.: Rib-gap defect with
micrognathia, malformed tracheal cartilages, and redundant skin: a
new pattern of defective development. J. Pediat. 69: 799-803, 1966.

13. Tachibana, K.; Yamamoto, Y.; Osaki, E.; Kuroki, Y.: Cerebro-costo-mandibular
syndrome: a case report and review of the literature. Hum. Genet. 54:
283-286, 1980.

14. Trautman, M. S.; Schelley, S. L.; Stevenson, D. K.: Cerebro-costo-mandibular
syndrome: a familial case consistent with autosomal recessive inheritance.
(Letter) J. Pediat. 107: 990-991, 1985.

*FIELD* CS

Thorax:
   Posterior rib gap defects;
   Flail chest

Mouth:
   Micrognathia;
   Short hard palate with central defect;
   Absent soft palate;
   Absent uvula;
   Glossoptosis

Skel:
   Costovertebral abnormalities

Neuro:
   Mental retardation

Resp:
   Neonatal respiratory distress

Growth:
   Intrauterine and postnatal growth retardation

Radiology:
   Deficiency in the posterior portion of affected ribs

Inheritance:
   Autosomal recessive vs. dominant

*FIELD* CN
Iosif W. Lurie - updated: 07/01/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 07/01/1996
mimadm: 6/25/1994
warfield: 4/6/1994
supermim: 3/16/1992
carol: 11/7/1991
carol: 10/2/1990
carol: 8/24/1990

*RECORD*
*FIELD* NO
117700
*FIELD* TI
*117700 CERULOPLASMIN; CP
HYPOCERULOPLASMINEMIA, INCLUDED;;
ACERULOPLASMINEMIA, INCLUDED
*FIELD* TX
At least 3 variants determined by codominant alleles have been
identified by starch gel electrophoresis (Shreffler et al., 1967).
Polymorphism has been found mainly in American blacks. Internal
duplication is a method of evolution of the genome illustrated by
ceruloplasmin (Dwulet and Putnam, 1981). From internal homology of amino
acid structure, Takahashi et al. (1983) concluded that the ceruloplasmin
molecule evolved by tandem triplication of ancestral genes. Like
transferrin (190000), ceruloplasmin is a plasma metalloprotein.
Ceruloplasmin (also known as ferroxidase; iron (II):oxygen
oxidoreductase, EC 1.16.3.1) is a blue alpha-2-glycoprotein that binds
90 to 95% of plasma copper and has 6 or 7 cupric ions per molecule.
Human ceruloplasmin is composed of a single polypeptide chain (Takahashi
et al., 1984). From a computer search of the protein and nucleic acid
sequence data banks of the National Biomedical Research Foundation,
Church et al. (1984) found evidence that factor V (227400), factor VIII
(306700), and ceruloplasmin may have had a common evolutionary origin.
Koschinsky et al. (1986) reported the nucleotide sequence of human
preceruloplasmin cDNA. The mRNA from human liver was found to be 3,700
nucleotides in size. Sequence homology with factor VIII was
demonstrated.

An abnormality of ceruloplasmin seems to be involved in Wilson disease
(277900); however, because there is reason to think that a locus other
than the polymorphic structural locus is involved, 2 separate asterisked
entries are included in the catalogs. Edwards et al. (1979) studied a
kindred in which 14 members in an autosomal dominant pattern had low
serum ceruloplasmin and low serum copper without the abnormalities of
Wilson disease. A physician, who had been followed for over 25 years
with low values, had remained completely well. Miyajima et al. (1987)
described a 52-year-old woman with familial hypoceruloplasminemia,
blepharospasm, retinal degeneration, and high density areas in the basal
ganglia and liver by CT scan. Studies showed accumulation of iron, not
copper, in liver and brain. Ceruloplasmin is involved in peroxidation of
Fe(II) transferrin to form Fe(III) transferrin. Blepharospasm has been
related to abnormality of the basal ganglia, as in
blepharospasm-oromandibular dystonia (Meige syndrome); see Casey (1980)
and Tanner et al. (1982).

Logan et al. (1994) reported the cases of 2 brothers with complete
ceruloplasmin deficiency. Both brothers presented in their late forties
with dementia and diabetes mellitus. Twelve relatives had partial
ceruloplasmin deficiency. There was no copper overload. Transmission of
the abnormality was autosomal recessive. DNA analysis showed genetic
linkage between the deficiency and various polymorphic markers flanking
the ceruloplasmin gene on 3q25. Ceruloplasmin catalyzes the oxidation of
ferrous iron to ferric iron. Both brothers had low serum iron and
increased liver iron. The index patient was given
ceruloplasmin-containing, fresh-frozen plasma, resulting in an increase
in serum iron that was dose dependent. Harris et al. (1996) described a
novel mutation in the ceruloplasmin gene in these 2 brothers
(117700.0004).

Morita et al. (1992) described a 55-year-old patient with complete
ceruloplasmin deficiency who presented with dementia, diabetes,
torticollis, chorea, and ataxia. In the Japanese family reported by
Morita et al. (1992), Yoshida et al. (1995) demonstrated a mutation in
the ceruloplasmin gene in 4 sibs with aceruloplasminemia, 3 of whom
showed extrapyramidal disorders, cerebellar ataxia, and diabetes
mellitus. A postmortem study of the proband demonstrated excessive iron
deposition, mainly in the brain, liver, and pancreas. In a patient with
hereditary ceruloplasmin deficiency, Okamoto et al. (1996) reported a
novel mutation, i.e., an insertion of adenine at amino acid 184 produced
a premature stop codon. They reviewed the findings in 4 pedigrees with
this condition and noted that consanguinity occurred in 3 of the 4
pedigrees. Clinical manifestations, which occurred after middle age,
included extrapyramidal signs, cerebellar ataxia, dementia, and memory
loss. Neuroimaging studies revealed iron deposition in the basal ganglia
and in the red and dentate nuclei. Diagnostic laboratory findings
included deficiency of ceruloplasmin, low serum iron, and high serum
ferritin. The hepatic iron content was high, but cirrhosis was not
usually present.

Klomp and Gitlin (1996) analyzed ceruloplasmin gene expression in the
brain. In situ hybridization utilizing ceruloplasmin cDNA clones
revealed abundant expression in specific populations of glial cells
within the brain microvasculature, surrounding dopaminergic melanized
neurons in the substantia nigra, and within the inner nuclear layer of
the retina. Klomp and Gitlin (1996) concluded that glial-cell specific
ceruloplasmin gene expression is essential for iron homeostasis and
neuronal survival in the human central nervous system.

Weitkamp (1983) found a peak lod score of 3.5 at theta about 0.15 for
linkage of CP to TF, which is located at 3q21. Homology argues for this
linkage; TF and CP are linked in cattle with lod score of 11.3 at 20%
recombination frequency in sires (Larsen, 1977). By Southern blot
analysis of human-mouse somatic cell hybrids, Naylor et al. (1985)
mapped the CP gene to chromosome 3. Royle et al. (1987) localized the CP
gene to 3q21-24 by analysis of somatic cell hybrid DNAs and in situ
hybridization. Riddell et al. (1987) identified a ceruloplasmin
pseudogene on chromosome 8. Koschinsky et al. (1987) isolated a
processed gene for human ceruloplasmin and mapped it to chromosome 8 by
somatic cell hybridization. Wang et al. (1988) localized the processed
pseudogene further to 8q21.13-q23.1 by in situ hybridization. They
pointed out that like all other processed pseudogenes described to date,
the gene is located on a chromosome different from the parent gene. Yang
et al. (1990) demonstrated 2 forms of CP which differed by the presence
or absence of 12 nucleotide bases encoding a deduced sequence of
gly-glu-tyr-pro in the carboxyl-terminal region of the molecule.
Alternative splicing was the apparent explanation and differential
expression of the 2 transcripts in different tissues with production of
isoforms from a single gene was demonstrated.

Daimon et al. (1995) cloned the ceruloplasmin gene, which spans
approximately 50 kb and is composed of 19 exons and 18 introns.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA
CP, IVSAS, G-A, -1
In the family with hypo- or aceruloplasminemia reported by Morita et al.
(1992), Yoshida et al. (1995) demonstrated a G-to-A transition at the
splice acceptor site, converting the canonical AG to AA immediately
before the exon beginning with nucleotide 3019 of the cDNA. The parents
were first cousins, thus indicating autosomal recessive inheritance,
which was supported by the demonstration of homozygosity in the affected
sibs. In this disorder, there is no copper overload. One of the 4
aceruloplasmic sibs was free of neurologic symptoms although he showed
iron deposition. The proband from whom information on the distribution
of iron deposits in the brain, liver, pancreas, heart, kidney, spleen,
and thyroid gland was obtained had died at the age of 60 years, having
shown dementia in the advanced stages of his disorder.

.0002
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA
CP, 5-BP INS, FS446TER
After the cloning of the Wilson disease gene, Harris et al. (1995)
investigated a number of patients referred for molecular diagnosis with
neurologic degeneration and low serum ceruloplasmin. In the course of
this analysis, they recognized several patients who did not have Wilson
disease. One such patient identified in Japan and reported as a case of
familial apoceruloplasmin deficiency (Miyajima et al., 1987) was found
to have a mutation in the CP gene. The patient was a Japanese woman, 61
years old at the time of study, who had had retinal degeneration and
blepharospasm for the previous 10 years. She had also developed cogwheel
rigidity and dysarthria. Her younger sister, who was asymptomatic at the
time of the original presentation despite undetectable CP, was 51 years
old and had recent onset of retinal degeneration and basal ganglia
symptoms. In each case, the absence of serum CP was associated with mild
anemia, low serum iron, and elevated serum ferritin. Magnetic resonance
imaging studies demonstrated changes in the basal ganglia suggestive of
elevated iron content in the brain. The patient's daughter was entirely
asymptomatic but had a serum CP concentration that was 50% of normal,
consistent with an obligate heterozygote. There was no consanguinity in
the family. Liver biopsy confirmed the presence of excess iron. Although
Southern blot analysis of the patient's DNA was normal, PCR
amplification of 18 of the 19 exons composing the CP gene revealed a
size difference in exon 7. Sequencing of this exon uncovered a 5-bp
insertion at amino acid 410, resulting in a frameshift mutation and a
truncated open reading frame after 445 amino acids. The patient's
daughter was heterozygous for the 5-bp insertion. The study by Harris et
al. (1995) demonstrated the essential role of ceruloplasmin in human
biology and identified aceruloplasminemia as an autosomal recessive
disorder of iron metabolism. The findings supported previous studies
that identified ceruloplasmin as a ferroxidase (Osaki et al., 1966) with
a role in the ferric iron uptake by transferrin. Consistent with this
concept, the anemia that develops in copper-deficient animals is
unresponsive to iron but is correctable by ceruloplasmin administration
(Lee et al., 1968). It is also consistent with the essential role of a
homologous copper oxidase in iron metabolism in yeast.

.0003
ACERULOPLASMINEMIA
CP, TRP858TER
Takahashi et al. (1996) reported a new ceruloplasmin mutation in a
kindred with aceruloplaminemia and expanded the information on the
clinical implications of the disorder. Their patient was a 45-year-old
woman who came to attention after a several-month history of difficulty
in walking and slurring of speech. She had previously been in excellent
health with the exception of insulin-dependent diabetes mellitus
beginning at age 31 years. Physical examination revealed ataxic gait,
scanning speech, and retinal degeneration. MRI of the brain was
consistent with increased basal ganglia iron content, and laboratory
studies revealed a low serum iron concentration and no detectable serum
ceruloplasmin. A G-to-A substitution in exon 15 resulted in a nonsense
mutation at amino acid 858 (trp858-to-ter). The patient's younger,
neurologically asymptomatic brother was also found to be homozygous for
this mutation. Thus, the authors found that aceruloplasminemia appears
to be a genetic cause of both diabetes and neurologic disease.

.0004
ACERULOPLASMINEMIA
CERULOPLASMIN BELFAST
CP, 1-BP DEL, FS789TER
In the 2 brothers reported by Harris et al. (1995), Harris et al. (1996)
found homozygosity for a single basepair deletion (2389G) in exon 13 of
the CP gene. The nucleotide sequence surrounded this deletion site
(TGGAGA) corresponded to a consensus sequence 'hotspot' for nucleotide
deletions (Krawczak and Cooper, 1991). The proband had been admitted to
hospital at the age of 49 years with a 6-week history of thirst and
polyuria and a 2-week history of progressive confusion. Neurologic
examination was normal. He was started on a diabetic diet and oral
sulphonylurea. At the age of 52, he suddenly left his work one day and
was found at home the next day sitting in a chair with the appearance of
not having been to bed. When asked why he was not at work he replied,
'What work?' Dementia progressed thereafter, confusion occurring
episodically. The younger brother, who worked as a railway laborer,
developed diabetes and mental slowing at the age of 47 years. The
symptoms seemed to have developed over a period of days and were
progressive thereafter. The abnormal ceruloplasmin in this case was
referred to as ceruloplasmin Belfast. The nucleotide deletion resulted
in a frameshift with change of 11 amino acids and a premature stop codon
at codon 789.

*FIELD* SA
Decker and Mohrenweiser (1978); Kellermann and Walter (1972); McCombs
and Bowman (1969); McCombs et al. (1970); Poulik  (1968); Schwartzman
et al. (1980); Shokeir and Shreffler (1970); Shokeir et al. (1967);
Stolc  (1984)
*FIELD* RF
1. Casey, D. E.: Pharmacology of blepharospasm-oromandibular dystonia
syndrome. Neurology 30: 690-695, 1980.

2. Church, W. R.; Jernigan, R. L.; Toole, J.; Hewick, R. M.; Knopf,
J.; Knutson, G. J.; Nesheim, M. E.; Mann, K. G.; Fass, D. N.: Coagulation
factors V and VIII and ceruloplasmin constitute a family of structurally
related proteins. Proc. Nat. Acad. Sci. 81: 6934-6937, 1984.

3. Daimon, M.; Yamatani, K.; Igarashi, M.; Fukase, N.; Kawanami, T.;
Kato, T.; Tominaga, M.; Sasaki, H.: Fine structure of the human ceruloplasmin
gene. Biochem. Biophys. Res. Commun. 208: 1028-1035, 1995.

4. Decker, R. S.; Mohrenweiser, H. W.: Identification of a new variant
of human ceruloplasmin. (Abstract) Am. J. Hum. Genet. 30: 26A, 1978.

5. Dwulet, F. E.; Putnam, F. W.: Internal duplication and evolution
of human ceruloplasmin. Proc. Nat. Acad. Sci. 78: 2805-2809, 1981.

6. Edwards, C. Q.; Williams, D. M.; Cartwright, G. E.: Hereditary
hypoceruloplasminemia. Clin. Genet. 15: 311-316, 1979.

7. Harris, Z. L.; Migas, M. C.; Hughes, A. E.; Logan, J. I.; Gitlin,
J. D.: Familial dementia due to a frameshift mutation in the caeruloplasmin
gene. Quart. J. Med. 89: 355-359, 1996.

8. Harris, Z. L.; Takahashi, Y.; Miyajima, H.; Serizawa, M.; MacGillivray,
R. T. A.; Gitlin, J. D.: Aceruloplasminemia: molecular characterization
of this disorder of iron metabolism. Proc. Nat. Acad. Sci. 92: 2539-2543,
1995.

9. Kellermann, G.; Walter, H.: On the population genetics of the
ceruloplasmin polymorphism. Humangenetik 15: 84-86, 1972.

10. Klomp, L. W. J.; Gitlin, J. D.: Expression of the ceruloplasmin
gene in the human retina and brain: implications for a pathogenic
model in aceruloplasminemia. Hum. Molec. Genet. 5: 1989-1996, 1996.

11. Koschinsky, M. L.; Chow, B. K.-C.; Schwartz, J.; Hamerton, J.
L.; MacGillivray, R. T. A.: Isolation and characterization of a processed
gene for human ceruloplasmin. Biochemistry 26: 7760-7767, 1987.

12. Koschinsky, M. L.; Funk, W. D.; van Oost, B. A.; MacGillivray,
R. T. A.: Complete cDNA sequence of human preceruloplasmin. Proc.
Nat. Acad. Sci. 83: 5086-5090, 1986.

13. Krawczak, M.; Cooper, D. N.: Gene deletions causing human genetic
disease: mechanisms of mutagenesis and the role of the local DNA sequence
environment. Hum. Genet. 86: 425-441, 1991.

14. Larsen, B.: On linkage relations of ceruloplasmin polymorphism
(Cp) in cattle. Animal Blood Groups Biochem. Genet. 8: 111-113,
1977.

15. Lee, G. R.; Nacht, S.; Lukens, J. N.; Cartwright, G. E.: Iron
metabolism in copper-deficient swine. J. Clin. Invest. 47: 2058-2069,
1968.

16. Logan, J. I.; Harveyson, K. B.; Wisdom, G. B.; Hughes, A. E.;
Archbold, G. P. R.: Hereditary caeruloplasmin deficiency, dementia
and diabetes mellitus. Quart. J. Med. 87: 663-670, 1994.

17. McCombs, M. L.; Bowman, B. H.: Demonstration of inherited ceruloplasmin
variants in human serum by acrylamide electrophoresis. Texas Rep.
Biol. Med. 27: 769-772, 1969.

18. McCombs, M. L.; Bowman, B. H.; Alperin, J. B.: A new ceruloplasmin
variant, CP Galveston. Clin. Genet. 1: 30-34, 1970.

19. Miyajima, H.; Nishimura, Y.; Mizoguchi, K.; Sakamoto, M.; Shimizu,
T.; Honda, N.: Familial apoceruloplasmin deficiency associated with
blepharospasm and retinal degeneration. Neurology 37: 761-767, 1987.

20. Morita, H.; Inoue, A.; Yanagisawa, N.: A case with ceruloplasmin
deficiency which showed dementia, ataxia and iron deposition in the
brain. Rinsho Shinkeigaku 32: 483-487, 1992.

21. Naylor, S. L.; Yang, F.; Cutshaw, S.; Barnett, D. R.; Bowman,
B. H.: Mapping ceruloplasmin cDNA to human chromosome 3. (Abstract) Cytogenet.
Cell Genet. 40: 711, 1985.

22. Okamoto, N.; Wada, S.; Oga, T.; Kawabata, Y.; Baba, Y.; Habu,
D.; Takeda, Z.; Wada, Y.: Hereditary ceruloplasmin deficiency with
hemosiderosis. Hum. Genet. 97: 755-758, 1996.

23. Osaki, S.; Johnson, D. A.; Frieden, E.: The possible significance
of the ferrous oxidase activity of ceruloplasmin in normal human serum. J.
Biol. Chem. 241: 2746-2751, 1966.

24. Poulik, M. D.: Heterogeneity and structure of ceruloplasmin. Ann.
N.Y. Acad. Sci. 151: 476-501, 1968.

25. Riddell, D. C.; Wang, H.; Royle, N. J.; Nigli, M.; Guinto, E.;
Kochinsky, M. L.; Irwin, D. M.; Cool, D.; MacGillivray, R. T. A.;
Hamerton, J. L.: Regional assignment for the human genes encoding
FII, FV, FXIII, ceruloplasmin and pseudoceruloplasmin. (Abstract) Cytogenet.
Cell Genet. 46: 682, 1987.

26. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

27. Royle, N. J.; Irwin, D. M.; Koschinsky, M. L.; MacGillivray, R.
T. A.; Hamerton, J. L.: Human genes encoding prothrombin and ceruloplasmin
map to 11p11-q12 and 3q21-24, respectively. Somat. Cell Molec. Genet. 13:
285-292, 1987.

28. Schwartzman, A. L.; Gaitskhoki, V. S.; L'vov, V. M.; Nosikov,
V. V.; Braga, E. M.; Frolova, L. Y.; Skobeleva, N. A.; Kisselev, L.
L.; Neifakh, S. A.: Complex molecular structure of the gene for rat
ceruloplasmin. Gene 11: 1-10, 1980.

29. Shokeir, M. H. K.; Shreffler, D. C.: Two new ceruloplasmin variants
in Negroes--data on three populations. Biochem. Genet. 4: 517-528,
1970.

30. Shokeir, M. H. K.; Shreffler, D. C.; Gall, J. C., Jr.: Further
electrophoretic variation in human ceruloplasmin.. (Abstract) Meeting,
Am. Soc. Hum. Genet., Toronto , 12/1/1967.

31. Shreffler, D. C.; Brewer, G. J.; Gall, J. C.; Honeyman, M. S.
: Electrophoretic variation in human serum ceruloplasmin: a new genetic
polymorphism. Biochem. Genet. 1: 101-116, 1967.

32. Stolc, V.: Genetic polymorphism of ceruloplasmin in the rat. J.
Hered. 75: 414-415, 1984.

33. Takahashi, N.; Bauman, R. A.; Ortel, T. L.; Dwulet, F. E.; Wang,
C.-C.; Putnam, F. W.: Internal triplication in the structure of human
ceruloplasmin. Proc. Nat. Acad. Sci. 80: 115-119, 1983.

34. Takahashi, N.; Ortel, T. L.; Putnam, F. W.: Single-chain structure
of human ceruloplasmin: the complete amino acid sequence of the whole
molecule. Proc. Nat. Acad. Sci. 81: 390-394, 1984.

35. Takahashi, Y.; Miyajima, H.; Shirabe, S.; Nagataki, S.; Suenaga,
A.; Gitlin, J. D.: Characterization of a nonsense mutation in the
ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum.
Molec. Genet. 5: 81-84, 1996.

36. Tanner, C. M.; Glantz, R. H.; Klawans, H. L.: Meige disease:
acute and chronic cholinergic effects. Neurology 32: 783-785, 1982.

37. Wang, H.; Koschinsky, M.; Hamerton, J. L.: Localization of the
processed gene for human ceruloplasmin to chromosome region 8q21.13-q23.1
by in situ hybridization. Cytogenet. Cell Genet. 47: 230-231, 1988.

38. Weitkamp, L. R.: Evidence for linkage between the loci for transferrin
and ceruloplasmin in man. Ann. Hum. Genet. 47: 293-297, 1983.

39. Yang, F.; Friedrichs, W. E.; Cupples, R. L.; Bonifacio, M. J.;
Sanford, J. A.; Horton, W. A.; Bowman, B. H.: Human ceruloplasmin:
tissue-specific expression of transcripts produced by alternative
splicing. J. Biol. Chem. 265: 10780-10785, 1990.

40. Yoshida, K.; Furihata, K.; Takeda, S.; Nakamura, A.; Yamamoto,
K.; Morita, H.; Hiyamuta, S.; Ikeda, S.; Shimizu, N.; Yanagisawa,
N.: A mutation in the ceruloplasmin gene is associated with systemic
hemosiderosis in humans. Nature Genet. 9: 267-272, 1995.

*FIELD* CS

Neuro:
   Wilson disease (277900);
   Basal ganglia signs;
   Dysarthria;
   Drooling;
   Ataxia;
   Tremor;
   Psychosis

Eyes:
   Blepharospasm;
   Retinal degeneration;
   Kaiser-Fleischer ring

Radiology:
   High density areas in the basal ganglia and liver by CT

Lab:
   Copper (or iron) accumulation in liver and brain;
   Low serum ceruloplasmin;
   Low serum copper

Inheritance:
   Autosomal Dominant (3q21-24);
   Wilson disease is recessive

*FIELD* CN
Moyra Smith - updated: 01/28/1997
Moyra Smith - updated: 5/12/1996
Alan F. Scott - updated: 6/26/1995

*FIELD* CD
Victor A. McKusick: 6/24/1986

*FIELD* ED
terry: 01/28/1997
mark: 1/27/1997
mark: 10/3/1996
terry: 9/9/1996
carol: 5/22/1996
carol: 5/12/1996
terry: 4/17/1996
mark: 3/7/1996
mark: 2/15/1996
terry: 2/8/1996
terry: 10/30/1995
mark: 3/17/1995
carol: 1/17/1995
mimadm: 6/25/1994
supermim: 3/16/1992

*RECORD*
*FIELD* NO
117800
*FIELD* TI
*117800 CERUMEN, VARIATION IN
*FIELD* TX
In Japanese, Matsunaga (1962) described a dimorphism of ear wax, the 2
types being wet and dry. This variation has been studied extensively in
Japan since at least 1934. Less attention has been given to this
variation elsewhere, probably because Caucasians and blacks have only
the wet type of cerumen. In 80 to 85% of Japanese, the cerumen is gray,
dry and brittle. It is referred to as 'rice-bran ear wax' in Japanese.
In the other Japanese, the cerumen is brown, sticky and wet. This is
referred to as 'honey ear wax,' 'oily ear wax' or 'cat ear wax.' In all
except about 0.5% of Japanese, classification is simple. Family studies
indicate monofactorial inheritance, with the rarer phenotype, wet wax,
being dominant. Wet cerumen is often associated with axillary odor,
which because of its rarity in Japan, is considered in the lay mind a
pathologic state requiring medical attention. Petrakis et al. (1967)
found a high frequency of dry cerumen in pure-blooded American Indians.
Ibraimov (1991) presented data on the high frequency of dry cerumen in
Mongoloid populations and low frequency among Europoids. Intermediate
frequencies were found among peoples of subequatorial Africa. No
qualitative differences in chemical composition have been identified
(Kataura and Kataura, 1967). Petrakis (1971) noted the positive
correlation between wet ear wax and breast cancer in several countries
and suggested an association. This hypothesis seems reasonable because
the ceruminous gland and breast are both apocrine and share biochemical
characteristics. Ing et al. (1973), in a study of Chinese women in Hong
Kong, could not confirm the association.

*FIELD* SA
Hyslop  (1971); Kataura and Kataura (1967); Martin and Jackson (1969);
Petrakis  (1977)
*FIELD* RF
1. Hyslop, N. E., Jr.: Ear wax and host defense.  (Editorial) New
Eng. J. Med. 284: 1099-1100, 1971.

2. Ibraimov, A. I.: Brief communication: cerumen phenotypes in certain
populations of Eurasia and Africa. Am. J. Phys. Anthrop. 84: 209-211,
1991.

3. Ing, R.; Petrakis, N. L.; Ho, H. C.: Evidence against association
between wet cerumen and breast cancer. Lancet I: 41 only, 1973.

4. Kataura, A.; Kataura, K.: The comparison of free and bound amino
acids between dry and wet types of cerumen. Tohoku J. Exp. Med. 91:
215-225, 1967.

5. Kataura, A.; Kataura, K.: The comparison of lipids between dry
and wet types of cerumen. Tohoku J. Exp. Med. 91: 227-237, 1967.

6. Martin, L. M.; Jackson, J. F.: Cerumen types in Choctaw Indians.
Science 163: 677-678, 1969.

7. Matsunaga, E.: The dimorphism in human normal cerumen. Ann.
Hum. Genet. 25: 273-286, 1962.

8. Petrakis, N. L.: Cerumen genetics and human breast cancer. Science 173:
347-349, 1971.

9. Petrakis, N. L.: Genetic cerumen type, breast secretory activity,
and breast cancer epidemiology. In: Mulvihill, J. J.; Miller, R. W.;
Fraumeni, J. F., Jr.: Genetics of Human Cancer.  New York: Raven
Press (pub.)  1977. Pp. 297-300.

10. Petrakis, N. L.; Molohan, K. T.; Tepper, D. J.: Cerumen in American
Indians: genetic implications of sticky and dry types. Science 158:
1192-1193, 1967.

*FIELD* CS

Ears:
   Ear wax types (wet and dry)

Oncology:
   Positive correlation between wet ear wax and breast cancer

Misc:
   Axillary odor association

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
warfield: 3/31/1994
carol: 4/10/1992
supermim: 3/16/1992
carol: 3/14/1991
carol: 3/13/1991

*RECORD*
*FIELD* NO
117850
*FIELD* TI
117850 CERVICAL HYPERTRICHOSIS WITH UNDERLYING KYPHOSCOLIOSIS
HYPERTRICHOSIS, POSTERIOR CERVICAL, WITH UNDERLYING KYPHOSCOLIOSIS
*FIELD* TX
Congenital localized hypertrichosis occurs most often over the spine,
usually in the sacral area, producing a 'faun tail.' Similar localized
hypertrichosis has been reported in the lumbar thoracic and cervical
regions; however, they represent important cutaneous markers of
underlying skeletal or neural abnormalities. Reed et al. (1989)
described a family in which members of 4 generations had cervical
hypertrichosis with underlying kyphoscoliosis. Although 3 males and 3
females were affected, there was no instance of male-to-male
transmission.

*FIELD* RF
1. Reed, O. M.; Mellette, J. R.; Fitzpatrick, J. E.: Familial cervical
hypertrichosis with underlying kyphoscoliosis. J. Am. Acad. Derm. 20:
1069-1072, 1989.

*FIELD* CS

Hair:
   Congenital cervical hypertrichosis;
   Sacral, lumbar, or thoracic localized hypertrichosis

Spine:
   Underlying kyphoscoliosis

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 7/13/1989

*FIELD* ED
mark: 3/28/1995
terry: 3/20/1995
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
117900
*FIELD* TI
117900 CERVICAL RIB
*FIELD* TX
Weston (1956) found cervical ribs or enlarged transverse processes in 14
of 20 members of a family. The anomaly was particularly striking among
the offspring of 2 affected parents, raising the question of
homozygosity. Schapera (1987) observed 9 affected persons in 5 sibships
of 3 generations (and, by implication, a fourth) of a South African
family. There was no instance of male-to-male transmission. Of the 9
affected persons, 5 were males. The expression varied from unilateral
enlargement of the transverse processes of C7 to bilateral complete
cervical ribs. The number of vertebrae was normal in all the affected
and unaffected members of the family. Two family members had experienced
severe neurovascular complications. Schapera (1987) suggested that this
represents autosomal dominant inheritance, especially when the full
range of expression is taken into account.

*FIELD* RF
1. Schapera, J.: Autosomal dominant inheritance of cervical ribs.
Clin. Genet. 31: 386-388, 1987.

2. Weston, W. J.: Genetically determined cervical ribs: a family
study. Brit. J. Radiol. 29: 455-456, 1956.

*FIELD* CS

Skel:
   Cervical ribs;
   Enlarged cervical transverse processes

Neuro:
   Neurovascular compression

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 8/27/1987

*RECORD*
*FIELD* NO
118000
*FIELD* TI
118000 CERVICAL VERTEBRAL BRIDGE
*FIELD* TX
A bony bridge (ponticulus posterius) on the first cervical vertebra,
roofing the groove occupied by the vertebral artery, behaves as a
dominant trait. The gene has a frequency of about 0.15.

*FIELD* SA
Selby et al. (1955)
*FIELD* RF
1. Selby, S.; Garn, S. M.; Kanareff, V.: The incidence and familial
nature of a bony bridge on the first cervical vertebra. Am. J. Phys.
Anthrop. 13: 129-141, 1955.

*FIELD* CS

Spine:
   Bony bridge on first cervical vertebra

Radiology:
   Roofed first cervical vertebral groove occupied by the vertebral artery

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
118005
*FIELD* TI
118005 CERVICAL VERTEBRAL DYSPLASIA
*FIELD* TX
Saltzman et al. (1991) described a kindred in which 9 members in 3
generations had cervical vertebral dysplasia. All of the affected
persons had had an abnormality of the first cervical vertebra, the
atlas. Some also had defects of the second cervical vertebra, the axis,
and vertebrae caudad to it. Two of the family members had symptoms. One
had a passively correctable tilt of the head, with an associated audible
clunk and hypoplasia of the left superior facet of the second cervical
vertebra. A second member of the family had developed suboccipital pain.
Radiographs showed anterior atlanto-occipital dislocation. These
symptoms were relieved by reduction and arthrodesis.

*FIELD* RF
1. Saltzman, C. L.; Hensinger, R. N.; Blane, C. E.; Phillips, W. A.
: Familial cervical dysplasia. J. Bone Joint Surg. 73A: 163-171,
1991.

*FIELD* CS

Spine:
   Cervical vertebral dysplasia;
   Head tilt;
   Cervical vertebral facet hypoplasia;
   Suboccipital pain

Radiology:
   Anterior atlanto-occipital dislocation

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 5/22/1991

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 5/22/1991

*RECORD*
*FIELD* NO
118100
*FIELD* TI
*118100 CERVICAL VERTEBRAL FUSION
KLIPPEL-FEIL SYNDROME
*FIELD* TX
C2-C3 fusion is the most common form of congenital fused cervical
vertebrae and is probably dominant with variable expression. The best
evidence for dominant inheritance was provided by Gunderson et al.
(1967).

*FIELD* SA
Gunderson and Lubs (1964)
*FIELD* RF
1. Gunderson, C. H.; Greenspan, R. H.; Glaser, G. H.; Lubs, H. A.
: The Klippel-Feil syndrome: genetic and clinical reevaluation of
cervical fusion. Medicine 46: 491-512, 1967.

2. Gunderson, C. H.; Lubs, H. A., Jr.: Familial C2-3 fusion.  (Abstract) Neurology 14:
272-273, 1964.

*FIELD* CS

Spine:
   C2-C3 fusion;
   Cervical vertebral fusion

Inheritance:
   Autosomal Dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986

*RECORD*
*FIELD* NO
^118150
*FIELD* TI
^118150 MOVED TO 107776
*FIELD* TX
This entry was incorporated into entry 107776 on 27 December 1996.

*FIELD* CN
Alan F. Scott - edited: 12/27/1996

*FIELD* CD
Victor A. McKusick: 1/3/1992
*FIELD* ED
mark: 12/27/1996
supermim: 3/16/1992
carol: 1/3/1992
*RECORD*
*FIELD* NO
118190
*FIELD* TI
*118190 HEAT SHOCK 60-KD PROTEIN 1; HSPD1
CHAPERONIN;;
HEAT-SHOCK PROTEIN-60; HSP60;;
GroEL HOMOLOG;;
CHAPERONIN 60 HOMOLOG;;
cpn60 HOMOLOG
*FIELD* TX
It was long assumed that all of the information necessary for proper
folding of proteins and their assembly into oligomeric complexes is
contained within the primary sequence of the polypeptides and that no
catalyst or other accessory proteins are involved in this process.
However, this basic tenet of biochemistry was seriously challenged by
the discovery of a class of proteins referred to as chaperonins, which
were shown to be involved in the folding and assembly of a number of
different proteins (Cheng et al., 1989; Ellis, 1990; Rothman, 1989).
Members of this family of proteins include the GroEL protein of E. coli
and a protein present in eukaryotic cell mitochondria referred to as
hsp60 in yeast or P1 in mammalian cells. In both prokaryotic and
eukaryotic systems, the synthesis of these proteins is induced in
response to stresses such as heat shock, which provides evidence that
these are members of the heat-shock family of proteins. Venner et al.
(1990) presented evidence of the existence of multiple copies of the
HSP60 gene in the human. All except one of these genes are nonfunctional
pseudogenes containing numerous changes such as base substitutions,
insertions, and deletions. The functional gene and the various
pseudogenes contain no introns.

Azem et al. (1994) performed chemical cross-linking and electron
microscopy studies on bacterial chaperonins GroEL and GroES to determine
how they interact with unfolded proteins. GroEL is an oligomer of 14
identical 57.3-kD subunits, with a structure of 2 stacked heptameric
rings arranged around a 2-fold axis of symmetry (Saibil et al., 1991).
It appears as a hollow cylinder. In the presence of ATP, 2 GroES (see
600141) rings (each made of 7 identical 10.4-kD subunits) can
successively bind a single GroEL core to make a functional symmetric
heterodimer. Although the central core of GroEL is obstructed by the 2
GroES rings at each end, this heterodimer can stably bind and assist the
refolding of the RuBisCo enzyme. While binding was thought to occur in
the central cavity, these data indicate that unfolded proteins may bind
and fold on the external envelope of some chaperonins (Azem et al.,
1994). Schmidt et al. (1994) suggested that the symmetric chaperonin
complex is functionally significant because complete folding of a
nonnative substrate protein in the presence of GroEL and GroES occurs
only in the presence of ATP, and not with ADP. Chaperonin-assisted
folding occurs by a catalytic cycle in which one ATP is hydrolyzed by
one ring of GroEL in a quantized manner with each turnover. Todd et al.
(1994) proposed a unifying model for chaperonin-facilitated protein
folding based on successive rounds of binding and release, and
partitioning between committed and kinetically trapped intermediates.

*FIELD* RF
1. Azem, A.; Kessel, M.; Goloubinoff, P.: Characterization of a functional
GroEL-14(GroES-7)-2 chaperonin hetero-oligomer. Science 265: 653-656,
1994.

2. Cheng, M. Y.; Hartl, F.-U.; Martin, J.; Pollock, R. A.; Kalousek,
F.; Neupert, W.; Hallberg, E. M.; Hallberg, R. L.; Horwich, A. L.
: Mitochondrial heat-shock protein hsp60 is essential for assembly
of proteins imported into yeast mitochondria. Nature 337: 620-625,
1989.

3. Ellis, R. J.: The molecular chaperone concept. Semin. Cell Biol. 1:
1-9, 1990.

4. Rothman, J. E.: Polypeptide chain binding proteins: catalysts
of protein folding and related processes in cells. Cell 59: 591-601,
1989.

5. Saibil, H.; Dong, Z.; Wood, S.; auf der Mauer, A.: Binding of
chaperonins. Nature 353: 25-26, 1991.

6. Schmidt, M.; Rutkat, K.; Rachel, R.; Pfeifer, G.; Jaenicke, R.;
Viitanen, P.; Lorimer, G.; Buchner, J.: Symmetric complexes of GroE
chaperonins as part of the functional cycle. Science 265: 656-659,
1994.

7. Todd, M. J.; Viitanen, P. V.; Lorimer, G. H.: Dynamics of the
chaperonin ATPase cycle: implications for facilitated protein folding.
Science 265: 659-666, 1994.

8. Venner, T. J.; Singh, B.; Gupta, R. S.: Nucleotide sequences and
novel structural features of human and Chinese hamster hsp60 (chaperonin)
gene families. DNA Cell Biol. 9: 545-552, 1990.

*FIELD* CD
Victor A. McKusick: 1/2/1991

*FIELD* ED
mark: 04/01/1996
carol: 10/11/1994
carol: 4/10/1992
supermim: 3/16/1992
carol: 2/1/1991
carol: 1/9/1991
carol: 1/2/1991

*RECORD*
*FIELD* NO
118200
*FIELD* TI
#118200 CHARCOT-MARIE-TOOTH DISEASE 1B; CMT1B
CMT, TYPE 1B;;
HEREDITARY MOTOR AND SENSORY NEUROPATHY;;
HMSN1;;
HEREDITARY MOTOR AND SENSORY NEUROPATHY 1B;;
HMSN 1B;;
CHARCOT-MARIE-TOOTH DISEASE, SLOW NERVE CONDUCTION TYPE;;
PERONEAL MUSCULAR ATROPHY
*FIELD* MN

Charcot-Marie-Tooth disease is a sensorineural polyneuropathy. Autosomal
dominant (CMT1), autosomal recessive (CMT2), and X-linked forms (CMTX)
have been recognized. The specific autosomal dominant form described
here (CMT1B) is a slow nerve conduction type (less than 38 m per sec),
determined by mutation in the myelin protein zero gene encoded by
chromosome 1q22 (Hayasaka et al., 1993). Mutation in the same gene can
produce a clinically related sensorineural polyneuropathy,
Dejerine-Sottas disease (145900). The gene for CMT1A is on chromosome 17
(118220). CMT2 is the moderately slow nerve conduction form of the
disease.

This disorder begins with atrophy and weakness of the peroneal muscles
and advances insidiously to involve other distal muscles of the leg and
arm. Deep tendon reflexes are diminished or absent and pes cavus is
commonly found. There may be hypertrophic neuropathy and elevated
cerebrospinal fluid protein. There is great variation in clinical signs,
age of onset, and severity within families.

Males tend to be more severely affected, whereas affected but
asymptomatic family members were more commonly female. Type I cases have
a peak age of onset of symptoms in the first decade of life. About
one-quarter of carriers identified by slow conduction times are
asymptomatic, though they may show mild signs on clinical examination
(Harding and Thomas, 1980).

Fifteen percent of cases are sporadic and, since there is a recessive
type, these present a counselling problem. The empirical risk for sibs
of an isolated case is about 1 in 6 (Harding and Thomas, 1980).

*FIELD* TX

DESCRIPTION

A number sign (#) is used with this entry because of the demonstration
that the causative mutation is located in the gene for myelin protein
zero (159440).

Charcot-Marie-Tooth disease is a sensorineural polyneuropathy. Autosomal
dominant, autosomal recessive, and X-linked forms have been recognized.
The specific autosomal dominant form described here is a slow nerve
conduction type, determined by mutation in the myelin protein zero gene
encoded by chromosome 1q22. Mutation in the same gene can produce a
clinically related sensorineural polyneuropathy, Dejerine-Sottas disease
(145900).

NOMENCLATURE

McAlpine (1989) proposed that the forms of CMT with very slow nerve
conduction be given the gene symbol CMT1A (118220) and CMT1B, CMT1A
being the gene on chromosome 17 and CMT1B being the gene on chromosome
1. Later, because of the finding that mutations in peripheral myelin
protein 22 (601097) caused CMT1A, the gene symbol PMP22 was used for the
17p12 locus. CMT2 was the proposed symbol for the autosomal locus
responsible for moderately slow nerve conduction form of the disease.
The X-linked locus was symbolized CMTX (302800). The genetic types
CMT1A, CMT1B, and CMT2 relate to the clinical types abbreviated HMSN1A,
HMSN1B, and HMSN2. A gene symbol beginning with the first letter of a
word such as hereditary, familial, or genetic is not acceptable. The
designation CMT2, or HMSN II, should, in the view of Harding (1989), be
confined to inherited axonal neuropathy.

CLINICAL FEATURES

In the family with Charcot-Marie-Tooth disease reported first in the lay
press by Verrill and followed up by England and Denny-Brown (1952),
members had sensory and trophic changes in addition to classic peroneal
muscular atrophy. Most have some sensory defect and this is not
surprising since the disorder is a neuropathy. Indeed, a case can be
made for referring to the several forms of Charcot-Marie-Tooth disease
as hereditary polyneuropathies.

Norstrand and Margulies (1958) observed affected members in 3
generations. Gastrointestinal symptoms in the form of chronic diarrhea,
nausea and vomiting were striking. Autopsy showed degeneration in the
lateral horn area of the spinal cord. Stark (1958) described a large
affected kindred. We have observed elevated cerebrospinal fluid protein,
hyperhidrosis and penetrating foot ulcers in a case of the dominant
form. This disorder begins with atrophy and weakness of the peroneal
muscles and advances insidiously to involve other distal muscles of the
leg and arm. Deep tendon reflexes are diminished or absent and pes cavus
is commonly found.

Bradley and Aguayo (1969) described a family in which persons in 3
generations had chronic sensorineural polyneuropathy. Alajouanine et al.
(1967) reported the phenomenal case of a woman who was a patient in La
Salpetriere, Paris, for 64 years. The diagnosis was made by Charcot in
1891. She died at age 80 years. Argyll-Robertson pupils and blindness
from optic atrophy began 40 to 50 years after onset of other signs of
disease. Whether this was an isolated case of the recessive form
(214400), which the authors favored, or a new mutant for the dominant
form was uncertain.

Kloepfer and Killian (1974) described an extensive kindred in Louisiana
in which 66 persons were judged to be heterozygous. Two marriages
between heterozygotes produced 5 persons judged to be homozygous. These
had onset of symptoms in early childhood with crippling evident by age
10. Heterozygotes were usually asymptomatic until their 20s or 30s. Two
living homozygotes had severe mixed sensory and motor polyneuropathy
with involvement of the facial nerves (Killian and Kloepfer, 1979).
Kyphoscoliosis, thickening of peripheral nerves, and pes cavus were
striking. In one, cerebrospinal fluid protein was markedly elevated and
peripheral nerve biopsy was consistent with hypertrophic interstitial
neuritis of Dejerine and Sottas. Other rare dominant conditions for
which the homozygous form has been observed include achondroplasia
(100800), hereditary telangiectasia (187300), two forms of brachydactyly
(112600, 114150), a form of stomatocytosis (185010) and distal myopathy
(160500).

The observations of Dyck and Lambert (1968) made it clear that cases
diagnosed as peroneal muscular atrophy on clinical grounds include more
than one genetic entity. Affected persons in some families showed
markedly reduced peripheral nerve conduction velocity, and nerve biopsy
displayed extensive segmental demyelination combined with concentric
proliferation of Schwann cells (hypertrophic neuropathy). In other
families affected persons showed relatively normal peripheral nerve
conduction velocity and no changes on nerve biopsy. They concluded that
in the latter families the disorder was a neuronal degeneration
affecting both anterior horn cells and cells in the dorsal root ganglia.
Dyck and Lambert (1968) suggested the existence of at least 3 entities:
1) a 'hypertrophic' neuropathy showing segmental demyelination in the
peripheral nerves with marked reduction in nerve conduction; 2) a
'neuronal' type, with axonal degeneration but normal nerve conduction;
3) a progressive 'spinal' form with profound distal weakness and atrophy
in the lower limbs with no sensory abnormality. Thus, in addition to the
autosomal dominant, autosomal recessive, and X-linked forms of the
Charcot-Marie-Tooth disease and in addition to amyloid neuropathy
(particularly of the Indiana or Rukavina type) and the distal form of
spinal muscular atrophy which are confused with CMT, hypertrophic
neuropathy of Dejerine-Sottas must be considered in connection with this
phenotype. Essentially the same conclusion was arrived at by Thomas et
al. (1974). They pointed out that members of one kindred might have
features leading to a label of either peroneal muscular atrophy,
hereditary hypertrophic neuropathy (145900) or Roussy-Levy syndrome
(180800). They suggested 'hereditary motor and sensory polyneuropathy'
as an adequate designation for this heterogeneous class.

Studying 109 persons from completed sibships at risk for dominant CMT in
15 unrelated families, Bird and Kraft (1978) concluded that penetrance
(as indicated by physical examination and nerve conduction) was 28%
complete in the first decade and essentially complete by the middle of
the third decade. The average age of onset was 12.2 years with a
standard deviation of 7.3. Persons over 27 years of age at risk but with
no clinical manifestations have less than 3% probability of having
inherited the gene. Satya-Murti et al. (1979) presented evidence
suggesting that the auditory nerves and spinal ganglia undergo the same
pathologic process as do peripheral nerves. They referred to the
condition as hereditary motor-sensory neuropathy.

Harding and Thomas (1980) confirmed division into type I with slow
conduction and type II with normal conduction (rate in the median nerve
below or above 38 meters per tenth second, respectively). They studied
228 patients (120 index cases and 108 affected relatives). Type I cases
numbered 173 and type II 55; 26 of the type I cases and 15 of the type
II cases were sporadic. Most cases of type I showed autosomal dominant
inheritance (39 families) but 4 probable autosomal recessive families
were observed. No X-linked recessive families were found. In both types,
males tended to be more severely affected, whereas affected but
asymptomatic family members were more commonly female. Type I cases had
a peak age of onset of symptoms in the first decade of life and in
comparison with type II had a greater tendency to show weakness of the
hands, upper limb tremors and ataxia, generalized tendon areflexia, and
more extensive distal sensory loss, sometimes with acrodystrophic
changes. Foot and spinal deformities were more frequent, probably
because of the early age of onset. Nerve thickening was confined to type
I cases. In type II cases, onset of symptoms was most often in the
second decade. Most type II cases were autosomal dominant but 2 probable
autosomal recessive and some sporadic cases were found.

Streib et al. (1984) described a family in which the 42-year-old
proposita and her 12-year-old son were typically affected, whereas the
father of the proposita was asymptomatic and had a normal neurologic
examination and normal foot arches but showed slowing of nerve
conduction velocities limited to the peroneal nerves. Marker testing
could not exclude paternity. Davis et al. (1978) reported a somewhat
similar family (their kindred 27); 2 sisters were severely affected
clinically and had nerve conduction velocities below 20 m/sec. The
mother was normal and the father was asymptomatic but had mild pes
cavus, slight peroneal weakness, and slow conduction (12 m/sec) in the
peroneal nerve. Conduction velocities were normal for median and ulnar
nerves. These may be examples of mosaicism in the father in each of
these cases.

The apparently enhanced neurotoxicity of vincristine in
Charcot-Marie-Tooth disease (Hogan-Dann et al., 1984) might be viewed as
an example of pharmacogenetics, comparable to the ill-effects of
barbiturates in acute intermittent porphyria. Patients with CMT syndrome
are particularly susceptible to vincristine neurotoxicity (Weiden and
Wright, 1972; Griffiths et al., 1985). In a brother and sister with type
I CMT disease and type II diabetes mellitus, Chan et al. (1987) found
diaphragmatic impairment to be severe in the sister and mild in the
brother. They suggested that nerve involvement may be part of the
clinical picture when diabetes mellitus is present.

Littler (1970) described a family in which peroneal muscular atrophy was
associated with heart block. Ten members of 3 generations were affected.
Three had both conditions, 6 had the cardiac defect alone, and 1 had the
neurologic disorder. Two patients developed complete heart block and one
of these had an artificial pacemaker inserted. Littler (1970) proposed
at least 3 genetic explanations: 2 independently segregating dominant
disorders, 2 linked genes, and pleiotropic effects of a single gene. Kay
et al. (1972) studied a myocardial biopsy specimen from the proband of
the family reported by Littler (1970). The ultrastructural changes were
similar to those previously described in simple myocardial hypertrophy
and hypertrophic obstructive cardiomyopathy (192600). These consisted of
the formation of cardiac 'villi' crowded with mitochondria, enhanced
micropinocytosis, and vacuolation of the subsarcolemmal cytoplasm. In a
kindred with presumed CMT1B because of linkage to 1q markers, Ionasescu
et al. (1992) described unusually early onset (before age 3 years) and
phrenic nerve involvement in the proposita, a 39-year-old woman who
required nocturnal ventilator support.

INHERITANCE

Charcot-Marie-Tooth disease is one of the entities that, like spastic
paraplegia and retinitis pigmentosa, demonstrate autosomal dominant
inheritance in some families, autosomal recessive inheritance in others,
and X-linked recessive inheritance in yet others (Allan, 1939).
Furthermore, linkage studies, reviewed later, indicate the existence of
at least 2 autosomal dominant forms caused by mutation on 1q or 17p
(601097).

MAPPING

Heimler et al. (1978) described a family in which the basal cell nevus
syndrome (109400) and Charcot-Marie-Tooth disease were transmitted
together through 3 generations.

Greene et al. (1980) reported 2 cases of CMT disease with malignant
melanoma (155600). One was clearly a dominant form of CMT. The other
patient, a male, had a brother with CMT. Although the association may
have occurred by chance, the authors raised the possibility of a shared
neural crest defect or genetic linkage.

A slow nerve conduction type of dominant Charcot-Marie-Tooth disease
(CMT1) was shown to be linked to the Duffy blood group locus (Bird et
al., 1980; Guiloff et al., 1982). Bird et al. (1982) found a maximum lod
score of 2.297 at recombination fraction of 0.1. Guiloff et al. (1982)
found that the combined male-female score at recombination fraction of
0.1 was 3.022. In a single family of type II (118210), they found 2
recombinants between Fy and CMT2 (out of 2 opportunities), suggesting
genetic distinctness. Stebbins and Conneally (1982) brought the
cumulative lod score to 6.06 at theta 0.10.

Dyck et al. (1983) restudied 2 kindreds with type I hereditary motor and
sensory neuropathy. To their surprise, in 1 large kindred which was
depended on heavily to establish the criteria for the definition of HMSN
I, no close linkage to Duffy was found. The second kindred showed
segregation consistent with linkage. They suggested that the
Duffy-unlinked form be called HMSN IA and the Duffy-linked form be
called HMSN IB. They could demonstrate no phenotypic differences between
the linked and unlinked forms. Dyck et al. (1983) also studied linkage
in a kindred with dominant spastic paraplegia, peroneal muscular
atrophy, and sensory loss (HMSN V in Dyck's numerology) and found no
linkage to Duffy or ABO but low positive lod scores with Rh (maximum lod
= 0.33 at theta 0.20). Bird et al. (1983) excluded linkage with Duffy in
a large 3-generation family with HMSN-1. They suggested that the form
not linked to Duffy (called by them HMSN1A, HMSN1B being the linked
form) may have less severe slowing of motor nerve conduction and less
prominent onion bulb changes on sural nerve biopsy. Leblhuber et al.
(1986) excluded tight linkage with the Duffy locus in a family with HMSN
I.

By family studies using DNA markers, Chance et al. (1987) concluded that
the probable limits of the locus are 1p22-q23. In the study of Ionasescu
et al. (1987), 13 families with CMT1 in which segregation at the Fy
locus rendered them informative for linkage failed to show linkage with
Duffy. On the other hand, on the basis of 9 informative families,
Ionasescu et al. (1987) found cosegregation consistent with linkage of
CMT1 and GBA (230800) at a theta of about 0.10. Ionasescu et al. (1987)
also found evidence of linkage of CMT1 to APOA2 (107670) at a theta of
about 0.20. In 16 CMT1 pedigrees, Griffiths et al. (1987, 1988) found no
linkage to REN (179820) or NGFB (162030). Although total lod scores
excluded close linkage of CMT1 to any of the markers used, individual
families showed probable linkage to Duffy, AT3, and/or AMY1. The results
indicated that a CMT1 gene is located between AMY1 at 1p21 and AT3 at
1q23 and that there is at least one other CMT1 gene.

Chance et al. (1987) found that neither CMT1 nor Duffy blood group was
tightly linked to AT3. They concluded that both loci must be close to
the centromere of chromosome 1. Middleton-Price et al. (1987) and
Middleton-Price et al. (1989) also failed to find linkage with Fy in 12
families. In 12 families with CMT1, Middleton-Price et al. (1987) found
strongly negative lod scores for linkage with Fy. They raised the
question as to whether reports of linkage may be based on a selection of
families that by chance show linkage, arguing that others do not because
of genetic heterogeneity. They pointed out that intrafamilial
variability is great so that the use of interfamilial variability as an
argument for genetic heterogeneity should be viewed with caution.

Patel et al. (1989) found an interstitial deletion of 1q23-q25 in a
patient with Charcot-Marie-Tooth disease, developmental delay, short
stature, and dysmorphic features. Lebo et al. (1989) mapped the CMT1B
gene to 1q21.1-q23.3 by spot blot analysis of sorted chromosomes,
analysis of cell lines with chromosome 1 deletions, linkage analysis,
and in situ hybridization. In a single extensively affected Indiana
kindred, multilocus linkage analysis performed by Lebo et al. (1989)
placed the CMT1B gene in the region of FCG2, the immunoglobulin G Fc
receptor II locus (146790). Indeed, no recombinants were observed in 17
informative meioses (lod = 5.1 at theta = 0.00). Since FCG2 has been
implicated in autoimmune disease and in the peripheral neuropathy caused
by autoimmune disease, Lebo et al. (1989) raised the possibility that
abnormality in this gene may be the 'cause' of CMT1B. They mapped the
FCG3 gene (146740) to within about 200 kb of the FCG2 gene. In 2
Duffy-linked families, Lebo et al. (1991) established that the CMT1B
gene is located in the 18 cM region between the AT3 gene (107300) and
the Duffy/sodium-potassium ATPase (182340) loci. Lebo et al. (1991)
presented a physical and genetic map of the entire chromosome 1 showing,
among other things, the breakpoints of 3 reciprocal translocations and 1
interstitial deletion used to sublocalize cloned DNAs by spot blot
analysis of sorted chromosomes. Linkage analysis by O'Connell et al.
(1989) had established a continuous chromosome-1 sex-averaged linkage
map of 464 cM. Lebo et al. (1991) also used multicolor fluorescence in
situ hybridization to orient the FCG2 gene and the anonymous clone 1054
on band 1q22. The 2 cloned fragments were on the same partially digested
900-kb MluI fragment detected by pulsed field gel electrophoresis. In
connection with the linkage studies, the results further refined the
CMT1B genetic location from an 18-cM interval to a 6-cM interval and
reduced the physical interval from 15% of chromosome 1 to 3% of
chromosome 1.

P(0), also known as myelin protein zero, is the major structural protein
of peripheral myelin. Hayasaka et al. (1993) and Oakey et al. (1992)
mapped the MPZ gene to 1q22-q23 in the same region as the CMT1B locus.
This prompted Hayasaka et al. (1993) to investigate MPZ as a candidate
gene in 2 affected pedigrees, which led to the demonstration of point
mutations.

HISTORY

The first clear descriptions of peroneal muscular atrophy were made
simultaneously by Charcot and Marie (1886) and Tooth (1886). (Brody and
Wilkins (1967) reprinted Charcot's description.) Confusion was
introduced by the description of Dejerine and Sottas (1893) of
hypertrophic neuropathy and the emergence, in 1926, of the concept of
Roussy-Levy syndrome. A semblance of order was restored by study of
nerve conduction, especially by Dyck and Lambert (1968).

*FIELD* SA
Bird and Griep (1981); Chance et al. (1987); Combarros et al. (1983);
Dawidenkow  (1927); Dawidenkow  (1927); Dyck  (1966); Dyck and Lambert
(1968); Dyck et al. (1963); Guiloff et al. (1982); Hayasaka et al.
(1993); Ionasescu et al. (1987); Ionasescu et al. (1987); Lucas and
Forster (1962); Macklin and Bowman (1926); Pollock et al. (1982);
Salisachs and Lapresle (1977)
*FIELD* RF
1. Alajouanine, T.; Castaigne, P.; Cambier, J.; Escourolle, R.: Maladie
de Charcot-Marie: etude anatomo-clinique d'une observation suivie
pendant 65 ans. Presse Med. 75: 2745-2750, 1967.

2. Allan, W.: Relation of hereditary pattern to clinical severity
as illustrated by peroneal atrophy. Arch. Intern. Med. 63: 1123-1131,
1939.

3. Bird, T. D.; Griep, E.: Pattern reversal visual evoked potentials:
studies in Charcot-Marie-Tooth hereditary neuropathy. Arch. Neurol. 38:
739-741, 1981.

4. Bird, T. D.; Kraft, G. H.: Charcot-Marie-Tooth disease: data for
genetic counseling relating age to risk. Clin. Genet. 14: 43-49,
1978.

5. Bird, T. D.; Ott, J.; Giblett, E. R.: Linkage of Charcot-Marie-Tooth
neuropathy to the Duffy locus on chromosome 1.(Abstract) Am. J. Hum.
Genet. 32: 99A, 1980.

6. Bird, T. D.; Ott, J.; Giblett, E. R.: Evidence for linkage of
Charcot-Marie-Tooth neuropathy to the Duffy locus on chromosome 1.
Am. J. Hum. Genet. 34: 388-394, 1982.

7. Bird, T. D.; Ott, J.; Giblett, E. R.; Chance, P. F.; Sumi, S. M.;
Kraft, G. H.: Genetic linkage evidence for heterogeneity in Charcot-Marie-Tooth
neuropathy (HMSN type I). Ann. Neurol. 14: 679-684, 1983.

8. Bradley, W. G.; Aguayo, A. J.: Hereditary chronic polyneuropathy:
electrophysiological and pathological studies in an affected family.
J. Neurol. Sci. 9: 131-154, 1969.

9. Brody, I. A.; Wilkins, R. H.: Charcot-Marie-Tooth disease. Arch.
Neurol. 17: 552-553, 1967.

10. Chan, C. K.; Mohsenin, V.; Loke, J.; Virgulto, J.; Sipski, M.
L.; Ferranti, R.: Diaphragmatic dysfunction in siblings with hereditary
motor and sensory neuropathy (Charcot-Marie-Tooth disease). Chest 91:
567-570, 1987.

11. Chance, P.; Dracopoli, N.; Bird, T.; Housman, D. E.; Summar, M.;
Ketting, R.: Linkage relationships of Charcot-Marie-Tooth neuropathy
(HMSNIb) to chromosome 1 markers.(Abstract) Cytogenet. Cell Genet. 46:
592, 1987.

12. Chance, P. F.; Murray, J. C.; Bird, T. D.; Kochin, R. S.: Genetic
linkage relationships of Charcot-Marie-Tooth disease (HMSN-Ib) to
chromosome 1 markers. Neurology 37: 325-329, 1987.

13. Charcot, J. M.; Marie, P.: Sur une forme particuliere d'atrophie
musculaire progressive, souvent familiale, debutant par les pieds
et les jambes et atteignant plus tard les mains. Rev. Med. 6: 97-138,
1886.

14. Combarros, O.; Calleja, J.; Figols, J.; Cabello, A.; Berciano,
J.: Dominantly inherited motor and sensory neuropathy type 1: genetic,
clinical, electrophysiological and pathological features in four families.
J. Neurol. Sci. 61: 181-191, 1983.

15. Davis, C. J. F.; Bradley, W. G.; Madrid, R.: The peroneal muscular
atrophy syndrome: clinical, genetic and electrophysiologic findings
and classification. J. Genet. Hum. 26: 311-349, 1978.

16. Dawidenkow, S.: Charcot-Marie type. Z. Ges. Neurol. Psychiat. 108:
344-445, 1927.

17. Dawidenkow, S.: Neurotic muscular atrophy of Charcot-Marie type.
Z. Ges. Neurol. Psychiat. 107: 259-320, 1927.

18. Dejerine, J.; Sottas, J.: Sur la nevrite interstitielle hypertrophique
et progressive de l'enfance. Comp. Rend. Soc. Biol. 45: 63-96,
1893.

19. Dyck, P. J.: Histologic measurements and fine structure of biopsied
sural nerve: normal, and in peroneal muscular atrophy, hypertrophic
neuropathy, and congenital sensory neuropathy. Mayo Clin. Proc. 41:
742-774, 1966.

20. Dyck, P. J.; Lambert, E. H.: Lower motor primary sensory neuron
diseases with peroneal muscular atrophy. I. Neurologic, genetic, and
electrophysiologic findings in hereditary polyneuronopathies. Arch.
Neurol. 18: 603-618, 1968.

21. Dyck, P. J.; Lambert, E. H.: Lower motor and primary sensory
neuron disease with peroneal muscular atrophy. II. Neurologic, genetic,
and electrophysiologic findings in various neuronal degenerations.
Arch. Neurol. 18: 619-625, 1968.

22. Dyck, P. J.; Lambert, E. H.; Mulder, D. W.: Charcot-Marie-Tooth
disease: nerve conduction and clinical studies of a large kinship.
Neurology 13: 1-11, 1963.

23. Dyck, P. J.; Ott, J.; Moore, S. B.; Swanson, C. J.; Lambert, E.
H.: Linkage evidence for genetic heterogeneity among kinships with
hereditary motor and sensory neuropathy, type I. Mayo Clin. Proc. 58:
430-435, 1983.

24. England, A. C.; Denny-Brown, D.: Sensory changes, and trophic
disorder, in peroneal muscular atrophy (Charcot-Marie-Tooth type).
Arch. Neurol. Psychiat. 67: 1-22, 1952.

25. Greene, M. H.; Mead, G. D.; Reimer, R. R.; Bergfeld, W. F.; Fraumeni,
J. F., Jr.: Malignant melanoma and Charcot-Marie-Tooth disease. Am.
J. Med. Genet. 5: 69-71, 1980.

26. Griffiths, J. D.; Stark, R. J.; Ding, J. C.; Cooper, I. A.: Vincristine
neurotoxicity in Charcot-Marie-Tooth syndrome. Med. J. Aust. 143:
305-306, 1985.

27. Griffiths, L. R.; Zwi, M. B.; McLeod, J. G.; Nicholson, G. A.
: Linkage studies on Charcot-Marie-Tooth neuropathy type 1.(Abstract) Cytogenet.
Cell Genet. 46: 624, 1987.

28. Griffiths, L. R.; Zwi, M. B.; McLeod, J. G.; Nicholson, G. A.
: Chromosome 1 linkage studies in Charcot-Marie-Tooth neuropathy type
1. Am. J. Hum. Genet. 42: 756-771, 1988.

29. Guiloff, R. J.; Thomas, P. K.; Contreras, M.; Armitage, S.; Schwarz,
G.; Sedgwick, E. M.: Evidence for linkage of type I hereditary motor
and sensory neuropathy to the Duffy locus on chromosome 1. Ann.
Hum. Genet. 46: 25-27, 1982.

30. Guiloff, R. J.; Thomas, P. K.; Contreras, M.; Armitage, S.; Schwarz,
G.; Sedgwick, E. M.: Linkage of autosomal dominant type I hereditary
motor and sensory neuropathy to the Duffy locus on chromosome 1. J.
Neurol. Neurosurg. Psychiat. 45: 669-674, 1982.

31. Harding, A.: Personal Communication. London, England  8/1/1989.

32. Harding, A. E.; Thomas, P. K.: The clinical features of hereditary
motor and sensory neuropathy types I and II. Brain 103: 259-280,
1980.

33. Hayasaka, K.; Himoro, M.; Sato, W.; Takada, G.; Uyemura, K.; Shimizu,
N.; Bird, T. D.; Conneally, P. M.; Chance, P. F.: Charcot-Marie-Tooth
neuropathy type 1B is associated with mutations of the myelin P(0)
gene. Nature Genet. 5: 31-34, 1993.

34. Hayasaka, K.; Himuro, M.; Wang, Y.; Takata, M.; Minoshima, S.;
Shimizu, N.; Miura, M.; Uyemura, K.; Takada, G.: Structure and chromosomal
localization of the gene encoding the human myelin protein zero (MPZ).
Genomics 17: 755-758, 1993.

35. Heimler, A.; Friedman, E.; Rosenthal, A.: Naevoid basal cell
carcinoma syndrome and Charcot-Marie-Tooth disease: two autosomal
dominant disorders segregating in a family. J. Med. Genet. 15:
288-291, 1978.

36. Hogan-Dann, C. M.; Fellmeth, W. G.; McGuire, S. A.; Kiley, V.
A.: Polyneuropathy following vincristine therapy in two patients
with Charcot-Marie-Tooth syndrome. J.A.M.A. 252: 2862-2863, 1984.

37. Ionasescu, V.; Anderson, R.; Burns, T.; Searby, C.; Ionasescu,
R.: Linkage between autosomal dominant Charcot-Marie-Tooth neuropathy
type 1 (CMT1) and apolipoprotein A2 (APOA2).(Abstract) Cytogenet.
Cell Genet. 46: 633, 1987.

38. Ionasescu, V.; Ferrell, R.; Murray, J.; Burns, T.; Ionasescu,
R.; Searby, C.: No linkage between autosomal dominant Charcot-Marie-Tooth
neuropathy type 1 and Duffy blood group (Fy).(Abstract) Cytogenet.
Cell Genet. 46: 633, 1987.

39. Ionasescu, V.; Ginns, E.; Burns, T.; Searby, C.; Ionasescu, R.
: Linkage between autosomal dominant Charcot-Marie-Tooth neuropathy
type 1 (CMT1) and human glucocerebrosidase (GBA).(Abstract) Cytogenet.
Cell Genet. 46: 633, 1987.

40. Ionasescu, V. V.; Trofatter, J.; Haines, J. L.; Ionasescu, R.;
Searby, C.: Charcot-Marie-Tooth neuropathy related to chromosome
1. Am. J. Med. Genet. 42: 728-732, 1992.

41. Kay, J. M.; Littler, W. A.; Meade, J. B.: Ultrastructure of myocardium
in familial heart block and peroneal muscular atrophy. Brit. Heart
J. 34: 1081-1084, 1972.

42. Killian, J. M.; Kloepfer, H. W.: Homozygous expression of a dominant
gene for Charcot-Marie-Tooth neuropathy. Ann. Neurol. 5: 515-522,
1979.

43. Kloepfer, H. W.; Killian, J. M.: Homozygous expression of a dominant
gene causing peroneal muscular atrophy (Charcot-Marie-Tooth disease).
Acta Genet. Med. Gemellol. 23: 217-220, 1974.

44. Leblhuber, F.; Reisecker, F.; Mayr, W. R.; Deisenhammer, E.:
Heterogeneity of hereditary motor and sensory neuropathy type I (HMSN
I): electroneurographical findings, visual evoked potentials and blood
group markers in a family with Charcot-Marie-Tooth disease (CMT).
Acta Neurol. Scand. 74: 145-149, 1986.

45. Lebo, R. V.; Chance, P. F.; Dyck, P. J.; Redila-Flores, M. T.;
Lynch, E. D.; Golbus, M. S.; Bird, T. D.; King, M. C.; Anderson, L.
A.; Hall, J.; Wiegant, J.; Jiang, Z.; Dazin, P. F.; Punnett, H. H.;
Schonberg, S. A.; Moore, K.; Shull, M. M.; Gendler, S.; Hurko, O.;
Lovelace, R. E.; Latov, N.; Trofatter, J.; Conneally, P. M.: Chromosome
1 Charcot-Marie-Tooth disease (CMT1B) locus in the Fc-gamma receptor
gene region. Hum. Genet. 88: 1-12, 1991.

46. Lebo, R. V.; et al.; et al.: Chromosome 1 Charcot-Marie-Tooth
locus in Fc-gamma-RII gene region.(Abstract) Am. J. Hum. Genet. 45
(suppl.): A148, 1989.

47. Lebo, R. V.; Lynch, E. D.; Wiegant, J.; Moore, K.; Trounstine,
M.; van der Ploeg, M.: Multicolor fluorescence in situ hybridization
and pulsed field electrophoresis dissect CMT1B gene region. Hum.
Genet. 88: 13-20, 1991.

48. Littler, W. A.: Heart block and peroneal muscular atrophy: a
family study. Quart. J. Med. 39: 431-439, 1970.

49. Lucas, G. J.; Forster, F. M.: Charcot-Marie-Tooth disease with
associated myopathy: a report of a family. Neurology 12: 629-636,
1962.

50. Macklin, M. T.; Bowman, J. T.: Inheritance of peroneal atrophy.
J.A.M.A. 86: 613-617, 1926.

51. McAlpine, P. J.: Personal Communication. Winnipeg, Manitoba,
Canada  9/14/1989.

52. Middleton-Price, H.; van den Berghe, J.; Harding, A.; Scott, J.;
Malcolm, S.: Analysis of markers on chromosome 1.(Abstract) Cytogenet.
Cell Genet. 46: 662, 1987.

53. Middleton-Price, H. R.; Harding, A. E.; Berciano, J.; Pastor,
J. M.; Huson, S. M.; Malcolm, S.: Absence of linkage of hereditary
motor and sensory neuropathy type I to chromosome 1 markers. Genomics 4:
192-197, 1989.

54. Norstrand, I. F.; Margulies, M. E.: Peripheral neuronopathy (Charcot-Marie-Tooth
disease) in association with gastrointestinal symptoms. New York
J. Med. 58: 863-867, 1958.

55. O'Connell, P.; Lathrop, G. M.; Nakamura, Y.; Leppert, M. L.; Ardinger,
R. H.; Murray, J. L.; Lalouel, J.-M.; White, R.: Twenty-eight loci
form a continuous linkage map of markers for human chromosome 1. Genomics 4:
12-20, 1989.

56. Oakey, R. J.; Watson, M. L.; Seldin, M. F.: Construction of a
physical map on mouse and human chromosome 1: comparison of 13 Mb
of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620,
1992.

57. Patel, P. I.; Franco, B.; Cook, J.; Ledbetter, D. H.; Frances,
S.; Lupski, J. R.: Charcot-Marie-Tooth disease, developmental delay,
short stature, and dysmorphic features in a patient with an interstitial
deletion of the long arm of chromosome 1 (1q23-1q25).(Abstract) Am.
J. Hum. Genet. 45 (suppl.): A211, 1989.

58. Pollock, M.; Nukada, H.; Kritchevsky, M.: Exacerbation of Charcot-Marie-Tooth
disease in pregnancy. Neurology 32: 1311-1314, 1982.

59. Salisachs, P.; Lapresle, J.: Argyll-Robertson-like pupils in
the neural type of Charcot-Marie-Tooth disease. Europ. Neurol. 16:
172-175, 1977.

60. Satya-Murti, S.; Cacace, A. T.; Hanson, P. A.: Abnormal auditory
evoked potentials in hereditary motor-sensory neuropathy. Ann. Neurol. 5:
445-448, 1979.

61. Stark, P.: Etude clinique et genetique d'une famille atteinte
d'atrophie musculaire progressive neurale (amyotrophie de Charcot-Marie).
J. Genet. Hum. 7: 1-32, 1958.

62. Stebbins, N. B.; Conneally, P. M.: Linkage of dominantly inherited
Charcot Marie Tooth neuropathy to the Duffy locus in an Indiana family.
(Abstract) Am. J. Hum. Genet. 34: 195A, 1982.

63. Streib, E. W.; Sun, S. F.; Kimberling, W.; Smith, S. A.: Hypertrophic
form of peroneal muscular atrophy (PMA): unusual nerve conduction
results. Muscle Nerve 7: 32-34, 1984.

64. Thomas, P. K.; Calne, D. B.; Stewart, G.: Hereditary motor and
sensory polyneuropathy (peroneal muscular atrophy). Ann. Hum. Genet. 38:
111-153, 1974.

65. Tooth, H. H.: The Peroneal Type of Progressive Muscular Atrophy.
London: H. K. Lewis (pub.)  1886.

66. Weiden, P. L.; Wright, S. E.: Vincristine neurotoxicity. New
Eng. J. Med. 286: 1369-1370, 1972.

*FIELD* CS

Muscle:
   Peroneal muscle atrophy and weakness;
   Distal arm and leg muscle atrophy and weakness

Neuro:
   Weak or absent deep tendon reflexes;
   Sensory defect;
   Chronic sensorineural polyneuropathy

Skin:
   Hyperhidrosis;
   Penetrating foot ulcers

Limbs:
   Pes cavus;
   Trophic limb changes

GI:
   Chronic diarrhea;
   Nausea;
   Vomiting

Cardiac:
   Heart block

Oncology:
   Enhanced neurotoxicity of vincristine

Misc:
   More severe in homozygotes

Lab:
   Spinal cord lateral horn area degeneration;
   Elevated cerebrospinal fluid protein;
   Reduced peripheral nerve conduction velocity;
   Nerve biopsy shows segmental demyelination combined with concentric
   proliferation of Schwann cells (hypertrophic neuropathy)

Inheritance:
   Autosomal dominant (1q21.1-q23.3), also another autosomal dominant
   (17p12-p11.2) form, as well as autosomal recessive, and X-linked forms

*FIELD* CN
Moyra Smith - Updated: 5/25/1996
Orest Hurko - updated: 3/22/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 06/19/1996
terry: 6/18/1996
carol: 5/29/1996
joanna: 5/29/1996
mark: 5/28/1996
carol: 5/25/1996
terry: 4/15/1996
mark: 3/22/1996
terry: 3/14/1996
mark: 3/5/1996
mark: 6/11/1995
pfoster: 1/17/1995
davew: 8/16/1994
hurko: 7/12/1994
jason: 6/10/1994
warfield: 4/7/1994

*RECORD*
*FIELD* NO
118210
*FIELD* TI
*118210 CHARCOT-MARIE-TOOTH DISEASE, NEURONAL TYPE, A; CMT2A
CMT2;;
HEREDITARY MOTOR SENSORY NEUROPATHY 2A;;
HMSN2A
*FIELD* TX
Physiologic studies demonstrate at 2 distinct forms of
Charcot-Marie-Tooth disease or CMT, slow conduction or Schwann cell type
and a separate axonal type without diffuse slowing of conduction
velocities. The axonal forms are less frequent, and are defined as
Charcot-Marie-Tooth disease 2 or hereditary motor and sensory neuropathy
2. Linkage studies support the existence of multiple genetic variants in
each of these autosomal dominant categories. See 118200 and 118220 for
autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth
disease. See 214400 (CMT4) and 302800 (CMTX) for autosomal recessive and
X-linked forms of Charcot-Marie-Tooth disease.

Berciano et al. (1986) described a large family with a neuronal form of
hereditary motor and sensory neuropathy. They referred to it as type II
HMSN, which is characterized by normal or slightly reduced nerve
conduction velocity and axonal loss with little evidence of
demyelination or hypertrophic changes in nerve biopsies. In the family
reported by Berciano et al. (1986), there were 5 instances of
male-to-male transmission.

In studies of 2 CMT2 pedigrees, Hentati et al. (1992) excluded the CMT2
locus from the region of chromosome 17 and the region of chromosome 1
where CMT1A (601097) and CMT1B (118200) have been located, respectively.
Thus, there is evidence of a fundamental distinction between the
hypertrophic and neuronal forms of Charcot-Marie-Tooth disease.
Furthermore, the CMT2 gene is not allelic to either of the CMT1 genes
mapped to date.

In linkage studies of 6 large autosomal dominant CMT2 families, Ben
Othmane et al. (1993) demonstrated linkage to a series of microsatellite
markers in the distal region of the short arm of chromosome 1. Using
admixture analysis and 2-point lod scores, they were able, however, to
demonstrate heterogeneity. Multipoint analysis examining the 'linked'
families showed that the most favored location of the CMT2 gene is
within the interval flanked by D1S244 and D1S228 in the region 1p36-p35.

The preferred symbol for the chromosome 1-linked variant is CMT2A, and
that for the chromosome 3-linked variant is CMT2B (600882).

*FIELD* RF
1. Ben Othmane, K.; Middleton, L. T.; Loprest, L. J.; Wilkinson, K.
M.; Lennon, F.; Rozear, M. P.; Stajich, J. M.; Gaskell, P. C.; Roses,
A. D.; Pericak-Vance, M. A.; Vance, J. M.: Localization of a gene
(CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2
to chromosome 1p and evidence of genetic heterogeneity. Genomics 17:
370-375, 1993.

2. Berciano, J.; Combarros, O.; Figols, J.; Calleja, J.; Cabello,
A.; Silos, I.; Coria, F.: Hereditary motor and sensory neuropathy
type II: clinicopathological study of a family. Brain 109: 897-914,
1986.

3. Hentati, A.; Lamy, C.; Melki, J.; Zuber, M.; Munnich, A.; de Recondo,
J.: Clinical and genetic heterogeneity of Charcot-Marie-Tooth disease. Genomics 12:
155-157, 1992.

*FIELD* CS

Muscle:
   Peroneal muscle atrophy and weakness;
   Distal arm and leg muscle atrophy and weakness

Neuro:
   Weak or absent deep tendon reflexes;
   Sensory defect;
   Chronic sensorineural polyneuropathy

Skin:
   Hyperhidrosis;
   Penetrating foot ulcers

Limbs:
   Pes cavus;
   Trophic limb changes

GI:
   Chronic diarrhea;
   Nausea;
   Vomiting

Cardiac:
   Heart block

Oncology:
   Enhanced neurotoxicity of vincristine

Misc:
   More severe in homozygotes

Lab:
   Normal or slightly reduced nerve conduction velocity;
   Axonal loss with little evidence of demyelination or hypertrophic
   changes in nerve biopsies

Inheritance:
   Autosomal dominant (1p36-p35), also other autosomal dominant forms,
   as well as autosomal recessive, and X-linked forms

*FIELD* CN
Orest Hurko - updated: 3/22/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 01/18/1997
terry: 4/15/1996
mark: 3/22/1996
terry: 3/14/1996
mark: 3/5/1996
mark: 10/19/1995
mimadm: 6/25/1994
carol: 8/23/1993
supermim: 3/16/1992
carol: 1/6/1992
carol: 11/14/1991

*RECORD*
*FIELD* NO
118220
*FIELD* TI
#118220 CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A; CMT1A
CHARCOT-MARIE-TOOTH DISEASE, SLOW NERVE CONDUCTION TYPE, UNLINKED;;
TO DUFFY;;
CMT-IA, UNLINKED TO DUFFY;;
HEREDITARY MOTOR AND SENSORY NEUROPATHY TYPE IA; HMSNIA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by duplication of, or mutation in, the gene for
peripheral myelin protein-22 (601097). Deletion of the PMP22 gene
results in hypertrophic neuropathy of Dejerine and Sottas (145900);
duplication of this gene has been found in some patients clinically
thought to have Dejerine-Sottas syndrome (see Silander et al., 1996).

Bird et al. (1983) and Dyck et al. (1983) reported families of typical
CMT-I (see 118200 for definition) except that linkage to Duffy blood
group was excluded. Whereas Dyck et al. (1983) could discern no
phenotypic differences between the linked and unlinked forms, Bird et
al. (1983) suggested that slowing of nerve conduction is less marked and
onion bulb formation on sural nerve biopsy less conspicuous in the
Duffy-unlinked form. Lupski et al. (1992) stated that CMT in all of its
forms is the most common inherited peripheral neuropathy in humans, with
a total prevalence rate of 1 in 2,500. The most common form is CMT1A, in
which the average age of onset of clinical symptoms is 12.2 +/- 7.3
years and in which slow nerve conduction velocity is highly diagnostic
and is a 100% penetrant phenotype independent of age (Lupski et al.,
1991, 1992). Berciano et al. (1994) observed that clinically normal
adult CMT1A patients are rare, but do exist. They referred to 1
duplication-positive woman who had normal neurologic examinations at
least up to the age of 31 even though her motor nerve conduction
velocities were 30 meters per second in the median nerve. This patient
had a clinically affected 4-year-old son. Berciano et al. (1994)
stressed the importance of doing not only neurologic examinations but
also electrophysiologic studies or DNA studies to exclude the diagnosis
of CMT1A. Hoogendijk et al. (1994) reviewed the clinical and
neurographic features of 44 affected individuals, aged 8 to 68 years
(mean 34 years), from 6 families with chromosome 17p duplication. Motor
nerve conduction velocity (MNCV) and, to a lesser extent, compound
muscle action potential amplitude were inversely related to clinical
severity. Neither clinical severity nor MNCV was significantly related
to age. They interpreted the findings as suggesting that the primary
pathologic process is not active, or only slightly active, after
childhood. Garcia et al. (1995) found remarkable concordance of nerve
conduction velocities in each of 2 pairs of male homozygotic twins with
a type 1A duplication. There was also congruity between the left and
right side of each twin as well as between twin brothers. However, there
was marked dissimilarity in the clinical severity in each of the twin
pairs, as well as asymmetric clinical involvement of each affected
individual. Palpable nerve enlargement was greater in the less affected
twins than in their more severely affected brothers. The marked
discrepancy between nerve conduction velocities and clinical weakness
suggested that other factors must be responsible.

Middleton-Price et al. (1989), Nicholson et al. (1989), and Vance et al.
(1989) presented evidence that one form of Charcot-Marie-Tooth disease
is determined by a mutation on chromosome 17. Middleton-Price et al.
(1989) found linkage to D17S58, which is located on 17p, 5.5 cM from the
centromere (maximum lod = 3.64 at theta = 0.15). Middleton-Price et al.
(1990) raised the lod score to 5.89 at theta = 0.0 for linkage to
D17S58. Nicholson et al. (1989) found a lod score of 3.7 at theta = 0.20
with D17S58. With the marker D17S71, they found a lod score of 15 at
theta = 0.02. Nicholson et al. (1989) concluded that the CMT locus is on
the distal side of both of these markers from the centromere. Vance et
al. (1989) obtained high lod scores with both markers in studies of 6
families. The families were referred to as Charcot-Marie-Tooth disease
type 1a, type 1b being the variety linked to Duffy blood group on
chromosome 1. Middleton-Price et al. (1989) referred to the condition as
hereditary motor and sensory neuropathy type I (HMSNI), also called the
hypertrophic form of Charcot-Marie-Tooth disease. In studies of 7
families, Chance et al. (1989, 1990) found a high probability of linkage
to chromosome 17 markers in 5. Of the other 2, linkage to Duffy blood
group was excluded in 1 (lod = -2.08 at theta = 0.1), while in the other
family there was a suggestion of linkage to Duffy (lod = 2.1 at theta =
0). These data suggested that there are at least 3 loci for autosomal
dominant type I CMT: one on chromosome 17, one on chromosome 1, and one
on a third as yet undetermined autosome. In the 2 families that did not
show linkage to chromosome 17, the disease was more severe than in the
chromosome 17 families.

Kloepfer and Killian (1974) described an extensive kindred in Louisiana
in which 66 persons were judged to be heterozygous. Two marriages
between heterozygotes produced 5 persons judged to be homozygous. These
had onset of symptoms in early childhood with crippling evident by age
10. Heterozygotes were usually asymptomatic until their 20s or 30s. Two
living homozygotes had severe mixed sensory and motor polyneuropathy
with involvement of the facial nerves (Killian and Kloepfer, 1979).
Kyphoscoliosis, thickening of peripheral nerves, and pes cavus were
striking. In one, cerebrospinal fluid protein was markedly elevated and
peripheral nerve biopsy was consistent with hypertrophic interstitial
neuritis of Dejerine and Sottas (145900). Other rare dominant conditions
for which the homozygous form has been observed include achondroplasia
(100800), hereditary telangiectasia (187300), two forms of brachydactyly
(112600, 114150), a form of stomatocytosis (185010) and distal myopathy
(160500).

Perhaps the families that appear to be unlinked to either the CMT1A or
CMT1B locus (Chance et al., 1990) should be reexamined.

In a multigeneration family in Belgium, Raeymaekers et al. (1989)
excluded chromosome 1 as the site of the mutation and demonstrated that
it was linked to D17S58 and D17S71, two markers on chromosome 17.
Multipoint linkage results indicated that the mutation is most likely
located on the short arm of chromosome 17, distal to D17S71. Both D17S71
and D17S58 are located in the pericentromeric region of 17p, separated
by a theta of 0.03. By further linkage studies in this family, Timmerman
et al. (1990) demonstrated that the CMT1A gene is located in the
chromosomal region 17p12-p11.2 between marker D17S71 and the gene for
myosin heavy chain polypeptide-2 of adult skeletal muscle (160740). In a
large French-Acadian kindred, Patel et al. (1990) confirmed the
localization of CMT1A to the pericentromeric region of chromosome 17.
McAlpine et al. (1990) provided linkage data on 5 Caucasian families
which excluded linkage of CMT1A to the Fy area of chromosome 1 and
demonstrated close linkage to D17S58, located at 17p11.2-p11.1; maximum
lod = 10.828 at theta = 0.0. The CMT1A locus appeared to be proximal to
MYH2, which maps to 17p13. By differential Alu-PCR of a rodent-human
hybrid cell containing only chromosome 17 and a rodent-human cell
containing only chromosome 17 with a deletion of the p11.2 band, Patel
et al. (1990) isolated a marker that showed linkage to CMT1A with a peak
lod score of 3.41 at a recombination fraction of 0.12. By multipoint
linkage analysis, Vance et al. (1991) localized the CMT1A gene to
17p11.2 and identified flanking DNA markers. Lebo et al. (1992) studied
the order of markers in the region of the CMT1A gene by means of
multicolor in situ hybridization which they showed could resolve loci
within 0.5 Mb on early-metaphase chromosomes.

In a review of hereditary motor and sensory neuropathies, Vance (1991)
pointed to the autosomal dominant 'Trembler' mutation (Tr) in the mouse
as a possibly homologous condition. A hypomyelin neuropathy with onion
bulb formation develops in older animals. Because of the extensive
homology of synteny between mouse 11 and human 17 (Green, 1989), it is
particularly attractive to think that these may be fundamentally the
same disorder. In 2 allelic forms of the Trembler mouse, Suter et al.
(1992,1992) demonstrated point mutations in 2 distinct putative
membrane-associated domains of a potentially growth-regulated 22-kD
protein, peripheral myelin protein-22 (Pmp22). PMP-22 is expressed by
Schwann cells and is localized mainly in compact peripheral nervous
system myelin. Baechner et al. (1995) demonstrated widespread
distribution of PMP22 RNA in several mesodermal and ectodermal tissues
of developing mice, as well as in the villi of the adult gut, suggesting
to them a broader biologic significance for Pmp22 in cell proliferation
or differentiation.

Patel et al. (1992) isolated cDNA and genomic clones for human PMP22
(601097) and showed by Southern analysis of somatic cell hybrids that
the gene maps to 17p12-p11.2. Furthermore, they found that it is
expressed at high levels in peripheral nervous tissue and is duplicated,
but not disrupted, in CMT1A patients. They suggested that a gene dosage
effect underlies, at least partially, the demyelinating neuropathy in
CMT1A. Valentijn et al. (1992) likewise showed that the PMP22 gene is
located within the CMT1A duplication and concluded that increased gene
dosage may be responsible for the disorder in CMT1A. PMP22 is an
integral membrane protein of 160 amino acids with 4 transmembrane
domains. Valentijn et al. (1992) used 2-color fluorescence in situ
hybridization (FISH) on interphase nuclei of fibroblasts to demonstrate
that the duplication is a direct tandem repeat: they observed red-green
for the normal chromosome and red-green-red-green for the chromosome
with the duplication; in none of the nuclei analyzed was the order
red-green-green-red or green-red-red-green, compatible with an inverted
repeat. Those families in which there is no duplication of the PMP22
gene may represent intragenic mutations comparable to those in the
Trembler mouse. Valentijn et al. (1992) indicated that one such family
had been identified and suggested that analysis of the PMP22 gene with
demonstration of mutation would provide final proof of its involvement
in CMT1A (see 601097.0002 for validation of this prediction). Using
pulsed field gel electrophoresis and YACs, Timmerman et al. (1992) also
demonstrated that the PMP22 gene is contained within the CMT1A
duplication. Matsunami et al. (1992) likewise used YACs to demonstrate
the presence of the PMP22 gene in the duplication. Takahashi et al.
(1992) mapped the PMP22 gene to 17p11.2 by FISH.

Schiavon et al. (1994) devised a rapid, informative, economical, and
easily interpretable nonradioactive test for detection of the CMT1A
duplication based on a microsatellite polymorphism. They found the CMT1A
duplication in 76% of 56 unrelated patients.

Lupski et al. (1993) studied 2 unrelated patients with both CMT1 and
NF1. Since both of these mutations map to the pericentric region of
chromosome 17, they investigated whether this might be a contiguous gene
syndrome. In both patients, however, the CMT1A was inherited from the
father, who did not have NF1. Furthermore, molecular analysis showed
that the CMT1A duplication was stable in the 2 patients. One patient
transmitted both disorders to her daughter. Thus, this was a chance
concurrence of 2 common disorders. Bosch et al. (1981) had also reported
the concurrence of these 2 conditions.

See 601097.0001 for discussion of the work of Lupski et al. (1991) and
others indicating that a DNA duplication on chromosome 17 in the
p12-p11.2 region is frequently the basis of CMT1A. See also 601097.0003
for point mutations in the PMP22 gene in families with nonduplication
CMT1A. Suter and Patel (1994) reviewed and discussed the curious finding
that gene dosage and point mutations affecting the same gene can lead to
a similar phenotype. They pointed to a possibly identical situation with
Pelizaeus-Merzbacher disease (312080) in which either deletion of the
entire locus encoding proteolipid protein (PLP) (Raskind et al., 1991),
as described in 312080.0006, or duplication of the PLP locus (Cremers et
al., 1987) can cause Pelizaeus-Merzbacher disease.

Matise et al. (1994) referred to the tandem duplication underlying CMT1A
as resulting in segmental trisomy. The search for the CMT1A disease gene
was misdirected and impeded because some chromosome 17 genetic markers
that are linked to CMT1A lie within the duplication. Matise et al.
(1994) demonstrated that the undetected presence of a duplication
distorts transmission ratios, hampers fine localization of the disease
gene, and increases false evidence of linkage heterogeneity. They
devised a likelihood-based method for detecting the presence of a
tandemly duplicated marker when one is suspected.

Hertz et al. (1994) demonstrated that a sporadic case of
Charcot-Marie-Tooth disease type 1A was due to de novo duplication of
the 17p12-p11.2 region, as had been found in most other sporadic cases.
In all 12 de novo CMT1A duplications reported to that time, the
duplication was of paternal origin. Sorour et al. (1995) described a
case of CMT1A with molecular duplication of 17p12-p11.2 and inheritance
of the duplication from a mosaic father. Whereas the patient had typical
clinical features, the father had minimal findings of CMT1A.

Pellegrino et al. (1996) illustrated how it is possible in some
instances to determine the genetic basis of clinical features in
chromosomal rearrangements. They reported a child with monosomy 10q and
dup(17p) resulting from an apparently balanced maternal translocation
t(10;17)(q26.3;p11.2). Manifestations of both the duplication and the
monosomy were present; however, the overall development was better than
that previously reported in either syndrome. The patient's motor
development was significantly more impaired than cognitive development,
and signs of a peripheral neuropathy were found and attributed to
duplication of 17p. Indeed, the patient was found to be trisomic for the
PMP22 gene resulting in demyelinating neuropathy. An elevated serum
alpha-fetoprotein had been detected at 16 weeks of gestation. The infant
showed bilateral inguinal hernias and hydroceles at birth, and
echocardiogram demonstrated ventriculoseptal defect and bicuspid aortic
valve. There was gastroesophageal reflux requiring Nissen fundoplication
with gastrostomy tube. The VSD closed spontaneously. Hypoplastic corpus
callosum was demonstrated by MRI. Terminal deletions of 10q had been
reported in 26 patients, resulting in a definite phenotype (Wulfsberg et
al., 1989). The manifestations included postnatal growth retardation,
microcephaly, down-slanting palpebral fissures, clinodactyly,
syndactyly, congenital heart disease, and urogenital anomalies, all of
which were present in the patient reported by Pellegrino et al. (1996).

To investigate the frequency of de novo CMT1A duplications, Blair et al.
(1996) examined 118 duplication-positive CMT1A families. In 10 of these
families it was demonstrated that the disease had arisen as the result
of a de novo mutation. They estimated that 10% or more of autosomal
dominant CMT1 families are due to de novo duplications. Using
polymorphic markers from within the duplicated region, they showed that
7 of the duplications were of paternal and 1 of maternal origin. This
was the first report of a de novo duplication of maternal origin.

Bort et al. (1997) reported that the prevalence of de novo mutation in
duplication positive CMTA1 families was 18.3%. They reported that the
ratio of maternal to paternal origin of the duplication was 1:8 in their
study.

Gabreels-Festen et al. (1995) compared the histology of peripheral nerve
in patients with duplication of the PMP22 gene to those with point
mutations. In the duplication cases, onion bulbs developed gradually in
the first years of life, and the ratio of the axon diameter versus the
fiber diameter was significantly lower than normal. In contrast, in
patients with point mutations in PMP22, nearly all myelinated fibers had
a high ratio of axon diameter versus fiber diameter, and onion bulbs
were abundant from an early age.

Huxley et al. (1996) constructed a mouse model for CMT1A by pronuclear
injection of a YAC containing the human PMP22 gene and a large
proportion of the region duplicated in CMT1A. They noted that CMT1A
represents a unique case in which partial trisomy of a major gene leads
to the pathology. Yeast artificial chromosomes are ideal for creating
animal models of overexpression of genes since they contain very large
stretches of DNA within which not only the structural gene but the long
range controlling elements that confer full levels of tissue-specific
expression may be present. In 1 transgenic line, about 8 copies of the
human DNA was integrated into a mouse chromosome. This mouse developed a
peripheral neuropathy closely similar to that seen in human CMT1A, with
progressive weakness of the hind legs, severe demyelination in the
peripheral nervous system, and the presence of onion bulb formations.

*FIELD* SA
Bridges  (1936); Gabreels-Festen et al. (1992); LeGuern et al. (1995);
Lorenzetti et al. (1995); Lupski et al. (1991); Ouvrier et al. (1987);
Patel et al. (1990)
*FIELD* RF
1. Baechner, D.; Liehr, T.; Hameister, H.; Alterberger, H.; Grehl,
H.; Suter, U.; Rautenstrauss, B.: Widespread expression of the peripheral
myelin protein-22 gene (pmp22) in neural and non-neural tissues during
murine development. J. Neurosci. Res. 42: 733-741, 1995.

2. Berciano, J.; Calleja, J.; Combarros, O.: Charcot-Marie-Tooth
disease.(Letter) Neurology 44: 1985-1986, 1994.

3. Bird, T. D.; Ott, J.; Giblett, E. R.; Chance, P. F.; Sumi, S. M.;
Kraft, G. H.: Genetic linkage evidence for heterogeneity in Charcot-Marie-Tooth
neuropathy (HMSN type I). Ann. Neurol. 14: 679-684, 1983.

4. Blair, I. P.; Nash, J.; Gordon, M. J.; Nicholson, G. A.: Prevalence
and origin of de novo duplications in Charcot-Marie-Tooth disease
type 1A: first report of a de novo duplication with a maternal origin. Am.
J. Hum. Genet. 58: 472-476, 1996.

5. Bort, S.; Martinez, F.; Palau, F.: Prevalence and parental origin
of de novo 1.5-Mb duplication in Charcot-Marie-Tooth disease type
1A. (Letter) Am. J. Hum. Genet. 60: 230-233, 1997.

6. Bosch, E. P.; Murphy, M. J.; Cancilla, P. A.: Peripheral neurofibromatosis
and peroneal muscular atrophy. Neurology 31: 1408-1414, 1981.

7. Bridges, C. B.: The Bar 'gene' a duplication. Science 83: 210-211,
1936.

8. Chance, P. F.; Bird, T. D.; Atkinson, D.; O'Connell, P.; Leppert,
M.; Lipe, H.; Ketting, R.; Lalouel, J.-M.; White, R. W.: Linkage
evidence for genetic heterogeneity in type I Charcot-Marie-Tooth neuropathy.
(Abstract) Am. J. Hum. Genet. 45 (suppl.): A135, 1989.

9. Chance, P. F.; Bird, T. D.; O'Connell, P.; Lipe, H.; Lalouel, J.-M.;
Leppert, M.: Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth
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Hum. Genet. 47: 915-925, 1990.

10. Cremers, F. P. M.; Pfeiffer, R. A.; van de Pol, T. J. R.; Hofker,
M. H.; Kruse, T. A.; Wieringa, B.; Ropers, H. H.: An interstitial
duplication of the X chromosome in a male allows physical fine mapping
of probes from the Xq13-q22 region. Hum. Genet. 77: 23-27, 1987.

11. Dyck, P. J.; Ott, J.; Moore, S. B.; Swanson, C. J.; Lambert, E.
H.: Linkage evidence for genetic heterogeneity among kinships with
hereditary motor and sensory neuropathy, type I. Mayo Clin. Proc. 58:
430-435, 1983.

12. Gabreels-Festen, A. A. W. M.; Bolhuis, P. A.; Hoogendijk, J. E.;
Valentijn, L. J.; Eshuis, E. J. H. M.; Gabreels, F. J. M.: Charcot-Marie-Tooth
disease type 1A: morphological phenotype of the 17p duplication event
versus PMP22 point mutations. Acta Neuropath. 90: 645-649, 1995.

13. Gabreels-Festen, A. A. W. M.; Joosten, E. M. G.; Gabreels, F.
J. M.; Jennekens, F. G. I.; Janssen-van Kempen, T. W.: Early morphological
features in dominantly inherited demyelinating motor and sensory neuropathy
(HMSN type I). J. Neurol. Sci. 107: 145-154, 1992.

14. Garcia, C. A.; Malamut, R. E.; England, J. D.; Parry, G. S.; Liu,
P.; Lupski, J. R.: Clinical variability in two pairs of identical
twins with Charcot-Marie-Tooth disease type 1A duplication. Neurology 45:
2090-2093, 1995.

15. Green, M. C.: Genetic variants and strains of the laboratory
mouse.  New York: Oxford Univ. Press (pub.)  1989.

16. Hertz, J. M.; Borglum, A. D.; Brandt, C. A.; Flint, T.; Bisgaard,
C.: Charcot-Marie-Tooth disease type 1A: the parental origin of a
de novo 17p11.2-p12 duplication. Clin. Genet. 46: 291-294, 1994.

17. Hoogendijk, J. E.; de Visser, M.; Bolhuis, P. A.; Hart, A. A.
M.; Ongerboer de Visser, B. W.: Hereditary motor and sensory neuropathy
type I: clinical and neurographical features of the 17p duplication
subtype. Muscle Nerve 17: 85-90, 1994.

18. Huxley, C.; Passage, E.; Manson, A.; Putzu, G.; Figarella-Branger,
D.; Pellissier, J. F.; Fontes, M.: Construction of a mouse model
of Charcot-Marie-Tooth disease type 1A by pronuclear injection of
human YAC DNA. Hum. Molec. Genet. 5: 563-569, 1996.

19. Killian, J. M.; Kloepfer, H. W.: Homozygous expression of a dominant
gene for Charcot-Marie-Tooth neuropathy. Ann. Neurol. 5: 515-522,
1979.

20. Kloepfer, H. W.; Killian, J. M.: Homozygous expression of a dominant
gene causing peroneal muscular atrophy (Charcot-Marie-Tooth disease). Acta
Genet. Med. Gemellol. 23: 217-220, 1974.

21. Lebo, R. V.; Lynch, E. D.; Bird, T. D.; Golbus, M. S.; Barker,
D. F.; O'Connell, P.; Chance, P. F.: Multicolor in situ hybridization
and linkage analysis order Charcot-Marie-Tooth type 1 (CMT1A) gene-region
markers. Am. J. Hum. Genet. 50: 42-55, 1992.

22. LeGuern, E.; Gouider, R.; Lopes, J.; Abbas, N.; Gugenheim, M.;
Tardieu, S.; Ravise, N.; Leger, J.-M.; Vallat, J.-M.; Bouche, P.;
Agid, Y.; Brice, A.; French CMT Collaborative Research Group: Constant
rearrangement of the CMT1A-REP sequences in HNPP patients with a deletion
in chromosome 17p11.2: a study of 30 unrelated cases. Hum. Molec.
Genet. 4: 1673-1674, 1995.

23. Lorenzetti, D.; Pareyson, D.; Sghirlanzoni, A.; Roa, B. B.; Abbas,
N. E.; Pandolfo, M.; Di Donato, S.; Lupski, J. R.: A 1.5-Mb deletion
in 17p11.2-p12 is frequently observed in Italian families with hereditary
neuropathy with liability to pressure palsies. Am. J. Hum. Genet. 56:
91-98, 1995.

24. Lupski, J. R.; Garcia, C. A.; Parry, G. J.; Patel, P. I.: Charcot-Marie-Tooth
polyneuropathy syndrome: clinical, electrophysiological, and genetic
aspects.In: Appel, S.: Current Neurology.  Chicago: Mosby-Yearbook
(pub.)  1991. Pp. 1-25.

25. Lupski, J. R.; Montes de Oca-Luna, R.; Slaugenhaupt, S.; Pentao,
L.; Guzzetta, V.; Trask, B. J.; Saucedo-Cardenas, O.; Barker, D. F.;
Killian, J. M.; Garcia, C. A.; Chakravarti, A.; Patel, P. I.: DNA
duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:
219-232, 1991.

26. Lupski, J. R.; Pentao, L.; Williams, L. L.; Patel, P. I.: Stable
inheritance of the CMT1A DNA duplication in two patients with CMT1
and NF1. Am. J. Med. Genet. 45: 92-96, 1993.

27. Lupski, J. R.; Wise, C. A.; Kuwano, A.; Pentao, L.; Parke, J.
T.; Glaze, D. G.; Ledbetter, D. H.; Greenberg, F.; Patel, P. I.:
Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nature
Genet. 1: 29-33, 1992.

28. Matise, T. C.; Chakravarti, A.; Patel, P. I.; Lupski, J. R.; Nelis,
E.; Timmerman, V.; Van Broeckhoven, C.; Weeks, D. E.: Detection of
tandem duplications and implications for linkage analysis. Am. J.
Hum. Genet. 54: 1110-1121, 1994.

29. Matsunami, N.; Smith, B.; Ballard, L.; Lensch, M. W.; Robertson,
M.; Albertsen, H.; Hanemann, C. O.; Muller, H. W.; Bird, T. D.; White,
R.; Chance, P. F.: Peripheral myelin protein-22 gene maps in the
duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth
1A. Nature Genet. 1: 176-179, 1992.

30. McAlpine, P. J.; Feasby, T. E.; Hahn, A. F.; Komarnicki, L.; James,
S.; Guy, C.; Dixon, M.; Qayyum, S.; Wright, J.; Coopland, G.; Lewis,
M.; Kaita, H.; Philipps, S.; Wong, P.; Koopman, W.; Cox, D. W.; Yee,
W. C.: Localization of a locus for Charcot-Marie-Tooth neuropathy
type Ia (CMT1A) to chromosome 17. Genomics 7: 408-415, 1990.

31. Middleton-Price, H. R.; Harding, A. E.; Monteiro, C.; Berciano,
J.; Malcolm, S.: Linkage of hereditary motor and sensory neuropathy
type I to the pericentromeric region of chromosome 17. Am. J. Hum.
Genet. 46: 92-94, 1990.

32. Middleton-Price, H. R.; Harding, A. E.; Monteiro, C. J.; Berciano,
J.; Malcolm, S.: Linkage of hereditary motor and sensory neuropathy
type I (HMSNI) to the pericentromeric region of chromosome 17.(Abstract) Cytogenet.
Cell Genet. 51: 1044, 1989.

33. Nicholson, G. A.; Mesterovic, N.; Ross, D. A.; Block, J.; McLeod,
J. G.: Linkage of the gene for Charcot-Marie-Tooth neuropathy.(Abstract) Cytogenet.
Cell Genet. 51: 1052-1053, 1989.

34. Ouvrier, R. A.; McLeod, J. G.; Conchin, T. E.: The hypertrophic
forms of hereditary motor and sensory neuropathy: a study of hypertrophic
Charcot-Marie-Tooth disease (HMSN type I) and Dejerine-Sottas disease
(HMSN type III) in childhood. Brain 110: 121-148, 1987.

35. Patel, P. I.; Franco, B.; Garcia, C.; Slaugenhaupt, S. A.; Nakamura,
Y.; Ledbetter, D. H.; Chakravarti, A.; Lupski, J. R.: Genetic mapping
of autosomal dominant Charcot-Marie-Tooth disease in a large French-Acadian
kindred: identification of new linked markers on chromosome 17. Am.
J. Hum. Genet. 46: 801-809, 1990.

36. Patel, P. I.; Garcia, C.; Montes de Oca-Luna, R.; Malamut, R.
I.; Franco, B.; Slaugenhaupt, S.; Chakravarti, A.; Lupski, J. R.:
Isolation of a marker linked to the Charcot-Marie-Tooth disease type
IA gene by differential Alu-PCR of human chromosome 17-retaining hybrids. Am.
J. Hum. Genet. 47: 926-934, 1990.

37. Patel, P. I.; Roa, B. B.; Welcher, A. A.; Schoener-Scott, R.;
Trask, B. J.; Pentao, L.; Snipes, G. J.; Garcia, C. A.; Francke, U.;
Shooter, E. M.; Lupski, J. R.; Suter, U.: The gene for the peripheral
myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease
type 1A. Nature Genet. 1: 159-165, 1992.

38. Pellegrino, J. E.; Pellegrino, L.; Spinner, N. B.; Sladky, J.;
Chance, P. F.; Zackai, E. H.: Developmental profile in a patient
with monosomy 10q and dup(17p) associated with a peripheral neuropathy. Am.
J. Med. Genet. 61: 377-381, 1996.

39. Raeymaekers, P.; Timmerman, V.; De Jonghe, P.; Swerts, L.; Gheuens,
J.; Martin, J.-J.; Muylle, L.; De Winter, G.; Vandenberghe, A.; Van
Broeckhoven, C.: Localization of the mutation in an extended family
with Charcot-Marie-Tooth neuropathy (HMSN I). Am. J. Hum. Genet. 45:
953-958, 1989.

40. Raskind, W. H.; Williams, C. A.; Hudson, L. D.; Bird, T. D.:
Complete deletion of the proteolipid protein gene (PLP) in a family
with X-linked Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 49:
1355-1360, 1991.

41. Schiavon, F.; Mostacciuolo, M. L.; Saad, F.; Merlini, L.; Siciliano,
G.; Angelini, C.; Danieli, G. A.: Non-radioactive detection of 17p11.2
duplication in CMT1A: a study of 78 patients. J. Med. Genet. 31:
880-883, 1994.

42. Silander, K.; Meretoja, P.; Nelis, E.; Timmerman, V.; Van Broeckhoven,
C.; Aula, P.; Savontaus, M.-L.: A de novo duplication in 17p11.2
and a novel mutation in the P(0) gene in two Dejerine-Sottas syndrome
patients. Hum. Mutat. 8: 304-310, 1996.

43. Sorour, E.; Thompson, P.; MacMillan, J.; Upadhyaya, M.: Inheritance
of CMT1A duplication from a mosaic father. J. Med. Genet. 32: 483-485,
1995.

44. Suter, U.; Moskow, J. J.; Welcher, A. A.; Snipes, G. J.; Kosaras,
B.; Sidman, R. L.; Buchberg, A. M.; Shooter, E. M.: A leucine-to-proline
mutation in the putative first transmembrane domain of the 22-kDa
peripheral myelin protein in the trembler-J mouse. Proc. Nat. Acad.
Sci. 89: 4382-4386, 1992.

45. Suter, U.; Patel, P. I.: Genetic basis of inherited peripheral
neuropathies. Hum. Mutat. 3: 95-102, 1994.

46. Suter, U.; Welcher, A. A.; Ozcelik, T.; Snipes, G. J.; Kosaras,
B.; Francke, U.; Billings-Gagliardi, S.; Sidman, R. L.; Shooter, E.
M.: Trembler mouse carries a point mutation in a myelin gene. Nature 356:
241-244, 1992.

47. Takahashi, E.; Takeda, O.; Himoro, M.; Nanao, K.; Takada, G.;
Hayasaka, K.: Localization of PMP-22 gene (candidate gene for the
Charcot-Marie-Tooth disease 1A) to band 17p11.2 by direct R-banding
fluorescence in situ hybridization. Jpn. J. Hum. Genet. 37: 303-306,
1992.

48. Timmerman, V.; Nelis, E.; Van Hul, W.; Nieuwenhuijsen, B. W.;
Chen, K. L.; Wang, S.; Othman, K. B.; Cullen, B.; Leach, R. J.; Hanemann,
C. O.; De Jonghe, P.; Raeymaekers, P.; van Ommen, G.-J. B.; Martin,
J.-J.; Muller, H. W.; Vance, J. M.; Fischbeck, K. H.; Van Broeckhoven,
C.: The peripheral myelin protein gene PMP-22 is contained within
the Charcot-Marie-Tooth disease type 1A duplication. Nature Genet. 1:
171-175, 1992.

49. Timmerman, V.; Raeymaekers, P.; De Jonghe, P.; De Winter, G.;
Swerts, L.; Jacobs, K.; Gheuens, J.; Martin, J.-J.; Vandenberghe,
A.; Van Broeckhoven, C.: Assignment of the Charcot-Marie-Tooth neuropathy
type 1 (CMT 1a) gene to 17p11.2-p12. Am. J. Hum. Genet. 47: 680-685,
1990.

50. Valentijn, L. J.; Bolhuis, P. A.; Zorn, I.; Hoogendijk, J. E.;
van den Bosch, N.; Hensels, G. W.; Stanton, V. P., Jr.; Housman, D.
E.; Fischbeck, K. H.; Ross, D. A.; Nicholson, G. A.; Meershoek, E.
J.; Dauwerse, H. G.; van Ommen, G.-J. B.; Baas, F.: The peripheral
myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease
type 1A. Nature Genet. 1: 166-170, 1992.

51. Vance, J. M.: Hereditary motor and sensory neuropathies. J.
Med. Genet. 28: 1-5, 1991.

52. Vance, J. M.; Barker, D.; Yamaoka, L. H.; Stajich, J. M.; Loprest,
L.; Hung, W.-Y.; Fischbeck, K.; Roses, A. D.; Pericak-Vance, M. A.
: Localization of Charcot-Marie-Tooth disease type 1a (CMT1A) to chromosome
17p11.2. Genomics 9: 623-628, 1991.

53. Vance, J. M.; Nicholson, G.; Yamaoka, L. H.; Stajich, J.; Stewart,
C. S.; Speer, C.; Hung, W.-Y.; Roses, A. D.; Barker, D.; Gaskell,
P. C.; Pericak-Vance, M. A.: Linkage of Charcot-Marie-Tooth neuropathy
type 1a to chromosome 17.(Abstract) Cytogenet. Cell Genet. 51: 1097-1098,
1989.

54. Wulfsberg, E. A.; Weaver, R. P.; Cunniff, C. M.; Jones, M. C.;
Jones, K. L.: Chromosome 10qter deletion syndrome: a review and report
of three new cases. Am. J. Med. Genet. 32: 364-367, 1989.

*FIELD* CS

Muscle:
   Peroneal muscle atrophy and weakness;
   Distal arm and leg muscle atrophy and weakness

Neuro:
   Weak or absent deep tendon reflexes;
   Sensory defect;
   Chronic sensorineural polyneuropathy;
   Liability to pressure palsies (.0004)

Skin:
   Hyperhidrosis;
   Penetrating foot ulcers

Limbs:
   Pes cavus;
   Trophic limb changes

GI:
   Chronic diarrhea;
   Nausea;
   Vomiting

Cardiac:
   Heart block

Oncology:
   Enhanced neurotoxicity of vincristine

Misc:
   More severe in homozygotes;
   Most common form;
   Average onset age 12 years

Lab:
   Slowing of nerve conduction less marked;
   Onion bulb formation on sural nerve biopsy less

Inheritance:
   Autosomal dominant (17p11.2), also other autosomal dominant forms,
   as well as autosomal recessive (.0005), and X-linked forms;
   DEJERINE-SOTTAS SYNDROME HMSN III (.0006, .0007)

Neuro:
   Neonatal hypotonia;
   Delayed motor milestones with normal speech development;
   Absent deep tendon reflexes;
   Distal decreased sensation in all limbs;
   Ataxia;
   Scanning speech;
   Nystagmus

Limbs:
   Pes cavus early;
   Marked distal lower leg atrophy;
   Intrinsic hand muscle weakness;
   Claw hand

Skel:
   Kyphoscoliosis

Muscle:
   Muscle weakness at birth;
   Muscle cramping;
   Fasciculations

Misc:
   Clinical features more severe than CMT type 1a;
   Exacerbations and remissions

Lab:
   Hypertrophic, demyelinating neuropathy

Inheritance:
   Autosomal dominant (17p11.2), also other autosomal dominant forms,
   as well as autosomal recessive (.0005), and X-linked forms

*FIELD* CN
Moyra Smith - updated: 01/27/1997
Moyra Smith - Updated: 6/13/1996
Moyra Smith - Updated: 5/25/1996
Orest Hurko - updated: 4/2/1996
Orest Hurko - updated: 4/1/1996
Orest Hurko - updated: 3/22/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/27/1997
jamie: 1/21/1997
terry: 1/14/1997
mark: 6/19/1996
carol: 6/13/1996
carol: 5/25/1996
terry: 4/15/1996
mark: 4/2/1996
terry: 4/1/1996
mark: 3/22/1996
terry: 3/14/1996
mark: 3/12/1996
mark: 3/5/1996
mark: 3/2/1996
mark: 2/28/1996
terry: 2/21/1996
terry: 2/20/1996
mark: 2/14/1996
terry: 2/8/1996
mark: 1/12/1996
mark: 9/22/1995
terry: 3/27/1995
carol: 3/2/1995
pfoster: 7/26/1994
jason: 7/19/1994
mimadm: 6/25/1994

*RECORD*
*FIELD* NO
118230
*FIELD* TI
118230 CHARCOT-MARIE-TOOTH DISEASE, GUADALAJARA NEURONAL TYPE
*FIELD* TX
Ruiz et al. (1987) described a father and 2 sons with clinical and
electrophysiological features of hereditary motor and sensory
neuropathy, neuronal type, with onset in infancy, as well as histologic
features of neurogenic myopathy. The 2 sons, aged 2 and 3.33 years,
showed congenital contraction deformities of the feet and delayed motor
development. All 3 also had laryngeal abnormalities, peculiar facies,
short neck, narrow shoulders, and protruding chest. Both sons showed
inspiratory stridor at birth as well as flexion contractures. The father
had stridor during the first months of life, crawled until 4 years of
age, and then began to walk with a clumsy gait and frequent falls.

*FIELD* RF
1. Ruiz, C.; Rivas, F.; Ramirez-Casillas, G.; Vazquez-Santana, R.;
Mendoza-Chalita, B.; Feria-Velasco, A.; Tapia-Arizmendi, G.; Cantu,
J. M.: A distinct congenital motor and sensory neuropathy (neuronal
type) with dysmorphic features in a father and two sons: a variant
of Charcot-Marie-Tooth disease. Clin. Genet. 31: 109-113, 1987.

*FIELD* CS

Muscle:
   Peroneal muscle atrophy and weakness;
   Distal arm and leg muscle atrophy and weakness

Neuro:
   Weak or absent deep tendon reflexes;
   Sensory defect;
   Chronic sensorineural polyneuropathy;
   Delayed motor development

Skin:
   Hyperhidrosis;
   Penetrating foot ulcers

Limbs:
   Congenital foot contraction deformities;
   Flexion contractures;
   Pes cavus;
   Trophic limb changes

Resp:
   Laryngeal abnormalities;
   Neonatal inspiratory stridor

Facies:
   Peculiar facies

Neck:
   Short neck

Thorax:
   Narrow shoulders;
   Protruding chest

GI:
   Chronic diarrhea;
   Nausea;
   Vomiting

Cardiac:
   Heart block

Oncology:
   Enhanced neurotoxicity of vincristine

Misc:
   More severe in homozygotes;
   Infantile onset

Lab:
   Normal or slightly reduced nerve conduction velocity;
   Axonal loss with little evidence of demyelination or hypertrophic
   changes in nerve biopsies

Inheritance:
   Autosomal dominant;
   also other autosomal dominant forms, as well as autosomal recessive,
   and X-linked forms

*FIELD* CD
Victor A. McKusick: 3/27/1987

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 3/27/1987

*RECORD*
*FIELD* NO
118300
*FIELD* TI
*118300 CHARCOT-MARIE-TOOTH DISEASE AND DEAFNESS
*FIELD* TX
Lemieux and Neemeh (1967) described 2 families, each with multiple cases
of CMT disease. In two of one family and one of the other, chronic
nephritis was also present. Foam cells were seen in the interstitium in
one, and two of the three had nerve deafness. These patients did not
have the nonspecific polyneuropathy, due possibly to chronic uremia,
occasionally associated with Alport syndrome. Amyloidosis, a cause of
nephritis and a condition misdiagnosed as CMT disease, was apparently
excluded. Hanson et al. (1970) reported a sporadic case. Kousseff et al.
(1982) and Kousseff (1982) described a family in which 82 persons in 7
generations appear to have had this disorder. Male-to-male transmission
was observed 13 times. Onset occurred in childhood with weakness of
peroneal muscles, followed by atrophy, pes calcaneovarus, steppage gait,
poor balance, and diminished sensation in the legs. Other distal muscles
of the arms and legs became involved, resulting in claw-hands, pes
cavus, hammer toes, and absent deep tendon reflexes. Neuropathy was
demonstrated by electromyography. Sensorineural hearing loss, which
became apparent in the second decade, was severe to profound in most
affected persons after the third decade. Pyeritz (1979) examined 3
affected members of 2 generations of a western Maryland kindred, and
Gummerson (1981) examined several members of a southern Pennsylvania
kindred in both of which classic CMT was always associated with
sensorineural deafness. No instance of renal disease occurred in either
pedigree. A common surname suggested that the kindreds were distantlyy
related. Hamiel et al. (1993) described as a 'new variant' a
3-generation family in which hereditary motor-sensory neuropathy with
sensorineural deafness became apparent in early childhood and infancy.
Both linkage to Duffy blood group, as demonstrated in the CMT1B form of
the disease (159440), and the duplication of the peripheral myelin
protein 22 gene (601097) usually found with CMT1A (118220), the
chromosome 17 form of the disease, were excluded. Male-to-male
transmission was observed.

See 214370 for a possibly autosomal recessive form of CMT-deafness
syndrome and 311070 for an X-linked disorder that includes optic atrophy
also.

*FIELD* RF
1. Gummerson, K. S.: Personal Communication. Baltimore, Md.  1981.

2. Hamiel, O. P.; Raas-Rothschild, A.; Upadhyaya, M.; Frydman, M.;
Sarova-Pinhas, I.; Brand, N.; Passwell, J. H.: Hereditary motor-sensory
neuropathy (Charcot-Marie-Tooth disease) with nerve deafness: a new
variant. J. Pediat. 123: 431-434, 1993.

3. Hanson, P. A.; Farber, R. E.; Armstrong, R. A.: Distal muscle
wasting, nephritis, and deafness. Neurology 20: 426-434, 1970.

4. Kousseff, B. G.: Inheritance of Charcot-Marie-Tooth disease with
sensorineural hearing loss.   (Abstract) Clin. Res. 30: 292A, 1982.

5. Kousseff, B. G.; Hadro, T. A.; Treiber, D. L.; Wollner, T.; Morris,
C.: Charcot-Marie-Tooth disease with sensorineural hearing loss--an
autosomal dominant trait. Birth Defects Orig. Art. Ser. 18: 223-228,
1982.

6. Lemieux, G.; Neemeh, J. A.: Charcot-Marie-Tooth disease and nephritis.
Canad. Med. Assoc. J. 97: 1193-1198, 1967.

7. Pyeritz, R. E.: Personal Communication. Baltimore, Md.  1979.

*FIELD* CS

Ears:
   Sensorineural hearing loss

GU:
   Nephritis

Muscle:
   Peroneal muscle weakness

Limbs:
   Pes calcaneovarus;
   Claw hand;
   Pes cavus;
   Hammertoes

Neuro:
   Steppage gait;
   Poor balance;
   Diminished leg sensation;
   Absent deep tendon reflexes

Misc:
   Childhood onset

Lab:
   Neuropathy by electromyography

Inheritance:
   Autosomal dominant;
   also an X-linked form (includes optic atrophy), and possibly an autosomal
   recessive form

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/05/1996
mimadm: 6/25/1994
carol: 1/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
118301
*FIELD* TI
118301 CHARCOT-MARIE-TOOTH DISEASE WITH PTOSIS AND PARKINSONISM
*FIELD* TX
Tandan et al. (1990) described an apparently 'new' disorder combining
neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and mild
dementia. The propositus, a 72-year-old man, had pes cavus, peripheral
neuropathy, ptosis, parkinsonism, hyperreflexia, orthostatic
hypotension, central hypoventilation, and mild dementia. Several family
members in 3 generations, with at least 1 instance of male-to-male
transmission, had pes cavus, neuropathy, ptosis, parkinsonism, and
dementia, although not all of the features were consistently present.
Survival past the seventh decade was common. Autopsy in 2 affected
members showed that the neuropathy was axonal; mild to moderate loss of
anterior horn cells in the spinal cord and pigmentary loss with gliosis
in the substantia nigra were other findings.

*FIELD* RF
1. Tandan, R.; Taylor, R.; Adesina, A.; Sharma, K.; Fries, T.; Pendlebury,
W.: Benign autosomal dominant syndrome of neuronal Charcot-Marie-Tooth
disease, ptosis, parkinsonism, and dementia. Neurology 40: 773-779,
1990.

*FIELD* CS

Muscle:
   Peroneal muscle atrophy and weakness;
   Distal arm and leg muscle atrophy and weakness

Neuro:
   Ptosis;
   Parkinsonism;
   Dementia;
   Hyperreflexia;
   Orthostatic hypotension;
   Central hypoventilation;
   Weak or absent deep tendon reflexes;
   Sensory defect;
   Chronic sensorineural polyneuropathy

Skin:
   Hyperhidrosis;
   Penetrating foot ulcers

Limbs:
   Pes cavus;
   Trophic limb changes

GI:
   Chronic diarrhea;
   Nausea;
   Vomiting

Cardiac:
   Heart block

Oncology:
   Enhanced neurotoxicity of vincristine

Misc:
   More severe in homozygotes

Lab:
   Mild to moderate loss of anterior horn cells in the spinal cord and
   substantia nigral pigmentary loss with gliosis;
   Normal or slightly reduced nerve conduction velocity;
   Axonal loss with little evidence of demyelination or hypertrophic
   changes in nerve biopsies

Inheritance:
   Autosomal dominant, also other autosomal dominant forms, as well as
   autosomal recessive, and X-linked forms

*FIELD* CD
Victor A. McKusick: 7/10/1990

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 7/10/1990

*RECORD*
*FIELD* NO
118330
*FIELD* TI
118330 CHEILITIS GLANDULARIS
*FIELD* TX
Cheilitis glandularis is characterized by enlargement and eversion of
the lower lip associated with hypertrophy of the labial mucous glands,
dilatation of the excretory ducts, and variable inflammation. In whites,
it is associated with a relatively high incidence of squamous cell
carcinoma of the lower lip, presumably due to actinic exposure of the
mucosa. Weir and Johnson (1971) described the disorder in a black man
and his son and daughter.

*FIELD* SA
Rada et al. (1985)
*FIELD* RF
1. Rada, D. C.; Koranda, F. C.; Katz, F. S.: Cheilitis glandularis-a
disorder of ductal ectasia. J. Derm. Surg. Oncol. 11: 372-375,
1985.

2. Weir, T. W.; Johnson, W. C.: Cheilitis glandularis. Arch. Derm. 103:
433-437, 1971.

*FIELD* CS

Mouth:
   Enlarged everted lower lip;
   Labial mucous gland hypertrophy;
   Dilatation of excretory ducts;
   Variable inflammation

Oncology:
   Increased lower lip squamous cell carcinoma

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 2/25/1988

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 2/25/1988

*RECORD*
*FIELD* NO
118350
*FIELD* TI
118350 CHEMODECTOMA, INTRAABDOMINAL, WITH CUTANEOUS ANGIOLIPOMAS
*FIELD* TX
Lee et al. (1977) described 2 brothers with cutaneous angiolipomas and
retroperitoneal chemodectomas. Both died of malignant dissemination of
the chemodectomas. Two other brothers died of tumors before age 45, and
one of them also had skin lumps. Thus, they may have been affected also.
See paragangliomata (168000).

*FIELD* RF
1. Lee, S. P.; Nicholson, G. I.; Hitchcock, G.: Familial abdominal
chemodectomas with associated cutaneous angiolipomas. Pathology 9:
173-177, 1977.

*FIELD* CS

Oncology:
   Cutaneous angiolipomas;
   Retroperitoneal chemodectomas

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/17/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
118400
*FIELD* TI
*118400 CHERUBISM
*FIELD* TX
Swelling of the lower face begins around the third or fourth year of
life and progresses until the late teens. The enlargement may be
exaggerated by enlargement of submandibular lymph nodes. X-ray reveals
multilocular cystic changes in the mandible and maxilla and often in the
anterior ends of the ribs. Though clinical swelling usually abates by
the third decade, radiographic changes commonly persist into the fourth
decade. The condition must be differentiated from Caffey disease
(114000) in which the x-ray appearance is different and involvement of
the skeleton, e.g., the tibia, is more widespread. It is, like Caffey
disease, a benign self-limited condition. The disorder has also been
called familial benign giant-cell tumor of the jaw, familial
multilocular cystic disease of the jaw, etc. Jones (1965) pointed out
that lack of signs or history in either parent does not exclude the
possibility of one's being affected. In one of his cases (he was the
first to describe the entity), the disorder would not have been
discovered, or even suspected, were it not that x-rays were made in
childhood in a deliberate search for the entity because of its
occurrence in other members of the family. Salinas et al. (1983)
reported 2 cases of cherubism with multilocular cystic lesions of the
ribs in addition to those of the mandible. In 1 of the patients, biopsy
of both the jaw and the rib lesions showed numerous multinucleated giant
cells in cellular fibrous tissue.

Quan et al. (1995) described cherubism in association with mental
retardation due to mosaicism for expansion and deletion of the FMR1 CGG
repeat, i.e., the fragile X syndrome (309550). Although these were
probably independent mutations, Quan et al. (1995) pointed out the
peculiarities of the inheritance of cherubism, which has been thought to
be an autosomal dominant: twice as many males are affected as females
and, while penetrance in males is 100%, penetrance in females is only
50-70%.

*FIELD* SA
Anderson and McClendon (1962); Burland  (1962); Khosla and Korobkin
(1970); Peters  (1979); Salzano and Ebling (1966); Thompson  (1959)
*FIELD* RF
1. Anderson, D. E.; McClendon, J. L.: Cherubism-hereditary fibrous
dysplasia of the jaws. I. Genetic considerations. Oral Surg. 15
(suppl. 2): 5-16, 1962.

2. Burland, J. G.: Cherubism: familial bilateral osseous dysplasia
of the jaws. Oral Surg. 15 (suppl. 2): 43-68, 1962.

3. Jones, W. A.: Cherubism: a thumbnail sketch of its diagnosis and
a conservative method of treatment. Oral Surg. 20: 648-653, 1965.

4. Khosla, V. M.; Korobkin, M.: Cherubism. Am. J. Dis. Child. 120:
458-461, 1970.

5. Peters, W. J. N.: Cherubism: a study of twenty cases from one
family. Oral Surg. 47: 307-311, 1979.

6. Quan, F.; Grompe, M.; Jakobs, P.; Popovich, B. W.: Spontaneous
deletion in the FMR1 gene in a patient with fragile X syndrome and
cherubism. Hum. Molec. Genet. 4: 1681-1684, 1995.

7. Salinas, C. F.; Bradford, B. F.; Laden, S. A.; Neville, B. W.:
Cherubism associated with rib anomalies.  (Abstract) Proc. Greenwood
Genet. Center 2: 129-130, 1983.

8. Salzano, F. M.; Ebling, H.: Cherubism in a Brazilian kindred.
Acta Genet. Med. Gemellol. 15: 296-301, 1966.

9. Thompson, N.: Cherubism: familial fibrous dysplasia of the jaws.
Brit. J. Plast. Surg. 12: 89-103, 1959.

*FIELD* CS

Facies:
   Round face;
   Broad cheeks;
   Hypertelorism;
   Maxillary enlargement;
   Lower face swelling;
   Enlarged submandibular lymph nodes;
   Prognathism

Teeth:
   Oligodontia;
   Malocclusion

Radiology:
   Multilocular cystic changes in mandible, maxilla and ribs

Lab:
   Numerous multinucleated giant cells in cellular fibrous tissue

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 9/22/1995
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
118420
*FIELD* TI
118420 CHIARI MALFORMATION TYPE I
*FIELD* TX
In the Chiari type I malformation, the cerebellar tonsils and a small
part of the medulla oblongata herniate through the foramen magnum, often
in association with syringomyelia (186700). (The Chiari type II
malformation, which in addition involves herniation of the vermis and
the fourth ventricle, is usually associated with hydrocephalus and
neural tube defects.) Coria et al. (1983) described a family in which
members in 3 generations showed Chiari I malformation in association
with marked occipital dysplasia causing a small and flat posterior
fossa, as demonstrated by plain skull x-ray films. Stovner et al. (1992)
described Chiari type I malformation in 2 adult monozygotic female
twins, their mother, and possibly in 2 of their 4 daughters. The
diagnosis was made by magnetic resonance imaging (MRI) and confirmed at
the time of surgery in 1 twin. Monozygosity of the twins was proved by
DNA typing. The twins were discordant for the extent of herniation of
the cerebellar tonsils, and syringomyelia was present in only 1.
Although the occipital squama appeared somewhat short in some of the
patients, no other bony abnormalities were found on MRI. The neural
deformities in this family were classified by Stovner et al. (1992) with
the familial craniocervical malformations. Neonatal pertussis resulting
in much coughing in one of the twins may have created a craniospinal
pressure gradient that increased the impaction of the cerebellar tonsils
in the foramen magnum and may have precipitated the development of
syringomyelia in the genetically predisposed twin. Symptoms in the adult
twins began in connection with or right after the first pregnancies. The
physical strains and hormonal changes of that period may have been
responsible.

*FIELD* RF
1. Coria, F.; Quintana, F.; Rebollo, M.; Combarros, O.; Berciano,
J.: Occipital dysplasia and Chiari type I deformity in a family.
J. Neurol. Sci. 62: 147-158, 1983.

2. Stovner, L. J.; Cappelen, J.; Nilsen, G.; Sjaastad, O.: The Chiari
type I malformation in two monozygotic twins and first-degree relatives.
Ann. Neurol. 31: 220-222, 1992.

*FIELD* CS

Neuro:
   Cerebellar tonsils and part of medulla oblongata herniated through
   the foramen magnum;
   Associated syringomyelia

Radiology:
   Small flat posterior fossa;
   Occipital dysplasia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 5/12/1992

*FIELD* ED
mimadm: 6/25/1994
carol: 6/11/1992
carol: 5/12/1992

*RECORD*
*FIELD* NO
118423
*FIELD* TI
*118423 CHIMERIN, N-; CHN
ALPHA-1-CHIMERIN
ALPHA-2-CHIMERIN, INCLUDED
*FIELD* TX
Hall et al. (1990) isolated a novel human brain cDNA sequence encoding
n-chimerin, a 34,000 M(r) protein. They found that the N-terminal half
shared almost 50% identity with sequences in the regulatory domain of
protein kinase C (176960); the C-terminal half had 42% identity with the
C-terminal region of BCR, the product of the breakpoint cluster region
gene involved in the Philadelphia chromosome translocation (151410).

Also known as alpha-1-chimerin, n-chimerin is a brain GTPase-activating
protein (GAP) for the RAS-related p21 (RAC). Hall et al. (1993) found
another form of chimerin, termed alpha-2-chimerin, and showed that it is
the product of an alternately spliced transcript of the human n-chimerin
gene. The mRNAs corresponding to the 2 forms of chimerin were expressed
differently. The single human n-chimerin gene was mapped to 2q31-q32.1
by Southern analysis of a hybrid cell DNA panel and by fluorescence in
situ hybridization.

*FIELD* RF
1. Hall, C.; Monfries, C.; Smith, P.; Lim, H. H.; Kozma, R.; Ahmed,
S.; Vanniasingham, V.; Leung, T.; Lim, L.: Novel human brain cDNA
encoding a 34,000 M(r) protein n-chimaerin, related to both the regulatory
domain of protein kinase C and BCR, the product of the breakpoint
cluster region gene. J. Molec. Biol. 211: 11-16, 1990.

2. Hall, C.; Sin, W. C.; Teo, M.; Michael, G. J.; Smith, P.; Dong,
J. M.; Lim, H. H.; Manser, E.; Spurr, N. K.; Jones, T. A.; Lim, L.
: Alpha-2-chimerin, an SH2-containing GTPase-activating protein for
the ras-related protein p21-rac derived by alternate splicing of the
human n-chimerin gene, is selectively expressed in brain regions and
testes. Molec. Cell. Biol. 13: 4986-4998, 1993.

*FIELD* CD
Victor A. McKusick: 4/5/1994

*FIELD* ED
carol: 4/5/1994

*RECORD*
*FIELD* NO
118425
*FIELD* TI
*118425 CHLORIDE CHANNEL 1, SKELETAL MUSCLE; CLCN1
CHLORIDE CHANNEL, MUSCLE; CLC1
*FIELD* TX
The muscle chloride channel CLC-1 regulates the electric excitability of
the skeletal muscle membrane. Skeletal muscle has an unusually high
resting Cl(-) conductance and in vitro studies suggest that reduction of
this conductance causes electrical instability and resulting myotonia in
both humans and animal models. Muscle Cl(-) conductance is predominantly
mediated by the CLC-1 chloride channel.

By homology screening with the major rat skeletal muscle chloride
channel CLC1, Koch et al. (1992) cloned a partial human CLC1 cDNA that
covered about 80% of the coding sequence. This region was 88% identical
to the rat channel in amino acid sequence. By blot hybridization to a
panel of chromosome 7-specific, human-mouse somatic cell hybrids, they
mapped the CLC1 gene to 7q32-qter. With RFLPs in the CLC1 gene, they
demonstrate that the locus is linked to the T-cell receptor beta locus
(186930) at 7q35; maximum lod = 5.23 at theta = 0.0. In the mouse, it
had previously been demonstrated that the corresponding loci are linked
on chromosome 6, which shows other evidence of homology of synteny to
human 7q (Steinmeyer et al., 1991). The gene is also symbolized CLCN1.

Using both a TCRB probe and a CLC1 probe, Koch et al. (1992)
demonstrated linkage to the recessive form of generalized myotonia
(Becker disease; 255700); maximum lod with CLC1 = 4.69 at theta = 0.0
and maximum lod with TCRB = 2.53 at theta = 0.0. The maximum multipoint
lod score was 5.79 at theta = 0.0. In one family with recessive myotonia
in 3 sons of consanguineous parents, an unusual RFLP pattern was found
and demonstrated to have been generated by a disease-causing mutation: a
T-to-G transversion in an exonic sequence predicting a phe-to-cys
exchange. The altered phe, located toward the end of a putative membrane
span, is highly conserved among different members of the voltage-gated
chloride ion channel family.

Koch et al. (1992) also studied linkage to CLC1 in 4 families with
myotonia congenita of the dominant form (Thomsen disease; 160800). They
found a maximum multipoint lod score of 4.58 at theta = 0.0. Thus, it
appeared that mutations in the CLC1 gene can cause either dominant or
recessive myotonia congenita. A recessive form was explicable on the
basis of total loss of function. A mutation acting dominantly in
producing Thomsen disease might be explained by a homomultimeric
structure of the channel, whereby the channel subunit encoded by the
mutated gene associates with and inactivates the functional subunits
encoded by the normal allele.

Lorenz et al. (1994) showed that the protein coding sequence of the
CLCN1 gene is organized into 23 exons. Its upstream region contains a
canonical TATA box, several consensus binding sites for myogenic
transcription factors, and 2 other putative regulatory elements.

By SSCP analysis, Meyer-Kleine et al. (1995) systematically screened the
open reading frame of the CLCN1 gene in 24 families and 17 single
unrelated patients with myotonia. By direct sequencing of aberrant
conformers, they found 15 different mutations in a total of 18 unrelated
families and 13 single patients. Of these, 10 were novel: 7 missense
mutations, 2 mutations leading to a frameshift, and 1 mutation predicted
to affect splicing. In their overall sample of 94 Becker myotonia
chromosomes, they were able to detect 48 (51%) mutant alleles. Three
mutations accounted for 32% of the Becker chromosomes in the German
population; these were phe413-to-cys (118425.0001), arg894-to-ter, and a
14-bp deletion in exon 13. They concluded that A437T is probably a
polymorphism. This had been described by Koty et al. (1994) as a
disease-causing mutation in an American family with Becker myotonia.
Meyer-Kleine et al. (1995) observed it in 3 myotonia families and in 5
of 200 control chromosomes. A mutant A437T cRNA was functionally
expressed in xenopus oocytes and found to induce currents that were
indistinguishable from wildtype currents. Meyer-Kleine et al. (1995)
also demonstrated that the R894X mutation can act as a recessive or a
dominant, probably depending on the genetic background. Functional
expression of the R894X mutant in xenopus oocytes revealed a large
reduction, but not complete abolition, of chloride currents. Further, it
had a weak dominant negative affect on wildtype currents in coexpression
studies. Reduction of currents predicted for heterozygous carriers were
close to the borderline value, sufficient to elicit myotonia.

In a screening of 6 unrelated patients with recessive Becker-type
myotonia, Mailander et al. (1996) identified 4 novel CLCN1 mutations and
a previously reported 14-bp deletion (118425.0009). Five patients were
homozygous and the sixth patient was a compound heterozygote.
Heterozygous carriers of the Becker mutation did not display any
clinical symptoms of myotonia; however, all heterozygous males, but none
of the heterozygous females, exhibited myotonic discharges in the
electromyogram, suggesting a gene-dosage effect of the mutations on
chloride conductance and a male predominance of subclinical myotonia.

Pusch et al. (1995) used a Xenopus transfection to demonstrate shifting
of the gating of CIC-1 toward positive voltages by 4 different mutations
identified in patients. When these mutant cDNAs were coexpressed with
wildtype subunits, they imposed altered voltage dependence on the
heteromeric channels which would then open only in a voltage range where
they could not contribute significantly to the repolarization of action
potentials. Without such repolarizations, sodium channels have enough
time to recover from inactivation leading to typical myotonic runs,
which are a series of repetitive action potentials.

ANIMAL MODEL

The adr mouse (Steinmeyer et al., 1991) is an authentic model of Becker
disease in the human.

Beck et al. (1996) noted that the current hypotheses regarding the
pathophysiology of myotonia congenita, or Thomsen disease (160800), were
initially formulated from studies of the myotonic goat, an unusual breed
afflicted with severe autosomal dominant congenital myotonia that
closely resembles the human disease clinically and in its mode of
inheritance. These animals are often referred to as 'fainting,'
'nervous,' 'stiff-legged,' or 'epileptic' goats because of their
tendency to develop severe acute muscle stiffness and become immobile
(and often fall) when attempting to make sudden forceful movements or
when startled. The pathogenesis of myotonia in the goat was elucidated
by Bryant and colleagues (Bryant, 1962, Lipicky and Bryant, 1966) who
first described a severely diminished resting chloride conductance in
muscle fibers from affected animals. The same group (Adrian and Bryant,
1974) also demonstrated that myotonia could be produced in normal
skeletal muscle fibers bathed in a chloride-free solution. Beck et al.
(1996) demonstrated the molecular basis for the decreased muscle
chloride conductance in this historically important animal model. They
found a single nucleotide change (GCC to CCC) causing the substitution
of proline for the conserved alanine-885 residue in the C-terminus in
the goat muscle chloride channel, 104 residues from the termination
codon. Heterologous expression of the mutation demonstrated a
substantial (+47 mV) shift in the midpoint of steady-state activation of
the channel, resulting in a diminished channel open probability at
voltages near the resting membrane potential of skeletal muscle.

*FIELD* AV
.0001
MYOTONIA CONGENITA, RECESSIVE BECKER TYPE
CLCN1, PHE413CYS
In 3 brothers with generalized myotonia congenita of the Becker type,
born of consanguineous parents, Koch et al. (1992) identified an unusual
RFLP associated with the CLC1 gene and demonstrated that it was
generated directly by a disease-causing mutation, a T-to-G transversion
predicted to cause a phe-to-cys exchange toward the end of putative
membrane span D8. The affected individuals were homozygous. Koch et al.
(1993) found the T-to-G missense mutation in 15% of chromosomes carrying
a gene for recessive myotonia congenita.

.0002
MYOTONIA CONGENITA, DOMINANT THOMSEN TYPE
CLCN1, GLY180GLU
By means of SSCP analysis, George et al. (1993) screened DNA from
members of 4 unrelated pedigrees with autosomal dominant myotonia
congenita (Thomsen disease; 160800). In 3 of the families, abnormal
bands were detected in all affected individuals, but in no unaffected
individuals. Direct sequencing revealed a G-to-A transition that
resulted in the substitution of glutamic acid for glycine-180, located
between the third and fourth predicted membrane-spanning segments. This
glycine residue is conserved in all known members of this class of
chloride channel proteins.

Fahlke et al. (1997) referred to this mutation as gly230glu (G230E).
They performed site-directed mutagenesis of the CLCN1 gene and used the
mutant form predicted to result in a substitution of glycine-230 by
glutamic acid between segments D3 and D4 to study pore properties of a
recombinant human muscle channel expressed in a mammalian cell line. The
G230E mutation caused substantial changes in anion and cation
selectivity, as well as a fundamental change in rectification of the
current-voltage relationship. Whereas wildtype channels were
characterized by pronounced inward rectification and a characteristic
pattern of selectivity, G230E exhibited outward rectification at
positive potentials and a different pattern of selectivity. Furthermore,
the cation-to-anion permeability ratio of the mutant was much greater
than that of the wildtype channel.

.0003
MYOTONIA CONGENITA, RECESSIVE BECKER TYPE
CLCN1, IVSDS, G-A, +1
In a German family with recessive myotonia, Lorenz et al. (1994) showed
by single-strand conformation polymorphism analysis (SSCA) that affected
members were compound heterozygotes. One mutation, a G-to-A transition
at nucleotide 979, affected a splice consensus site at the end of exon
8; on the other allele, a G-to-T transversion at nucleotide 1488 in exon
14 led to replacement of a positively charged arginine in a highly
conserved putative transmembrane domain by serine (R496S). Functional
expression of R496S cRNA in Xenopus oocytes yielded no detectable
currents. Furthermore, it did not suppress wildtype currents in
coexpression assay, confirming it as a recessive mutation.

The G-to-A mutation in exon 8 was stated to affect the last nucleotide
of the exon. If this interfered with mRNA splicing at that exon/intron
boundary, the translation product would be terminated by a stop codon
after 51 additional amino acids or other splice sites in the intron
might be used. Alternatively, if splicing were normal, this mutation
would lead to a substitution of isoleucine for valine at position 327
(V327I). Since this residue is not conserved among the members of this
gene family and most members have negatively charged glutamate residues
at this position, it is unlikely that such a substitution would have a
dramatic effect on channel function. This would argue for an aberrant
splicing as the effect of the G979A mutation.

.0004
MYOTONIA CONGENITA, RECESSIVE BECKER TYPE
CLCN1, ARG496SER
See 118425.0003 for a description of this mutation in compound
heterozygous state in a German family with recessive Becker type
myotonia congenita.

.0005
MYOTONIA CONGENITA, RECESSIVE BECKER TYPE
CLCN1, GLY482ARG
Koch et al. (1994) identified a G482R mutation in a family with
recessive Becker type myotonia congenita. It is remarkable that this
mutation producing a recessive phenotype is only 2 codons removed from
the pro480-to-leu mutation which results in the dominant Thomsen type of
myotonia congenita.

.0006
MYOTONIA CONGENITA, DOMINANT THOMSEN TYPE
CLCN1, PRO480LEU
Koch et al. (1994) identified a P480L mutation in the CLCN1 gene in a
family with myotonia congenita. Koch (1995) indicated that the myotonia
was of the dominant Thomsen type. Pusch et al. (1995) transfected cDNA
bearing this mutation into Xenopus oocytes, demonstrating a shift of the
gating toward positive voltages. In further structure studies, they
replaced isoleucine 290 by 18 different amino acids. Substitution with
valine shifted the gating by -17 milivolts. In all other replacements,
the gating was either shifted to more positive voltages or resulted in
no current above background.

.0007
MYOTONIA LEVIOR
CLCN1, GLN552ARG
Lehmann-Horn et al. (1995) stated that CLCN1 mutations had been
discovered in 6 families with Thomsen disease, including Dr. Thomsen's
own family, and that several other CLCN1 mutations had been found as the
cause of the recessive Becker type of myotonia. Lehmann-Horn et al.
(1995) commented that Becker himself, trying to classify all the many
myotonic kindreds available to him into either the dominant or the
recessive category, had found that many with a dominant mode of
inheritance exhibited a clinical picture that did not fit the classic
form of Thomsen disease. This puzzle was clarified by the finding of
mutations in the gene encoding the alpha subunit of the muscle sodium
channel (SCN4A; 170500). These atypical Thomsen cases, now classified as
potassium-aggravated myotonias, are more common than Thomsen disease. In
another form of dominant myotonia, referred to as myotonia levior,
chloride conductance measurements yielded ambiguous results (Iaizzo et
al., 1991). For that reason, Lehmann-Horn et al. (1995) searched
systematically for a CLCN1 mutation and, indeed, found a gln552-to-arg
substitution. Thus, the disease is a variant (or allelic form) of
Thomsen disease due to a mutation leading to low clinical expressivity.

The patients in the study of Lehmann-Horn et al. (1995) with myotonia
levior were 2 brothers of ages 27 and 25 at the time of report. Since
the age of approximately 5 years, they complained of impeded muscle
relaxation which was pronounced when exercise was initiated and was
similar in degree to their mother's myotonia. Clinical examination
showed normal development of skeletal muscles, lid lag, percussion
myotonia, mild myotonia (pronounced in the forearm muscles) with warm-up
phenomenon but no transient or permanent weakness. The EMG revealed
myotonic runs. Neither cooling of the forearm nor oral potassium load
affected myotonia or force. Muscle biopsy and CT scans of thigh and leg
muscles were normal.

.0008
THOMSEN DISEASE
CLCN1, ILE290MET
In several members of a typical Thomsen myotonia family, Lehmann-Horn et
al. (1995) found a C-to-G base change at position 870 of the CLCN1 cDNA;
it predicted an ile290-to-met substitution.

.0009
MYOTONIA CONGENITA
CLCN1, 14-BP DEL
In a family in which the index patient and his mother had been examined
by Becker (1977) who classified their disorder as dominant myotonia
congenita, Lehmann-Horn et al. (1995) found that the proband had
homozygosity for a deletion in exon 13 of CLCN1. This was precisely the
same 14-bp deletion (involving nucleotides 1437-1450) leading to a
premature stop codon as reported by Meyer-Kleine et al. (1994). In
heterozygous form, this deletion was observed in both non-myotonic sons
of the index patient and also in 2 index patients with a clinical
diagnosis of recessive myotonia congenita. In addition, the index
patient in the MC-3 family originally diagnosed by Becker (1977) was
found to be homozygous for a T-to-G transversion at nucleotide 352
located in exon 3, predicting a trp118-to-gly substitution. Since his
sons, who had neither clinical nor EMG myotonia, as well as 4 other
unrelated myotonia index patients of different ethnic origin and 7 out
of 205 healthy controls, were heterozygous for this base change, it was
considered to be a polymorphism.

.0010
BECKER DISEASE
CLCN1, GLU291LYS
Pusch et al. (1995) discovered this mutation in 2 siblings, both
compound heterozygotes for R894X/E291K. When cDNA was injected into
Xenopus oocytes for expression, E291K channels did not yield currents
between -140 and 100 milivolts, indicating that this mutation totally
abolished channel activity. In contrast to mutations in the neighboring
amino acid (118425.0006), all of which appear to act as dominants as a
result of interactions with wildtype monomers, the E291K mutation is a
recessive. Whereas the 290 mutants shift the voltage dependence of
chloride channels positive (via homomers or heteromers with wildtype
subunits), the E291K mutation shows no evidence of interaction nor does
it shift the voltage dependence.

*FIELD* RF
1. Adrian, R. H.; Bryant, S. H. :J. Physiol. 240: 505-515, 1974.

2. Beck, C. L.; Fahlke, C.; George, A. L., Jr.: Molecular basis for
decreased muscle chloride conductance in the myotonic goat. Proc.
Nat. Acad. Sci. 93: 11248-11252, 1996.

3. Becker, P. E.: Myotonia Congenita and Syndromes Associated With
Myotonia: Clinical-Genetic Studies of the Nondystrophic Myotonias.
Thieme, Stuttgart: Georg Thieme Publishers (pub.)  1977.

4. Bryant, S. H. :Fed. Proc. 21: 312 only, 1962.

5. Fahlke, C.; Beck, C. L.; George, A. L., Jr.: A mutation in autosomal
dominant myotonia congenita affects pore properties of the muscle
chloride channel. Proc. Nat. Acad. Sci. 94: 2729-2734, 1997.

6. George, A. L., Jr.; Crackower, M. A.; Abdalla, J. A.; Hudson, A.
J.; Ebers, G. C.: Molecular basis of Thomsen's disease (autosomal
dominant myotonia congenita). Nature Genet. 3: 305-310, 1993.

7. Iaizzo, P. A.; Franke, C.; Hatt, H.; Spittelmeister, W.; Ricker,
K.; Rudel, R.; Lehmann-Horn, F.: Altered sodium channel behaviour
causes myotonia in dominantly inherited myotonia congenita. Neuromusc.
Disord. 1: 47-53, 1991.

8. Koch, M. C.: Personal Communication. Marburg, Germany  1/12/1995.

9. Koch, M. C.; Meyer-Kleine, C.; Otto, M.; Ricker, K.; Lorenz, C.;
Steinmeyer, K.; Jentsch, T. J.: Mutations in the CLCN1 gene leading
to myotonia congenita Thomsen and generalized myotonia Becker. (Abstract) Am.
J. Hum. Genet. 55 (suppl.): A226, 1994.

10. Koch, M. C.; Ricker, K.; Otto, M.; Wolf, F.; Zoll, B.; Lorenz,
C.; Steinmeyer, K.; Jentsch, T. J.: Evidence for genetic homogeneity
in autosomal recessive generalised myotonia (Becker). J. Med. Genet. 30:
914-917, 1993.

11. Koch, M. C.; Steinmeyer, K.; Lorenz, C.; Ricker, K.; Wolf, F.;
Otto, M.; Zoll, B.; Lehmann-Horn, F.; Grzeschik, K.-H.; Jentsch, T.
J.: The skeletal muscle chloride channel in dominant and recessive
human myotonia. Science 257: 797-800, 1992.

12. Koty, P. P.; Marks, H. G.; Turel, A.; Flagler, D.; Angelini, C.;
Pegoraro, E.; Vancott, A. C.; Manchester, D.; Zonana, J.; Bird, T.
D.; Hoffman, E. P.: Linkage analysis of Thomsen and Becker myotonia
families. Am. J. Hum. Genet. (Suppl. 55) A227, 1994.

13. Lehmann-Horn, F.; Mailander, V.; Heine, R.; George, A. L.: Myotonia
levior is a chloride channel disorder. Hum. Molec. Genet. 4: 1397-1402,
1995.

14. Lipicky, R. J.; Bryant, S. H. :J. Gen. Physiol. 50: 89-111,
1966.

15. Lorenz, C.; Meyer-Kleine, C.; Steinmeyer, K.; Koch, M. C.; Jentsch,
T. J.: Genomic organization of the human muscle chloride channel
CLC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum.
Molec. Genet. 3: 941-946, 1994.

16. Mailander, V.; Heine, R.; Deymeer, F.; Lehmann-Horn, F.: Novel
muscle chloride channel mutations and their effects on heterozygous
carriers. Am. J. Hum. Genet. 58: 317-324, 1996.

17. Meyer-Kleine, C.; Ricker, K.; Otto, M.; Koch, M. C.: A recurrent
14 bp deletion in the CLCN1 gene associated with generalized myotonia
(Becker). Hum. Molec. Genet. 3: 1015-1016, 1994.

18. Meyer-Kleine, C.; Steinmeyer, K.; Ricker, K.; Jentsch, T. J.;
Koch, M. C.: Spectrum of mutations in the major human skeletal muscle
chloride channel gene (CLCN1) leading to myotonia. Am J. Hum. Genet. 57:
1325-1334, 1995.

19. Pusch, M.; Steinmeyer, K.; Koch, M. C.; Jentsch, T. J.: Mutations
in dominant human myotonia congenita drastically alter the voltage
dependence of the CIC-1 chloride channel. Neuron 15: 1455-1463,
1995.

20. Steinmeyer, K.; Klocke, R.; Ortland, C.; Gronemeier, M.; Jockusch,
H.; Grunder, S.; Jentsch, T. J.: Inactivation of muscle chloride
channel by transposon insertion in myotonic mice. Nature 354: 304-308,
1991.

*FIELD* CN
Victor A. McKusick - updated: 04/21/1997
Orest Hurko - updated: 3/9/1996

*FIELD* CD
Victor A. McKusick: 9/29/1992

*FIELD* ED
jenny: 04/21/1997
terry: 4/14/1997
mark: 2/23/1997
mark: 12/18/1996
jamie: 12/6/1996
terry: 12/4/1996
terry: 4/15/1996
mark: 3/9/1996
terry: 2/23/1996
mark: 2/22/1996
terry: 2/19/1996
mark: 1/19/1996
mark: 12/18/1995
joanna: 12/15/1995
mark: 12/15/1995
terry: 12/14/1995
terry: 12/13/1995
terry: 10/30/1995
mark: 9/7/1995
carol: 1/23/1995
jason: 7/27/1994
carol: 12/20/1993
carol: 4/29/1993

*RECORD*
*FIELD* NO
118430
*FIELD* TI
118430 CHLORPROPAMIDE-ALCOHOL FLUSHING; CPAF
*FIELD* TX
Leslie and Pyke (1978) observed CPAF in a mother and her 2 daughters
with diabetes mellitus. They were prompted thereby to study the response
to chlorpropamide and alcohol (in the form of sherry) in
noninsulin-dependent diabetics (sometimes known as maturity-onset or
type 2), in insulin-dependent diabetics (sometimes known as
juvenile-onset or type 1), and in normals. CPAF was common in the first
group and rare in the other two. Twin and family studies supported
autosomal dominant inheritance. In a second study, Pyke and Leslie
(1978) concluded that the CPAF test detects noninsulin-dependent
diabetes before the onset of glucose intolerance. About one-fifth of all
cases of noninsulin-dependent diabetes showed CPAF. Thus, a special
subclass was identified. They called this the Mason type after the first
family they observed (see 125850). They observed CPAF-positive families
in which onset of diabetes was late (after 30) and concluded that they
represent the same disorder. Known by the trade name Diabinase,
chlorpropamide is an oral hypoglycemic. The sulfonylurea oral
hypoglycemic agents other than chlorpropamide do not have a flushing
effect when taken with alcohol. Retinopathy is less prevalent and less
severe in patients with the flushing reaction (Leslie et al., 1979). The
flush can be reproduced in susceptible persons by infusion of a
met-enkephalin analog and blocked by naloxone (Leslie et al., 1979).
Facial temperature before the flush is lower in flushers than in
nonflushers (Leslie et al., 1979). Nondiabetic relatives of diabetic
flushers may show the same phenomenon. Aspirin suppresses the flush
(Strakosch et al., 1980). A prostaglandin-dependent step in the
mechanism of the flush was postulated.

*FIELD* SA
Cudworth  (1979); Dreyer et al. (1980); Kobberling and Weber (1980);
Leslie et al. (1979)
*FIELD* RF
1. Cudworth, A. G.: Type 2 (insulin-independent) diabetes--fibres
and flushers.  (Editorial) Diabetologia 17: 67-69, 1979.

2. Dreyer, M.; Kuhnau, J.; Rudiger, H. W.: Chlorpropamide-alcohol
flushing is not useful for individual genetic counseling of diabetic
patients. Clin. Genet. 18: 189-190, 1980.

3. Kobberling, J.; Weber, M.: Facial flushing after chlorpropamide-alcohol
and enkephalin.  (Letter) Lancet I: 538-539, 1980.

4. Leslie, R. D. G.; Barnett, A. H.; Pyke, D. A.: Diabetic retinopathy
and chlorpropamide alcohol flushing. Lancet I: 997-999, 1979.

5. Leslie, R. D. G.; Pyke, D. A.: Diabetic retinopathy and chlorpropamide-alcohol
flushing. Brit. Med. J. 2: 1519-1521, 1978.

6. Leslie, R. D. G.; Pyke, D. A.; Stubbs, W. A.: Sensitivity to enkephalin
as a cause of non-insulin-dependent diabetes. Lancet I: 341-343,
1979.

7. Pyke, D. A.; Leslie, R. D. G.: Chlorpropamide-alcohol flushing:
a definition of its relation to non-insulin-dependent diabetes. Brit.
Med. J. 2: 1521-1522, 1978.

8. Strakosch, C. R.; Jefferys, D. B.; Keen, H.: Blockade of chlorpropamide
alcohol flush by aspirin. Lancet I: 394-396, 1980.

*FIELD* CS

Skin:
   Alcohol induced flushing;
   Chlorpropamide induced flushing

Misc:
   Occurs in about one-fifth of noninsulin-dependent diabetics;
   Diabetic retinopathy less prevalent and less severe

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 10/21/1993
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
118440
*FIELD* TI
*118440 CHOLECYSTOKININ; CCK
*FIELD* TX
Cholecystokinin is a brain/gut peptide. In the gut, it induces the
release of pancreatic enzymes and the contraction of the gallbladder; in
the brain, its physiologic role is unclear. Takahashi et al. (1986)
determined the entire structure of the human CCK gene, which is 7 kb in
size and is separated into 3 exons. By chromosome sorting in combination
with velocity sedimentation and Southern hybridization, the human CCK
gene was mapped to 3pter-p21. S1 endonuclease analysis showed 2 putative
transcription initiation sites. By Southern analysis of DNA from
human-hamster hybrid cell lines, Lund et al. (1986) mapped CCK to
3pter-q12. Using 3 separate approaches, Friedman et al. (1989) mapped
the mouse equivalent to distal chromosome 9. They concluded that this
excludes cholecystokinin as an etiologic factor in the pathogenesis of
any of the known mouse obesity syndromes because these map to other
sites.

Friedman et al. (1992) demonstrated that Ewing sarcoma (133450) and
neuroepithelioma cells express the CCK gene--an almost unique finding
among tumor cells. Most, however, were unable to process the precursor
material sufficiently to generate immunoreactive CCK octapeptide-like
peptides. The findings support the view that Ewing sarcoma and
neuroepithelioma are derived from the same transformed cell type which
may serve to differentiate them from other types of pediatric tumors.

*FIELD* RF
1. Friedman, J. M.; Schneider, B. S.; Barton, D. E.; Francke, U.:
Level of expression and chromosome mapping of the mouse cholecystokinin
gene: implications for murine models of genetic obesity. Genomics 5:
463-469, 1989.

2. Friedman, J. M.; Vitale, M.; Maimon, J.; Israel, M. A.; Horowitz,
M. E.; Schneider, B. S.: Expression of the cholecystokinin gene in
pediatric tumors. Proc. Nat. Acad. Sci. 89: 5819-5823, 1992.

3. Lund, T.; Geurts van Kessel, A. H. M.; Haun, S.; Dixon, J. E.:
The genes for human gastrin and cholecystokinin are located on different
chromosomes. Hum. Genet. 73: 77-80, 1986.

4. Takahashi, Y.; Fukushige, S.; Murotsu, T.; Matsubara, K.: Structure
of human cholecystokinin gene and its chromosomal location. Gene 50:
353-360, 1986.

*FIELD* CD
Victor A. McKusick: 4/29/1987

*FIELD* ED
mark: 5/11/1995
carol: 8/17/1992
supermim: 3/16/1992
supermim: 3/20/1990
carol: 12/18/1989
ddp: 10/26/1989

*RECORD*
*FIELD* NO
118444
*FIELD* TI
*118444 CHOLECYSTOKININ A RECEPTOR, GALLBLADDER; CCKAR
*FIELD* TX
The cholecystokinin (CCK) family of peptide hormones (see 118440) have
been implicated in numerous important physiologic events. These appear
to be mediated through 2 general classes of receptors, A and B, based on
their binding affinities for CCK/gastrin family peptides. Boden et al.
(1995) compared the biologic and molecular properties of CCKA and CCKB
(118445) receptors. Ulrich et al. (1993) noted that, through binding to
class A receptors, CCK is a major physiologic mediator of gallbladder
contraction and pancreatic enzyme secretion. It appears to play a role
in slowing gastric emptying, relaxation of the sphincter of Oddi, and
potentiation of insulin secretion. Further, it has been implicated as a
mediator of pancreatic growth and tumorigenesis. Class A receptors have
also been described in the anterior pituitary, myenteric plexus, and
regions of the central nervous system, where they have been implicated
in the pathogenesis of feeding disorders, Parkinson disease,
schizophrenia, and drug addiction.

Ulrich et al. (1993) used a combination of hybridization screening of a
cDNA library and PCR to clone a 2.1-kb cDNA that encodes the human
gallbladder CCK receptor type A (CCKAR). Nucleotide sequence analysis
revealed an open reading frame encoding a 428-amino acid protein, with 7
putative transmembrane domains and a high degree of homology with the
cholecystokinin A receptor protein of rat and guinea pig. By PCR testing
of DNAs from a panel of human/hamster somatic cell hybrids, de Weerth et
al. (1993) assigned the CCKAR gene to chromosome 4. Samuelson et al.
(1995) mapped the murine homolog, Cckar, to mouse chromosome 5. Huppi et
al. (1995) likewise mapped the CCKAR gene to human chromosome 4 and
mouse chromosome 5. The human assignment was made by PCR analysis of
human/hamster hybrid DNAs; the mouse gene was mapped by interspecific
backcrosses. The region of mouse chromosome 5 shows conserved synteny
with human 4p16.2-p15.1, suggesting that as the location of the CCKAR
gene.

Funakoshi et al. (1995) found a defect in expression of the CCKAR gene
in both the fetal and the adult pancreas of a strain of rats (OLETF).
They proposed these rats as a useful model for determining CCK receptor
function.

*FIELD* RF
1. Boden, P.; Hall, M. D.; Hughes, J.: Cholecystokinin receptors. Cell.
Molec. Neurobiol. 15: 545-559, 1995.

2. de Weerth, A.; Pisegna, J. R.; Huppi, K.; Wank, S. A.: Molecular
cloning, functional expression and chromosomal localization of the
human cholecystokinin type A receptor. Biochem. Biophys. Res. Commun. 194:
811-818, 1993.

3. Funakoshi, A.; Miyasaka, K.; Shinozaki, H.; Masuda, M.; Kawanami,
T.; Takata, Y.; Kono, A.: An animal model of congenital defect of
gene expression of cholecystokinin (CCK)-A receptor. Biochem. Biophys.
Res. Commun. 210: 787-796, 1995.

4. Huppi, K.; Siwarski, D.; Pisegna, J. R.; Wank, S.: Chromosomal
localization of the gastric and brain receptors for cholecystokinin
(CCKAR and CCKBR) in human and mouse. Genomics 25: 727-729, 1995.

5. Samuelson, L. C.; Isakoff, M. S.; Lacourse, K. A.: Localization
of the murine cholecystokinin A and B receptor genes. Mammalian
Genome 6: 242-246, 1995.

6. Ulrich, C. D.; Ferber, I.; Holicky, E.; Hadac, E.; Buell, G.; Miller,
L. J.: Molecular cloning and functional expression of the human gallbladder
cholecystokinin A receptor. Biochem. Biophys. Res. Commun. 193:
204-211, 1993.

*FIELD* CN
Orest Hurko - updated: 4/1/1996

*FIELD* CD
Victor A. McKusick: 7/6/1993

*FIELD* ED
terry: 04/15/1996
mark: 4/1/1996
terry: 4/1/1996
terry: 3/26/1996
mark: 9/17/1995
carol: 8/23/1994
terry: 7/27/1994
carol: 9/20/1993
carol: 7/13/1993
carol: 7/6/1993

*RECORD*
*FIELD* NO
118445
*FIELD* TI
*118445 CHOLECYSTOKININ B RECEPTOR; CCKBR
GASTRIN RECEPTOR; GASR
*FIELD* TX
The cholecystokinin (CCK) family of peptides (see 118440) and their
receptors are widely distributed throughout the central nervous system
and gastrointestinal tract. The receptors can be divided into 2 subtypes
on the basis of their affinity for nonsulfated analogs of CCK. Type A
receptors, which have a high affinity only for sulfated CCK-8, are found
principally in the gastrointestinal tract and select areas of the CNS,
while type B (gastrin) receptors, having a high affinity for both
sulfated and nonsulfated CCK analogs, are found principally in the CNS
and select areas of the gastrointestinal tract. Highly selective,
nonpeptide antagonists have been developed that support this subtype
classification. In the CNS, type B receptors regulate anxiety, arousal,
neuroleptic activity, and opiate-induced analgesia. Outside the CNS,
they regulate gastric acid secretion and may play a role in
gastrointestinal motility and growth of normal and neoplastic
gastrointestinal tissue. The CCKB/gastrin receptor (CCKBR) can
selectively be blocked by nonpeptide benzodiazepine-based antagonists.
Beinborn et al. (1993) found that a single amino acid, valine-319, is
critical in determining the binding affinity for these nonpeptide
antagonists. They showed that it is the variability in the aliphatic
side chain of the amino acid in position 319 that confers antagonist
specificity and concluded that the residues underlying nonpeptide
antagonist affinity must differ from those that confer against
specificity.

Pisegna et al. (1992) used a rat type B receptor cDNA to isolate cDNA
for the human counterpart. They found that it encodes a 447-amino acid
protein with 90% identity to both rat type B CCK receptor and canine
gastrin receptor. Northern hybridization identified transcripts in
stomach, pancreas, brain, and gall bladder. Using a somatic cell hybrid
panel of human/hamster DNAs and Southern blot analysis, they
demonstrated that the CCKBR gene is located on chromosome 11. Expression
of the receptor of the cDNA in COS-7 cells was characteristic of a type
B CCK receptor pharmacology. Zimonjic et al. (1994) assigned the CCKBR
gene to 11p15.5-p15.4 by in situ hybridization.

Lee et al. (1993) presented Southern blot hybridization analyses of
human genomic DNA indicating that a single gene encodes both the brain
and the stomach CCK-B/gastrin receptors. They presented other data
indicating that the receptors of the brain and stomach are identical and
that a distinction between them is not valid.

Samuelson et al. (1995) mapped the mouse homolog, Cckbr, to mouse
chromosome 7, tightly linked to the beta-globin locus (Hbb). This
localization placed Cckbr in the same region as the mouse obesity
mutation tubby (tub). Since CCK can function as a satiety factor when
administered to rodents, localization of Cckbr near the tub mutation
identifies this receptor as a candidate gene for the obesity mutation.
Huppi et al. (1995) likewise mapped the CCKBR gene to human chromosome
11 and distal mouse chromosome 7.

*FIELD* RF
1. Beinborn, M.; Lee, Y.-M.; McBride, E. W.; Quinn, S. M.; Kopin,
A. S.: A single amino acid of the cholecystokinin-B/gastrin receptor
determines specificity for non-peptide antagonists. Nature 362:
348-350, 1993.

2. Huppi, K.; Siwarski, D.; Pisegna, J. R.; Wank, S.: Chromosomal
localization of the gastric and brain receptors for cholecystokinin
(CCKAR and CCKBR) in human and mouse. Genomics 25: 727-729, 1995.

3. Lee, Y.-M.; Beinborn, M.; McBride, E. W.; Lu, M.; Kolakowski, L.
F., Jr.; Kopin, A. S.: The human brain cholecystokinin-B/gastrin
receptor: cloning and characterization. J. Biol. Chem. 268: 8164-8169,
1993.

4. Pisegna, J. R.; de Weerth, A.; Huppi, K.; Wank, S. A.: Molecular
cloning of the human brain and gastric cholecystokinin receptor: structure,
functional expression and chromosomal localization. Biochem. Biophys.
Res. Commun. 189: 296-303, 1992.

5. Samuelson, L. C.; Isakoff, M. S.; Lacourse, K. A.: Localization
of the murine cholecystokinin A and B receptor genes. Mammalian
Genome 6: 242-246, 1995.

6. Zimonjic, D. B.; Popescu, N. C.; Matsui, T.; Ito, M.; Chihara,
K.: Localization of the human cholecystokinin-B/gastrin receptor
gene (CCKBR) to chromosome 11p15.5-p15.4 by fluorescence in situ hybridization.
Cytogenet. Cell Genet. 65: 184-185, 1994.

*FIELD* CD
Victor A. McKusick: 2/1/1993

*FIELD* ED
mark: 6/15/1995
carol: 8/23/1994
carol: 5/28/1993
carol: 5/7/1993
carol: 2/1/1993

*RECORD*
*FIELD* NO
118450
*FIELD* TI
*118450 CHOLESTASIS WITH PERIPHERAL PULMONARY STENOSIS
ARTERIOHEPATIC DYSPLASIA; AHD;;
SYNDROMATIC HEPATIC DUCTULAR HYPOPLASIA;;
ALAGILLE SYNDROME; AGS;;
ALAGILLE-WATSON SYNDROME; AWS
*FIELD* TX
In addition to neonatal jaundice, features of this syndrome include: in
the eye, posterior embryotoxon and retinal pigmentary changes; in the
heart, pulmonic valvular stenosis as well as peripheral arterial
stenosis; in the bones, abnormal vertebrae ('butterfly' vertebrae) and
decrease in interpediculate distance in the lumbar spine; in the nervous
system, absent deep tendon reflexes and poor school performance; in the
facies, broad forehead, pointed mandible and bulbous tip of the nose and
in the fingers, varying degrees of foreshortening (Watson and Miller,
1973; Alagille et al., 1975; Rosenfield et al., 1980). Few intrahepatic
bile ducts are demonstrable by histology of the liver. Henriksen et al.
(1977) reported affected father and daughter, Riely et al. (1979) and
Rosenfield et al. (1980) reported father and son, and LaBrecque and
Mitros (1982) described the condition in 4 generations of 1 kindred. In
the 3 cases studied by Berman et al. (1981), cholestasis was not
progressive and, although the SGPT was chronically elevated (122-520
units per liter), features of liver cell failure did not develop. Riely
et al. (1979) gave a useful differential diagnosis of familial
intrahepatic cholestasis: Zellweger syndrome (214100),
cholestasis-lymphedema syndrome (214900), Byler disease (211600), and
cholestasis with defective formation of cholic acid (214950).
Alpha-1-antitrypsin deficiency may present as neonatal cholestasis with
a paucity of intrahepatic bile ducts. Mueller et al. (1981) studied 7
patients in 5 families and reviewed 62 reported cases. Of the 69 cases,
death from cardiovascular or hepatic complications occurred by age 5
years in 16. In a longitudinal study, Dahms et al. (1982) sought to
account for the pathologic hallmark of arteriohepatic dysplasia, namely,
the paucity or absence of intrahepatic bile ducts. Liver biopsies under
6 months of age showed intrahepatic cholestasis and portal inflammation
and in 2 of 5 cases giant cell transformation. None showed congenital
absence of interlobular bile ducts; 3 of 5 had normal numbers of
interlobular bile ducts, and 2 of 5 had paucity. Three of 5 showed focal
destructive inflammation of interlobular bile ducts. All biopsies
performed later (ages 3 to 20 years) showed the characteristic paucity
or absence. By this time cholestasis and inflammation had largely
resolved but some fibrosis persisted. An acquired bile duct deficiency,
possibly due to destructive inflammation of duct epithelium, was
suggested. This disorder should be considered in all infants with
cholestasis. The histologic diagnosis may be difficult or impossible in
infancy. The diagnosis in that age group must rest on the syndromatic
features.

Mueller et al. (1984) reviewed phenotypic features of 56 reported cases
of Alagille syndrome and 7 of their own. They emphasized a
characteristic facies with prominent forehead and chin with deep-set
eyes and eye changes, usually asymptomatic: anterior chamber anomalies,
which may be associated with eccentric or ectopic pupils, and retinal
changes of chorioretinal atrophy and pigment clumping. Shulman et al.
(1984) described a kindred with 5 affected persons in 3 generations.
Severity varied widely. In 2 sisters, neonatal jaundice, peripheral
pulmonic stenosis, and characteristic facies including broad forehead,
deep-set eyes, prominent nose, and pointed chin were features. One died
at age 5 years of cirrhosis with portal hypertension and the other at 18
months of congestive heart failure. Their asymptomatic mother and
maternal aunt had similar facial appearance, pulmonic stenosis, skeletal
anomalies, and bilateral posterior embryotoxon. The maternal
grandfather, who refused evaluation, had a similar appearance, history
of liver disease, and a heart murmur. Rosenfield et al. (1980) described
abnormalities in the shape and segmentation of vertebral bodies and
short distal phalanges. LaBrecque et al. (1982) described 15 affected
persons in 4 generations. They demonstrated renal dysplasia, renal
artery stenosis and hypertension in some. Gonioscopy with demonstration
of embryotoxon is a valuable way to make the diagnosis in mildly
affected persons (Romanchuk et al., 1981). Raymond et al. (1989)
described Axenfeld anomaly in a 24-year-old black man with other signs
of Alagille syndrome: congenital intrahepatic biliary atresia, systolic
ejection murmur, short stature, butterfly vertebra at T-10, and hand
changes (short ulnae, short scaphoids, and short distal phalanges). In a
36-day-old male with typical features of Alagille syndrome, Rodriguez et
al. (1991) found associated caudal dysplasia sequence: imperforate anus,
rectourethral fistula, lumbosacral abnormalities, and dysplastic right
kidney. Hepatocellular carcinoma has been reported in children with
Alagille syndrome (Ong et al., 1986; Kaufman et al., 1987; Rabinovitz et
al., 1989) and in an adult with Alagille syndrome without cirrhosis
(Adams, 1986). Legius et al. (1990) speculated that loss of
heterozygosity for a cell-cycle-regulating gene rather than underlying
chronic liver disease may be the explanation of liver carcinoma. In a
19-year-old woman with Alagille syndrome diagnosed at the age of 8
years, Kato et al. (1994) described papillary thyroid carcinoma with
multiple lung metastases. They reviewed 12 reported cases of
hepatocellular carcinoma. Development of carcinoma was as early as age 2
years and as late as 48 years. Bucuvalas et al. (1993) concluded that
growth-retarded children with Alagille syndrome are insensitive to
growth hormone. They thought that the growth disturbance and metabolic
defects may be due in part to failure to increase IGF-I concentrations
in response to GH, implying that such patients may benefit from IGF-I
treatment.

AGS is one of the major forms of chronic liver disease in childhood with
severe morbidity and a mortality of 10 to 20%. To determine the rate of
new mutations and to develop criteria for detecting the disorder in
parents, Elmslie et al. (1995) systematically investigated parents in 14
families with an affected child. Clinical examination was supplemented
by liver function tests, echocardiography, radiographic examination of
the spine and forearm, ophthalmologic assessment, and chromosome
analysis. Six parents had typical anomalies in 2 or more systems,
pointing to the presence of autosomal dominant inheritance. In 3 cases,
the father was the affected parent, and in 3 the mother was affected. In
only one case had the affected parent previously suspected that he was
affected. All affected parents had posterior embryotoxon and at least
one other major syndromic feature. Five had abnormalities of the spine
and eye. In 3, midline notches on the vertebral end plates were present,
representing fused butterfly vertebrae. Four also had a short ulnar. Two
had anomalous optic discs and a pigmentary retinopathy. The mother in
one family and the father in a second had a history of unexplained
jaundice in infancy and recovered spontaneously. Systematic screening of
parents for the features defined in this study should improve the
accuracy of genetic counseling.

Martin et al. (1996) described 3 children with Alagille syndrome, in 2
of whom a unilateral multicystic dysplastic kidney was detected by
prenatal ultrasound; in the other, a solitary cortical cyst was found
later in childhood. All had normal renal function, growth, and liver
synthetic function but continued to have clinical and biochemical signs
of cholestasis. Thus the authors concluded that Alagille syndrome should
be included in the differential diagnosis of cystic kidney disorders
associated with cholestatic liver disease.

Byrne et al. (1986) described arteriohepatic dysplasia in a
small-for-gestational age white female infant who had deletion of
20p11.2. The child had multiple minor anomalies and severe jejunal
stenosis similar to the findings in 2 previously reported instances of
20p11.2 deletions. In addition, mild peripheral pulmonic stenosis,
skeletal anomalies, and cholestasis with paucity of intrahepatic bile
ducts were observed. The possibility of a gene for arteriohepatic
dysplasia at this site on chromosome 20 was raised by the authors.
Mueller (1987) presented a review. Schnittger et al. (1989) found an
interstitial deletion of chromosome 20 in a 20-year-old female with
typical signs. Considering the clinical similarity of 9 further cases
with a 20p deletion reported in the literature, Schnittger et al. (1989)
proposed that AWS is a 'contiguous gene syndrome' provisionally located
in the area 20p12.1-p11.23. Mujica et al. (1989) described Alagille
syndrome in association with an apparently balanced translocation
t(4;14)(q21;q21). In an 8-year-old boy with arteriohepatic dysplasia,
Zhang et al. (1990) demonstrated deletion of 20p12.3-p11.23. Legius et
al. (1990) found deletion of 20p11.2 in a patient with this syndrome.
They emphasized the peculiar face with parietal bossing and small
upturned nose. Anad et al. (1990) added 5 cases of 20p deletion to the
10 already known. Four had the features of Alagille syndrome.
Furthermore, they observed interstitial deletion of 20p in a mother and
son, both of whom had features of Alagille syndrome. Teebi et al. (1992)
described an Arab boy with this syndrome associated with a de novo
deletion of chromosome 20: 46,XY,del(20)(p11.2). By high resolution
banding techniques, nonradioactive in situ hybridization, and molecular
studies for allelic losses, Desmaze et al. (1992) found no evidence of
microdeletion of chromosome 20 in 14 patients with Alagille syndrome.
Studying a case of AGS with microdeletion in the short arm of chromosome
20 encompassing bands p12.3 to p11.23, Deleuze et al. (1994) showed that
3 genes were outside the deletion and thus excluded as candidate genes:
paired box-1 (PAX1; 167411), cystatin C (CST3; 105150), and hepatic
nuclear factor-3-beta (HNF3B; 600288).

Although autosomal dominant inheritance with reduced penetrance had been
suggested by the analysis of a limited number of families, no
statistical analysis had been performed prior to that done by
Dhorne-Pollet et al. (1994). They analyzed 33 families collected through
43 probands. They corroborated the autosomal dominant inheritance and
concluded that penetrance is 94% and that 15% of cases are sporadic.
Expressivity was variable; 26 persons (15 persons and 11 sibs) were
identified as presenting minor forms of the disease. Because the
individual manifestations are rare in the general population,
Dhorne-Pollet et al. (1994) assumed that the presence of only 1 feature
(the facies being excluded) was sufficient for considering a family
member to be affected with AGS. The frequency of butterfly-like
vertebrae is unknown but must be rare. Embryotoxon is the symptom of AGS
most frequent in the general population, affecting 8 to 10%. Among the
33 families, mothers were affected in 12 families and fathers were
affected in only 3.

Spinner et al. (1994) described a cytologically balanced t(2;20) in a
2-generation family with Alagille syndrome. The family was identified
through a proband with all 5 of the clinical criteria for diagnosis of
the disorder; clinical assessment of the family identified 2 other
affected individuals, who had less severe disease. Cosegregation of the
translocation with the clinical disorder indicated that the cytogenetic
rearrangement involved the AGS locus. Spinner et al. (1994) constructed
hybrids from the patients' cell lines and by studying these were able to
localize the translocation breakpoint distal to D20S61 and D20S56 within
band 20p12. Characteristic facies in the 15-year-old proband and her
subclinically affected father was illustrated, showing prominent
forehead, triangular facies, deep-set eyes, and a small, anteriorly
pointed chin. The proband's sister had hepatomegaly without jaundice and
a systolic murmur in infancy and had the same facial features. Failure
to thrive was present at 6 months of age. Biochemical evaluation at 2
years of age demonstrated mildly elevated transaminases and a moderately
elevated alkaline phosphatase. Eye examination demonstrated posterior
embryotoxon. The father demonstrated biochemical liver abnormalities,
including elevated transaminases and hypercholesterolemia, but no
clinically evident liver disease.

Hol et al. (1995) did linkage analysis in a 3-generation family with AGS
and in which the affected members had a normal karyotype. A lod score of
2.96 was obtained with D20S27 at no recombination. Combining D20S27 and
D20S61 to a single highly informative locus resulted in a maximum lod
score of 3.56 at theta = 0.0. Haplotype analysis positioned AGS between
D20S59 and D20S65, markers that define an interval of about 40 cM.
Allelic loss was not observed for the tested markers and no
abnormalities were detected in the PAX1 gene (167411), which because of
its location at 20p11.2 is considered a candidate gene for AGS.

Li et al. (1996) described a 6-year-old boy with Alagille syndrome and
hypoplastic corpus callosum. This patient had interstitial deletion of
the 20p12.2-p11.23 (or 20p13-p12.2) segment due to segregation of
maternal ins(7;20)(q11.23;p11.23p12.2 or p12.2p13). His elder brother,
who died of liver failure and tetralogy of Fallot, had not been studied
cytogenetically. Because the maternal phenotype was normal, Li et al.
(1996) concluded that the gene for Alagille syndrome would be located
within the deletion extent rather than at the insertion breakpoints.

By mapping with microsatellite markers in the Alagille region, Deleuze
et al. (1994) and Rand et al. (1995) concluded that submicroscopic
deletions are rarely the basis of Alagille syndrome in cytogenetically
normal patients.

Based on 56 of their own observations, Krantz et al. (1997) showed that
all affected persons have hepatic, cardiac, and facial abnormalities.
Vertebral defects were found in 59%, renal in 23%, and ocular in 83% of
examined patients. Two persons in their group had pancreatic
insufficiency. Visible defects involving 20p12 are relatively uncommon.
Krantz et al. (1997) reported only 2 visible rearrangements (1
apparently balanced translocation and 1 deletion) in a group of 56
persons, and only 1 more patient was found to have submicroscopic
deletion within 20p12. A low incidence of deletions argued for a single
gene etiology of the syndrome. Krantz et al. (1997) pictured the
supposedly characteristic facies of 5 patients, including a mother and
daughter and a father and daughter. Posterior embryotoxon in a father
and daughter with AGS was also pictured.

Pollet et al. (1995) established a YAC contig that spans the AGS region
that should be valuable for cloning candidate genes and searching for
DNA polymorphisms segregating with the disorder.

*FIELD* SA
Kocoshis et al. (1981); Riely et al. (1978); Riely et al. (1981);
Schnittger et al. (1989)
*FIELD* RF
1. Adams, P. C.: Hepatocellular carcinoma associated with arteriohepatic
dysplasia. Digest. Dis. Sci. 31: 438-442, 1986.

2. Alagille, D.; Odievre, M.; Gautier, M.; Dommergues, J. P.: Hepatic
ductular hypoplasia associated with characteristic facies, vertebral
malformations, retarded physical, mental and sexual development, and
cardiac murmur. J. Pediat. 86: 63-71, 1975.

3. Anad, F.; Burn, J.; Matthews, D.; Cross, I.; Davison, B. C. C.;
Mueller, R.; Sands, M.; Lillington, D. M.; Eastham, E.: Alagille
syndrome and deletion of 20p. J. Med. Genet. 27: 729-737, 1990.

4. Berman, M. D.; Ishak, K. G.; Schaefer, E. J.; Barnes, S.; Jones,
E. A.: Syndromatic hepatic ductular hypoplasia (arteriohepatic dysplasia):
a clinical and hepatic histologic study of three patients. Digest.
Dis. Sci. 26: 485-497, 1981.

5. Bucuvalas, J. C.; Horn, J. A.; Carlsson, L.; Balistreri, W. F.;
Chernausek, S. D.: Growth hormone insensitivity associated with elevated
circulating growth hormone-binding protein in children with Alagille
syndrome and short stature. J. Clin. Endocr. Metab. 76: 1477-1482,
1993.

6. Byrne, J. L. B.; Harrod, M. J. E.; Friedman, J. M.; Howard-Peebles,
P. N.: del(20p) with manifestations of arteriohepatic dysplasia. Am.
J. Med. Genet. 24: 673-678, 1986.

7. Dahms, B. B.; Petrelli, M.; Wyllie, R.; Henoch, M. S.; Halpin,
T. C.; Morrison, S.; Park, M. C.; Tavill, A. S.: Arteriohepatic dysplasia
in infancy and childhood: a longitudinal study of six patients. Hepatology 2:
350-358, 1982.

8. Deleuze, J.-F.; Hazan, J.; Dhorne, S.; Weissenbach, J.; Hadchouel,
M.: Mapping of microsatellite markers in the Alagille region and
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Hum. Genet. 2: 185-190, 1994.

9. Deleuze, J. F.; Dhorne, S.; Hazan, J.; Borghi, E.; Raynaud, N.;
Pollet, N.; Meunier-Rotival, M.; Deschatrette, J.; Alagille, D.; Hadchouel,
M.: Deleted chromosome 20 from a patient with Alagille syndrome isolated
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candidate genes. Mammalian Genome 5: 663-669, 1994.

10. Desmaze, C.; Deleuze, J. F.; Dutrillaux, A. M.; Thomas, G.; Hadchouel,
M.; Aurias, A.: Screening of microdeletions of chromosome 20 in patients
with Alagille syndrome. J. Med. Genet. 29: 233-235, 1992.

11. Dhorne-Pollet, S.; Deleuze, J.-F.; Hadchouel, M.; Bonaiti-Pellie,
C.: Segregation analysis of Alagille syndrome. J. Med. Genet. 31:
453-457, 1994.

12. Elmslie, F. V.; Vivian, A. J.; Gardiner, H.; Hall, C.; Mowat,
A. P.; Winter, R. M.: Alagille syndrome: family studies. J. Med.
Genet. 32: 264-268, 1995.

13. Henriksen, N. T.; Langmark, F.; Sorland, S. J.; Fausa, O.; Landaas,
A.; Aagenaes, O.: Hereditary cholestasis combined with peripheral
pulmonary stenosis and other anomalies. Acta Paediat. Scand. 66:
7-15, 1977.

14. Hol, F. A.; Hamel, B. C. J.; Geurds, M. P. A.; Hansmann, I.; Nabben,
F. A. E.; Daniels, O.; Mariman, E. C. M.: Localization of Alagille
syndrome to 20p11.2-p12 by linkage analysis of a three-generation
family. Hum. Genet. 95: 687-690, 1995.

15. Kato, Z.; Asano, J.; Kato, T.; Yamaguchi, S.; Kondo, N.; Orii,
T.: Thyroid cancer in a case with the Alagille syndrome. Clin. Genet. 45:
21-24, 1994.

16. Kaufman, S. S.; Wood, R. P.; Shaw, B. W., Jr.; Markin, R. S.;
Gridelli, B.; Vanderhoff, J. A.: Hepatocarcinoma in a child with
the Alagille syndrome. Am. J. Dis. Child. 141: 698-700, 1987.

17. Kocoshis, S. A.; Cottrill, C. M.; O'Connor, W. N.; Haugh, R.;
Johnson, G. L.; Noonan, J. A.: Congenital heart disease, butterfly
vertebrae, and extrahepatic biliary atresia: a variant of arteriohepatic
dysplasia?. J. Pediat. 99: 436-439, 1981.

18. Krantz, I. D.; Piccoli, D. A.; Spinner, N. B.: Alagille syndrome. J.
Med. Genet. 34: 152-157, 1997.

19. LaBrecque, D. R.; Mitros, F. A.: Autosomal dominant transmission
of arteriohepatic dysplasia to four generations of a single kindred.
(Abstract) Clin. Res. 30: 285A, 1982.

20. LaBrecque, D. R.; Mitros, F. A.; Nathan, R. J.; Romanchuk, K.
G.; Judisch, G. F.; El-Khoury, G. H.: Four generations of arteriohepatic
dysplasia. Hepatology 2: 467-474, 1982.

21. Legius, E.; Fryns, J.-P.; Eyskens, B.; Eggermont, E.; Desmet,
V.; de Bethune, G.; Van den Berghe, H.: Alagille syndrome (arteriohepatic
dysplasia) and del(20)(p11.2). Am. J. Med. Genet. 35: 532-535, 1990.

22. Li, P.-H.; Shu, S.-G.; Yang, C.-H.; Lo, F.-C.; Wen, M.-C.; Chi,
C.-S.: Alagille syndrome with interstitial 20p deletion derived from
maternal ins(7;20). Am. J. Med. Genet. 63: 537-541, 1996.

23. Martin, S. R.; Garel, L.; Alvarez, F.: Alagille's syndrome associated
with cystic renal disease. Arch. Dis. Child. 74: 232-235, 1996.

24. Mueller, R. F.: The Alagille syndrome (arteriohepatic dysplasia). J.
Med. Genet. 24: 621-626, 1987.

25. Mueller, R. F.; Pagon, R. A.; Haas, J. E.; Stephan, M. J.: Arteriohepatic
dysplasia: potentially lethal disorder of intrahepatic cholestasis
and-or congenital heart disease. (Abstract) Am. J. Hum. Genet. 33:
87A, 1981.

26. Mueller, R. F.; Pagon, R. A.; Pepin, M. G.; Haas, J. E.; Kawabori,
I.; Stevenson, J. G.; Stephan, M. J.; Blumhagen, J. D.; Christie,
D. L.: Arteriohepatic dysplasia: phenotypic features and family studies. Clin.
Genet. 25: 323-331, 1984.

27. Mujica, P.; Morali, A.; Vidailhet, M.; Pierson, M.; Gilgenkrantz,
S.: A case of Alagille's syndrome with translocation (4;14)(q21;q21). Ann.
Genet. 32: 117-119, 1989.

28. Ong, E.; Williams, S. M.; Anderson, J. C.; Kaplan, P. A.: MR
imaging of a hepatoma associated with Alagille syndrome. J. Comput.
Assist. Tomogr. 10: 1047-1049, 1986.

29. Pollet, N.; Dhorne-Pollet, S.; Deleuze, J.-F.; Boccaccio, C.;
Driancourt, C.; Raynaud, N.; Le Paslier, D.; Hadchouel, M.; Meunier-Rotival,
M.: Construction of a 3.7-Mb physical map within human chromosome
20p12 ordering 18 markers in the Alagille syndrome locus. Genomics 27:
467-474, 1995.

30. Rabinovitz, M.; Imperial, J. C.; Schade, R. R.; Van Thiel, D.
H.: Hepatocellular carcinoma in Alagille's syndrome: a family study. J.
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31. Rand, E. B.; Spinner, N. B.; Piccoli, D. A.; Whitington, P. F.;
Taub, R.: Molecular analysis of 24 Alagille syndrome families identifies
a single submicroscopic deletion and further localizes the Alagille
region within 20p12. Am. J. Hum. Genet. 57: 1068-1073, 1995.

32. Raymond, W. R.; Kearney, J. J.; Parmley, V. C.: Ocular findings
in arteriohepatic dysplasia (Alagille's syndrome). Arch. Ophthal. 107:
1077, 1989.

33. Riely, C. A.; Cotlier, E.; Jensen, P. S.; Klatskin, G.: Arteriohepatic
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34. Riely, C. A.; LaBrecque, D. R.; Ghent, C.; Horwich, A.; Klatskin,
G.: A father and son with cholestasis and peripheral pulmonary stenosis:
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1978.

35. Riely, C. A.; Rosenfield, N. S.; Cotlier, E.: Arteriohepatic
dysplasia. (Letter) Pediatrics 68: 464, 1981.

36. Rodriguez, J. I.; Rivera, T.; Palacios, J.: Alagille syndrome
associated with caudal dysplasia sequence. Am. J. Med. Genet. 40:
61-64, 1991.

37. Romanchuk, K. G.; Judisch, G. F.; LaBrecque, D. R.: Ocular findings
in arteriohepatic dysplasia (Alagille's syndrome). Canad. J. Ophthal. 16:
94-99, 1981.

38. Rosenfield, N. S.; Kelley, M. J.; Jensen, P. S.; Cotlier, E.;
Rosenfield, A. T.; Riely, C. A.: Arteriohepatic dysplasia: radiologic
features of a new syndrome. Am. J. Roentgen. 135: 1217-1223, 1980.

39. Schnittger, S.; Hoefers, C.; Beermann, F.; Heidemann, P.; Hansmann,
I.: Alagille-Watson syndrome is assigned to 20(p1.1-p1.2) and provisionally
to the region p11.23-p12.1. (Abstract) Cytogenet. Cell Genet. 51:
1074, 1989.

40. Schnittger, S.; Hoefers, C.; Heidemann, P.; Beermann, F.; Hansmann,
I.: Molecular and cytogenetic analysis of an interstitial 20p deletion
associated with syndromic intrahepatic ductular hypoplasia (Alagille
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41. Shulman, S. A.; Hyams, J. S.; Gunta, R.; Greenstein, R. M.; Cassidy,
S. B.: Arteriohepatic dysplasia (Alagille syndrome): extreme variability
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42. Spinner, N. B.; Rand, E. B.; Fortina, P.; Genin, A.; Taub, R.;
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two-generation family with Alagille syndrome: cytogenetic and molecular
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43. Teebi, A. S.; Krishna Murthy, D. S.; Ismail, E. A. R.; Redha,
A. A.: Alagille syndrome with de novo del(20)(p11.2). Am. J. Med.
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44. Watson, G. H.; Miller, V.: Arteriohepatic dysplasia: familial
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45. Zhang, F.; Deleuze, J. F.; Aurias, A.; Dutrillaux, A.-M.; Hugon,
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of the short arm of chromosome 20 in arteriohepatic dysplasia (Alagille
syndrome). J. Pediat. 116: 73-77, 1990.

*FIELD* CS

Growth:
   Failure to thrive

Facies:
   Unusual facies;
   Broad forehead;
   Pointed mandible;
   Bulbous nasal tip;
   Prominent forehead and chin

Eyes:
   Deep-set eyes;
   Posterior embryotoxon;
   Anterior chamber anomalies;
   Eccentric or ectopic pupils;
   Chorioretinal atrophy;
   Retinal pigment clumping

Cardiac:
   Pulmonic stenosis;
   Atrial septal defect;
   Ventricular septal defect;
   Congestive heart failure

Resp:
   Peripheral pulmonary stenosis

GI:
   Intrahepatic cholestasis;
   Imperforate anus;
   Rectourethral fistula;
   Fat malabsorption;
   Cirrhosis;
   Portal hypertension

Skin:
   Neonatal jaundice;
   Xanthomata

Heme:
   Hypersplenism

Skel:
   Rickets

Spine:
   Butterfly vertebrae;
   Decreased interpediculate distance in lumbar spine

Neuro:
   Absent deep tendon reflexes;
   Mild mental retardation

Limbs:
   Short ulnae;
   Short scaphoids;
   Short distal phalanges

GU:
   Renal dysplasia;
   Renal artery stenosis

Endo:
   Hypertension

Oncology:
   Hepatocellular carcinoma;
   Papillary thyroid carcinoma

Lab:
   Paucity of intrahepatic bile ducts;
   Intrahepatic cholestasis and portal inflammation;
   SGPT chronically elevated;
   Hypercholesterolemia;
   Hyperlipidemia

Inheritance:
   Autosomal dominant;
   possibly a contiguous gene syndrome in 20p12.1-p11.23

*FIELD* CN
Iosif W. Lurie - updated: 03/06/1997
Iosif W. Lurie - updated: 8/11/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/06/1997
terry: 3/5/1997
terry: 9/20/1996
mark: 9/10/1996
terry: 9/4/1996
carol: 8/11/1996
mark: 5/2/1996
terry: 4/22/1996
mark: 7/7/1995
carol: 1/6/1995
terry: 8/26/1994
jason: 7/27/1994
mimadm: 6/25/1994
carol: 10/21/1993

*RECORD*
*FIELD* NO
118455
*FIELD* TI
*118455 CYTOCHROME P450, SUBFAMILY VII; CYP7
CHOLESTEROL 7-ALPHA-HYDROXYLASE;;
CHOLESTEROL 7-ALPHA-MONOOXYGENASE
*FIELD* TX
Cholesterol 7-alpha-hydroxylase is a microsomal cytochrome P450 that
catalyzes the first step in bile acid synthesis. Cohen et al. (1992)
cloned the gene which they found spans 10 kb and contains 6 exons and 5
introns. The exon-intron boundaries are completely conserved between
human and rat genes. Sequencing of the 5-prime flanking region revealed
consensus recognition sequences for a number of liver-specific
transcription factors. Using both mouse-human somatic cell hybrids and
in situ chromosomal hybridization, Cohen et al. (1992) mapped the CYP7
gene to 8q11-q12. They found 4 single-stranded conformation-dependent
DNA polymorphisms and an Alu sequence-related polymorphism. Of the
persons analyzed, 80% were heterozygous for at least one of these 5
polymorphisms. The localization and characterization of the CYP7 gene as
well as the identification of polymorphisms provide molecular tools for
investigating the role of the gene in disorders of cholesterol and bile
acid metabolism. Paumgartner and Sauerbruch (1991) suggested that
cholesterol 7-alpha-hydroxylase is a candidate for a defect in gallstone
disease and Angelin et al. (1978, 1987) suggested that it might be
involved in familial hypertriglyceridemia. The central role of the
enzyme in cholesterol homeostasis renders the CYP7 gene a candidate for
determination of both primary hyper- and hypocholesterolemia.

*FIELD* RF
1. Angelin, B.; Einarsson, K.; Hellstrom, K.; Leijd, B.: Bile acid
kinetics in relation to endogenous triglyceride metabolism in various
types of hyperlipoproteinemia. J. Lipid Res. 19: 1004-1016, 1978.

2. Angelin, B.; Hershon, K. S.; Brunzell, J. D.: Bile acid metabolism
in hereditary forms of hypertriglyceridemia: evidence for an increased
synthesis rate in monogenic familial hypertriglyceridemia. Proc.
Nat. Acad. Sci. 84: 5434-5438, 1987.

3. Cohen, J. C.; Cali, J. J.; Jelinek, D. F.; Mehrabian, M.; Sparkes,
R. S.; Lusis, A. J.; Russell, D. W.; Hobbs, H. H.: Cloning of the
human cholesterol 7-alpha-hydroxylase gene (CYP7) and localization
to chromosome 8q11-q12. Genomics 14: 153-161, 1992.

4. Paumgartner, G.; Sauerbruch, T.: Gallstones: pathogenesis. Lancet 338:
1117-1121, 1991.

*FIELD* CD
Victor A. McKusick: 9/22/1992

*FIELD* ED
terry: 05/24/1996
carol: 5/11/1994
carol: 10/23/1992
carol: 9/22/1992

*RECORD*
*FIELD* NO
118457
*FIELD* TI
*118457 CHOLESTEROL CRYSTALLIZATION INHIBITOR; CCI
*FIELD* TX
Although about 50% of populations in developed countries have bile
supersaturated with cholesterol, only a small proportion of these
individuals develop gallstones. This fact suggested the existence of a
biliary protein that inhibits cholesterol crystallization. Ohya et al.
(1993) purified and characterized such a biliary glycoprotein which
consists of a heterodimer with subunits of molecular weight 63
kilodaltons and 58 kilodaltons. Each of the subunits is characterized by
an isoelectric point of 6.6 and shows comparable inhibitory activity.
Deglycosylation of the subunits shows that they share a similar, perhaps
identical polypeptide backbone of 35 kilodaltons. Differential subunit
glycosylation alone may account for the apparent heterodimeric
structure.

*FIELD* RF
1. Ohya, T.; Schwarzendrube, J.; Busch, N.; Gresky, S.; Chandler,
K.; Takabayashi, A.; Igimi, H.; Egami, K.; Holzbach, R. T.: Isolation
of a human biliary glycoprotein inhibitor of cholesterol crystallization.
Gastroenterology 104: 527-538, 1993.

*FIELD* CD
Victor A. McKusick: 9/17/1993

*FIELD* ED
carol: 9/17/1993

*RECORD*
*FIELD* NO
118470
*FIELD* TI
*118470 CHOLESTERYL ESTER TRANSFER PROTEIN, PLASMA; CETP
LIPID TRANSFER PROTEIN I
CETP DEFICIENCY, AUTOSOMAL RECESSIVE, INCLUDED
*FIELD* TX
The transfer of insoluble cholesteryl esters among lipoprotein particles
is a vital step in normal cholesterol homeostasis. One of the steps in
this process is the transfer of cholesteryl esters by a cholesteryl
ester transfer protein. Using a partial amino acid sequence from
purified CETP, Drayna et al. (1987) cloned and sequenced cDNA encoding
CETP from a human liver library. They used the sequenced cDNA to detect
CETP mRNA in a number of human tissues. Sparkes et al. (1987) used this
probe against DNA from a human/mouse somatic cell hybrid panel to assign
the gene to chromosome 16. In situ hybridization of the same probe to
metaphase chromosomes regionalized the gene to 16q21. See also Lusis et
al. (1987). This contributes a new marker for chromosome 16 inasmuch as
RFLPs of this gene have been reported (Drayna and Lawn, 1987). Kondo et
al. (1989) demonstrated an association between 1 allele of the CETP
locus, as demonstrated by a TaqI polymorphism, and plasma apoA-I
concentrations. The effect of the CETP alleles was limited to nonsmokers
in this study.

Koizumi et al. (1985) and Kurasawa et al. (1985) described 2 Japanese
families with CETP deficiency. Koizumi et al. (1985) found a 58-year-old
male and his 55-year-old sister with HDL cholesterol levels of 301 and
174 mg/dl, respectively. Both were asymptomatic without signs of
atherosclerosis, and there was no unusual amount of cardiovascular
disease in the family. Two other sibs and 4 offspring had levels of HDL
cholesterol in the range of 54 to 83 mg/dl. LDL cholesterol and
triglyceride levels were low in the affected brother and sister. Both
were shown to have a defect in the transfer of labeled cholesteryl ester
from HDL to VLDL plus LDL. Studies of a 35-year-old Japanese male by
Kurasawa et al. (1985) demonstrated an abnormally low triglyceride level
in HDL, consistent with the concept that CETP exchanges cholesteryl
ester in HDL for triglyceride in LDL or VLDL. Rats, dogs and pigs with
plasma CETP deficiency have been found to be relatively resistant to
atherosclerosis.

Cholesteryl ester transfer protein is also known as lipid transfer
protein I (Day et al., 1994). Lipid transfer protein II is also called
phospholipid transfer protein (172425).

In 3,469 men of Japanese ancestry in the Honolulu Heart Program, Zhong
et al. (1996) found a high prevalence of 2 different CETP gene
mutations: 5.1% for D442G (118470.0002) and 0.5% for the G-to-A
substitution in the intron 14 donor site (118470.0001). The mutations
were associated with decreased CETP (-35%) and increased HDL cholesterol
levels (+10% for D442G). However, the overall prevalence of definite CHD
was 21% in men with mutations and 16% in men without mutations.

*FIELD* AV
.0001
CETP DEFICIENCY
CETP, IVS14DS, G-A, +1
Using monoclonal antibodies, Brown et al. (1989) showed that 2 Japanese
sibs with markedly increased and enlarged HDL had absent CETP. They were
homozygous for a point mutation in the 5-prime splice donor site of
intron 14 of the CETP gene. The mutation was a change of the strictly
conserved G-T intron splice donor to A-T. The family illustrates the key
role of CETP in HDL metabolism. Plasma CETP catalyzes the transfer of
cholesteryl esters from HDL to other lipoproteins. Inazu et al. (1990)
identified the same CETP mutation in 4 additional Japanese families with
increased HDL levels, including a family reported by Saito (1984) with
unusual longevity and increased HDL levels (see
hyperalphalipoproteinemia; 143470). The lipoprotein phenotype of CETP
deficiency, which is characterized by both increased levels of HDL and
decreased levels of low-density lipoprotein (LDL), appeared to have
strong antiatherogenic potential. CETP deficiency appears to be a
frequent cause of increased HDL levels in the population of Japan,
possibly because of founder effect. Familial hypobetalipoproteinemia
(107730.0006) is another antiatherogenic mutation. The G-to-A mutation
was found in homozygous state in 2 patients by Yamashita et al. (1990).
Heterozygosity for the mutation was found in 2 other probands who
totally lacked CETP and whose lipoprotein patterns were similar to those
of the 2 homozygotes. They were presumably compound heterozygotes.
Compound heterozygotes associated with hyperalphalipoproteinemia are
described in 118470.0002.

.0002
CETP DEFICIENCY
CETP, ASP442GLY
Takahashi et al. (1993) reported 2 unrelated, healthy females who were
heterozygous for a G-to-A transition in exon 15 of the CETP gene,
resulting in a substitution of gly for asp at amino acid 442. Both women
had 3-fold increases in HDL concentrations and markedly decreased plasma
CETP mass and activity, suggesting that the mutation has dominant
effects on CETP and HDL in vivo. The dominant effect of the CETP
mutation raises the possibility that the active species of CETP is
multimeric. Inazu et al. (1994) found a heterozygote frequency of 7% for
the D442G mutation in a sample of 236 Japanese men. The heterozygote
frequency of the IVS14 splice mutation (118470.0001) was estimated to be
2%. The 2 mutations accounted for about 10% of the total variance of HDL
cholesterol values in the Japanese population studied.

Akita et al. (1994) found either the IVS14 splice mutation or the D442G
mutation, or both, in 44 out of 226 unrelated patients with
hyperalphalipoproteinemia (143470). The IVS14 mutation was found in 15
patients, including 4 compound heterozygotes for the 2 mutations; D442G
was identified in 33, including the 4 compound heterozygotes. Allelic
frequencies in the general population for the IVS14 and the D442G
mutations were 0.81% and 4.62%, respectively. The IVS14 mutation was
responsible for a more severe form of hyperalphalipoproteinemia.

Among 117 Japanese hyperalphalipoproteinemic subjects without the intron
14 splice defect (118470.0001), Sakai et al. (1995) found 3 homozygotes
(2.5%) and 34 heterozygotes (29.1%) for the asp442-to-gly mutation.
These results suggested that this mutation is as common as the intron 14
splice defect in Japanese hyperalphalipoproteinemic subjects. One of the
homozygotes was the patient previously described by Takahashi et al.
(1993) as having hyperalphalipoproteinemia with corneal opacity and
coronary heart disease. They had previously thought that this patient
was heterozygous.

.0003
CETP DEFICIENCY
CETP, IVS14DS, INS T, +3
Inazu et al. (1994) screened Japanese subjects with high-density
lipoprotein cholesterol levels in excess of 100 mg/dl by PCR
single-strand conformation polymorphism analysis of the CETP gene. They
found a novel intron 14 splice donor site mutation caused by a T
insertion at position +3 from the exon 14/intron 14 boundary. The
phenotype of a genetic compound heterozygote for this mutation and the
IVS14 splice mutation (118470.0001) was similar to that of the
homozygote for the latter mutation: no detectable CETP and markedly
increased HDL cholesterol levels.

*FIELD* RF
1. Akita, H.; Chiba, H.; Tsuchihashi, K.; Tsuji, M.; Kumagai, M.;
Matsuno, K.; Kobayashi, K.: Cholesteryl ester transfer protein gene:
two common mutations and their effect on plasma high-density lipoprotein
cholesterol content. J. Clin. Endocr. Metab. 79: 1615-1618, 1994.

2. Brown, M. L.; Inazu, A.; Hesler, C. B.; Agellon, L. B.; Mann, C.;
Whitlock, M. E.; Marcel, Y. L.; Milne, R. W.; Koizumi, J.; Mabuchi,
H.; Takeda, R.; Tall, A. R.: Molecular basis of lipid transfer protein
deficiency in a family with increased high-density lipoproteins. Nature 342:
448-451, 1989.

3. Day, J. R.; Albers, J. J.; Lofton-Day, C. E.; Gilbert, T. L.; Ching,
A. F. T.; Grant, F. J.; O'Hara, P. J.; Marcovina, S. M.; Adolphson,
J. L.: Complete cDNA encoding human phospholipid transfer protein
from human endothelial cells. J. Biol. Chem. 269: 9388-9391, 1994.

4. Drayna, D.; Jarnagin, A. S.; McLean, J.; Henzel, W.; Kohr, W.;
Fielding, C.; Lawn, R.: Cloning and sequencing of human cholesteryl
ester transfer protein cDNA. Nature 327: 632-634, 1987.

5. Drayna, D.; Lawn, R. M.: Multiple RFLPs at the human cholesteryl
ester transfer protein (CETP) locus. Nucleic Acids Res. 15: 4698
only, 1987.

6. Inazu, A.; Brown, M. L.; Hesler, C. B.; Agellon, L. B.; Koizumi,
J.; Takata, K.; Maruhama, Y.; Mabuchi, H.; Tall, A. R.: Increased
high-density lipoprotein levels caused by a common cholesteryl-ester
transfer protein gene mutation. New Eng. J. Med. 323: 1234-1238,
1990.

7. Inazu, A.; Jiang, X.-C.; Haraki, T.; Yagi, K.; Kamon, N.; Koizumi,
J.; Mabuchi, H.; Takeda, R.; Takata, K.; Moriyama, Y.; Doi, M.; Tall,
A.: Genetic cholesteryl ester transfer protein deficiency caused
by two prevalent mutations as a major determinant of increased levels
of high density lipoprotein cholesterol. J. Clin. Invest. 94: 1872-1882,
1994.

8. Koizumi, J.; Mabuchi, H.; Yoshimura, A.; Michishita, I.; Takeda,
M.; Itoh, H.; Sakai, Y.; Sakai, T.; Ueda, K.; Takeda, R.: Deficiency
of serum cholesteryl-ester transfer activity in patients with familial
hyperalphalipoproteinaemia. Atherosclerosis 58: 175-186, 1985.

9. Kondo, I.; Berg, K.; Drayna, D.; Lawn, R.: DNA polymorphism at
the locus for human cholesteryl ester transfer protein (CETP) is associated
with high density lipoprotein cholesterol and apolipoprotein levels. Clin.
Genet. 35: 49-56, 1989.

10. Kurasawa, T.; Yokoyama, S.; Miyake, Y.; Yamamura, T.; Yamamoto,
A.: Rate of cholesteryl ester transfer between high and low density
lipoproteins in human serum and a case with decreased transfer rate
in association with hyperalphalipoproteinemia. J. Biochem. 98: 1499-1508,
1985.

11. Lusis, A. J.; Zollman, S.; Sparkes, R. S.; Klisak, I.; Mohandas,
T.; Drayna, D.; Lawn, R. M.: Assignment of the human gene for cholesteryl
ester transfer protein to chromosome 16q12-16q21. Genomics 1: 232-242,
1987.

12. Saito, F.: A pedigree of homozygous familial hyperalphalipoproteinemia. Metabolism 33:
629-633, 1984.

13. Sakai, N.; Yamashita, S.; Hirano, K.; Menju, M.; Arai, T.; Kobayashi,
K.; Ishigami, M.; Yoshida, Y.; Hoshino, T.; Nakajima, N.; Kameda-Takemura,
K.; Matsuzawa, Y.: Frequency of exon 15 missense mutation (442D:G)
in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic
Japanese subjects. Atherosclerosis 114: 139-145, 1995.

14. Sparkes, R. S.; Drayna, D.; Mohandas, T.; Klisak, I.; Heinzmann,
C.; Lawn, R.; Lusis, A. J.: Assignment of cholesterol ester transfer
protein (CETP) gene to human 16q21. (Abstract) Cytogenet. Cell Genet. 46:
696 only, 1987.

15. Takahashi, K.; Jiang, X.-C.; Sakai, N.; Yamashita, S.; Hirano,
K.; Bujo, H.; Yamazaki, H.; Kusunoki, J.; Miura, T.; Kussie, P.; Matsuzawa,
Y.; Saito, Y.; Tall, A.: A missense mutation in the cholesteryl ester
transfer protein gene with possible dominant effects on plasma high
density lipoproteins. J. Clin. Invest. 92: 2060-2064, 1993.

16. Yamashita, S.; Hui, D. Y.; Sprecher, D. L.; Matsuzawa, Y.; Sakai,
N.; Tarui, S.; Kaplan, D.; Wetterau, J. R.; Harmony, J. A.: Total
deficiency of plasma cholesteryl ester transfer protein in subjects
homozygous and heterozygous for the intron 14 splicing defect. Biochem.
Biophys. Res. Commun. 170: 1346-1351, 1990.

17. Zhong, S.; Sharp, D. S.; Grove, J. S.; Bruce, C.; Yano, K.; Curb,
J. D.; Tall, A. R.: Increased coronary heart disease in Japanese-American
men with mutation in the cholesteryl ester transfer protein gene despite
increased HDL levels. J. Clin. Invest. 97: 2917-2923, 1996.

*FIELD* CS

Vascular:
   Decreased atherosclerosis

Misc:
   Unusual longevity

Lab:
   Cholesteryl ester transfer protein deficiency;
   Low LDL cholesterol and triglyceride levels;
   Increased and enlarged HDL

Inheritance:
   Autosomal dominant (16q21);
   some homozygotes or compound heterozygotes

*FIELD* CD
Victor A. McKusick: 6/30/1987

*FIELD* ED
mark: 09/19/1996
marlene: 8/15/1996
mark: 6/29/1995
carol: 11/29/1994
mimadm: 6/25/1994
carol: 10/29/1993
carol: 10/28/1992
carol: 4/28/1992

*RECORD*
*FIELD* NO
118480
*FIELD* TI
*118480 CHOLESTEROL REPRESSIBLE PROTEIN 39B; CHR39B
*FIELD* TX
See 134631.

*FIELD* CD
Victor A. McKusick: 9/23/1987
*FIELD* ED
carol: 10/5/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 9/23/1987
*RECORD*
*FIELD* NO
118485
*FIELD* TI
*118485 CYTOCHROME P450, SUBFAMILY XIA; CYP11A
CHOLESTEROL SIDE-CHAIN CLEAVAGE ENZYME;;
CYTOCHROME P450 SIDE-CHAIN CLEAVAGE ENZYME;;
CYTOCHROME P450SCC;;
CYTOCHROME P450C11A1
*FIELD* TX
In steroidogenic tissues such as adrenal cortex, testis, ovary, and
placenta, the initial and rate-limiting step in the pathway leading from
cholesterol to steroid hormones is the cleavage of the side chain of
cholesterol to yield pregnenolone. This reaction, known as cholesterol
side-chain cleavage, is catalyzed by a specific form of cytochrome P-450
called P450scc or P45011A, which is localized to the inner mitochondrial
membrane. The conversion of cholesterol to pregnenolone entails 3 steps,
all mediated by P450scc (EC 1.14.15.67). The 3 steps are:
20-hydroxylation, 22-hydroxylation, and cleavage of the C20-C22 bond to
produce pregnenolone and isocaproic acid. Morohashi et al. (1984) and
John et al. (1984) cloned the gene (which is single) from bovine
adrenal. There are at least 4 P450 genes expressed in the adrenal; one
of the others, that for steroid 21-hydroxylase (201910), is coded by
chromosome 6.

Chung et al. (1986) cloned and sequenced full-length human P450scc cDNA
and located the gene to chromosome 15 by Southern analysis of a panel of
mouse-human somatic cell hybrids. They concluded that the human P450SCC
gene is expressed in the placenta in early and mid-gestation because
primary cultures of placental tissue showed P450scc mRNA accumulation in
response to cyclic AMP. Nebert et al. (1987) cited evidence that the
genes for mitochondrial SCC and 11-beta-hydroxylase (202010) are members
of the same P450 gene family; therefore, they proposed calling the 2
subfamilies XIA and XIB, respectively. They called the 2 genes XIA1 and
XIB1; the gene symbols thus become CYP11A and CYP11B. Morohashi et al.
(1987) concluded that the cholesterol desmolase gene is at least 20 kb
long and is split into 9 exons by 8 introns.

Youngblood et al. (1989) demonstrated that the mouse homologs of CYP11A
and CYP19 are closely linked on mouse chromosome 9. Thus, it is possible
that the CYP11A gene is located in the region 15q21.1, the site of CYP19
in the human. Sparkes et al. (1991) mapped the CYP11A gene to 15q23-q24
by in situ hybridization.

CYP11A (or P450SCC) was thought to be the site of the mutation in
congenital lipoid hyperplasia of the adrenal (201710). As indicated by
evidence reviewed in 201710, this has proven not to be the case, at
least in the Oriental cases in which detailed studies have been done.

Slominski et al. (1996) presented evidence that the CYP11A1, CYP17
(202110), CYP21A2 (201910), and ACTHR (202200) genes are expressed in
skin (see 202200). The authors suggested that expression of these genes
may play a role in skin physiology and pathology and that cutaneous
proopiomelanocortin activity may be autoregulated by a feedback
mechanism involving glucocorticoids synthesized locally.

Because of evidence that an underlying disorder of androgen biosynthesis
and/or metabolism is involved in the etiology of polycystic ovary
syndrome (PCO; 184700), Gharani et al. (1997) examined the segregation
of the genes coding for 2 enzymes in the synthesis and metabolism of
androgens, cholesterol side chain cleavage enzyme (CYP11A) and aromatase
(CYP19; 107910), with the PCO phenotype in 20 multiply affected
families. All analyses excluded CYP19 cosegregation with PCO,
demonstrating that this locus is not a major determinant of risks for
the syndrome. On the other hand, their results provided evidence for
linkage to the CYP11A locus; nonparametric linkage (NPL) score = 3.03, p
= 0.003. Parametric analysis using a dominant model suggested genetic
heterogeneity, generating a maximum heterogeneity lod score of 2.7. An
association study of 97 consecutively identified Europids with PCO and
matched controls demonstrated significant allelic association with a
pentanucleotide repeat polymorphism in the 5-prime untranslated region
of the CYP11A gene in hirsute PCO subjects (p = 0.03). A strong
association was also found between alleles of this polymorphism and
total serum testosterone levels in both affected and unaffected
individuals (p = 0.002). The data of Gharani et al. (1997) demonstrated
that variation in CYP11A may play an important role in the etiology of
hyperandrogenemia which is a common characteristic of the polycystic
ovary syndrome.

*FIELD* RF
1. Chung, B.-C.; Matteson, K. J.; Voutilainen, R.; Mohandas, T. K.;
Miller, W. L.: Human cholesterol side-chain cleavage enzyme, P450scc:
cDNA cloning, assignment of the gene to chromosome 15, and expression
in the placenta. Proc. Nat. Acad. Sci. 83: 8962-8966, 1986.

2. Gharani, N.; Waterworth, D. M.; Batty, S.; White, D.; Gilling-Smith,
C.; Conway, G. S.; McCarthy, M.; Franks, S.; Williamson, R.: Association
of the steroid synthesis gene CYP11a with polycystic ovary syndrome
and hyperandrogenism. Hum. Molec. Genet. 6: 397-402, 1997.

3. John, M. E.; John, M. C.; Ashley, P.; MacDonald, R. J.; Simpson,
E. R.; Waterman, M. R.: Identification and characterization of cDNA
clones specific for cholesterol side-chain cleavage cytochrome P-450. Proc.
Nat. Acad. Sci. 81: 5628-5632, 1984.

4. Morohashi, K.; Fujii-Kuriyama, Y.; Okada, Y.; Sogawa, K.; Hirose,
T.; Inayama, S.; Omura, T.: Molecular cloning and nucleotide sequence
of cDNA for mRNA of mitochondrial cytochrome P-450(SCC) of bovine
adrenal cortex. Proc. Nat. Acad. Sci. 81: 4647-4651, 1984.

5. Morohashi, K.; Sogawa, K.; Omura, T.; Fujii-Kuriyama, Y.: Gene
structure of human cytochrome P-450(SCC), cholesterol desmolase. J.
Biochem. 101: 879-887, 1987.

6. Nebert, D. W.; Adesnik, M.; Coon, M. J.; Estabrook, R. W.; Gonzalez,
F. J.; Guengerich, F. P.; Gunsalus, I. C.; Johnson, E. F.; Kemper,
B.; Levin, W.; Phillips, I. R.; Sato, R.; Waterman, M. R.: The P450
gene superfamily: recommended nomenclature. DNA 6: 1-11, 1987.

7. Slominski, A.; Ermak, G.; Mihm, M.: ACTH receptor, CYP11A1, CYP17
and CYP21A2 genes are expressed in skin. J. Clin. Endocr. Metab. 81:
2746-2749, 1996.

8. Sparkes, R. S.; Klisak, I.; Miller, W. L.: Regional mapping of
genes encoding human steroidogenic enzymes: P450scc to 15q23-q24;
adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17
to 10q24-q25. DNA Cell Biol. 10: 359-365, 1991.

9. Youngblood, G. L.; Nesbitt, M. N.; Payne, A. H.: The structural
genes encoding P450SCC and P450AROM are closely linked on mouse chromosome
9. Endocrinology 125: 2784-2786, 1989.

*FIELD* CN
Victor A. McKusick - updated: 04/15/1997
Jennifer P. Macke - updated: 11/14/1996

*FIELD* CD
Victor A. McKusick: 2/23/1992

*FIELD* ED
jenny: 04/15/1997
terry: 4/9/1997
jamie: 11/14/1996
terry: 5/24/1996
carol: 12/18/1992
carol: 10/26/1992
supermim: 3/16/1992
carol: 2/23/1992

*RECORD*
*FIELD* NO
118490
*FIELD* TI
*118490 CHOLINE ACETYLTRANSFERASE; CHAT
*FIELD* TX
Cholinergic systems are implicated in numerous neurologic functions.
Alteration in some cholinergic neurons may account for the disturbances
of Alzheimer disease. Cholinergic neurons are best characterized by the
enzyme choline acetyltransferase (CHAT; EC 2.3.1.6), which catalyzes the
biosynthesis of acetylcholine. Barrard et al. (1987) isolated a cDNA
clone encoding the complete sequence of porcine CHAT. By use of this
clone in the study of DNA from a panel of human-rodent somatic cell
hybrids, Cohen-Haguenauer et al. (1990) demonstrated that the CHAT gene
is located on human chromosome 10. Strauss et al. (1991) confirmed the
mapping to chromosome 10 and regionalized the assignment to 10q11-q22.2
by in situ hybridization. Viegas-Pequignot et al. (1991) used a human
choline acetyltransferase genomic sequence and in situ hybridization
studies to sublocalize the gene to human chromosome 10q11.2. Toussaint
et al. (1992) isolated and partially sequenced a human CHAT genomic
clone. The fragment they studied contained the first 4 exons with an ACG
initiator codon and potential control regions including TATA, CAAT, GC
boxes, and several transcription control sequences. By analyzing cDNAs
from mouse spinal cord, Misawa et al. (1992) demonstrated 7 polymorphic
forms of ChAT resulting from the alternative splicing of 3 5-prime exons
named R, N, and M to exon 1 which contains the ATG initiation codon.
Chireux et al. (1995) identified 2 alternative first exons in human
choline acetyltransferase. They found regions homologous to rodent exons
R and M but found that rodent exon N was not conserved in the human
gene.

Cholinergic neurotransmission requires uptake of extracellular choline,
biosynthesis of acetylcholine from choline and acetyl-coenzyme A,
accumulation of acetylcholine into synaptic vesicles driven by proton
antiport, and quantal release of acetylcholine from synaptic vesicles
triggered by electrical depolarization of the cholinergic neuron.
Erickson et al. (1994) identified a rat protein homologous to C. elegans
UNC-17, based on reconstitution of acetylcholine transport in a
fibroblast cell line transfected with a clone from a rat
pheochromocytoma cDNA library encoding this protein. The distribution of
VACHT (600336) mRNA coincided with that reported for CHAT in the
peripheral and central cholinergic nervous system. Furthermore, Erickson
et al. (1994) found that the VACHT gene mapped to the same chromosomal
location, 10q11.2. The entire sequence of the human VACHT cDNA was
contained uninterrupted within the first intron of the CHAT gene locus.
Transcription of VACHT and CHAT mRNA from the same or contiguous
promoters within the single regulatory locus provided a previously
undescribed genetic mechanism for coordinate regulation of 2 proteins
whose expression is required to establish a mammalian neuronal
phenotype.

*FIELD* RF
1. Barrard, B. A.; Lottspeich, F.; Braun, A.; Barde, Y. A.; Mallet,
J.: cDNA cloning and complete sequence of porcine choline acetyltransferase:
in vitro translation of the corresponding RNA yields an active protein.
Proc. Nat. Acad. Sci. 84: 9280-9284, 1987.

2. Chireux, M. A.; Le Van Thai, A.; Weber, M. J.: Human choline acetyltransferase
gene: localization of alternative first exons. J. Neurosci. Res. 40:
427-438, 1995.

3. Cohen-Haguenauer, O.; Brice, A.; Berrard, S.; Van Cong, N.; Mallet,
J.; Frezal, J.: Localization of the choline acetyltransferase (CHAT)
gene to human chromosome 10. Genomics 6: 374-378, 1990.

4. Erickson, J. D.; Varoqui, H.; Schafer, M. K.-H.; Modi, W.; Diebler,
M.-F.; Weihe, E.; Rand, J.; Eiden, L. E.; Bonner, T. I.; Usdin, T.
B.: Functional identification of a vesicular acetylcholine transporter
and its expression from a 'cholinergic' gene locus. J. Biol. Chem. 269:
21929-21932, 1994.

5. Misawa, H.; Ishii, K.; Deguchi, T.: Gene expression of mouse choline
acetyltransferase: alternative splicing and identification of a highly
active promoter region. J. Biol. Chem. 267: 20392-20399, 1992.

6. Strauss, W. L.; Kemper, R. R.; Jayakar, P.; Kong, C. F.; Hersh,
L. B.; Hilt, D. C.; Rabin, M.: Human choline acetyltransferase gene
maps to region 10q11-q22.2 by in situ hybridization. Genomics 9:
396-398, 1991.

7. Toussaint, J. L.; Geoffroy, V.; Schmitt, M.; Werner, A.; Garnier,
J. M.; Simoni, P.; Kempf, J.: Human choline acetyltransferase (CHAT):
partial gene sequence and potential control regions. Genomics 12:
412-416, 1992.

8. Viegas-Pequignot, E.; Berrard, S.; Brice, A.; Apiou, F.; Mallet,
J.: Localization of a 900-bp-long fragment of the human choline acetyltransferase
gene to 10q11.2 by nonradioactive in situ hybridization. Genomics 9:
210-212, 1991.

*FIELD* CD
Victor A. McKusick: 12/15/1988

*FIELD* ED
O.: 8/15/1995
carol: 1/24/1995
supermim: 3/16/1992
carol: 2/1/1992
carol: 1/18/1991
carol: 1/16/1991

*RECORD*
*FIELD* NO
118491
*FIELD* TI
*118491 CHOLINE KINASE; CHK
CKI, YEAST, HUMAN COMPLEMENT OF
*FIELD* TX
Cholinephosphate cytidylyltransferase plays a major role in the
regulation of phosphatidylcholine synthesis. A regulatory role of
choline kinase in phosphatidylcholine synthesis has also been suggested.
To elucidate the regulatory mechanism of choline kinase, Hosaka et al.
(1992) cloned a human choline kinase cDNA by complementation of the
yeast choline kinase mutation, cki, from a human glioblastoma cDNA
expression library. The deduced sequence of the human enzyme comprised
456 amino acids with a calculated relative molecular mass of 52,065. The
human enzyme resembled the rat liver enzyme over the entire sequence. It
also resembled the yeast enzyme in the carboxy-terminal region, but not
in the amino-terminal region.

*FIELD* RF
1. Hosaka, K.; Tanaka, S.; Nikawa, J.; Yamashita, S.: Cloning of
a human choline kinase cDNA by complementation of the yeast cki mutation.
FEBS Lett. 304: 229-232, 1992.

*FIELD* CD
Victor A. McKusick: 6/17/1994

*FIELD* ED
jason: 6/17/1994

*RECORD*
*FIELD* NO
118493
*FIELD* TI
*118493 CHOLINERGIC RECEPTOR, MUSCARINIC, 2; CHRM2
ACETYLCHOLINE RECEPTOR, MUSCARINIC, 2
*FIELD* TX
See 118510. Bonner (1990) indicated that the CHRM2 gene maps to 7q35-q36
by in situ hybridization (Bonner et al., 1991). Badner et al. (1995)
mapped the gene to 7q31-q35 by multipoint linkage analysis.

*FIELD* RF
1. Badner, J. A.; Yoon, S. W.; Turner, G.; Bonner, T. I.; Detera-Wadleigh,
S. D.: Multipoint genetic linkage analysis of the m2 human muscarinic
receptor gene. Mammalian Genome 6: 489-490, 1995.

2. Bonner, T. I.: Personal Communication. Bethesda, Md.  9/21/1990.

3. Bonner, T. I.; Modi, W. S.; Seuanez, H. N.; O'Brien, S. J.: Chromosomal
mapping of five human genes encoding muscarinic acetylcholine receptors.
(Abstract) Cytogenet. Cell Genet. 58: 1850-1851, 1991.

*FIELD* CD
Victor A. McKusick: 11/6/1990

*FIELD* ED
terry: 10/30/1995
mark: 10/5/1995
supermim: 3/16/1992
carol: 11/6/1990

*RECORD*
*FIELD* NO
118494
*FIELD* TI
*118494 CHOLINERGIC RECEPTOR, MUSCARINIC, 3; CHRM3
ACETYLCHOLINE RECEPTOR, MUSCARINIC, 3
*FIELD* TX
See 118510. Bonner (1990) indicated that the CHRM3 gene maps to 1q41-q44
by in situ hybridization.

*FIELD* RF
1. Bonner, T. I.: Personal Communication. Bethesda, Md.  9/21/1990.

*FIELD* CD
Victor A. McKusick: 11/6/1990

*FIELD* ED
supermim: 3/16/1992
carol: 11/6/1990

*RECORD*
*FIELD* NO
118495
*FIELD* TI
*118495 CHOLINERGIC RECEPTOR, MUSCARINIC, 4; CHRM4
ACETYLCHOLINE RECEPTOR, MUSCARINIC, 4
*FIELD* TX
See 118510. Detera-Wadleigh et al. (1989) described an SstI polymorphism
for the CHRM4 gene. They stated that the gene maps to 11p. By the study
of somatic cell hybrids and by both isotopic and nonisotopic in situ
hybridization, Bonner et al. (1991) assigned the CHRM4 gene to
11p12-p11.2. Grewal et al. (1992) mapped the CHRM4 gene to the same
region by linkage with DNA markers.

*FIELD* RF
1. Bonner, T. I.; Modi, W. S.; Seuanez, H. N.; O'Brien, S. J.: Chromosomal
mapping of five human genes encoding muscarinic acetylcholine receptors.
(Abstract) Cytogenet. Cell Genet. 58: 1850-1851, 1991.

2. Detera-Wadleigh, S. D.; Wiesch, D.; Bonner, T. I.: An SstI polymorphism
for the human muscarinic acetylcholine receptor gene, m4 (CHRM4).
Nucleic Acids Res. 17: 6431 only, 1989.

3. Grewal, R. P.; Martinez, M.; Hoehe, M.; Bonner, T. I.; Gershon,
E. S.; Detera-Wadleigh, S.: Genetic linkage mapping of the m4 human
muscarinic receptor (CHRM4). Genomics 13: 239-240, 1992.

*FIELD* CD
Victor A. McKusick: 9/9/1990

*FIELD* ED
carol: 5/22/1992
supermim: 3/16/1992
carol: 3/4/1992
carol: 2/21/1992
carol: 8/8/1991
supermim: 9/28/1990

*RECORD*
*FIELD* NO
118496
*FIELD* TI
*118496 CHOLINERGIC RECEPTOR, MUSCARINIC, 5; CHRM5
ACETYLCHOLINE RECEPTOR, MUSCARINIC, 5
*FIELD* TX
See 118510. Bonner (1990) indicated that the CHRM5 gene maps to 15q26 by
in situ hybridization.

*FIELD* RF
1. Bonner, T. I.: Personal Communication. Bethesda, Md.  9/21/1990.

*FIELD* CD
Victor A. McKusick: 12/18/1990

*FIELD* ED
supermim: 3/16/1992
carol: 12/18/1990

*RECORD*
*FIELD* NO
118502
*FIELD* TI
*118502 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 2; CHRNA2
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-2 SUBUNIT
*FIELD* TX
By genomic Southern analysis of hamster/human somatic cell hybrid DNAs,
Anand and Lindstrom (1992) mapped the gene encoding the alpha-2 subunit
of the human neuronal nicotinic acetylcholine receptor to chromosome 8.
The corresponding gene is located on chromosome 14 in the mouse (Bessis
et al., 1990).

*FIELD* RF
1. Anand, R.; Lindstrom, J.: Chromosomal localization of seven neuronal
nicotinic acetylcholine receptor subunit genes in humans. Genomics 13:
962-967, 1992.

2. Bessis, A.; Simon-Chazottes, D.; Devillers-Thiery, A.; Guenet,
J.-L.; Changeux, J.-P.: Chromosomal localization of the mouse genes
coding for alpha-2, alpha-3, alpha-4 and beta-2 subunits of neuronal
nicotinic acetylcholine receptor. FEBS Lett. 264: 48-52, 1990.

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
carol: 5/16/1994
carol: 8/31/1992
carol: 8/14/1992

*RECORD*
*FIELD* NO
118503
*FIELD* TI
*118503 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 3; CHRNA3
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-3 SUBUNIT
*FIELD* TX
Boulter et al. (1990) found that 3 genes encoding subunits of the
neuronal nicotinic acetylcholine receptor, alpha-3, alpha-5, and beta-4,
are clustered within a 68-kb segment of the rat genome. By somatic cell
hybrid analysis, Eng et al. (1991) mapped 3 cDNAs corresponding to these
genes to human chromosome 15 and to mouse chromosome 9. Linkage analysis
using CEPH pedigrees showed that the CHRNA5 gene was closely linked to 5
DNA markers on chromosome 15. Using interspecies crosses in mice, they
found that the Acra-5 gene was closely linked to the Mpi-1 locus
(154550). Thus, the human gene is probably in the region 15q22-qter,
where the human MPI gene is located. Raimondi et al. (1992) mapped the
CHRNA3, CHRNA5 (118505), and CHRNB4 (118509) genes to 15q24 by in situ
hybridization. Furthermore, by Southern blot analysis of 2 genomic
clones, Raimondi et al. (1992) demonstrated that the 3 genes are
physically linked. Anand and Lindstrom (1992) confirmed the assignment
to human chromosome 15 by genomic Southern analysis of human/hamster
somatic cell hybrid DNAs. They similarly confirmed the assignment of
CHRNA5 and CHRNB4 to chromosome 15. Their table 4 provided a
comprehensive listing of the chromosomal location of mouse and human
acetylcholinesterase receptor subunit genes.

*FIELD* RF
1. Anand, R.; Lindstrom, J.: Chromosomal localization of seven neuronal
nicotinic acetylcholine receptor subunit genes in humans. Genomics 13:
962-967, 1992.

2. Boulter, J.; O'Shea-Greenfield, A.; Duvoisin, R. M.; Connolly,
J. G.; Wada, E.; Jensen, A.; Gardner, P. D.; Ballivet, M.; Deneris,
E. S.; McKinnon, D.; Heinemann, S.; Patrick, J.: Alpha3, alpha5 and
beta4: three members of the rat neuronal nicotinic acetylcholine receptor-related
gene family form a gene cluster. J. Biol. Chem. 265: 4472-4482,
1990.

3. Eng, C. M.; Kozak, C. A.; Beaudet, A. L.; Zoghbi, H. Y.: Mapping
of multiple subunits of the neuronal nicotinic acetylcholine receptor
to chromosome 15 in man and chromosome 9 in mouse. Genomics 9:
278-282, 1991.

4. Raimondi, E.; Rubboli, F.; Moralli, D.; Chini, B.; Fornasari, D.;
Tarroni, P.; De Carli, L.; Clementi, F.: Chromosomal localization
and physical linkage of the genes encoding the human alpha-3, alpha-5,
and beta-4 neuronal nicotinic receptor subunits. Genomics 12: 849-850,
1992.

*FIELD* CD
Victor A. McKusick: 1/29/1991

*FIELD* ED
carol: 8/14/1992
carol: 4/1/1992
supermim: 3/16/1992
carol: 2/27/1992
carol: 2/21/1991
carol: 1/29/1991

*RECORD*
*FIELD* NO
118504
*FIELD* TI
*118504 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-4 SUBUNIT
*FIELD* TX
By genomic Southern blot analysis of hamster/human somatic cell hybrid
DNAs, Anand and Lindstrom (1992) mapped the gene encoding the alpha-4
subunit of the human neuronal nicotinic acetylcholine receptor to
chromosome 20. Pilz et al. (1992) likewise mapped the gene to human
chromosome 20 by Southern blot analysis of human/rodent somatic cell
hybrids. The corresponding gene is located on chromosome 2 in the mouse
(Bessis et al., 1990).

Steinlein et al. (1994) positioned CHRNA4 on a contig between D20S24 and
D20S20. The contig was mapped by fluorescence in situ hybridization to
20q13.2-q13.3. The 2 markers were separated by 160 kb. Steinlein et al.
(1994) suggested that the location of CHRNA4 makes it a possible
candidate gene for either benign neonatal familial convulsions (BFNC1;
121200) or the electroencephalographic variant pattern 1 (EEGV1;
130180).

Beck et al. (1994) demonstrated a nonsense mutation in the CHRNA4 gene
(118504.0001) that cosegregated with the 20q-linked form of benign
neonatal familial convulsions. Steinlein et al. (1995) demonstrated a
missense mutation in the CHRNA4 gene (118504.0002) associated with
autosomal dominant nocturnal frontal lobe epilepsy (600513), which had
previously been mapped to 20q. Indeed, the mutation was sought because
CHRNA4 maps to the same region of 20q and the gene is expressed in all
layers of the frontal cortex.

Monteggia et al. (1995) obtained the full length cDNA sequence for the
alpha-4 neuronal nicotinic acetylcholine receptor subunit. The predicted
amino acid sequence is 89% similar to rat sequence, with most
differences in the cytoplasmic domain. Transfection of expression
vectors for the alpha-4 and beta-2 subunits into HEK293 cells resulted
in the formation of binding sites with the expected high affinity for
cytosine.

Steinlein et al. (1996) determined that the CHRNA4 gene consists of 6
exons distributed over approximately 17 kb of genomic DNA.

*FIELD* AV
.0001
EPILEPSY, BENIGN NEONATAL, TYPE 1
CHRNA4, SER-TER
Approximately 80% of pedigrees with benign familial neonatal convulsions
show linkage to 20q13.3; the CHRNA4 gene maps to the same area. In 1 of
20 French BFNC1 pedigrees fulfilling the criteria for the clinical
diagnosis of this disorder, Beck et al. (1994) identified a nonsense
mutation in exon 5, which converted a serine codon to a stop codon. The
mutation was a C-to-G transversion at nucleotide 208. This was said to
be the first example of a human idiopathic epilepsy caused by mutation
directly affecting a neurotransmitter receptor in the CNS.

.0002
EPILEPSY, NOCTURNAL FRONTAL LOBE
ENFL
CHRNA4, SER248PHE
In a large Australian kindred, autosomal dominant nocturnal frontal lobe
epilepsy was mapped to 20q13.2-q13.3 by Phillips et al. (1995). In
affected members of the same family, Steinlein et al. (1995) used
single-strand conformation analysis to detect an abnormality which by
direct sequencing was demonstrated to be a C-to-T transition. It
resulted in replacement of the neutral serine by the complex aromatic
phenylalanine (ser248-to-phe) in the sixth amino acid position of the
transmembrane domain 2 (M2). They suggested that the mutation caused
reduced receptor function.

Forman et al. (1996) suggested an alternative mechanism for pathogenesis
of epilepsy associated with this CHRNA4 mutation. From studies of the
mouse muscle alpha-1 nicotinic receptor (100690) noted in Forman et al.
(1995), Forman et al. (1996) speculated that the mutation in CHRNA4 may
cause receptor hyperactivity that could lead to epileptic activity.

*FIELD* RF
1. Anand, R.; Lindstrom, J.: Chromosomal localization of seven neuronal
nicotinic acetylcholine receptor subunit genes in humans. Genomics 13:
962-967, 1992.

2. Beck, C.; Moulard, B.; Steinlein, O.; Guipponi, M.; Vallee, L.;
Montpied, P.; Baldy-Moulnier, M.; Malafosse, A.: A nonsense mutation
in the alpha-4 subunit of the nicotinic acetylcholine receptor (CHRNA4)
cosegregates with 20q-linked benign neonatal familial convulsions
(EBN1). Neurobiol. Dis. 1: 95-99, 1994.

3. Bessis, A.; Simon-Chazottes, D.; Devillers-Thiery, A.; Guenet,
J.-L.; Changeux, J.-P.: Chromosomal localization of the mouse genes
coding for alpha-2, alpha-3, alpha-4 and beta-2 subunits of neuronal
nicotinic acetylcholine receptor. FEBS Lett. 264: 48-52, 1990.

4. Forman, S. A.; Miller, K. W.; Yellen, G.: A discrete site for
general anesthetics on a postsynaptic receptor. Molec. Pharm. 48:
574-581, 1995.

5. Forman, S. A.; Yellen, G.; Thiele, E. A.: Alternative mechanism
for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation.
(Letter) Nature Genet. 13: 396-397, 1996.

6. Monteggia, L. M.; Gopalakrishnan, M.; Touma, E.; Idler, K. B.;
Nash, N.; Arneric, S. P.; Sullivan, J. P.; Giordano, T.: Cloning
and transient expression of genes encoding the human alpha-4 and beta-2
neuronal nicotinic acetylcholine receptor (nAChR) subunits. Gene 155:
189-193, 1995.

7. Phillips, H. A.; Scheffer, I. E.; Berkovic, S. F.; Hollway, G.
E.; Sutherland, G. R.; Mulley, J. C.: Localization of a gene for
autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nature
Genet. 10: 117-118, 1995.

8. Pilz, A. J.; Willer, E.; Povey, S.; Abbott, C. M.: The genes coding
for phosphoenolpyruvate carboxykinase-1 (PCK1) and neuronal nicotinic
acetylcholine receptor alpha-4 subunit (CHRNA4) map to human chromosome
20, extending the known region of homology with mouse chromosome 2. Ann.
Hum. Genet. 56: 289-293, 1992.

9. Steinlein, O.; Smigrodzki, R.; Lindstrom, J.; Anand, R.; Kohler,
M.; Tocharoentanaphol, C.; Vogel, F.: Refinement of the localization
of the gene for neuronal nicotinic acetylcholine receptor alpha-4
subunit (CHRNA4) to human chromosome 20q13.2-q13.3. Genomics 22:
493-495, 1994.

10. Steinlein, O.; Weiland, S.; Stoodt, J.; Propping, P.: Exon-intron
structure of the human neuronal nicotinic acetylcholine receptor alpha-4
subunit (CHRNA4). Genomics 32: 289-294, 1996.

11. Steinlein, O. K.; Mulley, J. C.; Propping, P.; Wallace, R. H.;
Phillips, H. A.; Sutherland, G. R.; Scheffer, I. E.; Berkovic, S.
F.: A missense mutation in the neuronal nicotinic acetylcholine receptor
alpha-4 subunit is associated with autosomal dominant nocturnal frontal
lobe epilepsy. Nature Genet. 11: 201-203, 1995.

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
terry: 08/09/1996
terry: 7/31/1996
mark: 3/25/1996
terry: 3/14/1996
mark: 10/10/1995
terry: 9/7/1995
A.F.: 8/4/1995
carol: 2/4/1993
carol: 8/31/1992
carol: 8/14/1992

*RECORD*
*FIELD* NO
118505
*FIELD* TI
*118505 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 5; CHRNA5
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-5 SUBUNIT
*FIELD* TX
See 118503. Chini et al. (1992) demonstrated that the CHRNA5 gene, like
the gene for alpha-bungarotoxin receptor (113955), is expressed in both
neuronal and nonneuronal human cell lines and is therefore not
neuron-specific.

*FIELD* RF
1. Chini, B.; Clementi, F.; Hukovic, N.; Sher, E.: Neuronal-type
alpha-bungarotoxin receptors and the alpha-5-nicotinic receptor subunit
gene are expressed in neuronal and nonneuronal human cell lines. Hum.
Genet. 89: 1572-1576, 1992.

*FIELD* CD
Victor A. McKusick: 1/29/1991

*FIELD* ED
carol: 3/27/1992
supermim: 3/16/1992
carol: 1/29/1991

*RECORD*
*FIELD* NO
118507
*FIELD* TI
*118507 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, BETA POLYPEPTIDE 2; CHRNB2
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, BETA-2 SUBUNIT
*FIELD* TX
By genomic Southern analysis of hamster/human somatic cell hybrid DNAs,
Anand and Lindstrom (1992) mapped the gene encoding the beta-2 subunit
of the human neuronal nicotinic acetylcholine receptor to chromosome 1.
The corresponding gene is located on chromosome 3 in the mouse (Bessis
et al., 1990). The CHRNB2 gene is probably located in the 1p21 region
because the corresponding gene in the mouse is closely linked to the
amylase gene locus.

Picciotto et al. (1995) disrupted the CHRNB2 mouse homolog in embryonic
stem (ES) cells to generate 'knockout' mice deficient in this subunit.
Homozygous mice were viable, mated normally, and showed no obvious
physical deficits. However, their brains showed absence of high-affinity
binding sites for nicotine, and electrophysiologic recordings from brain
slices showed that thalamic neurons did not respond to nicotine
application. Furthermore, behavioral tests demonstrated that nicotine no
longer augmented the performance of the deficient mice on passive
avoidance, a test of associative memory. Paradoxically, mutant mice were
able to perform better than their nonmutant sibs on this task.

*FIELD* RF
1. Anand, R.; Lindstrom, J.: Chromosomal localization of seven neuronal
nicotinic acetylcholine receptor subunit genes in humans. Genomics 13:
962-967, 1992.

2. Bessis, A.; Simon-Chazottes, D.; Devillers-Thiery, A.; Guenet,
J.-L.; Changeux, J.-P.: Chromosomal localization of the mouse genes
coding for alpha-2, alpha-3, alpha-4 and beta-2 subunits of neuronal
nicotinic acetylcholine receptor. FEBS Lett. 264: 48-52, 1990.

3. Picciotto, M. R.; Zoli, M.; Lena, C.; Bessis, A.; Lallemand, Y.;
LeNovere, N.; Vincent, P.; Pich, E. M.; Brulet, P.; Changeux, J.-P.
: Abnormal avoidance learning in mice lacking functional high-affinity
nicotine receptor in the brain. Nature 374: 65-67, 1995.

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
carol: 3/19/1995
carol: 8/31/1992
carol: 8/14/1992

*RECORD*
*FIELD* NO
118508
*FIELD* TI
*118508 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, BETA POLYPEPTIDE 3; CHRNB3
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, BETA-3 SUBUNIT
*FIELD* TX
By genomic Southern analysis of hamster/human somatic cell hybrid DNAs,
Anand and Lindstrom (1992) mapped the gene encoding the beta-3 subunit
of the human neuronal nicotinic acetylcholine receptor to chromosome 8.
They indicated that the location of the corresponding gene in the mouse
genome was not known. Koyama et al. (1994) used an exon amplification
method to construct a transcriptional map of human chromosome 8. With
this method, transcribed sequences from defined regions of genomic DNA
could be efficiently isolated using cosmid clones mapped to chromosome
8. Sequence analysis revealed identity of a particular exon
amplification fragment to the CHRNB3 gene. This transcribed fragment was
isolated from a cosmid clone that had previously been mapped to 8p11.2
by fluorescence in situ hybridization.

*FIELD* RF
1. Anand, R.; Lindstrom, J.: Chromosomal localization of seven neuronal
nicotinic acetylcholine receptor subunit genes in humans. Genomics 13:
962-967, 1992.

2. Koyama, K.; Sudo, K.; Nakamura, Y.: Mapping of the human nicotinic
acetylcholine receptor beta-3 gene (CHRNB3) within chromosome 8p11.2.
Genomics 21: 460-461, 1994.

*FIELD* CD
Victor A. McKusick: 8/14/1992

*FIELD* ED
jason: 6/9/1994
carol: 8/14/1992

*RECORD*
*FIELD* NO
118509
*FIELD* TI
*118509 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, BETA POLYPEPTIDE 4; CHRNB4
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, BETA-4 SUBUNIT
*FIELD* TX
See 118503.

*FIELD* CD
Victor A. McKusick: 1/29/1991
*FIELD* ED
supermim: 3/16/1992
carol: 1/29/1991
*RECORD*
*FIELD* NO
118510
*FIELD* TI
*118510 CHOLINERGIC RECEPTOR, MUSCARINIC, 1; CHRM1
ACETYLCHOLINE RECEPTOR, MUSCARINIC, 1
*FIELD* TX
Goyal (1989) stated that 5 distinct but related muscarinic receptors had
been identified, with apparent molecular weights ranging from 51,452 to
66,127. These glycosylated proteins have single chains of 460 to 590
amino acids that are thought to span the plasma membrane 7 times,
creating 4 extracellular domains, 7 helical hydrophobic transmembrane
domains, and 4 intracellular domains. Each protein is the product of a
different gene without introns in the coding sequence, and the amino
acid sequences in the receptor subtypes are remarkably homologous among
different animal species (Bonner et al., 1987; Peralta et al., 1987;
Bonner et al., 1988; Liao et al., 1989). The nomenclature is confusing
(Eglen and Whiting, 1986; Goyal, 1989). In structure and evolution,
muscarinic receptors are quite distinct from their pharmacologic kin,
the nicotinic receptors (see 100690, 100710, 100720, 100730). By means
of analysis of somatic cell hybrids and by both isotopic and nonisotopic
in situ hybridization, Bonner et al. (1991) assigned the CHRM1 gene to
11q12-q13.

*FIELD* RF
1. Bonner, T. I.; Buckley, N. J.; Young, A. C.; Brann, M. R.: Identification
of a family of muscarinic acetylcholine receptor genes. Science 237:
527-532, 1987.

2. Bonner, T. I.; Modi, W. S.; Seuanez, H. N.; O'Brien, S. J.: Chromosomal
mapping of five human genes encoding muscarinic acetylcholine receptors.
(Abstract) Cytogenet. Cell Genet. 58: 1850-1851, 1991.

3. Bonner, T. I.; Young, A. C.; Brann, M. R.; Buckley, N. J.: Cloning
and expression of the human and rat m5 muscarinic acetylcholine genes.
Neuron 1: 403-410, 1988.

4. Eglen, R. M.; Whiting, R. L.: Muscarinic receptor subtypes: a
critique of the current classification and a proposal for a working
nomenclature. J. Auton. Pharm. 6: 323-346, 1986.

5. Goyal, R. K.: Muscarinic receptor subtypes: physiology and clinical
implications. New Eng. J. Med. 321: 1022-1029, 1989.

6. Liao, C. F.; Themmen, A. P.; Joho, R.; Barberis, C.; Birnbaumer,
M.; Birnbaumer, L.: Molecular cloning and expression of a fifth muscarinic
acetylcholine receptor. J. Biol. Chem. 264: 7328-7337, 1989.

7. Peralta, E. G.; Ashkenazi, A.; Winslow, J. W.; Smith, D. H.; Ramachandran,
J.; Capon, D. J.: Distinct primary structures, ligand-binding properties
and tissue-specific expression of four human muscarinic acetylcholine
receptors. EMBO J. 6: 3923-3929, 1987.

*FIELD* CD
Victor A. McKusick: 10/17/1989

*FIELD* ED
supermim: 3/16/1992
carol: 2/27/1992
carol: 2/21/1992
carol: 8/8/1991
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
118511
*FIELD* TI
*118511 CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 7; CHRNA7
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-7 SUBUNIT
SCHIZOPHRENIA, NEUROPHYSIOLOGIC DEFECT IN, INCLUDED
*FIELD* TX
Chini et al. (1994) isolated cDNA and genomic clones coding for the
human alpha-7 neuronal nicotinic receptor subunit, the major component
of brain nicotinic receptors that are blocked by alpha-bungarotoxin. The
CHRNA7 cDNA encodes a mature protein of 479 amino acids that is highly
homologous to the rat alpha-7 neuronal nicotinic subunit (90%). By
fluorescence in situ hybridization, Chini et al. (1994) mapped the
CHRNA7 gene to 15q14, a region frequently rearranged in patients
carrying a bisatellite chromosome 15 with a large inverted duplication
(Wisniewski et al., 1979). This chromosomal aberration is associated
with mental retardation and with epileptic crises, which are sometimes
resistant to therapy. Since the number of alpha-bungarotoxin binding
sites, mainly composed of alpha-7 subunits, is related to seizure
sensitivity in a mouse strain, Chini et al. (1994) suggested a role for
the CHRNA7 gene in the epileptic seizures of these patients. Three other
nicotinic receptor subunit genes are located on chromosome 15; the
alpha-3 (CHRNA3; 118503), alpha-5 (CHRNA5; 118505), and beta-4 (CHRNB4;
118509) genes are clustered on band 15q24. By fluorescence in situ
hybridization, Orr-Urtreger et al. (1995) confirmed the assignment of
this gene to 15q13-q14. They had previously mapped the mouse homolog
(symbolized Acra7) to a homologous region on chromosome 7 by analyzing a
panel of DNA samples from an interspecific backcross.

Freedman et al. (1997) noted that various psychophysiologic studies
demonstrate altered brain functions in schizophrenic patients and their
relatives that may reflect inherited traits. Many findings indicate
basic deficits in the regulation of response to sensory stimuli that may
underlie patients' symptoms, such as hallucinations and delusions. In
addition to hearing voices, patients often attend to apparently
extraneous stimuli in their surroundings that normal individuals
generally ignore. Such symptoms suggest that the neuronal mechanisms
responsible for the filtering or gating of sensory input to higher brain
centers are deficient. One method developed for examining such neuronal
mechanisms compares the responses to the first and second of paired
stimuli. The first stimulus elicits excitatory response that also
activates inhibitory mechanisms, which then diminish the excitatory
response to the second stimulus. The ratio of the amplitude of the
second response to the first is inversely related to the strength of
inhibition. Freedman et al. (1997) used this method to study the
response to auditory stimuli in schizophrenia, using an electrically
positive evoked potential occurring 50 ms after an auditory stimulus
(P50). Inhibition of the P50 response to a second identical stimulus,
presented 50 ms after the first, is diminished in schizophrenics. The
defect is associated with attentional disturbances in schizophrenia.
Freedman et al. (1997) studied 9 families with multiple cases of
schizophrenia. Decreased P50 inhibition occurred not only in most
schizophrenics, but also in many of their nonschizophrenic relatives, in
a distribution consistent with inherited vulnerability for the disease.
Neurobiologic investigations involving humans and animal models
indicated that decreased function of the alpha-7-nicotinic cholinergic
receptor could underlie the physiologic defect. Freedman et al. (1997)
performed a genome-wide linkage analysis, assuming autosomal dominant
transmission, and showed that the defect is linked (maximum lod = 5.3
with zero recombination) to a dinucleotide polymorphism at 15q13-q14,
the site of the CHRNA7 gene. It was considered relevant that many
schizophrenics are heavy smokers. The authors speculated that heavy use
of nicotine and nicotine dependency may represent self-treatment for the
defect at the alpha-7-nicotinic receptor.

*FIELD* RF
1. Chini, B.; Raimond, E.; Elgoyhen, A. B.; Moralli, D.; Balzaretti,
M.; Heinemann, S.: Molecular cloning and chromosomal localization
of the human alpha-7-nicotinic receptor subunit gene (CHRNA7). Genomics 19:
379-381, 1994.

2. Freedman, R.; Coon, H.; Myles-Worsley, M.; Orr-Urtreger, A.; Olincy,
A.; Davis, A.; Polymeropoulos, M.; Holik, J.; Hopkins, J.; Hoff, M.;
Rosenthal, J.; Waldo, M. C. and 11 others: Linkage of a neurophysiological
deficit in schizophrenia to a chromosome 15 locus. Proc. Nat. Acad.
Sci. 94: 587-592, 1997.

3. Orr-Urtreger, A.; Seldin, M. F.; Baldini, A.; Beaudet, A. L.:
Cloning and mapping of the mouse alpha-7-neuronal nicotinic acetylcholine
receptor. Genomics 26: 399-402, 1995.

4. Wisniewski, L.; Hassold, T.; Heffelfinger, J.; Higgins, J. V.:
Cytogenetic and clinical studies in five cases of inv dup (15). Hum.
Genet. 50: 259-270, 1979.

*FIELD* CN
Victor A. McKusick - updated: 02/12/1997

*FIELD* CD
Victor A. McKusick: 2/15/1994

*FIELD* ED
mark: 02/12/1997
terry: 2/6/1997
terry: 4/18/1995
carol: 2/15/1994

*RECORD*
*FIELD* NO
118600
*FIELD* TI
*118600 CHONDROCALCINOSIS, FAMILIAL ARTICULAR
CALCIUM GOUT;;
CALCIUM PYROPHOSPHATE ARTHROPATHY;;
CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE; CPPD;;
CHONDROCALCINOSIS 1; CCAL1
*FIELD* TX
Familial articular chondrocalcinosis is a chronic articular disease
characterized by acute intermittent attacks of arthritis; the presence
of calcium hypophosphate crystals in synovial fluid, cartilage and
periarticular soft tissue; and, by x-ray, evidence of calcium deposition
in articular cartilage. Chondrocalcinosis occurs in 3 forms: a
hereditary form; a form associated with metabolic disorders such as
hyperparathyroidism, hemochromatosis, hypothyroidism and Wilson disease;
and a sporadic form, which may in some cases represent the hereditary
form. Under the designation of chondrocalcinosis articularis, Aschoff et
al. (1966) described a family with 4 affected persons in 2 generations.
The disorder was manifested clinically by episodic inflammatory
involvement, acute or subacute, of one or more joints. Calcified hyaline
and fibrous cartilage is demonstrable by x-ray, particularly in large
joints. In articular cartilage a dense narrow band follows the contour
of the epiphysis. Reginato et al. (1970) observed an unusually high
frequency among natives of the Chiloe Island group. Twenty-eight
patients were observed of whom 19 were aggregated in 6 kindreds.
Parent-child involvement with no male-to-male transmission was observed
in 3 of the families. In the other 3 families one or both parents were
not screened. Since the Chiloe group lives in an isolated area and is
presumably inbred, recessive inheritance remains a possibility. In these
cases involvement was polyarticular. Ankylosing of joints was a new
feature observed in this study. Rodriguez-Valverde et al. (1980) studied
the first-degree relatives of 46 cases in northern Spain and found that
5 cases were familial. In these 5 families, a total of 17 persons showed
calcified cartilage radiographically. All were in the same generation,
although not always in the same sibship. Inbreeding (type unspecified)
was stated for 4 of the 5 kindreds. In a further study,
Rodriguez-Valverde et al. (1988) identified 13 pedigrees through a
systematic radiologic survey of the first-degree relatives of 76
probands. Thirty women and 11 men in 25 sibships were affected. The
disease was of early onset in only 4 pedigrees. The clinical
manifestations in these 4 pedigrees were similar to those found in the
kindreds with late onset. Autosomal dominant inheritance was supported.
In Spain, Fernandez Dapica and Gomez-Reino (1986) found a 28.1%
prevalence of chondrocalcinosis in 149 relatives of 32 patients with
calcium pyrophosphate dihydrate deposition (CPPD) disease. No clinical
or radiologic differences between sporadic and familial cases were
found. The features were similar to those of the Chiloe islanders with
familial chondrocalcinosis as reported by Reginato (1976). Fernandez
Dapica and Gomez-Reino (1986) concluded that the findings support the
idea that the disorder was carried to Chile by Spanish immigrants. In a
study of 35 patients with chondrocalcinosis in Spain, Balsa et al.
(1990) found a prevalence of familial disease of 26%. They suggested
autosomal dominant inheritance with variable penetrance and more severe
involvement in homozygotes.

Depressed activity of synovial pyrophosphohydrolase was suggested by the
findings of Good and Starkweather (1969). This was not pursued further
(Good, 1974). Autosomal dominant inheritance for a form of
chondrocalcinosis is strongly supported by the pedigree reported by van
der Korst et al. (1974). Father-to-son transmission was noted.
Twenty-two cases in 2 generations were observed. Acute attacks occurred
in only 14 of the 22 and 6 of the 14 had not yet sought medical care.
Gaudreau et al. (1981) described articular chondrocalcinosis in 9
persons in 3 generations of a Quebec family (presumably French
Canadian). Extensive calcification of the cartilage of the pinnae and of
intervertebral discs was demonstrated. In 12 affected members of a
single kindred (Gaucher et al., 1977), Lust et al. (1981) found that
cultured fibroblasts and lymphocytes had a concentration of
intracellular inorganic pyrophosphate 2 times greater than that in cells
from unaffected family members and normal, unrelated volunteers. Bjelle
et al. (1982) studied 2 extensive, affected Swedish kindreds that
supported autosomal dominant inheritance. Of persons over 50 years of
age, 47% had experienced acute attacks of arthritis and/or had joint
calcifications. Back pain was frequent, but no ankylosis or deformity
was observed. As compared with 50 sporadic cases observed in the same
area of Sweden, the familial cases had an earlier onset, a greater
number of involved joints, and more frequent peripheral joint
involvement. Back pain was more frequent, and calcification of
intervertebral discs was found only in the hereditary cases. Bjelle et
al. (1982) demonstrated a genealogic link between 3 Swedish families,
thus showing probable founder effect similar to that found in Slovakia,
France and Chile. No connection to other European families was found. In
an Ashkenazi Jewish kindred, Eshel et al. (1990) found 7 members with a
medical history of this disorder and in the most recent generations 5
members with direct evidence of the disorder. Symptoms started in the
third decade and radiologic evidence developed by the fourth decade. The
joints commonly affected were knees, wrists, and elbows. The course was
chronic with acute, exercise-induced exacerbations.

Doherty et al. (1991) reported 5 unrelated English kindreds with
familial chondrocalcinosis due to CPPD crystal deposition. The largest
pedigree was unique in that affected family members also suffered
recurrent benign fits in childhood, permitting clear delineation of
phenotype at a young age--a major advantage in a condition that usually
shows late onset. The pattern of inheritance in this extended pedigree
was consistent with autosomal dominant transmission with 100%
penetrance. Hughes et al. (1995) described the clinical phenotype, which
included recurrent benign seizures that developed in the second half of
the first year of life, occurred with a frequency of 3-9 per year,
ceased around age 6 years, and were not associated with physical or
mental retardation. Acute attacks of pseudogout associated with
radiographic polyarticular chondrocalcinosis developed in the late third
and early fourth decades. These attacks continued against a subsequent
background of chronic or intermittent arthralgia. Chronic inflammatory
arthritis or deformity did not develop and functional outcome was good
in general. By a genome wide screen using highly informative
microsatellite polymorphisms, Hughes et al. (1995) succeeded in mapping
the mutant gene in this kindred to 5p. A maximum multipoint lod score of
4.6 was obtained for the location of the gene between D5S810 and D5S416.

Baldwin et al. (1995) described a large New England family with
early-onset CPDD and severe degenerative osteoarthritis. They
demonstrated genetic linkage between the disease in this family and DNA
markers on 8q, with a multipoint lod score of 4.06. It was unclear
whether the primary event causing the disease is deposition of
calcium-containing crystals in joint tissue (caused by a defect in a
CPDD gene) that progresses to severe degenerative osteoarthritis or
whether degenerative changes in cartilage (resulting from mutation in an
osteoarthritis gene) enhances deposition of calcium-containing crystals.

Nosology and Nomenclature: The form of chondrocalcinosis in the family
reported by Baldwin et al. (1995) appears to be different from the form
of chondrocalcinosis in the family reported by Hughes et al. (1995):
they map to 8q and 5p, respectively, and whereas there was associated
early-onset osteoarthritis in the family of Baldwin et al. (1995), there
was no chronic arthritis or deformity in the family reported by Hughes
et al. (1995). Here we are using the symbol CCAL1 for the 5p-linked
chondrocalcinosis with absent or inconspicuous chronic joint changes and
CCAL2 for the 8q-linked chondrocalcinosis with early-onset
osteoarthritis (600668).

*FIELD* SA
Bjelle et al. (1982); Gaucher et al. (1986); Lust et al. (1981); McCarty
(1976); McCarty and Haskins (1963); McCarty et al. (1962); Moskowitz
and Katz (1964); Reginato et al. (1975); Reginato et al. (1974); Richardson
et al. (1983); Twigg et al. (1964); Valsik et al. (1963)
*FIELD* RF
1. Aschoff, H.; Boehm, P.; Schoen, E. J.; Schurholz, K.: Hereditaere
Chondrocalcinosis articularis. Untersuchung einer Familie. Humangenetik 3:
98-103, 1966.

2. Baldwin, C. T.; Farrer, L. A.; Adair, R.; Dharmavaram, R.; Jimenez,
S.; Anderson, L.: Linkage of early-onset osteoarthritis and chondrocalcinosis
to human chromosome 8q. Am. J. Hum. Genet. 56: 692-697, 1995.

3. Balsa, A.; Martin-Mola, E.; Gonzalez, T.; Cruz, A.; Ojeda, S.;
Gijon-Banos, J.: Familial articular chondrocalcinosis in Spain. Ann.
Rheum. Dis. 49: 531-535, 1990.

4. Bjelle, A.; Edvinsson, U.; Hagstam, A.: Pyrophosphate arthropathy
in two Swedish families. Arthritis Rheum. 25: 66-74, 1982.

5. Bjelle, A.; Nordstrom, S.; Hagstam, A.: Hereditary pyrophosphate
arthropathy (familial articular chondrocalcinosis) in Sweden. Clin.
Genet. 21: 174-180, 1982.

6. Doherty, M.; Hamilton, E.; Henderson, J.; Misra, H.; Dixey, J.
: Familial chondrocalcinosis due to calcium pyrophosphate dihydrate
crystal deposition in English families. Brit. J. Rheum. 30: 10-15,
1991.

7. Eshel, G.; Gulik, A.; Halperin, N.; Avrahami, E.; Schumacher, H.
R.; McCarty, D. J.; Caspi, D.: Hereditary chondrocalcinosis in an
Ashkenazi Jewish family. Ann. Rheum. Dis. 49: 528-530, 1990.

8. Fernandez Dapica, M. P.; Gomez-Reino, J. J.: Familial chondrocalcinosis
in the Spanish population. J. Rheum. 13: 631-633, 1986.

9. Gaucher, A.; Faure, G.; Netter, P.; Pourel, J.: Les chondrocalcinoses
articulaires familiales. Presse Med. 15: 250-254, 1986.

10. Gaucher, A.; Faure, G.; Netter, P.; Pourel, J.; Raffoux, C.; Streiff,
F.; Tongio, M.-M.; Mayer, S.: Hereditary diffuse articular chondrocalcinosis:
dominant manifestation without close linkage with the HLA system in
a large pedigree. Scand. J. Rheum. 6: 217-221, 1977.

11. Gaudreau, A.; Camerlain, M.; Pibarot, M.-L.; Beauregard, G.; Lebrun,
A.; Petitclerc, C.: Familial articular chondrocalcinosis in Quebec.
Arthritis Rheum. 24: 611-615, 1981.

12. Good, A. E.: Personal Communication. Madison, Wis.  1974.

13. Good, A. E.; Starkweather, W. H.: Synovial fluid pyrophosphate
phosphohydrolase (PPPH) in pseudogout, gout and rheumatoid arthritis.
(Abstract) Arthritis Rheum. 12: 298 only, 1969.

14. Hughes, A. E.; McGibbon, D.; Woodward, E.; Dixey, J.; Doherty,
M.: Localisation of a gene for chondrocalcinosis to chromosome 5p.
Hum. Molec. Genet. 4: 1225-1228, 1995.

15. Lust, G.; Faure, G.; Netter, P.; Gaucher, A.; Seegmiller, J. E.
: Evidence of a generalized metabolic defect in patients with hereditary
chondrocalcinosis: increased inorganic pyrophosphate in cultured fibroblasts
and lymphoblasts. Arthritis Rheum. 24: 1517-1521, 1981.

16. Lust, G.; Faure, G.; Netter, P.; Seegmiller, J. E.: Increased
pyrophosphate in fibroblasts and lymphoblasts from patients with hereditary
diffuse articular chondrocalcinosis. Science 214: 809-810, 1981.

17. McCarty, D. J., Jr.: Proceedings of conference on pseudogout
and pyrophosphate metabolism. Arthritis Rheum. 19: 275-508, 1976.

18. McCarty, D. J., Jr.; Haskins, M. E.: The roentgenographic aspects
of pseudo-gout (articular chondrocalcinosis): an analysis of 20 cases.
Am. J. Roentgen. 90: 1248-1257, 1963.

19. McCarty, D. J., Jr.; Kohn, N. N.; Faires, J. S.: The significance
of calcium phosphate crystals in the synovial fluid of arthritic patients.
The 'pseudogout syndrome.' I. Clinical aspects. Ann. Intern. Med. 56:
711-737, 1962.

20. Moskowitz, R.; Katz, D.: Chondrocalcinosis (pseudogout syndrome):
a family study. J.A.M.A. 188: 867-871, 1964.

21. Reginato, A. J.: Articular chondrocalcinosis in the Chiloe islanders.
Arthritis Rheum. 19: 395-404, 1976.

22. Reginato, A. J.; Hollander, J. L.; Martinez, V.; Valenzuela, F.;
Schiapachasse, V.; Covarrubias, E.; Jacobelli, S.; Arinoviche, R.;
Silcox, D.; Ruiz, F.: Familial chondrocalcinosis in the Chiloe Islands,
Chile. Ann. Rheum. Dis. 34: 260-268, 1975.

23. Reginato, A. J.; Schumacher, H. R.; Martinez, V. A.: The articular
cartilage in familial chondrocalcinosis: light and electron microscopic
study. Arthritis Rheum. 17: 977-992, 1974.

24. Reginato, A. J.; Valenzuela, F.; Martinez, V. A.; Passano, G.;
Doza, S.: Polyarticular and familial chondrocalcinosis. Arthritis
Rheum. 13: 197-213, 1970.

25. Richardson, B. C.; Chafetz, N. I.; Ferrell, L. D.; Zulman, J.
I.; Genant, H. K.: Hereditary chondrocalcinosis in a Mexican-American
family. Arthritis Rheum. 26: 1387-1396, 1983.

26. Rodriguez-Valverde, V.; Tinture, T.; Zuniga, M.; Pena, J.; Gonzalez,
A.: Familial chondrocalcinosis: prevalence in northern Spain and
clinical features in five pedigrees. Arthritis Rheum. 23: 471-478,
1980.

27. Rodriguez-Valverde, V.; Zuniga, M.; Casanueva, B.; Sanchez, S.;
Merino, J.: Hereditary articular chondrocalcinosis: clinical and
genetic features in 13 pedigrees. Am. J. Med. 84: 101-106, 1988.

28. Twigg, H. L.; Zvaifler, N. J.; Nelson, C. W.: Chondrocalcinosis.
Radiology 82: 655-659, 1964.

29. Valsik, J.; Zitman, D.; Sitaj, S.: Articular chondrocalcinosis.
II. Genetic study. Ann. Rheum. Dis. 22: 153-157, 1963.

30. van der Korst, J. K.; Geerards, J.; Driessens, F. C. M.: A hereditary
type of idiopathic articular chondrocalcinosis: survey of a pedigree.
Am. J. Med. 56: 307-314, 1974.

*FIELD* CS

Growth:
   Normal

Joints:
   Arthropathy;
   Acute intermittent arthritis;
   Ankylosis

Radiology:
   Chondrocalcinosis

Lab:
   Normal serum calcium;
   Calcium pyrophosphate crystals in synovial fluid;
   Depressed activity of synovial pyrophosphohydrolase

Inheritance:
   Autosomal dominant with variable penetrance, more severe in homozygotes

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 8/18/1995
terry: 7/28/1995
mimadm: 6/25/1994
carol: 10/21/1993
supermim: 3/16/1992
carol: 3/2/1992

*RECORD*
*FIELD* NO
118610
*FIELD* TI
118610 CHONDROCALCINOSIS DUE TO APATITE CRYSTAL DEPOSITION
FAMILIAL APATITE DISEASE
*FIELD* TX
Marcos et al. (1981) described a family in which the mother (aged 67)
and 2 daughters and 2 sons (aged 48, 45, 34, and 33) had
chondrocalcinosis. They showed that the deposits were not calcium
pyrophosphate (see 118600) but rather carbonate calcium hydroxyapatite.
The clinical features were morning stiffness, pain, and limitation of
motion of the dorsolumbar spine in 4, associated with arthritis of the
small joints of the hands in 3, shoulder periarthritis in 2, and
costochondral pain in 1. In 4, multiple intervertebral disk
calcifications, mainly in the nucleus pulposus, were seen
radiographically. Periarticular calcific deposits, costal cartilage
calcifications, and degenerative changes in the small joints of the
hands were seen also. None had cartilage calcification in the knees,
pubic symphysis, or triangular ligament of the carpus. Thus, there are
clinical differences from the calcium pyrophosphate form of the disease.
Calcific periarthritis was reported in identical twins by Cannon and
Schmid (1973) and in a proband whose relatives had calcification of
intervertebral disks by Zaphiropoulos (1973).

*FIELD* RF
1. Cannon, R. B.; Schmid, F. R.: Calcific periarthritis involving
multiple sites in identical twins. Arthritis Rheum. 16: 303-305,
1973.

2. Marcos, J. C.; de Benyacar, M. A.; Garcia-Morteo, O.; Arturi, A.
S.; Maldonado-Cocco, J. A.; Morales, V. H.; Laguens, R. P.: Idiopathic
familial chondrocalcinosis due to apatite crystal deposition. Am.
J. Med. 71: 557-564, 1981.

3. Zaphiropoulos, G.: Recurrent calcific periarthritis involving
multiple sites. Proc. Roy. Soc. Med. 66: 351-352, 1973.

*FIELD* CS

Growth:
   Normal

Joints:
   Arthropathy;
   Morning stiffness;
   Arthritis of small hand joints;
   Shoulder periarthritis

Spine:
   Dorsolumbar spine pain and limitation of motion

Thorax:
   Costochondral pain

Radiology:
   Chondrocalcinosis;
   Multiple intervertebral disk calcifications;
   Periarticular calcific deposits;
   Costal cartilage calcifications

Lab:
   Calcium hydroxyapatite crystals in joints

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
118650
*FIELD* TI
*118650 CHONDRODYSPLASIA PUNCTATA
CHONDRODYSTROPHIA CALCIFICANS CONGENITA;;
CONRADI-HUNERMANN DISEASE
*FIELD* TX
Spranger et al. (1971) concluded that the form of chondrodysplasia
punctata to which the Conradi-Hunermann eponym is appropriately applied
has predominantly epiphyseal, frequently asymmetric calcifications and
dysplastic skeletal changes, a relatively good prognosis, and autosomal
dominant inheritance. They concluded that cataracts occur in only 17% of
cases as compared with a frequency of 72% in the rhizomelic form which
is recessive (215100) and usually lethal in the first year of life. Skin
changes occur in about 28% of cases of both forms. Happle (1981)
suggested that cataracts are consistently absent in the autosomal
dominant form and present in about two-thirds of the rhizomelic and
X-linked dominant (302950) forms. Conditions confused with
chondrodysplasia punctata include Zellweger cerebrohepatorenal syndrome
and multicentric epiphyseal ossification in multiple epiphyseal
dysplasia. Bergstrom et al. (1972) described affected mother and child.
The mother was born with short femora and humeri, the left leg shorter
than the right, saddle nose, frontal bossing, flexion contractures at
the hips and knees, left talipes equinovarus and hyperkeratosis with
erythema of the left side of the body. The son lived only one hour. In a
study from the pediatrics department of Spranger (Rittler et al., 1990),
a mild form of chondrodysplasia punctata with possible autosomal
dominant inheritance was supported. Patients with this form, which was
referred to as the Sheffield type, had characteristic face and symmetric
stippling of upper and/or lower limbs that disappeared with age. The
patients reported by Sheffield et al. (1976) were sporadic. A female
patient observed by Silverman (1961, 1969) had a similarly affected
brother and apparently a male cousin with the same disorder. Their
fathers appeared unaffected but this is not unexpected since the bone
changes disappear during childhood. The brother of the original patient
had a daughter who was similarly affected (Vinke and Duffy, 1974).

Maternal ingestion of coumarin anticoagulant during pregnancy can result
in a phenocopy of the dominant form of chondrodysplasia punctata,
including hypoplasia of the nasal bones to produce koala bear facies
(Becker et al., 1975; Pettifor and Benson, 1975; Shaul et al., 1975). In
addition to severe hypoplasia of the nose (sometimes with choanal
atresia), stippled epiphyses and coronal vertebral clefts are observed.
Various vitamin K antagonists produce this picture. The only difference
from chondrodysplasia punctata may be the absence of skin and hair
changes. Warfarin inhibits synthesis of gamma-carboxyglutamic acid which
is involved in both clotting and calcification. See review by Gallop et
al. (1980). Harrod and Sherrod (1981) demonstrated that warfarin
embryopathy can show familial aggregation; 2 sibs from pregnancies
during which their mother took warfarin for thrombophlebitis showed
signs, whereas a third sib from a pregnancy without warfarin ingestion
was unaffected.

*FIELD* SA
Jenkins and Noll (1978); Silengo et al. (1980); Stenflo and Suttie
(1977); Suttie  (1985); Trowitzsch et al. (1986); Whitfield  (1980)
*FIELD* RF
1. Becker, M. H.; Genieser, N. B.; Finegold, M.; Miranda, D.; Spackman,
T.: Chondrodysplasia punctata: is maternal warfarin therapy a factor?.
Am. J. Dis. Child. 129: 356-359, 1975.

2. Bergstrom, K.; Gustavson, K.-H.; Jorulf, H.: Chondrodystrophia
calcificans congenita (Conradi's disease) in a mother and her child.
Clin. Genet. 3: 158-161, 1972.

3. Gallop, P. M.; Lian, J. B.; Hauschka, P. V.: Carboxylated calcium-binding
proteins and vitamin K. New Eng. J. Med. 302: 1460-1466, 1980.

4. Happle, R.: Cataracts as a marker of genetic heterogeneity in
chondrodysplasia punctata. Clin. Genet. 19: 64-66, 1981.

5. Harrod, M. J. E.; Sherrod, P. S.: Warfarin embryopathy in siblings.
Obstet. Gynec. 57: 673-676, 1981.

6. Jenkins, T.; Noll, B.: Chondrodysplasia punctata: report of parent-to-child
transmission. S. Afr. Med. J. 54: 22-25, 1978.

7. Pettifor, J. M.; Benson, R.: Congenital malformations associated
with the administration of oral anticoagulants during pregnancy. J.
Pediat. 86: 459-462, 1975.

8. Rittler, M.; Menger, H.; Spranger, J.: Chondrodysplasia punctata,
tibia-metacarpal (MT) type. Am. J. Med. Genet. 37: 200-208, 1990.

9. Shaul, W. L.; Emery, H.; Hall, J. G.: Chondrodysplasia punctata
and maternal warfarin use during pregnancy. Am. J. Dis. Child. 129:
360-362, 1975.

10. Sheffield, L. J.; Danks, E. M.; Mayne, V.; Hutchinson, L. A.:
Chondrodysplasia punctata: 23 cases of a mild and relatively common
variety. J. Pediat. 89: 916-923, 1976.

11. Silengo, M. C.; Luzzatti, L.; Silverman, F. N.: Clinical and
genetic aspects of Conradi-Hunermann disease: a report of three familial
cases and review of the literature. J. Pediat. 97: 911-917, 1980.

12. Silverman, F.: Dysplasies epiphysaires. Ann. Radiol. 4: 9-10,
1961.

13. Silverman, F.: Discussion on the relation between stippled epiphyses
and the multiple forms of epiphyseal dysplasia. Birth Defects Orig.
Art. Ser. V(4): 68-70, 1969.

14. Spranger, J. W.; Opitz, J. M.; Bidder, U.: Heterogeneity of chondrodysplasia
punctata. Humangenetik 11: 190-212, 1971.

15. Stenflo, J.; Suttie, J. W.: Vitamin K-dependent formation of
gamma-carboxyglutamic acid. Ann. Rev. Biochem. 46: 157-172, 1977.

16. Suttie, J. W.: Vitamin K-dependent carboxylase. Ann. Rev. Biochem. 54:
459-477, 1985.

17. Trowitzsch, E.; Richter, R.; Eisenberg, W.; Kallfelz, H. C.:
Severe pulmonary arterial stenoses in Conradi-Hunermann disease. Europ.
J. Pediat. 145: 116-118, 1986.

18. Vinke, T. H.; Duffy, F. P.: Chondrodystrophia calcificans congenita:
report of 2 cases. J. Bone Joint Surg. 29A: 509-514, 1974.

19. Whitfield, M. F.: Chondrodysplasia punctata after warfarin in
early pregnancy: case report and summary of the literature. Arch.
Dis. Child. 55: 139-142, 1980.

*FIELD* CS

Growth:
   Moderate growth deficiency

Skel:
   Chondrodysplasia punctata

Spine:
   Scoliosis

Limbs:
   Limb asymmetry;
   Talipes equinovarus

Joints:
   Flexion contractures of hips and knees

Skin:
   Hyperkeratosis with erythema

Hair:
   Sparse hair;
   Coarse hair

Head:
   Frontal bossing

Facies:
   Koala bear facies;
   Nasal bone hypoplasia

Eyes:
   Cataracts

Misc:
   Relatively good prognosis

Radiology:
   Predominantly epiphyseal, frequently asymmetric calcifications and
   dysplastic skeletal changes

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 10/21/1993
supermim: 3/16/1992
carol: 10/24/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
118651
*FIELD* TI
118651 CHONDRODYSPLASIA PUNCTATA, TIBIA-METACARPAL TYPE
CHONDRODYSPLASIA PUNCTATA, MT TYPE
*FIELD* TX
Rittler et al. (1990) described 7 sporadic cases of what appeared to be
a new form of chondrodysplasia punctata. Two of the cases had been
reported previously by Burck et al. (1980) and Burck (1982). The
principal clinical manifestations were flat midface and nose, short
limbs, and otherwise normal development. Consistent radiologic
manifestations in the newborn infant were discrete calcific stippling,
coronal clefts of vertebral bodies, short tibias, and short second and
third metacarpal bones. Radiologic findings in the older child included
shortness of the tibias and of the third and fourth metacarpals.
Occurrence in both males and females, advanced paternal age in 1 case,
and absence of parental consanguinity were compatible with autosomal
dominant mutation. The same disorder was reported by Haynes and Wangner
(1951) and by Asanti and Heikel (1963).

*FIELD* RF
1. Asanti, R.; Heikel, P.-E.: Chondroangiopathia calcarea or punctata.
Ann. Paediat. Fenn. 9: 280-289, 1963.

2. Burck, U.: Mesomelic dysplasia with punctata epiphyseal calcifications--a
new entity of chondrodysplasia punctata?. Europ. J. Pediat. 138:
67-72, 1982.

3. Burck, U.; Schaefer, E.; Held, K. R.: Mesomelic dysplasia with
short ulna, long fibula, brachymetacarpy and micrognathia: clinical
and radiological differential diagnostic features. Pediat. Radiol. 9:
161-165, 1980.

4. Haynes, E. R.; Wangner, W. M. F.: Chondroangioapathia calcarea
seu punctata: review and case report. Radiology 57: 547-550, 1951.

5. Rittler, M.; Menger, H.; Spranger, J.: Chondrodysplasia punctata,
tibia-metacarpal (MT) type. Am. J. Med. Genet. 37: 200-208, 1990.

*FIELD* CS

Facies:
   Flat midface;
   Flat nose

Limbs:
   Short limbs

Radiology:
   Discrete calcific stippling;
   Coronal clefts of vertebral bodies;
   Short tibias;
   Short second and third or third and fourth metacarpals

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/24/1990

*FIELD* ED
mimadm: 6/25/1994
warfield: 4/6/1994
carol: 3/25/1992
supermim: 3/16/1992
carol: 10/24/1990

*RECORD*
*FIELD* NO
118661
*FIELD* TI
*118661 CHONDROITIN SULFATE PROTEOGLYCAN 2; CSPG2
VERSICAN;;
CHONDROITIN SULFATE PROTEOGLYCAN CORE PROTEIN, CARTILAGE
*FIELD* TX
Large chondroitin sulfate proteoglycans were first identified in hyaline
cartilage where they specifically interact with hyaluronan and form
large supramolecular complexes. Together with other matrix
glycoproteins, they provide mechanical support and a fixed negative
charge. Such molecules exist also in a variety of soft tissues where
they may play additional physiologic roles (Kjellen and Lindahl, 1991).
Zimmermann and Ruoslahti (1989) cloned and sequenced the cDNA of the
core protein of fibroblast chondroitin sulfate proteoglycan. They
designated it versican in recognition of its versatile modular
structure. Decorin (125255) and biglycan (301870) are 2 other soft
tissue proteoglycans.

Doege et al. (1990) cloned cDNA for chondroitin sulfate proteoglycan
core protein and sequenced 2 distinct subclones. Finkelstein et al.
(1991) used these clones as probes to examine the core protein in cases
of achondroplasia (100800) and pseudoachondroplasia (177150) by 2
molecular genetic approaches: (1) Southern blot analysis to look for
gross alterations in the gene, and (2) a genetic linkage approach using
RFLPs in multiplex families. No gross alterations at the CSPG2 locus
were noted in 37 persons with achondroplasia or in 5 persons with
pseudoachondroplasia. Furthermore, allelic frequencies of
CSPG2-associated RFLPs were not significantly different among controls
and patients with either condition. In one 3-generation family with
achondroplasia, close linkage to the CSPG2 locus was excluded using a
BglII polymorphism. Similarly, in a 3-generation family with
pseudoachondroplasia, the CSPG2 gene was not tightly linked to a disease
phenotype. The distinctness of CSPG1 (155760) and CSPG2 was uncertain
until both genes had been mapped. Whereas CSPG1 is located on chromosome
15, Iozzo et al. (1992) demonstrated that the CSPG2 gene is located on
chromosome 5. They used a combination of human/rodent somatic cell
hybrids including a panel of hybrids containing partial deletions of
chromosome 5 and narrowed the assignment to 5q12-q14, with the precise
site likely to be 5q13.2, by in situ hybridization. Naso et al. (1995)
reported that murine versican is 89% identical to human versican at the
amino acid level and is highly expressed in mouse embryos at days 13,
14, and 18. Using interspecific backcross analysis, they assigned the
Cspg2 gene to mouse chromosome 13, in a region that is syntenic with 5q.

Naso et al. (1994) showed that the human versican gene contains 15 exons
spanning over 90 kb. One of these, exon 7, is used in an alternative
splice variant. The authors sequenced the 5-prime promoter-containing
region of the gene and found that it contained numerous binding sites
for transactivators such as AP2 (107580) and Sp1 (189906). They used
transient transfection studies to show that the promoter functioned well
in both mesenchymal and epithelial cells. The authors used deletion
studies to also show that this 5-prime region (to ~ -630) contains both
strong enhancer and strong negative regulatory elements.

*FIELD* RF
1. Doege, K.; Rhodes, C.; Sasaki, M.; Hassell, J. R.; Yamada, Y.:
Molecular biology of cartilage proteoglycan (aggrecan) and link protein.
In: Sandel, L. J.; Boyd, C. D.: Extracellular Matrix Genes.  New
York: Academic Press (pub.)  1990. Pp. 137-152.

2. Finkelstein, J. E.; Doege, K.; Yamada, Y.; Pyeritz, R. E.; Graham,
J. M., Jr.; Moeschler, J. B.; Pauli, R. M.; Hecht, J. T.; Francomano,
C. A.: Analysis of the chondroitin sulfate proteoglycan core protein
(CSPGCP) gene in achondroplasia and pseudoachondroplasia. Am. J.
Hum. Genet. 48: 97-102, 1991.

3. Iozzo, R. V.; Naso, M. F.; Cannizzaro, L. A.; Wasmuth, J. J.; McPherson,
J. D.: Mapping of the versican proteoglycan gene (CSPG2) to the long
arm of human chromosome 5 (5q12-5q14). Genomics 14: 845-851, 1992.

4. Kjellen, L.; Lindahl, U.: Proteoglycans: structures and interactions.
Annu. Rev. Biochem. 60: 443-475, 1991.

5. Naso, M. F.; Morgan, J. L.; Buchberg, A. M.; Siracusa, L. D.; Iozzo,
R. V.: Expression pattern and mapping of the murine versican gene
(Cspg2) to chromosome 13. Genomics 29: 297-300, 1995.

6. Naso, M. F.; Zimmermann, D. R.; Iozzo, R. V.: Characterization
of the complete genomic structure of the human versican gene and functional
analysis of its promoter. J. Biol. Chem. 269: 32999-33008, 1994.

7. Zimmermann, D. R.; Ruoslahti, E.: Multiple domains of the large
fibroblast proteoglycan, versican. EMBO J. 8: 2975-2981, 1989.

*FIELD* CN
Alan F. Scott - updated: 3/27/1996

*FIELD* CD
Victor A. McKusick: 2/13/1991

*FIELD* ED
terry: 04/17/1996
mark: 3/27/1996
mark: 10/3/1995
warfield: 3/21/1994
carol: 10/21/1993
carol: 4/16/1993
carol: 1/14/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
118670
*FIELD* TI
118670 CHONDRONECTIN; CHN
*FIELD* TX
Chondronectin is a distinct glycoprotein similar in structure and
function to fibronectin. It is present in plasma in the concentration of
about 20 micrograms per ml. In tissues, it is limited to cartilage and
vitreous, which are also the sites of type II collagen, and functions in
relation to chondrocytes and type II collagen in the way that
fibronectin functions in relation to other cells and types I and III
collagen (Kleinman et al., 1981). It also binds chondroitin sulfate and
heparin (Kleinman, 1982).

*FIELD* RF
1. Kleinman, H. K.: Personal Communication. Bethesda, Md.  1/7/1982.

2. Kleinman, H. K.; Klebe, R. J.; Martin, G. R.: Role of collagenous
matrices in the adhesion and growth of cells. J. Cell Biol. 88:
473-485, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 8/1/1994
terry: 7/27/1994
warfield: 4/7/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
118700
*FIELD* TI
*118700 CHOREA, HEREDITARY BENIGN; BCH
HEREDITARY PROGRESSIVE CHOREA WITHOUT DEMENTIA
*FIELD* TX
Pincus and Chutorian (1967) and Haerer et al. (1967) described an
early-onset, nonprogressive form of chorea not associated with
intellectual deterioration. The latter report concerned a black family.
Possible dominant inheritance was demonstrated in 2 families by Chun et
al. (1973). Bird et al. (1976) pointed out that this is a socially
embarrassing condition and perhaps for that reason may be associated
with behavioral problems and learning difficulties. For purposes of
genetic counseling and prognostication, it is obviously important to
distinguish this disorder from Huntington disease (HD; 143100). Harper
(1978) favored autosomal dominant inheritance with reduced penetrance in
females. He pointed out that male-to-male transmission occurred in the
families of Pincus and Chutorian (1967) and possibly in the family of
Sadjadpour and Amato (1973). Furthermore, X-linked inheritance appears
to be excluded by the apparent transmission through an unaffected male
in Pincus and Chutorian's family. Robinson and Thornett (1985) reported
a 10-year-old boy with this disorder whose father was the only other
affected person known in the family. Corticosteroids given in multiple
courses because of asthma invariably was associated with an abrupt
improvement in frequency and amplitude of his chorea. The authors
suggested that the improvement resulted from modulation of
neurotransmitter function by the agent. Schady and Meara (1988)
described a family in which chorea began in childhood and affected
predominantly the head, face, and arms. Dysarthria appeared later,
followed in 2 family members by elements of an axial dystonia. There was
no intellectual impairment. Unlike previously described families,
symptoms progressed steadily up to the eighth decade, causing
considerable physical disability. Schady and Meara (1988) described the
use of the label 'benign' and concurred with Behan and Bone (1977) that
the most accurate term was 'hereditary chorea without dementia.'

Quarrell et al. (1988) studied 5 families. They found that the D4S10
(probe G8) marker is not closely linked, thus excluding the possibility
that benign hereditary chorea is allelic with Huntington disease.
Furthermore, when the expanded repeat sequence was discovered as the
basis of Huntington disease, these families were restudied by MacMillan
et al. (1993). In 4 of the families, the (CAG)n repeat was not found; in
1 family, expanded repeats were found. Because of the small size of the
family and the uninformativeness of G8 typing, this linkage to 4p16
could not be excluded in the original study of this family. Yapijakis et
al. (1995) likewise excluded linkage to the HD locus in a Greek family.

*FIELD* SA
Bird and Hall (1978); Stapert et al. (1985)
*FIELD* RF
1. Behan, P. O.; Bone, I.: Hereditary chorea without dementia. J.
Neurol. Neurosurg. Psychiat. 40: 687-691, 1977.

2. Bird, T. D.; Carlson, C. B.; Hall, J. G.: Familial essential ('benign')
chorea. J. Med. Genet. 13: 357-362, 1976.

3. Bird, T. D.; Hall, J. G.: Additional information on familial essential
(benign) chorea.  (Letter) Clin. Genet. 14: 271-272, 1978.

4. Chun, R. W. M.; Daly, R. F.; Mansheim, B. J., Jr.; Wolcott, G.
J.: Benign familial chorea with onset in childhood. J.A.M.A. 225:
1603-1607, 1973.

5. Haerer, A. F.; Currier, R. D.; Jackson, J. F.: Hereditary nonprogressive
chorea of early onset. New Eng. J. Med. 276: 1220-1224, 1967.

6. Harper, P. S.: Benign hereditary chorea: clinical and genetic
aspects. Clin. Genet. 13: 85-95, 1978.

7. MacMillan, J. C.; Morrison, P. J.; Nevin, N. C.; Shaw, D. J.; Harper,
P. S.; Quarrell, O. W. J.; Snell, R. G.: Identification of an expanded
CAG repeat in the Huntington's disease gene (IT15) in a family reported
to have benign hereditary chorea. J. Med. Genet. 30: 1012-1013,
1993.

8. Pincus, J. H.; Chutorian, A.: Familial benign chorea with intention
tremor: a clinical entity. J. Pediat. 70: 724-729, 1967.

9. Quarrell, O. W. J.; Youngman, S.; Sarfarazi, M.; Harper, P. S.
: Absence of close linkage between benign hereditary chorea and the
locus D4S10 (probe G8). J. Med. Genet. 25: 191-194, 1988.

10. Robinson, R. O.; Thornett, C. E. E.: Benign hereditary chorea--response
to steroids. Dev. Med. Child Neurol. 27: 814-821, 1985.

11. Sadjadpour, K.; Amato, R. S.: Hereditary nonprogressive chorea
of early onset: a new entity?. Adv. Neurol. 1: 79-91, 1973.

12. Schady, W.; Meara, R. J.: Hereditary progressive chorea without
dementia. J. Neurol. Neurosurg. Psychiat. 51: 295-297, 1988.

13. Stapert, J. L. R. H.; Busard, B. L. S. M.; Gabreels, F. J. M.;
Renier, W. O.; Colon, E. J.; Verhey, F. H. M.: Benign (nonparoxysmal)
familial chorea of early onset: an electroneurophysiological examination
of two families. Brain Dev. 7: 38-42, 1985.

14. Yapijakis, C.; Kapaki, E.; Zournas, C.; Rentzos, M.; Loukopoulos,
D.; Papageorgiou, C.: Exclusion mapping of the benign hereditary
chorea gene from the Huntington's disease locus: report of a family.
Clin. Genet. 47: 133-138, 1995.

*FIELD* CS

Neuro:
   Chorea;
   No intellectual deterioration;
   Behavioral problems;
   Learning difficulties;
   Late dysarthria

Misc:
   Early-onset, nonprogressive

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 6/8/1995
davew: 8/17/1994
mimadm: 6/25/1994
terry: 5/16/1994
carol: 1/19/1994
carol: 3/31/1992

*RECORD*
*FIELD* NO
118750
*FIELD* TI
118750 CHOREOATHETOSIS, FAMILIAL INVERTED
INFANTILE CHOREOATHETOSIS OF FISHER
*FIELD* TX
Fisher et al. (1979) described a family with a seemingly 'new' form of
progressive choreoathetosis. Onset was infantile. The movements
predominantly affected the legs and also impaired gait. No dementia,
seizures, or rigidity was noted. It was designated 'inverted' because of
the predominant involvement of the legs, an unusual feature among the
choreas. Four generations, 5 sibships and 10 individuals were affected,
with male-to-male transmission. The authors felt that it was
distinguishable from benign hereditary chorea by its progressive nature;
benign chorea remains static from early childhood and may even improve.
In addition, pyramidal tract signs, demonstrated in some cases of the
inverted form, have not been observed in benign chorea. In addition to
familial benign chorea (118700) and Huntington disease (143100),
familial choreoathetosis also occurs in a familial paroxysmal form
(118800), which may be precipitated by sudden movements, i.e.,
kinesigenic (128200); with Lesch-Nyhan syndrome (308000); with Wilson
disease (277900); with dominant acanthocytosis (100500) and sometimes
with familial basal ganglion calcification (114100).

*FIELD* RF
1. Fisher, M.; Sargent, J.; Drachman, D.: Familial inverted choreoathetosis.
Neurology 29: 1627-1631, 1979.

*FIELD* CS

Neuro:
   Progressive choreoathetosis;
   Impaired gait;
   Predominant leg involvement;
   Occasional pyramidal tract signs;
   No dementia, seizures, or rigidity

Misc:
   Infantile onset

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 4/13/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
118800
*FIELD* TI
*118800 CHOREOATHETOSIS, FAMILIAL PAROXYSMAL; FPD1
PAROXYSMAL DYSTONIC CHOREOATHETOSIS; PDC;;
MOUNT-REBACK SYNDROME;;
NONKINESIGENIC CHOREOATHETOSIS
*FIELD* TX
Mount and Reback (1940) described a family with many members in 5
generations affected by paroxysmal choreoathetosis which was thought to
be separate from Huntington chorea. The attacks lasted only a few
minutes, occurred a few times a day and were not accompanied by
unconsciousness. Alcohol, coffee, hunger, fatigue and tobacco were
precipitating factors. Affected persons were said to be scattered
throughout the South from South Carolina to Oklahoma. Wagner et al.
(1966) observed affected persons in 3 generations. Richards and Barnett
(1968) suggested that it be called paroxysmal dystonic choreoathetosis
to distinguish it from the more frequently reported movement-induced
(kinetogenic) familial (or nonfamilial) paroxysmal choreoathetosis with
which it is often confused. They also suggested use of the eponym
Mount-Reback for the dystonic form. Muller and Kupke (1990) referred to
this disorder as paroxysmal dystonic choreoathetosis. See dystonia,
familial paroxysmal (128200). Walker (1980) provided follow-up on the
Mount-Reback kindred. He observed a son and daughter of their proband.
The movement disorder could be recognized in the first week of life. The
attacks were usually preceded by an aura. The Canadian family reported
by Richards and Barnett (1968) was the only one Walker (1980) considered
identical to that of Mount and Reback. Walker (1980) raised the
possibility that these 2 kindreds are related because of similar origin
in the British Isles and commonality of some family names. Byrne et al.
(1991) presented a family with paroxysmal dystonic choreoathetosis
transmitted as a dominant trait through 5 generations. The family was
unusual in that several of the affected members showed interruption of
the episodes by short periods of sleep. Also, age of onset was highly
variable and some of the affected persons showed prominent myokymia. The
overlapping features suggested a relationship between this disorder and
familial paroxysmal ataxia with myokymia (160120).

Demirkiran and Jankovic (1995) studied 46 patients with paroxysmal
dyskinesias. They introduced a new classification: kinesigenic, induced
by movement; nonkinesigenic; exertion-induced; and hypnogenic, induced
by sleep. Of their 46 patients, only 2 had a positive family history, 1
with kinesigenic, the other with hypnogenic dyskinesia. In the 23 other
patients in which an etiology could be identified, this included
psychogenic, cerebrovascular, multiple sclerosis, encephalitis, cerebral
trauma, peripheral trauma, migraine, and kernicterus. Patients with
kinesigenic dyskinesias responded more frequently to anticonvulsant
medication than those with nonkinesigenic dyskinesias.

Fouad et al. (1996) performed linkage studies in a large 5-generation
Italian family with 20 affected members, using 99 markers uniformly
distributed throughout the autosomes. Positive lod scores were found
with marker D2S102 at 2q31-q36; maximum lod = 4.64 at theta = 0.
Additional markers were used to refine the location of the PDC locus to
a 10-cM region between markers D2S128 (proximal) and D2S126 (distal).
Fink et al. (1996) evaluated 28 members of an affected American kindred
of Polish descent and also showed tight linkage between the disease
locus and microsatellite markers on distal 2q (2q33-q35); a maximum
2-point lod score of 4.77 at theta = 0 was found with marker D2S173.
Fouad et al. (1996) and Fink et al. (1996) noted that other forms of
paroxysmal neurologic disorders (e.g., hypo- and hyperkalemic periodic
paralysis; 170400 and 170500) are due to mutation in ion channel genes
and that a cluster of sodium channel genes is located on distal
chromosome 2. Fouad et al. (1996) suggested that AE3 (106195), which
maps near the PDC locus, is an excellent candidate gene.

*FIELD* SA
Hudgins and Corbin (1966); Kato and Araki (1969); Stevens  (1966);
Walker  (1981); Williams and Stevens (1963)
*FIELD* RF
1. Byrne, E.; White, O.; Cook, M.: Familial dystonic choreoathetosis
with myokymia; a sleep responsive disorder. J. Neurol. Neurosurg.
Psychiat. 54: 1090-1092, 1991.

2. Demirkiran, M.; Jankovic, J.: Paroxysmal dyskinesias: clinical
features and classification. Ann. Neurol. 38: 571-579, 1995.

3. Fink, J. K.; Rainier, S.; Wilkowski, J.; Jones, S. M.; Kume, A.;
Hedera, P.; Albin, R.; Mathay, J.; Girbach, L.; Varvil, T.; Otterud,
B.; Leppert, M.: Paroxysmal dystonic choreoathetosis: tight linkage
to chromosome 2q. Am. J. Hum. Genet. 59: 140-145, 1996.

4. Fouad, G. T.; Servidei, S.; Durcan, S.; Bertini, E.; Ptacek, L.
J.: A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome
2q. Am. J. Hum. Genet. 59: 135-139, 1996.

5. Hudgins, R. L.; Corbin, K. B.: An uncommon seizure disorder: familial
paroxysmal choreoathetosis. Brain 89: 199-204, 1966.

6. Kato, M.; Araki, S.: Paroxysmal kinesigenic choreoathetosis. Arch.
Neurol. 20: 508-513, 1969.

7. Mount, L. A.; Reback, S.: Familial paroxysmal choreoathetosis:
preliminary report on a hitherto undescribed clinical syndrome. Arch.
Neurol. Psychiat. 44: 841-847, 1940.

8. Muller, U.; Kupke, K. G.: The genetics of primary torsion dystonia. Hum.
Genet. 84: 107-115, 1990.

9. Richards, R. N.; Barnett, H. J.: Paroxysmal dystonic choreoathetosis:
a family study and review of the literature. Neurology 18: 461-469,
1968.

10. Stevens, H. F.: Paroxysmal choreo-athetosis: a form of reflex
epilepsy. Arch. Neurol. 14: 415-420, 1966.

11. Wagner, G. S.; McLees, B. D.; Hatcher, M. A., Jr.: Familial paroxysmal
choreo-athetosis. (Abstract) Neurology 16: 307, 1966.

12. Walker, E. S.: Personal Communication. Brooklyn, N. Y.  2/26/1980.

13. Walker, E. S.: Familial paroxysmal dystonic choreoathetosis:
a neurologic disorder simulating psychiatric illness. Johns Hopkins
Med. J. 148: 108-113, 1981.

14. Williams, J.; Stevens, H.: Familial paroxysmal choreo-athetosis. Pediatrics 31:
656-659, 1963.

*FIELD* CS

Neuro:
   Paroxysmal dystonic choreoathetosis;
   No unconsciousness;
   Occasional prominent myokymia

Misc:
   Precipitated by alcohol, coffee, hunger, fatigue and tobacco

Inheritance:
   Autosomal dominant

*FIELD* CN
Iosif W. Lurie - updated: 7/3/1996
Orest Hurko - updated: 4/1/1996
Orest Hurko - updated: 2/5/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/06/1997
carol: 7/3/1996
terry: 4/15/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 2/5/1996
terry: 1/31/1996
mimadm: 6/25/1994
warfield: 4/7/1994
carol: 10/21/1993
supermim: 3/16/1992
carol: 2/20/1992
carol: 8/24/1990

*RECORD*
*FIELD* NO
118820
*FIELD* TI
*118820 CHORIONIC SOMATOMAMMOTROPIN B; CSH2; CSB
*FIELD* TX
See 150200.

*FIELD* CD
Victor A. McKusick: 11/30/1987
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 11/30/1987
*RECORD*
*FIELD* NO
118825
*FIELD* TI
*118825 CHOROIDEREMIA-LIKE; CHML
*FIELD* TX
Using the mouse homolog of the human choroideremia cDNA as a probe,
Cremers et al. (1992) identified a homologous human gene which they
designated CHML for choroideremia-like. The cDNA encompassed an open
reading frame of 1,968 bp. By hybridization to a panel of human-rodent
somatic cell hybrids, they localized the gene to 1q31-qter. Since by
linkage analysis the gene for Usher syndrome type II (USH2; 276901) is
located in the same region and because of the clinical similarities
between choroideremia and Usher syndrome type II, they suggested that
CHML is a candidate gene for that disorder. The existence of the CHML
gene may explain why deletion of the X-linked gene for RAB
geranylgeranyltransferase, component A (303100) results only in retinal
degeneration. One would expect that this molecule would be crucial for
secretion and exocytosis in all cells. The product of the CHML gene,
REP-2, supports geranylgeranylation of most Rab proteins and may
substitute for REP-1 in tissues other than retina. Van Bokhoven et al.
(1994) mapped the CHML gene to 1q42-qter by study of a human/rodent
hybrid cell line. USH2 mapped to the same chromosomal segment as
evidenced by the fact that the D1S58, a polymorphic marker previously
shown to be located proximal to the USH2 locus, was also assigned to the
1q42-qter segment. To investigate a possible role of the CHML gene and
the pathogenesis of USH2, van Bokhoven et al. (1994) investigated 10
Dutch and 9 Danish USH2 patients for point mutations in the open reading
frame of the CHML gene. Using PCR/single-strand conformation
polymorphism analysis and direct sequencing, they found no
disease-specific mutations and concluded that the CHML is not involved
in the pathogenesis of Usher syndrome, type II.

*FIELD* RF
1. Cremers, F. P. M.; Molloy, C. M.; van de Pol, D. J. R.; van den
Hurk, J. A. J. M.; Bach, I.; Geurts van Kessel, A. H. M.; Ropers,
H.-H.: An autosomal homologue of the choroideremia gene colocalizes
with the Usher syndrome type II locus on the distal part of chromosome
1q. Hum. Molec. Genet. 1: 71-75, 1992.

2. van Bokhoven, H.; van Genderen, C.; Molloy, C. M.; van de Pol,
D. J. R.; Cremers, C. W. R. J.; van Aarem, A.; Schwartz, M.; Rosenberg,
T.; Geurts van Kessel, A. H. M.; Ropers, H.-H.; Cremers, F. P. M.
: Mapping of the choroideremia-like (CHML) gene at 1q42-qter and mutation
analysis in patients with Usher syndrome type II. Genomics 19:
385-387, 1994.

*FIELD* CS

Eyes:
   ? Usher syndrome type II (USH2;
   276901) candidate

Misc:
   Choroideremia-like gene

Inheritance:
   Autosomal dominant (1q41-qter)

*FIELD* CD
Victor A. McKusick: 10/2/1992

*FIELD* ED
carol: 7/6/1995
mimadm: 6/25/1994
carol: 12/22/1993
carol: 10/2/1992

*RECORD*
*FIELD* NO
118830
*FIELD* TI
*118830 CHYLOMICRONEMIA, FAMILIAL, DUE TO CIRCULATING INHIBITOR OF LIPOPROTEIN
LIPASE
HYPERLIPOPROTEINEMIA, TYPE IC
*FIELD* TX
Brunzell et al. (1983) described a mother and her son with
hyperlipoproteinemia type I (the chylomicronemia syndrome), very low
levels of postheparin plasma lipolytic activity, and circulating
inhibitor of lipoprotein lipase, who differed from subjects with
lipoprotein lipase deficiency (238600) in that the enzyme was present in
adipose tissue at much higher levels than those seen in normal subjects.
They also differed from subjects with deficiency of apolipoprotein C-II
(207750) in that apolipoprotein C-II was present in their plasma in
normal or elevated amounts. They appeared to have an inhibitor to
lipoprotein lipase activity that inhibited that activity eluted from
adipose tissue with heparin and that activity present in postheparin of
normals. The inhibitor was nondialyzable, heat-stable, and sensitive to
repeated freezing and thawing; it appeared to be present in the
nonlipoprotein fraction of plasma. The same abnormality may have been
present in her father and grandson; if the latter is true, this would be
an instance of male-to-male transmission. The mother was a 47-year-old
white woman who was found to have massive hypertriglyceridemia after
developing eruptive xanthomas on the outer aspects of both feet. Plasma
triglyceride level was 3,865 mg/dl. She had a history of recurrent
undiagnosed abdominal pain since the age of 16 years. Alcohol intake was
minimal and she was not taking any hormone preparations. The spleen was
palpable. She was not obese. Dietary fat restriction reduced
triglyceride levels and prevented recurrent attacks of pancreatitis. Her
father had died at age 39 years after surgery for acute abdominal pain.
Her only son, aged 21 years, had marked hypertriglyceridemia but was
asymptomatic and had no xanthomas or hepatosplenomegaly. She had a
grandson who at 4 months of age had grossly lipemic plasma with
triglyceride of 2400 mg/dl and cholesterol of 246 mg/dl.

*FIELD* RF
1. Brunzell, J. D.; Miller, N. E.; Alaupovic, P.; St. Hilaire, R.
J.; Wang, C. S.; Sarson, D. L.; Bloom, S. R.; Lewis, B.: Familial
chylomicronemia due to a circulating inhibitor of lipoprotein lipase
activity. J. Lipid Res. 24: 12-19, 1983.

*FIELD* CS

GI:
   Recurrent abdominal pain;
   Splenomegaly;
   Recurrent pancreatitis attacks

Lab:
   Chylomicronemia;
   Hyperlipoproteinemia type I;
   Very low postheparin plasma lipolytic activity;
   High adipose tissue lipoprotein lipase;
   Normal or elevated plasma apolipoprotein C-II;
   Lipoprotein lipase inhibitor activity

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 11/13/1987

*FIELD* ED
mimadm: 6/25/1994
warfield: 3/31/1994
supermim: 3/16/1992
carol: 5/8/1991
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
118840
*FIELD* TI
*118840 CHROMATE RESISTANCE; CHR
*FIELD* TX
In interspecies human-Chinese hamster ovary (CHO) cell hybrids, Dana and
Wasmuth (1982) showed that resistance to concentrations of sodium
chromate that normally are cytotoxic is determined by a gene on
chromosome 5 in man. The biochemical nature of the mutation that results
in chromate resistance is unknown. Emetine resistance (130620) and
temperature-sensitive leucyl-tRNA synthetase (151350) are also
determined by genes on human chromosome 5. The synteny of the 3 loci has
been long maintained in evolution, evidenced by the fact that the 3 loci
are linked on the long arm of Chinese hamster chromosome 2. Dana and
Wasmuth (1982) did cytogenetic and biochemical analyses of spontaneous
segregants from Chinese hamster-human interspecific hybrid cells (which
contained human chromosome 5 and expressed the 4 syntenic genes LEUS,
HEXB, EMTB, and CHR), the hybrid cell being subjected to selective
conditions requiring them to retain the LEUS gene. From these analyses,
Dana and Wasmuth (1982) concluded that the order is as listed above and
that the specific locations are: LEUS, 5pter-5q1; HEXB, 5q13; EMTB,
5q23-5q35; CHR, 5q35. The product of the CHR locus appears to be
involved in sulfate transport (Dana and Wasmuth, 1982).

*FIELD* SA
Dana and Wasmuth (1982)
*FIELD* RF
1. Dana, S.; Wasmuth, J. J.: Selective linkage disruption in human-Chinese
hamster cell hybrids: deletion mapping of the leuS, hexB, emtB, and
chr genes on human chromosome 5. Molec. Cell. Biol. 2: 1220-1228,
1982.

2. Dana, S.; Wasmuth, J. J.: Linkage of the leuS, emtE, and chr genes
on chromosome 5 in humans and expression of human genes encoding protein
synthetic components in human-Chinese hamster hybrids. Somat. Cell
Genet. 8: 245-264, 1982.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
118850
*FIELD* TI
*118850 CHORIONIC GONADOTROPIN, ALPHA CHAIN; CGA
GLYCOPROTEIN HORMONES, ALPHA CHAIN;;
CG-ALPHA;;
FSH-ALPHA; FSHA;;
LH-ALPHA; LHA;;
TSH-ALPHA; TSHA
*FIELD* TX
Bordelon and Kohler (1975) concluded that the structural gene for this
peptide hormone may be on chromosome 18. This study was done by
hybridization of hormone-producing human choriocarcinoma cells with
mouse cells. Both the alpha and the beta chains have been completely
sequenced (Morgan et al., 1975). Using the fluorescence-activated cell
sorter to separate groups of chromosomes and the recombinant
DNA-generated probe for the alpha-hCG gene, Lebo (1980) concluded that
the gene is on either chromosome 5 or 6. The inconsistent finding of
man-rodent hybrids may indicate the expression of a rodent gene of hCG
in response to a human regulator. In man there is only a single gene for
the alpha polypeptide of the 4 glycoprotein hormones: CG (118860), FSH
(136530), LH (152780), and TSH (188540). The common alpha chain and the
hormone-specific beta chain of these related hormones have molecular
weights of 14,000 and 17,000, respectively (Chin, 1982).

By in situ hybridization, Trent (1982) concluded that chromosome 18
carries the (an) HCG locus. That the alpha subunit of all 4 glycoprotein
hormones is coded by a single gene was demonstrated by Fiddes and
Goodman (1981) and Boothby et al. (1981). The 5-prime untranslated
portion bears sequence homology to the corresponding part of the growth
hormone gene. By use of restriction probes in human-rodent hybrids,
Naylor et al. (1983) assigned the alpha subunit to chromosome 6 and the
beta subunit to chromosome 19. Special attention was paid to the
exclusion of chromosomes 10 and 18 as sites of these genes. CGA mapped
to the 6q12-6q21 region. The alpha and beta genes are on mouse
chromosomes 4 and 7, respectively. Mouse 7 carries 2 other homologs of
human 19: Pep-7 and Gpi (homologous to PEPD and GPI). Hardin et al.
(1983), by Southern blot analysis of DNA from somatic cell hybrids and
by in situ hybridization, concluded that the alpha-HCG gene is on
chromosome 18 (p11). A full-length cDNA probe for the alpha subunit was
used in these studies. The reason for the discrepancy with the studies
that place the alpha subunit on chromosome 6 is unknown. Hoshina et al.
(1984) found at least 2 polymorphic sites in its 3-prime flanking region
detected by restriction enzymes HindIII and EcoRI. In family studies, as
expected, only a paternal genetic contribution was found in most
hydatidiform moles. However, one uncommon pattern of DNA polymorphism,
homozygosity for absent EcoRI site and presence of the HindIII site,
predominated in choriocarcinoma. Thus, the authors suggested that moles
with this uncommon pattern are particularly prone to development of
choriocarcinoma.

*FIELD* SA
Bordelon-Riser et al. (1979); Fiddes and Goodman (1979); Heitz et
al. (1983); Ruddon et al. (1979)
*FIELD* RF
1. Boothby, M.; Ruddon, R. W.; Anderson, C.; McWilliams, D.; Boime,
I.: A single gonadotropin alpha-subunit gene in normal tissue and
tumor-derived cell lines. J. Biol. Chem. 256: 5121-5127, 1981.

2. Bordelon, M.; Kohler, P. O.: Synthesis of human glycoprotein hormone
in somatic cell hybrids. (Abstract) J. Cell Biol. 67: 37A only,
1975.

3. Bordelon-Riser, M. E.; Siciliano, M. J.; Kohler, P. O.: Necessity
for two human chromosomes for human chorionic gonadotropin production
in human-mouse hybrids. Somat. Cell Genet. 5: 597-613, 1979.

4. Chin, W. W.: Personal Communication. Boston, Mass.  2/15/1982.

5. Fiddes, J. C.; Goodman, H. M.: Isolation, cloning and sequence
analysis of the cDNA for the alpha-subunit of human chorionic gonadotropin. Nature 281:
351-356, 1979.

6. Fiddes, J. C.; Goodman, H. M.: The gene encoding the common alpha
subunit of the four human glycoprotein hormones. J. Molec. Appl.
Genet. 1: 3-18, 1981.

7. Hardin, J. W.; Riser, M. E.; Trent, J. M.; Kohler, P. O.: The
chorionic gonadotropin alpha-subunit gene is on human chromosome 18
in JEG cells. Proc. Nat. Acad. Sci. 80: 6282-6285, 1983.

8. Heitz, P. U.; Kasper, M.; Kloppel, G.; Polak, J. M.; Vaitukaitis,
J. L.: Glycoprotein-hormone alpha-chain production by pancreatic
endocrine tumors: a specific marker for malignancy--immunocytochemical
analysis of tumors of 155 patients. Cancer 51: 277-282, 1983.

9. Hoshina, M.; Boothby, M. R.; Hussa, R. D.; Pattillo, R. A.; Camel,
H. M.; Boime, I.: Segregation patterns of polymorphic restriction
sites of the gene encoding the alpha subunit of human chorionic gonadotropin
in trophoblastic disease. Proc. Nat. Acad. Sci. 81: 2504-2507, 1984.

10. Lebo, R. V.: Personal Communication. San Francisco, Calif.
1/14/1980.

11. Morgan, F. J.; Birken, S.; Canfield, R. E.: The amino acid sequence
of human chorionic gonadotropin: the alpha subunit and beta subunit. J.
Biol. Chem. 250: 5247-5258, 1975.

12. Naylor, S. L.; Chin, W. W.; Goodman, H. M.; Lalley, P. A.; Grzeschik,
K.-H.; Sakaguchi, A. Y.: Chromosome assignment of the genes encoding
the alpha and beta subunits of the glycoprotein hormones in man and
mouse. Somat. Cell Genet. 9: 757-770, 1983.

13. Ruddon, R. W.; Hanson, C. A.; Addison, N. J.: Synthesis and processing
of human chorionic gonadotropin subunits in cultured choriocarcinoma
cells. Proc. Nat. Acad. Sci. 76: 5143-5147, 1979.

14. Trent, J.: Personal Communication. Tucson, Ariz.  11/23/1982.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 08/21/1996
terry: 5/13/1994
mimadm: 4/18/1994
warfield: 4/7/1994
carol: 5/26/1993
supermim: 3/16/1992
carol: 3/2/1992

*RECORD*
*FIELD* NO
118860
*FIELD* TI
*118860 CHORIONIC GONADOTROPIN, BETA CHAIN; CGB
*FIELD* TX
Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced by
trophoblastic cells of the placenta beginning 10 to 12 days after
conception. Maintenance of the fetus in the first trimester of pregnancy
requires the production of hCG, which binds to the corpus luteum of the
ovary which is stimulated to produce progesterone which in turn
maintains the secretory endometrium. See 118850. Boorstein et al. (1982)
concluded that the beta subunit of CG is encoded by at least 8 genes
arranged in tandem and inverted pairs. They stated that 'until sequence
analysis is complete, we cannot exclude the possibility that the eight
genes include some pseudogenes or the related gene, beta-LH.' The beta
subunits of luteinizing hormone (LHB) and CG show about 82% amino acid
homology. The homology with beta-FSH and beta-TSH is much lower.
Policastro et al. (1983, 1986) found 6 nonallelic copies of the CGB gene
and a single copy LHB gene. All were contained in a single 58-kb EcoRI
fragment. The hCG beta-subunit is unique in the family of
beta-containing glycoprotein hormones in that it contains an extension
of 29 amino acids at its COOH end.

By use of restriction probes in human-rodent hybrids, Naylor et al.
(1983) assigned the alpha subunit to chromosome 6 and the beta subunit
to chromosome 19. Special attention was paid to the exclusion of
chromosomes 10 and 18 as sites of these genes. CGA mapped to the
6q12-6q21 region. The alpha and beta genes are on mouse chromosomes 4
and 7, respectively. Mouse 7 carries 2 other homologs of human 19: Pep-7
and Gpi (homologous to PEPD and GPI). In somatic cell hybrids, Julier et
al. (1984) used a cDNA probe for the beta unit of CG (CGB) and one for
the beta unit of pituitary luteinizing hormone to assign these loci to
chromosome 19. Strict concordance between permissivity of hybrid cells
to enteroviruses (determined by specific cell receptors coded by human
chromosome 19) and the presence of LHB and CGB sequences confirmed the
assignment. Graham et al. (1987) isolated a cosmid clone containing the
entire CGB cluster. The restriction map of this clone was determined by
an indirect-end-label FIGE (field inversion gel electrophoresis) method.
Analysis of this cosmid clone showed that human genomic DNA contains 6
CGB genes. Warburton et al. (1990) used expression of the CGB gene as
well as the presence of the INSR (147670) and APOC2 (207750) genes to
test for the retention of a single chromosome 19 in rodent-human hybrids
created by the new method they devised. Human lymphoblastoid lines were
infected with the retroviral vector SP-1, which contains the bacterial
his-D gene, allowing mammalian cells to grow in the presence of
histidinol. They then used microcell fusion of the infected
lymphoblastoid cells with CHO cells to produce hybrids containing single
human chromosomes retained by histidinol selection. The retroviral
vector integrates into human chromosomes singly and with precisely
defined ends, facilitating the analysis of the integration site. The
histidinol dehydrogenase gene from Salmonella typhimurium codes for the
enzyme that converts histidinol to histidine. Mammalian cells lacking
this gene are killed by histidinol through competition with histidine
for the histidyl-tRNA synthetase.

Kaposi sarcoma (148000) occurs more often in men than in women.
Lunardi-Iskander et al. (1995) described an immortalized Kaposi sarcoma
cell line from an AIDS patient and showed that these cells produce
malignant metastatic tumors in nude mice but are killed in vitro and in
vivo (apparently by apoptosis) by the beta-chain of human chorionic
gonadotropin. Chorionic gonadotropin also killed cells of another
neoplastic cell line established from a non-HIV-associated Kaposi
sarcoma, as well as the hyperplastic Kaposi sarcoma cells from clinical
specimens grown in short-term culture, but did not kill normal
endothelial cells. The results had implications for the hormonal
treatment of this tumor.

*FIELD* SA
Fiddes and Goodman (1980); Julier et al. (1984); Talmadge et al. (1984)
*FIELD* RF
1. Boorstein, W. R.; Vamvakopoulos, N. C.; Fiddes, J. C.: Human chorionic
gonadotropin beta-subunit is encoded by at least eight genes arranged
in tandem and inverted pairs. Nature 300: 419-422, 1982.

2. Fiddes, J. C.; Goodman, H. M.: The cDNA for the beta-subunit of
human chorionic gonadotropin suggests evolution of a gene by readthrough
into the 3-prime-untranslated region. Nature 286: 684-687, 1980.

3. Graham, M. Y.; Otani, T.; Boime, I.; Olson, M. V.; Carle, G. F.;
Chaplin, D. D.: Cosmid mapping of the human chorionic gonadotropin
beta subunit genes by field-inversion gel electrophoresis. Nucleic
Acids Res. 15: 4437-4448, 1987.

4. Julier, C.; Weil, D.; Couillin, P.; Cote, J. C.; Boue, A.; Thririon,
J. P.; Kaplan, J. C.; Junien, C.: Confirmation of the assignment
of the genes coding for human chorionic gonadotropin beta subunit
to chromosome 19.  (Abstract) Cytogenet. Cell Genet. 37: 501-502,
1984.

5. Julier, C.; Weil, D.; Couillin, P.; Cote, J. C.; Van Cong, N.;
Foubert, C.; Boue, A.; Thirion, J. P.; Kaplan, J. C.; Junien, C.:
The beta chorionic gonadotropin-beta luteinizing gene cluster maps
to human chromosome 19. Hum. Genet. 67: 174-177, 1984.

6. Lunardi-Iskander, Y.; Bryant, J. L.; Zeman, R. A.; Lam, V. H.;
Samaniego, F.; Besnier, J. M.; Hermans, P.; Thierry, A. R.; Gill,
P.; Gallo, R. C.: Tumorigenesis and metastasis of neoplastic Kaposi's
sarcoma cell line in immunodeficient mice blocked by a human pregnancy
hormone. Nature 375: 64-68, 1995.

7. Naylor, S. L.; Chin, W. W.; Goodman, H. M.; Lalley, P. A.; Grzeschik,
K.-H.; Sakaguchi, A. Y.: Chromosome assignment of the genes encoding
the alpha and beta subunits of the glycoprotein hormones in man and
mouse. Somat. Cell Genet. 9: 757-770, 1983.

8. Policastro, P.; Ovitt, C. E.; Hoshina, M.; Fukuoka, H.; Boothby,
M. R.; Biome, I.: The beta-subunit of human chorionic gonadotropin
is encoded by multiple genes. J. Biol. Chem. 258: 11492-11499,
1983.

9. Policastro, P. F.; Daniels-McQueen, S.; Carle, G.; Boime, I.:
A map of the hCG-beta-LH-beta gene cluster. J. Biol. Chem. 261:
5907-5916, 1986.

10. Talmadge, K.; Vamvakopoulos, N. C.; Fiddes, J. C.: Evolution
of the genes for the beta subunits of human chorionic gonadotropin
and luteinizing hormone. Nature 307: 37-40, 1984.

11. Warburton, D.; Gersen, S.; Yu, M.-T.; Jackson, C.; Handelin, B.;
Housman, D.: Monochromosomal rodent-human hybrids from microcell
fusion of human lymphoblastoid cells containing an inserted dominant
selectable marker. Genomics 6: 358-366, 1990.

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
mark: 6/13/1995
terry: 5/13/1994
carol: 4/10/1992
supermim: 3/16/1992
supermim: 3/27/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
118865
*FIELD* TI
118865 CHOROIDAL OSTEOMA, BILATERAL
*FIELD* TX
Choroidal osteoma is a benign tumor found in the peripapillary region,
most characteristically in one eye of otherwise healthy, young females.
Histopathologic changes include bone formation with trabeculae,
blood-filled cavernous spaces, and cells typical of bone formation,
i.e., osteoblasts, osteocytes, and osteoclasts. In each of 2 families,
choroidal osteoma has been observed in 2 successive generations. Noble
(1990) described a family in which a girl and her monozygotic twin
brothers had bilateral choroidal osteomas. The tumors showed growth
between ages 11 and 13 years in the sister. The twin brothers' tumors
remained stable between 9 and 11 years except for a new, isolated lesion
in one eye of one of them. Their mother had a yellow mottling situated
nasal to the disk in each eye resembling in appearance that in one eye
in one of the twins. She showed no calcium on ultrasonography. Cuhna
(1984) observed an affected mother and daughter: the 33-year-old mother
had visual acuity reduced to the finger counting range in each eye since
age 11 years and had bilateral peripapillary atrophic chorioretinal
lesions. Her 5-year-old daughter had bilateral yellow-white lesions
associated with bilateral macular hemorrhages. The familial occurrence
as well as the bilaterality is consistent with the origin of the
osteomas in a choristoma. A choristoma is a benign tumefaction of a
chorista, which is an embryonic tissue rest composed of cellular and
tissue elements not normally present at the affected site.

*FIELD* RF
1. Cuhna, S. L.: Osseous choristoma of the choroid: a familial disease.
Arch. Ophthal. 102: 1052-1054, 1984.

2. Noble, K. G.: Bilateral choroidal osteoma in three siblings. Am.
J. Ophthal. 109: 656-660, 1990.

*FIELD* CS

Eyes:
   Peripapillary benign choroidal osteoma

Oncology:
   Benign tumefaction of a chorista (embryonic tissue rest)

Lab:
   Histopathology shows bone formation with trabeculae, blood-filled
   cavernous spaces, and cells typical of bone formation (osteoblasts,
   osteocytes, and osteoclasts)

*FIELD* CD
Victor A. McKusick: 10/8/1990

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 10/8/1990

*RECORD*
*FIELD* NO
118870
*FIELD* TI
*118870 CHROMOSOMAL PROTEIN, NONHISTONE-1; NHCP1
*FIELD* TX
The work of Paulson and Laemmli (1977) indicated the importance of
nonhistone protein in determining the structure of metaphase
chromosomes. The histone-depleted chromosome consists of a scaffold, or
core, which has the shape characteristic of the metaphase chromosome,
surrounded by a halo of DNA. The halo consists of many loops of DNA,
each with its base anchored in the scaffold. Most of the loops are 10-30
micrometers (30-90 kb) long. Bode et al. (1981) studied a series of
hybrid mouse erythroleukemia cell lines containing only 1 human
chromosome, a 16. In the 2-dimensional electrophoretogram, a nonhistone
chromosomal protein of isoelectric point 6.2 and molecular weight of
65,000 daltons was identified. This protein comigrated with a nonhistone
chromosomal protein present in human cell lines, including that used as
the parent in the human-mouse hybrid, but not in the mouse
erythroleukemia parent before fusion.

*FIELD* RF
1. Bode, V.; Deisseroth, A.; Hendrick, D.: Expression of human and
mouse non-histone chromosomal proteins in hybrid mouse erythroleukemia
cells containing a single human chromosome. Proc. Nat. Acad. Sci. 78:
2815-2819, 1981.

2. Paulson, J. R.; Laemmli, U. K.: The structure of histone-depleted
metaphase chromosomes. Cell 12: 817-828, 1977.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
carol: 3/6/1990
ddp: 10/26/1989
root: 11/2/1988
carol: 10/7/1988

*RECORD*
*FIELD* NO
118880
*FIELD* TI
*118880 CHROMOSOMAL PROTEIN, NONHISTONE-2; NHCP2
*FIELD* TX
See 118870. Alevy and Fleischman (1980) assigned the gene for this
chromosomal protein to chromosome 7. They demonstrated correlation
between the protein, identified by means of a species-specific antiserum
and gel electrophoresis, and the presence of human chromosome 7 in a
mouse-human hybrid cell.

*FIELD* RF
1. Alevy, Y. G.; Fleischman, J. B.: Immunospecific isolation of a
human chromatin fraction from mouse-human hybrid cells. Molec. Immun. 17:
275-280, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/10/1988
carol: 10/7/1988
marie: 3/25/1988

*RECORD*
*FIELD* NO
118888
*FIELD* TI
*118888 CHYMOTRYPSIN-LIKE PROTEASE; CTRL
*FIELD* TX
Guided by the identification of a CpG island in a 40-kb cosmid insert,
Larsen et al. (1993) identified a cluster of 5 unrelated human genes on
16q22.1. One of these was located between the gene encoding the putative
subunit of the proteasome complex (MECL1; 176847) and a protein serine
kinase gene (177015). The sequence of the protein was compared to
protein sequences in the SWISSPROT database and identified as that of a
chymotrypsin-like protease (CTRL). This gene has 7 exons, covers about 2
kb, and is transcribed in the same direction as the LCAT (245900) and
the proteasome gene, from which it is immediately downstream. See also
601405.

*FIELD* RF
1. Larsen, F.; Solheim, J.; Kristensen, T.; Kolsto, A.-B.; Prydz,
H.: A tight cluster of five unrelated human genes on chromosome 16q22.1. Hum.
Molec. Genet. 2: 1589-1595, 1993.

*FIELD* CD
Victor A. McKusick: 10/18/1993

*FIELD* ED
randy: 08/31/1996
carol: 10/18/1993

*RECORD*
*FIELD* NO
118890
*FIELD* TI
*118890 CHYMOTRYPSINOGEN B; CTRB
*FIELD* TX
Alpha-chymotrypsin (EC 3.4.21.1) is one of a family of serine proteases
secreted into the gastrointestinal tract as the inactive precursor
chymotrypsinogen. The zymogen is activated by proteolytic cleavage by
trypsin. Sakaguchi et al. (1982) and Honey et al. (1984) assigned the
human chymotrypsinogen B gene to chromosome 16 by using a cloned rat
CTRB sequence as probe DNA from human-mouse somatic cell hybrids.
Elastase (130120), also a serine protease, with amino acid sequence
homology to chymotrypsinogen B, is located on chromosome 12. Although
not a serine protease, haptoglobin (HP; 140100) shares about 19% amino
acid sequence homology with chymotrypsin (Bowman, 1983); the genes for
both map to chromosome 16. It is almost certain that CTRB is on 16q
because it is one of 7 genes that are on 16 in man and on chromosome 8
in the mouse (Barton et al., 1986); the other 6 are on 16q, whereas
human 16p, which carries the alpha-globin gene cluster, appears to be
homologous to mouse 11. Because a cell line hemizygous for 16q23-qter is
heterozygous for CTRB and because CTRB is absent in a cell line deleted
for 16pter-p11.2, this locus can be assigned to 16p11.1-q22 (Reeders,
1987). Using RFLPs for CTRB, tyrosine aminotransferase (TAT; 276600),
and HP, Westphal et al. (1987) analyzed linkage in 13 informative
families. TAT and HP are known to reside at 16q22. The most likely order
was found to be HP--7 cM--TAT--9 cM--CTRB. By pulsed field gel
electrophoresis, a maximum physical distance of about 700 kb was
obtained between HP and TAT, which contrasts with the genetic distance
of 7 cM (approximate confidence limits, 2-18 cM). The physical distance
between TAT and HP is about 10 times shorter than might be expected for
a genetic length of 7 cM. On average, one expects 1 cM to correspond to
1,000 kb in the human genome; however, recombination is undoubtedly not
uniform. Several instances of increased recombination rate within small
regions of the genome are known. Observations in cases of deletion cited
by Westphal et al. (1987) suggested that CTRB may be in 16q22.2,
telomeric to both HP and TAT. Using a cDNA probe for the rat CTRB gene
to analyze 2 overlapping interstitial deletions on human chromosome 16q
by Southern blot analysis, Natt et al. (1989) concluded that CTRB lies
in the shortest region of overlap, band 16q22.3 (taking other published
data into account). Chen et al. (1991) mapped 12 genes and 33 anonymous
DNA probes on 16q. They concluded that the CTRB gene lies in band
16q23.2-q23.3. Tomita et al. (1989) isolated a cDNA clone encoding
prechymotrypsinogen from a human pancreas cDNA library and determined
its nucleotide sequence. The coding region contains 789 bp. The
predicted product consisted of 263 amino acids, including 18 amino acids
for a signal peptide. Southern blot analyses using the cloned cDNA as a
probe showed that human genomic DNA carries at least 2 genes that are
related to chymotrypsinogen.

*FIELD* SA
Natt et al. (1989)
*FIELD* RF
1. Barton, D. E.; Yang-Feng, T. L.; Francke, U.: The human tyrosine
aminotransferase gene mapped to the long arm of chromosome 16 (region
16q22-q24) by somatic cell hybrid analysis and in situ hybridization.
Hum. Genet. 72: 221-224, 1986.

2. Bowman, B. H.: Personal Communication. San Antonio, Texas  10/31/1983.

3. Chen, L. Z.; Harris, P. C.; Apostolou, S.; Baker, E.; Holman, K.;
Lane, S. A.; Nancarrow, J. K.; Whitmore, S. A.; Stallings, R. L.;
Hildebrand, C. E.; Richards, R. I.; Sutherland, G. R.; Callen, D.
F.: A refined physical map of the long arm of human chromosome 16.
Genomics 10: 308-312, 1991.

4. Honey, N. K.; Sakaguchi, A. Y.; Quinto, C.; MacDonald, R. J.; Bell,
G. I.; Craik, C.; Rutter, W. J.; Naylor, S. L.: Chromosomal assignment
of human genes for serine proteases trypsin, chymotrypsin B and elastase.
Somat. Cell Molec. Genet. 10: 369-376, 1984.

5. Natt, E.; Magenis, R. E.; Zimmer, J.; Mansouri, A.; Scherer, G.
: Regional assignment of the loci for uvomorulin (UVO) and chymotrypsinogen
B (CTRB) with the help of two overlapping deletions on the long arm
of chromosome 16. Cytogenet. Cell Genet. 50: 145-148, 1989.

6. Natt, E.; Magenis, R. E.; Zimmer, J.; Mansouri, A.; Scherer, G.
: Regional assignment of the loci for uvomorulin (UVO) and chymotrypsinogen
B (CTRB) on human chromosome 16q.  (Abstract) Cytogenet. Cell Genet. 51:
1050-1051, 1989.

7. Reeders, S. T.: Personal Communication. Oxford, England  1/15/1987.

8. Sakaguchi, A. Y.; Naylor, S. L.; Quinto, C.; Rutter, W. J.; Shows,
T. B.: The chymotrypsinogen B gene (CTRB) is on human chromosome
16. Cytogenet. Cell Genet. 32: 313 only, 1982.

9. Tomita, N.; Izumoto, Y.; Horii, A.; Doi, S.; Yokouchi, H.; Ogawa,
M.; Mori, T.; Matsubara, K.: Molecular cloning and nucleotide sequence
of human pancreatic prechymotrypsinogen cDNA. Biochem. Biophys.
Res. Commun. 158: 569-575, 1989.

10. Westphal, E.-M.; Burmeister, M.; Wienker, T. F.; Lehrach, H.;
Bender, K.; Scherer, G.: Tyrosine aminotransferase and chymotrypsinogen
B are linked to haptoglobin on human chromosome 16q: comparison of
genetic and physical distances. Genomics 1: 313-319, 1987.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
warfield: 4/7/1994
carol: 10/5/1993
supermim: 3/16/1992
carol: 5/21/1991
carol: 8/24/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
118900
*FIELD* TI
118900 CIRRHOSIS, FAMILIAL
*FIELD* TX
Joske and Laurence (1970) described a family in which the father and 4
of 10 children had chronic liver disease and raised immunoglobulin
levels. A possible nongenetic basis is suggested by the example of
hepatitis-associated antigen (HAA), or Australian antigen, in a mother
and 3 children ascertained through one of the children who had neonatal
giant cell hepatitis (Bancroft et al., 1971). Nasrallah et al. (1978)
described a family in which the mother and all 6 of her sons but none of
her 5 daughters had HBs antigenemia. The mother and her husband were
second cousins; see 209800 for a discussion of recessive inheritance of
persistent antigenemia. Percutaneous liver biopsies showed no evidence
of liver disease in the mother but all 6 sons had evidence of chronic
active hepatitis progressing to cirrhosis.

*FIELD* RF
1. Bancroft, W. H.; Warkel, R. L.; Talbert, A. A.; Russell, P. K.
: Family with hepatitis-associated antigen: spectrum of liver pathology.
J.A.M.A. 217: 1817-1820, 1971.

2. Joske, R. A.; Laurence, B. H.: Familial cirrhosis with autoimmune
features and raised immunoglobulin levels. Gastroenterology 59:
546-552, 1970.

3. Nasrallah, S. M.; Nassar, V. H.; Shammaa, M. H.: Genetic and immunological
aspects of familial chronic active hepatitis (type B). Gastroenterology 75:
302-306, 1978.

*FIELD* CS

GI:
   Chronic liver disease;
   Chronic active hepatitis;
   Cirrhosis

Immunology:
   Raised immunoglobulin levels

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
118910
*FIELD* TI
*118910 CHROMOGRANIN A; CHGA
SECRETORY PROTEIN I
PARATHYROID SECRETORY PROTEIN, INCLUDED;;
PSP, INCLUDED;;
PANCREASTATIN, INCLUDED;;
CHROMOSTATIN, INCLUDED
*FIELD* TX
Chromogranin A is a protein costored and coreleased with catecholamines
from storage granules in the adrenal medulla. Secretory protein I
(parathyroid secretory protein; PSP) is a protein costored and
coreleased with parathyroid hormone from storage granules in the
parathyroid gland. Its function is unknown. Like PTH (168450), its
secretion is inversely proportional to extracellular calcium
concentration. Bhargava et al. (1983) showed that the degree of
phosphorylation of PSP is also inversely proportional to serum calcium,
and that PSP is the major phosphorylated protein released by the
parathyroid gland. Cohn et al. (1982) demonstrated a close similarity of
these 2 proteins in amino acid composition, physical properties, and
immunologic crossreactivity. Kruggel et al. (1985) determined the amino
terminal sequences of bovine and human adrenal medullary chromogranin A;
the sequences are identical to each other and also to the published
sequence of secretory protein I. O'Connor and Deftos (1986) showed that
chromogranin A is secreted by a great variety of peptide-producing
endocrine neoplasms: pheochromocytoma, parathyroid adenoma, medullary
thyroid carcinoma, carcinoids, oat-cell lung cancer, pancreatic
islet-cell tumors, and aortic-body tumor. Deftos et al. (1986) cloned
cDNA for CHGA using mRNA from CHGA-producing medullary thyroid carcinoma
cells in an expression vector, gt11. Konecki et al. (1987) isolated a
full-length clone encoding human chromogranin A from a lambda-gt10 cDNA
library of a human pheochromocytoma. The nucleotide sequence showed that
human chromogranin A is a 439-residue protein preceded by an 18-residue
signal peptide. Sequence findings suggested that pancreastatin is
derived from chromogranin A itself rather than from a protein that is
only similar to chromogranin A. The pancreastatin sequence contained in
human chromogranin A is flanked by sites for proteolytic processing. In
man, pancreastatin may be important for the physiologic homeostasis of
blood insulin levels as well as pathologic aberrations such as diabetes
mellitus. Wu et al. (1991) found that the chromogranin A gene has 8
exons and 7 introns spanning about 11 kb.

Using immunohistochemistry on plastic sections, Cetin et al. (1993)
investigated the occurrence and cellular distribution of CHGA,
pancreastatin, and chromostatin (CST), a CHGA-derived bioactive peptide,
in human endocrine pancreas of healthy and disease states and in the
adrenal medulla. In the normal and diabetic pancreas, CST
immunoreactivity was localized exclusively in beta cells, which were
mostly unreactive for PST and CHGA. Both latter peptides were confined
mainly to glucagon (alpha) cells. Insulinoma cells displayed strong
insulin, PST, and CHGA immunoreactivities, but they were faintly
immunoreactive for CST or unreactive. Adrenal chromaffin cells exhibited
strong immunoreactivity for CHGA but lacked CST and PST
immunoreactivities. Based on the peculiar distribution pattern of CST,
PST, and CHGA, Cetin et al. (1993) suggested that CHGA is differentially
processed in chromaffin and islet tissues and in insulinoma cells. The
unique cellular localization of CST in the endocrine pancreas of normal
and pathologic conditions may indicate that CST is involved in beta-cell
function.

Murray et al. (1987) mapped CHGA to chromosome 14 by probing DNA from a
hybrid cell panel with specific cDNA. Using a cDNA clone for the
chromogranin A gene, Modi et al. (1989) mapped the gene to 14q32 by
Southern blot analysis of human-rodent somatic cell hybrid DNAs and by
in situ hybridization. Simon-Chazottes et al. (1993) demonstrated that
the chromogranin A gene is present in single dose in both the mouse and
rat. Analysis of the allele distribution in an interspecific mouse
backcross by single-strand conformation polymorphism positioned the Chga
locus on mouse chromosome 12. By study of a rat/mouse somatic cell
hybrid panel, they determined that the corresponding gene is on rat
chromosome 6. In each case (mouse, rat, and human), chromogranin A is
encoded in a conserved region with nearby markers, including the
immunoglobulin heavy chain locus.

*FIELD* SA
Angeletti  (1986); Hagn et al. (1986); Modi et al. (1989)
*FIELD* RF
1. Angeletti, R. H.: Chromogranins and neuroendocrine secretion.
(Editorial) Lab. Invest. 55: 387-390, 1986.

2. Bhargava, G.; Russell, J.; Sherwood, L. M.: Phosphorylation of
parathyroid secretory protein. Proc. Nat. Acad. Sci. 80: 878-881,
1983.

3. Cetin, Y.; Aunis, D.; Bader, M.-F.; Galindo, E.; Jorns, A.; Bargsten,
G.; Grube, D.: Chromostatin, a chromogranin A-derived bioactive peptide,
is present in human pancreatic insulin (beta) cells. Proc. Nat.
Acad. Sci. 90: 2360-2364, 1993.

4. Cohn, D. V.; Zangerle, R.; Fischer-Colbrie, R. R.; Chu, L. L. H.;
Elting, J. J.; Hamilton, J. W.; Winkler, H.: Similarity of secretory
protein I from parathyroid gland to chromogranin A from the adrenal
medulla. Proc. Nat. Acad. Sci. 79: 6056-6059, 1982.

5. Deftos, L. J.; Murray, S. S.; Burton, D. W.; Parmer, R. J.; O'Connor,
D. T.; Delegeane, A. M.; Mellon, P. L.: A cloned chromogranin A (CgA)
cDNA detects a 2.3kb mRNA in diverse neuroendocrine tissues. Biochem.
Biophys. Res. Commun. 137: 418-423, 1986.

6. Hagn, C.; Schmid, K. W.; Fischer-Colbrie, R.; Winkler, H.: Chromogranin
A, B, and C in human adrenal medulla and endocrine tissues. Lab.
Invest. 55: 405-411, 1986.

7. Konecki, D. S.; Benedum, U. M.; Gerdes, H.-H.; Huttner, W. B.:
The primary structure of human chromogranin A and pancreastatin. J.
Biol. Chem. 262: 17026-17030, 1987.

8. Kruggel, W.; O'Connor, D. T.; Lewis, R. V.: The amino terminal
sequences of bovine and human chromogranin A and secretory protein
I are identical. Biochem. Biophys. Res. Commun. 127: 380-383, 1985.

9. Modi, W. S.; Levine, M. A.; Dean, M.; Seuanez, H.; O'Brien, S.
J.: The chromogranin A gene: chromosome assignment and RFLP analysis.
(Abstract) Cytogenet. Cell Genet. 51: 1046 only, 1989.

10. Modi, W. S.; Levine, M. A.; Seuanez, H. N.; Dean, M.; O'Brien,
S. J.: The human chromogranin A gene: chromosome assignment and RFLP
analysis. Am. J. Hum. Genet. 45: 814-818, 1989.

11. Murray, S. S.; Deaven, L. L.; Burton, D. W.; O'Connor, D. T.;
Mellon, P. L.; Deftos, L. J.: The gene for human chromogranin A (CgA)
is located on chromosome 14. Biochem. Biophys. Res. Commun. 142:
141-146, 1987.

12. O'Connor, D. T.; Deftos, L. J.: Secretion of chromogranin A by
peptide-producing endocrine neoplasms. New Eng. J. Med. 314: 1145-1151,
1986.

13. Simon-Chazottes, D.; Wu, H.; Parmer, R. J.; Rozansky, D. J.; Szpirer,
J.; Levan, G.; Kurtz, T. W.; Szpirer, C.; Guenet, J. L.; O'Connor,
D. T.: Assignment of the chromogranin A (Chga) locus to homologous
regions on mouse chromosome 12 and rat chromosome 6. Genomics 17:
252-255, 1993.

14. Wu, H.-J.; Rozansky, D. J.; Parmer, R. J.; Gill, B. M.; O'Connor,
D. T.: Structure and function of the chromogranin A gene: clues to
evolution and tissue-specific expression. J. Biol. Chem. 266: 13130-13134,
1991.

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
carol: 10/21/1993
carol: 7/19/1993
carol: 4/28/1993
supermim: 3/16/1992
carol: 9/20/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
118920
*FIELD* TI
*118920 CHROMOGRANIN B; CHGB
SECRETOGRANIN I; SCG1
*FIELD* TX
Chromogranin B (secretogranin I) is a tyrosine-sulfated secretory
protein found in a wide variety of peptidergic endocrine cells. Benedum
et al. (1987) isolated a 2.5-kb cDNA clone from a cDNA library of human
pheochromocytoma. Chromogranin B is a 657 amino acid long polypeptide of
76 kilodaltons and is preceded by a cleaved end-terminal signal peptide
of 20 residues. Chromogranin B was assigned to chromosome 20 by Craig et
al. (1986). Craig et al. (1987) showed by in situ hybridization that the
CHGB locus is on 20pter-p12. Jenkins et al. (1991) mapped the murine
gene, symbolized Scg-1, to chromosome 2 by in situ hybridization and by
interspecific backcross analysis.

*FIELD* RF
1. Benedum, U. M.; Lamouroux, A.; Konecki, D. S.; Rosa, P.; Hille,
A.; Baeuerle, P. A.; Frank, R.; Lottspeich, F.; Mallet, J.; Huttner,
W. B.: The primary structure of human secretogranin I (chromogranin
B): comparison with chromogranin A reveals homologous terminal domains
and a large intervening variable region. EMBO J. 6: 1203-1211,
1987.

2. Craig, S. P.; Lamouroux, A.; Mallet, J.; Huttner, W.; Craig, I.
W.: Localisation of the gene for chromogranin B to chromosome 20..
(Abstract) 7th Int. Cong. Hum. Genet., Berlin 1986.

3. Craig, S. P.; Lamouroux, A.; Mallet, J.; Huttner, W.; Craig, I.
W.: Localisation of the human gene for secretogranin 1 (chromogranin
B) to chromosome 20.  (Abstract) Cytogenet. Cell Genet. 46: 600
only, 1987.

4. Jenkins, N. A.; Mattei, M.-G.; Gilbert, D. J.; Linard, C. G.; Mbikay,
M.; Chretien, M.; Copeland, N. G.: Assignment of secretogranin I
locus to mouse chromosome 2 by in situ hybridization and interspecific
backcross analysis. Genomics 11: 479-480, 1991.

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
warfield: 3/21/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 11/13/1991
carol: 11/6/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
118930
*FIELD* TI
*118930 CHROMOGRANIN C; CHGC
SECRETOGRANIN II; SCG2
*FIELD* TX
The chromogranin that Fischer-Colbrie et al. (1987) chose to term
'chromogranin C' is a protein of apparent molecular mass 86,000 which
was first detected in anterior pituitary by labeling with (35)S-sulfate
(Rosa and Zanini, 1981). Subsequently, it was shown to be present also
in adrenal medulla (Rosa and Zanini, 1983).

Mahata et al. (1996) determined that the secretogranin II gene, which
they symbolized SCG2, is located on 2q35-q36 using fluorescence in situ
hybridization. They also showed that the rat gene maps to chromosome 9,
and the mouse gene to chromosome 1. Like the chromogranin A and
chromogranin B genes, the SCG2 gene is in a chromosomal region of
homology of synteny among the 3 species evaluated. Mahata et al. (1996)
stated that the 3 genes in the human and the other species appeared to
have been derived from a common ancestor.

*FIELD* RF
1. Fischer-Colbrie, R.; Hagn, C.; Schober, M.: Chromogranins A, B,
and C: widespread constituents of secretory vesicles. Ann. N.Y.
Acad. Sci. 493: 120-134, 1987.

2. Mahata, S. K.; Kozak, C. A.; Szpirer, J.; Szpirer, C.; Modi, W.
S.; Gerdes, H.-H.; Huttner, W. B.; O'Connor, D. T.: Dispersion of
chromogranin/secretogranin secretory protein family loci in mammalian
genomes. Genomics 33: 135-139, 1996.

3. Rosa, P.; Zanini, A.: Characterization of adenohypophysial polypeptides
by two-dimensional gel electrophoresis. II. Sulfated and glycosylated
polypeptides. Molec. Cell. Endocr. 24: 181-193, 1981.

4. Rosa, P.; Zanini, A.: Purification of a sulfated secretory protein
from the adenohypophysis: immunochemical evidence that similar macromolecules
are present in other glands. Europ. J. Cell Biol. 31: 94-98, 1983.

*FIELD* CD
Victor A. McKusick: 1/13/1989

*FIELD* ED
mark: 04/17/1996
terry: 4/10/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 1/13/1989

*RECORD*
*FIELD* NO
118938
*FIELD* TI
*118938 CHYMASE, HEART; CYH
CHYMASE, MAST CELL
*FIELD* TX
Urata et al. (1991) cloned the gene for the chymotrypsin-like serine
proteinase in human heart, human heart chymase, that is the most
catalytically efficient enzyme thus far described for the cleavage of
angiotensin I to yield angiotensin II and the dipeptide his-leu.
Compared to other chymases, this enzyme also had an unusually high
degree of specificity for the substrate angiotensin I. The deduced amino
acid sequence showed a high degree of homology to other members of the
chymase subfamily. However, this gene lacked mast cell-specific
sequences found in the 5-prime and 3-prime untranslated regions of the
rat chymase II gene (118940). In addition, human heart chymase contained
clusters of unique amino acid sequences located at key positions
probably involved in substrate binding.

The heart, a target organ for angiotensin II (106150), has a dual
pathway for its formation, namely, via angiotensin I-converting enzyme
(106180) and chymase. Urata et al. (1993) did in situ hybridization
studies suggesting that cardiac mast cells, mesenchymal interstitial
cells, and endothelial cells are the cellular sites of synthesis of
angiotensin II and storage of chymase.

*FIELD* RF
1. Urata, H.; Boehm, K. D.; Philip, A.; Kinoshita, A.; Gabrovsek,
J.; Bumpus, F. M.; Husain, A.: Cellular localization and regional
distribution of an angiotensin II-forming chymase in the heart. J.
Clin. Invest. 91: 1269-1281, 1993.

2. Urata, H.; Kinoshita, A.; Perez, D. M.; Misono, K. S.; Bumpus,
F. M.; Graham, R. M.; Husain, A.: Cloning of the gene and cDNA for
human heart chymase. J. Biol. Chem. 266: 17173-17179, 1991.

*FIELD* CD
Victor A. McKusick: 11/6/1991

*FIELD* ED
carol: 6/23/1993
supermim: 3/16/1992
carol: 11/13/1991
carol: 11/6/1991

*RECORD*
*FIELD* NO
118940
*FIELD* TI
*118940 CHYMASE 1, MAST CELL; CMA1
*FIELD* TX
Chymase is a major secreted protease of mast cells with suspected roles
in vasoactive peptide generation, extracellular matrix degradation, and
regulation of gland secretion. Caughey et al. (1991) cloned and
sequenced the gene which was found to code for a preproenzyme with a
19-amino acid signal peptide, an acidic 2-amino acid propeptide, and a
226-amino acid catalytic domain. In the phase and placement of introns,
the organization of the human chymase gene is similar to that of several
other granule-associated leukocyte serine proteases including lymphocyte
granzymes, neutrophil cathepsin G and elastase. However, its
organization differs from that of mast cell tryptase. By a study of
hamster-human hybrid DNAs, Caughey et al. (1991) assigned the gene to
human chromosome 14, which is the site of related genes. From studies of
YACs and cosmid clones, Caughey et al. (1993) demonstrated that the mast
cell chymase gene is located at 14q11.2 in the same cluster as the genes
for 3 other proteases, T-cell receptor alpha/delta (TCRA; 186880/TCRD;
186810), neutrophil cathepsin G (CTSG; 116830), and the lymphocyte
cathepsin G-like proteins CGL1 (123910) and CGL2 (116831). They found
that CMA1 maps to a site within 150 kb of the cathepsin G gene. The gene
order is: cen--TCRA/TCRD--CGL1--CGL2--CTSG--CMA. In some cells, the
chymase and cathepsin G genes were cotranscribed; in others, they
appeared to be capable of independent regulation.

*FIELD* SA
Caughey et al. (1991)
*FIELD* RF
1. Caughey, G. H.; Schaumberg, T. H.; Zerweck, E. H.; Butterfield,
J. H.; Hanson, R. D.; Silverman, G. A.; Ley, T. J.: The human mast
cell chymase gene (CMA1): mapping to the cathepsin G/granzyme gene
cluster and lineage-restricted expression. Genomics 15: 614-620,
1993.

2. Caughey, G. H.; Zerweck, E. H.; Vanderslice, P.: Structure, chromosomal
assignment, and deduced amino acid sequence of a gene for human mast
cell chymase. (Abstract) Clin. Res. 39: 319A only, 1991.

3. Caughey, G. H.; Zerweck, E. H.; Vanderslice, P.: Structure, chromosomal
assignment, and deduced amino acid sequence of a human gene for mast
cell chymase. J. Biol. Chem. 266: 12956-12963, 1991.

*FIELD* CD
Victor A. McKusick: 5/9/1991

*FIELD* ED
mark: 10/04/1996
carol: 3/19/1993
supermim: 3/16/1992
carol: 9/6/1991
carol: 5/9/1991

*RECORD*
*FIELD* NO
118943
*FIELD* TI
118943 CHYMOSIN PSEUDOGENE; CYMP
PROCHYMOSIN, INCLUDED
*FIELD* TX
Chymosin (EC 3.4.23.4) is an aspartyl proteinase with an exceedingly
high specificity. The enzyme cleaves only the phenylalanine-methionine
peptide bond between amino acid residues 105 and 106 in kappa-casein,
leading to the coagulation of milk. In the biotechnological industry,
chymosin has a wide use in cheese manufacturing as the coagulant of
milk. Chymosin is synthesized in the chief and mucous neck cells of the
gastric glands in the fourth stomach of newborn calves. The enzyme is
synthesized as an enzymatically inactive precursor, preprochymosin. In
the process of secretion, preprochymosin, comprising 381 amino acids, is
processed by the signal peptidase into an inactive 365-amino acid
prochymosin. At low pH, prochymosin undergoes autocatalytic cleavage of
42 N-terminal amino acids, yielding active chymosin. Chymosin is also
found in other mammalian species, e.g., the newborn pig, cat, seal, and
lamb. The presence of chymosin in humans is a matter of controversy. Ord
et al. (1990) cloned a human genomic sequence homologous to the bovine
prochymosin gene. The sequence showed a 1-bp deletion and a 2-bp
deletion in the human sequence corresponding to bovine prochymosin exons
4 and 6, respectively. There also was a terminator codon in the open
reading frame corresponding to bovine prochymosin exon 5. Thus, this
genomic sequence apparently represents a human prochymosin pseudogene.
No functional gene was identified. Using DNA obtained from human/hamster
somatic cell hybrids as a PCR template, Kolmer et al. (1991) mapped the
human prochymosin pseudogene to chromosome 1. Foltmann (1992) gave a
review.

*FIELD* RF
1. Foltmann, B.: Chymosin: a short review on foetal and neonatal
gastric proteases. Scand. J. Clin. Lab. Invest. 52 (suppl. 210):
65-79, 1992.

2. Kolmer, M.; Ord, T.; Alhonen, L.; Hyttinen, J.-M.; Saarma, M.;
Villems, R.; Janne, J.: Assignment of human prochymosin pseudogene
to chromosome 1. Genomics 10: 496-498, 1991.

3. Ord, T.; Kolmer, M.; Villems, R.; Saarma, M.: Structure of the
human genomic region homologous to the bovine prochymosin-encoding
gene. Gene 91: 241-246, 1990.

*FIELD* CD
Victor A. McKusick: 6/24/1991

*FIELD* ED
mark: 02/21/1997
carol: 12/30/1992
supermim: 3/16/1992
carol: 3/3/1992
carol: 2/28/1992
carol: 8/7/1991
carol: 6/24/1991

*RECORD*
*FIELD* NO
118945
*FIELD* TI
*118945 CILIARY NEUROTROPHIC FACTOR; CNTF
*FIELD* TX
Barbin et al. (1984) described the neurotrophic activity of ciliary
neurotrophic factor purified from chick eye employing a survival assay
for neurons from chick embryonic ciliary ganglia. In addition to
neurotrophic effects on parasympathetic neurons, CNTF was shown to have
activities on sympathetic and sensory neurons. CNTF was purified to
homogeneity from rat and rabbit sciatic nerve, enabling the isolation of
cDNAs encoding the factor. Based on the cDNA sequences, Lam et al.
(1991) designed synthetic oligonucleotide probes which were used in the
isolation of the human CNTF gene. They described the amino acid sequence
of human CNTF as well as the organization of the gene which was located
on chromosome 11 by analysis of human-hamster somatic cell hybrids. The
human protein showed approximately 85% identity with CNTF of rat and
rabbit. It is of note that brain-derived neurotrophic factor (113505) is
located on 11p13 and that neurotrophic factor 3 (162660) is located on
chromosome 12, which shows considerable homeology with chromosome 11.
Kaupmann et al. (1991) demonstrated that the homologous gene is on mouse
chromosome 19 and that its expression is unaffected in the mouse
neurologic mutant Wobbler (wr), a form of spinal muscular atrophy. Using
a rodent/human somatic cell DNA mapping panel and fluorescence in situ
hybridization, Lev et al. (1993) localized the CNTF gene to the proximal
region of 11q. In addition, they identified a polymorphic tandem CA/GT
dinucleotide repeat associated with the human CNTF gene. To sublocalize
the CNTF gene on chromosome 11, Giovannini et al. (1993) isolated cosmid
clones containing the gene by use of a chromosome 11-specific library.
Using these clones in fluorescence in situ hybridization, they found
that the gene maps at an FLpter of 0.46, corresponding to a cytogenetic
band position of 11q12.2, according to the method of Lichter et al.
(1990). Yokoji et al. (1995) isolated a full-length cDNA for human
ciliary neurotrophic factor from a sciatic nerve cDNA library,
determined its structure, and localized it to chromosome 11q12 by
fluorescence in situ hybridization.

Homozygous pmn/pmn mice have a progressive motor neuronopathy which
becomes evident in the hind limbs at the end of the third postnatal
week; all the mice die of respiratory paralysis 6 or 7 weeks after
birth. Sendtner et al. (1992) found that treatment with ciliary
neurotrophic factor prolonged survival and greatly improved motor
function in these mice and reduced the morphologic manifestations of the
neural degeneration, even though treatment did not start until the first
symptoms of disease had become apparent and substantial degenerative
changes were already present. Because CNTF has a short half-life and
because pmn mice do not tolerate daily injections of CNTF and are too
small to accommodate infusion pumps, the agent was delivered by
intraperitoneal injection of a mouse cell line transfected with a
genomic construct that releases high quantities of biologically active
CNTF. The mode of action is not known. The CNTF and the CNTF-processing
pathways are not perturbed in pmn. Furthermore, CNTF appears not to be
involved in motor neuron survival during development. The observations,
whatever their explanation, hold hope for the treatment of amyotrophic
lateral sclerosis (105400) and related disorders. Masu et al. (1993)
extended our understanding of the physiologic function of CNTF. They
abolished CNTF gene expression by homologous recombination in mice and
found that progressive atrophy and loss of motor neurons occurred in
adult mice, accompanied by a small but significant reduction in muscle
strength. The authors stated that these studies demonstrated that
expression of the gene is not necessary for the development of spinal
motor neurons as assessed by morphologic criteria, but that it is
essential for maintenance of function in motor neurons in the postnatal
period.

Similar findings to the lack of effects in the CNTF knockout mice were
the findings by Takahashi et al. (1994) that approximately 2.5% of the
Japanese population are homozygous for mutations that inactivate the
CNTF gene (see 118945.0001). These individuals lacking CNTF are
seemingly not adversely affected in any way and have not been shown to
have any associated neurologic abnormalities. CNTF lacks a signal
peptide and is found stored inside adult glial cells, perhaps awaiting
release by some mechanism induced by injury. It may act in response to
injury or other stresses and not be essential during development. On the
other hand, DeChiara et al. (1995) found that null mutations in the CNTF
receptor gene (118946) led to perinatal death of the mice or severe
motor neuron deficits. Thus, the authors concluded that CNTFR is
critical for the developing nervous system, most likely by serving as a
receptor for a second, developmentally important, CNTF-like ligand.

*FIELD* AV
.0001
CILIARY NEUROTROPHIC FACTOR POLYMORPHISM
CNTF, IVS1AS G-A, -6, 4BP INS, FS63TER
Takahashi et al. (1994) identified an apparent polymorphism of the CNTF
gene. An acceptor splice site mutation caused aberrant mRNA splicing and
abolished expression of CNTF protein. The specific change was a G-to-A
transition at position -6 of the acceptor splice site leading to
insertion of 4 additional ribonucleotides at the beginning of the next
exon. This caused a frameshift from amino acid 39, resulting in a stop
codon 24 amino acids downstream. (The normal open reading frame codes
for 200 amino acids.) The aberrant mRNA was predicted to code for a
truncated protein of 62 amino acids. Analysis of tissue samples and
transfection of CNTF minigenes into cultured cells demonstrated to
Takahashi et al. (1994) that the mutated allele expressed only the
mutated mRNA species. Studies with an antiserum that recognized both the
normal and mutated CNTF showed complete lack of CNTF immunoreactivity in
peripheral nerve tissue from a homozygous mutant subject. In 391
Japanese people tested, 61.9% were normal homozygotes, 39.8%
heterozygotes, and 2.3% mutant homozygotes. The distribution of the 3
genotypes were similar in healthy and neurologic disease subjects,
indicating that human CNTF deficiency is not causally related to
neurologic diseases.

*FIELD* RF
1. Barbin, G.; Manthorpe, M.; Varon, S.: Purification of the chick
eye ciliary neuronotrophic factor. J. Neurochem. 43: 1468-1478,
1984.

2. DeChiara, T. M.; Vejsada, R.; Poueymirou, W. T.; Acheson, A.; Suri,
C.; Conover, J. C. Friedman, B.; McClain, J.; Pan, L.; Stahl, N.;
Ip, N. Y.; Kato, A.; Yancopoulos, G. D.: Mice lacking the CNTF receptor,
unlike mice lacking CNTF, exhibit profound motor neuron deficits at
birth. Cell 83: 313-322, 1995.

3. Giovannini, M.; Romo, A. J.; Evans, G. A.: Chromosomal localization
of the human ciliary neurotrophic factor gene (CNTF) to 11q12 by fluorescence
in situ hybridization. Cytogenet. Cell Genet. 63: 62-63, 1993.

4. Kaupmann, K.; Sendtner, M.; Stockli, K. A.; Jockusch, H.: The
gene for ciliary neurotrophic factor (CNTF) maps to murine chromosome
19 and its expression is not affected in the hereditary motoneuron
disease 'Wobbler' of the mouse. Europ. J. Neurosci. 3: 1182-1186,
1991.

5. Lam, A.; Fuller, F.; Miller, J.; Kloss, J.; Manthorpe, M.; Varon,
S.; Cordell, B.: Sequence and structural organization of the human
gene encoding ciliary neurotrophic factor. Gene 102: 271-276, 1991.

6. Lev, A. A.; Rosen, D. R.; Kos, C.; Clifford, E.; Landes, G.; Hauser,
S. L.; Brown, R. H., Jr.: Human ciliary neurotrophic factor: localization
to the proximal region of the long arm of chromosome 11 and association
with CA/GT dinucleotide repeat. Genomics 16: 539-541, 1993.

7. Lichter, P.; Tang, C. C.-J.; Call, K.; Hermanson, G.; Evans, G.
A.; Housman, D.; Ward, D. C.: High-resolution mapping of human chromosome
11 by in situ hybridization with cosmid clones. Science 247: 64-69,
1990.

8. Masu, Y.; Wolf, E.; Holtmann, B.; Sendtner, M.; Brem, G.; Thoenen,
H.: Disruption of the CNTF gene results in motor neuron degeneration.
Nature 365: 27-32, 1993.

9. Sendtner, M.; Schmalbruch, H.; Stockli, K. A.; Carroll, P.; Kreutzberg,
G. W.; Thoenen, H.: Ciliary neurotrophic factor prevents degeneration
of motor neurons in mouse mutant progressive motor neuronopathy. Nature 358:
502-504, 1992.

10. Takahashi, R.; Yokoji, H.; Misawa, H.; Hayashi, M.; Hu, J.; Deguchi,
T.: A null mutation in the human CNTF gene is not causally related
to neurological diseases. Nature Genet. 7: 79-84, 1994.

11. Yokoji, H.; Ariyama, T.; Takahashi, R.; Inazawa, J.; Misawa, H.;
Deguchi, T.: cDNA cloning and chromosomal localization of the human
ciliary neurotrophic factor gene. Neurosci. Lett. 185: 175-178,
1995.

*FIELD* CN
Orest Hurko - updated: 6/13/1995

*FIELD* CD
Victor A. McKusick: 10/4/1991

*FIELD* ED
mark: 06/12/1996
terry: 6/5/1996
terry: 4/15/1996
mark: 3/26/1996
terry: 3/22/1996
carol: 6/10/1994
carol: 10/29/1993
carol: 6/7/1993
carol: 5/27/1993
carol: 5/26/1993

*RECORD*
*FIELD* NO
118946
*FIELD* TI
*118946 CILIARY NEUROTROPHIC FACTOR RECEPTOR; CNTFR
*FIELD* TX
Davis et al. (1991) used the 'tagged-ligand panning' procedure to clone
a receptor for ciliary neurotrophic factor (118945). This receptor is
expressed exclusively in the nervous system and skeletal muscle. The
CNTF receptor was found to have a structure unrelated to the receptors
utilized by the nerve growth factor family of neurotrophic molecules,
but instead is most homologous to the receptor for a cytokine,
interleukin-6 (IL6; 147620). This similarity suggested that the CNTF
receptor, like the IL6 receptor, requires a second, signal-transducing
component. In contrast to all known receptors, the CNTF receptor is
anchored to cell membranes by a glycosyl-phosphatidylinositol linkage.
Donaldson et al. (1993) mapped the CNTFR gene to chromosome 9 by PCR on
a panel of human/CHO somatic cell hybrids and regionalized the
assignment to 9p13 by PCR on a panel of radiation hybrids.

By interspecific backcross linkage analysis, Pilz et al. (1995) mapped
the Cntfr gene to mouse chromosome 4. By fluorescence in situ
hybridization, Valenzuela et al. (1995) mapped the CNTFR gene to 9p13,
and by interspecific backcross linkage analysis, they mapped the gene to
mouse chromosome 4 in a region of known homology of synteny to 9p.
Valenzuela et al. (1995) found that the human and mouse genes have an
identical intron/exon structure that correlates well with the domain
structure of the protein. The signal peptide and the immunoglobulin-like
domain are each encoded by a single exon, the cytokine receptor-like
domain is distributed among 4 exons, and the C-terminal
glycosylphosphatidylinositol recognition domain is encoded by the final
coding exon. The position of the introns within the cytokine
receptor-like domain corresponds to that found in other members of the
cytokine receptor superfamily.

Although mice that are homozygous for an inactivated CNTF gene develop
normally and initially thrive and only later in adulthood exhibit very
mild loss of motor neurons with resulting minor muscle weakness,
DeChiara et al. (1995) found that mice homozygous for 'knockout' of the
CNTFR gene died perinatally and displayed severe motor neuron deficits.
Thus, the authors concluded that CNTFR is critical for the developing
nervous system, most likely by serving as a receptor for a second,
developmentally important, CNTF-like ligand.

*FIELD* RF
1. Davis, S.; Aldrich, T. H.; Valenzuela, D. M.; Wong, V.; Furth,
M. E.; Squinto, S. P.; Yancopoulos, G. D.: The receptor for ciliary
neurotrophic factor. Science 253: 59-63, 1991.

2. DeChiara, T. M.; Vejsada, R.; Poueymirou, W. T.; Acheson, A.; Suri,
C.; Conover, J. C. Friedman, B.; McClain, J.; Pan, L.; Stahl, N.;
Ip, N. Y.; Kato, A.; Yancopoulos, G. D.: Mice lacking the CNTF receptor,
unlike mice lacking CNTF, exhibit profound motor neuron deficits at
birth. Cell 83: 313-322, 1995.

3. Donaldson, D. H.; Britt, D. E.; Jones, C.; Jackson, C. L.; Patterson,
D.: Localization of the gene for the ciliary neurotrophic factor
receptor (CNTFR) to human chromosome 9. Genomics 17: 782-784, 1993.

4. Pilz, A.; Woodward, K.; Povey, S.; Abbott, C.: Comparative mapping
of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25:
139-149, 1995.

5. Valenzuela, D. M.; Rojas, E.; Le Beau, M. M.; Espinosa, R., III;
Brannan, C. I.; McClain, J.; Masiakowski, P.; Ip, N. Y.; Copeland,
N. G.; Jenkins, N. A.; Yancopoulos, G. D.: Genomic organization and
chromosomal localization of the human and mouse genes encoding the
alpha receptor component for ciliary neurotrophic factor. Genomics 25:
157-163, 1995.

*FIELD* CD
Victor A. McKusick: 10/21/1991

*FIELD* ED
mark: 03/26/1996
terry: 3/22/1996
carol: 2/10/1995
carol: 9/15/1993
supermim: 3/16/1992
carol: 10/25/1991
carol: 10/21/1991

*RECORD*
*FIELD* NO
118950
*FIELD* TI
*118950 CITRATE SYNTHASE, MITOCHONDRIAL; CS
CLARA CELL SECRETORY PROTEIN; CCSP
*FIELD* TX
Clara cell secretory protein is an abundant component of airway
secretions and has the ability to bind small hydrophobic molecules. The
structural locus for this enzyme was assigned to chromosome 12 by cell
hybridization studies (van Heyningen et al., 1973; Wijnen et al., 1977;
Herbschleb-Voogt et al., 1978). By study of cells trisomic for
12pter-p11, Mattei et al. (1982) assigned CS to 12p11-qter. Stripp et
al. (1994) presented data supporting the notion that the CCSP genes from
the rat and mouse and the uteroglobin gene (192020) in rabbit are
homologs.

*FIELD* SA
Craig  (1973)
*FIELD* RF
1. Craig, I. W.: Procedure for the analysis of citrate synthase in
somatic hybrids. Biochem. Genet. 9: 351-358, 1973.

2. Herbschleb-Voogt, E.; Monteba-van Heuvel, M.; Wijnen, L. M. M.;
Westerveld, A.; Pearson, P. L.; Meera Khan, P.: Chromosomal assignment
and regional localization of CS, ENO-2, GAPDH, LDH-B, PEPB, and TPI
in man-rodent cell hybrids. Cytogenet. Cell Genet. 22: 482-486,
1978.

3. Mattei, J. F.; Baeteman, M. A.; Mattei, M. G.; Ardissonne, J. P.;
Giraud, F.: Regional assignments of CS and ENO2 on chromosome 12.
(Abstract) Cytogenet. Cell Genet. 32: 297 only, 1982.

4. Stripp, B. R.; Huffman, J. A.; Bohinski, R. J.: Structure and
regulation of the murine Clara cell secretory protein gene. Genomics 20:
27-35, 1994.

5. van Heyningen, V.; Craig, I.; Bodmer, W.: Genetic control of mitochondrial
enzymes in human-mouse somatic cell hybrids. Nature 245: 509-512,
1973.

6. Wijnen, L. M. M.; Grzeschik, K.-H.; Pearson, P. L.; Meera Khan,
P.: Direct assignment of citrate synthase (CS) gene to human chromosome
12 in man-mouse cell hybrids. Hum. Genet. 39: 339-344, 1977.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 5/31/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/24/1986

*RECORD*
*FIELD* NO
^118953
*FIELD* TI
^118953 MOVED TO 192020
*FIELD* TX
This entry was incorporated into entry 192020 on 17 January 1997.

*FIELD* CD
Victor A. McKusick: 10/2/1991
*FIELD* ED
mark: 01/17/1997
mark: 6/27/1995
carol: 3/25/1992
supermim: 3/16/1992
carol: 10/2/1991
*RECORD*
*FIELD* NO
118955
*FIELD* TI
*118955 CLATHRIN, HEAVY CHAIN; CLTC
*FIELD* TX
Clathrin is a major protein component of the cytoplasmic face of
intracellular organelles, called coated vesicles and coated pits. These
specialized organelles are involved in the intracellular trafficking of
receptors and endocytosis of a variety of macromolecules. Clathrin
molecules have a triskelion structure composed of 3 noncovalently bound
heavy chains and 3 light chains. Dodge et al. (1991) isolated a 916-bp
cDNA for the heavy chain of clathrin. Southern analysis of human/rodent
somatic cell hybrids localized the CLTC gene to chromosome 17.
Additional analyses using panels of human/rodent somatic cell hybrids
with specific chromosomal translocations and deletions mapped the human
clathrin heavy chain gene to 17q11-qter.

*FIELD* RF
1. Dodge, G. R.; Kovalszky, I.; McBride, O. W.; Yi, H. F.; Chu, M.;
Saitta, B.; Stokes, D. G.; Iozzo, R. V.: Human clathrin heavy chain
(CLTC): partial molecular cloning, expression, and mapping of the
gene to human chromosome 17q11-qter. Genomics 11: 174-178, 1991.

*FIELD* CD
Victor A. McKusick: 9/12/1991

*FIELD* ED
supermim: 3/16/1992
carol: 9/12/1991

*RECORD*
*FIELD* NO
118960
*FIELD* TI
*118960 CLATHRIN, LIGHT CHAIN A; CLTA
LCA
*FIELD* TX
Clathrin is the main structural component of the lattice covering the
cytoplasmic face of the coated pits and coated vesicles in which
specific macromolecules are entrapped in the process of
receptor-mediated endocytosis. Clathrin is a large, soluble protein
composed of heavy chains (molecular size, about 192 kD) and light chains
(molecular size, about 32-38 kD). Two major classes of clathrin light
chains, referred to as LCA and LCB, have been identified. (The gene is
also symbolized CLTA.) The structure of these light chains was studied
by Kirchhausen et al. (1987). The clathrin unit that assembles into
coats had 3 extended legs, 500 angstroms in length, splayed out in a
pinwheel-like structure (triskelion). Each of the legs is built from a
single heavy chain, with a light chain bound to each proximal segment.
At least 4 distinct forms of clathrin light chains are found in
mammalian cells. This molecular variability derives from tissue-specific
patterns of expression of LCA and LCB genes (Jackson et al., 1987).
Brodsky et al. (1987) identified that part of the light-chain sequence
that mediates heavy-chain binding and is the region of strongest
homology with intermediate filament proteins. Sequence analysis shows an
overall homology of 60% between LCA and LCB and the presence of
brain-specific insertion sequences. LCA and LCB (118970) are coded by
distinct genes. Jackson and Parham (1988) compared cDNAs encoding the
brain and nonbrain forms of human LCA and LCB with their homologs in cow
and rat. The significant differences that distinguish LCA from LCB and
the brain from the nonbrain forms show remarkable preservation in all 3
species. Each clathrin triskelion consists of 3 heavy chains and 3 light
chains. In the brain, tissue-specific mRNA splicing yields larger forms
of LCA and LCB, containing additional insertion sequences of 30 and 18
amino acids, respectively.

By Southern blot analysis on genomic DNA extracted from a panel of
mouse-human somatic cell hybrids and by isotopic in situ hybridization,
Ponnambalam et al. (1994) assigned the CLTA gene to human 12q23-q24.

*FIELD* RF
1. Brodsky, F. M.; Galloway, C. J.; Blank, G. S.; Jackson, A. P.;
Seow, H.-F.; Drickamer, K.; Parham, P.: Localization of clathrin
light-chain sequences mediating heavy-chain binding and coated vesicle
diversity. Nature 326: 203-205, 1987.

2. Jackson, A. P.; Parham, P.: Structure of human clathrin light
chains: conservation of light chain polymorphism in three mammalian
species. J. Biol. Chem. 263: 16688-16695, 1988.

3. Jackson, A. P.; Seow, H.-F.; Holmes, N.; Drickamer, K.; Parham,
P.: Clathrin light chains contain brain-specific insertion sequences
and a region of homology with intermediate filaments. Nature 326:
154-159, 1987.

4. Kirchhausen, T.; Scarmato, P.; Harrison, S. C.; Monroe, J. J.;
Chow, E. P.; Mattaliano, R. J.; Ramachandran, K. L.; Smart, J. E.;
Ahn, A. H.; Brosius, J.: Clathrin light chains LCA and LCB are similar,
polymorphic, and share repeated heptad motifs. Science 236: 320-324,
1987.

5. Ponnambalam, S.; Jackson, A. P.; LeBeau, M. M.; Pravtcheva, D.;
Ruddle, F. H.; Alibert, C.; Parham, P.: Chromosomal location and
some structural features of human clathrin light-chain genes (CLTA
and CLTB). Genomics 24: 440-444, 1994.

*FIELD* CD
Victor A. McKusick: 4/27/1987

*FIELD* ED
mark: 02/23/1997
terry: 6/18/1996
carol: 1/18/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
carol: 3/1/1989
carol: 12/22/1988

*RECORD*
*FIELD* NO
118970
*FIELD* TI
*118970 CLATHRIN, LIGHT CHAIN B; CLTB; LCB
*FIELD* TX
See CLTA (118960). By Southern blot analysis carried out on genomic DNA
extracted from a panel of mouse-human somatic cell hybrids and by
isotopic in situ hybridization, Ponnambalam et al. (1994) assigned the
CLTB gene to human 4q2-q3.

*FIELD* RF
1. Ponnambalam, S.; Jackson, A. P.; LeBeau, M. M.; Pravtcheva, D.;
Ruddle, F. H.; Alibert, C.; Parham, P.: Chromosomal location and
some structural features of human clathrin light-chain genes (CLTA
and CLTB). Genomics 24: 440-444, 1994.

*FIELD* CD
Victor A. McKusick: 7/7/1987

*FIELD* ED
carol: 1/18/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 7/7/1987

*RECORD*
*FIELD* NO
118980
*FIELD* TI
118980 CLAVICLE, PSEUDARTHROSIS OF, CONGENITAL
*FIELD* TX
Gibson and Carroll (1970) described this in at least 12 members of 3
generations, with male-to-male transmission. All affected persons were
of 'short stature and several of them had a high palatal arch and
irregular upper dentition.' Thus, it is not certain that this disorder
is distinct from cleidocranial dysplasia (119600). Ahmadi and Steel
(1977) found reports of 102 cases. They commented that the frequency of
bilateral involvement was about 10%. Further, they wrote: 'one of the
striking and interesting features of the disease is the marked
predominance for the right side. In fact, there is only one documented
case of a left-sided congenital pseudarthrosis of the clavicle. However,
this case was associated with dextrocardia.' They noted that the
clavicle is the first bone to ossify. They reported 5 cases, of which 3
represented the very rare form of left-sided involvement with
dextrocardia. Schnall et al. (1988) reported 6 symptomatic children with
unilateral pseudarthrosis of the clavicle. All cases were sporadic. The
authors reported that the anomaly is 'commonly seen' in their neonatal
intensive care unit. Most of these presumably 'heal' by themselves.

*FIELD* RF
1. Ahmadi, B.; Steel, H. H.: Congenital pseudarthrosis of the clavicle.
Clin. Orthop. 126: 130-134, 1977.

2. Gibson, D. A.; Carroll, N.: Congenital pseudoarthrosis of the
clavicle. J. Bone Joint Surg. 52B: 629-643, 1970.

3. Schnall, S. B.; King, J. D.; Marrero, G.: Congenital pseudarthrosis
of the clavicle: a review of the literature and surgical results of
six cases. J. Pediat. Orthop. 8: 316-321, 1988.

*FIELD* CS

Skel:
   Congenital pseudoarthrosis of clavicle

Growth:
   Short stature

Mouth:
   High arched palate

Teeth:
   Irregular upper teeth

Inheritance:
   Autosomal dominant;
   ? variant cleidocranial dysplasia (119600)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 5/23/1988
carol: 5/18/1988

*RECORD*
*FIELD* NO
118990
*FIELD* TI
*118990 CLEAVAGE SIGNAL-1 PROTEIN; CS1
*FIELD* TX
Mammalian fertilization involves the fusion of sperm and egg surface
membranes resulting in resumption of meiosis. Sperm surface molecules
have been shown to be transferred to the egg membrane during
fertilization. Thus, the sperm cell can share in or impart antigenic
specificities to fertilized ova and cleaving embryos. The molecules that
are incorporated into the oocyte may provide an extranuclear signal to
the oocyte to cleave. The sperm surface antigen involved in some step of
early cleavage of the fertilized oocyte is a doublet of proteins of
approximately 14 kD and 18 kD. Antibodies to this protein inhibit early
cleavage of the oocyte without affecting pronuclear formation. Javed and
Naz (1992) cloned human CS1 cDNA, which is 1,828 bp long. The start
codon assigned to the first ATG (bp 98-100) encoded a protein with 249
amino acid residues terminating at TAA (bp 845-847). The cDNA had a
97-bp 5-prime and a 984-bp 3-prime untranslated region. The potential
polyadenylation signal (5-prime--AATAAA) was at bp 1803-1808. No
homology was found to any known sequence, indicating that CS1 is a
unique protein. In a rabbit reticulocyte in vitro translation system,
the transcribed CS1 RNA produced a 33-kD CS1 protein. The 2 parts of the
antigen are presumably derived from 1 transcript.

*FIELD* RF
1. Javed, A. A.; Naz, R. K.: Human cleavage signal-1 protein; cDNA
cloning, transcription and immunological analysis. Gene 112: 205-211,
1992.

*FIELD* CD
Victor A. McKusick: 6/15/1992

*FIELD* ED
warfield: 4/6/1994
carol: 6/15/1992

*RECORD*
*FIELD* NO
119000
*FIELD* TI
*119000 CLEFT CHIN
CHIN DIMPLE
*FIELD* TX
A bony peculiarity underlies the Y-shaped fissure of the chin. Guenther
(1939) found 9 cases in 5 generations, and von Meirowsky (1924) reported
25 cases in 4 generations. By casual observation, I found it in 3
generations, and Gorlin (1982) noted it in 4 generations. A publishing
colleague (P21,446) who has this trait is in the third generation of
affected males in his family. In general, females appear to be less
conspicuously affected than males. The movie star Kirk Douglas shows the
trait. There is an old English saying concerning the trait, 'Dimpled
chin, devil within.'

*FIELD* SA
Lebow and Sawin (1941)
*FIELD* RF
1. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.  1982.

2. Guenther, H.: Anomalien und Anomaliekomplexe in der Gegend des
ersten Schlundbogens. Z. Menschl. Vererb. Konstitutionsl. 23: 43-52,
1939.

3. Lebow, M. R.; Sawin, P. B.: Inheritance of human facial features:
a pedigree study involving length of face, prominent ears and chin
cleft. J. Hered. 32: 127-132, 1941.

4. von Meirowsky, (NI): Kleine Beitraege zur Vererbungswissenschaft.
Arch. Rass. Ges. Biol. 16: 439-443, 1924.

*FIELD* CS

Facies:
   Y-shaped fissure of chin;
   Peculiarity of mandible

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 7/25/1994
mimadm: 6/25/1994
warfield: 4/7/1994
supermim: 3/16/1992
carol: 3/4/1992
carol: 2/28/1992

*RECORD*
*FIELD* NO
119100
*FIELD* TI
*119100 CLEFT HAND AND ABSENT TIBIA
APLASIA OF TIBIA WITH ECTRODACTYLY;;
TIBIAL APLASIA WITH SPLIT-HAND/SPLIT-FOOT DEFORMITY;;
SPLIT-HAND/FOOT MALFORMATION WITH LONG BONE DEFICIENCY; SHFLD;;
ECTRODACTYLY WITH APLASIA OF LONG BONES
*FIELD* TX
Roberts (1967) described a family in which persons in 4 generations had
one cleft hand with a missing middle finger and flexed ring finger; one
person also had grossly deformed legs with missing tibias requiring
amputation and a sib had only the severe leg deformity. Another member
had absent forearms with the leg deformity. Majewski et al. (1985)
stated that this disorder was first described by Otto (1950) in a fetus
and that the first familial instance was published by White and Baker
(1888). Majewski et al. (1985) reported 6 families and concluded that
the disorder is autosomal dominant with markedly reduced penetrance. In
addition to bilateral aplasia of the tibias and split-hand/split-foot
deformity (the full-blown syndrome), malformations may include distal
hypoplasia or bifurcation of the femurs, hypo- or aplasia of the ulnas,
and minor anomalies such as aplasia of the patellas, hypoplastic big
toes, and cup-shaped ears. They stated that the mildest visible
manifestation may be hypoplastic big toes, whereas the severest is
tetramonodactyly or transverse hemimelia. Richieri-Costa et al. (1987)
described a family in which 2 girls, offspring of consanguineous
parents, had different limb anomalies: the tibial aplasia-ectrodactyly
syndrome in one and the Gollop-Wolfgang complex (228250) in the other.
Sener et al. (1989) described a 19-year-old man with bilateral
involvement of the hands and legs. His parents were first cousins. A
great-great-grandfather through both his mother and his father was said
to have had grossly deformed legs with unilateral split-hand. Der
Kaloustian and Mnaymneh (1973) described this syndrome in the offspring
of parents related as first cousins once removed. Another member of the
family related as a first cousin to the proband's mother and as a first
cousin once removed to the proband's father was identically affected.
Both Sener et al. (1989) and Der Kaloustian and Mnaymneh (1973) favored
autosomal dominant inheritance with reduced penetrance, despite the
consanguinity in these families. Zlotogora (1994) analyzed published
pedigrees with nonsyndromal ectrodactyly and other limb defects (usually
tibial aplasia or hypoplasia) in at least one family member. In this
group of families, penetrance was only 0.66. Sometimes obligatory
carriers of the gene were unaffected for several generations. To explain
this phenomenon, Zlotogora (1994) proposed the influence of another gene
and raised the possibility of trinucleotide repeat expansion.

One form of ectrodactyly (absence of the middle rays, i.e., the central
digits of the hands and/or feet) results from mutation at a locus
(SHFM1; 183600) in 7q21.2-q22.1. Marinoni et al. (1994) described a
large family in which ectrodactyly was associated with long bone
deficiency in the form of aplasia of bones of the lower leg or forearm
in an autosomal dominant pattern. Linkage to markers in the 7q21-q22
region was excluded.

*FIELD* RF
1. Der Kaloustian, V. M.; Mnaymneh, W. A.: Bilateral tibial aplasia
with lobster-claw hands: a rare genetic entity. Acta Paediat. Scand. 62:
77-78, 1973.

2. Majewski, F.; Kuster, W.; ter Haar, B.; Goecke, T.: Aplasia of
tibia with split-hand/split-foot deformity: report of six families
with 35 cases and considerations about variability and penetrance. Hum.
Genet. 70: 136-147, 1985.

3. Marinoni, J.-C.; Boyd, E.; Sherman, S.; Schwartz, C.: Familial
split hand/split foot long bone deficiency does not segregate with
markers linked to the SHFD1 locus in 7q21.3-q22.1. Hum. Molec. Genet. 3:
1355-1357, 1994.

4. Richieri-Costa, A.; Brunoni, D.; Laredo-Filho, J.; Kasinski, S.
: Tibial aplasia-ectrodactyly as variant expression of the Gollop-Wolfgang
complex: report of a Brazilian family. Am. J. Med. Genet. 28: 971-980,
1987.

5. Roberts, J. A. F.: Genetic Prognosis. An Introduction to Medical
Genetics..  London: Oxford Univ. Press (pub.)  (4th ed.): 1967.
Pp. 253-280.

6. Sener, R. N.; Isikan, E.; Diren, H. B.; Sayli, B. S.; Sener, F.
: Bilateral split-hand with bilateral tibial aplasia. Pediat. Radiol. 19:
258-260, 1989.

7. White, W. H.; Baker, H.: Case of congenital deformity of femora,
absence of tibiae, and malformation of the feet and hands. Trans.
Clin. Soc. London 21: 295-297, 1888.

8. Zlotogora, J.: On the inheritance of the split hand/split foot
malformation. Am. J. Med. Genet. 53: 29-32, 1994.

*FIELD* CS

Limbs:
   Cleft hand;
   Absent middle finger;
   Flexed ring finger;
   Absent tibia;
   Absent forearm;
   Tetramonodactyly;
   Transverse hemimelia;
   Hypoplastic big toes

Ears:
   Cup-shaped ears

Radiology:
   Distal hypoplasia or bifurcation of the femurs;
   Ulnar hypoplasia/aplasia;
   Patellar aplasia

Inheritance:
   Autosomal dominant

*FIELD* CN
Iosif W. Lurie - updated: 08/13/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 08/13/1996
carol: 1/18/1995
davew: 8/18/1994
mimadm: 6/25/1994
warfield: 4/6/1994
supermim: 3/16/1992
carol: 7/9/1991

*RECORD*
*FIELD* NO
119300
*FIELD* TI
*119300 CLEFT LIP AND/OR PALATE WITH MUCOUS CYSTS OF LOWER LIP
LIP-PIT SYNDROME; LPS;;
VAN DER WOUDE SYNDROME; VDWS; VWS
PIT, INCLUDED
*FIELD* TX
In 3 generations of a family Levy (1962) found malformations of the
lower lip consisting of symmetrical lumps. Two sibs had cleft palate in
addition to the lip anomaly. The literature on this syndrome was
analyzed by van der Woude (1954) who found confirmation for the
autosomal dominant mode of inheritance. It is possible that in some
affected families, because of the variable expressivity of the gene, the
syndrome is expressed only as pits. Baker (1964) reported such a
pedigree with affected members in 3 generations showing pits as the only
malformation. On the other hand, only harelip and/or cleft palate
without pits could segregate in families as a dominant trait. Test and
Falls (1947) described the condition transmitted through 5 generations.
The rule that cleft palate alone and cleft lip with or without cleft
palate behave differently does not hold in this disorder in which either
type of cleft alone or the two in combination may occur. Janku et al.
(1980) traced the van der Woude syndrome through 7 generations. Lip
pits, the most common manifestation, were present in 88% of the affected
and were the only manifestation in 64%. Clefts of lip and palate
occurred in 21%. Penetrance was 96.7%. Ranta and Rintala (1983) analyzed
the 'microforms' of the van der Woude syndrome in cases of cleft palate.
Conical elevations (CE) on the lower lip at the site of sinuses were
present in 39.3% of cleft palate cases, 0.8% of cleft lip with or
without cleft palate cases, and 0.7% of noncleft cases. In CP cases with
CE, the familial occurrence of clefts was statistically higher (30%)
than in CP cases without CE. The corresponding figures for hypodontia
were 40.7% and 24.7%, respectively. See review by Schinzel and Klausler
(1986). Burdick et al. (1987) reported 2 unrelated families from the
area of Beijing, China. Ankyloglossia was found in the proband in each
family. Sorricelli et al. (1966) also described this association.

Bocian and Walker (1987) described a patient with an interstitial
deletion of chromosome 1q, del(1q32-q41). Among other anomalies, the
patient had congenital lower lip pits similar to those found in
association with the van der Woude syndrome and with the popliteal
pterygium syndrome (119500). Bocian and Walker (1987) suggested that the
van der Woude syndrome may be due to a submicroscopic deletion of
chromosome 1q in the area stated. A tentative assignment of the locus,
symbolized PIT, to 1q32-q41 was made on the basis of this report. Sander
et al. (1994) reported a microdeletion involving 1q32-q41 in a family
with VDWS. They found allelic loss of the stable and highly polymorphic
microsatellite D1S205. They estimated that the upper bound of the size
of the deletion was 4 Mb. Wienker et al. (1987) excluded linkage of VDWS
with a considerable number of marker loci in studies of a kindred
segregating for the disorder through 5 generations. Only linkage with
Duffy blood group (110700) showed a uniformly positive lod score (lod =
1.31 at theta = 0.0). Murray et al. (1988) found linkage of LPS to the
renin gene (REN; 179820); lod = 4.62 at theta = 0.04. Studies by
Nishimura et al. (1989) raised the maximum lod score to 8.62 at theta =
0.02 for linkage of LPS and REN. Murray et al. (1988) and Nishimura et
al. (1989) also adopted a candidate gene approach and investigated
whether the laminin B2 (150290) gene might be the site of the mutation
in VDWS. The finding of several recombinants ruled out this possibility.
Nishimura et al. (1989) used the same approach to investigate decay
accelerating factor (125240) as the site of the mutation and found no
recombinants (lod = 2.22). Murray et al. (1990) reported a multipoint
linkage analysis that indicated flanking of the VDWS locus by REN and
D1S65 at a lod score of 10.83.

Schutte et al. (1996) constructed a 3.5-Mb YAC contig and sequence
tagged site (STS) map extending from D1S245 to D1S414 in the region
containing the VWS locus. They also carried out deletion mapping on a
somatic cell hybrid derived from a patient with VWS due to a
microdeletion. Analysis of this hybrid and genetic analysis in an
additional family narrowed the VWS critical region to a 1.6-cM region
flanked by D1S491 and D1S205. The authors noted that the STS markers
that flank this critical region and the proximal and distal ends of the
microdeletion are present in a single 850-kb YAC.

*FIELD* SA
Bowers  (1970); Burdick et al. (1985); Cervenka et al. (1967); Eastman
et al. (1978); Schneider  (1973); Shprintzen et al. (1980)
*FIELD* RF
1. Baker, B. R.: A family with bilateral congenital pits of the inferior
lip. Oral Surg. 18: 494-497, 1964.

2. Bocian, M.; Walker, A. P.: Lip pits and deletion 1q32-q41. Am.
J. Med. Genet. 26: 437-443, 1987.

3. Bowers, D. G.: Congenital lower lip sinuses with cleft palate. Plast.
Reconst. Surg. 45: 151-154, 1970.

4. Burdick, A. B.; Bixler, D.; Puckett, C. L.: Genetic analysis in
families with van der Woude syndrome. J. Craniofac. Genet. Dev. Biol. 5:
181-208, 1985.

5. Burdick, A. B.; Lian, M.; Zhuohua, D.; Ning, G.: Van der Woude
syndrome in two families in China. J. Craniofac. Genet. Dev. Biol. 7:
413-418, 1987.

6. Cervenka, J.; Gorlin, R. J.; Anderson, V. E.: The syndrome of
pits of the lower lip and cleft lip and/or palate: genetic considerations. Am.
J. Hum. Genet. 19: 416-432, 1967.

7. Eastman, J. R.; Bixler, D.; Escobar, V.: Linkage studies in van
der Woude syndrome. J. Med. Genet. 15: 217-281, 1978.

8. Janku, P.; Robinow, M.; Kelly, T.; Bralley, R.; Baynes, A.; Edgerton,
M. T.: The van der Woude syndrome in a large kindred: variability,
penetrance, genetic risks. Am. J. Med. Genet. 5: 117-123, 1980.

9. Levy, J.: Zwillinge in einer Familie mit Unterlippenmissbildung. Acta
Genet. Statist. Med. 12: 33-40, 1962.

10. Murray, J. C.; Nishimura, D.; Ardinger, H.; Buetow, K.; Spence,
A.; Falk, R.; Falk, P.; Sparkes, R.; Gardner, R. J. M.; Glinski, L.;
Pauli, R.; Nakamura, Y.; Green, P.; Yamada, Y.: Linkage of van der
Woude syndrome to markers on chromosome 1q and exclusion of laminin
B2 as a candidate gene. (Abstract) Am. J. Hum. Genet. 43: A153 only,
1988.

11. Murray, J. C.; Nishimura, D. Y.; Buetow, K. H.; Ardinger, H. H.;
Spence, M. A.; Sparkes, R. S.; Falk, R. E.; Falk, P. M.; Gardner,
R. J. M.; Harkness, E. M.; Glinski, L. P.; Pauli, R. M.; Nakamura,
Y.; Green, P. P.; Schinzel, A.: Linkage of an autosomal dominant
clefting syndrome (van der Woude) to loci on chromosome 1q. Am. J.
Hum. Genet. 46: 486-491, 1990.

12. Nishimura, D. Y.; Buetow, K. H.; Spence, M. A.; Gardner, R. J.
M.; Pauli, R.; Nakamura, Y.; Green, P.; Schinzel, A.; Murray, J. C.
: Linkage of van der Woude syndrome (LPS) to renin on 1q. (Abstract) Cytogenet.
Cell Genet. 51: 1053 only, 1989.

13. Ranta, R.; Rintala, A. E.: Correlations between microforms of
the van der Woude syndrome and cleft palate. Cleft Palate J. 20:
158-162, 1983.

14. Sander, A.; Schmelzle, R.; Murray, J.: Evidence for a microdeletion
in 1q32-41 involving the gene responsible for Van der Woude syndrome. Hum.
Molec. Genet. 3: 575-578, 1994.

15. Schinzel, A.; Klausler, M.: The van der Woude syndrome (dominantly
inherited lip pits and clefts). J. Med. Genet. 23: 291-294, 1986.

16. Schneider, E. L.: Lip pits and congenital absence of second premolars:
varied expression of the lip pits syndrome. J. Med. Genet. 10: 346-349,
1973.

17. Schutte, B. C.; Sander, A.; Malik, M.; Murray, J. C.: Refinement
of the Van der Woude gene location and construction of a 3.5-Mb YAC
contig and STS map spanning the critical region in 1q32-q41. Genomics 36:
507-514, 1996.

18. Shprintzen, R. J.; Goldberg, R. B.; Sidoti, E. J.: The penetrance
and variable expression of the van der Woude syndrome: implications
for genetic counseling. Cleft Palate J. 17: 52-57, 1980.

19. Sorricelli, D. A.; Bell, L.; Alexander, W. A.: Congenital fistulas
of the lower lip. Oral Surg. 21: 511-516, 1966.

20. Test, A. R.; Falls, H. F.: Dominant inheritance of cleft lip
and palate in five generations. J. Oral Surg. 5: 292-297, 1947.

21. van der Woude, A.: Fistula labii inferioris congenita and its
association with cleft lip and palate. Am. J. Hum. Genet. 6: 244-256,
1954.

22. Wienker, T. F.; Hudek, G.; Bissbort, S.; Mayerova, A.; Mauff,
G.; Bender, K.: Linkage studies in a pedigree with van der Woude
syndrome. J. Med. Genet. 24: 160-161, 1987.

*FIELD* CS

Mouth:
   Lower lip pits;
   Cleft lip;
   Cleft palate;
   Lower lip cysts;
   Ankyloglossia

Inheritance:
   Autosomal dominant (1q32)

*FIELD* CN
Moyra Smith - updated: 01/11/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 01/11/1997
jamie: 1/8/1997
mimadm: 6/25/1994
jason: 6/17/1994
carol: 4/10/1992
supermim: 3/16/1992
carol: 3/2/1992
carol: 6/24/1991

*RECORD*
*FIELD* NO
119500
*FIELD* TI
*119500 CLEFT LIP/PALATE, PARAMEDIAN MUCOUS CYSTS OF THE LOWER LIP, POPLITEAL
PTERYGIUM, DIGITAL AND GENITAL ANOMALIES
POPLITEAL PTERYGIUM SYNDROME; PPS;;
FACIOGENITOPOPLITEAL SYNDROME
*FIELD* TX
Klein (1962) described a mother and a daughter with the features of this
syndrome and suggested dominant inheritance. Gorlin et al. (1976)
favored autosomal dominant inheritance with variable expressivity and
incomplete penetrance; likewise, Escobar and Weaver (1978) concluded
that autosomal dominant inheritance is usual. Lewis (1948) described
brother and sister with cleft palate and webbing of the lower limbs
whose father had harelip and cleft palate. The webbing extended from the
region of the ischial tuberosities to the heels. (Surgeons must be aware
that the sciatic nerve may be situated in the web.) The girl was said to
have 'bilateral incomplete harelip.' Hecht and Jarvinen (1967) observed
affected mother and 2 sons in one family and affected mother and son and
daughter in a second. The observation of affected father and son by
Lewis (1948) excludes X-linked inheritance. Pterygium of the neck and
arms does not occur in this syndrome. An intercrural pterygium, if
present, causes distortion of the genitalia. Bifid scrotum and
cryptorchidism are the rule in males and hypoplasia of the labia majora
in females. Congenital ankyloblepharon filiforme occurs in some cases.
The epithelial strands connecting the eyelids in ankyloblepharon
filiforme have their counterpart in symmetrical epithelial strands
running from the maxilla, as pictured by Rintala et al. (1970). Pfeiffer
et al. (1970) described affected father and 2 sons with predominantly
unilateral popliteal pterygium, anomalies of the skin around the nails,
syndactyly, abnormality of the scrotum or cryptorchidism, cleft lip and
palate, congenital fistulae of the lower lip, congenital bands of mucous
membranes between jaws, and ankyloblepharon filiforme adnatum. Kind
(1970) described affected mother and daughter. In addition to bilateral
popliteal pterygium, aplasia of the labia majora, ankyloblepharon
filiforme, filiform bands between the jaws, lip pits and cleft palate
were present. See Noonan syndrome (163950). Froster-Iskenius (1990)
provided an extensive review. Kopits (1937) described 4 cases, 3 of them
belonging to the same family, and gave details of the operative
techniques used. Cleft palate with or without cleft lip is found in 91
to 97% of cases. Paramedian sinuses or pits of the lower lip are said to
occur in 45.6%. These are feature of the lip-pit or Van der Woude
syndrome (119300), which has been mapped to 1q32. It will be of interest
to determine whether the popliteal pterygium syndrome is an allele of
the lip-pit syndrome. Over two-fifths of patients have intraoral tissue
bands (syngnathia) impeding mouth opening. Ankyloblepharon filiforme
adnatum occurs in about one-fifth of cases. About one-third of cases
have a distinctive nail anomaly with a pyramidal skinfold extending from
the base to the tip of the nails. Genital anomalies in females include
hypoplastic labia majora as well as hypoplastic vagina and uterus. Males
have cryptorchidism and bifid or absent scrotum; the penis is usually
normal-sized. Hunter (1990) described a family ascertained through an
infant with most of the major signs of the popliteal pterygium syndrome.
The mother, who had a repaired cleft palate and toe syndactyly, had been
aware that her syndactyly was familial. She showed a hint of popliteal
webbing. The infant proband showed ankyloblepharon, cleft lip, and oral
synechiae, as well as lower lip pits, complete cleft palate, mild
intracrural webbing and hypoplasia of the labia majora, popliteal
webbing more marked on the right, and marked dimpling over the elbows
and knees. Variable skin syndactyly involved the third and fourth
fingers of both hands, fourth and fifth toes of both feet, and the
second and third toes of the left foot.

Syndactyly is a useful diagnostic sign in PPS because it is not seen in
most of the syndromes that should be considered in the differential
diagnosis. In the reported cases reviewed by Hunter (1990), syndactyly
of the toes was reported in 57% and of the hands in 16%; overall, 59% of
patients had some form of syndactyly. In the hands, fusion of fingers 3
and 4 was the most common type of syndactyly. Thus, the syndactyly in
PPS most closely resembles type I zygodactyly (185900).

Soekarman et al. (1995) described 2 families in which the popliteal
pterygium syndrome occurred in 3 successive generations. While
expression of the syndrome was relatively mild in the first and second
generations, the patients in the third generation showed the full-blown
syndrome. Differential diagnosis between mildly affected patients with
the popliteal pterygium syndrome and those with Van der Woude syndrome
is difficult and may even be impossible. Indeed, Soekarman et al. (1995)
suggested that their observations support the hypothesis that the 2
syndromes are variants of the same disorder. Gorlin et al. (1990)
suggested that a pathognomonic sign is a typical, triangular overgrowth
of skin over the nail of the first toe. They suggested that if this sign
is present in a patient in combination with cleft palate and/or lip,
even without popliteal webbing, the diagnosis of PPS should be made.

*FIELD* SA
Bixler et al. (1973); Frohlich et al. (1977); Gorlin et al. (1968);
Pashayan and Lewis (1980)
*FIELD* RF
1. Bixler, D.; Poland, C., III; Nance, W. E.: Phenotypic variation
in the popliteal pterygium syndrome. Clin. Genet. 4: 220-228, 1973.

2. Escobar, V.; Weaver, D. D.: The facio-genito-popliteal syndrome.
Birth Defects Orig. Art. Ser. XIV(6B): 185-192, 1978.

3. Frohlich, G. S.; Starzer, K. L.; Tortora, J. M.: Popliteal pterygium
syndrome: report of a family. J. Pediat. 90: 91-93, 1977.

4. Froster-Iskenius, U. G.: Popliteal pterygium syndrome. J. Med.
Genet. 27: 320-326, 1990.

5. Gorlin, R. J.; Cohen, M. M., Jr.; Levin, L. S.: Popliteal pterygium
syndrome (facio-genito-popliteal syndrome). In: Syndromes of the Head
and Neck.  Oxford Univ. Press (pub.)  1990. ). Pp. 629-631..

6. Gorlin, R. J.; Pindborg, J. J.; Cohen, M. M., Jr.: Cleft lip-palate,
popliteal pterygium digital and genital anomalies. Syndromes of the
Head and Neck.  New York: Blakiston Division, McGraw-Hill (pub.)
(2nd ed.): 1976. Pp. 121-124.

7. Gorlin, R. J.; Sedano, H. O.; Cervenka, J.: Popliteal pterygium
syndrome: a syndrome comprising cleft lip-palate, popliteal and intercrural
pterygia, digital and genital anomalies. Pediatrics 41: 503-509,
1968.

8. Hecht, F.; Jarvinen, J. M.: Heritable dysmorphic syndrome with
normal intelligence. J. Pediat. 70: 927-935, 1967.

9. Hunter, A.: The popliteal pterygium syndrome: report of a new
family and review of the literature. Am. J. Med. Genet. 36: 196-208,
1990.

10. Kind, H. P.: Popliteales Pterygiumsyndrom. Helv. Paediat. Acta 25:
508-516, 1970.

11. Klein, D.: Un curieux syndrome hereditaire: cheilo-palatoschizis
avec fistules de la levre inferieure associe a une syndactylie, une
onychodysplasie particuliere, un pterygion poplite unilateral et des
pieds varus equins. J. Genet. Hum. 11: 65-71, 1962.

12. Kopits, E.: Die als 'Flughaut' bezeichneten Missbildungen und
deren operative Behandlung (Musculo-dysplasia congenita). Arch.
Orthop. Unfallchir. 37: 539-541, 1937.

13. Lewis, E.: Congenital webbing of the lower limbs. Proc. Roy.
Soc. Med. 41: 864 only, 1948.

14. Pashayan, H. M.; Lewis, M. B.: A family with the popliteal pterygium
syndrome. Cleft Palate J. 17: 48-51, 1980.

15. Pfeiffer, R. A.; Tuente, W.; Reinken, M.: Das Kniepterygium-Syndrom,
ein autosomal-dominant vererbtes Missbildungssyndrom. Z. Kinderheilk. 108:
103-116, 1970.

16. Rintala, A. E.; Lahti, A. Y.; Gylling, U. S.: Congenital sinuses
of the lower lip in connection with cleft lip and palate. Cleft
Palate J. 7: 336-346, 1970.

17. Soekarman, D.; Cobben, J. M.; Vogels, A.; Spauwen, P. H.; Fryns,
J. P.: Variable expression of the popliteal pterygium syndrome in
two 3-generation families. Clin. Genet. 47: 169-174, 1995.

*FIELD* CS

Mouth:
   Lower lip pits;
   Cleft lip;
   Cleft palate;
   Lower lip cysts;
   Filiform alveolar bands;
   Ankyloglossia

GU:
   Bifid scrotum;
   Cryptorchidism;
   Hypoplastic labia majora;
   Hypoplastic vagina and uterus

Skin:
   Popliteal pterygium;
   Intercrural pterygium;
   Dimpling over elbows and knees;
   Variable skin syndactyly fingers and toes

Nails:
   Pyramidal skinfold from base to tip of nails

Eyes:
   Congenital ankyloblepharon filiforme

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 7/10/1995
mark: 6/27/1995
davew: 7/28/1994
mimadm: 6/25/1994
carol: 6/1/1994
supermim: 3/16/1992

*RECORD*
*FIELD* NO
119530
*FIELD* TI
*119530 OROFACIAL CLEFT 1; OFC1
CLEFT LIP WITH OR WITHOUT CLEFT PALATE;;
OROFACIAL CLEFT, NONSYNDROMIC; OFC
*FIELD* TX
Over 200 syndromes, including a number that are either chromosomal or
mendelian in causation, have cleft lip and/or palate as feature(s)
(Gorlin, 1982). As precise a diagnosis as possible is necessary before
falling back on empiric risk figures for genetic counseling. It is clear
from family studies that isolated cleft palate (119540) is genetically
distinct from cleft lip with or without cleft palate. Cleft lip with or
without cleft palate appears to have complex genetics. Curtis et al.
(1961) estimated that the risk of recurrence in subsequently born
children is 4% if one child has it, 4% if one parent has it, 17% if one
parent and one child have it, and 9% if two children have it. The
syndrome of cleft lip with or without cleft palate in association with
mucous pits of the lower lip is inherited as an autosomal dominant
(119300). Carter et al. (1982) followed up on the families of cases of
cleft lip, with or without cleft palate, operated on at The Hospital for
Sick Children ('Great Ormond St.'), London, between 1920 and 1939, to
obtain information on the proportion affected of children and
grandchildren. The probands were those who had survived, were
successfully traced, and found to have had at least 1 child. Patients of
the 1920-1939 period traced through a child, either normal or affected,
were excluded, as were patients with recognized syndromes. The
proportion affected of children of probands was 3.15%, of sibs 2.79%,
and of parents 1.18%. The lower proportion of parents affected was
attributed to reduced reproductive fitness of patients born 2
generations ago. The proportion affected of nephews and nieces, aunts
and uncles, and grandchildren was 0.47%, 0.59% and 0.8%, respectively.
The proportion affected of first cousins was 0.27%. The birth frequency
in England was estimated to be about 0.1%. The proportion of sibs
affected increased with increasing severity of the malformation in the
proband, when the proband was female, and when the proband had an
affected parent or already had 1 affected sib. Carter et al. (1982)
concluded that the most economical explanation of the findings is the
multifactorial threshold model and that a single mutant gene in
unlikely. Chung et al. (1986) analyzed the genetics of cleft lip with or
without cleft palate (CL/P), on a comparative basis, in the Danish
(Bixler et al., 1971; Melnick et al., 1980) and Japanese (Koguchi, 1975)
data. Japanese are known to have a higher population incidence of CL/P
and yet a lower recurrence risk among relatives than is true in
Caucasian populations. Chung et al. (1986) concluded that the Danish
data is best explained by a combination of major gene action and
multifactorial inheritance. The major gene was thought to be recessive
with a frequency of 0.035. Heritability was estimated as 0.97. On the
contrary, the Japanese data could best be accounted for only by
multifactorial inheritance with the heritability estimate of 0.77.
Following previous studies suggesting that symmetry for certain
bilaterally represented features may be an indicator of genetic
predisposition to cleft lip with or without cleft palate, Crawford and
Sofaer (1987) devised an asymmetry score which correctly classified 85%
of familial cleft patients and unrelated noncleft controls. Applying the
same stepwise logistic regression to sporadic cases, 26% fell into the
range occupied by the majority of familial patients, suggesting that
these had a high level of genetic predisposition. In West Bengal, India,
Ray et al. (1993) ascertained 90 extended families having one or more
individuals affected with CL/P. They concluded that the hypothesis of
major-locus inheritance alone could not be rejected. Among major-locus
models examined, strictly recessive inheritance was rejected, but
codominant and dominant models were not. Neither the addition of a
multifactorial component nor the addition of a proportion of sporadic
cases to the major-locus model improved the fit of the data.

Ardinger et al. (1989) observed a significant association between 2
RFLPs at the transforming growth factor alpha (190170) locus and the
occurrence of clefting. The authors suggested that either the TGFA gene
or DNA sequences adjacent to the locus contribute to the development of
some cases of cleft lip with or without cleft palate in humans. However,
in a study of 7 families with CL/P segregating in a dominant manner, the
TGFA haplotype associations reported by Ardinger et al. (1989) were not
seen, and in 1 family clefting did not cosegregate with TGFA, thus
ruling out tight linkage (Hecht et al., 1990, 1991). On the other hand,
Chenevix-Trench et al. (1991) confirmed the existence of an excess
frequency of the same TaqI allele found by Ardinger et al. (1989).
Vintiner et al. (1992) studied 8 families with cleft lip with or without
cleft palate inherited in an apparently autosomal dominant manner and
excluded linkage with TGFA. In a study of 3 RFLPs at the TGFA locus in
60 unrelated British Caucasian subjects with nonsyndromic cleft
lip/palate and 60 controls, Holder et al. (1992) found a highly
significant association between the TaqI RFLP and the occurrence of
clefting, and no significant association with the other 2 RFLPs.
Chenevix-Trench et al. (1992) extended their analysis of the TGFA TaqI
RFLP to 2 other TGFA RFLPs and 7 other RFLPs at 5 candidate genes.
Significant associations with the TGFA TaqI and BamHI RFLPs were
confirmed. Of particular interest, in view of the known teratogenic role
of retinoic acid, was a significant association with a PstI RFLP of RARA
(180240) (P = 0.016, not corrected for multiple testing). The effect on
risk of the A2 allele appeared to be additive; although the A2A2
homozygote only has an odds ratio of about 2 and recurrence risk to
first-degree relatives of 1.06, because it is so common, it may account
for as much as a third of the attributable risk of clefting. There was
no evidence of interaction between the TGFA and RARA polymorphisms on
risk, but jointly they appeared to account for almost half the
attributable risk of clefting. Sassani et al. (1993) and Shiang et al.
(1993) likewise found a significant association between TGFA alleles and
CL/P. Sequence analysis of the variants disclosed a cluster of 3
variable sites within 30 bp of each other in the 3-prime untranslated
region previously associated with an antisense transcript in the TGFA
gene (Shiang et al., 1993). Farrall et al. (1993) attempted to resolve
the apparent paradox concerning the role of TGFA in CL/P: the very
strong support from population-based studies for TGFA as a
susceptibility locus but the seeming exclusion of TGFA as a candidate
locus by linkage studies in a series of multiplex CL/P families (Hecht
et al., 1991).

Studies to determine whether women who smoke during early pregnancy are
at increased risk of delivering infants with orofacial clefts have
yielded conflicting results. In part, the inconclusive or contradictory
findings result from inadequate study design. Using a large
population-based case-control study, Shaw et al. (1996) investigated
whether parental peri-conceptional cigarette smoking was associated with
an increased risk for having offspring with orofacial clefts. They also
investigated the influence of genetic variation at the TGFA locus on the
relation between smoking and clefting. They found that risks associated
with maternal smoking were most elevated for isolated cleft lip with or
without cleft palate and for isolated cleft palate when mothers smoked
20 or more cigarettes/day. Analyses controlling for the potential
influence of other variables did not reveal substantially different
results. Clefting risks were even greater for infants with the TGFA
allele previously associated with clefting whose mothers smoked 20 or
more cigarettes/d. These risks for white infants ranged from 3-fold to
11-fold across phenotypic groups. Paternal smoking was not associated
with clefting among the offspring of nonsmoking mothers, and passive
smoke exposures were associated with at most slightly increased risks.
Shaw et al. (1996) concluded that this is an example of gene-environment
interaction in the occurrence of orofacial clefting.

Eiberg et al. (1987) selected 58 pedigrees with nonsyndromic orofacial
cleft from among a comprehensive collection of Danish cases for
suggestiveness of autosomal dominant inheritance. Linkage with 42
non-DNA polymorphic marker systems was investigated. Both cleft lip with
or without cleft palate and cleft palate alone were, for the purpose of
linkage analysis, scored as if being due to an autosomal dominant gene
with complete penetrance. Linkage was found with clotting factor XIIIA
(134570); for males alone, the maximal lod score was 3.40 at theta =
0.00; for females alone, 0.30 at theta = 0.21; and for these combined,
3.66 at theta = 0.00 for males, and theta = 0.26 for females. The
findings were taken to suggest that since F13A is located on the distal
portion of 6p, a major locus for nonsyndromic orofacial cleft is also
located in this region. Since both cleft lip with or without cleft
palate and isolated cleft palate pedigrees contributed to the positive
score, it is possible that the locus on 6p carries 2 cleft alleles. In a
study of 12 autosomal dominant families with nonsyndromic cleft lip with
or without cleft palate, Hecht et al. (1993) excluded linkage with HLA
and F13A. Multipoint analysis showed no evidence of a clefting locus in
a region spanning 54 cM on 6p in these CL/P families.

Using 13 microsatellite markers specific for 4q in a study of 7 of 8
persons with CL/P in a 5-generation family, Beiraghi et al. (1994) found
evidence of linkage between the phenotype and 2 markers, D4S175 (maximum
lod = 2.27 at theta = 0) and D4S192 (maximum lod = 1.93 at theta = 0).
No linkage with markers on chromosome 6 was found in this family.

Temple et al. (1989) described cleft lip and palate in 3 generations of
each of 2 families; in 1 family, there was an instance of male-to-male
transmission. Hecht (1990) presented the pedigrees of 11 families with
multigenerational involvement of cleft lip and palate. One family had
affected persons in 3 successive generations. Hecht et al. (1991)
performed complex segregation analysis of nonsyndromic cleft lip with or
without cleft palate in 79 families ascertained through a proband
diagnosed at the Mayo clinic. In one analysis, the dominant or
codominant mendelian major locus models of inheritance provided the most
parsimonious fit. In another, the multifactorial threshold model and the
mixed model were also consistent with the data. However, the high
heritability (0.93) in the multifactorial threshold model suggested that
any random exogenous factors were unlikely to be the underlying
mechanism, and the mixed model indicated that this high heritability was
accounted for by a major dominant locus component. Thus, the best
explanation for the findings of the study was a putative major locus
associated with markedly decreased penetrance. In a reanalysis of
recurrence patterns from several family studies of CL/P, Mitchell and
Risch (1992) found that the recurrence patterns in first-degree
relatives were compatible with expectations for either a multifactorial
threshold trait or a generalized (precise mode of inheritance
unspecified) single-major-locus trait. The use of multiple thresholds
based on proband sex, defect bilaterality, or palate involvement did not
help to discriminate between these models. They concluded, however, that
the pattern of recurrence among MZ twins and more remote relatives is
not consistent with the single-major-locus inheritance but is compatible
with either a multifactorial threshold model or a model specifying
multiple interacting loci. For such a model, no single locus could
account for more than a 6-fold increase in risk to first-degree
relatives. Between 1980 and 1987 in Shanghai, the birth incidence of
nonsyndromic CL/P was 1.11/1,000, with a male/female ratio of 1.42
(Marazita et al., 1992). Marazita et al. (1992) analyzed family data
from almost 2,000 probands ascertained from among individuals operated
on during the years 1956-1983 at surgical hospitals in Shanghai. They
rejected the hypothesis of no familial transmission and of
multifactorial inheritance alone. Of the major locus models, the
autosomal recessive was significantly more likely. They concluded that
the best-fitting, most parsimonious model for CL/P in Shanghai is that
of an autosomal recessive major locus. By linkage studies, Hecht et al.
(1992) excluded the region of chromosome 1q which carries the lip-pit
syndrome (van der Woude syndrome; VWS; 119300) as the site of the
mutation in this disorder and in isolated cleft palate.

Several studies had demonstrated an association between facial shape in
parents and the presence of oral clefts in their offspring. It was
assumed that facial shape was one predisposing component among many in a
multifactorial model of inheritance. By cephalometric analysis of a
large family with 5 generations of affected individuals, Ward et al.
(1994) concluded that facial shape can be used to identify presumed
carriers of a major gene associated with an increased risk for oral
clefts. Discriminant function analysis indicated that at-risk
individuals could be recognized through a combination of increased
midfacial and nasal cavity widths, reduced facial height, and a flat
facial profile. The use of this approach in providing critical
information needed in the search for molecular markers that segregate
with the genetic risk for clefting was emphasized.

Davies et al. (1995) used YAC clones from contigs in 6p25-p23 to
investigate 3 unrelated patients with cleft lip/palate who showed
abnormalities of 6p. Case 1 had bilateral cleft lip and palate, and a
balanced translocation reported as 46,XY,t(6,7)(p23;q36.1). Case 2 had
multiple anomalies, including cleft lip and palate and was reported as
46,XX,del(6)(p23;pter). Case 3 had bilateral cleft lip and palate and
carried a balanced translocation reported as t(6;9)(p23;q22.3). Davies
et al. (1995) identified 2 YAC clones, both of which crossed the
breakpoint in cases 1 and 3 and were deleted in case 2. These clones
mapped to 6p24.3 and, therefore, suggested the presence of a locus for
orofacial clefting in that region.

It is noteworthy that there is some homology of synteny between human 6p
and mouse chromosome 13. Furthermore, Wakasugi et al. (1988)
demonstrated an autosomal dominant mutation of facial development in a
transgenic mouse. The facial malformation was characterized by a short
snout and a twisted upper jaw. The malformation of the nasal and
premaxillary bone was considered to be secondary to a developmental
defect in the first branchial arch. In the attempt to establish a mouse
model of familial amyloid polyneuropathy, they microinjected the cloned
human mutant transthyretin gene (176300) into fertilized eggs. They
demonstrated that the insertion occurred in chromosome 13 of the mouse.
These results were thought to indicate that the malformation was due to
the insertional disruption of a host gene; however, the possibility that
this mutation was caused by an inappropriate expression of the injected
gene remained to be investigated.

Stein et al. (1995) tested linkage of 22 candidate genes to CL/P in 11
multigenerational families, and excluded 21 of these candidates. APOC2
(207750), which is located at 19q13.1 (or 19q13.2) and which is linked
to the proto-oncogene BCL3 (109560), gave suggestive evidence for
linkage to CL/P. The study was expanded to include a total of 39
multigenerational CL/P families. Linkage was tested in all the families,
using an anonymous marker, D19S178, and intragenic markers in BCL3 and
APOC2. Linkage was tested under 2 models, autosomal dominant with
reduced penetrance and affecteds only. Homogeneity testing on the
2-point data gave evidence of heterogeneity at APOC2 under the
affecteds-only model. Both models showed evidence of heterogeneity, with
43% of families linked at zero recombination to BCL3 when marker data
from BCL3 and APOC2 were included. A maximum multipoint lod score of
7.00 at BCL3 was found among the 17 families that had posterior
probabilities greater than 50% in favor of linkage. The transmission
disequilibrium test provided additional evidence for linkage with 3
alleles of BCL3 more often transmitted to affected children. The results
were interpreted as suggesting that BCL3, or a nearby gene, plays a role
in the etiology of CL/P in some families.

Wyszynski et al. (1997) pursued the question raised by the suggestion
that BCL3 on 19q, or a nearby gene, may play a role in the etiology of
nonsyndromic cleft lip with or without cleft palate in some families.
They tested 30 U.S. and 11 Mexican multiplex families for 4 markers on
19q. While likelihood-based linkage analysis failed to show significant
evidence of linkage, the transmission disequilibrium test indicated
highly significant deviation from independent assortment of allele 3 at
the BCL3 marker in both data sets and for allele 13 of the D19S178
marker in the Mexican data set. These results supported an association,
possibly due to linkage disequilibrium, between chromosome 19 markers
and a putative CL/P locus.

The division of clefts of the face into those that include the secondary
palate only (the posterior or soft palate) or cleft palate only, and
those that involve the primary palate and encompass clefts of the lip
with or without the palate is valid, not only on genetic grounds, but
also on embryologic grounds, since the primary and secondary palates
form independently. Only in the van der Woude syndrome (119300) is a
mixing of embryologic and genetic types, i.e., cleft palate only in some
individuals and cleft lip with or without cleft palate in others, seen
with any frequency (Burdick et al., 1985). Murray (1995) reviewed the
genetic and exogenous factors in the causation of facial clefts that
have been demonstrated or suspected. He concluded that 'the strongest
evidence implicates a primary gene on 6p and a role of transforming
growth factor alpha as a modifier of clefting status.'

Mitchell and Christensen (1996) linked data from 2 centralized data
repositories in Denmark, the Danish Central Person Registry and the
Danish Facial Cleft Database, and estimated the risks to first, second,
and third-degree relatives of 3,073 CL/P probands born in Denmark from
1952 to 1987. Analyses of these data excluded single locus and additive
multilocus inheritance and provided evidence that CL/P is most likely
determined by the effects of multiple interacting loci. Under a
multiplicative model, no single locus could account for more than a
3-fold increase in risk to first-degree relatives. These data provided
further evidence that nonparametric linkage methods, for example,
affected relative pair studies, are likely to represent a more realistic
approach for identifying CL/P susceptibility loci, than are traditional
pedigree-based methods. However, at least 100 and, more realistically,
several hundred affected sibpairs are likely to be required to detect
linkage to CL/P susceptibility loci.

Amos et al. (1996) provided data supporting linkage and association
between chromosome 19 markers in the vicinity of BCL3 and orofacial
cleft. They also presented the TDT reanalysis of all the affected
individuals from the study of Stein et al. (1995) because they had
detected an error in the program used for the transmission
disequilibrium test (Amos et al. (1996)).

*FIELD* SA
Cohen  (1978); Eiberg et al. (1987); Hecht et al. (1991); Lynch and
Kimberling (1981); Shields et al. (1979); Van Dyke et al. (1980)
*FIELD* RF
1. Amos, C.; Gasser, D.; Hecht, J. T.: Nonsyndromic cleft lip with
or without cleft palate: new BCL3 information. (Letter) Am. J. Hum.
Genet. 59: 743-744, 1996.

2. Amos, C.; Stein, J.; Mulliken, J. B.; Stal, S.; Malcolm, S.; Winter,
R.; Blanton, S. H.; Seemanova, E.; Gasser, D. L.; Hecht, J. T.: Nonsyndromic
cleft lip with or without cleft palate: Erratum. (Letter) Am. J.
Hum. Genet. 59: 744 only, 1996.

3. Ardinger, H. H.; Buetow, K. H.; Bell, G. I.; Bardach, J.; VanDemark,
D. R.; Murray, J. C.: Association of genetic variation of the transforming
growth factor-alpha gene with cleft lip and palate. Am. J. Hum. Genet. 45:
348-353, 1989.

4. Beiraghi, S.; Foroud, T.; Diouhy, S.; Bixler, D.; Conneally, P.
M.; Delozier-Blanchet, D.; Hodes, M. E.: Possible localization of
a major gene for cleft lip and palate to 4q. Clin. Genet. 46: 255-256,
1994.

5. Bixler, D.; Fogh-Andersen, P.; Conneally, P. M.: Incidences of
cleft lip and palate in offspring of cleft parents. Clin. Genet. 6:
83-97, 1971.

6. Burdick, A. B.; Bixler, D.; Puckett, C. L.: Genetic analysis in
families with van der Woude syndrome. J. Craniofac. Genet. Dev. Biol. 5:
181-208, 1985.

7. Carter, C. O.; Evans, K.; Coffey, R.; Roberts, J. A. F.; Buck,
A.; Roberts, M. F.: A three generation family study of cleft lip
with or without cleft palate. J. Med. Genet. 19: 246-261, 1982.

8. Chenevix-Trench, G.; Jones, K.; Green, A.; Martin, N.: Further
evidence for an association between genetic variation in transforming
growth factor alpha and cleft lip and palate. (Letter) Am. J. Hum.
Genet. 48: 1012-1013, 1991.

9. Chenevix-Trench, G.; Jones, K.; Green, A. C.; Duffy, D. L.; Martin,
N. G.: Cleft lip with or without cleft palate: associations with
transforming growth factor alpha and retinoic acid receptor loci. Am.
J. Hum. Genet. 51: 1377-1385, 1992.

10. Chung, C. S.; Bixler, D.; Watanabe, T.; Koguchi, H.; Fogh-Andersen,
P.: Segregation analysis of cleft lip with or without cleft palate:
a comparison of Danish and Japanese data. Am. J. Hum. Genet. 39:
603-611, 1986.

11. Cohen, M. M., Jr.: Syndromes with cleft lip and cleft palate. Cleft
Palate J. 15: 306-328, 1978.

12. Crawford, F. C.; Sofaer, J. A.: Cleft lip with or without cleft
palate: identification of sporadic cases with a high level of genetic
predisposition. J. Med. Genet. 24: 163-169, 1987.

13. Curtis, E. J.; Fraser, F. C.; Warburton, D.: Congenital cleft
lip and palate. Am. J. Dis. Child. 102: 853-857, 1961.

14. Davies, A. F.; Stephens, R. J.; Olavesen, M. G.; Heather, L.;
Dixon, M. J.; Magee, A.; Flinter, F.; Ragoussis, J.: Evidence of
a locus for orofacial clefting on human chromosome 6p24 and STS content
map of the region. Hum. Molec. Genet. 4: 121-128, 1995.

15. Eiberg, H.; Bixler, D.; Nielsen, L. S.; Conneally, P. M.; Mohr,
J.: Suggestion of linkage of a major locus for nonsyndromic orofacial
cleft with F13A and tentative assignment to chromosome 6. Clin. Genet. 32:
129-132, 1987.

16. Eiberg, H.; Bixler, D.; Nielsen, L. S.; Conneally, P. M.; Mohr,
J.: Suggestion of linkage of a major locus for nonsyndromic orofacial
cleft with F13A, and tentative assignment to chromosome 6. (Abstract) Cytogenet.
Cell Genet. 46: 609, 1987.

17. Farrall, M.; Buetow, K. H.; Murray, J. C.: Resolving an apparent
paradox concerning the role of TGFA in CL/P. (Letter) Am. J. Hum.
Genet. 52: 434-436, 1993.

18. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.
1982.

19. Hecht, J. T.: Dominantly inherited cleft lip and palate. (Letter) J.
Med. Genet. 27: 597, 1990.

20. Hecht, J. T.; Wang, Y.; Blanton, S. H.; Daiger, S. P.: Van der
Woude syndrome and nonsyndromic cleft lip and palate. (Letter) Am.
J. Hum. Genet. 51: 442-444, 1992.

21. Hecht, J. T.; Wang, Y.; Blanton, S. H.; Daiger, S. P.; Michels,
V. V.: Nonsyndromic cleft lip with or without cleft palate: no evidence
of linkage to transforming growth factor alpha. (Abstract) Am. J.
Hum. Genet. 47: A220, 1990.

22. Hecht, J. T.; Wang, Y.; Blanton, S. H.; Michels, V. V.; Daiger,
S. P.: Cleft lip and palate: no evidence of linkage to transforming
growth factor alpha. Am. J. Hum. Genet. 49: 682-686, 1991.

23. Hecht, J. T.; Wang, Y.; Connor, B.; Blanton, S. H.; Daiger, S.
P.: Nonsyndromic cleft lip and palate: no evidence of linkage to
HLA or factor 13A. Am. J. Hum. Genet. 52: 1230-1233, 1993.

24. Hecht, J. T.; Yang, P.; Michels, V. V.; Buetow, K. H.: Complex
segregation analysis of nonsyndromic cleft lip and palate. Am. J.
Hum. Genet. 49: 674-681, 1991.

25. Holder, S. E.; Vintiner, G. M.; Farren, B.; Malcolm, S.; Winter,
R. M.: Confirmation of an association between RFLPs at the transforming
growth factor-alpha locus and non-syndromic cleft lip and palate. J.
Med. Genet. 29: 390-392, 1992.

26. Koguchi, H.: Recurrence rate in offspring and siblings of patients
with cleft lip and/or cleft palate. Jpn. J. Hum. Genet. 20: 207-221,
1975.

27. Lynch, H. T.; Kimberling, W. J.: Genetic counseling in cleft
lip and cleft palate. Plast. Reconst. Surg. 68: 800-815, 1981.

28. Marazita, M. L.; Hu, D.-N.; Spence, M. A.; Liu, Y.-E.; Melnick,
M.: Cleft lip with or without cleft palate in Shanghai, China: evidence
for an autosomal major locus. Am. J. Hum. Genet. 51: 648-653, 1992.

29. Melnick, M.; Bixler, D.; Fogh-Andersen, P.; Conneally, P. M.:
Cleft lip +/- cleft palate: an overview of the literature and an analysis
of Danish cases born between 1941 and 1968. Am. J. Med. Genet. 6:
83-97, 1980.

30. Mitchell, L. E.; Christensen, K.: Analysis of the recurrence
patterns for nonsyndromic cleft lip with or without cleft palate in
the families of 3,073 Danish probands. Am. J. Med. Genet. 61: 371-376,
1996.

31. Mitchell, L. E.; Risch, N.: Mode of inheritance of nonsyndromic
cleft lip with or without cleft palate: a reanalysis. Am. J. Hum.
Genet. 51: 323-332, 1992.

32. Murray, J. C.: Face facts: genes, environment, and clefts. (Editorial) Am.
J. Hum. Genet. 57: 227-232, 1995.

33. Ray, A. K.; Field, L. L.; Marazita, M. L.: Nonsyndromic cleft
lip with or without cleft palate in West Bengal, India: evidence for
an autosomal major locus. Am. J. Hum. Genet. 52: 1006-1011, 1993.

34. Sassani, R.; Bartlett, S. P.; Feng, H.; Goldner-Sauve, A.; Haq,
A. K.; Buetow, K. H.; Gasser, D. L.: Association between alleles
of the transforming growth factor-alpha locus and the occurrence of
cleft lip. Am. J. Med. Genet. 45: 565-569, 1993.

35. Shaw, G. M.; Wasserman, C. R.; Lammer, E. J.; O'Malley, C. D.;
Murray, J. C.; Basart, A. M.; Tolarova, M. M.: Orofacial clefts,
parental cigarette smoking, and transforming growth factor-alpha gene
variants. Am. J. Hum. Genet. 58: 551-561, 1996.

36. Shiang, R.; Lidral, A. C.; Ardinger, H. H.; Buetow, K. H.; Romitti,
P. A.; Munger, R. G.; Murray, J. C.: Association of transforming
growth-factor alpha gene polymorphisms with nonsyndromic cleft palate
only (CPO). Am. J. Hum. Genet. 53: 836-843, 1993.

37. Shields, E. D.; Bixler, D.; Fogh-Andersen, P.: Facial clefts
in Danish twins. Cleft Palate J. 16: 1-6, 1979.

38. Stein, J.; Mulliken, J. B.; Stal, S.; Gasser, D. L.; Malcolm,
S.; Winter, R.; Blanton, S. H.; Amos, C.; Seemanova, E.; Hecht, J.
T.: Nonsyndromic cleft lip with or without cleft palate: evidence
of linkage to BCL3 in 17 multigenerational families. Am. J. Hum.
Genet. 57: 257-272, 1995.

39. Temple, K.; Calvert, M.; Plint, D.; Thompson, E.; Pembrey, M.
: Dominantly inherited cleft lip and palate in two families. J. Med.
Genet. 26: 386-389, 1989.

40. Van Dyke, D. C.; Goldman, A. S.; Spielman, R. S.; Zmijewski, C.
M.; Oka, S. W.: Segregation of HLA in sibs with cleft lip or cleft
lip and palate: evidence against genetic linkage. Cleft Palate J. 17:
189-193, 1980.

41. Vintiner, G. M.; Holder, S. E.; Winter, R. M.; Malcolm, S.: No
evidence of linkage between the transforming growth factor-alpha gene
in families with apparently autosomal dominant inheritance of cleft
lip and palate. J. Med. Genet. 29: 393-397, 1992.

42. Wakasugi, S.; Iwanaga, T.; Inomoto, T.; Tengan, T.; Maeda, S.;
Uehira, M.; Araki, K.; Miyazaki, J.; Eto, K.; Shimada, K.; Yamamura,
K.: An autosomal dominant mutation of facial development in a transgenic
mouse. Develop. Genet. 9: 203-212, 1988.

43. Ward, R. E.; Bixler, D.; Jamison, P. L.: Cephalometric evidence
for a dominantly inherited predisposition to cleft lip-cleft palate
in a single large kindred. Am. J. Med. Genet. 50: 57-63, 1994.

44. Wyszynski, D. F.; Maestri, N.; McIntosh, I.; Smith, E. A.; Lewanda,
A. F.; Garcia-Delgado, C.; Vinageras-Guarneros, E.; Wulfsberg, E.;
Beaty, T. H.: Evidence for an association between markers on chromosome
19q and non-syndromic cleft lip with or without cleft palate in two
groups of multiplex families. Hum. Genet. 99: 22-26, 1997.

*FIELD* CS

Mouth:
   Nonsyndromic cleft lip with or without cleft palate

Inheritance:
   Autosomal dominant form (? 6p);
   usually multifactorial

*FIELD* CN
Iosif W. Lurie - updated: 9/9/1996

*FIELD* CD
Victor A. McKusick: 8/12/1987

*FIELD* ED
terry: 12/26/1996
terry: 11/13/1996
terry: 10/9/1996
randy: 9/9/1996
mark: 3/6/1996
terry: 3/5/1996
mark: 2/26/1996
terry: 2/20/1996
mark: 8/29/1995
carol: 2/6/1995
mimadm: 6/25/1994
terry: 5/13/1994
warfield: 4/7/1994
pfoster: 4/4/1994

*RECORD*
*FIELD* NO
119540
*FIELD* TI
119540 CLEFT PALATE; CP
PALATE, CLEFT, ISOLATED
*FIELD* TX
Cleft palate as an isolated malformation behaves as an entity distinct
from cleft lip with or without cleft palate. Curtis et al. (1961)
estimated that the risk of recurrence in subsequently born children is
about 2% if 1 child has it, 6% if 1 parent has it, and 15% if 1 parent
and 1 child have it. As for cleft lip with or without cleft palate, as
well as many other relatively frequent congenital malformations, the
genetics is apparently complex. Shields et al. (1981) analyzed family
data on 561 Danish probands with nonsyndromic isolated cleft palate and
concluded that neither a multifactorial-threshold model nor a single
major locus model is completely compatible with the distribution of
cases. They proposed the existence of 2 classes of nonsyndromic cleft
palate: (1) familial CP, which appears to have an autosomal dominant
component to its etiology, and (2) nonfamilial CP, which, by
demonstrating an increasing frequency of CP with time and a maternal age
effect, appears to be related to environmental factors. Carter et al.
(1982) reported the findings in a large series of patients who had been
treated surgically for nonsyndromic cleft palate between 1920 and 1939.
The probands for the family study were 167 who could be traced and who
had had children. Of their 384 children, 11 had cleft palate (2.9%); of
their 398 sibs, 5 had cleft palate; of their 117 grandchildren, 1 was
affected and of their 517 nephews and nieces, 1 was affected. The
authors suggested that the etiology is probably heterogeneous with some
families showing modified dominant inheritance. In studies of 15
sibships with 2 or more sibs with isolated cleft palate, Van Dyke et al.
(1983) could demonstrate no close linkage with HLA. Dominantly inherited
cleft soft palate in 4 generations has been reported (Jenkins and Stady,
1980); see 119570. Also see 303400 for X-linked cleft palate.
Christensen et al. (1992) found that in the Danish population surgical
files provided more than 95% ascertainment for cleft lip (with or
without cleft palate) without associated malformations/syndromes
(119530). However, surgical files were a poor source for studying
isolated cleft palate and could not be used to study the prevalence of
associated malformations or syndromes. The male:female ratio was 0.88 in
surgically treated cases of CP, but was 1.5 in nonoperated CP cases,
making the overall sex ratio for CP 1.1 (95% confidence limits
0.86-1.4). The sex ratio for CP without associated malformations was 1.1
with similar confidence limits. One of the major criteria in CP
multifactorial threshold models, namely, higher CP liability among male
CP relatives, must be reconsidered if other studies confirm that a CP
sex-ratio reversal to male predominance occurs when high ascertainment
is achieved.

The transforming growth-factor alpha (190170) has been implicated as a
susceptibility locus for nonsyndromic cleft lip with or without cleft
palate (119530). Shiang et al. (1993) and Hwang et al. (1995) suggested
that it may also play a role in the etiology of nonsyndromic CP.
Christensen and Mitchell (1996) estimated the prevalence of nonsyndromic
CP in Denmark, obtained estimates of the risks to first-, second-, and
third-degree relatives, and analyzed the data for mode of inheritance. A
total of 2,301 CP cases were born in Denmark during 1936-87; 1,952
(84.8%) of these cases were nonsyndromic. This corresponded to a point
prevalence of 5.1 nonsyndromic CP cases/10,000 live births. The
corresponding figure for the period 1952-87 was 5.8/10,000 live births.
The recurrence risks for the 3 classes of relatives of 1,364
nonsyndromic CP probands was 2.74%, 0.28%, and 0.00%, respectively.
Analyses of these data were considered consistent with CP being
determined by several interacting loci.

*FIELD* SA
Shields et al. (1979)
*FIELD* RF
1. Carter, C. O.; Evans, K.; Coffey, R.; Roberts, J. A. F.; Buck,
A.; Roberts, M. F.: A family study of isolated cleft palate. J.
Med. Genet. 19: 329-331, 1982.

2. Christensen, K.; Holm, N. V.; Olsen, J.; Kock, K.; Fogh-Andersen,
P.: Selection bias in genetic-epidemiological studies of cleft lip
and palate. Am. J. Hum. Genet. 51: 654-659, 1992.

3. Christensen, K.; Mitchell, L. E.: Familial recurrence-pattern
analysis of nonsyndromic isolated cleft palate: a Danish registry
study. Am. J. Hum. Genet. 58: 182-190, 1996.

4. Curtis, E. J.; Fraser, F. C.; Warburton, D.: Congenital cleft
lip and palate. Am. J. Dis. Child. 102: 853-857, 1961.

5. Hwang, S. J.; Beaty, T. H.; Panny, S. R.; Street, N. A.; Joseph,
J. M.; Gordon, S.; McIntosh, I.; Francomano, C. A.: Association study
of transforming growth factor alpha (TGF-alpha) TaqI polymorphism
and oral clefts: indication of gene-environment interaction in a population-based
sample of infants with birth defects. Am. J. Epidemiol. 141: 629-636,
1995.

6. Jenkins, M.; Stady, C.: Dominant inheritance of cleft of the soft
palate. Hum. Genet. 53: 341-342, 1980.

7. Shiang, R.; Lidral, A. C.; Ardinger, H. H.; Buetow, K. H.; Romitti,
P. A.; Munger, R. G.; Murray, J. C.: Association of transforming
growth-factor alpha gene polymorphisms with nonsyndromic cleft palate
only (CPO). Am. J. Hum. Genet. 53: 836-843, 1993.

8. Shields, E. D.; Bixler, D.; Fogh-Andersen, P.: Facial clefts in
Danish twins. Cleft Palate J. 16: 1-6, 1979.

9. Shields, E. D.; Bixler, D.; Fogh-Andersen, P.: Cleft palate: a
genetic and epidemiologic investigation. Clin. Genet. 20: 13-24,
1981.

10. Van Dyke, D. C.; Goldman, A. S.; Spielman, R. S.; Zmijewski, C.
M.: Segregation of HLA in families with oral clefts: evidence against
linkage between isolated cleft palate and HLA. Am. J. Med. Genet. 15:
85-88, 1983.

*FIELD* CS

Mouth:
   Isolated cleft palate

Inheritance:
   ? Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/06/1996
mark: 1/25/1996
terry: 1/23/1996
davew: 6/27/1994
mimadm: 6/25/1994
carol: 9/28/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
119550
*FIELD* TI
*119550 CLEFT PALATE-LATERAL SYNECHIA SYNDROME
CPLS SYNDROME
*FIELD* TX
Fuhrmann et al. (1972) described a new syndrome of cleft palate combined
with multiple cordlike adhesions between the free borders of the palate
and lateral parts of the tongue and floor of the mouth. The full
syndrome occurred in 5 persons, a sixth had cleft palate only, and an
unaffected male transmitted the disorder to 2 children with different
mothers. The disorder is distinct from the ankyloglosson superius
syndrome. Syngnathia congenita is characterized by atypical congenital
adhesions in the buccal cavity. Mouth opening is restricted by adhesions
between the mandibular and maxillary alveolar ridges. Gassner et al.
(1979) reported the disorder in mother and child. They suspected that
this is the same disorder as the CPLS syndrome. Gorlin (1982) saw the
syndrome in a father and son.

*FIELD* RF
1. Fuhrmann, W.; Koch, F.; Schweckendiek, W.: Autosomal dominante
Vererbung von Gaumenspalte und Synechien zwischen Gaumen und Mundboden
oder Zunge. Humangenetik 14: 196-203, 1972.

2. Gassner, I.; Muller, W.; Rossler, H.; Kofler, J.; Mitterstieler,
G.: Familial occurrence of syngnathia congenita syndrome. Clin.
Genet. 15: 241-244, 1979.

3. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.  1982.

*FIELD* CS

Mouth:
   Cleft palate;
   Lateral synechia;
   Cord-like adhesions between tongue and floor of mouth

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
warfield: 4/7/1994
supermim: 3/16/1992
carol: 2/28/1992
carol: 8/24/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
119570
*FIELD* TI
119570 CLEFT SOFT PALATE
*FIELD* TX
Jenkins and Stady (1980) described a family with simple cleft palate
(cleft of the soft palate) in 7 males of 5 sibships in 4 generations.

*FIELD* RF
1. Jenkins, M.; Stady, C.: Dominant inheritance of cleft of the soft
palate. Hum. Genet. 53: 341-342, 1980.

*FIELD* CS

Mouth:
   Cleft soft palate

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
119580
*FIELD* TI
119580 CLEFTING, ECTROPION, AND CONICAL TEETH
ECTROPION, INFERIOR, WITH CLEFT LIP AND/OR PALATE;;
ELSCHNIG SYNDROME;;
BLEPHARO-CHEILO-DONTIC SYNDROME
*FIELD* TX
Allanson and McGillivray (1985) reported a family in which many members
of 4 generations had a syndrome of cleft lip and/or palate, ectropion of
the lower eyelids with ocular hypertelorism, and conical teeth with
variable expression consistent with autosomal dominant inheritance. The
ectropion suggested Treacher Collins syndrome (154400). Gorlin et al.
(1976) noted that Zellweger had observed mother and son with clefting,
ectropion and limb reduction defects, and some 4 sporadic cases have
been reported.

An association of ectropion of the lower eyelids, hypertelorism and
cleft lip and palate was described by Elschnig (1912) although it is not
clear that Elschnig recognized the clinical constellation as a distinct
entity. Allanson and McGillivray (1985) reported a family in which many
members of 4 generations had a syndrome of cleft lip and/or palate,
ectropion of the lower eyelids with ocular hypertelorism, and conical
teeth with variable expression consistent with autosomal dominant
inheritance. The ectropion suggested Treacher Collins syndrome (154400).
Falace and Hall (1989) presented a 5 generation kindred, where out of 12
affected persons 8 had abnormal teeth, 4 had euryblepharon (eyelids with
abnormally wide lid opening), and 2 had clefts. Gorlin et al. (1996)
reported 2 mother-child pairs and 4 sporadic cases of this syndrome, one
of whom was first reported by Piper (1957). Among the patients reported
by Gorlin et al. (1996), ectropion of the lower lids and bilateral cleft
lip/palate were among the most common findings and distichiasis of the
upper eyelids a less common observation. Gorlin et al. (1996) proposed
the term blepharo-cheilo-dontic (BCD) syndrome for this autosomal
dominant condition, and suggested that affected persons reported by
Korula et al. (1995) actually had the same syndrome (600990). Similar
manifestations were found in a girl described by Martinez et al. (1987)
although she also had syndactyly.

*FIELD* RF
1. Allanson, J. E.; McGillivray, B. C.: Familial clefting syndrome
with ectropion and dental anomaly--without limb anomalies. Clin.
Genet. 27: 426-429, 1985.

2. Elschnig, A.: Zur Kenntnis der Anomalien der Lidspaltenform. Klin
Mbl Augenheilkd 50: 17-30, 1912.

3. Falace, P. B.; Hall, B. D.: Congenital euryblepharon with ectropion
and dental anomaly: An autosomal dominant clefting disorder with marked
variability of expression. Proc Greenwood Genet Ctr. 8: 208-209,
1989.

4. Gorlin, R. J.; Pindburg, J. J.; Cohen, M. M., Jr.: Syndromes of
the Head and Neck.  New York: McGraw-Hill (pub.)  1976.

5. Gorlin, R. J.; Zellweger, H.; Curtis, M. W.; Wiedemann, H.-R.;
Warburg, M.; Majewski, F.; Gillessen-Kaesbach, G.; Prahl-Andersen,
B.; Zackai, E.: Blepharo-Cheilo-Dontic (BCD) syndrome. Am. J. Med.
Genet. 65: 109-112, 1996.

6. Korula, S.; Wilson, L.; Salamonson, J.: Distinct craniofacial
syndrome of lagophthalmia and bilateral cleft lip and palate. Am.
J. Med. Genet. 59: 229-233, 1995.

7. Martinez, B. R.; Monasterio, L. A.; Pinheiro, M.; Freire-Maia,
N.: Cleft lip/palate-oligodontia-syndactyly-hair alterations, a new
syndrome: Review of the conditions combining ectodermal dysplasia
and cleft lip/palate. Am. J. Med. Genet. 27: 23-31, 1987.

8. Piper, H. F.: Augenartliche Befunde bei fruhkindlichen Entwicklungsstorungen. Mschr.
Kinderheilkd. 105: 170-176, 1957.

*FIELD* CS

Mouth:
   Cleft lip and/or palate

Eyes:
   Ectropion of lower eyelids;
   Ocular hypertelorism

Teeth:
   Conical teeth

Inheritance:
   Autosomal dominant

*FIELD* CN
Iosif W. Lurie - updated: 1/8/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/11/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
mimadm: 6/25/1994
warfield: 3/15/1994
carol: 10/21/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
119600
*FIELD* TI
*119600 CLEIDOCRANIAL DYSPLASIA; CCD
CLEIDOCRANIAL DYSOSTOSIS; CLCD
*FIELD* TX
Features include persistently open skull sutures with bulging calvaria,
hypoplasia or aplasia of the clavicles permitting abnormal facility in
apposing the shoulders, wide pubic symphysis, short middle phalanx of
the fifth fingers, dental anomalies, and often vertebral malformation.
One of the most colorful families was described by Jackson (1951). The
condition occurred in many descendants of a Chinese man named Arnold who
embraced the Mohammedan religion and 7 wives in South Africa. Jackson
(1951) was able to trace 356 descendants, of whom 70 were affected by
the 'Arnold head.' For translation of original description by Marie and
Sainton (1898), see Bick (1968). Ramesar et al. (1996) estimated that
more than 1000 descendants of the first progenitor now have the
disorder. The family with delayed eruption of deciduous and permanent
teeth reported by Arvystas (1976) probably had cleidocranial dysplasia.

Pycnodysostosis (265800) and mandibuloacral dysplasia (248370) are
disorders to be considered in the differential diagnosis of
cleidocranial dysplasia. Acroosteolysis and bone sclerosis with tendency
to fracture are differentiating features of pycnodysostosis. Dore et al.
(1987) described a 34-year-old woman with cleidocranial dysostosis and
scoliosis diagnosed at age 13 years. The scoliosis continued to progress
after skeletal maturation. Syringomyelia was diagnosed at the age of 34.
They pointed to reports of 2 previous patients with cleidocranial
dysostosis and syringomyelia and suggested that this association may be
a more common problem than generally recognized.

Sillence et al. (1987) proposed the gene symbol CCD for the mutation in
both mouse and man; this symbol has also been used for 'central core
disease' (117000). Jensen (1990) studied development in 7 males and 10
females, aged 5 to 46 years, with CCD; 11 were followed longitudinally.
Height and radius length were decreased, especially in females.
Longitudinal data showed growth retardation and slightly retarded
skeletal maturation throughout childhood. The metacarpophalangeal
pattern profile demonstrated great variation in bone length, presumably
resulting from extra epiphyses in metacarpals II and V and from multiple
cone-shaped epiphyses. Jensen (1990) concluded that CCD is a generalized
skeletal dysplasia. Chitayat et al. (1992) described the range of
variability in affected members in 3 generations of a family. The
propositus presented with respiratory distress due to a narrow thorax.
The clavicles were hypoplastic with discontinuity in the central
portions. A 17-year-old aunt of the proposita showed large fontanels and
multiple wormian bones as well as a wide symphysis pubis with hypoplasia
of the iliac bones. The 25-year-old mother of the proposita showed
typical hand abnormalities by x-ray: thin metacarpal and metatarsal
diaphyses of digits 2 to 5 and short middle phalanx of fingers 2 and 5.
The grandmother likewise showed wormian bones. On the basis of a review
of 13 patients, Reed and Houston (1993) concluded that underossification
of the hyoid bone can be added to the delayed ossification that affects
the skull, teeth, pelvis, and extremities in CCD.

Brueton et al. (1992) described 3 patients with features of
cleidocranial dysplasia associated with rearrangements of chromosome
8q22. Two were mother and daughter; the third was an unrelated infant.
Nienhaus et al. (1993) proposed that the gene may be located on either
the long arm or the short arm of chromosome 6. They observed a male
patient with a pericentric inversion of chromosome 6 and classic CCD
together with mild-to-moderate mental retardation, hearing deficiency,
and unusual facial appearance.

In 2 kindreds with typical features of CCD, Mundlos et al. (1995) used
the candidate gene approach to map the disorder to 6p. Linkage was
established between CCD and 4 loci--D6S426, D6S451, D6S459, and TCTE1
(186975)--that span a region of 10 cM on 6p. One highly polymorphic
microsatellite from this region, D6S459, showed allelic loss in all
affected members of 1 family with 2 different sets of primers. The
presence of a deletion in this area was confirmed by Southern blot
analysis using a probe derived from the amplification product of the
D6S459 marker. Thus, the CCD gene was assigned to 6p21. The observations
of Nienhaus et al. (1993) are consistent with the assignment to 6p. The
possibility of another locus on chromosome 8 is not completely excluded;
this could be an instance of genetic heterogeneity.

Feldman et al. (1995) performed linkage studies in 5 families with CCD,
including 24 affected and 20 unaffected individuals, using
microsatellite markers spanning 2 candidate regions on chromosomes 8q
and 6. The strongest support for linkage was with the 6p marker D6S282,
with a 2-point lod score of 4.84 at theta = 0.03. The multipoint lod
score was 5.70 for location in the 19-cM interval between D6S282 and
D6S291. Feldman et al. (1995) pointed out that the gene for bone
morphogenetic protein-6 (BMP6; 112266) is located on chromosome 6 and
that comparative mapping based on mouse-human homology (Copeland et al.,
1993) would place BMP6 on human 6p, thus making BMP6 a candidate gene
for CCD. Narahara et al. (1995) observed CCD in association with a
t(6;18)(p12;q24) translocation. Gelb et al. (1995) confirmed linkage of
CCD to 6p21. Based on their data and those described by Mundlos et al.
(1995), they further refined the localization of CCD to a 6-cM region of
6p21 that includes a microdeletion at D6S459. Ramesar et al. (1996)
investigated the original family from South Africa and also showed
linkage to 6p21.3-p21.1. The maximum lod score was 7.14 at theta = 0.00
with marker D6S459. Using their own and previous mapping data, they
refined the localization of the CCD gene to a 4- to 5-cM region between
D6S451 and D6S465.

Sillence et al. (1987) described cleidocranial dysplasia in mice. The
change was radiation-induced and inherited as an autosomal dominant with
variable expressivity but almost complete penetrance. The homozygous
state was lethal in utero. The features were variable clavicular
hypoplasia, delayed closure of cranial fontanelles and sutures, and
variable hypoplasia of pelvic bones, in particular, ischiopubic rami.
Selby et al. (1993) investigated the interactions between 2 unlinked
genes causing a semidominant skeletal dysplasia in mice: cleidocranial
dysplasia (Ccd) and 'short digits' (Dsh). Each mutant is a homozygous
lethal. The Ccd mutation was reported by Selby and Selby (1978). Selby
et al. (1993) found that mice who were heterozygous for both mutations
showed 7 different synergistic interactions, including one that yielded
an entirely new abnormality not predicted from any abnormalities found
in either of the single homozygotes. Although Selby et al. (1993) did
not expect to find antagonistic interactions, they in fact found 3 in
the double heterozygote. In all cases, the effects of Dsh were either
partly or completely suppressed by Ccd. A classic example of comb shape
in chickens in which interaction of 2 mutations at different loci led to
a completely new phenotype was cited.

In a discussion of genetic skeletal dysplasias in the Museum of
Pathological Anatomy in Vienna, Beighton et al. (1993) pictured the
skeleton of a 25-year-old man with cleidocranial dysplasia who died in
1909 of tuberculous pneumonia. The skeleton showed the characteristic
hypoplasia of the clavicles in association with a large, patent anterior
fontanel. Other minor features were bilateral genu valgum and slight
medial bowing of the tibia and fibula.

*FIELD* SA
Harris et al. (1977); Kalliala and Taskinen (1962); Lechelle et al.
(1936); Levin and Sonnenschein (1963)
*FIELD* RF
1. Arvystas, M. G.: Familial generalized delayed eruption of the
dentition with short stature. Oral Surg. 41: 235-243, 1976.

2. Beighton, P.; Sujansky, E.; Patzak, B.; Portele, K. A.: Genetic
skeletal dysplasias in the Museum of Pathological Anatomy, Vienna.
Am. J. Med. Genet. 47: 843-847, 1993.

3. Bick, E. M.: The classic: on hereditary cleido-cranial dysostosis
(transl.). Clin. Orthop. 58: 5-7, 1968.

4. Brueton, L. A.; Reeve, A.; Ellis, R.; Husband, P.; Thompson, E.
M.; Kingston, H. M.: Apparent cleidocranial dysplasia associated
with abnormalities of 8q22 in three individuals. Am. J. Med. Genet. 43:
612-618, 1992.

5. Chitayat, D.; Hodgkinson, K. A.; Azouz, E. M.: Intrafamilial variability
in cleidocranial dysplasia: a three generation family. Am. J. Med.
Genet. 42: 298-303, 1992.

6. Copeland, N. G.; Jenkins, N. A.; Gilbert, D. J.; Eppig, J. T.;
Maltais, L. J.; Miller, J. C.; Dietrich, W. F.; Weaver, A.; Lincoln,
S. E.; Steen, R. G.; Stein, L. D.; Nadeau, J. H.; Lander, E. S.:
A genetic linkage map of the mouse: current applications and future
prospects. Science 262: 57-66, 1993.

7. Dore, D. D.; MacEwen, G. D.; Boulos, M. I.: Cleidocranial dysostosis
and syringomyelia: review of the literature and case report. Clin.
Orthop. Rel. Res. 214: 229-234, 1987.

8. Feldman, G. J.; Robin, N. H.; Brueton, L. A.; Robertson, E.; Thompson,
E. M.; Siegel-Bartelt, J.; Gasser, D. L.; Bailey, L. C.; Zackai, E.
H.; Muenke, M.: A gene for cleidocranial dysplasia maps to the short
arm of chromosome 6. Am. J. Hum. Genet. 56: 938-943, 1995.

9. Gelb, B. D.; Cooper, E.; Shevell, M.; Desnick, R. J.: Genetic
mapping of the cleidocranial dysplasia (CCD) locus on chromosome band
6p21 to include a microdeletion. Am. J. Med. Genet. 58: 200-205,
1995.

10. Harris, R. J.; Gaston, G. W.; Avery, J. E.; McCuen, J. M.: Mandibular
prognathism and apertognathia associated with cleidocranial dysostosis
in a father and son. Oral Surg. 44: 830-836, 1977.

11. Jackson, W. P. U.: Osteo-dental dysplasia (cleido-cranial dysostosis).
The 'Arnold head.'. Acta Med. Scand. 139: 292-307, 1951.

12. Jensen, B. L.: Somatic development in cleidocranial dysplasia.
Am. J. Med. Genet. 35: 69-74, 1990.

13. Kalliala, E.; Taskinen, P. J.: Cleidocranial dysostosis: report
of six typical cases and one atypical case. Oral Surg. 15: 808-822,
1962.

14. Lechelle, P.; Thevenard, A.; Mignot, H.: Dysostose cleido-cranienne
avec malformations vertebrales multiples et troubles nerveux: caractere
familial des malformations. Bull. Mem. Soc. Med. Hop. Paris 52:
1526-1530, 1936.

15. Levin, E. J.; Sonnenschein, H.: Cleidocranial dysostosis. New
York J. Med. 63: 1562-1566, 1963.

16. Marie, P.; Sainton, P.: On hereditary cleido-cranial dysostosis.
Rev. Neurol. 6: 835 only, 1898.

17. Mundlos, S.; Mulliken, J. B.; Abramson, D. L.; Warman, M. L.;
Knoll, J. H. M.; Olsen, B. R.: Genetic mapping of cleidocranial dysplasia
and evidence of a microdeletion in one family. Hum. Molec. Genet. 4:
71-75, 1995.

18. Narahara, K.; Tsuji, K.; Yokoyama, Y.; Seino, Y.: Cleidocranial
dysplasia associated with a t(6;18)(p12;q24) translocation. (Letter) Am.
J. Med. Genet. 56: 119-120, 1995.

19. Nienhaus, H.; Mau, U.; Zang, K. D.; Henn, W.: Pericentric inversion
of chromosome 6 in a patient with cleidocranial dysplasia. Am. J.
Med. Genet. 46: 630-631, 1993.

20. Ramesar, R. S.; Greenberg, J.; Martin, R.; Goliath, R.; Bardien,
S.; Mundlos, S.; Beighton, P.: Mapping of the gene for cleidocranial
dyslasia in the historical Cape Town (Arnold) kindred and evidence
for locus homogeneity. J. Med. Genet. 33: 511-514, 1996.

21. Reed, M. H.; Houston, C. S.: Abnormal ossification of the hyoid
bone in cleidocranial dysplasia. Canad. Assoc. Radiol. J. 44: 277-279,
1993.

22. Selby, P. B.; Bolch, S. N.; Mierzejewski, V. S.; McKinley, T.
W., Jr.; Raymer, G. D.: Synergistic interactions between two skeletal
mutations in mice: individual and combined effects of the semidominants
cleidocranial dysplasia (Ccd) and short digits (Dsh). J. Hered. 84:
466-474, 1993.

23. Selby, P. B.; Selby, P. R.: Gamma-ray-induced dominant mutations
that cause skeletal abnormalities in mice. II. Description of proved
mutations. Mutat. Res. 51: 199-236, 1978.

24. Sillence, D. O.; Ritchie, H. E.; Selby, P. B.: Skeletal anomalies
in mice with cleidocranial dysplasia. Am. J. Med. Genet. 27: 75-85,
1987.

*FIELD* CS

Growth:
   Moderate short stature

Head:
   Brachycephaly;
   Arnold head

Facies:
   Midfacial hypoplasia

Mouth:
   Delayed eruption of deciduous teeth;
   Delayed eruption of permanent teeth;
   Supernumerary teeth

Spine:
   Spina bifida occulta;
   Wide sacroiliac joints

Thorax:
   Hypoplastic/aplastic clavicles;
   Abnormal facility in apposing the shoulders;
   Narrow thorax;
   Short ribs

Resp:
   Respiratory distress

Pelvis:
   Hypoplastic pubic bones;
   Wide pubic symphysis

Hips:
   Hypoplastic acetabulum;
   Hip dislocation

Limbs:
   Brachydactyly;
   Acrooseolysis

Joints:
   Joint laxity

Neuro:
   Syringomyelia

Radiology:
   Persistently open skull sutures with bulging calvaria;
   Short fifth finger middle phalanx;
   Thin metacarpal and metatarsal diaphyses of digits 2 to 5;
   Multiple cone-shaped epiphyses;
   Slightly retarded skeletal maturation throughout childhood

Inheritance:
   Autosomal dominant

*FIELD* CN
Iosif W. Lurie - updated: 06/26/1996

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
carol: 06/26/1996
mark: 9/13/1995
carol: 2/6/1995
pfoster: 8/18/1994
mimadm: 6/25/1994
carol: 8/30/1993
carol: 7/6/1992

*RECORD*
*FIELD* NO
119650
*FIELD* TI
119650 CLEIDORHIZOMELIC SYNDROME
*FIELD* TX
Wallis et al. (1988) reported the cases of a mother and son with an
inherited skeletal disorder manifested mainly by rhizomelic short
stature and lateral clavicular defects. The propositus, a 6-month-old
boy, had rhizomelic shortening, particularly in the arms, and
protuberances over the lateral aspects of the clavicles. On radiographs
the lateral third of the clavicles had a bifid appearance resulting from
an abnormal process or protuberance arising from the fusion center. The
22-year-old mother had a height of 142 cm with an arm span of 136 cm and
rhizomelic shortness of the limbs, maximal in the arms, and
abnormalities of the acromioclavicular joints. Both the mother and the
son had marked bilateral clinodactyly of the fifth fingers associated
with hypoplastic middle phalanx. Wallis et al. (1988) proposed the
designation 'cleidorhizomelic syndrome,' a mnemonically felicitous
choice.

*FIELD* RF
1. Wallis, C.; Zieff, S.; Goldblatt, J.: Newly recognized autosomal
dominant syndrome of rhizomelic shortness with clavicular defect.
Am. J. Med. Genet. 31: 881-885, 1988.

*FIELD* CS

Growth:
   Rhizomelic short stature

Thorax:
   Lateral clavicular defects

Joints:
   Abnormal acromioclavicular joints

Limbs:
   Fifth finger clinodactyly;
   Hypoplastic fifth finger middle phalanx

Radiology:
   Bifid lateral third of clavicles

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 1/13/1989

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 1/13/1989

*RECORD*
*FIELD* NO
119800
*FIELD* TI
119800 CLUBFOOT
TALIPES EQUINOVARUS
*FIELD* TX
Although genetic factors are clearly important, simple inheritance has
not been established. Palmer (1964) suggested that two types may exist:
(1) a group with normal sex ratio, normal maternal age curve, recurrence
risk of about 10% and probable dominant inheritance with about 40%
penetrance; and (2) a group born to younger mothers with preponderance
of males and no clear pattern of inheritance. Book (1948) had estimated
that the risk of recurrence in subsequently born children is between 3
and 8% if one child is affected and about 10% if one child and one
parent are affected. Clubfoot is a feature of diastrophic dwarfism
(222600). Wang et al. (1988) used updated data on clubfoot families
originally reported by Palmer (1964) and concluded that the segregation
pattern in these families is best explained by assuming the action of a
major gene with additional contribution of multifactorial inheritance.
The mixed model suggested that the major gene behaves largely as a
dominant.

*FIELD* SA
Alberman  (1965); Ching et al. (1969); Wynne-Davies  (1964)
*FIELD* RF
1. Alberman, E. D.: The causes of congenital club foot. Arch. Dis.
Child. 40: 548-554, 1965.

2. Book, J. A.: A contribution to the genetics of congenital clubfoot.
Hereditas 34: 289-300, 1948.

3. Ching, G. H. S.; Chung, C. S.; Nemechek, R. W.: Genetic and epidemiological
studies of clubfoot in Hawaii: ascertainment and incidence. Am.
J. Hum. Genet. 21: 566-580, 1969.

4. Palmer, R. M.: Hereditary clubfoot. Clin. Orthop. 33: 138-146,
1964.

5. Wang, J.; Palmer, R. M.; Chung, C. S.: The role of major gene
in clubfoot. Am. J. Hum. Genet. 42: 772-776, 1988.

6. Wynne-Davies, R.: Family studies and the cause of congenital club
foot: talipes equinovarus, talipes calcaneo-valgus and metatarsus
varus. J. Bone Joint Surg. 46B: 445-476, 1964.

*FIELD* CS

Skel:
   Club foot;
   Talipes equinovarus

Inheritance:
   Usually multifactorial or part of a syndrome;
   ? autosomal dominant with low penetrance

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
carol: 5/11/1988

*RECORD*
*FIELD* NO
119900
*FIELD* TI
*119900 CLUBBING OF DIGITS
*FIELD* TX
Familial clubbing may be more frequent in blacks than in whites. It is
uncertain whether familial clubbing is distinct from
pachydermoperiostosis (167100). Fischer et al. (1964) reported black
families that showed strong sex influence, with males only or
predominantly affected. A particularly striking example (P16329) of
clubbing in a black father and 2 sons without accompanying features of
pachydermoperiostosis leaves no doubt in my mind of the reality of this
entity.

*FIELD* SA
Bhate et al. (1978); Curth et al. (1961)
*FIELD* RF
1. Bhate, D. V.; Pizarro, A. J.; Greenfield, G. B.: Idiopathic hypertrophic
osteoarthropathy without pachyderma. Radiology 129: 379-381, 1978.

2. Curth, H. O.; Firschein, I. L.; Alpert, M.: Familial clubbed fingers.
Arch. Derm. 83: 828-836, 1961.

3. Fischer, D. S.; Singer, D. H.; Feldman, S. M.: Clubbing, a review,
with emphasis on hereditary acropachy. Medicine 43: 459-479, 1964.

*FIELD* CS

Skel:
   Clubbing;
   Acropachy

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 10/17/1986

*RECORD*
*FIELD* NO
119915
*FIELD* TI
119915 CLUSTER HEADACHE, FAMILIAL
*FIELD* TX
The classification for headache disorders of the International Headache
Society (1988) listed the following criteria for cluster headache: at
least 5 attacks of severe unilateral orbital, supraorbital, and/or
temporal pain, lasting 15 to 180 minutes, associated with at least 1 of
8 local autonomic signs, and occurring once every other day to 8 per
day. Spierings and Vincent (1992) described 3 males, an 8-year-old boy,
his father and his paternal grandfather, with seemingly typical cluster
headaches. The headaches responded to oxygen inhalation and to treatment
with verapamil but were not prevented by propranolol and amitriptyline,
which are effective medications in migraine. The 8-year-old boy suffered
from headaches from the age of 4 years. He had pain in the right eye
occurring 3 times a week, usually between 12:30 and 1:00 p.m., and
lasting 30 to 60 minutes. His father had onset at 37 years of age, with
headaches located around and behind the right eye lasting 30 to 90
minutes. They were associated with tearing of that eye and running of
the right nostril. The paternal grandfather had had 3 episodes of
headache, each occurring daily for 4 to 7 weeks, when he was 51, 58, and
67 years of age. They were located in the left eye and were associated
with tearing of that eye and running of the left nostril.

Russell et al. (1995) investigated the mode of inheritance of cluster
headache in 370 families in Denmark. Of the 370 probands, 25 had 36
relatives with cluster headache. The segregation analysis suggested to
the authors that cluster headache has an autosomal dominant gene with a
penetrance of 0.3. to 0.34 in males and 0.17 to 0.21 in females. The
gene was thought to be present in 3-4% of males and 7-10% of females
with cluster headache.

*FIELD* RF
1. International Headache Society: Classification and diagnostic
criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8:
1-96, 1988.

2. Russell, M. B.; Andersson, P. G.; Thomsen, L. L.; Iselius, L.:
Cluster headache is an autosomal dominantly inherited disorder in
some families: a complex segregation analysis. J. Clin. Genet. 32:
954-956, 1995.

3. Spierings, E. L. H.; Vincent, A. J. P. E.: Familial cluster headache:
occurrence in three generations. Neurology 42: 1399-1400, 1992.

*FIELD* CS

Neuro:
   Cluster headache;
   Attacks of severe unilateral orbital, supraorbital, and/or temporal
   pain;
   Local autonomic signs

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 9/9/1992

*FIELD* ED
mark: 03/26/1997
mark: 1/19/1996
mimadm: 6/25/1994
carol: 9/9/1992

*RECORD*
*FIELD* NO
120000
*FIELD* TI
120000 COARCTATION OF AORTA
*FIELD* TX
Gough (1961) described the anomaly in father and son. He found 6 other
reports of familial coarctation. In a systematic study of coarctation,
Boon and Roberts (1976) discerned familial aggregation with
multifactorial inheritance. Recurrence risks in sibs was about 0.5% for
coarctation and 1.0% for any form of congenital heart defect. Beekman
and Robinow (1985) described coarctation of the aorta in 4 generations.
In 2 members of the family, mother and son, in the third and fourth
generations, the coarctation was minimal; in the mother, for example, a
gradient in the aorta was demonstrated mainly after peak exercise.
Gerboni et al. (1993) found congenital heart disease in 5 members of 3
generations of a family. In 4 of the 5, mild or severe coarctation of
the aorta, either isolated or in association with other cardiac defects,
was found. In 1 fetus at risk, echocardiography at 26 weeks revealed
hypoplastic left heart and severe narrowing of the aortic isthmus, which
was confirmed after birth.

*FIELD* RF
1. Beekman, R. H.; Robinow, M.: Coarctation of the aorta inherited
as an autosomal dominant trait. Am. J. Cardiol. 56: 818-819, 1985.

2. Boon, A. R.; Roberts, D. F.: A family study of coarctation of
the aorta. J. Med. Genet. 13: 420-433, 1976.

3. Gerboni, S.; Sabatino, G.; Mingarelli, R.; Dallapiccola, B.: Coarctation
of the aorta, interrupted aortic arch, and hypoplastic left heart
syndrome in three generations. J. Med. Genet. 30: 328-329, 1993.

4. Gough, J. H.: Coarctation of the aorta in father and son. Brit.
J. Radiol. 34: 670-674, 1961.

*FIELD* CS

Cardiac:
   Coarctation of aorta;
   Congenital heart defect;
   Hypoplastic left heart;
   Narrow aortic isthmus

Inheritance:
   Most likely multifactorial;
   ? autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 6/1/1993
carol: 10/7/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
120040
*FIELD* TI
120040 COCHLEOSACCULAR DEGENERATION OF THE INNER EAR WITH PROGRESSIVE CATARACTS
*FIELD* TX
Description of cochleosaccular dysplasia of the inner ear in
congenitally deaf patients is attributed to Scheibe (1892). Inner ear
pathologic changes limited to the cochlea and saccule have been
described as the cause of both congenital deafness and progressive
postnatal sensorineural hearing loss. It should be called
cochleosaccular dysplasia when it refers to disordered development
causing congenital deafness, and cochleosaccular degeneration when it
refers to postnatal deterioration of a normally developed inner ear
causing progressive sensorineural hearing loss. Cochleosaccular
dysplasia was the abnormality observed in the syndrome of deafness with
diverticula of the small bowel and progressive sensory neuropathy
(221400). Nadol and Burgess (1982) described a family in which
progressive deafness due to cochleosaccular degeneration of the inner
ear was associated with progressive cataracts. The proband died at the
age of 65 years of multiple injuries sustained in a motorcycle accident.
He had congenital cataract in the right eye and subsequently developed a
cataract in his left eye; cataract extractions were performed at the age
of about 42. Hearing loss was first noted at the age of 26. He developed
difficulty with balance at age 58, coincident with rapid deterioration
in hearing. Staggering gait suggesting that he was drunk was noted. The
association of deafness and cataracts with the same natural history as
that in the proband was documented in at least 6 members of 5 different
sibships in 4 generations with 3 instances of male-to-male transmission
of the full syndrome. Progressive deafness was said to have been present
in 9 other individuals although the presence of cataracts was
incompletely determined. Guala et al. (1992) observed what appeared to
be the same condition in 8 members of 4 generations. There was again no
instance of male-to-male transmission.

*FIELD* RF
1. Guala, A.; Germinetti, V.; Sebastiani, F.; Silengo, M. C.: A syndrome
of progressive sensorineural deafness and cataract inherited as an
autosomal dominant trait. Clin. Genet. 41: 293-295, 1992.

2. Nadol, J. B., Jr.; Burgess, B.: Cochleosaccular degeneration of
the inner ear and progressive cataracts inherited as an autosomal
dominant trait. Laryngoscope 92: 1028-1037, 1982.

3. Scheibe, A.: A case of deaf-mutism, with auditory atrophy and
anomalies of development in the membranous labyrinth of both ears.
Arch. Otolaryng. 21: 12-22, 1892.

*FIELD* CS

Ears:
   Congenital deafness;
   Cochleosaccular dysplasia of inner ear

Eyes:
   Progressive cataracts

Neuro:
   Staggering gait

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 10/9/1991

*FIELD* ED
mimadm: 6/25/1994
carol: 7/15/1992
carol: 3/25/1992
supermim: 3/16/1992
carol: 10/14/1991
carol: 10/9/1991

*RECORD*
*FIELD* NO
120050
*FIELD* TI
*120050 COCKSACKIE B3 VIRUS SUSCEPTIBILITY; CXB3S; CB3S
*FIELD* TX
From study of somatic cell hybrids, Gerald and Bruns (1978) suggested
that susceptibility to the Coxsackie B3 virus is determined by a locus
on chromosome 19 (as is also susceptibility to poliovirus, 173850; Echo
11 virus, 129150; and baboon virus, 109180). As their name indicates,
the picornaviruses are very small and have RNA as their genetic
material. They are among the most limited in the range of species they
attack; thus, it is perhaps not surprising to find that specific genes
are involved in determination of susceptibility.

*FIELD* RF
1. Gerald, P. S.; Bruns, G. A.: Genetic determinants of viral susceptibility.
Birth Defects Orig. Art. Ser. XIV(6A): 1-7, 1978.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 9/30/1987
marie: 12/15/1986

*RECORD*
*FIELD* NO
120070
*FIELD* TI
*120070 COLLAGEN, TYPE IV, ALPHA-3 CHAIN; COL4A3
COLLAGEN OF BASEMENT MEMBRANE, ALPHA-3 CHAIN
*FIELD* TX
Butkowski et al. (1987) identified a third alpha chain of basement
membrane collagen, type IV. Studying in particular the noncollagenous
part of the alpha-3(IV) chain, Saus et al. (1988) concluded that
collagen IV is comprised of a third chain (alpha-3) together with the 2
classical ones, alpha-1 and alpha-2 (120130) (120090). They also
concluded that the epitope to which the major reactivity of
autoantibodies are targeted in the glomerular basement membrane in
patients with Goodpasture syndrome (233450) is localized to a
noncollagenous domain (NC1) of the alpha-3(IV) chain. See also Butkowski
et al. (1989). Morrison et al. (1991) sequenced a partial cDNA encoding
the COL4A3 gene and assigned it to 2q35-q37 by a combination of somatic
cell hybrid studies and in situ hybridization. Turner et al. (1992)
confirmed the identity of the Goodpasture antigen as the noncollagenous
domain of the alpha-3 chain of type IV collagen. Furthermore, they
localized the COL4A3 gene to 2q36-q37 by analysis of somatic cell
hybrids and by in situ hybridization. Although the primary defect in
Alport syndrome involves the COL4A5 gene (303630), the pathogenesis of
the syndrome probably involves type IV collagen molecules containing the
alpha-3(IV) chain: Hudson et al. (1992) demonstrated that the
Goodpasture autoantigen is the target alloantigen in posttransplant
anti-GBM (glomerular basement membrane) nephritis in patients with
Alport syndrome. Kalluri et al. (1994) further confirmed the unique
capacity of alpha-3(IV)NC1 dimer from bovine kidney to engage aberrantly
the immune system of rabbits to respond to self, mimicking the
organ-specific form of the human disease, whereas the other chains of
type IV collagen were nonpathogenic. The hexamer of alpha3-(IV) NC1 was
nonpathogenic, suggesting the exposure of a pathogenic epitope upon
dissociation of hexamer into dimers. Exposure of the pathogenic epitope
by infection or organic solvents, events that are thought often to
precede Goodpasture syndrome, may be a principal factor in the etiology
of the disease.

In a patient with deletion of 2q35-q36, Pasteris et al. (1992)
demonstrated that the COL4A3 gene was deleted, as was also the PAX3
(193500) gene, which was situated proximally. The deletion was estimated
to be less than 12.5 megabases.

Lemmink et al. (1994) demonstrated mutation in the COL4A3 gene as the
basis of autosomal recessive Alport syndrome (203780).

The form of autosomal recessive Alport syndrome due to mutation in the
COL4A3 gene is referred to here as type I and that due to mutation in
the COL4A4 gene is referred to as type II.

ANIMAL MODEL

Canine X-linked hereditary nephritis is an animal model for human
X-linked hereditary nephritis (Alport syndrome) (301050) characterized
by the presence of a premature stop codon in the alpha-5 chain of
collagen type IV. Thorner et al. (1996) examined expression of the
canine collagen type IV genes in the kidney. They detected alpha-3,
alpha-4 (120131), and alpha-5 chains in the noncollagenous domain of
type IV collagen isolated from normal dog glomeruli but not in affected
dog glomeruli. In addition to a significantly reduced level of COL4A5
gene expression (approximately 10% of normal), expression of the COL4A3
and COL4A4 genes was also decreased to 14-23% and 11-17%, respectively.
These findings suggested to Thorner et al. (1996) a mechanism which
coordinates the expression of these 3 basement membrane proteins.

Cosgrove et al. (1996) produced a mouse model for the autosomal form of
Alport syndrome by a COL4A3 knockout. The mice developed progressive
glomerulonephritis with microhematuria and proteinuria. End-stage renal
disease developed at about 14 weeks of age. Transmission electron
microscopy (TEM) of glomerular basement membranes (GBM) during
development of renal pathology revealed focal multilaminated thickening
and thinning beginning in the external capillary loops at 4 weeks and
spreading throughout the GBM by 8 weeks. By 14 weeks, half of the
glomeruli were fibrotic with collapsed capillaries. Immunofluorescence
analysis of the GBM showed the absence of type IV collagen alpha-3,
alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2
chains, which are normally localized to the mesangial matrix. Northern
blot analysis using probes specific for the collagen chains demonstrated
the absence of COL4A3 in the knockout, whereas mRNAs for the remaining
chains were unchanged. The progression of Alport renal disease was
correlated in time and space with the accumulation of fibronectin
(135600), heparan sulfate proteoglycan, laminin-1 (see 150320), and
entactin (131390) in the GBM of the affected animals.

*FIELD* AV
.0001
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE I
COL4A3, 5-BP DEL, EX5
Mochizuki et al. (1994) demonstrated that 1 patient with autosomal
recessive Alport syndrome was heterozygous and another homozygous for a
deletion of 5 nucleotides in exon 5 resulting in a markedly truncated
COL4A3 protein.

.0002
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE I
COL4A3, ARG43TER
By studies of the 5 exons encoding the noncollagenous domain of the
COL4A3 protein by single-strand conformation polymorphism (SSCP)
analysis followed by sequencing, Lemmink et al. (1994) demonstrated that
a patient with autosomal recessive Alport syndrome was a compound
heterozygote for an arg43-to-ter mutation in exon 5 and a ser86-to-ter
mutation in exon 4.

.0004
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE I
COL4A3, 5-BP DEL
In family VB with autosomal recessive Alport syndrome, Mochizuki et al.
(1994) demonstrated homozygosity for a 5-bp CTTTT deletion in the NC1
domain of COL4A3. There are ten 5-bp deletions that would result in the
observed sequence difference. All of them produce a frameshift and have
precisely the same effect on the amino acid sequence: a missense
sequence of 33 amino acids and premature chain termination. The change
occurred in exon 5. There are also 5 possible 5-prime bp tandem repeats.
A 'replication slippage' at any of the 10 points could cause the
observed change. The female proband in this family had sensorineural
deafness hematuria from 4 years of age, and typical ultrastructural
lesions of Alport syndrome on electron microscopy of renal biopsy.
Hemodialysis was started at age 9. Renal allograft was received at age
10, following which she developed anti-GBM nephritis. In a competitive
ELISA, binding of the patient's serum was inhibited by increasing
concentrations of Goodpasture sera which contains autoantibodies
directed toward the NC1 domain of COL4A3. The patient's brother had
hematuria, deafness, and deteriorating renal function. The parents were
asymptomatic. They were not known to be related, but their ancestors
originated from the same small village in The Netherlands.

.0005
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE I
COL4A3, EX5, C-T
In family DU, a girl with Alport syndrome was found to be homozygous for
a C-to-T transition in exon 5 of COL4A3, counting from the 3-prime end
(Quinones et al., 1992). This mutation replaced an arginine codon with a
stop codon in the NC1 domain, shortening the alpha-3(IV) chain by 190
amino acids; it was expected to disrupt 11 of the intermolecular
disulfide bonds that stabilize the homodimerization of NC1 domains. The
proband was an 11-year-old Belgium girl who was found to have end-stage
renal disease. Proteinuria and microhematuria had been discovered at the
age of 7. At age 11, the patient had renal transplant from her mother.
At age 16, no rejection or anti-GMB nephritis had developed. At age 13,
an audiogram showed bilateral sensorineural hearing loss. The parents
were first cousins. Both had normal renal function and urinalysis.

.0006
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE I
COL4A3, ALU, INS, EX6
In the process of screening the illegitimate transcripts of COL4A3 in
lymphocytes from a patient with autosomal recessive Alport syndrome,
Knebelmann et al. (1995) discovered an antisense Alu sequence that had
been spliced into the mature transcript after a G-to-T transversion
activated a cryptic splice site located in the Alu element within intron
V. The resultant 74-bp insertion was at the junction of exons IV or V
and VI in the final transcript. This was the first observation of a
splicing abnormality in the COL4A3 gene in autosomal recessive Alport
syndrome.

*FIELD* RF
1. Butkowski, R. J.; Langeveld, J. P. M.; Wieslander, J.; Hamilton,
J.; Hudson, B. G.: Localization of the Goodpasture epitope to a novel
chain of basement membrane collagen. J. Biol. Chem. 262: 7874-7877,
1987.

2. Butkowski, R. J.; Wieslander, J.; Kleppel, M.; Michael, A. F.;
Fish, A. J.: Basement membrane collagen in the kidney: regional localization
of novel chains related to collagen IV. Kidney Int. 35: 1195-1202,
1989.

3. Cosgrove, D.; Meehan, D. T.; Grunkemeyer, J. A.; Kornak, J. M.;
Sayers, R.; Hunter, W. J.; Samuelson, G. C.: Collagen COL4A3 knockout:
a mouse model for autosomal Alport syndrome. Genes Dev. 10: 2981-2992,
1996.

4. Hudson, B. G.; Kalluri, R.; Gunwar, S.; Weber, M.; Ballester, F.;
Hudson, J. K.; Noelken, M. E.; Sarras, M.; Richardson, W. R.; Saus,
J.; Abrahamson, D. R.; Glick, A. D.; Haralson, M. A.; Helderman, J.
H.; Stone, W. J.; Jacobson, H. R.: The pathogenesis of Alport syndrome
involves type IV collagen molecules containing the alpha-3(IV) chain:
evidence from anti-GBM nephritis after renal transplantation. Kidney
Int. 42: 179-187, 1992.

5. Kalluri, R.; Gattone, V. H., II; Noelken, M. E.; Hudson, B. G.
: The alpha-3 chain of type IV collagen induces autoimmune Goodpasture
syndrome. Proc. Nat. Acad. Sci. 91: 6201-6205, 1994.

6. Knebelmann, B.; Forestier, L.; Drouot, L.; Quinones, S.; Chuet,
C.; Benessy, F.; Saus, J.; Antignac, C.: Splice-mediated insertion
of an Alu sequence in the COL4A3 mRNA causing autosomal recessive
Alport syndrome. Hum. Molec. Genet. 4: 675-679, 1995.

7. Lemmink, H. H.; Mochizuki, T.; van den Heuvel, L. P. W. J.; Schroder,
C. H.; Barrientos, A.; Monnens, L. A. H.; van Oost, B. A.; Brunner,
H. G.; Reeders, S. T.; Smeets, H. J. M.: Mutations in the type IV
collagen alpha-3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum.
Molec. Genet. 3: 1269-1273, 1994.

8. Mochizuki, T.; Lemmink, H. H.; Mariyama, M.; Antignac, C.; Gubler,
M.-C.; Pirson, Y.; Verellen-Dumoulin, C.; Chan, B.; Schroder, C. H.;
Smeets, H. J.; Reeders, S. T.: Identification of mutations in the
alpha-3(IV) and alpha-4(IV) collagen genes in autosomal recessive
Alport syndrome. Nature Genet. 8: 77-81, 1994.

9. Morrison, K. E.; Mariyama, M.; Yang-Feng, T. L.; Reeders, S. T.
: Sequence and localization of a partial cDNA encoding the human alpha3
chain of type IV collagen. Am. J. Hum. Genet. 49: 545-554, 1991.

10. Pasteris, N. G.; Trask, B.; Sheldon, S.; Gorski, J. L.: A chromosome
deletion 2q35-36 spanning loci HuP2 and COL4A3 results in Waardenburg
syndrome type III (Klein-Waardenburg syndrome). (Abstract) Am. J.
Hum. Genet. 51 (suppl.): A224, 1992.

11. Quinones, S.; Bernal, D.; Garcia-Sogo, M.; Elena, S. F.; Saus,
J.: Exon/intron structure of the human alpha-3(IV) gene encompassing
the Goodpasture antigen (alpha-3(IV)NC1): identification of a potentially
antigenic region at the triple helix/NC1 domain junction. J. Biol.
Chem. 267: 19780-19784, 1992.

12. Saus, J.; Wieslander, J.; Langeveld, J. P. M.; Quinones, S.; Hudson,
B. G.: Identification of the Goodpasture antigen as the alpha-3(IV)
chain of collagen IV. J. Biol. Chem. 263: 13374-13380, 1988.

13. Thorner, P. S.; Zheng, K.; Kalluri, R.; Jacobs, R.; Hudson, B.
G.: Coordinate gene expression of the alpha-3, alpha-4, and alpha-5
chains if collagen type IV. J. Biol. Chem. 271: 13821-13828, 1996.

14. Turner, N.; Mason, P. J.; Brown, R.; Fox, M.; Povey, S.; Rees,
A.; Pusey, C. D.: Molecular cloning of the human Goodpasture antigen
demonstrates it to be the alpha-3 chain of type IV collagen. J. Clin.
Invest. 89: 592-601, 1992.

*FIELD* CN
Victor A. McKusick - updated: 02/11/1997
Perseveranda M. Cagas - updated: 9/4/1996

*FIELD* CD
Victor A. McKusick: 10/18/1988

*FIELD* ED
terry: 02/11/1997
terry: 2/4/1997
mark: 9/4/1996
mark: 3/7/1996
mark: 1/25/1996
terry: 1/22/1996
mark: 6/7/1995
terry: 10/25/1994
jason: 7/12/1994
carol: 12/15/1992
carol: 8/13/1992
carol: 5/26/1992

*RECORD*
*FIELD* NO
120080
*FIELD* TI
#120080 COLCHICINE RESISTANCE
COLCHICINE SENSITIVITY; CLCS
*FIELD* TX
A number sign (#) is used with this entry because mutation in the PGY1
gene (171050) has been found to cause colchicine resistance.

Chamla et al. (1980) described variants of human cells with altered
colchicine sensitivity. These cell lines showed cross-resistance to
daunomycin, emetine, vinblastine, and vincristine, and collateral
sensitivity to xylocaine. Colchicine-resistant mutants of Chinese
hamster ovary (CHO) cells have been found to have a change in the entry
of drugs into cells, altered binding of colchicine to its intracellular
target, or an altered tubulin. Chamla and Begueret (1982) showed that
the 'defect' was one of decreased permeability to the drug.

*FIELD* RF
1. Chamla, Y.; Begueret, J.: Colchicine resistance in human cell
lines: pleiotropic phenotype and decreased membrane permeability.
Hum. Genet. 61: 73-75, 1982.

2. Chamla, Y.; Roumy, M.; Lassegues, M.; Battin, J.: Altered sensitivity
to colchicine and PHA in human cultured cells. Hum. Genet. 53:
249-253, 1980.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
supermim: 3/16/1992
carol: 1/30/1992
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/2/1989

*RECORD*
*FIELD* NO
120090
*FIELD* TI
*120090 COLLAGEN, TYPE IV, ALPHA-2 CHAIN; COL4A2
COLLAGEN OF BASEMENT MEMBRANE, ALPHA-2 CHAIN
*FIELD* TX
See COL4A1 (120130). Type IV collagen is associated with laminin,
entactin, and heparan sulfate proteoglycans to form the sheetlike
basement membranes that separate epithelium from connective tissue. The
dispersion of the other collagen genes helps to avoid unequal
crossingover. Because the alpha-1 and alpha-2 chains of type IV collagen
are highly divergent, close proximity on chromosome 13 carries less
hazard of a disruptive event than might otherwise be the case. On the
other hand, their coordinate regulation may be enhanced by the close
situation. Brazel et al. (1988) determined sequences of cDNA and protein
of the N-terminal 60% of the COL4A2 chain. Aligning the 2-alpha chains
of type IV collagen from the N-terminus, they concluded that the alpha-2
chain has 43 more amino acids than the alpha-1 chain. Twenty-one of
these additional residues form a disulfide-bridged loop within the
triple helix, which is unique among all known collagens. The Goodpasture
antigen appears to be part of the type IV collagen molecule.
Abnormalities in or absence of the Goodpasture antigen has been claimed
in Alport disease (104200, 203780, 301050).

By study of somatic cell hybrids and by in situ hybridization, Griffin
et al. (1987) found that the alpha-2 chain is located in 13q34. By
Southern analysis of DNA from hybrid cells, Solomon et al. (1987)
likewise found that the alpha-2 chain of collagen maps to chromosome 13.
Killen et al. (1987) presented the partial amino acid sequence of the
COL4A2 gene and mapped the gene to 13q34 by somatic cell hybridization
and in situ hybridization. Boyd et al. (1988) also mapped COL4A2 to
13q33-q34 by Southern analysis of DNA from somatic cell hybrids and by
in situ hybridization. Using interspecific and intersubspecific mapping
panels, Koizumi et al. (1995) mapped Col4a2 to the centromeric region of
mouse chromosome 8.

The two subunit genes COL4A1 (120130) and COL4A2 are transcribed
divergently from a common promoter. They both contain activating
elements which are indispensable for efficient transcription. Moreover,
Haniel et al. (1995) demonstrated a novel silencer element within the
human COL4A2 gene and localized it by deletion mapping to a 24-bp region
within the third intron of the gene. The element is able to inhibit the
promoters of both COL4A genes, as well as the unrelated herpes simplex
virus thymidine kinase promoter, largely independent of its position and
orientation relative to the transcription start site of the promoter.
The silencer element is specifically recognized by a a nuclear protein
called SILBF. Mutation studies and deletion analysis by Haniel et al.
(1995) demonstrated that binding of SILBF is not only necessary but also
sufficient for the silencing function.

*FIELD* RF
1. Boyd, C. D.; Toth-Fejel, S.; Gadi, I. K.; Litt, M.; Condon, M.
R.; Kolbe, M.; Hagen, I. K.; Kurkinen, M.; Mackenzie, J. W.; Magenis,
E.: The genes coding for human pro alpha-1(IV) collagen and pro alpha-2(IV)
collagen are both located at the end of the long arm of chromosome
13. Am. J. Hum. Genet. 42: 309-314, 1988.

2. Brazel, D.; Pollner, R.; Oberbaumer, I.; Kuhn, K.: Human basement
membrane collagen (type IV): the amino acid sequence of the alpha-2(IV)
chain and its comparison with the alpha-1(IV) chain reveals deletions
in the alpha-1(IV) chain. Europ. J. Biochem. 172: 35-42, 1988.

3. Griffin, C. A.; Emanuel, B. S.; Hansen, J. R.; Cavenee, W. K.;
Myers, J. C.: Human collagen genes encoding basement membrane alpha-1(IV)
and alpha-2(IV) chains map to the distal long arm of chromosome 13.
Proc. Nat. Acad. Sci. 84: 512-516, 1987.

4. Haniel, A.; Welge-Lussen, U.; Kuhn, K.; Poschl, E.: Identification
and characterization of a novel transcriptional silencer in the human
collagen type IV gene COL4A2. J. Biol. Chem. 270: 11209-11215,
1995.

5. Killen, P. D.; Francomano, C. A.; Yamada, Y.; Modi, W. S.; O'Brien,
S. J.: Partial structure of the human alpha-2(IV) collagen chain
and chromosomal localization of the gene (COL4A2). Hum. Genet. 77:
318-324, 1987.

6. Koizumi, T.; Hendel, E.; Lalley, P. A.; Tchetgen, M.-B. N.; Nadeau,
J. H.: Homologs of genes and anonymous loci on human chromosome 13
map to mouse chromosomes 8 and 14. Mammalian Genome 6: 263-268,
1995.

7. Solomon, E.; Hall, V.; Kurkinen, M.: The human alpha-2(IV) collagen
gene, COL4A2, is syntenic with the alpha-1(IV) gene, COL4A1, on chromosome
13. Ann. Hum. Genet. 51: 125-127, 1987.

*FIELD* CN
Richard Anderson - updated: 6/19/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/07/1996
mark: 5/11/1995
supermim: 3/16/1992
carol: 3/27/1991
carol: 3/14/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120100
*FIELD* TI
*120100 COLD HYPERSENSITIVITY
COLD URTICARIA, FAMILIAL
*FIELD* TX
Familial cold urticaria was first described by Kile and Rusk (1940).
After exposure to cold the patient develops urticarial wheals, pain and
swelling of joints, chills and fever. Amyloidosis is also a feature of
the syndrome of urticaria, deafness and amyloidosis (191900), a separate
although somewhat similar entity. McKusick and Goodman (1962) noted that
systemic amyloidosis is a complication of this condition and that
amyloid nephropathy is a frequent cause of death. Doeglas (1973)
examined 21 members of a kindred and found 10 affected. One of the 10
had leukocytosis during an attack. Derbes and Coleman (1972) reviewed
the literature on familial cold urticaria and described several similar
disorders to provide a basis for differential diagnosis. Ormerod et al.
(1993) studied 8 of 20 affected members from a 46-member family.
Urticaria was maximal in early adult life. Three patients responded
favorably to treatment with stanozolol. The authors suggested that this
disorder, like hereditary angioedema (106100), involves deficiency of an
inhibitory factor. Zip et al. (1993) reported a large and extensively
affected family. They found reports of 10 pedigrees, 7 from the United
States and 1 each from Holland, France, and South Africa. Their own
family showed transmission through 6 generations and by inference 8
generations. The onset of the disorder was in infancy. The onset of
symptoms after cold challenge was delayed (one half to 6 hours). Zip et
al. (1993) tabulated the differences between idiopathic acquired cold
urticaria and familial cold urticaria. In the familial form, the lesions
tend to be erythematous rather than urticarial and to be accompanied by
fever, chills, arthralgias, and stiffness. Leukocytosis is present,
whereas it is absent in acquired cold urticaria, duration of the
episodes is much longer, passive transfer is negative, and mast cell
degranulation is absent.

*FIELD* SA
Doeglas et al. (1974); Doeglas and Bleumink (1974); Hendrik and Bleumink
(1974); Kaplan et al. (1981); Mathews  (1981); Shepard  (1971); Soter
et al. (1976); Tindall et al. (1969); Vlagopoulos et al. (1975); Wasserman
et al. (1977); Witherspoon et al. (1948)
*FIELD* RF
1. Derbes, V. J.; Coleman, W. P.: Familial cold urticaria. Ann.
Allergy 30: 335-341, 1972.

2. Doeglas, H. M. G.: Familial cold urticaria. Arch. Derm. 107:
136-137, 1973.

3. Doeglas, H. M. G.; Bernini, L. F.; Fraser, G. R.; Van Loghem, E.;
Meera Khan, P.; Nyenhuis, L. E.; Pearson, P. L.: A kindred with familial
cold urticaria: linkage analysis. J. Med. Genet. 11: 31-34, 1974.

4. Doeglas, H. M. G.; Bleumink, E.: Familial cold urticaria: clinical
findings. Arch. Derm. 110: 382-388, 1974.

5. Hendrik, M. G.; Bleumink, E.: Familial cold urticaria. Arch.
Derm. 110: 382-388, 1974.

6. Kaplan, A. P.; Garofalo, J.; Sigler, R.; Hauber, T.: Idiopathic
cold urticaria: in vitro demonstration of histamine release upon challenge
of skin biopsies. New Eng. J. Med. 305: 1074-1077, 1981.

7. Kile, R. L.; Rusk, H. A.: A case of cold urticaria with unusual
family history. J.A.M.A. 114: 1067-1068, 1940.

8. Mathews, K. P.: Exploiting the cold-urticaria model.  (Editorial) New
Eng. J. Med. 305: 1090-1091, 1981.

9. McKusick, V. A.; Goodman, R. M.: Pinnal calcification: observations
in systemic diseases not associated with disordered calcium metabolism.
J.A.M.A. 179: 230-232, 1962.

10. Ormerod, A. D.; Smart, L.; Reid, T. M. S.; Milford-Ward, A.:
Familial cold urticaria: investigation of a family and response to
stanozolol. Arch. Derm. 129: 343-346, 1993.

11. Shepard, M. K.: Cold hypersensitivity. Birth Defects Orig.
Art. Ser. VII(8): 352 only, 1971.

12. Soter, N. A.; Wasserman, S. I.; Austen, K. F.: Cold urticaria:
release into the circulation of histamine and eosinophil chemotactic
factor of anaphylaxis during cold challenge. New Eng. J. Med. 294:
687-690, 1976.

13. Tindall, J. P.; Beeker, S. K.; Rosse, W. F.: Familial cold urticaria:
a generalized reaction involving leukocytosis. Arch. Intern. Med. 124:
129-134, 1969.

14. Vlagopoulos, T.; Townley, R.; Villacorte, G.: Familial cold urticaria.
Ann. Allergy 34: 366-369, 1975.

15. Wasserman, S. I.; Soter, N. A.; Center, D. M.; Austen, K. F.:
Cold urticaria: recognition and characterization of a neutrophil chemotactic
factor which appears in serum during experimental cold challenge.
J. Clin. Invest. 60: 189-196, 1977.

16. Witherspoon, F. G.; White, C. B.; Bazemore, J. M.; Hailey, H.
: Familial urticaria due to cold. Arch. Derm. Syph. 58: 52-55,
1948.

17. Zip, C. M.; Ross, J. B.; Greaves, M. W.; Scriver, C. R.; Mitchell,
J. J.; Zoar, S.: Familial cold urticaria. Clin. Exp. Derm. 18:
338-341, 1993.

*FIELD* CS

Skin:
   Urticarial wheals after exposure to cold

Joints:
   Joint pain;
   Joint swelling

Misc:
   Chills;
   Fever;
   Systemic amyloidosis

GU:
   Amyloid nephropathy

Lab:
   Leukocytosis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 10/19/1993
carol: 5/14/1993
supermim: 3/16/1992
carol: 8/24/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120105
*FIELD* TI
*120105 COLIPASE, PANCREATIC; CLPS
*FIELD* TX
Pancreatic colipase is a 12-kD polypeptide cofactor for pancreatic
lipase (EC 3.1.1.3; 246600), an enzyme essential for the absorption of
dietary long-chain triglyceride fatty acids. Colipase is thought to
anchor lipase noncovalently to the surface of lipid micelles,
counteracting the destabilizing influence of intestinal bile salts.
Using primers derived from the known amino acid sequence, Davis et al.
(1991) employed the PCR to produce a cDNA clone corresponding to the
complete coding region of the human procolipase mRNA. By the study of
mouse/human somatic cell hybrids, they determined that the gene is
located in the region 6pter-p21.1. Sims and Lowe (1992) confirmed the
assignment of the CLPS gene to chromosome 6 by blots of hamster-human
somatic cell hybrid DNA using the entire colipase cDNA. They found that
the gene has 3 exons and that the 5-prime-flanking region contains a
TATA box, a GC box, and a 28-bp region with homology to the rat
pancreatic-specific enhancer.

*FIELD* RF
1. Davis, R. C.; Xia, Y.; Mohandas, T.; Schotz, M. C.; Lusis, A. J.
: Assignment of the human pancreatic colipase gene to chromosome 6p21.1
to pter. Genomics 10: 262-265, 1991.

2. Sims, H. F.; Lowe, M. E.: The human colipase gene: isolation,
chromosomal location, and tissue-specific expression. Biochemistry 31:
7120-7125, 1992.

*FIELD* CD
Victor A. McKusick: 2/5/1991

*FIELD* ED
mark: 11/27/1996
carol: 10/26/1993
carol: 10/1/1992
supermim: 3/16/1992
carol: 8/7/1991
carol: 4/18/1991
carol: 2/7/1991

*RECORD*
*FIELD* NO
120110
*FIELD* TI
*120110 COLLAGEN, TYPE X, ALPHA 1; COL10A1
*FIELD* TX
Type X is a short-chain minor collagen of cartilage (Schmid and
Linsenmayer, 1985). During development and growth of long bones,
chondrocytes pass sequentially through a proliferative, a hypertrophic
and a degenerative stage, each characterized by a particular set of
collagen types. Proliferative (stage I) chondrocytes synthesize type II
collagen as the major collagen and types IX and XI as the minor
collagens. Hypertrophic (stage II) chondrocytes localized in the
columnar, calcifying cartilage are characterized by the synthesis of
types X and II collagen. Kirsch and von der Mark (1991) isolated human
type X collagen from fetal human growth plate cartilage and purified it
to homogeneity. They raised an antiserum against the purified protein
and used the antibody to show the distribution of type X collagen in
fetal human growth plate cartilage and in the calcifying zone of fetal
human sternum. Possible involvement of the COL10A1 gene in
chondrodysplasias and other disorders of cartilage such as
osteoarthrosis was suggested.

With consensus primers based on the nucleotide sequence of the chicken
type X collagen gene, Apte et al. (1991) used PCR with human genomic DNA
as template to isolate a 289-bp fragment for part of the carboxyl
non-triple helical domain of the human gene. Using the PCR clone as a
probe for in situ hybridization of human metaphase chromosome spreads
and for Southern analysis of a panel of human-hamster somatic cell
hybrid DNAs, they assigned the COL10A1 locus to 6q21-q22. Thomas et al.
(1991) likewise assigned COL10A1 to 6q21-q22.3 by a combination of
somatic cell hybrid screening and in situ hybridization. Apte et al.
(1992) demonstrated that this gene is located on mouse chromosome 10.

Thomas et al. (1991) reported the complete primary sequence of type X
collagen. Collagen X is a homotrimer containing 3 identical chains with
a relative molecular mass of 59,000. The triple helical domain is
approximately half the size of that in collagen of types I, II, and III.
The localization of collagen X and its transient expression at sites of
calcification suggests that it is associated with events in the later
stages of endochondral bone formation. Collagen X possesses striking
structural similarities to collagen VIII (120251), another short-chain
collagen found predominantly in Descemet membrane, the specialized
basement membrane synthesized by corneal endothelial cells. Two exons of
169 bp and 2,940 bp encode the complete primary translation product
which consists of a putative signal-peptide sequence (18 amino acids),
an N-terminal noncollagenous domain (38 amino acids), a triple helix
(463 amino acids), and a C-terminal noncollagenous domain (161 amino
acids). A single 3,200-bp intron separates the 2 exons.

Using PCR and the single-strand conformation polymorphism technique
(SSCP), Sweetman et al. (1992) identified 7 sequence changes in the
coding region of the COL10A1 gene. Six of these were shown to be
polymorphic in nature and were used to demonstrate discordant
segregation between the COL10A1 locus and both achondroplasia (100800)
and pseudoachondroplasia (177150). The seventh sequence change resulted
in a val-to-met substitution in the carboxyl-terminal domain of the
molecule and was identified only in 2 persons with hypochondroplasia
(146000) from a single family. Segregation analysis in this family was
inconclusive; thus the significance of the substitution remained
uncertain.

Warman et al. (1993) proved that mutation in the COL10A1 gene is
responsible for Schmid metaphyseal chondrodysplasia (MCDS; 156500). A
number of COL10A1 mutations have been identified in patients with Schmid
metaphyseal chondrodysplasia; each is within the carboxy-terminal
noncollagenous domain and it has been suggested that the phenotype is
the result of the inability of the mutant polypeptide to initiate trimer
formation (Warman et al., 1993; McIntosh et al., 1994, 1995).

Jacenko et al. (1993) produced a spondylometaphyseal dysplasia in mice
by a transgenic dominant negative mutation in type X collagen. Of
interest, Rosati et al. (1994) observed normal long bone growth and
development in mice expressing no type X collagen. This finding supports
the contention that Schmid metaphyseal chondrodysplasia is the result of
a dominant negative effect of mutant collagen polypeptide and not the
deficiency of normal type X collagen as suggested previously (Warman et
al., 1993; McIntosh et al., 1994, 1995)

Wallis et al. (1996) reviewed the 21 known mutations in the COL10A1 gene
that have been associated with the Schmid type of metaphyseal
chondrodysplasia and noted that all occur in the region of COL10A1
encoding the carboxy-terminal (NC1) domain. They contended that the
restricted distribution of COL10A1 mutations causing MCDS argues against
haploinsufficiency being the mutation mechanism in this disorder.

Warman et al. (1993) and Wallis et al. (1996) found no mutations in the
COL10A1 gene in patients with other types of metaphyseal
chondrodysplasia.

*FIELD* AV
.0001
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, 13-BP DEL, FS671TER
In a Mormon kindred reported by Stephens (1943) as an example of
achondroplasia and studied by Caffey and Christensen (1963), Warman et
al. (1993) identified a 13-bp deletion starting with basepair 1856 in
heterozygous state in the COL10A1 gene. The mutation produced a
frameshift that altered the highly conserved C-terminal domain of the
alpha-1(X) chain and reduced the length of the polypeptide by 9
residues.

.0002
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, TYR598ASP
Using PCR and SSCP techniques to analyze the coding and upstream
promoter regions of the COL10A1 gene, Wallis et al. (1994) identified a
single bp transition that led to substitution of the highly conserved
amino acid residue tyrosine at position 598 by aspartic acid in 5
affected members of a family with Schmid type metaphyseal
chondrodysplasia.

.0003
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, LEU614PRO
In a sporadic case of Schmid type metaphyseal chondrodysplasia, Wallis
et al. (1994) demonstrated substitution of leucine-614 by proline in the
COL10A1 gene. Both this and the tyr598-to-asp mutation (120110.0002)
were present in heterozygous state and were located in the part of the
gene effecting amino acid substitutions within the carboxyl-terminal
domain of the type X collagen chains.

.0004
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, CYS591ARG
Using PCR and SSCP analyses to examine the coding region of the COL10A1
gene, McIntosh et al. (1994) identified a single bp T-to-C transition
that led to the substitution of the cysteine residue at position 591 by
arginine in a single, sporadic case. This residue is conserved across
species and may be essential for intermolecular disulfide bridge
formation prior to triple helix formation. Of interest, the proband's
unaffected mother proved to be a somatic mosaic for the cys591-to-arg
mutation.

.0005
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, 1-BP DEL, FS621TER
In a sporadic case of Schmid metaphyseal chondrodysplasia, a single base
deletion of C1856 was identified by PCR and SSCP analysis which would be
predicted to introduce a premature termination codon after amino acid
620 (McIntosh et al., 1994).

.0006
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, 2-BP DEL, FS665TER
A 2-bp deletion was identified in a sporadic case of Schmid metaphyseal
chondrodysplasia which would be predicted to introduce a premature stop
codon after amino acid 664 (McIntosh et al., 1994).

.0007
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, 10-BP DEL, FS
Heteroduplex analysis of PCR-amplified genomic DNA identified a 10-bp
deletion in COL10A1 starting from nucleotide 1867 that segregated with
Schmid metaphyseal chondrodysplasia in a 5-generation pedigree
(Dharmavaram et al., 1994). The deletion overlaps that identified by
Warman et al. (1993) (120110.0001) and gives rise to the same downstream
protein sequence.

.0008
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, 2-BP DEL, FS626TER
Another 2-bp deletion was identified in a sporadic case by McIntosh et
al. (1995), coincidentally at the same position as the deletion of the
single base at 1856 in 120110.0005 and the start of the 13-bp deletion
described previously (120110.0001). A premature termination codon after
amino acid 625 is predicted to result from this frameshift mutation.

.0009
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, TYR628TER
A nonsense mutation was identified in a sporadic case of Schmid
metaphyseal chondrodysplasia by McIntosh et al. (1995).

.0010
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, TRP651TER
Using PCR and SSCP, McIntosh et al. (1995) identified a trp651-to-ter
mutation in a sporadic case of Schmid metaphyseal chondrodysplasia.

.0011
METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE
COL10A1, TRP651ARG
In a Japanese family with Schmid metaphyseal chondrodysplasia, Pokharel
et al. (1995) found that affected members had a T-to-C transition at
nucleotide 1951 that resulted in replacement of tryptophan by arginine
at residue 651 (W651R). This novel mutation seemed to have the same
impact on bone development as the W651X mutation (120110.0010).

*FIELD* RF
1. Apte, S.; Mattei, M.-G.; Olsen, B. R.: Cloning of human alpha-1(X)
collagen DNA and localization of the COL10A1 gene to the q21-q22 region
of human chromosome 6. FEBS Lett. 282: 393-396, 1991.

2. Apte, S. S.; Seldin, M. F.; Hayashi, M.; Olsen, B. R.: Cloning
of the human and mouse type X collagen genes and mapping of the mouse
type X collagen gene to chromosome 10. Europ. J. Biochem. 206:
217-224, 1992.

3. Caffey, J. P.; Christensen, W. R.: Personal Communication. Pittsburgh,
Pa. and Salt Lake City, Utah  1963.

4. Dharmavaram, R. M.; Elberson, M. A.; Peng, M.; Kirson, L. A.; Kelley,
T. E.; Jimenez, S. A.: Identification of a mutation in type X collagen
in a family with Schmid metaphyseal chondrodysplasia. Hum. Molec.
Genet. 3: 507-509, 1994.

5. Jacenko, O.; Lu Valle, P. A.; Olsen, B. R.: Spondylometaphyseal
dysplasia in mice carrying a dominant negative mutation in a matrix
protein specific for cartilage-to-bone transition. Nature 365:
56-61, 1993.

6. Kirsch, T.; von der Mark, K.: Isolation of human type X collagen
and immunolocalization in fetal human cartilage. Europ. J. Biochem. 196:
575-580, 1991.

7. McIntosh, I.; Abbot, M. H.; Francomano, C. A.: Concentration of
mutations causing Schmid metaphyseal chondrodysplasia in the C-terminal
noncollagenous domain of type X collagen. Hum. Mut. 5: 121-125,
1995.

8. McIntosh, I.; Abbot, M. H.; Warman, M. L.; Olsen, B. R.; Francomano,
C. A.: Additional mutations of type X collagen confirm COL10A1 as
the Schmid metaphyseal chondrodysplasia locus. Hum. Molec. Genet. 3:
303-307, 1994.

9. Pokharel, R. K.; Alimsardjono, H.; Uno, K.; Fujii, S.; Shiba, R.;
Matsuo, M.: A novel mutation substituting tryptophan with arginine
in the carboxyl-terminal, noncollagenous domain of collagen X in a
case of Schmid metaphyseal chondrodysplasia. Biochem. Biophys. Res.
Commun. 217: 1157-1162, 1995.

10. Rosati, R.; Horan, G. S. B.; Pinero, G. J.; Garofalo, S.; Keene,
D. R.; Horton, W. A.; Vuorio, E.; de Crombrugghe, B.; Behringer, R.
R.: Normal long bone growth and development in type X collagen-null
mice. Nature Genet. 8: 129-135, 1994.

11. Schmid, T. M.; Linsenmayer, T. F.: Immunohistochemical localization
of short chain cartilage collagen (type X) in avian tissues. J.
Cell Biol. 100: 598-605, 1985.

12. Stephens, F. E.: An achondroplastic mutation and the nature of
its inheritance. J. Hered. 34: 229-235, 1943.

13. Sweetman, W. A.; Rash, B.; Sykes, B.; Beighton, P.; Hecht, J.
T.; Zabel, B.; Thomas, J. T.; Boot-Handford, R.; Grant, M. E.; Wallis,
G. A.: SSCP and segregation analysis of the human type X collagen
gene (COL10A1) in heritable forms of chondrodysplasia. Am. J. Hum.
Genet. 51: 841-849, 1992.

14. Thomas, J. T.; Cresswell, C. J.; Rash, B.; Hoyland, J.; Freemont,
A. J.; Grant, M. E.; Boot-Handford, R. P.: The human collagen X gene:
complete primary sequence and reexpression in osteoarthritis. Biochem.
Soc. Trans. 19: 804-808, 1991.

15. Thomas, J. T.; Cresswell, C. J.; Rash, B.; Nicolai, H.; Jones,
T.; Solomon, E.; Grant, M. E.; Boot-Handford, R. P.: The human collagen
X gene: complete primary translated sequence and chromosomal localization.
Biochem. J. 280: 617-623, 1991.

16. Wallis, G. A.; Rash, B.; Sweetman, W. A.; Thomas, J. T.; Super,
M.; Evans, G.; Grant, M. E.; Boot-Handford, R. P.: Amino acid substitutions
of conserved residues in the carboxyl-terminal domain of the alpha-I(X)
chain of type X collagen occur in two unrelated families with metaphyseal
chondrodysplasia type Schmid. Am. J. Hum. Genet. 54: 169-178, 1994.

17. Wallis, G. A.; Rash, B.; Sykes, B.; Bonaventure, J.; Maroteaux,
P.; Zabel, B.; Wynne-Davies, R.; Grant, M. E.; Boot-Handford, R. P.
: Mutations within the gene encoding the alpha-1(X) chain of type
X collagen (COL1A1) cause metaphyseal chondrodysplasia type Schmid
but not several other forms of metaphyseal chondrodysplasia. J.
Med. Genet. 33: 450-457, 1996.

18. Warman, M. L.; Abbott, M.; Apte, S. S.; Hefferon, T.; McIntosh,
I.; Cohn, D. H.; Hecht, J. T.; Olsen, B. R.; Francomano, C. A.: A
type X collagen mutation causes Schmid metaphyseal chondrodysplasia.
Nature Genet. 5: 79-82, 1993.

*FIELD* CN
Iosif W. Lurie - updated: 7/4/1996

*FIELD* CD
Victor A. McKusick: 2/26/1988

*FIELD* ED
carol: 07/10/1996
carol: 7/9/1996
carol: 7/4/1996
mark: 3/4/1996
terry: 2/23/1996
pfoster: 3/2/1995
warfield: 4/7/1994
carol: 4/1/1994
carol: 10/26/1993
carol: 9/17/1993
carol: 9/9/1993

*RECORD*
*FIELD* NO
120120
*FIELD* TI
*120120 COLLAGEN, TYPE VII, ALPHA-1; COL7A1
LONG-CHAIN COLLAGEN;;
LC COLLAGEN
*FIELD* TX
From human chorioamniotic membranes, Bentz et al. (1983) isolated a
distinctive type of collagen which from its amino acid composition and
other characteristics must be the product of a previously unrecognized
gene. It consists of 3 identical alpha chains, each with a molecular
weight of about 170,000. The authors gave this collagen the trivial name
long-chain (LC) collagen and suggested that it be referred to as type
VII collagen. Collagen VII has a triple-helical domain almost half again
longer than the type I collagen triple helix. Collagen VII is the main
constituent of anchoring fibrils, which in the skin are located below
the basal lamina at the dermal-epidermal basement membrane zone. The
collagen VII molecules form disulfide bond stabilized dimeric aggregates
by lateral accretion in a nonstaggered array (Burgeson et al., 1985). By
Northern hybridization studies using a cDNA, Ryynanen et al. (1992)
demonstrated a 9-kb mRNA transcript with a high level of expression in
epidermal keratinocytes and in an oral epidermoid carcinoma cell line
and with considerably lower expression in skin fibroblasts. Indirect
immunofluorescence of skin from a 19-week fetus showed type VII collagen
gene expression at the dermal-epidermal basement membrane zone. They
interpreted these results as indicating that epidermal keratinocytes may
be the primary cell source of type VII collagen in developing human
skin. Tanaka et al. (1992) isolated a cDNA of approximately 1 kb from a
human keratinocyte library. The deduced primary structure of the clone
reflected the noncollagenous domain of type VII collagen that may be
involved in cell attachment. The region showed weak homology
(approximately 23%) to the cell attachment domain of fibronectin.
Greenspan (1993) described the carboxyl-terminal half of type VII
collagen and the intron/exon organization of the corresponding region of
the COL7A1 gene. Christiano et al. (1994) found that the COL7A1 gene has
118 exons, more than any previously described gene. Despite this
complexity, COL7A1 is compact. Consisting of 31,132 bp from
transcription start site to polyadenylation site, it is only about 3
times the size of type VII collagen mRNA. Thus, COL7A1 introns are
small. A 71-nucleotide COL7A1 intron is the smallest intron reported in
a collagen gene, and only 1 COL7A1 intron is greater than 1 kb long.
Christiano et al. (1994) stated that the type VII collagen mRNA is
approximately 9.2 kb long, with an open reading frame of 8,833
nucleotides encoding 2,944 amino acids. They reported the complete cDNA
and primary amino acid sequences and also described polymorphisms in the
gene.

Parente et al. (1991) cloned a cDNA for type VII collagen and used it
for chromosomal in situ hybridization to localize the COL7A1 gene to
3p21. By fluorescence in situ hybridization, Greenspan et al. (1993)
narrowed the assignment to 3p21.3. Knowlton et al. (1991) and Ryynanen
et al. (1991) mapped the COL7A1 gene to chromosome 3 by analysis of
human-rodent somatic cell hybrids. By use of interspecific backcross
mapping, Li et al. (1993) showed that the corresponding gene is located
on chromosome 9 in the mouse.

Knowlton et al. (1991) and Ryynanen et al. (1991) demonstrated close
linkage (with no recombination) of COL7A1 to autosomal dominant
dystrophic epidermolysis bullosa (DEB; see 131750). In a study of 19
informative families with recessive DEB (226600), Hovnanian et al.
(1992) found a maximum lod score of 3.95 at theta = 0.0 with no
recombinants. Also, Uitto et al. (1992) demonstrated absolute linkage
between a PvuII RFLP of the COL7A1 gene and dominant dystrophic
epidermolysis bullosa; in 4 informative families a combined lod score of
14.6 at theta = 0 was found, with no recombinants. Thus, 2 forms of
epidermolysis bullosa, one dominant and one recessive, are due to
mutations in the same gene. It is likely that the mutations with
heterozygous expression produce a change in the protein gene product
causing 'protein suicide,' i.e., disruption in the formation of the
trimeric collagen molecule. On the other hand, the recessive mutations
may cause a change in the gene product of such a nature that all the
gene product must be of the mutant type for the phenotype to be
expressed. Christiano et al. (1995) described nonsense mutations
resulting in a premature termination codon in the amino-terminal portion
of the COL7A1 gene in 4 COL7A1 alleles from 3 unrelated patients with
severe, mutilating recessive DEB (see 120120.0005). One of the patients
was a compound heterozygote. Heterozygous carriers of the nonsense
mutations were clinically unaffected although they showed a 50%
reduction in anchoring fibrils.

Type VII collagen appears to be restricted to the basement membrane zone
beneath stratified squamous epithelia. Within the cutaneous basement
membrane zone, type VII collagen localizes to the lamina densa and
sub-lamina densa areas in the upper papillary dermis. More precisely,
immunolocalization demonstrated that type VII collagen is a major
collagenous component of anchoring fibrils. The acquired form of
epidermolysis bullosa, EB acquisata (EBA), is an autoimmune disorder
resulting from autoantibodies to type VII collagen. By Western
immunoblotting analysis with sera from 19 patients with EBA, using
bacterial collagenase- or pepsin-resistant portions of type VII collagen
and a panel of 12 recombinant fusion proteins corresponding to
approximately 80% of the primary sequence of the COL7A1 polypeptide,
Lapiere et al. (1993) identified 4 major immunodominant epitopes within
the noncollagenous (NC1) domain. The pattern of epitopes recognized by
the sera from 3 patients with bullous systemic lupus erythematosus
(BSLE) was similar to that found with EBA, suggesting that the same
epitopes could serve as autoantigens in both blistering conditions. In
contrast, sera from healthy controls or from patients with unrelated
blistering skin diseases did not react with type VII collagen epitopes.
Lapiere et al. (1993) postulated that such antibodies could disrupt the
assembly of type VII collagen into anchoring fibrils and/or interfere
with their interactions with other extracellular matrix molecules within
the cutaneous basement membrane zone.

Hovnanian et al. (1995) used COL7A1 gene analysis for successful
first-trimester prenatal diagnosis in 6 families at risk for recurrence
of generalized recessive DEB. The disorder was of the severe
Hallopeau-Siemens form in 5 families and the generalized nonmutilating
form in 1. In all cases analysis of fetal DNA from amniotic fluid cells
showed that the fetus had inherited at least one normal COL7A1 allele.

Zelickson et al. (1995) studied the descendants of the original family
with Bart syndrome (132000), a skin disorder involving congenital
localized absence of skin and deformity of nails, and found linkage of
the disorder to 3p, at or near the site of the COL7A1 gene. Christiano
et al. (1996) performed mutation analysis in this family using
electrophoretic heteroduplex analysis followed by direct nucleotide
sequencing (see 120120.0008).

Christiano et al. (1996) demonstrated the wide variability in the
phenotype of DEB and the differences in patterns of inheritance with
various glycine substitutions in the triple-helical region of type VII
collagen. They reported 6 new families and compared the results with
other data. Among the 6 families, 2 demonstrated a mild phenotype, and
the inheritance was consistent with the dominantly inherited form of
DEB. In the 4 other families, the mutation was silent in the
heterozygous state but, when present in the homozygous state or combined
with a second mutation, resulted in a recessively inherited DEB
phenotype. Christiano et al. (1996) stated that the COL7A1 gene is,
therefore, unique among the collagen genes in that different glycine
substitutions can be either silent in heterozygotes or can result in a
dominantly inherited DEB. Inspection of the location of the glycine
substitutions along the COL7A1 polypeptide suggested to the authors that
the consequences of the mutations, in terms of phenotype and pattern of
inheritance, are position-independent. In an accompanying article
Christiano et al. (1996) described compound heterozygosity in twins with
severe DEB. The twins had inherited from the father a recessive
deletion/insertion mutation and from the mother a dominant-negative
maternal glycine substitution. Careful questioning of the mother
revealed that she and her father had a history of shedding of toenails
and an occasional poor healing of erosions, consistent with a mild form
of dominantly inherited DEB. The mutation from the father was a 2-bp
deletion/1-bp insertion in exon 56 (designated 5103CC-to-G by the
authors) which resulted in a frameshift and a downstream premature
termination codon. The mutation from the mother was a
glycine-to-arginine substitution in exon 91 (G2351R).

*FIELD* AV
.0001
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE
COL7A1, MET-LYS
In an African-American family in which 4 individuals related as first
cousins once removed had autosomal recessive epidermolysis bullosa
dystrophica, Christiano et al. (1993) used single-strand conformation
polymorphism (SSCP) electrophoresis and sequencing to demonstrate a
T-to-A transversion resulting in substitution of lysine for methionine
in type VII collagen. The mutation was homozygous in 2 affected sibs,
while their unaffected mother and half brother were heterozygous. The
mutation resided in a highly conserved region of the C-terminus of type
VII collagen and was not found in 194 alleles from unrelated, unaffected
African-American individuals when screened with a restriction analysis
based on a new restriction site for the endonuclease EarI created by the
mutation.

.0002
EPIDERMOLYSIS BULLOSA DYSTROPHICA, DOMINANT
COL7A1, GLY2040SER
Christiano et al. (1994) searched for mutations in dominant dystrophic
EB by PCR amplification of genomic segments of COL7A1, followed by
heteroduplex analysis. Examination of the PCR fragment corresponding to
exon 73 of COL7A1 revealed a marked shift in the electrophoretic pattern
in patients from a large Finnish dominant dystrophic EB family that had
previously been shown to demonstrate linkage to the COL7A1 locus.
Sequence analysis demonstrated a G-to-A transition at nucleotide 6118 in
the triple helical domain, which converted glycine residue 2040 to
serine. The clinical phenotype in this family was interpreted as arising
through a dominant negative mutation in type VII collagen, resulting in
the formation of structurally abnormal anchoring fibrils.

.0003
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE
COL7A1, 1BP INS, INS2470G, FS, TER
In a 35-year-old Hispanic male with extreme fragility of the skin and
the mucous membranes of the upper gastrointestinal tract, leading to
extensive mutilating scarring and joint contractures, Christiano et al.
(1996) found compound heterozygosity for 2 nonsense mutations. One was
an insertion of an additional G to the 2 Gs in position 2470-2471 in
exon 19 of the COL7A1 cDNA. This insertion, 2470insG, resulted in a
frameshift that caused a premature stop codon 120 bp downstream of the
site of the nucleotide insertion. The mutation was predicted to result
in a truncated alpha-1(VII) chain that terminated within the domain
encoded by exon 20. The other allele showed deletion of 1 of the 4 Gs in
position 3858-3861 within exon 31 of the COL7A1 cDNA (120120.0004). This
deletion, called 3858delG, resulted in a frameshift and a premature
termination codon 111 bp downstream from the site of the nucleotide
deletion. The premature termination codon was predicted to result in a
truncated alpha-1(VII) chain that terminated within exon 32.

.0004
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE
COL7A1, 1BP DEL, DEL3858G, FS, TER
See 120120.0003 and Christiano et al. (1996).

.0005
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE
COL7A1, TYR311TER
In 3 Japanese brothers with severe, mutilating recessive dystrophic EB
(Hallopeau-Siemens type), Christiano et al. (1995) found compound
heterozygosity for 2 different mutations, both of which resulted in a
premature termination codon in the COL7A1 gene. One mutation was a
change of codon 311 from TAC to TAA, changing tyrosine to a stop codon.
The other mutation was a deletion of nucleotide 5818 (120120.0006), a
cytosine, which led to a frameshift and a premature termination codon
(TGA) 64 amino acids downstream in exon 73 of COL7A1.

.0006
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE
COL7A1, 1BP DEL, DEL5818C, FS, TER
See 120120.0005 and Christiano et al. (1995).

.0007
EPIDERMOLYSIS BULLOSA, PRETIBIAL
COL7A1, GLY2623CYS
In a large 5-generation family of Taiwanese descent with pretibial
epidermolysis bullosa (131850), Christiano et al. (1995) identified a
G-to-T transversion at nucleotide position 7687 of their sequence, which
resulted in a glycine-to-cysteine substitution (G2623C) in exon 105 of
the COL7A1 gene. The mutation was confirmed in affected family members
using the loss of a SmaI restriction site, and when used for linkage
analysis, together with an intragenic PvuII polymorphism in several
flanking markers, resulted in a lod score of 3.61 at theta = 0.0 in this
family. Thus, the Cockayne-Touraine form (131800) of epidermolysis
bullosa, the Pasini form (131750), and the pretibial variant are
allelic, resulting from different glycine substitution mutations in the
type VII collagen gene.

.0008
EPIDERMOLYSIS BULLOSA DYSTROPHICA, BART SYNDROME TYPE
COL7A1, GLY2003ARG
Studying the original family with Bart syndrome reported by Bart et al.
(1966), Christiano et al. (1996) demonstrated a G-to-A transition at
nucleotide 6007 within exon 73 of COL7A1 that resulted in a
gly2003-to-arg substitution (GGG-to-AGG) within the triple-helical
domain of type VII collagen in affected individuals. Thus, in this
family Bart syndrome is a clinical variant of dominant dystrophic
epidermolysis bullosa. The affected persons were heterozygous for the
mutation. Previously defined mutations in exon 73, e.g., gly2040-to-ser
(120120.0002), occurred in families with the feature of the
Cockayne-Touraine or Pasini type. Thus, the clinical differences in the
phenotype of the several forms of dominant dystrophic EB must result
from the specific location of the glycine substitutions within exon 73.

.0009
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE, LOCALISATA VARIANT
COL7A1, IVS3DS, G-A, -2
Gardella et al. (1996) identified 2 splicing mutations of COL7A1 in a
patient affected by the localisata variant of recessive epidermolysis
bullosa. This variant is a mild form of RDEB in which blistering and
scarring are predominantly localized to the extremities. One mutation is
a paternally inherited A-to-G transition at position -2 of the donor
splice site of intron 3. The second mutation is a maternally inherited
G-to-A transition at position -1 of the donor splice site of intron 95
(120120.0010). The mutations result in aberrant forms of mRNA.
Allele-specific analysis of the transcripts indicated to Gardella et al.
(1996) that the maternal mutation did not completely abolish correct
splicing of COL7A1 pre-mRNA and that synthesis of a certain level of
functional protein was observed. This result was compatible with the
mild phenotype observed in the patient.

.0010
EPIDERMOLYSIS BULLOSA DYSTROPHICA, RECESSIVE, LOCALISATA VARIANT
COL7A1, IVS95DS, G-A, -1
See 120120.0009 and Gardella et al. (1996). This mutation resulted in
aberrant forms of mRNA from COL7A1.

*FIELD* RF
1. Bart, B. J.; Gorlin, R. J.; Anderson, V. E.; Lynch, F. W.: Congenital
localized absence of skin and associated abnormalities resembling
epidermolysis bullosa: a new syndrome. Arch. Derm. 93: 296-304,
1966.

2. Bentz, H.; Morris, N. P.; Murray, L. W.; Sakai, L. Y.; Hollister,
D. W.; Burgeson, R. E.: Isolation and partial characterization of
a new human collagen with an extended triple-helical structural domain. Proc.
Nat. Acad. Sci. 80: 3168-3172, 1983.

3. Burgeson, R. E.; Morris, N. P.; Murray, L. W.; Duncan, K. G.; Keene,
D. R.; Sakai, L. Y.: The structure of type VII collagen. Ann. N.Y.
Acad. Sci. 460: 47-57, 1985.

4. Christiano, A. M.; Anton-Lamprecht, I.; Amano, S.; Ebschner, U.;
Burgeson, R. E.; Uitto, J.: Compound heterozygosity for COL7A1 mutations
in twins with dystrophic epidermolysis bullosa: a recessive paternal
deletion/insertion mutation and a dominant negative maternal glycine
substitution result in a severe phenotype. Am. J. Hum. Genet. 58:
682-693, 1996.

5. Christiano, A. M.; Bart, B. J.; Epstein, E. H., Jr.; Uitto, J.
: Genetic basis of Bart's syndrome: a glycine substitution mutation
in the type VII collagen gene. J. Invest. Derm. 106: 778-780, 1996.

6. Christiano, A. M.; Greenspan, D. S.; Hoffman, G. G.; Zhang, X.;
Tamai, Y.; Lin, A. N.; Dietz, H. C.; Hovnanian, A.; Uitto, J.: A
missense mutation in type VII collagen in two affected siblings with
recessive dystrophic epidermolysis bullosa. Nature Genet. 4: 62-66,
1993.

7. Christiano, A. M.; Greenspan, D. S.; Lee, S.; Uitto, J.: Cloning
of human type VII collagen: complete primary sequence of the alpha-1(VII)
chain and identification of intragenic polymorphisms. J. Biol. Chem. 269:
20256-20262, 1994.

8. Christiano, A. M.; Hoffman, G. G.; Chung-Honet, L. C.; Lee, S.;
Cheng, W.; Uitto, J.; Greenspan, D. S.: Structural organization of
the human type VII collagen gene (COL7A1), composed of more exons
than any previously characterized gene. Genomics 21: 169-179, 1994.

9. Christiano, A. M.; Lee, J. Y.-Y.; Chen, W. J.; LaForgia, S.; Uitto,
J.: Pretibial epidermolysis bullosa: genetic linkage to COL7A1 and
identification of a glycine-to-cysteine substitution in the triple-helical
domain of type VII collagen. Hum. Molec. Genet. 4: 1579-1583, 1995.

10. Christiano, A. M.; McGrath, J. A.; Tan, K. C.; Uitto, J.: Glycine
substitutions in the triple-helical region of type VII collagen result
in a spectrum of dystrophic epidermolysis bullosa phenotypes and patterns
of inheritance. Am. J. Hum. Genet. 58: 671-681, 1996.

11. Christiano, A. M.; Ryynanen, M.; Uitto, J.: Dominant dystrophic
epidermolysis bullosa: identification of a gly-to-ser substitution
in the triple-helical domain of type VII collagen. Proc. Nat. Acad.
Sci. 91: 3549-3553, 1994.

12. Christiano, A. M.; Suga, Y.; Greenspan, D. S.; Ogawa, H.; Uitto,
J.: Premature termination codons on both alleles of the type VII
collagen gene (COL7A1) in three brothers with recessive dystrophic
epidermolysis bullosa. J. Clin. Invest. 95: 1328-1334, 1995.

13. Gardella, R.; Belletti, L.; Zoppi, N.; Marini, D.; Barlati, S.;
Colombi, M.: Identification of two splicing mutations in the collagen
type VII gene (COL7A1) of a patient affected by the localisata variant
of recessive dystrophic epidermolysis bullosa. Am. J. Hum. Genet. 59:
292-300, 1996.

14. Greenspan, D. S.: The carboxyl-terminal half of type VII collagen,
including the non-collagenous NC-2 domain and intron/exon organization
of the corresponding region of the COL7A1 gene. Hum. Molec. Genet. 2:
273-278, 1993.

15. Greenspan, D. S.; Byers, M. G.; Eddy, R. L.; Hoffman, G. G.; Shows,
T. B.: Localization of the human collagen gene COL7A1 to 3p21.3 by
fluorescence in situ hybridization. Cytogenet. Cell Genet. 62: 35-36,
1993.

16. Hovnanian, A.; Duquesnoy, P.; Blanchet-Bardon, C.; Knowlton, R.
G.; Amselem, S.; Lathrop, M., II; Dubertret, L.; Uitto, J.; Goossens,
M.: Genetic linkage of recessive dystrophic epidermolysis bullosa
to the type VII collagen gene.(Abstract) Clin. Res. 40: 188A, 1992.

17. Hovnanian, A.; Hilal, L.; Blanchet-Bardon, C.; Bodemer, C.; de
Prost, Y.; Stark, C. A.; Christiano, A. M.; Dommergues, M.; Terwilliger,
J. D.; Izquierdo, L.; Conteville, P.; Dumez, Y.; Uitto, J.; Goossens,
M.: DNA-based prenatal diagnosis of generalized recessive dystrophic
epidermolysis bullosa in six pregnancies at risk for recurrence. J.
Invest. Derm. 104: 456-461, 1995.

18. Knowlton, R. G.; Ryynanen, M.; Parente, M. G.; Chung, L. C.; Chu,
M.-L.; Uitto, J.: Genetic linkage of dominant dystrophic epidermolysis
bullosa to the type VII collagen gene on chromosome 3.(Abstract) Am.
J. Hum. Genet. 49 (suppl.): 16, 1991.

19. Lapiere, J.-C.; Woodley, D. T.; Parente, M. G.; Iwasaki, T.; Wynn,
K. C.; Christiano, A. M.; Uitto, J.: Epitope mapping of type VII
collagen: identification of discrete peptide sequences recognized
by sera from patients with acquired epidermolysis bullosa. J. Clin.
Invest. 92: 1831-1839, 1993.

20. Li, K.; Christiano, A. M.; Copeland, N. G.; Gilbert, D. J.; Chu,
M.-L.; Jenkins, N. A.; Uitto, J.: cDNA cloning and chromosomal mapping
of the mouse type VII collagen gene (Col7a1): evidence for rapid evolutionary
divergence of the gene. Genomics 16: 733-739, 1993.

21. Parente, M. G.; Chung, L. C.; Ryynanen, J.; Woodley, D. T.; Wynn,
K. C.; Bauer, E. A.; Mattei, M.-G.; Chu, M.-L.; Uitto, J.: Human
type VII collagen: cDNA cloning and chromosomal mapping of the gene. Proc.
Nat. Acad. Sci. 88: 6931-6935, 1991.

22. Ryynanen, J.; Sollberg, S.; Parente, M. G.; Chung, L. C.; Christiano,
A. M.; Uitto, J.: Type VII collagen gene expression by cultured human
cells and in fetal skin: abundant mRNA and protein levels in epidermal
keratinocytes. J. Clin. Invest. 89: 163-168, 1992.

23. Ryynanen, M.; Knowlton, R. G.; Parente, M. G.; Chung, L. C.; Chu,
M.-L.; Uitto, J.: Human type VII collagen: genetic linkage of the
gene (COL7A1) on chromosome 3 to dominant dystrophic epidermolysis
bullosa. Am. J. Hum. Genet. 49: 797-803, 1991.

24. Tanaka, T.; Takahashi, K.; Furukawa, F.; Imamura, S.: Molecular
cloning and characterization of type VII collagen cDNA. Biochem.
Biophys. Res. Commun. 183: 958-963, 1992.

25. Uitto, J.; Ryynanen, M.; Christiano, A. M.; Hovnanian, A.; Frantz,
R.; Bauer, E. A.; Knowlton, R. G.: Genetic linkage of the type VII
collagen gene (COL7A1) to dominant dystrophic epidermolysis bullosa
(DDEB) in families with abnormal anchoring fibrils.(Abstract) Clin.
Res. 40: 188A, 1992.

26. Zelickson, B.; Matsumura, K.; Kist, D.; Epstein, E. H., Jr.; Bart,
B. J.: Bart's syndrome: ultrastructure and genetic linkage. Arch.
Derm. 131: 663-668, 1995.

*FIELD* CN
Moyra Smith - updated: 10/1/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/01/1996
mark: 10/1/1996
terry: 6/12/1996
terry: 6/4/1996
mark: 4/26/1996
terry: 4/19/1996
joanna: 4/18/1996
mark: 11/6/1995
carol: 12/22/1994
jason: 6/7/1994
carol: 10/29/1993
carol: 10/26/1993
carol: 6/18/1993

*RECORD*
*FIELD* NO
120130
*FIELD* TI
*120130 COLLAGEN, TYPE IV, ALPHA-1 CHAIN; COL4A1
COLLAGEN OF BASEMENT MEMBRANE, ALPHA-1 CHAIN
*FIELD* TX
Types I, II, and III collagen, the so-called interstitial collagens, are
in many ways distinct from basement membrane collagen. Type IV collagen
does not form ordered fibrillar structures; rather, a meshwork is formed
by 4 molecules held together at the ends. Both disulfide and typical
lysyl-derived collagen crosslinks are involved (Kuhn, 1982). Crouch et
al. (1980) presented evidence that type IV procollagen contains 2
distinct chains. The collagen IV molecule is a heterodimer of 2 alpha-1
chains and 1 alpha-2 chain (Mayne et al., 1984). There are presumably 2
gene loci responsible for the alpha-1 and alpha-2 chains of type IV
collagen. Using a cloned gene as a probe on Southern blots of DNA from a
panel of interspecies somatic cell hybrids, Solomon et al. (1985)
assigned one of the collagen IV genes, COL4A1, to chromosome 13.
Pihlajaniemi et al. (1985) used dual-laser sorted chromosomes and
spot-blot analysis to assign genomic DNA sequences coding for COL4A1 to
chromosome 13. By in situ hybridization, Boyd et al. (1986) localized
the gene to the end of the long arm of chromosome 13. Southern and
spot-blot hybridization showed that these genomic sequences were present
only once per haploid genome. Emanuel et al. (1986) assigned COL4A1 to
the telomeric region of 13q (13q34) by in situ hybridization. Bowcock et
al. (1987) found that the COL4A1 locus is linked to D13S3, which in turn
has been assigned to 13q33-q34 by in situ hybridization. They found a
maximum lod score of 16.5 at theta = 0.01. Griffin et al. (1987) showed
by in situ hybridization and Southern blot analysis of DNA from somatic
cell hybrids that the COL4A2 gene is also on the distal long arm of
chromosome 13, apparently closely linked to the alpha-1(IV) gene. By
means of pulsed-field gel electrophoresis (PFGE) and infrequently
cutting restriction enzymes, Cutting et al. (1987) showed that the
COL4A1 and COL4A2 genes are separated by no more than 400 kb. Using
RFLPs identified within the two genes, Hebert et al. (1987) also showed
that COL4A1 and COL4A2 are closely linked. Bowcock et al. (1988) found
that the COL4A1 and COL4A2 genes are linked, with a maximum likelihood
estimate of recombination of 0.028 at a lod score of 19.98. This and the
lack of linkage disequilibrium are inconsistent with relatively high
recombination between the 2 loci--higher than expected for 2 genes that
lie within 650 kb of each other. Koizumi et al. (1995) used
interspecific and intersubspecific mapping panels to locate the Col4a1
gene to the centromeric region of mouse chromosome 8. COL4A2 (120090)
and coagulation factor X (F10; 227600) mapped to the same region, thus
defining a new region of homology of synteny between mouse chromosome 8
and human chromosome 13.

Poschl et al. (1988) isolated and sequenced a 2.2-kb genomic fragment
that contained the 5-prime terminal exons of both COL4A1 and COL4A2. The
2 genes were found to be arranged in opposite directions, head-to-head,
separated only by 127 bp. The connecting segment apparently contained
promoters of both genes as indicated by the existence of typical
sequence motifs. Poschl et al. (1988) interpreted the findings as
suggesting that the 2 genes have a common, bidirectional promoter.
Soininen et al. (1988) found that the COL4A1 and COL4A2 genes are
encoded on opposite DNA strands from loci that are so closely located
that they may be separated by as little as 42 base pairs. This was the
first description of 2 structural genes from a complex organism coding
for 2 polypeptide chains of the same protein molecule but having
overlapping 5-prime flanking regions. Many of the genes of simple
organisms with small genomes are encoded on opposite DNA strands so that
the genes either overlap or 1 gene is nested within another gene. Tsonis
and Goetinck (1988) pointed out structural relatedness of the Drosophila
homeotic gene 'spalt' and the alpha-1 chain of type IV collagen. This
may reflect a role of extracellular products of homeotic genes in
cell-to-cell interactions. Burbelo et al. (1988) found a similar
situation in the mouse where the collagen genes exist in a head-to-head
arrangement on opposite strands separated by 130 base pairs; they are
regulated by a bidirectional promoter located between the 2 genes
working in concert with an enhancer located in the first intron of the
COL4A1 gene. Wieslander et al. (1984, 1985) presented immunochemical
evidence that the Goodpasture antibodies react with
collagenase-resistant parts of the type IV collagen molecule. About 5%
of cases of glomerulonephritis are mediated by autoantibodies to
glomerular basement membrane (GBM). Most of these patients present with
Goodpasture syndrome (glomerulonephritis and pulmonary hemorrhage).
Butkowski et al. (1987) localized the Goodpasture epitope to a novel
chain of type IV collagen composed of 3 distinctive subunits--M1, M2*,
and M3. The Goodpasture epitope was found to be situated exclusively on
M2*. Turner et al. (1992) demonstrated that the Goodpasture antigen is
the alpha-3 chain of type IV collagen (COL4A3; 120070).

*FIELD* SA
Brinker et al. (1985); Cutting et al. (1988); Soininen et al. (1986);
Soininen et al. (1986)
*FIELD* RF
1. Bowcock, A. M.; Hebert, J. M.; Christiano, A. M.; Wijsman, E.;
Cavalli-Sforza, L. L.; Boyd, C. D.: The pro alpha 1 (IV) collagen
gene is linked to the D13S3 locus at the distal end of human chromosome
13q. Cytogenet. Cell Genet. 45: 234-236, 1987.

2. Bowcock, A. M.; Hebert, J. M.; Wijsman, E.; Gadi, I.; Cavalli-Sforza,
L. L.; Boyd, C. D.: High recombination between two physically close
human basement membrane collagen genes at the distal end of chromosome
13q. Proc. Nat. Acad. Sci. 85: 2701-2705, 1988.

3. Boyd, C. D.; Weliky, K.; Toth-Fejel, S.; Deak, S. B.; Christiano,
A. M.; Mackenzie, J. W.; Sandell, L. J.; Tryggvason, K.; Magenis,
E.: The single copy gene coding for human alpha-1(IV) procollagen
is located at the terminal end of the long arm of chromosome 13. Hum.
Genet. 74: 121-125, 1986.

4. Brinker, J. M.; Gudas, L. J.; Loidl, H. R.; Wang, S.-Y.; Rosenbloom,
J.; Kefalides, N. A.; Myers, J. C.: Restricted homology between human
alpha-1 type IV and other procollagen chains. Proc. Nat. Acad. Sci. 82:
3649-3653, 1985.

5. Burbelo, P. D.; Martin, G. R.; Yamada, Y.: Alpha-1(IV) and alpha-2(IV)
collagen genes are regulated by a bidirectional promoter and a shared
enhancer. Proc. Nat. Acad. Sci. 85: 9679-9682, 1988.

6. Butkowski, R. J.; Langeveld, J. P. M.; Wieslander, J.; Hamilton,
J.; Hudson, B. G.: Localization of the Goodpasture epitope to a novel
chain of basement membrane collagen. J. Biol. Chem. 262: 7874-7877,
1987.

7. Crouch, E.; Sage, H.; Bornstein, P.: Structural basis for apparent
heterogeneity of collagens in human basement membranes: type IV procollagen
contains two distinct chains. Proc. Nat. Acad. Sci. 77: 745-749,
1980.

8. Cutting, G. R.; Kazazian, H. H., Jr.; Antonarakis, S. E.; Killen,
P. D.; Yamada, Y.; Francomano, C. A.: Macrorestriction analysis maps
COL4A1 and COL4A2 collagen genes within a 400 kb region on chromosome
13q34.   (Abstract) Am. J. Hum. Genet. 41: A163, 1987.

9. Cutting, G. R.; Kazazian, H. H., Jr.; Antonarakis, S. E.; Killen,
P. D.; Yamada, Y.; Francomano, C. A.: Macrorestriction mapping of
COL4A1 and COL4A2 collagen genes on human chromosome 13q34. Genomics 3:
256-263, 1988.

10. Emanuel, B. S.; Sellinger, B. T.; Gudas, L. J.; Myers, J. C.:
Localization of the human procollagen alpha-1(IV) gene to chromosome
13q34 by in situ hybridization. Am. J. Hum. Genet. 38: 38-44, 1986.

11. Griffin, C. A.; Emanuel, B. S.; Hansen, J. R.; Cavenee, W. K.;
Myers, J. C.: Human collagen genes encoding basement membrane alpha-1(IV)
and alpha-2(IV) chains map to the distal long arm of chromosome 13.
Proc. Nat. Acad. Sci. 84: 512-516, 1987.

12. Hebert, J. M.; Bowcock, A. M.; Wijsman, E.; Gadi, I.; Boyd, C.;
Cavalli-Sforza, L. L.: The genes for pro-alpha-1 (IV) collagen, pro-alpha-2
(IV) collagen and the D13S3 locus are linked at 13q34.   (Abstract) Am.
J. Hum. Genet. 41: A169, 1987.

13. Koizumi, T.; Hendel, E.; Lalley, P. A.; Tchetgen, M.-B. N.; Nadeau,
J. H.: Homologs of genes and anonymous loci on human chromosome 13
map to mouse chromosomes 8 and 14. Mammalian Genome 6: 263-268,
1995.

14. Kuhn, K.: Personal Communication. Munich, Germany  1/7/1982.

15. Mayne, R.; Wiedemann, H.; Irwin, M. H.; Sanderson, R. D.; Fitch,
J. M.; Linsenmayer, T. F.; Kuhn, K.: Monoclonal antibodies against
chicken type IV and V collagens: electron microscopic mapping of the
epitopes after rotary shadowing. J. Cell Biol. 98: 1637-1644, 1984.

16. Pihlajaniemi, T.; Tryggvason, K.; Myers, J. C.; Kurkinen, M.;
Lebo, R.; Cheung, M.-C.; Prockop, D. J.; Boyd, C. D.: cDNA clones
coding for the pro-alpha-1(IV) chain of human type IV procollagen
reveal an unusual homology of amino acid sequences in two halves of
the carboxyl terminal domain. J. Biol. Chem. 260: 7681-7687, 1985.

17. Poschl, E.; Pollner, R.; Kuhn, K.: The genes for the alpha-1(IV)
and alpha-2(IV) chains of human basement membrane collagen type IV
are arranged head-to-head and separated by a bidirectional promoter
of unique structure. EMBO J. 7: 2687-2695, 1988.

18. Soininen, R.; Chow, L.; Kurkinen, M.; Tryggvason, K.; Prockop,
D. J.: The gene for the alpha-1(IV) chain of human type IV procollagen:
the exon structures do not coincide with the two structural subdomains
in the globular carboxy-terminus of the protein. EMBO J. 5: 2821-2823,
1986.

19. Soininen, R.; Huotari, M.; Hostikka, S. L.; Prockop, D. J.; Tryggvason,
K.: The structural genes for alpha-1 and alpha-2 chains of human
type IV collagen are divergently encoded on opposite DNA strands and
have an overlapping promoter region. J. Biol. Chem. 263: 17217-17220,
1988.

20. Soininen, R.; Tikka, L.; Chow, L.; Pihlajaniemi, T.; Kurkinen,
M.; Prockop, D. J.; Boyd, C. D.; Tryggvason, K.: Large introns in
the 3-prime end of the gene for the pro-alpha1(IV) chain of human
basement membrane collagen. Proc. Nat. Acad. Sci. 83: 1568-1572,
1986.

21. Solomon, E.; Hiorns, L. R.; Spurr, N.; Kurkinen, M.; Barlow, D.;
Hogan, B. L. M.; Dalgleish, R.: Chromosomal assignments of the genes
coding for human types II, III and IV collagen: a dispersed gene family.
Proc. Nat. Acad. Sci. 82: 3330-3334, 1985.

22. Tsonis, P.; Goetinck, P. F.: The Drosophila homoeotic gene spalt
is structurally related to collagen alpha-1(IV) chain.   (Letter) Collagen
Rel. Res. 8: 451-452, 1988.

23. Turner, N.; Mason, P. J.; Brown, R.; Fox, M.; Povey, S.; Rees,
A.; Pusey, C. D.: Molecular cloning of the human Goodpasture antigen
demonstrates it to be the alpha-3 chain of type IV collagen. J.
Clin. Invest. 89: 592-601, 1992.

24. Wieslander, J.; Barr, J. F.; Butkowski, R. J.; Edwards, S. J.;
Bygren, P.; Heinegard, D.; Hudson, B. G.: Goodpasture antigen of
the glomerular basement membrane: localization to noncollagenous regions
of type IV collagen. Proc. Nat. Acad. Sci. 81: 3838-3842, 1984.

25. Wieslander, J.; Langeveld, J.; Butkowski, R.; Jodlowski, M.; Noelken,
M.; Hudson, B. G.: Physical and immunochemical studies of the globular
domain of type IV collagen: cryptic properties of the Goodpasture
antigen. J. Biol. Chem. 260: 8564-8570, 1985.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/07/1996
mark: 5/11/1995
warfield: 4/7/1994
carol: 5/26/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 3/2/1990

*RECORD*
*FIELD* NO
120131
*FIELD* TI
*120131 COLLAGEN, TYPE IV, ALPHA-4 CHAIN; COL4A4
COLLAGEN OF BASEMENT MEMBRANE, ALPHA-4 CHAIN
*FIELD* TX
Butkowski et al. (1987) and Saus et al. (1988) identified 2 type IV
collagen alpha chains distinct from the alpha-1 (COL1A1; 120130) and
alpha-2 (120090) chains. These are designated alpha-3 (120070) and
alpha-4. Gunwar et al. (1990) characterized further the alpha-4 chain of
type IV collagen. Mariyama et al. (1992) isolated partial cDNAs for the
COL4A4 gene. On the basis of comparisons of the deduced peptide
sequences of all 5 chains of type IV collagen, Mariyama et al. (1992)
concluded that they can be divided into 2 families: those that resemble
alpha-1 (COL4A1, COL4A3, and COL4A5); and those that resemble alpha-2
(COL4A2 and COL4A4). COL4A1 and COL4A2 map to 13q34 and are transcribed
from opposite DNA strands using a common bidirectional promoter that
allows coordinate regulation of the 2 chains. These 2 chains are
commonly found together in basement membrane and form heterotrimers.
Whereas alpha-1(IV) and alpha-2(IV) are found in all basement membranes
studied, alpha-3(IV) and alpha-4(IV) are found only in a subset of
basement membranes. They are always found together, however. In view of
these relationships and the structural similarities between the 2 pairs
of collagen chains, Mariyama et al. (1992) hypothesized that COL4A3 and
COL4A4 might have a genomic organization similar to that of COL4A1 and
COL4A2. Indeed, by analysis of somatic cell hybrids and by in situ
hybridization, they found that the 2 genes map to the same region,
2q35-q37. Whether the genomic organization is similar to that of the
pair on chromosome 13 was under investigation. Kamagata et al. (1992)
compared the COL4A4 chain with the other 4 chains of type IV collagen.
Using a human genomic DNA fragment for in situ hybridization, they
mapped the COL4A4 gene to 2q35-q37.1.

The COL4A3 and COL4A4 genes are arranged in a head-to-head manner on 2q
and the entire transcription units of both genes have been cloned in a
single YAC. Mutations in one or the other gene have been identified in
cases of autosomal recessive Alport syndrome (203780) which is
characterized by parental consanguinity, severe disease beginning in the
first decade of life in females, and asymptomatic parents. Out of 7
families with presumed autosomal recessive Alport syndrome, Mochizuki et
al. (1994) demonstrated COL4A3 mutations in 2 and COL4A4 mutations in 2.

Leinonen et al. (1994) determined the entire sequence of the COL4A4
gene. The complete translation product has 1,690 amino acid residues and
the processed polypeptide contains 1,652 residues. There is a 38-residue
putative signal peptide, a 1,421-residue collagenous domain starting
with a 23-residue noncollagenous sequence, and a 231-residue NC1 domain.
Differences and similarities with the other component chains of type IV
collagen were detailed.

Using cDNA probes generated from normal dog kidney, Thorner et al.
(1996) compared the nucleotide and deduced amino acid sequences of
normal canine and human alpha-1 type IV collagen to the alpha-4 type IV
and alpha-6 type IV (303631) chains. They found that the canine
sequences are over 88% identical at the DNA level and over 92% identical
at the protein level to the respective human alpha chains. The positions
of the cysteine residues are conserved between all canine alpha type IV
chains and between each canine and human alpha IV chain.

The form of autosomal recessive Alport syndrome due to mutation in the
COL4A3 gene is referred to here as type I and that due to mutation in
the COL4A4 gene is referred to as type II.

ANIMAL MODEL

Canine X-linked hereditary nephritis is an animal model for human
X-linked hereditary nephritis (Alport syndrome) (301050) characterized
by the presence of a premature stop codon in the alpha-5 chain (303630)
of collagen type IV. Thorner et al. (1996) examined expression of the
canine collagen type IV genes in the kidney. They detected alpha-3,
alpha-4, and alpha-5 chains in the noncollagenous domain of type IV
collagen isolated from normal dog glomeruli but not in affected dog
glomeruli. In addition to a significantly reduced level of COL4A5 gene
expression (approximately 10% of normal), expression of the COL4A3 and
COL4A4 genes was also decreased to 14-23% and 11-17%, respectively.
These findings suggested to Thorner et al. (1996) a mechanism that
coordinates the expression of these 3 basement membrane proteins.

*FIELD* AV
.0001
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE II
COL4A4, GLY-SER
In family BE, Mochizuki et al. (1994) found that 2 sisters were
homozygous for a G-to-A transition in a portion of the gene representing
a segment of the 3-prime third of the alpha-4(IV) collagenous domain.
The mutation resulted in a substitution of a serine residue for a
glycine residue that is part of the gly-X-Y collagenous repeat. There
was good reason to consider that this mutation was pathogenic: both
affected females were homozygous, whereas the asymptomatic parents and
unaffected brother were heterozygous. The mutant allele was not observed
in 32 unrelated persons from the same North African population. Similar
glycine-to-serine substitutions have been observed in the fibrillar
collagens encoded by the COL1A1 and COL1A2 genes in osteogenesis
imperfecta. Moreover, Mochizuki et al. (1994) stated that a
serine-for-glycine substitution had been observed in the alpha-5(IV)
chain in a patient with X-linked Alport syndrome. It is noteworthy that
the glycine-to-serine mutations in both the COL4A4 and COL4A5 genes are
recessive, whereas similar mutations in fibrillar collagens are
dominant.

In the BE family, end-stage renal disease developed in the older sister
at the age of 14, but no deafness or ocular abnormalities had been
observed. The other sister was noted at age 11 to have the nephrotic
syndrome without a decrease in renal function; likewise, no deafness or
ocular abnormalities were found. The parents were Berberians from
Algeria, were consanguineous, and tested negative for hematuria and
proteinuria.

.0002
ALPORT SYNDROME, AUTOSOMAL RECESSIVE, TYPE II
COL4A4, SER-TER
In the Italian family GA, Mochizuki et al. (1994) observed a homozygous
substitution of A for C in the collagenous domain of alpha-4(IV). The
mutation replaced a serine codon with a stop codon causing premature
chain termination and shortening of the chain by 453 amino acids. The
parents shared the same surname and originated from the same village in
Italy. Two sisters had died, apparently of Alport syndrome.

.0003
HEMATURIA, BENIGN FAMILIAL
BFH
COL4A4, GLY897GLU
Benign familial hematuria (BFH; 141200) is characterized by autosomal
dominant inheritance, thinning of the glomerular basement membrane
(GBM), and normal renal function. It is frequent in patients with
persistent microscopic hematuria, but cannot be clinically
differentiated from the initial stages of Alport syndrome (301050,
104200), a severe GBM disorder which progresses to renal failure.
Lemmink et al. (1996) demonstrated linkage of BFH with the COL4A3 and
COL4A4 genes at 2q35-q37 and went on to demonstrate a GGG-to-GAG
transition in codon 897 of COL4A4 resulting in substitution of a
glutamic acid residue for glycine. The G-to-A mutation in this family
introduced a novel site for the restriction enzyme AluI, by which the
members of the family were screened. All affected members of the family
in 3 generations were heterozygous. The index patient, a member of the
third generation, presented with hematuria at the age of 5 years. Family
history was negative for renal failure and deafness. Electron microscopy
of a renal biopsy specimen showed regions with malformations of the GBM
typical for Alport syndrome and regions that were thin. Microscopic
hematuria was present in many relatives, including the 75-year-old
paternal grandfather who had a normal serum creatinine concentration.
The family was complicated by the fact that the mother of the index case
also had microscopic hematuria as did many of her relatives. She did not
carry the gly897-to-glu mutation nor was another mutation identified.
The index patient, 16 years old at the time of the report, had developed
proteinuria and may have inherited a COL4A4 gene mutation from both
parents. Lemmink et al. (1996) speculated that this might account for
the histological changes in the GBM suggesting Alport syndrome.
Homozygous mutations in COL4A3 and COL4A4 have been identified in
autosomal recessive Alport syndrome.

*FIELD* RF
1. Butkowski, R. J.; Langeveld, J. P. M.; Wieslander, J.; Hamilton,
J.; Hudson, B. G.: Localization of the Goodpasture epitope to a novel
chain of basement membrane collagen. J. Biol. Chem. 262: 7874-7877,
1987.

2. Gunwar, S.; Saus, J.; Noelken, M. E.; Hudson, B. G.: Glomerular
basement membrane: identification of a fourth chain, alpha-4, of type
IV collagen. J. Biol. Chem. 265: 5466-5469, 1990.

3. Kamagata, Y.; Mattei, M.-G.; Ninomiya, Y.: Isolation and sequencing
of cDNAs and genomic DNAs encoding the alpha 4 chain of basement membrane
collagen type IV and assignment of the gene to the distal long arm
of human chromosome 2. J. Biol. Chem. 267: 23753-23758, 1992.

4. Leinonen, A.; Mariyama, M.; Mochizuki, T.; Tryggvason, K.; Reeders,
S. T.: Complete primary structure of the human type IV collagen alpha-4(IV)
chain: comparison with structure and expression of the other alpha(IV)
chains. J. Biol. Chem. 269: 26172-26177, 1994.

5. Lemmink, H. H.; Nillesen, W. N.; Mochizuki, T.; Schroder, C. H.;
Brunner, H. G.; van Oost, B. A.; Monnens, L. A. H.; Smeets, H. J.
M.: Benign familial hematuria due to mutation of the type IV collagen
alpha-4 gene. J. Clin. Invest. 98: 1114-1118, 1996.

6. Mariyama, M.; Zheng, K.; Yang-Feng, T. L.; Reeders, S. T.: Colocalization
of the genes for the alpha-3(IV) and alpha-4(IV) chains of type IV
collagen to chromosome 2 bands q35-q37. Genomics 13: 809-813, 1992.

7. Mochizuki, T.; Lemmink, H. H.; Mariyama, M.; Antignac, C.; Gubler,
M.-C.; Pirson, Y.; Verellen-Dumoulin, C.; Chan, B.; Schroder, C. H.;
Smeets, H. J.; Reeders, S. T.: Identification of mutations in the
alpha-3(IV) and alpha-4(IV) collagen genes in autosomal recessive
Alport syndrome. Nature Genet. 8: 77-81, 1994.

8. Saus, J.; Wieslander, J.; Langeveld, J. P. M.; Quinones, S.; Hudson,
B. G.: Identification of the Goodpasture antigen as the alpha-3(IV)
chain of collagen IV. J. Biol. Chem. 263: 13374-13380, 1988.

9. Thorner, P. S.; Zheng, K.; Kalluri, R.; Jacobs, R.; Hudson, B.
G.: Coordinate gene expression of the alpha-3, alpha-4, and alpha-5
chains if collagen type IV. J. Biol. Chem. 271: 13821-13828, 1996.

*FIELD* CN
Perseveranda M. Cagas - updated: 9/4/1996

*FIELD* CD
Victor A. McKusick: 3/1/1990

*FIELD* ED
mark: 10/17/1996
mark: 10/9/1996
mark: 9/4/1996
mark: 3/7/1996
mark: 1/25/1996
terry: 1/23/1996
terry: 12/22/1994
carol: 10/26/1993
carol: 9/15/1993
carol: 9/8/1993
carol: 6/29/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
120140
*FIELD* TI
*120140 COLLAGEN, TYPE II, ALPHA-1 CHAIN; COL2A1
COLLAGEN, TYPE II;;
COLLAGEN OF CARTILAGE
CHONDROCALCIN, INCLUDED
*FIELD* TX
See collagen of skin, tendon and bone--alpha-1 polypeptide (120150).
Cartilage collagen is also called collagen II. The same type of collagen
occurs in the vitreous. Herein may be the explanation for ocular
abnormality in some chondrodysplasias such as spondyloepiphyseal
dysplasia congenita (183900). Strom and Upholt (1984) isolated
overlapping genomic DNA clones containing most of the coding sequences
for chicken type II procollagen. They found that the chicken type II
gene is 2 to 3 times more compact than the chicken type I alpha-2 gene
due to smaller introns. The coding sequence shows about 75% homology
with type I alpha-1 and 63 to 67% homology with type I alpha-2 and type
III sequences. Base composition and codon usage of type II are very
similar to alpha-1(I) and different from alpha-2(I) and type III. The
chicken type II gene appears to be present in single copy per haploid
genome. Strom (1984) purported to find abnormality of the type II
collagen gene in achondroplasia. If such a defect is present, one might
expect ocular abnormality in achondroplasia inasmuch as type II collagen
is present in vitreous. SED congenita is a more plausible candidate for
a structural defect of type II collagen because it is a dominant
disorder that combines skeletal dysplasia with vitreous degeneration and
deafness (experimental studies with antibodies to type II collagen
indicate that this collagen type is represented in the inner ear; Yoo et
al., 1983). The work of Strom (1984) may be technically flawed. The
first evidence for a defect in COL2A1 in Langer-Saldino achondrogenesis
(200610) and in SED congenita (183900) was the finding of abnormal
patterns of digestion of type II collagen by cyanogen bromide, as
demonstrated by Horton (1987). Confirmation of the defect was provided
by demonstration of point mutations in COL2A1 in each of these disorders
(see allelic variants).

Sangiorgi et al. (1984) isolated from a cartilage cDNA library a bovine
clone encoding the pro-alpha-1(II) collagen chain. Because of the close
homology of bovine and human collagens, the bovine clone could be used
to isolate the corresponding gene from a human genomic library. Analysis
of DNA from human-mouse cell hybrids localized the COL2A1 gene to
chromosome 12. The results were confirmed by similar experiments with
the bovine cDNA probe. Using a cloned gene as a probe on Southern blots
of DNA from a panel of interspecies somatic cell hybrids, Solomon et al.
(1985) also assigned the COL2A1 locus to chromosome 12. By somatic cell
hybrid studies and in situ hybridization, Huerre-Jeanpierre et al.
(1986) assigned COL2A1 to 12q13.1-q13.2 and COL3A1 to 2q31-q32.3. Law et
al. (1986) used a cosmid clone of the entire COL2A1 gene in Southern
analysis of DNA from somatic cell hybrids containing segments of
chromosome 12. Two hybrids contained a similar terminal deletion of
12q14.3-qter but 1 was positive for the gene and 1 negative. This led
Law et al. (1986) to conclude that the gene is located in 12q14.3.
Takahashi et al. (1990) described a 'new' nonisotopic method of in situ
hybridization. It involved replication of R-bands by incorporation of
bromodeoxyuridine (BrdU) into cells synchronized with thymidine.
Fluorescent signals could be detected on R-banded prometaphases stained
with propidium iodide. They illustrated the strength of the system by
refining the localization of the COL2A1 gene to 12q13.11-q13.12. By
nonisotopic in situ hybridization, Takahashi et al. (1990) showed that
the COL2A1 gene is immediately proximal to the fragile site
fra(12)(q13.1).

The following is an account of a temporarily confusing aspect of the
collagen II gene. Weiss et al. (1982) described a collagen gene isolated
in a 40-kb cosmid clone, cosHco11, which has some sequence homology to
the alpha-1(I) gene, but which is clearly a different gene. Using this
collagen alpha-1(I)-like probe on Southern blots of DNA from somatic
cell hybrids, Solomon et al. (1984) found that the gene segregated with
chromosome 12 and is not syntenic with the alpha-2(I) gene assigned to
chromosome 7 (120160) or the alpha-1(I) gene assigned to chromosome 17
(120150). This gene contains an RFLP with HindIII. A 300-base pair
deletion in the alpha-1(I)-like gene mapped by Solomon et al. (1984) was
demonstrated by Pope et al. (1984) in a father and son with one form of
Ehlers-Danlos syndrome II. The deletion was found at or near the 3-prime
end of the gene and was not identified in other cases of ED II or in 400
normal controls. It was found, however, in 4 babies with lethal
osteogenesis imperfecta congenita. The father and son with ED II and the
deletion showed altered collagen fibril size and shape. Subsequently,
the 'alpha-1(I)-like' gene was shown to encode the alpha subunit of
cartilage collagen and it was further shown that there is a polymorphism
in this gene that is frequent in Asiatic Indians (Sykes et al., 1985).
Of the 4 cases of Pope et al. (1984), 3 originated from India or Sri
Lanka. This experience illustrates the hazards of confusing polymorphism
with pathology. By comparison of amino acid sequences, van der Rest et
al. (1986) showed that chondrocalcin is the C-propeptide of type II
procollagen. Chondrocalcin is a calcium-binding protein found in
developing fetal cartilage matrix and in growth plate cartilage when and
where mineralization occurs in the lower hypertrophic zone. It appears
to play a role in enchondral ossification. The new evidence on its
identity to C-propeptide indicates that it is also important in assembly
of the triple helix of type II collagen. See 156550 for evidence of
abnormal processing of the C-propeptide of type II collagen resulting in
imperfect fibril assembly and the clinical disorder called Kniest
dysplasia. Lovell-Badge et al. (1987) introduced a cosmid containing the
human type II collagen gene, including 4.5 kb of 5-prime and 2.2 kb of
3-prime flanking DNA, into mouse embryonic cells in vitro. Human type II
collagen mRNA was found only in tissues that showed transcription from
the endogenous (mouse) gene, and human type II collagen was found in
cartilage. The findings indicated that the cis-acting requirements for
correct temporal and spatial regulation of the gene were fulfilled by
the introduced DNA. Francomano et al. (1987) demonstrated absolute
linkage of COL2A1 and Stickler syndrome; a total lod score of 3.96 at
theta = 0.0 was obtained. Knowlton et al. (1989) found tight linkage (no
recombination) of the COL2A1 gene with a precocious form of familial
primary generalized osteoarthritis associated with chondrodysplasia.
Godfrey and Hollister (1988) presented evidence that the patient they
studied was heterozygous for an abnormal pro-alpha-1(II) chain which
impaired the assembly and/or folding of type II collagen. Vissing et al.
(1989) demonstrated that the mutation in the type II procollagen gene
was a single base change that converted the codon for glycine (GGC) at
amino acid 943 to a codon for serine (AGC). The substitution disrupted
the invariant Gly-X-Y structural motif necessary for perfect helix
formation and led to an excessive overmodification, intracellular
retention, and reduced secretion of type II collagen. Knowlton et al.
(1990) studied a family in which precocious osteoarthritis was
associated with mild chondrodysplasia. A 16-year-old male, for example,
had osteoarthritis of the middle metacarpophalangeal joints and hips as
well as bilateral osteochondritis dissecans of the capitellum. A
38-year-old female had also osteoarthritis of the spine, wrists,
proximal interphalangeal joints, and distal interphalangeal joints.
Vertebral bodies were flattened with Schmorl nodes. Linkage analysis
suggested that the mutation is in the COL2A1 locus with a maximum lod
score of 2.39 in multipoint analysis. Morphometrics demonstrated a short
trunk producing abnormally low upper segment to lower segment ratio.

Not only is abnormality of type II collagen involved in the
sensorineural deafness that accompanies hereditary disorders such as
spondyloepiphyseal dysplasia congenita and Stickler syndrome (108300)
but type II collagen may also be the target of an autoimmune process in
some cases of acquired bilateral progressive sensorineural hearing loss
(Helfgott et al., 1991).

Vandenberg et al. (1991) found that transgenic mice carrying a partially
deleted human COL2A1 gene developed the phenotype of a chondrodysplasia
with dwarfism, short and thick limbs, short snout, cranial bulge, cleft
palate, and delayed mineralization of bone. In cultured chondrocytes
from transgenic mice, the minigene was expressed as shortened
pro-alpha-1(II) chains that were disulfide-linked to normal mouse type
II collagen chains. Therefore, the phenotype was probably explained by
depletion of endogenous mouse type II procollagen through the phenomenon
of procollagen suicide. Garofalo et al. (1991) generated transgenic mice
harboring a glycine-to-cysteine mutation at residue 85 of the triple
helical domain of mouse type II collagen. Offspring displayed severe
chondrodysplasia with short limbs and trunk, craniofacial deformities,
and cleft palate. Affected pups died of acute respiratory distress
caused by inability to inflate the lungs at birth. Electron microscopic
analysis showed a pronounced decrease in the number of typical thin
cartilage collagen fibrils, distension of the rough endoplasmic
reticulum of chondrocytes, and the presence of abnormally large banded
collagen fibril bundles. Garofalo et al. (1991) postulated that the
abnormally thick collagen bundles were related to a defect in
crosslinking. Similarities to the chondrodysplasias of the
spondyloepiphyseal dysplasia group were pointed out.

Li et al. (1995) used homologous recombination in embryonic stem cells
to prepare transgenic mice with an inactivated COL2A1 gene. Heterozygous
mice had a minimal phenotypic changes. Homozygous mice developed were
delivered vaginally but died either just before or shortly after birth.
In these mice the cartilage consisted of highly disorganized
chondrocytes with a complete lack of extracellular fibrils discernable
by electron microscopy. There was no endochondral bone or epiphyseal
growth plate in long bones; however, many skeletal structures such as
the cranium and ribs were normally developed and mineralized. The
results demonstrated that a well-organized cartilage matrix is required
as a primary tissue for development of some components of the skeleton
but is not essential for others. Spector et al. (1996) compared
radiographs of the hands and knees, presence of Heberden nodes and pain
assessment between 130 identical and 120 nonidentical female twins, aged
48 to 70, years in Great Britain. The authors calculated the genetic
influence for this disorder to be from 39 to 65% in this group of women
with average age-of-onset osteoarthritis. Kaprio et al. (1996)
corroborated the results of Spector et al. (1996) for women but not for
men.

Meulenbelt et al. (1996) determined the allele frequencies and pairwise
linkage disequilibria of RFLPs distributed over the COL2A1 gene in a
population of unrelated Dutch Caucasians. Their data indicated that
disease-related population studies should include a minimum of 4 RFLPs.

*FIELD* AV
.0001
SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA
COL2A1, 1EX DEL
In a case of autosomal dominant spondyloepiphyseal dysplasia congenita
(183900), Lee et al. (1989) demonstrated a single exon deletion in
heterozygous state.

.0002
ACHONDROGENESIS-HYPOCHONDROGENESIS, TYPE II
COL2A1, GLY943SER
In a case of type II achondrogenesis-hypochondrogenesis (200610),
Vissing et al. (1989) demonstrated heterozygosity for a single base
change that converted glycine-943 to serine; the codon change was GGC to
AGC.

.0003
OSTEOARTHRITIS WITH MILD CHONDRODYSPLASIA
COL2A1, ARG519CYS
In the kindred described by Knowlton et al. (1990), Ala-Kokko et al.
(1990) found change from arginine to cysteine at position 519 of the
alpha-1(II) chain. In an affected family member who underwent hip
surgery, Eyre et al. (1991) demonstrated that approximately one-fourth
of the alpha-1(II) chains present in the polymeric extracellular
collagen of the patient's cartilage contained the arg519-to-cys
substitution. The protein exhibited other abnormal properties including
disulfide-bonded alpha-1(II) dimers and signs of posttranslational
overmodification. Holderbaum et al. (1993) referred to 2 further
families with the arg519-to-cys mutation. They reported studies
suggesting that the mutation arose independently in at least 2 of the 3
known affected families. Williams et al. (1995) found the same mutation
in a fourth family with early-onset osteoarthritis and late-onset
spondyloepiphyseal dysplasia.

.0004
SPONDYLOEPIPHYSEAL DYSPLASIA
COL2A1, 45BP DUP, EX48
In a sporadic case of spondyloepiphyseal dysplasia, Tiller et al. (1990)
found an internal tandem duplication of 45 base pairs within exon 48 of
COL2A1, resulting in the addition of 15 amino acids to the
triple-helical domain of the protein. The abnormal molecule showed
excessive posttranslational modification. The mutation was not carried
by either parent, indicating a new dominant mutation. DNA sequence
homology in the area of the duplication suggested that the mutation may
have arisen by unequal crossover between related sequences.

.0005
ARTHROOPHTHALMOPATHY, HEREDITARY
STICKLER SYNDROME
COL2A1, ARG732TER
In a family with Stickler syndrome, Ahmad et al. (1990, 1991) found a
single base mutation altering the arginine at amino acid 732 of the
triple helical domain of COL2A1 to a stop codon. The mutation altered a
CG dinucleotide and converted the codon CGA to TGA. This mutation was
located in exon 40. Ahmad et al. (1991) noted that the mutation produced
marked changes in the eye, which contains only small amounts of type II
collagen, but had relatively mild effects on the many cartilaginous
structures of the body that are rich in the same protein.

.0006
SPONDYLOEPIPHYSEAL DYSPLASIA, NAMAQUALAND TYPE
NSED HIP DYSPLASIA, NAMAQUALAND TYPE
COL2A1
Beighton et al. (1984) concluded that the skeletal disorder they
identified in 45 persons in 5 generations of a kindred of mixed ancestry
in Namaqualand, South Africa, represented a distinct entity. Discomfort
in the hips develops in childhood and the course is progressive, with
handicap in middle age. General health is good, height is not
significantly reduced, and no extraskeletal involvement has been
identified. The major changes are in the femoral capital epiphyses,
which are flattened and fragmented; secondary degenerative arthropathy
develops at a later stage. Platyspondyly of variable but mild degree is
present in about 60% of affected persons. Other minor changes, including
iliac exostoses, are present in some. The pedigree findings indicate
autosomal dominant inheritance. Learmonth et al. (1987) pointed out that
the maximal changes in the femoral capital epiphyses lead to severe
progressive degenerative osteoarthropathy of the hip joint that
frequently necessitates prosthetic joint replacement in adulthood. Sher
et al. (1991) showed by linkage studies that NSED and the COL2A1 gene
are closely linked with no recombination (lod = 7.98).

.0007
HYPOCHONDROGENESIS
COL2A1, GLY574SER
In a case of hypochondrogenesis, Horton et al. (1992) detected a subtle
mutation in the COL2A1 gene by use of a chondrocyte culture system and
PCR-cDNA scanning analysis. Chondrocytes obtained from cartilage
biopsies were dedifferentiated and expanded in monolayer culture and
then redifferentiated by culture over agarose. Single-strand
conformation polymorphism and direct sequencing analysis identified a
G-to-A transition, resulting in substitution of glycine by serine at
amino acid 574 in the triple-helical domain of type II procollagen. The
morphologic assessment of cartilage-like structures produced in culture
and electrophoretic analysis of collagens synthesized by the cultured
chondrocytes suggested that the glycine substitution interfered with
conversion of type II procollagen to collagen, impaired intracellular
transport and secretion of the molecule, and disrupted collagen fibril
assembly.

.0008
ARTHROOPHTHALMOPATHY, HEREDITARY
STICKLER SYNDROME
COL2A1, 1BP DEL, FS42TER, EX40
In a family with Stickler syndrome, Brown et al. (1992) found that 4
affected members had deletion of a single basepair resulting in a
translational frameshift in exon 40 of the COL2A1 gene. The mutation was
not found in any of 5 clinically unaffected family members or in any of
15 unrelated control patients. All affected members had abnormal
vitreous syneresis and all had retinal perivascular pigmentation.
Retinal detachments occurred in 3 of the 4 affected patients. Three of
the 4 had peripheral cortical 'wedge' cataracts, and the fourth had
extensive nuclear sclerosis. In all 4 affected patients, there were
abnormalities of the palate: bilateral torus palatini, linea alba with
submucous cleft palate, bifid uvula, and 'notched' hard palate. All
patients reported severe joint pains, and radiologic changes suggesting
epiphyseal dysplasia were found in all 4. One patient had had left total
hip replacement at a relatively young age. Palatal and ocular changes
were illustrated by photographs, and radiographs of the skeletal changes
were presented. The deletion was reported to involve a thymidine
nucleotide at position 18 of exon 40. This resulted in a translational
frameshift, with formation of a nonsense codon, TGA, downstream in exon
42, leading to premature termination of translation at that point. The
deletion also created a new MspI restriction site.

.0009
HYPOCHONDROGENESIS
COL2A1, GLY853GLU
In an infant with a severe form of skeletal dysplasia who required
continuous respiratory support until his death at 3 months of age,
Bogaert et al. (1992) demonstrated a gly853-to-glu mutation resulting
from a GGA-to-GAA transition in the COL2A1 gene. The patient was
heterozygous. The radiologic features were thought to be those of
hypochondrogenesis. Unilateral polydactyly had been noted at birth.

.0010
ARTHROOPHTHALMOPATHY, HEREDITARY
STICKLER SYNDROME
COL2A1, ARG9TER
In a family with Stickler syndrome, Ahmad et al. (1993) found a
single-base mutation that converted codon 9 of the COL2A1 gene. (The
amino acids of the alpha-1 chain were numbered with the standard
convention in which the first amino acid in the triple-helical domain is
numbered as +1 (Baldwin et al., 1989).) The mutation changed a CGA codon
(arginine) to TGA (stop) codon. This mutation was located in exon 7. The
PCR products contained both C and T, indicating that the patient was
heterozygous for the mutation. The proband had been identified in a
cleft palate clinic at the age of 1 year. He had severe myopia and was
at the eighth percentile for height. Pelvic x-rays demonstrated small
femoral heads with dumbbell-shaped enlargements of both ends of the
femurs. Members in 3 generations and 4 sibships had severe myopia, often
with other ocular manifestations.

.0011
SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA
COL2A1, GLY997SER
Cole et al. (1993) found that a child with SED congenita was
heterozygous for a G-to-A transition in exon 48 of the COL2A1 gene that
resulted in the substitution of glycine-997 by serine in the triple
helical domain of the type II collagen chain.

.0012
KNIEST DYSPLASIA
COL2A1, 28BP DEL
Winterpacht et al. (1993) demonstrated a 28-bp deletion spanning the
3-prime exon/intron boundary of exon 12 in a 2-year-old girl with Kniest
dysplasia (156550). The mother presented with a milder phenotype
consistent with the Stickler syndrome. She was shown to have mosaicism
for the same deletion.

.0013
SPONDYLOMETAPHYSEAL DYSPLASIA
COL2A1, GLY154ARG
In a patient with severe osteochondrodysplasia that might be best
designated as spondylometaphyseal dysplasia (SMD), Vikkula et al. (1993)
demonstrated a G-to-A mutation at nucleotide 1063, which resulted in the
conversion of gly154 to arg. This was a heterozygous de novo mutation
which was not found in any other skeletal dysplasia patient studied in
Finland.

.0014
WAGNER SYNDROME
COL2A1, GLY67ASP
In a family in which affected members had clinical characteristics
typical of Wagner syndrome (143200), namely, early-onset cataracts,
lattice degeneration of the retina, and retinal detachment without
involvement of nonocular tissues, Korkko et al. (1993) identified a
substitution of aspartate for glycine at position 67 in the alpha-1
chain of type II collagen. Since the original family described by Wagner
(1938) was found not to be linked to the COL2A1 gene, there are, it
seems, 2 forms of this disorder. The form due to mutation in the COL2A1
gene can be called Wagner syndrome type II. Comparison with previously
reported mutations suggested to Korkko et al. (1993) that premature
termination codons in the COL2A1 gene are a frequent cause of the
Stickler syndrome, but mutations in the COL2A1 gene that replace glycine
codons with codons for a bulkier amino acid can produce a broad spectrum
of disorders ranging from lethal chondrodysplasia to a syndrome
involving only ocular tissues, similar to the disorder originally
described by Wagner (1938).

.0015
STICKLER SYNDROME
COL2A1, PRO846TER
In a family with Stickler syndrome in members of 4 successive
generations, Ritvaniemi et al. (1993) found a deletion of a T in the
third base position of the codon CCT for proline at position 846 of the
alpha-1 chain. The deletion of the T shifted the reading frame and
generated premature termination. Ritvaniemi et al. (1993) stated that
this was the fourth example of a premature termination codon causing
Stickler syndrome.

.0016
SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA
COL2A1, ARG789CYS
In a 4-year-old girl with clinical and radiographic features typical of
SED congenita, Chan et al. (1993) found heterozygosity for a C2913T
transition in exon 14 resulting in the substitution of arginine-789 by
cysteine. The mutation resulted in the loss of an MaeII cleavage site
that was used to confirm the fact that the proband was heterozygous and
that neither parent had the mutation. Type II collagen extracted from
cartilage and from cultured chondrocytes was approximately one-third of
the mutant type and secretion of molecules containing mutant chains was
impaired. The thermal stability of the collagen extracted from cartilage
was normal, however.

.0017
SPONDYLOEPIMETAPHYSEAL DYSPLASIA, STRUDWICK TYPE
SEMD, STRUDWICK TYPE
COL2A1, GLY709CYS
Tiller et al. (1993) demonstrated that cartilage from 2 patients with
SEMD Strudwick contained both normal alpha-1(II) collagen chains and
chains that were posttranslationally overmodified. Cyanogen bromide
peptide analysis and protein microsequencing of type II collagen from 1
patient demonstrated an amino acid substitution, gly709-to-cys, in the
abnormal alpha chains. Direct DNA sequencing showed heterozygosity for a
GGC-to-TGC transversion at the last glycine codon of exon 39.

.0018
SPONDYLOEPIPHYSEAL DYSPLASIA WITH PRECOCIOUS OSTEOARTHRITIS
COL2A1, ARG75CYS
In a family living in the Chiloe Islands, Chile, Williams et al. (1993)
demonstrated an arg75-to-cys mutation in the COL2A1 gene as the basis of
spondyloepiphyseal dysplasia with shortened metacarpals and metatarsals,
precocious osteoarthritis, and periarticular apatite-like calcific
deposits. Seven individuals were involved in 3 generations of the
family. The affected members were heterozygous for the defect. The
proband was a 40-year-old woman with short fourth and fifth metatarsals
and intermittent acute pain and swelling in her knees, ankles, and
proximal interphalangeal joints since the age of 12 years. As a result
of severe degenerative joint disease, she underwent total hip
replacement at age 35; this was complicated by marked heterotopic
periarticular calcification. Complete physical examination,
anthropometric measurements, and radiographic studies of the spine and
peripheral joints in 16 family members revealed that 7 had
spondyloepiphyseal dysplasia tarda, brachydactyly, precocious
osteoarthritis, and periarticular calcification, while 2 others had the
same syndrome without brachydactyly (Reginato et al., 1994). The
inheritance was autosomal dominant, and the disease cosegregated with
the arg75-to-cys mutation of COL2A1. The relationship of this type of
SEDT to familial calcium pyrophosphate dihydrate deposition disease
(118600) and idiopathic hip dysplasia, both endemic in Chiloe Islanders,
required further investigation.

.0019
KNIEST DYSPLASIA
COL2A1, IVS20AS, A-G, -2, 18BP DEL
Winterpacht et al. (1994) investigated the molecular defect in a girl
with Kniest dysplasia and her father who had a very mild form of
spondyloepiphyseal dysplasia congenita (SEDC) with premature
osteoarthrosis. The father was found to be a mosaic for a mutation that
was present in nonmosaic state in the child: an A-to-G transition at the
3-prime end of intron 20 affecting the highly conserved AG dinucleotide
of the acceptor splice site. The result was the utilization of a cryptic
AG splice site located 18-bp downstream and a resulting inframe deletion
of 18 bp from the mRNA. This situation has similarities to that
described in 120140.0012.

.0020
KNIEST DYSPLASIA
COL2A1, GLY103ASP
Wilkin et al. (1994) used SSCP to analyze an amplified genomic DNA
fragment containing exon 12, under suspicion because of its deletion in
a previously reported patient (120140.0012), from 7 individuals with
Kniest dysplasia. An abnormality was identified in 1 patient who was
found on DNA sequence analysis to be heterozygous for a G-to-A
transition that implied substitution of glycine-103 of the triple
helical domain by aspartate. The mutation was not observed in DNA from
either of the clinically unaffected parents. Protein microsequencing
demonstrated expression of the abnormal allele in cartilage.

.0021
ACHONDROGENESIS, TYPE II
COL2A1, GLY769SER
In a fetus with type II achondrogenesis, Chan et al. (1995) described
heterozygosity for a G-to-A transition at nucleotide 2853 in exon 441 of
the COL2A1 gene, resulting in a gly769-to-ser substitution within the
triple helical domain of the type II collagen chain. The result was
complete absence of type II collagen in cartilage, which had a
gelatinous composition. Types I and III collagens were the main species
found in cartilage and synthesized by cultured chondrocytes along with
cartilage type XI collagen (120280). Cultured chondrocytes produced a
trace amount of type II collagen that was retained within the cells and
not secreted. In situ hybridization of cartilage sections showed that
the chondrocytes produced both type I and type II collagen mRNA. Chan et
al. (1995) noted that the gly769 substitution is situated close to the
mammalian collagenase cleavage site at gly775/leu776. The abnormality
was detected by ultrasonography at 19 weeks of gestation when severe
shortening of the limbs and trunk and marked edema around the neck was
noted. The pregnancy was terminated at 20 weeks of gestation. External
examination showed very short limbs, large head, short trunk, bulging
abdomen, and edema of the head and neck. Radiographs, which were
presented by Chan et al. (1995), showed very short tubular bones with
metaphyseal expansion and cupping, absent ossification of the vertebrae
and sacrum, small iliac wings with absent ossification of the pubis and
ischium, and short ribs, but relatively normal ossification of the
calvarium.

.0022
ACHONDROGENESIS, TYPE II
COL2A1, GLY691ARG
Mortier et al. (1995) examined a male fetus by ultrasound during the
third trimester and observed polyhydramnios and severe short-limb
dwarfism. The parents elected to induce delivery at 31 weeks of
gestation and the neonate died soon after birth. There was severe
shortening of the limbs and chest with distention of the abdomen. The
head was relatively large and the neck appeared short. Radiographs
showed absence of ossification of all the vertebral bodies. The chest
appeared bell-shaped with mild shortening of the ribs. Anterior and
posterior ends of the ribs were flared and cupped. The width of the
iliac wings was increased and the greater sciatic notch was wide. The
ischium and pubis were not ossified. All the long bones were markedly
shortened with flared and cupped metaphyses. Electron microscopy showed
inclusion bodies of dilated rough endoplasmic reticulum in chondrocytes
and the presence of sparse collagen fibers in the cartilage matrix.
Protein analysis of collagen from cartilage indicated posttranslational
overmodification of the major cyanogen bromide peptides and suggested a
mutation near the carboxyl terminus of the type II collagen molecule.
Mortier et al. (1995) referred to reports of 3 other dominant mutations
in the COL2A1 gene resulting in substitutions for triple helical glycine
residues near the carboxy-terminal end of the alpha-1(II) chain and
causing hypochondrogenesis. Mortier et al. (1995) demonstrated a single
base change (G-to-C) that resulted in the substitution of glycine-691 by
arginine in the type II collagen triple helical domain.

.0023
ARTHROOPHTHALMOPATHY, HEREDITARY
STICKLER SYNDROME
COL2A1, 1BP DEL, EX50, FS, TER
By direct sequencing of the COL2A1 gene, Ahmad et al. (1995)
demonstrated that affected members of a family with Stickler syndrome
had a single base deletion in exon 50, resulting in a premature stop
codon in exon 51 in the globular C-propeptide of the COL2A1 gene. The
deletion involved a cytosine at position 92 in exon 50. Three
generations were affected in the family. The proband was referred for
cataract and total retinal detachment in 1 eye at the age of 3 years.
Marked genu valgum, hyperextensibility of joints, cleft palate, and
flattened facies were noted. Mild hearing loss was also documented. The
father's left eye had been blind since the age of 8 years secondary to a
detached retina. Retinal detachment on the right occurred at the age of
39 years. He also showed hyperextensibility of joints and some spinal
changes. The proband's paternal uncle suffered detached left retina
after diving into a swimming pool at age 15 years. Hyperextensibility of
joints and loss of hearing in the left ear were noted at the age of 35
years. Hyperextensible joints were present in other relatives and Pierre
Robin syndrome was noted in some.

.0024
ARTHROOPHTHALMOPATHY, HEREDITARY
STICKLER SYNDROME
COL2A1, IVS17AS A-G, -2, 16BP DEL, EX 18
In the original Minnesota kindred on the basis of which Stickler et al.
(1965) defined the Stickler syndrome (108300), Williams et al. (1996)
identified a splice site mutation in the COL2A1 gene. They used
conformational sensitive gel electrophoresis (SSGE) to screen for
mutations in the entire gene. They noted a prominent heteroduplex in the
PCR product from a region of the gene including exons 17 to 20. Direct
sequencing of PCR-amplified genomic DNA identified an A-to-G transition
at the -2 position at the 3-prime acceptor splice site of IVS17.
Sequencing of DNA from affected and unaffected family members confirmed
that the mutation segregated with the disease phenotype. RT-PCR analysis
of poly(A)+ RNA demonstrated that the mutant allele utilized a cryptic
splice site in exon 18 of the gene, eliminating 16 bp at the start of
exon 18. This frameshift eventually resulted in a premature termination
codon. Williams et al. (1996) stated that this was the first report of a
splice site mutation in classical Stickler syndrome. They provided a
satisfying historical context in which to view COL2A1 mutations in this
disorder.

*FIELD* SA
Cheah et al. (1985); Eng and Strom (1985); Francomano et al. (1987);
Huerre-Jeanpierre et al. (1985); Law et al. (1985); Nunez et al. (1985);
Sangiorgi et al. (1985); Stoker et al. (1985); Strom et al. (1984);
Sykes et al. (1985); Takahashi et al. (1990); Yoo et al. (1983); Young
et al. (1984)
*FIELD* RF
1. Ahmad, N. N.; Ala-Kokko, L.; Knowlton, R. G.; Jimenez, S. A.; Weaver,
E. J.; Maguire, J. I.; Tasman, W.; Prockop, D. J.: Stop codon in
the procollagen II gene (COL2A1) in a family with the Stickler syndrome
(arthro-ophthalmopathy). Proc. Nat. Acad. Sci. 88: 6624-6627, 1991.

2. Ahmad, N. N.; Ala-Kokko, L.; Knowlton, R. G.; Weaver, E. J.; Maguire,
J. I.; Tasman, W.; Prockop, D. J.: A stop codon in the gene for type
II procollagen (COL2A1) causes one variant of arthro-ophthalmopathy
(the Stickler syndrome).(Abstract) Am. J. Hum. Genet. 47 (suppl.):
A206 only, 1990.

3. Ahmad, N. N.; Dimascio, J.; Knowlton, R. G.; Tasman, W. S.: Stickler
syndrome: a mutation in the nonhelical 3-prime end of type II procollagen
gene. Arch. Ophthal. 113: 1454-1457, 1995.

4. Ahmad, N. N.; McDonald-McGinn, D. M.; Zackai, E. H.; Knowlton,
R. G.; LaRossa, D.; DiMascio, J.; Prockop, D. J.: A second mutation
in the type II procollagen gene (COL2A1) causing Stickler syndrome
(arthro-ophthalmopathy) is also a premature termination codon. Am.
J. Hum. Genet. 52: 39-45, 1993.

5. Ala-Kokko, L.; Baldwin, C. T.; Moskowitz, R. W.; Prockop, D. J.
: Single base mutation in the type II procollagen gene (COL2A1) as
a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc.
Nat. Acad. Sci. 87: 6565-6568, 1990.

6. Baldwin, C. T.; Reginato, A. M.; Smith, C.; Jimenez, S. A.; Prockop,
D. J.: Structure of cDNA clones coding for human type II procollagen:
the alpha-1(II) chain is more similar to the alpha-1(I) chain than
two other alpha chains of fibrillar collagens. Biochem. J. 262:
521-528, 1989.

7. Beighton, P.; Christy, G.; Learmonth, I. D.: Namaqualand hip dysplasia:
an autosomal dominant entity. Am. J. Med. Genet. 19: 161-169, 1984.

8. Bogaert, R.; Tiller, G. E.; Weis, M. A.; Gruber, H. E.; Rimoin,
D. L.; Cohn, D. H.; Eyre, D. R.: An amino acid substitution (gly853-to-glu)
in the collagen alpha-1(II) chain produces hypochondrogenesis. J.
Biol. Chem. 267: 22522-22526, 1992.

9. Brown, D. M.; Nichols, B. E.; Weingeist, T. A.; Sheffield, V. C.;
Kimura, A. E.; Stone, E. M.: Procollagen II gene mutation in Stickler
syndrome. Arch. Ophthal. 110: 1589-1593, 1992.

10. Chan, D.; Cole, W. G.; Chow, C. W.; Mundlos, S.; Bateman, J. F.
: A COL2A1 mutation in achondrogenesis type II results in the replacement
of type II collagen by type I and III collagens in cartilage. J.
Biol. Chem. 270: 1747-1753, 1995.

11. Chan, D.; Taylor, T. K. F.; Cole, W. G.: Characterization of
an arginine 789 to cysteine substitution in alpha-1(II) collagen chains
of a patient with spondyloepiphyseal dysplasia. J. Biol. Chem. 268:
15238-15245, 1993.

12. Cheah, K. S. E.; Stoker, N. G.; Griffin, J. R.; Grosveld, F. G.;
Solomon, E.: Identification and characterization of the human type
II collagen gene (COL2A1). Proc. Nat. Acad. Sci. 82: 2555-2559,
1985.

13. Cole, W. G.; Hall, R. K.; Rogers, J. G.: The clinical features
of spondyloepiphyseal dysplasia congenita resulting from the substitution
of glycine 997 by serine in the alpha-1(II) chain of type II collagen. J.
Med. Genet. 30: 27-35, 1993.

14. Eng, C. E. L.; Strom, C. M.: Analysis of three restriction fragment
length polymorphisms in the human type II procollagen gene. Am. J.
Hum. Genet. 37: 719-732, 1985.

15. Eyre, D. R.; Weis, M. A.; Moskowitz, R. W.: Cartilage expression
of a type II collagen mutation in an inherited form of osteoarthritis
associated with a mild chondrodysplasia. J. Clin. Invest. 87: 357-361,
1991.

16. Francomano, C. A.; Liberfarb, R. M.; Hirose, T.; Maumenee, I.
H.; Streeten, E. A.; Meyers, D. A.; Pyeritz, R. E.: The Stickler
syndrome: evidence for close linkage to the structural gene for type
II collagen. Genomics 1: 293-296, 1987.

17. Francomano, C. A.; Maumenee, I.; Liberfarb, R.; Pyeritz, R. E.
: Cosegregation of Stickler syndrome and type II collagen gene alleles.(Abstract) Cytogenet.
Cell Genet. 46: 615 only, 1987.

18. Garofalo, S.; Vuorio, E.; Metsaranta, M.; Rosati, R.; Toman, D.;
Vaughan, J.; Lozano, G.; Mayne, R.; Ellard, J.; Horton, W.; de Crombrugghe,
B.: Reduced amounts of cartilage collagen fibrils and growth plate
anomalies in transgenic mice harboring a glycine-to-cysteine mutation
in the mouse type II procollagen alpha-1-chain gene. Proc. Nat. Acad.
Sci. 88: 9648-9652, 1991.

19. Godfrey, M.; Hollister, D. W.: Type II achondrogenesis-hypochondrogenesis:
identification of abnormal type II collagen. Am. J. Hum. Genet. 43:
904-913, 1988.

20. Helfgott, S. M.; Mosciscki, R. A.; San Martin, J.; Lorenzo, C.;
Kieval, R.; McKenna, M.; Nadol, J.; Trentham, D. E.: Correlation
between antibodies to type II collagen and treatment outcome in bilateral
progressive sensorineural hearing loss. Lancet 337: 387-389, 1991.

21. Holderbaum, D.; Malemud, C. J.; Moskowitz, R. W.; Haqqi, T. M.
: Human cartilage from late stage familial osteoarthritis transcribes
type II collagen mRNA encoding a cysteine in position 519. Biochem.
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22. Horton, W. A.: Personal Communication. Houston, Texas  1987.

23. Horton, W. A.; Machado, M. A.; Ellard, J.; Campbell, D.; Bartley,
J.; Ramirez, F.; Vitale, E.; Lee, B.: Characterization of a type
II collagen gene (COL2A1) mutation identified in cultured chondrocytes
from human hypochondrogenesis. Proc. Nat. Acad. Sci. 89: 4583-4587,
1992.

24. Huerre-Jeanpierre, C.; Mattei, M.-G.; Weil, D.; Grzeschik, K.
H.; Chu, M.-L.; Sangiorgi, F. O.; Sobel, M. E.; Ramirez, F.; Junien,
C.: Further evidence for the dispersion of the human fibrillar collagen
genes. Am. J. Hum. Genet. 38: 26-37, 1986.

25. Huerre-Jeanpierre, C.; Mattei, M. G.; Weil, D.; Grzeschik, K.
H.; Sangiorgi, F. O.; Ramirez, F.; Junien, C.: The gene for human
alpha-1 type II collagen (COL2A1) maps to band 12q131.(Abstract) Cytogenet.
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26. Kaprio, J.; Kujala, U. M.; Peltonen, L.; Koskenvuo, M.: Genetic
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27. Knowlton, R. G.; Katzenstein, P.; Moskowitz, R. W.; Weaver, E.
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28. Knowlton, R. G.; Katzenstein, P. L.; Moskowitz, R. W.; Weaver,
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29. Korkko, J.; Ritvaniemi, P.; Haataja, L.; Kaariainen, H.; Kivirikko,
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(COL2A1) that substitutes aspartate for glycine alpha-I-67 and that
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30. Law, M. L.; Tung, L.; Morse, H. G.; Berger, R.; Jones, C.; Cheah,
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to 12q14.3. Ann. Hum. Genet. 50: 131-137, 1986.

31. Law, M. L.; Tung, L.; Morse, H. G.; Berger, R.; Jones, C.; Cheah,
K. S. E.; Stoker, N. G.; Solomon, E.: Regional assignment of the
human type II collagen gene (COL2A1) on chromosome 12.(Abstract) Cytogenet.
Cell Genet. 40: 678 only, 1985.

32. Learmonth, I. D.; Christy, G.; Beighton, P.: Namaqualand hip
dysplasia: orthopaedic implications. Clin. Orthop. 218: 142-147,
1987.

33. Lee, B.; Vissing, H.; Ramirez, F.; Rogers, D.; Rimoin, D.: Identification
of the molecular defect in a family with spondyloepiphyseal dysplasia. Science 244:
978-980, 1989.

34. Li, S. W.; Prockop, D. J.; Helminen, H.; Fassler, R.; Lapvetelainen,
T.; Kiraly, K.; Peltarri, A.; Arokoski, J.; Lui, H.; Arita, M.; Khillan,
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for collagen II develop a skeleton with membranous and periosteal
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35. Lovell-Badge, R. H.; Bygrave, A.; Bradley, A.; Robertson, E.;
Tilly, R.; Cheah, K. S. E.: Tissue-specific expression of the human
type II collagen gene in mice. Proc. Nat. Acad. Sci. 84: 2803-2807,
1987.

36. Meulenbelt, I.; Williams, C. J.; te Koppele, J. M.; van de Giessen,
G. C.; Slagboom, P. E.: Population haplotype analysis and evolutionary
relations of the COL2A1 gene. Ann. Hum. Genet. 60: 189-199, 1996.

37. Mortier, G. R.; Wilkin, D. J.; Wilcox, W. R.; Rimoin, D. L.; Lachman,
R. S.; Eyre, D. R.; Cohn, D. H.: A radiographic, morphologic, biochemical
and molecular analysis of a case of achondrogenesis type II resulting
from substitution for a glycine residue (gly691-to-arg) in the type
II collagen trimer. Hum. Molec. Genet. 4: 285-288, 1995.

38. Nunez, A. M.; Francomano, C.; Young, M. F.; Martin, G. R.; Yamada,
Y.: Isolation and partial characterization of genomic clones coding
for a human pro-alpha-1(II) collagen chain and demonstration of restriction
fragment length polymorphism at the 3-prime end of the gene. Biochemistry 24:
6343-6348, 1985.

39. Pope, F. M.; Cheah, K. S. E.; Nicholls, A. C.; Price, A. B.; Grosveld,
F. G.: Lethal osteogenesis imperfecta congenita and a 300 base pair
gene deletion for alpha-1-like collagen. Brit. Med. J. 288: 431-434,
1984.

40. Reginato, A. J.; Passano, G. M.; Neumann, G.; Falasca, G. F.;
Diaz-Valdez, M.; Jimenez, S. A.; Williams, C. J.: Familial spondyloepiphyseal
dysplasia tarda, brachydactyly, and precocious osteoarthritis associated
with an arginine75-to-cysteine mutation in the procollagen type II
gene in a kindred of Chiloe Islanders. I. Clinical, radiographic,
and pathologic findings. Arthritis Rheum. 37: 1078-1086, 1994.

41. Ritvaniemi, P.; Hyland, J.; Ignatius, J.; Kivirikko, K. I.; Prockop,
D. J.; Ala-Kokko, L.: A fourth example suggests that premature termination
codons in the COL2A1 gene are a common cause of the Stickler syndrome:
analysis of the COL2A1 gene by denaturing gradient gel electrophoresis. Genomics 17:
218-221, 1993.

42. Sangiorgi, F.; Huerre-Jeanpierre, C.; Weil, D.; Grzeschik, K.
H.; Junien, C.; Sobel, M.; Ramirez, F.: Chromosomal assignment of
the human type II collagen gene.(Abstract) Am. J. Hum. Genet. 36:
208S only, 1984.

43. Sangiorgi, F. O.; Benson-Chanda, V.; de Wet, W. J.; Sobel, M.
E.; Tsipouras, P.; Ramirez, F.: Isolation and partial characterization
of the entire human pro-alpha-1(II) collagen gene. Nucleic Acids
Res. 13: 2207-2225, 1985.

44. Sher, C.; Ramesar, R.; Martell, R.; Learmonth, I.; Tsipouras,
P.; Beighton, P.: Mild spondyloepiphyseal dysplasia (Namaqualand
type): genetic linkage to the type II collagen gene (COL2A1). Am.
J. Hum. Genet. 48: 518-524, 1991.

45. Solomon, E.; Hiorns, L. R.; Cheah, K. S. E.; Parkar, M.; Weiss,
E.; Flavell, R. A.: Assignment of a human alpha-1(I)-like collagen
gene to chromosome 12, by molecular hybridization.(Abstract) Cytogenet.
Cell Genet. 37: 588-589, 1984.

46. Solomon, E.; Hiorns, L. R.; Spurr, N.; Kurkinen, M.; Barlow, D.;
Hogan, B. L. M.; Dalgleish, R.: Chromosomal assignments of the genes
coding for human types II, III and IV collagen: a dispersed gene family. Proc.
Nat. Acad. Sci. 82: 3330-3334, 1985.

47. Spector, T. D.; Cicuttini, F.; Baker, J.; Loughlin, J.; Hart,
D.: Genetic influences on osteoarthritis in women: a twin study. Brit.
Med. J. 312: 940-944, 1996.

48. Stickler, G. B.; Belau, P. G.; Farrell, F. J.; Jones, J. D.; Pugh,
D. G.; Steinberg, A. G.; Ward, L. E.: Hereditary progressive arthro-ophthalmopathy. Mayo
Clin. Proc. 40: 433-455, 1965.

49. Stoker, N. G.; Cheah, K. S. E.; Griffin, J. R.; Pope, F. M.; Solomon,
E.: A highly polymorphic region 3-prime to the human type II collagen
gene. Nucleic Acids Res. 13: 4613-4622, 1985.

50. Strom, C. M.: Achondroplasia due to DNA insertion into the type
II collagen gene.(Abstract) Pediat. Res. 18: 226A only, 1984.

51. Strom, C. M.; Eddy, R. L.; Shows, T. B.: Localization of human
type II procollagen gene (COL2A1) to chromosome 12. Somat. Cell Molec.
Genet. 10: 651-655, 1984.

52. Strom, C. M.; Upholt, W. B.: Isolation and characterization of
genomic clones corresponding to the human type II procollagen gene. Nucleic
Acids Res. 12: 1025-1038, 1984.

53. Sykes, B.; Smith, R.; Vipond, S.; Paterson, C.; Cheah, K.; Solomon,
E.: Exclusion of the alpha-1(II) cartilage collagen gene as the mutant
locus in type IA osteogenesis imperfecta. J. Med. Genet. 22: 187-191,
1985.

54. Sykes, B. C.; Ogilvie, D. J.; Wordsworth, B. P.: Lethal osteogenesis
imperfecta and a collagen gene deletion: length polymorphism provides
an alternative explanation. Hum. Genet. 70: 35-37, 1985.

55. Takahashi, E.; Hori, T.; O'Connell, P.; Leppert, M.; White, R.
: R-banding and nonisotopic in situ hybridization: precise localization
of the human type II collagen gene (COL2A1). Hum. Genet. 86: 14-16,
1990.

56. Takahashi, E.; Hori, T.; Sutherland, G. R.: Mapping of the human
type II collagen gene (COL2A1) proximal to fra(12)(q13.1) by nonisotopic
in situ hybridization. Cytogenet. Cell Genet. 54: 84-85, 1990.

57. Tiller, G. E.; Rimoin, D. L.; Murray, L. W.; Cohn, D. H.: Tandem
duplication within a type II collagen gene (COL2A1) exon in an individual
with spondyloepiphyseal dysplasia. Proc. Nat. Acad. Sci. 87: 3889-3893,
1990.

58. Tiller, G. E.; Weis, M. A.; Lachman, R. S.; Cohn, D. H.; Rimoin,
D. L.; Eyre, D. R.: A dominant mutation in the type II collagen gene
(COL2A1) produces spondyloepimetaphyseal dysplasia (SEMD), Strudwick
type.(Abstract) Am. J. Hum. Genet. 53 (suppl.): A209 only, 1993.

59. Vandenberg, P.; Khillan, J. S.; Prockop, D. J.; Helminen, H.;
Kontusaari, S.; Ala-Kokko, L.: Expression of a partially deleted
gene of a human type II procollagen (COL2A1) in transgenic mice produces
a chondrodysplasia. Proc. Nat. Acad. Sci. 88: 7640-7644, 1991.

60. van der Rest, M.; Rosenberg, L. C.; Olsen, B. R.; Poole, A. R.
: Chondrocalcin is identical with the C-propeptide of type II procollagen. Biochem.
J. 237: 923-925, 1986.

61. Vikkula, M.; Ritvaniemi, P.; Vuorio, A. F.; Kaitila, I.; Ala-Kokko,
L.; Peltonen, L.: A mutation in the amino-terminal end of the triple
helix of type II collagen causing severe osteochondrodysplasia. Genomics 16:
282-285, 1993.

62. Vissing, H.; D'Alessio, M.; Lee, B.; Ramirez, F.; Godfrey, M.;
Hollister, D. W.: Glycine to serine substitution in the triple helical
domain of pro-alpha-1(II) collagen results in a lethal perinatal form
of short-limbed dwarfism. J. Biol. Chem. 264: 18265-18267, 1989.

63. Wagner, H.: Ein bisher unbeknantes Erbleiden des Auges (degeneratio
hyaloideo-retinalis hereditaria), beobachtet im Kanton, Zurich. Klin.
Mbl. Augenheilk. 100: 840-857, 1938.

64. Weiss, E. H.; Cheah, S. E.; Grosveld, F. G.; Dahl, H. H. M.; Solomon,
E.; Flavell, R. A.: Isolation and characterization of a human collagen
alpha1(I)-like gene from a cosmid library. Nucleic Acids Res. 10:
1981-1992, 1982.

65. Wilkin, D. J.; Bogaert, R.; Lachman, R. S.; Rimoin, D. L.; Eyre,
D. R.; Cohn, D. H.: A single amino acid substitution (G103D) in the
type II collagen triple helix produces Kniest dysplasia. Hum. Molec.
Genet. 3: 1999-2003, 1994.

66. Williams, C. J.; Considine, E. L.; Knowlton, R. G.; Reginato,
A.; Neumann, G.; Harrison, D.; Buxton, P.; Jimenez, S.; Prockop, D.
J.: Spondyloepiphyseal dysplasia and precocious osteoarthritis in
a family with an arg75-to-cys mutation in the procollagen type II
gene (COL2A1). Hum. Genet. 92: 499-505, 1993.

67. Williams, C. J.; Ganguly, A.; Considine, E.; McCarron, S.; Prockop,
D. J.; Walsh-Vockley, C.; Michels, V. V.: A(-2)-to-G transition at
the 3-prime acceptor splice site of IVS17 characterizes the COL2A1
gene mutation in the original Stickler syndrome kindred. Am. J. Med.
Genet. 63: 461-467, 1996.

68. Williams, C. J.; Rock, M.; Considine, E.; McCarron, S.; Gow, P.;
Ladda, R.; McLain, D.; Michels, V. M.; Murphy, W.; Prockop, D. J.;
Ganguly, A.: Three new point mutations in type II procollagen (COL2A1)
and identification of a fourth family with the COL2A1 arg519-to-cys
base substitution using conformation sensitive gel electrophoresis. Hum.
Molec. Genet. 4: 309-312, 1995.

69. Winterpacht, A.; Hilbert, M.; Schwarze, U.; Mundlos, S.; Spranger,
J.; Zabel, B. U.: Kniest and Stickler dysplasia phenotypes caused
by collagen type II gene (COL2A1) defect. Nature Genet. 3: 323-326,
1993.

70. Winterpacht, A.; Schwarze, U.; Mundlos, S.; Menger, H.; Spranger,
J.; Zabel, B.: Alternative splicing as the result of a type II procollagen
gene (COL2A1) mutation in a patient with Kniest dysplasia. Hum. Molec.
Genet. 3: 1891-1893, 1994.

71. Yoo, T. J.; Tomoda, K.; Stuart, J. M.; Cremer, M. A.; Townes,
A. S.; Kang, A. H.: Type II collagen-induced autoimmune sensorineural
hearing loss and vestibular dysfunction in rats. Ann. Otol. Rhinol.
Laryng. 92: 267-271, 1983.

72. Yoo, T. J.; Tomoda, K.; Stuart, J. M.; Kang, A. H.; Townes, A.
S.: Type II collagen-induced autoimmune otospongiosis: a preliminary
report. Ann. Otol. Rhinol. Laryng. 92: 103-108, 1983.

73. Young, M. F.; Vogeli, G.; Nunez, A. M.; Fernandez, M. P.; Sullivan,
M.; Sobel, M. E.: Isolation of cDNA and genomic DNA clones encoding
type II collagen. Nucleic Acids Res. 12: 4207-4228, 1984.

*FIELD* CN
Cynthia K. Ewing - updated: 10/14/1996
Lori M. Kelman - updated: 10/6/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/17/1997
terry: 12/17/1996
jamie: 11/13/1996
jamie: 10/23/1996
jamie: 10/16/1996
jamie: 10/14/1996
mark: 10/6/1996
mark: 6/25/1996
terry: 6/14/1996
mark: 3/15/1996
mark: 3/3/1996
terry: 2/23/1996
mark: 3/31/1995
davew: 6/27/1994
jason: 6/24/1994
terry: 5/13/1994
mimadm: 4/13/1994
warfield: 4/7/1994

*RECORD*
*FIELD* NO
120150
*FIELD* TI
*120150 COLLAGEN, TYPE I, ALPHA-1 CHAIN; COL1A1
COLLAGEN OF SKIN, TENDON AND BONE, ALPHA-1 CHAIN
*FIELD* TX
Collagen has a triple-stranded ropelike coiled structure. The major
collagen of skin, tendon and bone is the same protein containing two
alpha-1 polypeptide chains and one alpha-2 chain. Although these are
long (the procollagen chain has a molecular weight of about 120,000,
before the 'registration peptide' is cleaved off; see 225410), each
messenger RNA is monocistronic (Lazarides and Lukens, 1971). Differences
in the collagens from these three tissues are a function of the degree
of hydroxylation of proline and lysine residues, aldehyde formation for
cross-linking, and glycosylation. The alpha-1 chain of the collagen of
cartilage and that of the collagen of basement membrane are determined
by different structural genes. The collagen of cartilage contains only
one type of polypeptide chain, alpha-1, and this is determined by a
distinct locus. The fetus contains a fetal collagen of distinctive
structure. The genes for types I, II, and III collagens, the
interstitial collagens, exhibit an unusual and characteristic structure
of a large number of relatively small exons (54 and 108 bp) at
evolutionarily conserved positions along the length of the triple
helical Gly-X-Y portion (Boedtker et al., 1983). The family of collagen
proteins consists of a minimum of 9 types of collagen molecules whose
constituent chains are encoded by a minimum of 17 genes (Ninomiya and
Olsen, 1984).

Tromp et al. (1988) characterized for the first time a full-length cDNA
clone for the COL1A1 gene. Sundar Raj et al. (1977) used the methods of
cell hybridization and microcell hybridization to assign a collagen I
gene to chromosome 17. Solomon and Sykes (1979) concluded, incorrectly
as it turned out, that both the alpha-1 and the alpha-2 genes of
collagen I are on chromosome 7. Solomon and Sykes (1979) also presented
evidence that the alpha-1 chains of collagen III are also coded by
chromosome 7. Church et al. (1981) assigned a structural gene for
corneal type I procollagen to chromosome 7 by somatic cell hybridization
involving corneal stromal fibroblasts. Because they had previously
assigned a gene for skin type I procollagen to chromosome 17, they
wondered whether skin and corneal type I collagen may be under separate
control. Huerre et al. (1982) used a cDNA probe in both mouse-man and
Chinese hamster-man somatic cell hybrids to demonstrate cosegregation
with human chromosome 17. In situ hybridization using the same probe
indicated that the gene is in the middle third of the long arm, probably
in band 17q21 or 17q22. By chromosome-mediated gene transfer (CMGT),
Klobutcher and Ruddle (1979) transferred the genes for thymidine kinase,
galactokinase and type I procollagen (gene for alpha-1 polypeptide). The
data indicated the following gene order: centromere--GALK--(TK1-COL1A1).
Later studies (Ruddle, 1982) put the growth hormone gene cluster between
GALK and (TK1-COL1A1). A HindIII restriction site polymorphism in the
alpha-1(I) gene was described by Driesel et al. (1982), who probably
unjustifiably stated that the gene is on chromosome 7. By in situ
hybridization, Retief et al. (1985) concluded that the alpha-1(I) and
alpha-2(I) genes are located in bands 17q21.31-q22.05 and 7q21.3-q22.1,
respectively. Sippola-Thiele et al. (1986) commented on the limited
number of informative RFLPs in the collagen genes, especially COL1A1.
They proposed a method for assessing RFLPs that were otherwise
undetectable in total human genomic DNA. Using the centromere-based
locus D17Z1, Tsipouras et al. (1988) found a recombination fraction of
0.20 with COL1A1. Furthermore, they demonstrated that COL1A1 and GH1
(139250) show a recombination fraction of 0.10. They proposed that the
most likely order is D17Z1--COL1A1--GH1. Byrne and Church (1983) had
concluded that both subunits of type I collagen, alpha-1 and alpha-2,
are coded by chromosome 16 in the mouse. SOD-1 (147450), which in man is
on chromosome 21, is also carried by mouse 16. It may have been type VI
collagen (120220, 120240) that they dealt with; both COL6A1 and COL6A2
are coded by human chromosome 21. (In fact, the Col6a-1 and Col6a-2
genes are carried by mouse chromosome 10 (Justice et al., 1990).) Munke
et al. (1986) showed that the alpha-1 gene of type I collagen is located
on mouse chromosome 11; the Moloney murine leukemia virus is stably
integrated into this site when microinjected into the pronuclei of
fertilized eggs. This insertion results in a lethal mutation through
blockage of the developmentally regulated expression of the gene
(Schnieke et al., 1983).

Pope et al. (1985) described a substitution of cysteine in the
C-terminal end of the alpha-1 collagen chain in a 9-year-old boy with
mild OI of Sillence type I. They assumed that this was a substitution
for either arginine or serine (which could be accomplished by a single
base change) because substitution of cysteine for glycine produced a
much more drastic clinical picture. In a neonatal lethal case of OI
congenita, Barsh and Byers (1981) demonstrated a defect in pro-alpha-1
chains (see 166210). Byers et al. (1988) found an insertion in one
COL1A1 allele in an infant with OI II. One alpha-1 chain was normal in
length, whereas the other contained an insertion of approximately 50-70
amino acid residues within the triple helical domain defined by amino
acids 123-220. The structure of the insertion was consistent with
duplication of an approximately 600-bp segment in 1 allele. Brookes et
al. (1989) used an S1 nuclease directed cleavage of heteroduplex DNA
molecules formed between genomic material and cloned sequences to search
for mutations in the COL1A1 gene in 5 cases in which previous linkage
studies had shown the mutation to be located in the COL1A1 gene and in 4
cases in which a COL1A1 null allele had been identified by protein and
RNA studies. No abnormality was found in the complete 18 kb COL1A1 gene
or in 2 kb of 5-prime flanking sequence. The method used was known to
permit the detection of short length variations of the order of 4 bp in
heterozygous subjects but not single base pair alterations. Thus,
Brookes et al. (1989) suggested that single base pair alterations may be
the predominant category of mutation in type I OI. COL1A1 and NGFR
(162010) are in the same restriction fragment. In a 3-generation family
with OI type I, Willing et al. (1990) found that all affected members
had one normal COL1A1 allele and another from which the intragenic EcoRI
restriction site near the 3-prime end of the gene was missing. They
found, furthermore, a 5-bp deletion at the EcoRI site which changed the
translational reading frame and predicted the synthesis of a
pro-alpha-1(I) chain that extended 84 amino acids beyond the normal
termination. Although the mutant chain was synthesized in an in vitro
translation system, they were unable to detect its presence in intact
cells, suggesting that it is unstable and rapidly destroyed in one of
the cell's degradative pathways.

Cohn et al. (1990) demonstrated a clear instance of paternal germline
mosaicism as the cause of 2 offspring with OI type I by different women.
Both affected infants had a G-to-A change that resulted in substitution
of aspartic acid for glycine at position 883 of the alpha-1 chain of
type I collagen. Although not detected in the father's skin fibroblasts,
the mutation was detected in somatic DNA from the father's hair root
bulbs and lymphocytes. It was also found in the father's sperm where
about 1 in 8 sperm carried the mutation, suggesting that at least 4
progenitor cells populate the germ line in human males. The father was
clinically normal. In an infant with perinatal lethal OI (OI type II),
Wallis et al. (1990) demonstrated both normal and abnormal type I
procollagen molecules. The abnormal molecules had substitution of
arginine for glycine at position 550 of the triple-helical domain as a
result of a G-to-A transition in the first base of the glycine codon.
The father was shown to be mosaic for this mutation, which accounted for
about 50% of the COL1A1 alleles in his fibroblasts, 27% of those in
blood cells, and 37% of those in sperm. The father was short of stature;
he had bluish sclerae, grayish discoloration of the teeth (which were
small), short neck, barrel-shaped chest, right inguinal hernia, and
hyperextensible fingers and toes. A triangular-shaped head had been
noted at birth and he was thought to have hydrocephalus. No broken bones
had been noted at that time. He had had only 1 fracture, that of the
clavicle at age 8 years.

Cole et al. (1990) reported the clinical features of 3 neonates with
lethal perinatal OI resulting from a substitution of glycine by arginine
in the COL1A1 gene product. The mutations were gly391-to-arg,
gly667-to-arg, and gly976-to-arg. All 3 were small, term babies who died
soon after birth. The ribs were broad and continuously beaded in the
first, discontinuously beaded in the second, and slender with few
fractures in the third. The overall radiographic classifications were
type IIA, IIA/IIB, and IIB, respectively. The findings suggested that
there was a gradient of bone modeling capacity from the slender and
overmodeled bones associated with the mutation nearest the COOH-end of
the molecule to absence of modeling with that nearest the NH2-end.

Dermal fibroblasts from most persons with OI type I produce about half
the normal amount of type I procollagen as a result of decreased
synthesis of one of its constituent chains, namely, the alpha-1 chain.
Willing et al. (1992) used a polymorphic MnlI restriction endonuclease
site in the 3-prime-untranslated region of COL1A1 to distinguish the
transcripts of the 2 alleles in 23 heterozygotes from 21 unrelated
families with OI type I. In each case there was marked diminution in
steady-state mRNA levels from one COL1A1 allele. They demonstrated that
loss of an allele through deletion or rearrangement was not the cause of
the diminished COL1A1 mRNA levels. Primer extension with
nucleotide-specific chain termination allowed identification of the
mutant allele in cell strains that were heterozygous for an expressed
polymorphism. Willing et al. (1992) suggested that the method is
applicable to sporadic cases, to small families, and to large families
in which key persons are uninformative at the polymorphic sites used in
linkage analysis.

Willing et al. (1993) pointed out that the abnormally low ratio of
COL1A1 mRNA to COL1A2 mRNA in fibroblasts cultured from OI type I
patients is an indication of a defect in the COL1A1 gene in the great
majority of patients with this form of OI. Pereira et al. (1993)
established a line of transgenic mice that expressed moderate levels of
an internally deleted human COL1A1 gene. The gene construct was modeled
after a sporadic inframe deletion that produced a lethal variant of OI.
About 6% of the transgenic mice had a lethal phenotype with extensive
fractures at birth, and 33% had fractures but were viable. The remaining
61% of the transgenic mice had no apparent fractures as assessed by
x-ray examination on the day of birth. Brother-sister matings produced 8
litters in which approximately 40% of the mice had the lethal phenotype,
indicating that expression of the transgene was more lethal in
homozygous mice. The shortened collagen polypeptide chains synthesized
from the human transgene were thought to bind to and produce degradation
of the normal collagen genes synthesized from the normal mouse alleles.
Khillan et al. (1994) extended these studies using an antisense gene.
The strategy of specifically inhibiting expression of a gene with
antisense RNA generated from an inverted gene was introduced in 1984
(Izant and Weintraub, 1984; Mizuno et al., 1984; and Pestka et al.,
1984). Khillan et al. (1994) assembled an antisense gene that was
similar to the internally deleted COL1A1 minigene used by Pereira et al.
(1993) except that the 3-prime half of the gene was inverted so as to
code for an antisense RNA. Transgenic mice expressing the antisense gene
had a normal phenotype, apparently because the antisense gene contained
human sequences instead of mouse sequences. Two lines of mice expressing
the antisense gene were bred to 2 lines of transgenic mice expressing
the mini-gene. In mice that inherited both genes, the incidence of the
lethal fragile bone phenotype was reduced from 92 to 27%. The effect of
the antisense gene was directly demonstrated by an increase in the ratio
of normal mouse pro-alpha-1(I) chains to human mini-chains in tissues
from mice that inherited both genes and had a normal phenotype. The
results raised the possibility that chimeric gene constructs that
contain intron sequences and in which only the first half of a gene is
inverted may be particularly effective as antisense genes.

Pereira et al. (1994) used an inbred strain of transgenic mice
expressing a mutated COL1A1 gene to demonstrate interesting features
concerning phenotypic variability and incomplete penetrance. These
phenomena are striking in families with osteogenesis imperfecta and are
usually explained by differences in genetic background or in
environmental factors. The inbred strain of transgenic mice expressing
an internally deleted COL1A1 gene was bred to wildtype mice of the same
strain so that the inheritance of proneness to fracture could be
examined in a homogeneous genetic background. To minimize the effects of
environmental factors, the phenotype was evaluated in embryos that were
removed from the mother one day before term. Examination of stained
skeletons from 51 transgenic embryos from 11 separate litters
demonstrated that approximately 22% had a severe phenotype with
extensive fractures of both long bones and ribs, approximately 51% had a
mild phenotype with fractures of ribs only, and approximately 27% had no
fractures. The ratio of steady-state levels of the mRNA from the
transgene to the level of mRNA from the endogenous gene was the same in
all transgenic embryos. The results demonstrated that the phenotypic
variability and incomplete penetrance were not explained by variation in
genetic background or levels in gene expression. Pereira et al. (1994)
concluded from these results that phenotypic variation may be an
inherent characteristic of the mutated collagen gene.

Byers (1993) counted a total of approximately 70 point mutations
identified in the helical portion of the alpha-1 peptide, approximately
10 exon skipping mutations, and about 6 point mutations in the
C-propeptide.

Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and
cytoplasm of dermal fibroblasts from most subjects with type I
osteogenesis imperfecta (166200). Willing et al. (1995) investigated
whether mutations involving key regulatory sequences in the COL1A1
promoter, such as the TATAAA and CCAAAT boxes, are responsible for the
reduced levels of mRNA. They used PCR-amplified genomic DNA in
conjunction with denaturing gradient gel electrophoresis and SSCP to
screen the 5-prime untranslated domain, exon 1, and a small portion of
intron 1 of the COL1A1 gene. In addition, direct sequence analysis was
performed on an amplified genomic DNA fragment that included the TATAAA
and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in
whom no causative mutation was known, Willing et al. (1995) identified
no mutations in the promoter region and there was 'little evidence of
sequence diversity among any of the 40 subjects.'

Whereas most cases of severe osteogenesis imperfecta result from
mutations in the coding region of the COL1A1 or COL1A2 genes yielding an
abnormal collagen alpha-chain, many patients with mild OI show evidence
of a null allele due to a premature stop mutation in the mutant RNA
transcript. As indicated in 120150.0046, mild OI in one case resulted
from a null allele arising from a splice donor mutation where the
transcript containing the included intron was sequestered in the
nucleus. Nuclear sequestration precluded its translation and thus
rendered the allele null. Using RT-PCR and SSCP of COL1A1 mRNA from
patients with mild OI, Redford-Badwal et al. (1996) identified 3
patients with distinct null-producing mutations identified from the
mutant transcript within the nuclear compartment. In a fourth patient
with a gly-to-arg expressed point mutation, they found the mutant
transcript in both the nucleus and the cytoplasm.

Willing et al. (1996) analyzed the effects of nonsense and frameshift
mutations on steady state levels of COL1A1 mRNA. Total cellular and
nuclear RNA was analyzed. They found that mutations which predict
premature termination reduce steady-state amounts of COL1A1 mRNA from
the mutant allele in both nuclear and cellular mRNA. The investigators
concluded that premature termination mutations have a predictable and
uniform effect on COL1A1 gene expression which ultimately leads to
decreased production of type I collagen and to the mild phenotype
associated with OI type I. Willing et al. (1996) reported that mutations
which lead to premature translation termination appear to be the most
common molecular cause of OI type I. They identified 21 mutations, 15 of
which lead to premature termination as a result of translational
frameshifts or single-nucleotide substitutions. Five mutations were
splicing defects leading to cryptic splicing or intron retention within
the mature mRNA. Both of these alternative splicing pathways indirectly
lead to frameshifts and premature termination in downstream exons.

Dermatofibrosarcoma protuberans, an infiltrative skin tumor of
intermediate malignancy, presents specific cytogenetic features such as
reciprocal translocations t(17;22)(q22;q13) and supernumerary ring
chromosomes derived from t(17;22). Simon et al. (1997) characterized the
breakpoints from translocations and rings in dermatofibrosarcoma
protuberans and its juvenile form, giant cell fibroblastoma, on the
genomic and RNA levels. They found that these rearrangements fuse the
PDGFB gene (190040) and the COL1A1 gene. Simon et al. (1997) commented
that PDGFB has transforming activity and is a potent mitogen for a
number of cell types, but its role in oncogenic processes was not fully
understood. They noted that neither COL1A1 nor PDGFB had hitherto been
implicated in tumor translocations. The gene fusions deleted exon 1 of
PDGFB and released this growth factor from its normal regulation; see
190040.0002.

(The amino acid numbering system for collagen involves assigning number
1 to the first glycine of the triple helical domain of an alpha chain.
The numbers for the alpha-1 chain of type I collagen can be converted to
positions in the pro-alpha-1 chain by adding 156, and the numbers for
the alpha-2 chain can be converted to the human pro-alpha-2 chain by
adding 68.)

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2
genes accessible on the World Wide Web.

*FIELD* AV
.0001
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY97ASP
Byers (1990) provided information about this mutation.

.0002
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY94CYS
Starman et al. (1989) described a patient with OI type II in whom a
population of alpha-1(I) chains had a substitution of cysteine for
glycine at position 94.

.0003
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A1, GLY175CYS
In a patient with 'moderately severe' OI, de Vries and de Wet (1986,
1987) found a substitution of cysteine for glycine-175. Four persons in
3 generations were affected with striking variability in severity of
fractures, deformity, and hearing loss, as well as presence or absence
of blue sclerae and Wormian bones.

.0004
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY391ARG
Bateman et al. (1987) characterized a structural defect of the alpha-1
chain of type I collagen in a baby with the lethal perinatal form of OI.
The glycine residue at position 391 had been replaced by arginine. The
substitution was associated with increased enzymatic hydroxylation of
neighboring regions of the alpha-1 chain. This finding suggested that
the sequence abnormality had interfered with the propagation of the
triple helix across the mutant region. The abnormal collagen was not
incorporated into the more insoluble fraction of bone collagen. The baby
appeared to be heterozygous for the sequence abnormality, and, since the
parents did not show any evidence of the defect, the authors concluded
that the baby had a new mutation. The amino acid substitution could
result from a single nucleotide change in the codon GGC (glycine) to
produce the codon CGC (arginine).

.0005
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY526CYS
In a patient with OI type III, Starman et al. (1989) identified a
population of alpha-1(I) chains in which the glycine at position 526 was
replaced by cysteine.

.0006
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY559ASP
Byers (1990) characterized this mutation in a patient with OI type II.

.0007
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY673ASP
Byers (1990) described this mutation in a patient with type II OI.

.0008
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY667ARG
This mutation was originally thought to be a substitution of
gly664-to-arg in the alpha-1(I) chain, but in fact alters residue 667
from glycine to arginine, according to Byers (1990). Bateman et al.
(1988) originally described the mutation.

.0009
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY691CYS
Bateman et al. (1988) described this mutation in a patient with type II
OI.

.0010
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY718CYS
Starman et al. (1989) characterized this mutation in a patient with type
II OI.

.0011
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY748CYS
In a fetus with severe OI congenita, Vogel et al. (1987) found that a
single nucleotide change, converting glycine 748 to cysteine in the
alpha-1(I) chain, was responsible for destabilizing the triple helix and
resulted in the lethal disorder. About 80% of the type I procollagen
synthesized by the fibroblasts of the fetus had a decreased thermal
stability. The fibroblasts of both parents were normal, indicating that
this was a new mutation. Vogel et al. (1988) showed that the procollagen
synthesized by the proband's cells is resistant to cleavage by
procollagen N-proteinase, a confirmation-sensitive enzyme. Vogel et al.
(1988) presented several space-filling models that might explain how the
structure of the N-proteinase cleavage site could be affected by an
amino acid substitution over 700 amino acid residues away.

.0012
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A1, GLY832SER
Marini et al. (1989) characterized this mutation in a patient with OI
type IV. Also see Marini et al. (1993).

.0013
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY844SER
Pack et al. (1989) described this mutation in a patient with OI type
III. An unusual biochemical feature of this mutation was normal thermal
stability of the intact type I collagen; multiple other mutations in
which glycine is replaced result in significantly diminished thermal
stability of the type I collagen molecule.

.0014
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY847ARG
Wallis et al. (1990) described this mutation.

.0015
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY883ASP
Cohn et al. (1990) reported this mutation in a patient with OI type II.
Recurrence of the OI type II phenotype in this family was explained by
the finding of both somatic and germline mosaicism for this mutation in
the father of the proband.

.0016
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY904CYS
Constantinou et al. (1989) characterized this mutation in a patient with
the perinatal lethal form of OI (OI type II). The mutation caused the
synthesis of type I procollagen that was posttranslationally
overmodified, secreted at a decreased rate, and had a decreased thermal
stability. Constantinou et al. (1990) demonstrated that the proband's
mother had the same single base mutation as the proband. However, she
had no fractures and no signs of OI except short stature, slightly blue
sclerae, and mild frontal bossing; as a child, she had the triangular
facies frequently seen in patients with OI. On repeated subculturing,
the proband's fibroblasts grew more slowly than the mother's, but they
continued to synthesize large amounts of the mutated procollagen in
passages 7-14. In contrast, the mother's fibroblasts synthesized
decreasing amounts of the mutated procollagen after passage 11. Also,
the relative amount of the mutated allele in the mother's fibroblasts
decreased with the passage number. In addition, the ratio of the mutated
allele to the normal allele in leukocyte DNA from the mother was half
the value in fibroblast DNA from the proband. Constantinou et al. (1990)
concluded that the simplest interpretation of the findings was that the
mother was mildly affected because she was mosaic for the mutation that
produced a lethal phenotype in 1 of her 3 children. See also Cohn et al.
(1990) and Wallis et al. (1990).

.0017
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY913SER
Byers (1990) described this mutation.

.0018
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY988CYS
Steinmann et al. (1984) reported the protein abnormality in a cell line
established from a patient with OI type II. Cohn et al. (1986)
characterized the mutation.

.0019
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY1009SER
Byers (1990) characterized this mutation.

.0020
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, EX22DEL
Wallis et al. (1989) described a mutation in COL1A1 resulting in the
deletion of exon 22 during RNA processing. The phenotype was progressive
deforming OI (OI type III).

.0021
OSTEOGENESIS IMPERFECTA
COL1A1, GLY1017CYS
In a patient with 'moderately severe' OI, Steinmann et al. (1986)
described an abnormal cysteine residue in cyanogen bromide peptide 6 of
an alpha-1(I) chain. According to Byers (1990), the mutation causes
substitution of cysteine for gly1017.

.0022
OSTEOGENESIS IMPERFECTA
COL1A1, GLY?CYS
Cohn et al. (1988) described a substitution of cysteine for glycine in
the carboxy-terminal region of an alpha-1(I) chain in a patient with
mild OI.

.0023
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, 9BP DEL
In a patient with the perinatal lethal form of OI, Wallis et al. (1989)
described the heterozygous deletion of codons 874-876.

.0024
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, FS
Willing et al. (1990) reported a frameshift mutation near the 3-prime
end of COL1A1 resulting in the phenotype of OI type I.

.0025
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, INS NT4088
In a patient with the perinatal lethal form of OI, Bateman et al. (1989)
reported an insertion mutation 5-prime to nucleotide 4088 of COL1A1.

.0026
EHLERS-DANLOS SYNDROME, TYPE VII-A
COL1A1, EX6DEL
Cole et al. (1986) studied the collagen of a 3-month-old girl judged to
have type VII E-D. She was born with bilateral dislocation of the hips
and knees and mildly hyperelastic skin. Collagen fibrils in the skin
were irregular in outline and varied widely in diameter. They found
deletion of 24 amino acids (positions 136-159) from pro-alpha-1(I). The
deleted segment normally contains the small globular region of the
NH2-propeptide, the procollagen N-proteinase cleavage site, the
NH2-telopeptide, and the first triplet of the helix of the alpha-1(I)
collagen chain. Loss of the procollagen N-proteinase cleavage site
accounts for the persistence of NH2-propeptide despite normal activity
of N-proteinase. Collagen production by mutant fibroblasts was doubled,
possibly due to reduced feedback inhibition by NH2-propeptide. The child
was heterozygous and a new mutant. The parents did not show the
deletion. The deleted peptide corresponded precisely to the sequence
coded by exon 6 of the normal pro-alpha-1(I) gene (Chu et al., 1984). At
4 years 7 months, the face had a chubby appearance due to laxity of
facial tissues. Height was at the 3rd centile. The short stature was
thought to be due in part to progressive right thoracolumbar scoliosis.
A large inguinal hernia was present. Weil et al. (1989) found that this
patient had an unusual splicing mutation resulting in lack of exon 6
sequences in the transcripts from the COL1A1 gene. Analysis of cloned
genomic fragments showed that one of the proband's alleles had
substitution of an A for a G in the last nucleotide of exon 6. The
change converted the normal met(ATG) codon to ile(ATA) and, in addition,
obliterated an NcoI restriction site. The latter change was exploited to
demonstrate that the unaffected parents lacked the mutation. Further
confirmation of the missplicing was obtained by transient expression.
Weil et al. (1989) demonstrated the production of relatively low amounts
of correctly spliced molecules harboring the ile substitution. D'Alessio
et al. (1991) found that a child with type VII EDS was heterozygous for
a structural defect in the amino-terminus of the pro-alpha-1(I)
collagen. They demonstrated that the structural defect of the protein
was the result of a single base substitution (A for G) at position -1 of
the splice donor site of intron 6 of the COL1A1 gene. The affected
allele produced transcripts lacking exon 6 sequences and, in lesser
amounts, normally spliced transcripts. The rate of exon 6 skipping was
temperature dependent, for it appeared to decrease substantially when
the patient's fibroblasts were incubated at 31 degrees C. This mutation
was identical to that described by Weil et al. (1989).

.0027
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, INS4088T
In a baby with perinatal lethal OI and x-ray changes most consistent
with OI IIB, Cole et al. (1990) found heterozygosity for insertion of a
single uridine nucleotide after basepair 4088 of the prepro-alpha-1(I)
mRNA of type I collagen. (Type II OI can be subclassified into types
IIA, IIB, and IIC (Sillence et al., 1984; Thompson et al., 1987). Type
IIA has broad, crumpled long bones and ribs with severe platyspondyly,
very poor ossification of the skull, and perinatal death. Type IIB has
discontinuously beaded ribs, crumpled femora, angulated tibiae, better
modeled humeri, more normal vertebrae, better ossification of the skull,
and survival, at times, beyond the perinatal period. Type IIC has thin,
cylindrical, and dysplastic long bones and thin, beaded ribs with
stillbirth.) Cole et al. (1990) suggested that OI IIB can be further
subclassified into 2 groups, one with mutations in the helical portion
and both normal and mutant type I collagen in the tissues, and the
other, representative of this case, with carboxy-terminal propeptide
mutations and a severe type I collagen deficiency, but without mutant
collagen in the tissues.

.0028
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, GLY178CYS
By chemical cleavage of DNA-DNA heteroduplexes, Valli et al. (1991)
detected a single basepair mismatch in the COL1A1 gene in a patient with
moderately severe osteogenesis imperfecta. The mismatch was found in
about one-half of the heteroduplex molecules formed between the
patient's mRNA and a normal cDNA probe. Sequencing demonstrated a single
G-to-T substitution as the first base of the triplet coding for residue
178 of the triple helical domain of the protein, leading to a
glycine-to-cysteine substitution. Allele-specific oligonucleotide (ASO)
hybridization to amplified DNA confirmed a de novo point mutation in the
proband's genome.

.0029
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY541ASP
See Zhuang et al. (1991).

.0030
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY154ARG
In 2 unrelated individuals with a progressive deforming variety of OI,
Pruchno et al. (1991) found the same new dominant mutation, a
substitution of arginine for glycine-154. The mutation occurred at a CpG
dinucleotide in a manner consistent with deamination of a methylated
cytosine residue. The findings indicated that the type III OI phenotype,
previously thought to be inherited in an autosomal recessive manner
(259420), can result from new dominant mutations in the COL1A1 gene.
Zhuang et al. (1996) found this mutation in a father and his 3 children.

.0031
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY1003SER
In 2 unrelated infants with perinatal lethal OI, Pruchno et al. (1991)
observed a de novo dominant mutation that resulted in substitution of
serine for glycine-1003. This mutation occurred at a CpG dinucleotide in
a manner consistent with deamination of a methylated cytosine residue.
Zhuang et al. (1996) found the same mutation in a father and his 3
children. The phenotypes of the patients included manifestations of
types I and III/IV osteogenesis imperfecta, but appeared to be milder
than the phenotype of the previously described 2 unrelated patients with
the G415C mutation. Zhuang et al. (1996) speculated that other mutations
in the type I collagen genes, environmental factors, mosaic status of
the father, or genes at different loci might be responsible for the
variable phenotype. They cited the evidence presented by Aitchison et
al. (1988) and by Wallis et al. (1993) from linkage studies, indicating
that genes other than the type 1 collagen genes may be involved in
causing or modifying OI. The finding that allelic variants of the
vitamin D receptor gene (277440) may correlate with low bone density
provided another plausible explanation for a more severe phenotype in
some individuals with OI due to identical mutations in the genes for
type I collagen.

.0032
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY637VAL
In a case of lethal osteogenesis imperfecta, Tsuneyoshi et al. (1991)
demonstrated substitution of valine for glycine-637.

.0033
OSTEOGENESIS IMPERFECTA, TYPE III/IV
COL1A1, GLY415CYS
In a male in his late 50s with osteogenesis imperfecta thought to be of
either type III or type IV, Nicholls et al. (1991) described
heterozygosity for a substitution of cysteine for glycine at residue
415. Codon 415 was changed from GGC to TGC. The patient's first recorded
fracture occurred at 6 weeks of age. Over the next 16 years he suffered
more than 270 fractures leading to progressive skeletal deformity. His
sclerae were reportedly bluish at birth but had become paler with age--a
characteristic of type III OI. He had developed conductive hearing loss
in his 20s, a feature not previously described in either type III or
type IV. His teeth had been said to have been yellowish brown. The
clinical phenotype and the position of the mutation conformed to the
prediction of Starman et al. (1989) that the gly-to-cys mutations in the
alpha-1(I) chain show a gradient of severity decreasing from the
C-terminus to the N-terminus.

.0034
OSTEOGENESIS IMPERFECTA
COL1A1, GLY85ARG
Deak et al. (1991) reported a 56-year-old male with mild osteogenesis
imperfecta who underwent surgery for severe aortic valve regurgitation.
He was of normal stature, with barrel chest and very pale blue sclera.
Radiologic examination showed kyphoscoliosis and multiple compression
fractures throughout the dorsal spine, although there was no history of
spontaneous fractures. The aortic regurgitation was thought to be part
of the connective tissue abnormality. Enlargement of the aortic root and
mucinous degeneration of the aortic valve such as were found in this
patient had been observed by Weisinger et al. (1975) and others. Deak et
al. (1991) demonstrated substitution of arginine for glycine-85 in one
of the 2 alpha-1(I) procollagen chains.

.0035
OSTEOGENESIS IMPERFECTA, TYPE IIC
COL1A1, GLY1006VAL
In an infant with perinatal lethal osteogenesis imperfecta of the most
severe clinical form, OI IIC, with premature rupture of membranes,
severe antepartum hemorrhage, stillbirth, severe short-limbed dwarfism,
and extreme osteoporosis, Cole et al. (1992) found a glycine-to-valine
substitution at residue 1006 in the triple helical domain of the alpha-1
chain of type I collagen.

.0036
OSTEOGENESIS IMPERFECTA, TYPE IIA
COL1A1, GLY973VAL
Cole et al. (1992) found substitution of valine for glycine at residue
973 in the triple helical domain of the alpha-1 chain of type I collagen
in an infant born prematurely as a result of premature rupture of
membranes and severe antepartum hemorrhage. The infant had the
radiographic features of OI IIA.

.0037
OSTEOGENESIS IMPERFECTA, TYPE IIA
COL1A1, GLY256VAL
In an infant with OI IIA, Cole et al. (1992) found substitution of
valine for glycine at residue 256 in the triple helical domain of the
alpha-1 chain of type I collagen. Severe osteogenesis imperfecta can
result from substitutions for glycine as far toward the amino-terminal
as position 256. Cole et al. (1992) suggested that the type of glycine
substitution which includes, in addition to valine, cysteine, arginine,
aspartic acid, serine, alanine, tryptophan, and glutamic acid, and the
site and surrounding sequences are probably important factors in
determining the severity of the phenotype, i.e., whether it is OI I/IV,
OI II, or OI III.

.0038
OSTEOPOROSIS, IDIOPATHIC
OSTEOPENIC NONFRACTURE SYNDROME
COL1A1, GLY43CYS
Shapiro et al. (1992) described studies of a woman who at the age of 38,
while still premenopausal, was found to have osteopenia, short stature,
hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue
sclerae. There was no history of vertebral or appendicular fracture. Hip
and vertebral bone mineral density measurements were consistent with
marked fracture risk. A basepair mismatch between the proband and
control COL1A1 cDNA was detected by chemical cleavage with
hydroxylamine:piperidine. Nucleotide sequence analysis demonstrated a
G-to-T substitution in codon 43, replacing the expected glycine (GGT)
residue with cysteine (TGT). Two of the woman's 4 children were
similarly affected.

.0039
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, IVS14DS, G-A, +5
In a fetus with type II OI, Bonadio et al. (1990) demonstrated
homozygosity for a G-to-A transition at the moderately conserved +5
position within the splice donor site of the COL1A1 gene. The mutation
reduced the efficiency of normal splice site selection since the exon
upstream of the mutation was spliced alternatively. The extent of
alternative splicing was sensitive to the temperature at which the
mutant cells were grown, suggesting that the mutation directly affected
spliceosome assembly. The G-to-A transition appeared to be heterozygous
at the level of mRNA and protein because it was unable to disrupt
completely the normal exon 14 splicing. Bonadio et al. (1990) suggested
that low level expression of alternative splicing (as could occur with
heterozygous mutation) might be associated with mild dysfunction of
connective tissue and perhaps, therefore, a phenotype different from
osteogenesis imperfecta. The parents were unrelated and in their
thirties at the time of the offspring's conception; neither parent had
clinical signs or symptoms of OI. The diagnosis of short-limbed dwarfism
was made on the fetus at 5 months of gestation and pregnancy was
terminated electively. At autopsy, the fetus had all the characteristics
of osteogenesis imperfecta congenita. DNA studies in both parents showed
absence of the mutation in all cells studied (Bonadio, 1990). Bonadio
(1990) found evidence suggesting uniparental disomy for chromosome 17. A
new mutation in 1 parent combined with uniparental disomy would explain
the functional homozygosity of the mutation in the fetus. Bonadio (1992)
had not had an opportunity to study the possibility further.

.0040
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, GLY901SER
Mottes et al. (1992) identified a GGC (gly) to AGC (ser) transition in
codon 901 of the COL1A1 gene in an 8-year-old boy with repeated
fractures of both femora. Intramedullar rodding had been performed at
the age of 3 years. His mother, 44 years old at the time of his birth,
was short (140 cm) and had mild hypoacusis from age 40 and moderate
osteoporosis but had never had fractures. The mother was likewise
heterozygous for the gly901-to-ser mutation. The mild phenotype was
surprising in light of the usual experience that glycine substitutions
in the C-terminal region of the collagen triple helix cause lethal OI.
The patient was classified as OI type IB on the basis of the absence of
dentinogenesis imperfecta (see 166240).

.0041
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY802VAL
In the surviving child in a family in which the 2 sibs had clinical and
radiologic features typical of lethal OI (Cohen-Solal et al., 1991),
Bonaventure et al. (1992) used chemical cleavage of cDNA-RNA
heteroduplexes to identify a mismatch in COL1A1 cDNA. The mismatch was
subsequently confirmed by sequencing a PCR-amplified fragment and was
demonstrated to be due to a G-to-T transition in the second base of the
first codon of exon 41 resulting in the substitution of glycine-802 by
valine. The mutation impaired collagen secretion by dermal fibroblasts.
The overmodified chains were retained intracellularly. The mutant allele
was demonstrated in the mother's leukocytes but not in her fibroblasts,
and collagen synthesized by the fibroblasts of both parents was normal.
The findings suggested the presence of somatic and germline mosaicism in
the phenotypically normal mother, explaining the recurrence of OI.

.0042
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY352SER
In a 6.5-year-old girl with 'moderately severe OI,' Marini et al. (1993)
observed substitution of serine for glycine-352 in the alpha-1 chain of
type I collagen. This substitution was produced by a G-to-A transition
in 1 allele.

.0043
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, EX15-16 DUP
In an infant with the lethal form of osteogenesis imperfecta, Cohn et
al. (1993) characterized a tandem duplication mutation within the COL1A1
gene. The structure of the mutation was consistent with unequal crossing
over within a 15-bp region of sequence identity between exons 14 and 17.
The recombination produced a new 81-bp 17/14 hybrid exon and complete
duplication of exons 15 and 16. The sequence implied duplication of 60
amino acid residues within the triple helical domain with preservation
of the gly-X-Y repeat. The process was thought to mimic that by which
the triple helical domain of fibrillar collagen genes arose in evolution
by repeated tandem duplication of an ancestral unit exon.

.0044
OSTEOGENESIS IMPERFECTA, TYPE II/III
COL1A1, GLY415SER
In a female infant who died in her first hour of life because of
respiratory failure and showed the features of severe osteogenesis
imperfecta thought to fall between type II and type III of Sillence,
Mottes et al. (1993) demonstrated by chemical cleavage of mismatched
bases and subsequent sequencing a G-to-A transition that caused
substitution of gly415 with serine. The same mutation was found in the
clinically normal father's spermatozoa and lymphocytes. Mosaicism in the
father's germline explained the occurrence in the family of 2 later
pregnancies in which OI was documented by radiographs and ultrasound
investigations.

.0045
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY565VAL
In an infant with osteogenesis imperfecta type IIA born of a 37-year-old
mother and a 39-year-old father, Mackay et al. (1993) mapped the defect
in type I collagen to alpha-1 cyanogen bromide peptide 7, a region
corresponding to 271 amino acid residues of either the alpha-1 or the
alpha-2 chain of type I collagen. Polymerase chain reaction
amplification of the corresponding region of the alpha-1(I) mRNA
followed by SSCP analysis of restriction enzyme digests of the PCR
products allowed further mapping of the mutation to a small region of
the COL1A1 gene. A heterozygous G-to-T transversion within the last
splicing codon of exon 32 was identified by DNA sequence analysis. This
mutation had resulted in the substitution of glycine-565 by a valine
residue. The mutation was shown to have occurred de novo.

.0046
OSTEOGENESIS IMPERFECTA, TYPE I
COL1A1, IVS26DS, G-A, +1
Stover et al. (1993) demonstrated defective splicing of mRNA from one
COL1A1 allele in a patient with mild type I OI. Genovese et al. (1989)
had demonstrated that dermal fibroblasts from this patient showed a
novel species of COL1A1 mRNA in the nuclear compartment of cells; that
it was not collinear with a cDNA probe, and, therefore, with the fully
spliced COL1A1 mRNA, was indicated by indirect RNase protection assays.
Stover et al. (1993) showed that a G-to-A transition in the first
position of the donor site of intron 26 resulted in the inclusion of the
entire sequence in the mature mRNA that accumulated in the nuclear
compartment. The retained intron contained an inframe stop codon and
introduced an out-of-frame insertion within the collagen mRNA producing
stop codons downstream of the insertion. These changes probably
accounted for the failure of the mutant RNA to appear in the cytoplasm.
Unlike other splice site mutations within collagen mRNA that resulted in
exon skipping and a truncated but inframe RNA transcript, this mutation
did not result in production of a defective COL1A1 chain. Instead, the
mild nature of the disease in this patient reflected failure to process
a defective mRNA and, thus, the absence of a protein product from the
mutant allele.

.0047
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A1, GLY355ASP
Raghunath et al. (1994) developed a method for early prenatal diagnosis
of molecular disorders involving types I and III collagens. The method
took advantage of the fact that isolated chorionic villi contain
significant amounts of collagen in their extracellular matrix and
synthesize collagens in vitro. They correctly predicted a healthy fetus
and an embryo affected with lethal osteogenesis imperfecta in
consecutive pregnancies from a couple in which the asymptomatic mother
was a somatic mosaic for a COL1A1 G-to-A transition resulting in
substitution of glycine-355 by aspartic acid. Steinmann (1994) stated
that this is the sixth gly-to-asp substitution in the alpha-1(I) chain,
all of which have been associated with lethal OI regardless of position
of the mutation. This was, furthermore, the ninth example of molecularly
proven mosaicism. The asymptomatic mother was 153 cm tall and was
shorter by 12 to 22 cm than her female first-degree relatives.

.0048
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY862SER
Namikawa et al. (1995) observed a gly862-to-ser substitution in 2 sibs
with type III osteogenesis imperfecta. Each was heterozygous. The
mutation was also detected in various paternal tissues; the mutant
allele accounted for approximately 11% of the COL1A1 alleles in blood,
24% of those in fibroblasts, and 43% of those in sperm. The father was
phenotypically normal. The parents were nonconsanguineous. The firstborn
child died of respiratory failure at age 3 years after repeated hospital
admissions for recurrent fractures and respiratory insufficiency. The
second-born child was identified as having OI by ultrasonography at 32
weeks gestation on the basis of angulated femoral bones. The father had
no history of fractures or other indications of connective tissue
disease. His height was 173 cm (73% percentile for a 30-to-39-year-old
Japanese male) and he was taller than his father. His weight was at the
62nd percentile. Skin, joints, sclera, and teeth were normal. Germline
mosaicism was obviously responsible for the recurrence. Namikawa et al.
(1995) pointed out that there is a cluster of gly-to-ser substitutions
associated with nonlethal phenotypes (gly832-to-ser, gly844-to-ser, and
gly901-to-ser (120150.0040), with gly862-to-ser in the middle) and that
this nonlethal cluster is located between 2 lethal clusters.

.0049
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, GLY661SER
Nuytinck et al. (1996) observed this mutation in a severely affected
infant with type III OI. The same mutation in the COL1A2 gene
(120160.0030) results in a much milder phenotype, namely post menopausal
osteoporosis.

.0050
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A1, LEU-PRO, C-TER PROPEPTIDE
Oliver et al. (1996) described unusual molecular findings in a young
girl who presented with severe type III OI. Her otherwise healthy mother
had pale blue sclerae and recurrent joint dislocations of the ankles,
shoulders, knees, elbows, wrists, and neck from 8 years of age. She
suffered dislocation of the left hip during the pregnancy. The maternal
grandfather was 177 cm tall and had recurrent dislocations of the right
elbow and right knee since age 10 years. He had pale blue sclerae from
childhood. He developed progressive deafness of the left ear, and later
Meniere disease. The proposita had dark blue sclerae and multiple old
and new fractures at birth. Subsequently she suffered at least 200
fractures, mostly of the femurs. At 3 years of age the sclerae were pale
blue. There was a severe pectus carinatum. The skin was abnormally soft,
and there was marked generalized joint laxity. The broad forehead and
triangular shaped face were typical of OI. Teeth and hearing were normal
and she did not bruise easily. Skin fibroblast cultures from the child
produced both normal and post-translationally overmodified type I
collagen. Cyanogen bromide peptide maps of the abnormal protein
indicated a C-terminal mutation. Examination of the C-propeptide
sequences demonstrated 2 heterozygous single base changes in the child.
One, an A-to-C transversion changing threonine to proline at residue 29
of the COL1A2 C-propeptide, was also present in the mother and maternal
grandfather but not in 50 unrelated controls. The second mutation, a
T-to-C transition, altered the last amino acid residue of the COL1A1
C-propeptide from leucine to proline and had occurred de novo in the
affected child. The latter mutation was thought to be responsible for
OI. Oliver et al. (1996) stated that the most frequent cause of excess
post-translational modification of collagens is the substitution of
glycine in 1 gly-X-Y repeat unit of the triple helix. No such mutation
was detected in the proband. They commented that the change in the
COL1A2 gene may have been related to the connective tissue
manifestations in the mother and maternal grandfather.

.0051
OSTEOPOROSIS, SUSCEPTIBILITY TO
SP1 BINDING SITE MUTATION
COL1A1, IVS1, 2046G-T
Screening the COL1A1 transcriptional control regions by PCR-SSCP in a
sample of 50 subjects, Grant et al. (1996) found 3 polymorphisms in the
first intron, 2 of which were rare (allele frequency approximately 4%
and 3%) and 1 common (allele frequency approximately 22%). The common
polymorphism was characterized as a G-to-T substitution at the first
base of a consensus site for the transcription factor Sp1 (189906) in
the first intron of COL1A1 (nucleotide 2046). Grant et al. (1996)
devised a PCR-based screen and studied allele distribution in 2
populations of British women, 1 in Aberdeen and 1 in London. They found
that the G/T polymorphism was significantly related to bone mass and
osteoporotic fracture. G/T heterozygotes had significantly lower bone
mineral density (BMD) than G/G homozygotes (SS) in both populations, and
BMD was lower still in G/T homozygotes (ss). The unfavorable Ss and ss
genotypes were over-represented in patients with severe osteoporosis
(166710) and vertebral fractures (54%), as compared with controls (27%)
equivalent to a relative risk of 2.97 for vertebral fracture in
individuals who carried the 's' allele.

.0052
DISSECTION OF CERVICAL ARTERIES, SUSCEPTIBILITY TO
COL1A1, GLY13ALA
Mayer et al. (1996) described a G-to-C transversion in 1 COL1A1 allele
resulting in a gly13-to-ala substitution in the triple helical domain of
the pro-alpha-1(I) collagen chain. The mutation was found in a
35-year-old woman who presented with spontaneous dissection of the right
internal carotid artery and the right vertebral artery after scuba
diving but with on obvious head or neck trauma. Other than a history of
easy bruising and bluish sclerae, she had no evidence of a connective
tissue disorder. There had been no bone fractures or dental problems nor
was there family history of vasculopathy.

.0053
OSTEOGENESIS IMPERFECTA, TYPE II, THIN-BONE TYPE
COL1A1, TRP94CYS
Cole et al. (1996) described an infant with lethal perinatal
osteogenesis imperfecta resulting from the substitution of trp94 by
cysteine (Y94C) in the C-terminal propeptide of the pro-alpha-1(I)
chain. The infant was born at 38 weeks' gestation with numerous
fractures of the limbs, skull, and ribs, and with subarachnoid and
subdural hemorrhages. Death from respiratory distress occurred within
hours of birth. The limbs and torso were of normal length, shape, and
proportion. All bones were relatively normal in shape and the long bones
showed normal metaphyseal modeling. These clinical and radiographic
features were similar to those observed in another baby with OI II
resulting from a mutation of the C-terminal propeptide of the
pro-alpha-1 chains (Bateman et al., 1989; Cole et al., 1990), but
dissimilar from those reported in babies with OI II resulting from
helical mutations of type 1 collagen. Cole et al. (1996) stated that the
infant's Y94C mutation disturbed procollagen folding and retarded the
formation of disulfide-linked trimers. The endoplasmic reticulum
resident molecular chaperone BiP, which binds to malfolded proteins, was
induced and bound to type I procollagen produced by the OI fibroblasts.
Unassembled mutant pro-alpha-1 chains were also retained in the rough
endoplasmic reticulum.

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56. Munke, M.; Harbers, K.; Jaenisch, R.; Francke, U.: Chromosomal
mapping of four different integration sites of Moloney murine leukemia
virus including the locus for alpha-1(I) collagen in mouse. Cytogenet.
Cell Genet. 43: 140-149, 1986.

57. Namikawa, C.; Suzumori, K.; Fukushima, Y.; Sasaki, M.; Hata, A.
: Recurrence of osteogenesis imperfecta because of paternal mosaicism:
gly862-to-ser substitution in a type I collagen gene (COL1A1). Hum.
Genet. 95: 666-670, 1995.

58. Nicholls, A. C.; Oliver, J.; Renouf, D. V.; Keston, M.; Pope,
F. M.: Substitution of cysteine for glycine at residue 415 of one
allele of the alpha-1(I) chain of type I procollagen in type III/IV
osteogenesis imperfecta. J. Med. Genet. 28: 757-764, 1991.

59. Ninomiya, Y.; Olsen, B. R.: Synthesis and characterization of
cDNA encoding a cartilage-specific short collagen. Proc. Nat. Acad.
Sci. 81: 3014-3018, 1984.

60. Nuytinck, L.; Dalgleish, R.; Spotila, L.; Renard, J.-P.; Van Regemorter,
N.; De Paepe, A.: Substitution of glycine-661 by serine in the alpha-1(I)
and alpha-2(I) chains of type I collagen results in different clinical
and biochemical phenotypes. Hum. Genet. 97: 324-329, 1996.

61. Oliver, J. E.; Thompson, E. M.; Pope, F. M.; Nicholls, A. C.:
Mutation in the carboxy-terminal propeptide of the pro-alpha1(I) chain
of type I collagen in a child with severe osteogenesis imperfecta
(OI type III): possible implications for protein folding. Hum. Mutat. 7:
318-326, 1996.

62. Pack, M.; Constantinou, C. D.; Kalia, K.; Nielsen, K. B.; Prockop,
D. J.: Substitution of serine for alpha-1(I)-glycine 844 in a severe
variant of osteogenesis imperfecta minimally destabilizes the triple
helix of type I procollagen: the effects of glycine substitutions
on thermal stability are either position or amino acid specific. J.
Biol. Chem. 264: 19694-19699, 1989.

63. Pereira, R.; Halford, K.; Sokolov, B. P.; Khillan, J. S.; Prockop,
D. J.: Phenotypic variability and incomplete penetrance of spontaneous
fractures in an inbred strain of transgenic mice expressing a mutated
collagen gene (COL1A1). J. Clin. Invest. 93: 1765-1769, 1994.

64. Pereira, R.; Khillan, J. S.; Helminen, H. J.; Hume, E. L.; Prockop,
D. J.: Transgenic mice expressing a partially deleted gene for type
I procollagen (COL1A1): a breeding line with a phenotype of spontaneous
fractures and decreased bone collagen and mineral. J. Clin. Invest. 91:
709-716, 1993.

65. Pestka, S.; Daugherty, B. L.; Jung, V.; Hotta, K.; Pestka, R.
K.: Anti-mRNA: specific inhibition of translation of single mRNA
molecules. Proc. Nat. Acad. Sci. 81: 7525-7528, 1984.

66. Pope, F. M.; Nicholls, A. C.; McPheat, J.; Talmud, P.; Owen, R.
: Collagen genes and proteins in osteogenesis imperfecta. J. Med.
Genet. 22: 466-478, 1985.

67. Pruchno, C. J.; Cohn, D. H.; Wallis, G. A.; Willing, M. C.; Starman,
B. J.; Zhang, X.; Byers, P. H.: Osteogenesis imperfecta due to recurrent
point mutations at CpG dinucleotides in the COL1A1 gene of type I
collagen. Hum. Genet. 87: 33-40, 1991.

68. Raghunath, M.; Steinmann, B.; Delozier-Blanchet, C.; Extermann,
P.; Superti-Furga, A.: Prenatal diagnosis of collagen disorders by
direct biochemical analysis of chorionic villus biopsies. Pediat.
Res. 36: 441-448, 1994.

69. Redford-Badwal, D. A.; Stover, M. L.; Valli, M.; McKinstry, M.
B.; Rowe, D. W.: Nuclear retention of COL1A1 messenger RNA identifies
null alleles causing mild osteogenesis imperfecta. J. Clin. Invest. 97:
1035-1040, 1996.

70. Retief, E.; Parker, M. I.; Retief, A. E.: Regional chromosome
mapping of human collagen genes alpha 2(I) and alpha 1(I) (COLIA2
and COLIA1). Hum. Genet. 69: 304-308, 1985.

71. Ruddle, F. H.: Personal Communication. New Haven, Connecticut
5/4/1982.

72. Schnieke, A.; Harbers, K.; Jaenisch, R.: Embryonic lethal mutation
in mice induced by retrovirus insertion into the alpha-1 (I) collagen
gene. Nature 304: 315-320, 1983.

73. Shapiro, J. R.; Stover, M. L.; Burn, V. E.; McKinstry, M. B.;
Burshell, A. L.; Chipman, S. D.; Rowe, D. W.: An osteopenic nonfracture
syndrome with features of mild osteogenesis imperfecta associated
with the substitution of a cysteine for glycine at triple helix position
43 in the pro-alpha-1(I) chain of type I collagen. J. Clin. Invest. 89:
567-573, 1992.

74. Sillence, D. O.; Barlow, K. K.; Garber, A. P.; Hall, J. G.; Rimoin,
D. L.: Osteogenesis imperfecta type II: delineation of the phenotype
with reference to genetic heterogeneity. Am. J. Med. Genet. 17:
407-423, 1984.

75. Simon, M.-P.; Pedeutour, F.; Sirvent, N.; Grosgeorge, J.; Minoletti,
F.; Coindre, J.-M.; Terrier-Lacombe, M.-J.; Mandahl, N.; Craver, R.
D.; Blin, N.; Sozzi, G.; Turc-Carel, C.; O'Brien, K. P.; Kedra, D.;
Fransson, I.; Guilbaud, C.; Dumanski, J. P.: Deregulation of the
platelet-derived growth factor B-chain gene via fusion with collagen
gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nature
Genet. 15: 95-98, 1997.

76. Sippola-Thiele, M.; Tromp, G. C.; Prockop, D. J.; Ramirez, F.
: Assessment of small polymorphisms in defined human collagen gene
segments. Hum. Genet. 72: 245-247, 1986.

77. Solomon, E.; Hiorns, L.; Sheer, D.; Rowe, D.: Confirmation that
the type I collagen gene on chromosome 17 is COL1A1(alpha-1(I)), using
a human genomic probe. Ann. Hum. Genet. 48: 39-42, 1984.

78. Solomon, E.; Hiorns, L. R.; Cheah, K. S. E.; Parkar, M.; Weiss,
E.; Flavell, R. A.: Assignment of a human alpha-1(I)-like collagen
gene to chromosome 12, by molecular hybridization.(Abstract) Cytogenet.
Cell Genet. 37: 588-589, 1984.

79. Solomon, E.; Sykes, B.: Assignment of alpha-1 (I), alpha-2, and
possibly alpha-1 (III), chains of human collagen to chromosome 7.(Abstract) Cytogenet.
Cell Genet. 25: 205, 1979.

80. Starman, B. J.; Eyre, D.; Charbonneau, H.; Harrylock, M.; Weis,
M. A.; Weiss, L.; Graham, J. M., Jr.; Byers, P. H.: Osteogenesis
imperfecta: the position of substitution for glycine by cysteine in
the triple helical domain of the pro-alpha-1(I) chains of type I collagen
determines the clinical phenotype. J. Clin. Invest. 84: 1206-1214,
1989.

81. Steinmann, B.: Personal Communication. Zurich, Switzerland
11/28/1994.

82. Steinmann, B.; Nicholls, A.; Pope, F. M.: Clinical variability
of osteogenesis imperfecta reflecting molecular heterogeneity: cysteine
substitutions in the alpha-1(I) collagen chain producing lethal and
mild forms. J. Biol. Chem. 261: 8958-8964, 1986.

83. Steinmann, B.; Rao, V. H.; Vogel, A.; Bruckner, P.; Gitzelmann,
R.; Byers, P. H.: Cysteine in the triple-helical domain of one allelic
product of the alpha-1(I) gene of type I collagen produces a lethal
form of osteogenesis imperfecta. J. Biol. Chem. 250: 11129-11139,
1984.

84. Stover, M. L.; Primorac, D.; Liu, S. C.; McKinstry, M. B.; Rowe,
D. W.: Defective splicing of mRNA from one COL1A1 allele of type
I collagen in nondeforming (type I) osteogenesis imperfecta. J. Clin.
Invest. 92: 1994-2002, 1993.

85. Sundar Raj, C. V.; Church, R. L.; Klobutcher, L. A.; Ruddle, F.
H.: Genetics of the connective tissue proteins: assignment of the
gene for human type I procollagen to chromosome 17 by analysis of
cell hybrids and microcell hybrids. Proc. Nat. Acad. Sci. 74: 4444-4448,
1977.

86. Thompson, E. M.; Young, I. D.; Hall, C. M.; Pembrey, M. E.: Recurrence
risks and prognosis in severe sporadic osteogenesis imperfecta. J.
Med. Genet. 24: 390-405, 1987.

87. Tromp, G.; Kuivaniemi, H.; Stacey, A.; Shikata, H.; Baldwin, C.
T.; Jaenisch, R.; Prockop, D. J.: Structure of a full-length cDNA
clone for the prepro-alpha-1(I) chain of human type I procollagen. Biochem.
J. 253: 919-922, 1988.

88. Tsipouras, P.; Schwartz, R. C.; Phillips, J. A., III; Willard,
H. F.: A centromere-based linkage group on the long arm of human
chromosome 17. Cytogenet. Cell Genet. 47: 109-110, 1988.

89. Tsuneyoshi, T.; Westerhausen, A.; Constantinou, C. D.; Prockop,
D. J.: Substitutions for glycine alpha-1-637 and glycine alpha-2-694
of type I procollagen in lethal osteogenesis imperfecta: the conformational
strain on the triple helix introduced by a glycine substitution can
be transmitted along the helix. J. Biol. Chem. 266: 15608-15613,
1991.

90. Valli, M.; Mottes, M.; Tenni, R.; Sangalli, A.; Gomez Lira, M.;
Rossi, A.; Antoniazzi, F.; Cetta, G.; Pignatti, P. F.: A de novo
G to T transversion in a pro-alpha-1(I) collagen gene for a moderate
case of osteogenesis imperfecta: substitution of cysteine for glycine
178 in the triple helical domain. J. Biol. Chem. 266: 1872-1878,
1991.

91. Vogel, B. E.; Doelz, R.; Kadler, K. E.; Hojima, Y.; Engel, J.;
Prockop, D. J.: A substitution of cysteine for glycine 748 of the
alpha-1 chain produces a kink at this site in the procollagen I molecule
and an altered N-proteinase cleavage site over 225 nm away. J. Biol.
Chem. 263: 19249-19255, 1988.

92. Vogel, B. E.; Minor, R. R.; Freund, M.; Prockop, D. J.: A point
mutation in a type I procollagen gene converts glycine 748 of the
alpha-1 chain to cysteine and destabilizes the triple helix in a lethal
variant of osteogenesis imperfecta. J. Biol. Chem. 262: 14737-14744,
1987.

93. Wallis, G. A.; Starman, B. J.; Byers, P. H.: Clinical heterogeneity
of OI explained by molecular heterogeneity and somatic mosaicism.(Abstract) Am.
J. Hum. Genet. 45: A228, 1989.

94. Wallis, G. A.; Starman, B. J.; Zinn, A. B.; Byers, P. H.: Variable
expression of osteogenesis imperfecta in a nuclear family is explained
by somatic mosaicism for a lethal point mutation in the alpha-1(I)
gene (COL1A1) of type I collagen in a parent. Am. J. Hum. Genet. 46:
1034-1040, 1990.

95. Wallis, G. A.; Sykes, B.; Byers, P. H.; Mathew, C. G.; Viljoen,
D.; Beighton, P.: Osteogenesis imperfecta type III: mutations in
the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily
responsible. J. Med. Genet. 30: 492-496, 1993.

96. Weil, D.; D'Alessio, M.; Ramirez, F.; de Wet, W.; Cole, W. G.;
Chan, D.; Bateman, J. F.: A base substitution in the exon of a collagen
gene causes alternative splicing and generates a structurally abnormal
polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBO
J. 8: 1705-1710, 1989.

97. Weisinger, B.; Glassman, E.; Spencer, F. C.; Berger, A.: Successful
aortic valve replacement for aortic regurgitation associated with
osteogenesis imperfecta. Brit. Heart J. 37: 475-477, 1975.

98. Willing, M. C.; Cohn, D. H.; Byers, P. H.: Frameshift mutation
near the 3-prime end of the COL1A1 gene of type I collagen predicts
an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta
type I. J. Clin. Invest. 85: 282-290, 1990.

99. Willing, M. C.; Deschenes, S. P.; Slayton, R. L.; Roberts, E.
J.: Premature chain termination is a unifying mechanism for COL1A1
null alleles in osteogenesis imperfecta type I cell strains. Am.
J. Hum. Genet. 59: 799-809, 1996.

100. Willing, M. C.; Pruchno, C. J.; Atkinson, M.; Byers, P. H.:
Osteogenesis (sic) imperfecta type I is commonly due to a COL1A1 null
allele of type I collagen. Am. J. Hum. Genet. 51: 508-515, 1992.

101. Willing, M. C.; Pruchno, C. J.; Byers, P. H.: Molecular heterogeneity
in osteogenesis imperfecta type I. Am. J. Med. Genet. 45: 223-227,
1993.

102. Willing, M. C.; Slayton, R. L.; Pitts, S. H.; Deschenes, S. P.
: Absence of mutations in the promoter of the COL1A1 gene of type
I collagen in patients with osteogenesis imperfecta type I. J. Med.
Genet. 32: 697-700, 1995.

103. Zhuang, J.; Constantinou, C. D.; Ganguly, A.; Prockop, D. J.
: A single base mutation in type I procollagen (COL1A1) that converts
glycine alpha(1)-541 to aspartate in a lethal variant of osteogenesis
imperfecta: detection of the mutation with a carbodiimide reaction
of DNA heteroduplexes and direct sequencing of products of the PCR. Am.
J. Hum. Genet. 48: 1186-1191, 1991.

104. Zhuang, J.; Tromp, G.; Kuivaniemi, H.; Castells, S.; Prockop,
D. J.: Substitution of arginine for glycine at position 154 of the
alpha-1 chain of type I collagen in a variant of osteogenesis imperfecta:
comparison to previous cases with the same mutation. Am. J. Med.
Genet. 61: 111-116, 1996.

*FIELD* CN
Victor A. McKusick - updated: 03/21/1997
Moyra Smith - updated: 11/12/1996
Orest Hurko - updated: 11/6/1996
Alan F. Scott - updated: 2/20/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/21/1997
terry: 3/17/1997
terry: 1/27/1997
jamie: 1/21/1997
mark: 1/15/1997
jenny: 1/14/1997
mark: 11/12/1996
mark: 11/6/1996
terry: 10/23/1996
mark: 10/5/1996
terry: 6/7/1996
terry: 5/30/1996
terry: 3/29/1996
mimman: 3/27/1996
mark: 3/4/1996
mark: 2/27/1996
terry: 2/20/1996
mark: 2/5/1996
terry: 2/1/1996
mark: 10/22/1995
carol: 3/19/1995
terry: 11/1/1994
davew: 8/5/1994
warfield: 4/7/1994
mimadm: 2/11/1994

*RECORD*
*FIELD* NO
120160
*FIELD* TI
*120160 COLLAGEN, TYPE I, ALPHA-2 POLYPEPTIDE; COL1A2
COLLAGEN OF SKIN, TENDON AND BONE, ALPHA-2 CHAIN
*FIELD* TX
Junien et al. (1982) assigned the gene for the alpha-2 polypeptide of
collagen I to chromosome 7 by means of molecular hybridization in
subclones of somatic cell hybrids, using a cDNA probe. Other
chromosomes, including 17, could be excluded. Using an EcoRI fragment
cloned from the COL1A2 gene in somatic cell hybrids containing an X/7
translocation, Solomon et al. (1983) concluded that the alpha-2 gene of
type I collagen is in the 7pter-q22 portion of chromosome 7. By use of a
cDNA probe in cells of a patient trisomic for 7q, Junien et al. (1984)
narrowed the assignment to 7q21. By in situ hybridization, Retief et al.
(1985) concluded that the alpha-1(I) and alpha-2(I) genes are located in
bands 17q21.31-q22.05 and 7q21.3-q22.1, respectively. Kere et al. (1989)
described the linkage relationships of the COL1A2 locus and the
erythropoietin (EPO) and plasminogen activator type I (PLANH1).
Moreover, the same authors used pulsed field gel electrophoresis
technology to construct a 3-megabase physical map including COL1A2 and 3
anonymous DNA segments. Shupp Byrne and Church (1983) assigned the genes
for the the alpha-1 and the alpha-2 chains of type I collagen to mouse
chromosome 16. Munke et al. (1986) corrected the assignment of Cola-1 to
mouse chromosome 11 where it formed part of an evolutionarily conserved
linkage group with homologous genes on human chromosome 17. Similarly,
by a combination of somatic cell hybrid analysis and genetic linkage,
Irving et al. (1989) demonstrated that the Cola-2 gene is located on
mouse chromosome 6 where it is linked to the MET protooncogene locus.

In a patient with osteogenesis imperfecta (OI), the son of third-cousin
parents, Myers et al. (1985) found a homozygous frameshift mutation in
the portion of the COL1A2 gene coding the COOH-propeptide. The type I
procollagen secreted by his fibroblasts contained only pro-alpha-1(I)
homotrimers, although pro-alpha-2(I) chains were found intracellularly
(Deak et al., 1983). Dickson et al. (1984) used nuclease S1 mapping to
demonstrate the homozygous defect in the patient's mRNA coding for the
pro-alpha-2(I) COOH-propeptide and a heterozygous pattern in the
asymptomatic parents. Clinically, the patient's OI was moderate in
severity and, according to other reports, was accompanied by blue
sclerae. This is recessive inheritance of moderate OI. (The reports by
Myers et al. (1985), Pope et al. (1985), and Nicholls et al. (1979,
1984) concern the same patient.) Wallis et al. (1986) concluded from
linkage studies using 3 DNA polymorphisms associated with the COL1A2
gene that the defect in a 'significant proportion of cases' of
osteogenesis imperfecta type I is located in that gene. They quoted
others as showing that mutations in the COL1A2 gene can produce not only
OI type I but also OI types II, III and IV. Knisely et al. (1988) found
a karyotypic abnormality involving the COL1A2 gene in an infant who died
of complications of osteogenesis imperfecta at 22 days of age. The
infant had an inversion, inv(7)(p13q22). The mother carried the same
inversion. The authors suggested that damage to 1 COL1A2 gene caused by
the inversion might have contributed to disease in the infant if a
mutation affecting the other allele was present. Knisely et al. (1989)
reported that the type I procollagen chains were completely normal in
both parents of the case reported by Knisely et al. (1988), which led
them to conclude that the rearrangement involving chromosome 7 had
nothing to do with the mutation in the COL1A2 gene in the child. An
amino acid substitution in the alpha-2 chain, rendering procollagen
resistant to procollagen N-peptidase, is apparently present in one form
of Ehlers-Danlos syndrome type VII (130060), and some evidence suggests
a defect in the alpha-2 chain in some cases of the Marfan syndrome
(154700). Minor et al. (1986) observed one case of E-D VII in which a
structural abnormality of the alpha-2 chain of type I collagen was
responsible for resistance to cleavage of procollagen. Sasaki et al.
(1987) described a form of Ehlers-Danlos syndrome with deficiency of
pro-alpha-2 chains of type I procollagen. The patient was a 30-year-old
man known to have had aortic regurgitation for 3 years. Since infancy he
had suffered from hypermobility of the joints, hyperextensibility of the
skin, and prolongation of wound healing. Aortic valve replacement was
performed. Histologically, the aortic valve showed abundant alcian
blue-positive myxomatous matrix accompanied by scattered mesenchymal
cells instead of normal collagen fibers with fibroblasts. Similar but
less conspicuous changes were found in the aorta itself. A biopsy
specimen of the skin showed thin, somewhat fragmentary collagen fibers,
while elastic fibers appeared normal. Analysis of collagen produced by
cultured fibroblasts showed a lack of detectable pro-alpha-2 chains of
type I procollagen. The intracellular degradation rate of newly
synthesized collagen was higher than that of normal cells, resulting in
the reduction of net collagen production. By electrophoretic studies of
collagen excreted from cultured skin fibroblasts, Tsukahara et al.
(1988) found an alpha-2 chain with an anomaly of small molecular size in
mother and daughter. Only the daughter showed clinical abnormality:
loose, wrinkled skin and other features of cutis laxa, together with
fragility, bruisability, and hyperextensibility of the skin, with poor
wound healing and 'cigarette paper' scars. The father and another
daughter were normal clinically. Into 1-cell mouse embryos, Khillan et
al. (1986) injected a hybrid gene made from DNA 2 kb upstream from the
COL1A2 gene and the bacterial gene for chloramphenicol acetyltransferase
(CAT). They established a number of transgenic mouse strains and found
that the promoter contained information for stage- and tissue-specific
expression of the COL1A2 gene. For example, the level of CAT activity
was higher in extracts of tail (a structure rich in tendon) than in any
other tissue tested. De Wet et al. (1987) isolated 60 kb of cloned DNA
containing the entire COL1A2 gene and 22 kb of flanking sequences. Like
the homologous avian gene, the 1,366 amino acid residues of the human
prepropolypeptide chain are encoded by 52 exons. Analysis of the 5-prime
and 3-prime untranslated regions conclusively established the nature of
5 polymorphic mRNA transcripts. The exons are equally distributed as
follows: 6 in the N-propeptide domain, 42 in the alpha-chain region, and
4 in the C-propeptide domain. Kuivaniemi et al. (1988) characterized a
full-length cDNA clone for the COL1A2 gene. Hata et al. (1988) described
a patient with a variety of Ehlers-Danlos syndrome and complete absence
of pro-alpha-2(I) chains and their derivatives in tissues. The patient's
fibroblasts contained less than 10% of the normal mRNA for this chain,
but the DNA contained a normal number of COL1A2 genes. They interpreted
the findings to indicate that the patient was homozygous for a
functionally defective COL1A2 gene. (A seemingly late-appended paragraph
on mode of inheritance suggested that the patient was a compound
heterozygote. Homozygosity makes much more sense. One would expect that
the heterozygotes would be normal or near normal.) Tromp and Prockop
(1988) studied a mutant allele for COL1A2, which had previously been
demonstrated to encode a shortened pro-alpha-2 type I chain lacking most
or all of exon 28. The mutant allele had a single base substitution
which caused efficient splicing of RNA from the last codon of exon 27 to
the first codon of exon 29, completely excluding exon 28. Superti-Furga
et al. (1989) reported a family in which osteogenesis imperfecta linked
to COL1A2 and associated with a structural defect in the triple helical
region of the alpha-2 chains resulted in a very mild clinical picture in
some individuals in whom the diagnosis of OI had not been made, mainly
because of the lack of fractures, and severe OI in others. All affected
members showed dentinogenesis imperfecta and myopia. The findings
confirmed that mutations in the triple helical region of the alpha-2
chains produce a milder phenotype than do corresponding mutations in the
alpha-1 chains, but indicated that, in addition to defects in the type I
collagen molecule, other factors must modulate the degree of bone
involvement. In 4 out of 60 persons with deforming (nonlethal) varieties
of osteogenesis imperfecta, Cohn and Byers (1991) demonstrated alpha-2
chains with a cysteine residue in the triple helix, a domain from which
it is normally excluded. The clinical differences among these 4
individuals and the heterogeneity in the locations of the cysteine
residues suggested that the position of the substitution within the
chain is important in determining the clinical phenotype. Spotila et al.
(1992) identified partial isodisomy for maternal chromosome 7 in a
30-year-old man who was 143.7 cm tall and weighed 36.6 kg. He had
greatly reduced bone mineral density values (below the second percentile
for his age and gender at all sites measured). The sclerae were slightly
blue; hearing was within normal limits. Uniparental disomy (UPD) for
chromosome 7 had been reported previously in 2 unrelated probands
discovered because of cystic fibrosis. The proband of Spotila et al.
(1991) was identified initially during a screening of relatives of a
woman with postmenopausal osteoporosis resulting from a gly661-to-ser
(120160.0030) mutation of the COL1A2 gene. The woman was heterozygous
for the mutation as were a cousin and 2 of her 3 sons. The third son,
subsequently shown to have UPD, was apparently homozygous, although his
father had only the normal allele. Like the previously reported cases of
maternal disomy for chromosome 7, the proband had retarded growth and
short stature. At 5 loci, of which the mother and father did not share
alleles, the proband had inherited only the maternal allele. He was
homozygous for all informative loci examined with the exception of 1
locus on the proximal short arm of chromosome 7. Thus, the UPD was
probably the result of fertilization of a maternal gamete disomic for
chromosome 7, with either a nullisomic sperm or a normal sperm followed
by loss of the paternal homolog.

Pepe (1993) described an ACT trinucleotide repeat VNTR within intron 12
of the COL1A2 gene. Six alleles were detected with repeats varying from
6 to 12 times. Because of a high level of heterozygosity, the use of
this polymorphism in the diagnosis of osteogenesis imperfecta by the
linkage principle and in forensic applications was suggested.
Furthermore, the possibility that instability of the trinucleotide
repeat might lead to abnormalities such as in the unexplained
collagenopathies or suspected collagenopathies was raised.

Conventional numbering for the alpha-2(I) amino acid residues excludes
the N- and C-terminal domains and begins with the first glycine at the
N-terminal end of the triple-helical domain. This numbering system is
used in the following list of allelic variants.

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2
genes accessible on the World Wide Web.

*FIELD* AV
.0001
EHLERS-DANLOS SYNDROME, TYPE VII
COL1A2, EX6DEL
From studies of type I collagen in a case of Ehlers-Danlos syndrome type
VII, Eyre et al. (1985) concluded that one allele of the COL1A2 gene
carried a de novo mutation that resulted in deletion of 15 to 20
residues in the junction domain that spans the N-propeptidase cleavage
site and the N-telopeptide cross-linking sequence.

.0002
EHLERS-DANLOS SYNDROME, TYPE VII
COL1A2, EX6DEL, IVS6DS, T-C, +2
Wirtz et al. (1987) described a patient with Ehlers-Danlos type VII
caused by a deletion of 18 amino acids of the N-telopeptide of the
pro-alpha-2 chain of type I collagen. The heterozygous defect in this
patient could be due to genomic deletion of exon 6, which codes for the
residues 54-70, or, alternatively, may have resulted from an RNA
splicing defect. Weil et al. (1988) found substitution of C for T in the
obligatory GT dinucleotide of the 5-prime splice site sequence of intron
6 and showed that the mutation was responsible for abnormal splicing of
exons 5 and 7 with deletion of exon 6. The patient studied by Weil et
al. (1988) was Libyan; Ho et al. (1994) observed the identical mutation
in a Chinese patient and concluded that the mutation destroyed the
consensus GT dinucleotide at the 5-prime splice donor site of intron 6,
resulting in the loss of exon 6 by exon skipping.

.0003
EHLERS-DANLOS SYNDROME, TYPE VII
COL1A2, EX6DEL, ATAgt-ATgt, IVS6
In a patient with E-D VII, Weil et al. (1989) demonstrated a de novo
G-to-A substitution of the last nucleotide of exon 6 in 1 allele of the
COL1A2 gene, resulting in substitution of ile (ATA) for the normal met
(ATG) and producing some mRNA transcripts from which exon 6 sequences
had been outspliced. (At the splice site in ATAgt, the second A was
deleted.) Unexpectedly, the expression of the alternative splicing in
this patient was found to be temperature-dependent; in cellula,
missplicing was effectively abolished at 31 degrees C and gradually
increased to 100% at 39 degrees C. In contrast, in the patient who had a
substitution in the obligatory GT dinucleotide of the 5-prime splice
site of intron 6 of COL1A2 (120160.0002), complete outsplicing of exon 6
sequences was found at all temperatures.

.0004
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A2, GLY1012ARG
In a patient with osteogenesis imperfecta of Sillence type IV (166220),
Wenstrup et al. (1988) found an arginine for glycine substitution at
position 1012, the last triple-helical glycine. Increased
posttranslational modification along the entire triple-helical domain
resulted.

.0005
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A2, EX1, FS
In a patient with osteogenesis imperfecta of Sillence type III (259420),
Pihlajaniemi et al. (1984) demonstrated a 4-nucleotide frameshift
deletion in exon 1 which instigated the use of a new termination codon 4
nucleotides 3-prime to the original site.

.0006
OSTEOGENESIS IMPERFECTA, ATYPICAL
COL1A2, EX11DEL
In a boy with 'atypical' OI and his asymptomatic mother, Kuivaniemi et
al. (1988) found deletion of 19 bp at the junction of IVS 10 and exon 11
causing abnormal splicing between exons 10 and 12 and a shortened
pro-alpha-2 chain of type I collagen.

.0007
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, DEL 7EX, CODONS 586-765
Willing et al. (1988) characterized a de novo 4.5-kb deletion in the
paternally derived COL1A2 allele found in a patient with perinatal
lethal OI. The intron-to-intron deletion removed the 7 exons that encode
residues 586-765 of the triple helical domain of the chain. A block in
secretion appeared to result from improper assembly of the triple helix.
The lethal effect may have been due in part to decreased secretion of
normal collagen and secretion of a small amount of abnormal collagen
that disrupts matrix formation.

.0008
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY907ASP
In an infant with a lethal variety of OI, Baldwin et al. (1989) found a
G-to-A change that converted glycine-907 to aspartic acid. The change
resulted in decreased thermal stability of type I collagen synthesized
by the patient's fibroblasts.

.0009
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, EX33DEL
In a lethal form of OI, Baldwin et al. (1988) found deletion of 54 bp
corresponding to exon 33.

.0010
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY547ASP
By RNA sequence analysis, Bonadio et al. (1988) demonstrated
heterozygosity for a glycine-to-aspartic acid substitution at position
547 in a case of perinatal lethal OI.

.0011
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY865SER
Using the Cotton chemical cleavage method to localize and characterize
single bp mRNA mutations, Lamande et al. (1989) demonstrated
substitution of serine for glycine at position 865.

.0013
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A2, GLY646CYS
Wenstrup et al. (1990) found a substitution of cystine for glycine-646
in a family with mild OI. Wenstrup et al. (1993) described the mutation
in 2 families with type IV OI.

.0014
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A2, EX26DEL
In a family with mild OI, Wenstrup et al. (1990) found that alpha-2(I)
mRNA was shortened by the 54 bp coded by exon 26.

.0015
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY976ASP
Byers (1990) provided information on this mutation.

.0016
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY805ASP
Byers (1990) provided information on this mutation.

.0017
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY259CYS
Byers (1990) provided information on this mutation. Wenstrup et al.
(1993) reported this mutation in a single family. The phenotype was said
to be 'moderately severe' or 'severe deforming,' suggesting that this
may be OI type III.

.0018
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, EX28DEL
In a case of type II osteogenesis imperfecta (166210), Tromp and Prockop
(1988) found that the previously demonstrated shortened pro-alpha-2
chain of type I collagen resulted from deletion of exon 28 which in turn
resulted from substitution of G for A at the 3-prime end of intron 27.

.0019
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY472CYS
Edwards et al. (1990) demonstrated somatic mosaicism for this mutation
in the father of 2 children with lethal OI, each from a different
partner. The mutation was found in 33% of sperm, 67% of lymphocytes, and
100% of dermal fibroblasts. The authors hypothesized that the mutation
occurred very early in development in a cell that gave rise to both
ectodermal and mesodermal cell lineages. Edwards et al. (1992) stated
that despite the high level of mosaicism detected in somatic tissues,
the only phenotypic manifestation of OI in the proband (the father) was
that he was shorter than his unaffected male relatives and had mild
dentinogenesis imperfecta. Thermal stability of type I collagen
molecules containing the substitution was decreased but to a lesser
extent than that for a nonlethal glycine-to-cysteine substitution at
residue 259 of the alpha-2(I) (120160.0017) chain, indicating that this
measure of molecular stability may be of limited use in explaining the
pathogenesis of OI. Edwards et al. (1992) stated that this was the
second family in which recurrence of lethal OI had resulted from
parental germline mosaicism for a dominant lethal mutation and the
fourth family in which there was molecular evidence of parental
mosaicism for a mutation that produced lethal OI. The mosaic parent in
all 4 families was also mosaic for the mutation in somatic tissues.
Since the mutation was detected in blood from all 4 mosaic individuals
but not in DNA from cultured fibroblasts in one, blood may be the best
parental somatic tissue to examine for mutation found in a sporadic
affected infant.

.0020
MARFAN SYNDROME, ATYPICAL
MARFAN VARIANT
COL1A2, ARG618GLN
Byers et al. (1981) found 2 species of the alpha-2 chain of type I
collagen in 1 of 11 Marfan patients studied; one of the alpha-2 chains
was normal while the other contained a 20-amino acid insertion in the
amino-terminal propeptide. This alteration in chain size probably
accounted for the 5- to 10-fold increase in collagen extraction into
nondenaturing solvents from this patient's skin compared to controls.
The patient of Byers et al. (1981) was a 39-year-old woman who had
unaffected parents and 2 unaffected sibs. Features were equinovarus
deformities of both feet at birth; arachnodactyly first noted at age 9
and lumbar scoliosis and heart murmur first noted at age 10. Aortic and
mitral regurgitation with dilated root of the aorta prompted surgical
replacement of the aortic valve and a portion of the ascending aorta at
age 37. Her height was 164.5 cm, span 178 cm, upper segment to lower
segment ratio 0.80. No lens dislocation was detected. She showed
bluish-gray sclerae and mild myopia. Mild pectus carinatum was present,
as well as long slender limbs with increased mobility in all joints
except the fourth and fifth fingers which bilaterally showed marked
camptodactyly. Henke et al. (1985) suggested that there was a
38-basepair insertion in the COL1A2 gene that caused the Marfan
syndrome. Dalgleish et al. (1986) found, however, that this is a common
polymorphism of the COL1A2 gene. Among 28 normal persons, 12 were
homozygous for the large oligo, 12 were heterozygous, and 4 were
homozygous for the small oligo. Phillips et al. (1990) further studied
the patient and demonstrated a single base change, resulting in
substitution of arginine-618 by glutamine at the Y position of a gly-X-Y
repeat. Family studies indicated that the substitution was inherited
from the patient's father who also produced abnormally migrating
pro-alpha-2(I) collagen chains and shared some of the abnormal skeletal
features. The single base change at nucleotide 2258 resulted in a new
Bsu36I (SauI, MstII) restriction site detectable in genomic DNA by
Southern blot analysis when probed with a COL1A2 fragment. Analyses of
103 chromosomes in 52 controlled individuals were negative for the new
site, indicating that the substitution is not a common polymorphism.

.0021
EHLERS-DANLOS SYNDROME, TYPE VII
COL1A2, IVS6DS, G-A, +1
Vasan et al. (1991) studied the patient with EDS VII reported by Minor
et al. (1986), whose fibroblasts synthesized shortened pro-alpha-2(I)
chains. They found a G-to-A transition at the first nucleotide of intron
6. This change in the GT consensus splice site produced efficient exon
skipping. The mutation was sporadic and present in heterozygous state.
Vasan et al. (1991) pointed out that other cases of EDS VII had single
base mutations causing skipping of exon 6 in either the COL1A1 or the
COL1A2 gene. Lehmann et al. (1994) identified the same mutation in a
Lebanese child of Arabic descent.

.0022
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, IVS33DS, G-A, +5
In a case of lethal osteogenesis imperfecta, Ganguly et al. (1991) found
substitution of adenine for guanine at position +5 of the donor splice
site of intron 33. One allele in the patient lacked the 54 basepairs of
exon 33.

.0023
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A2, GLY586VAL
Bateman et al. (1991) used the chemical cleavage method for detecting
mismatched bases in heteroduplexes formed between patient mRNA and
control cDNA probes to demonstrate a single base mutation in a sporadic
case of type IV osteogenesis imperfecta. A G-to-U change at basepair
2162 of the COL1A2 mRNA resulted in the substitution of glycine by
valine at amino acid position 586 of the helix. Disruption of the
critical gly-X-Y repeating unit resulted in helix destabilization, as
evidenced by decreased thermal stability. The rapid detection of the OI
mutation by the chemical cleavage method permitted application of the
technique to prenatal diagnosis in the next pregnancy by chorion villus
sampling.

.0024
EHLERS-DANLOS SYNDROME, TYPE VII
COL1A2, IVS6DS, G-A, +1
In a 29-year-old male with bilateral hip dislocation at birth and with
other features of the Ehlers-Danlos syndrome type VII, Nicholls et al.
(1991) found that a deletion of 54 basepairs of exon 6 was due to a
single base change from G to A at the first nucleotide of intron 6. The
change mutated the obligatory GT-dinucleotide splicing signal to AT and
led to exon skipping with splicing from exon 5 to exon 7. Loss of exon 6
sequences resulted in the loss of the procollagen-N-propeptidase
cleavage site and of a lysine residue that normally participates in
covalent intermolecular crosslinking within collagen fibers. The proband
was heterozygous. His daughter, born with bilateral hip dislocation,
joint hyperflexibility, feet in the equinovarus position, and
hyperextensible skin, was also affected. This is one of the few examples
of observation of transmission of this disorder.

In a child with type VII EDS, Watson et al. (1992) found the same G-to-A
transition at the first nucleotide of intron 6 in one of the COL1A2
alleles. Half of the cDNA clones prepared from the proband's
pro-alpha-2(I) mRNA lacked exon 6. The clinical features of the patient
and her family had previously been described by Viljoen et al. (1987).
The mother and her 4 children had generalized articular laxity, joint
dislocations and subluxations, and wormian bones in the skull. They
suggested that the last feature may be more common in EDS VII than
realized.

.0025
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY694ARG
In a case of lethal osteogenesis imperfecta, Tsuneyoshi et al. (1991)
demonstrated substitution of arginine for glycine-694.

.0026
OSTEOGENESIS IMPERFECTA, ATYPICAL, WITH JOINT HYPERMOBILITY
COL1A2, IVS9DS, 11-BP DEL, EX9DEL
Nicholls et al. (1992) identified a novel mutation involving deletion of
the 54 basepairs comprising exon 9. The 8 affected individuals in 6
sibships of 4 generations of a family were all short and showed marked
joint laxity, particularly in the hands, moderate hyperextensibility of
the skin, blue sclerae, and easy bruising. Many had a history of
late-onset fractures (from early adulthood) occurring spontaneously or
after minor trauma. There was radiologic evidence of moderate to severe
premature osteoporosis, particularly in affected females. Although no
male-to-male transmission was observed, the pedigree was compatible with
autosomal dominant inheritance and the mutation was demonstrated to be
in heterozygous state in each of the affected persons. The deletion of
exon 9 was shown to be due to an 11-bp deletion in the donor splice site
of IVS9. Extending from bp 3 through bp 13 of IVS9, the deletion
disrupted the normal GTAAGT 5-prime splice signal.

.0027
EHLERS-DANLOS SYNDROME, TYPE VII
COL1A2, IVS5AS, G-C, -1
In a mother and son with type VII Ehlers-Danlos syndrome, Chiodo et al.
(1992) found heterozygosity for loss of the N-proteinase cleavage site
in the alpha-2 chain of type I collagen due to inactivation of the
3-prime splice site of intron 5 by an AG-to-AC mutation and the
activation of a cryptic AG splice acceptor site corresponding to
positions +14 and +15 of exon 6. The mother, aged 30 years, had
congenital dislocations of the hips and severe laxity of other joints.
Her son, who was also born with dislocated hips, died suddenly at 3
months of age.

.0029
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY580ASP
Niyibizi et al. (1992) demonstrated a gly580-to-asp substitution in the
COL1A2 gene in a case of lethal neonatal osteogenesis imperfecta. The
infant died at 6 months of age of progressive respiratory insufficiency.
They demonstrated that the mutant molecules in this heterozygote
represented a surprisingly high percentage of total collagen isolated
from cortical bone; the ratio of mutant to normal chains in bone was
0.7/1. They suggested that in this case the tissue abnormalities
resulted more from the presence of mutant protein than from an
underexpression of matrix.

.0030
OSTEOPOROSIS, POSTMENOPAUSAL
COL1A2, GLY661SER
Spotila et al. (1991) demonstrated a gly661-to-ser mutation in the
COL1A2 gene in a woman with features suggestive of postmenopausal
osteoporosis. Maternal isodisomy for chromosome 7 was described in a
member of this family (Spotila et al., 1992). The 52-year-old proband
was 7 years postmenopausal and had severe osteopenia with a compression
fracture of the ninth thoracic vertebra. She had a history of 5 previous
fractures, showed slightly blue sclerae, and was slightly hard of
hearing. In the report by Spotila et al. (1992), the female proband who
was heterozygous for the gly661-to-ser mutation was reported to be also
heterozygous for variation at codon 459 of the COL1A2 gene (proline or
alanine). Nuytinck et al. (1996) found that the same mutation, G661S, in
the COL1A1 gene (120150.0049) resulted in a severe form of osteogenesis
imperfecta when in heterozygous state. The predominant role of mutations
in the COL1A1 gene over the same mutation in the COL1A2 gene in
determining clinical outcome was illustrated. Studies of the type I
collagen heterotrimers in a woman with post-menopausal osteoporosis, in
her 2 heterozygous sons, and in her son who was homozygous as a result
of uniparental isodisomy revealed only mild overmodification, this being
slightly less evident in the heterozygote than in the homozygote. On the
other hand, the degree of overmodification of the collagen alpha chains
was much more marked in the case of the COL1A1 mutation, correlating
with phenotypic severity. The mother and the heterozygous sons had a
bone mineral density (BMD) of more than standard deviations below
normal, whereas the BMD values were 5 standard deviations below normal
in the homozygous son.

.0031
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A2, VAL255DEL
In a patient with type III OI, Molyneux et al. (1993) demonstrated
deletion of the final 3 bases of exon 19 in one COL1A2 allele. In an
RNase A protection analysis, cleavage of the hybrid formed between a
normal COL2A1 sequence and RNA isolated from the patient indicated the
presence of a mismatch. The deletion was then demonstrated by sequencing
PCR-amplified DNA from the region of the mismatch. The deletion resulted
in the loss of amino acid 255 (a valine) of the triple helical region of
half of the alpha-2 (I) collagen chains but did not disrupt the splicing
of the heterogeneous nuclear RNA. The deletion was not present in either
parent. The report provided evidence that OI type III can behave as a
dominant and not always as a recessive (see 259420).

.0032
EHLERS-DANLOS SYNDROME, TYPE VIIB
COL1A2, IVS5AS, G-C, -1
Carr et al. (1994) showed that the type VIIB Ehlers-Danlos syndrome
present in a 32-year-old woman and her affected relatives resulted from
mutation in 1 COL1A2 allele: an AG-to-AC mutation at the splice acceptor
site of intron 5. The mutation activated a cryptic AG splice acceptor
site corresponding to positions +14 and +15 of exon 6. In contrast to
previous reports, only 5, rather than all 18, amino acids encoded by
exon 6 were deleted in the proband. The deleted peptide removed the
amino-proteinase cleavage site, but not the nearby lysine crosslinking
site in the amino-telopeptide of the alpha-2(I) chain. The proband was
born with bilateral hip dislocation, bilateral knee subluxation, and
generalized joint hypermobility, as well as bilateral inguinal hernias
and an umbilical hernia. Facial features included a depressed nasal
bridge. Throughout her life, she had multiple fractures of the small
bones of her hands and feet following moderate trauma. An affected
brother underwent total hip replacement at age 35. He had been born with
bilateral hip dislocation which led to subsequent osteoarthritis of the
hips. He displayed marked swan neck deformities of his hands and had
undergone reconstructive surgery in an attempt to reduce the
deformities. He had suffered multiple fractures of the metacarpals,
distal radius, distal ulnar, as well as a fracture of the patella and
olecranon. Frequency of fractures reduced markedly after his teenage
years. His nasal bridge was also depressed. Electron microscopy of the
proband's dermis, as well as deep fascia and hip joint capsule from the
affected brother, showed that collagen fibrils in transverse section
were nearly circular but with irregular margins. The history of frequent
fractures found in this family is atypical for type VIIB Ehlers-Danlos
syndrome and indicates an overlap with osteogenesis imperfecta.

.0033
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A2, GLY859SER
In a 35-year-old woman with type III osteogenesis imperfecta, Rose et
al. (1994) identified a gly859-to-ser substitution in the alpha-2 chain
of type I collagen. The patient had many fractures at birth and
continued to fracture periodically. At the age of 35, she was 94 cm
tall, walked with the help of a cane, and had slightly blue sclerae and
diminished hearing. Rose et al. (1994) identified the same mutation in
another patient in whom skeletal anomalies were detected in utero at 15
weeks' gestation. X-rays at the time of birth demonstrated diminished
calvarial mineralization but no wormian bones, thin cortices of all long
bones, marked bowing of both femurs, recent fracture of the right
humeral shaft, and narrow thoracic cage, but no acute or healing rib
fractures. By age 5 years, he was not able to walk due to multiple and
recurrent fractures, was well below the fifth percentile in height, and
had a very large head size. These patients were heterozygous, consistent
with the conclusion that most type III OI is inherited as an autosomal
dominant. An exception is the form of type III OI in the black South
African population (Beighton and Versfeld, 1985) which seems to be
inherited as an autosomal recessive and may not be the result of
mutations in the COL1A1 or COL1A2 gene (Wallis et al., 1993); see
259420.

.0034
OSTEOGENESIS IMPERFECTA, TYPE II
COL1A2, GLY502SER
In 3 unrelated individuals with perinatal lethal osteogenesis
imperfecta, Rose et al. (1994) found heterozygosity for a G-to-A
transition at a CpG dinucleotide resulting in a gly502-to-ser
substitution in the alpha-2 chain of type I collagen. Steinmann (1995)
remarked on how amazingly similar the x-ray appearance of the 3 cases
was: poor mineralization of the calvarium, small chest, thin ribs with
discontinuous beading and some fractures and calluses; some flattening
of thoracic vertebrae; short, broad femurs with fractures; broad,
angulated tibias; and thin, angulated fibulas with fractures.

.0035
OSTEOGENESIS IMPERFECTA, TYPE IV
COL1A2, 9-BP DEL, GPP-DEL
Lund et al. (1996) defined the molecular defect in COL1A2 in a family
with OI type IV in 3 generations: the grandmother, a son and daughter of
hers, and a daughter of the daughter. The color of the sclerae was
normal. There were no signs of dentinogenesis imperfecta and hearing was
normal. The grandmother was more mildly affected than her descendants;
she was 168 cm tall and was fully mobile throughout her life, whereas
the daughter and granddaughter were 146 cm and 148 cm tall,
respectively, and walked with crutches. Sequencing of the COL1A2 gene
indicated a 9-bp deletion of nucleotides 3418 to 3426, corresponding to
the deletion of codons 1003 to 1006 of the gene and 3 amino acids,
gly-pro-pro, of the protein.

.0036
OSTEOGENESIS IMPERFECTA, SEVERE, WITH VERY MILD OSTEOGENESIS IMPERFECTA
COL1A2, IVS21DS, G-A, +5, EX21DEL
In an 8-year-old boy referred for dental assessment of dentinogenesis
imperfecta, Nicholls et al. (1996) found joint hypermobility and some
features of mild osteogenesis imperfecta although he had suffered few
fractures. He had fractured his left tibia after a minor fall at age 5
and his right tibia after a substantial fall from a skateboard 1 year
later. Subsequently he had broken bones in hands and feet after
substantial falls and refractured his right tibia in a fall down 5
flights of stairs. The sclerae were pale blue. Dental examination and
x-rays showed typical changes of dentinogenesis imperfecta type I. The
boy was at the 25th centile for height and weight. Lumbar spine x-rays
showed mild osteoporosis. Analysis of the collagens produced by both
gingival and skin fibroblast cultures showed the synthesis and
intracellular retention of an abnormal alpha-2(I) chain that migrated
faster than normal on SDS-PAGE. The denaturation temperature of the
mutant protein was some 6 degrees centigrade below normal. At 37 degrees
centigrade secretion of abnormal protein was not detectable, but at a
lower temperature (30 degrees centigrade) some was secreted into the
medium. Cyanogen bromide peptide mapping of the intracellular protein
indicated a probable deletion in the N-terminal peptide. RT-PCR
amplification of mRNA coding for this peptide revealed a heterozygous
deletion of the 108-bp exon 21 of COL1A2. Sequencing identified a G-to-A
transition in the moderately conserved +5 position of the IVS21 5-prime
consensus splice site, causing the skipping of exon 21. Hybridization
with allele-specific oligonucleotides showed no other family member with
this base change. Since the deletion was associated with the negative
allele of a PvuII polymorphism in exon 25 of COL1A2, Nicholls et al.
(1996) could demonstrate that the mutant pre-mRNA was alternatively
spliced, yielding both full-length and deleted transcripts. Family
genotype analysis indicated that the mutation had originated in the
father's gene. The father and other members of the family lacked the
mutation.

.0037
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A2, GLY1006ALA
In a patient with OI type III, Lu et al. (1995) demonstrated a G-to-C
mutation at position 3287 (exon 49) that converted the GGC codon for
glycine-1006 to GCC for alanine in the triple helical domain of the
COL1A2 gene.

.0038
OSTEOGENESIS IMPERFECTA, TYPE III
COL1A2, GLY586VAL
In a child with osteogenesis imperfecta type III and a substitution of
glycine-586 by valine in the triple helical domain of the alpha-2(I)
chain of type I collagen, Cole et al. (1996) found that the skeleton was
severely porotic but contained lamellar bone and Haversian systems. From
early childhood, structural failure of the bone resulted in the
disruption of growth plates, progressive bone deformities, and severe
growth retardation. Her development was prospectively recorded over 14
years. Her sclerae faded to a slightly bluish tint at 14 years of age.
She had severe dentinogenesis imperfecta of her primary and secondary
dentition. During the study, she did not develop basilar compression.
She had mild conductive hearing loss. (The authors referred to the
mutation as occurring at glycine-585 in the title, but used glycine-586
in the article. MHP.)

*FIELD* SA
Brebner et al. (1985); Byers et al. (1980); Dickson et al. (1985);
Grobler-Rabie et al. (1985); Grobler-Rabie et al. (1985); Junien et
al. (1983); Kuivaniemi et al. (1988); Myers et al. (1981); Peltonen
et al. (1980); Phillips et al. (1990); Rose et al. (1994); Sillence
et al. (1979); Weil et al. (1990); Weil et al. (1989); Wirtz et al.
(1987); Wozney et al. (1981)
*FIELD* RF
1. Baldwin, C. T.; Constantinou, C.; Dumars, K. W.; Prockop, D. J.
: A single base mutation that converts glycine 907 of the alpha-2(I)
chain of type I procollagen to aspartate in a lethal variant of osteogenesis
imperfecta. J. Biol. Chem. 264: 3002-3006, 1989.

2. Baldwin, C. T.; Ganguly, A.; Rooney, J.; Hosomi, S.; Conway, D.
M.; Prockop, D. J.: Exon 33 of pro-alpha-2(I) collagen is deleted
in mRNAs from a patient with osteogenesis imperfecta: localization
of the mutation with carbodiimide. (Abstract) Collagen Rel. Res. 8:
508A only, 1988.

3. Bateman, J. F.; Hannagan, M.; Chan, D.; Cole, W. G.: Characterization
of a type I collagen alpha-2(I) glycine-586 to valine substitution
in osteogenesis imperfecta type IV: detection of the mutation and
prenatal diagnosis by a chemical cleavage method. Biochem. J. 276:
765-770, 1991.

4. Beighton, P.; Versfeld, G. A.: On the paradoxically high relative
prevalence of osteogenesis imperfecta type III in the black population
of South Africa. Clin. Genet. 27: 398-401, 1985.

5. Bonadio, J.; Patterson, E.; Smiley, E.: RNA sequence analysis
of perinatal lethal OI mutations. (Abstract) Collagen Rel. Res. 8:
506A, 1988.

6. Brebner, D. K.; Grobler-Rabie, A. F.; Bester, A. J.; Mathew, C.
G.; Boyd, C. D.: Two new polymorphic markers in the human pro-alpha-2(I)
collagen gene. Hum. Genet. 70: 25-27, 1985.

7. Byers, P. H.: Personal Communication. Seattle, Washington  2/1990.

8. Byers, P. H.; Barsh, G. S.; Rowe, D. W.; Peterson, K. E.; Holbrook,
K. A.; Shapiro, J.: Biochemical heterogeneity in osteogenesis imperfecta.
(Abstract) Am. J. Hum. Genet. 32: 37A only, 1980.

9. Byers, P. H.; Siegel, R. C.; Peterson, K. E.; Rowe, D. W.; Holbrook,
K. A.; Smith, L. T.; Chang, Y.-H.; Fu, J. C. C.: Marfan syndrome:
abnormal alpha-2 chain in type I collagen. Proc. Nat. Acad. Sci. 78:
7745-7749, 1981.

10. Carr, A. J.; Chiodo, A. A.; Hilton, J. M. N.; Chow, C. W.; Hockey,
A.; Cole, W. G.: The clinical features of Ehlers-Danlos syndrome
type VIIB resulting from a base substitution at the splice acceptor
site of intron 5 of the COL1A2 gene. J. Med. Genet. 31: 306-311,
1994.

11. Chiodo, A.; Hockey, A.; Cole, W. G.: A base substitution at the
splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic
splice site within exon 6 and generates abnormal type I procollagen
in a patient with Ehlers-Danlos syndrome type VII. J. Biol. Chem. 267:
6361-6369, 1992.

12. Cohn, D. H.; Byers, P. H.: Cysteine in the triple helical domain
of the pro-alpha-2(I) chain of type-I collagen in nonlethal forms
of osteogenesis imperfecta. Hum. Genet. 87: 167-172, 1991.

13. Cole, W. G.; Chan, D.; Chow, C. W.; Rogers, J. G.; Bateman, J.
F.: Disrupted growth plates and progressive deformities in osteogenesis
imperfecta as a result of the substitution of glycine 585 by valine
in the alpha-2(I) chain of type I collagen. J. Med. Genet. 33: 968-971,
1996.

14. Dalgleish, R.: The human type I collagen mutation database. Nucleic
Acids Res. 25: 181-187, 1997.

15. Dalgleish, R.; Williams, G.; Hawkins, J. R.: Length polymorphism
in the pro alpha-2(I) gene: an alternative explanation in a case of
Marfan syndrome. Hum. Genet. 73: 91-92, 1986.

16. Deak, S. B.; Nicholls, A.; Pope, F. M.; Prockop, D. J.: The molecular
defect in a nonlethal variant of osteogenesis imperfecta. J. Biol.
Chem. 258: 15192-15197, 1983.

17. de Wet, W.; Bernard, M.; Benson-Chanda, V.; Chu, M.-L.; Dickson,
L.; Weil, D.; Ramirez, F.: Organization of the human pro-alpha-2(I)
collagen gene. J. Biol. Chem. 262: 16032-16036, 1987.

18. Dickson, L. A.; de Wet, W.; Di Liberto, M.; Weil, D.; Ramirez,
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the human pro-alpha-2(I) collagen gene. Nucleic Acids Res. 13: 3427-3438,
1985.

19. Dickson, L. A.; Pihlajaniemi, T.; Deak, S.; Pope, F. M.; Nicholls,
A.; Prockop, D. J.; Myers, J. C.: Nuclease S1 mapping of a homozygous
mutation in the carboxy-propeptide-coding region of the pro-alpha-2(I)
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20. Edwards, M. J.; Byers, P. H.; Cohn, D. H.: Mild osteogenesis
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21. Edwards, M. J.; Wenstrup, R. J.; Byers, P. H.; Cohn, D. H.: Recurrence
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22. Eyre, D. R.; Shapiro, F. D.; Aldridge, J. F.: A heterozygous
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23. Ganguly, A.; Baldwin, C. T.; Strobel, D.; Conway, D.; Horton,
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25. Grobler-Rabie, A. F.; Wallis, G.; Brebner, D. K.; Beighton, P.;
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26. Hata, R.; Kurata, S.; Shinkai, H.: Existence of malfunctioning
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27. Henke, E.; Leader, M.; Tajima, S.; Pinnell, S.; Kaufman, R.:
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28. Ho, K. K. Y.; Kong, R. Y. C.; Kuffner, T.; Hsu, L. H. S.; Ma,
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29. Irving, N. G.; Hardy, J. A.; Bahary, N.; Friedman, J. M.; Brown,
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31. Junien, C.; Huerre, C.; Rethore, M. O.: Regional assignment of
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32. Junien, C.; Weil, D.; Myers, J. C.; Van Cong, N.; Chu, M.-L.;
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33. Kere, J.; Donis-Keller, H.; de la Chapelle, A.: Refinement of
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35. Knisely, A. S.; Abuelo, D.; Byers, P. H.: Lethal osteogenesis
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36. Knisely, A. S.; Richardson, A.; Abuelo, D.; Casey, S.; Singer,
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38. Kuivaniemi, H.; Tromp, G.; Chu, M.-L.; Prockop, D. J.: Structure
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39. Lamande, S. R.; Dahl, H.-H. M.; Cole, W. G.; Bateman, J. F.:
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40. Lehmann, H. W.; Mundlos, S.; Winterpacht, A.; Brenner, R. E.;
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45. Munke, M.; Harbers, K.; Jaenisch, R.; Francke, U.: Chromosomal
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46. Myers, J. C.; Chu, M.-L.; Faro, S. H.; Clark, W. J.; Prockop,
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51. Nicholls, A. C.; Osse, G.; Schloon, H. G.; Lenard, H. G.; Deak,
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52. Nicholls, A. C.; Pope, F. M.; Schloon, H.: Biochemical heterogeneity
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53. Niyibizi, C.; Bonadio, J.; Byers, P. H.; Eyre, D. R.: Incorporation
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54. Nuytinck, L.; Dalgleish, R.; Spotila, L.; Renard, J.-P.; Van Regemorter,
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55. Peltonen, L.; Palotie, A.; Prockop, D. J.: A defect in the structure
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56. Pepe, G.: A highly polymorphic (ACT)n VNTR (variable nucleotide
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57. Phillips, C. L.; Shrago, A. W.; Pinnell, S. R.; Wenstrup, R. J.
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58. Phillips, C. L.; Shrago-Howe, A. W.; Pinnell, S. R.; Wenstrup,
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1990.

59. Pihlajaniemi, T.; Dickson, L. A.; Pope, F. M.; Korhonen, V. M.;
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60. Pope, F. M.; Nicholls, A. C.; McPheat, J.; Talmud, P.; Owen, R.
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61. Retief, E.; Parker, M. I.; Retief, A. E.: Regional chromosome
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62. Rose, N. J.; Mackay, K.; Byers, P. H.; Dalgleish, R.: A gly859-to-ser
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63. Rose, N. J.; Mackay, K.; De Paepe, A.; Steinmann, B.; Punnett,
H. H.; Dalgleish, R.: Three unrelated individuals with perinatally
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substitutions in the alpha-2-chain of type I collagen. Hum. Genet. 94:
497-503, 1994.

64. Sasaki, T.; Arai, K.; Ono, M.; Yamaguchi, T.; Furuta, S.; Nagai,
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1987.

65. Shupp Byrne, D. E.; Church, R. L.: Assignment of the genes for
mouse type I procollagen to chromosome 16 using mouse fibroblast-Chinese
hamster somatic cell hybrids. Somat. Cell Genet. 9: 313-331, 1983.

66. Sillence, D. O.; Senn, A.; Danks, D. M.: Genetic heterogeneity
in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979.

67. Solomon, E.; Hiorns, L.; Dalgleish, R.; Tolstoshev, P.; Crystal,
R.; Sykes, B.: Regional localization of the human alpha-2(I) collagen
gene on chromosome 7 by molecular hybridization. Cytogenet. Cell
Genet. 35: 64-66, 1983.

68. Spotila, L. D.; Constantinou, C. D.; Sereda, L.; Ganguly, A.;
Riggs, B. L.; Prockop, D. J.: Mutation in a gene for type I procollagen
(COL1A2) in a woman with postmenopausal osteoporosis: evidence for
phenotypic and genotypic overlap with mild osteogenesis imperfecta. Proc.
Nat. Acad. Sci. 88: 5423-5427, 1991.

69. Spotila, L. D.; Sereda, L.; Prockop, D. J.: Partial isodisomy
for maternal chromosome 7 and short stature in an individual with
a mutation at the COL1A2 locus. Am. J. Hum. Genet. 51: 1396-1405,
1992.

70. Steinmann, B.: Personal Communication. Zurich, Switzerland
2/17/1995.

71. Superti-Furga, A.; Pistone, F.; Romano, C.; Steinmann, B.: Clinical
variability of osteogenesis imperfecta linked to COL1A2 and associated
with a structural defect in the type I collagen molecule. J. Med.
Genet. 26: 358-362, 1989.

72. Tromp, G.; Prockop, D. J.: Single base mutation in the pro-alpha-2(I)
collagen gene that causes efficient splicing of RNA from exon 27 to
exon 29 and synthesis of a shortened but in-frame pro-alpha-2(I) chain. Proc.
Nat. Acad. Sci. 85: 5254-5258, 1988.

73. Tsukahara, M.; Shinkai, H.; Asagami, C.; Eguchi, T.; Kajii, T.
: A disease with features of cutis laxa and Ehlers-Danlos syndrome:
report of a mother and daughter. Hum. Genet. 78: 9-12, 1988.

74. Tsuneyoshi, T.; Westerhausen, A.; Constantinou, C. D.; Prockop,
D. J.: Substitutions for glycine alpha-1-637 and glycine alpha-2-694
of type I procollagen in lethal osteogenesis imperfecta: the conformational
strain on the triple helix introduced by a glycine substitution can
be transmitted along the helix. J. Biol. Chem. 266: 15608-15613,
1991.

75. Vasan, N. S.; Kuivaniemi, H.; Vogel, B. E.; Minor, R. R.; Wootton,
J. A. M.; Tromp, G.; Weksberg, R.; Prockop, D. J.: A mutation in
the pro-alpha-2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos
syndrome type VII: evidence suggesting that skipping of exon 6 in
RNA splicing may be a common cause of the phenotype. Am. J. Hum.
Genet. 48: 305-317, 1991.

76. Viljoen, D.; Goldblatt, J.; Thompson, D.; Beighton, P.: Ehlers-Danlos
syndrome: yet another type? Clin. Genet. 32: 196-201, 1987.

77. Wallis, G.; Beighton, P.; Boyd, C.; Mathew, C. G.: Mutations
linked to the pro alpha-2(I) collagen gene are responsible for several
cases of osteogenesis imperfecta type I. J. Med. Genet. 23: 411-416,
1986.

78. Wallis, G. A.; Sykes, B.; Byers, P. H.; Mathew, C. G.; Viljoen,
D.; Beighton, P.: Osteogenesis imperfecta type III: mutations in
the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily
responsible. J. Med. Genet. 30: 492-496, 1993.

79. Watson, R. B.; Wallis, G. A.; Holmes, D. F.; Viljoen, D.; Byers,
P. H.; Kadler, K. E.: Ehlers Danlos syndrome type VIIB: incomplete
cleavage of abnormal type I procollagen by N-proteinase in vitro results
in the formation of copolymers of collagen and partially cleaved pNcollagen
that are near circular in cross-section. J. Biol. Chem. 267: 9093-9100,
1992.

80. Weil, D.; Bernard, M.; Combates, N.; Wirtz, M. K.; Hollister,
D. W.; Steinmann, B.; Ramirez, F.: Identification of a mutation that
causes exon skipping during collagen pre-mRNA splicing in an Ehlers-Danlos
syndrome variant. J. Biol. Chem. 263: 8561-8564, 1988.

81. Weil, D.; D'Alessio, M.; Ramirez, F.; de Wet, W.; Cole, W. G.;
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82. Weil, D.; D'Alessio, M.; Ramirez, F.; Eyre, D. R.: Structural
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16007-16011, 1990.

83. Weil, D.; D'Alessio, M.; Ramirez, F.; Steinmann, B.; Wirtz, M.
K.; Glanville, R. W.; Hollister, D. W.: Temperature-dependent expression
of a collagen splicing defect in the fibroblasts of a patient with
Ehlers-Danlos syndrome type VII. J. Biol. Chem. 264: 16804-16809,
1989.

84. Wenstrup, R.; Shrago, A.; Phillips, C.; Byers, P.; Cohn, D.:
Osteogenesis imperfecta type IV: analysis for mutations in alpha-2(I)
chains of type I collagen by alpha-2(I)-specific cDNA synthesis and
polymerase chain reaction. Ann. N.Y. Acad. Sci. 580: 546-548, 1990.

85. Wenstrup, R. J.; Cohn, D. H.; Cohen, T.; Byers, P. H.: Arginine
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87. Willing, M. C.; Cohn, D. H.; Starman, B.; Holbrook, K. A.; Greenberg,
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8398-8404, 1988.

88. Wirtz, M. K.; Glanville, R. W.; Steinmann, B.; Rao, V. H.; Hollister,
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A20 only, 1987.

89. Wirtz, M. K.; Glanville, R. W.; Steinmann, B.; Rao, V. H.; Hollister,
D. W.: Ehlers-Danlos syndrome type VIIB: deletion of 18 amino acids
comprising the N-telopeptide region of a pro-alpha-2(I) chain. J.
Biol. Chem. 262: 16376-16385, 1987.

90. Wozney, J.; Hanahan, D.; Tate, V.; Boedtker, H.; Doty, P.: Structure
of the pro-alpha-2(I) collagen gene. Nature 294: 129-135, 1981.

*FIELD* CN
Victor A. McKusick - updated: 3/21/1997
Iosif W. Lurie - updated: 9/11/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
jenny: 03/25/1997
jenny: 3/25/1997
terry: 3/21/1997
terry: 1/27/1997
jamie: 1/21/1997
terry: 1/14/1997
carol: 9/15/1996
carol: 9/11/1996
terry: 7/2/1996
terry: 6/27/1996
mark: 3/4/1996
terry: 2/21/1996
carol: 3/19/1995
mimadm: 12/22/1994
terry: 7/28/1994
davew: 7/19/1994
jason: 7/14/1994
warfield: 4/8/1994

*RECORD*
*FIELD* NO
120165
*FIELD* TI
*120165 COLLAGEN, FACIT-LIKE
D6S228E;;
COLLAGEN, TYPE IX-LIKE;;
COL9A1L
*FIELD* TX
By cross hybridization using a chicken type V collagen probe, Yoshioka
et al. (1992) isolated from a human rhabdomyosarcoma cell line a 1.8-kb
cDNA encoding portion of a novel collagen chain with a structure like
that of the FACIT class of macromolecules. (Types IX (120210), XII
(120320), and XIV (120324) of collagen are believed to provide molecular
connections between fibrils and/or between fibrils and other components
of the extracellular matrix. Structurally, these macromolecules exhibit
stretches of triple helical sequences interrupted by noncollagenous
domains (NC domains), containing cysteinyl residues. Based on these
characteristics, they are called FACIT for fibril-associated collagens
with interrupted triple helices.) The novel collagen chain was
arbitrarily termed alpha-1(Y). It was assigned the D number D6S228E (E =
expressed). By in situ hybridization, the gene was assigned to 6q12-q14
where the COL9A1 gene has been located.

*FIELD* RF
1. Yoshioka, H.; Zhang, H.; Ramirez, F.; Mattei, M.-G.; Moradi-Ameli,
M.; van der Rest, M.; Gordon, M. K.: Synteny between the loci for
a novel FACIT-like collagen locus (D6S288E) and alpha-1(IX) collagen
(COL9A1) on 6q12-q14 in humans. Genomics 13: 884-886, 1992.

*FIELD* CD
Victor A. McKusick: 6/29/1992

*FIELD* ED
carol: 6/29/1992

*RECORD*
*FIELD* NO
120170
*FIELD* TI
*120170 COLLAGEN, FETAL MEMBRANE, B POLYPEPTIDE
COLLAGEN, TYPE V, B POLYPEPTIDE
*FIELD* TX
See 120190.

*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 6/3/1987
reenie: 6/4/1986
*RECORD*
*FIELD* NO
120180
*FIELD* TI
*120180 COLLAGEN, TYPE III; COL3A1
COLLAGEN, FETAL
*FIELD* TX
See collagen of skin, tendon and bone--alpha-1 polypeptide (120150).
Fetal (and blood vessel) collagen is also called collagen III. Its
synthesis is defective in Ehlers-Danlos syndrome, type IV (130050,
225350). See 130050 for description of use of a RFLP of the COL3A1 locus
to demonstrate by the linkage principle that the defect in type IV
Ehlers-Danlos syndrome is in that gene. Using a cloned gene as a probe
on Southern blots of DNA from a panel of interspecies somatic cell
hybrids, Solomon et al. (1985) assigned the COL3A1 locus to chromosome
2. Mudryj et al. (1985) independently assigned COL3A1 to 2q. Emanuel et
al. (1985) concluded that both the alpha-1(III) and the alpha-2(V)
procollagen genes map to 2q24.3-q31. To the time of this report, this
was the only example of synteny of procollagen genes. Type IV collagen
has 3 varieties of alpha chains. Type V collagen has a specific
pericellular distribution and is not considered an interstitial
collagen. By somatic cell hybrid studies and in situ hybridization,
Huerre-Jeanpierre et al. (1986) assigned COL2A1 to 12q13.1-q13.2 and
COL3A1 to 2q31-q32.3. Tsipouras et al. (1988) demonstrated that the
COL3A1 locus and the COL5A2 (120190) locus are very close together; they
found a maximum lod score of 9.33 at a recombination fraction of 0.00.
Cutting et al. (1990) showed by pulsed field gel electrophoresis that
the COL3A1 and COL5A2 genes are in the same 35 kb segment. Janeczko and
Ramirez (1989) presented the nucleotide and amino acid sequences of type
III collagen. To define the limits of the homologous segment between
human chromosome 2 and proximal mouse chromosome 1, Schurr et al. (1990)
determined the segregation of the mouse homologs of 7 human genes
located on 2q with anchor loci on mouse chromosome 1. They concluded
that COL3A1 and COL6A3 defined the limits of a homologous segment that
in the mouse covers slightly more than 30 cM. They suggested that the
order of loci in this segment of the mouse chromosome might be the same
as the order in the human homolog.

Byers (1993) estimated that there are approximately 25 known mutations
in the COL3A1 gene. These are divided about equally between point
mutations which change a gly residue to another amino acid and exon
skipping mutations. In the case of the COL1A1 gene, exon skipping
mutations are much less frequent than point mutations. The COL3A1 gene
also has an unusually high frequency of multi-exon deletions.

To study directly the role of COL3A1 in development and disease, Liu et
al. (1997) inactivated the murine Col3a1 gene in embryonic stem cells by
homologous recombination. The mutated allele was transmitted through the
mouse germline and homozygous mutant animals were derived from
heterozygous intercrosses. About 10% of the homozygous mutant animals
survived to adulthood but had a much shorter lifespan compared with
wildtype mice. The major cause of death in mutant mice was rupture of
the major blood vessels, similar to patients with type IV Ehlers-Danlos
syndrome. Ultrastructural analysis of tissues from mutant mice revealed
that type III collagen is essential for normal collagen I
fibrillogenesis in the cardiovascular system and other organs.

*FIELD* AV
.0001
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY790SER
Tromp et al. (1989) found substitution of serine for glycine-790 in type
III collagen. The mutation probably made the procollagen molecule
unusually sensitive to proteases because it caused local unfolding of
the triple helix and exposed the adjacent arginine residue. The patient
had type IV Ehlers-Danlos syndrome. This patient had been thought to
carry an amino acid insertion because of the slower migration of the
pro-alpha chains of type III collagen (Stolle et al., 1985). The
clinical features were reported by Pyeritz et al. (1984); the
16-year-old man presented with a right neck mass that developed suddenly
at age 14 after forceful spitting and was shown by angiography to be an
aneurysm arising at the origin of the right subclavian. His father died
after several operations for spontaneous massive intraabdominal
hemorrhage. His aunt died of a rent in the abdominal aorta that occurred
spontaneously in the first stage of labor. His uncle required colostomy
after spontaneous rupture of the bowel and died several years later of
spontaneous rupture of the splenic artery.

.0002
AORTIC ANEURYSM
COL3A1, GLY619ARG
In a 37-year-old female captain in the U. S. Air Force who was studied
because several relatives had died of ruptured aortic aneurysms
(100070), Kontusaari et al. (1990) found heterozygosity for a single
base mutation that converted the codon for glycine-619 in type III
procollagen to arginine. The collagen produced had decreased temperature
for thermal unfolding. The same mutation was found in DNA extracted from
pathologic specimens from her mother, who had died at the age of 34 of
aortic aneurysm, and a maternal aunt, who died at the age of 55 of the
same cause. DNA from samples of saliva showed that the woman's daughter,
son, brother, and an aunt also had the mutation. Kuivaniemi et al.
(1991) described the same family in brief.

.0003
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY883ASP
See Tromp et al. (1989).

.0004
ARTERIAL ANEURYSMS, FAMILIAL
COL3A1, IVS20DS, G-A, +1
In a family with arterial aneurysms and easy bruisability but without
the usual changes of Ehlers-Danlos syndrome type IV, Kontusaari et al.
(1990) found substitution of A for G at the first nucleotide of intron
20. As a result, the consensus sequence of GT found in most of the
introns of eukaryotic genes was converted to AT. In this family, 2
brothers had died in their mid-thirties of ruptured aortic aneurysms.
The father had died at age 43 of ruptured abdominal aneurysm (100700).
Presumably, none of the patients had thin skin that made venous patterns
prominent and did not have ecchymoses and scarring over bony
prominences. Kuivaniemi et al. (1990) reported that the intron 20
mutation caused both use of a cryptic splice site and retention of all
the intron sequences.

.0005
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS16DS, G-A, +1
In a patient with type IV E-D, Kuivaniemi et al. (1990) found a
G(+1)-to-A mutation in intron 16, which caused extensive exon skipping.
The patient was a 36-year-old pregnant woman who had thin skin with
abnormally prominent superficial blood vessels. She had a minimal degree
of joint hypermobility and a history of 2 surgical procedures for
correction of patellar dislocations. Caesarean section was performed
because of premature ruptured membranes. The infant developed severe
bleeding and died 4 hours later. The patient's tissues appeared to be
unusually friable at surgery. The only other affected relative was a
brother who died at the age of 20 of a ruptured cervical artery
sustained during karate practice.

.0006
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS42DS, G-A, +1
Kuivaniemi et al. (1990) found that a G-to-A mutation at the first
nucleotide in intron 42 caused efficient use of a single cryptic splice
site. The patient was a 22-year-old woman who died suddenly from a
ruptured dissecting aortic aneurysm. She had thin and transparent skin
with abnormally prominent blood vessels. She had mild hypermobility of
the joints, congenital dislocation of the hips, and a torn knee
ligament. She had a history of bouts of abdominal pain and urinary tract
infections as well as pyloric stenosis in infancy. There was no evidence
of E-D syndrome in other members of the family, including an
11-month-old daughter.

.0007
COLLAGEN TYPE III POLYMORPHISM
COL3A1, ALA531THR
Zafarullah et al. (1990) demonstrated a change from GCT (ala) to ACT
(thr) in the codon for amino acid 531 of the triple helix. On the basis
of a study of 122 chromosomes, the frequency of the alanine allele was
0.68.

.0008
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS37DS, G-T, +5
In a middle-aged woman with bleeding tendency who had had a major
stroke, Wu et al. (1991) demonstrated that the COL3A1 gene had a G-to-T
transversion at the fifth nucleotide of intron 37. This resulted in the
formation of 2 different mutant species of mRNA through aberrant RNA
splicing.

.0009
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, 7.5-KB DEL
In a patient with severe E-D IV, Superti-Furga et al. (1988) showed that
fibroblasts synthesized normal-sized and shortened type III procollagen
chains. Comparison of the triple-helical domains of these 2 peptides and
coarse Southern blot analysis of the patient's DNA suggested a large
deletion in the middle portion of the COL3A1 gene. Lee et al. (1991)
showed that the structural defect resulted from exon-to-intron
recombination that deleted 16 exons of the triple-helical coding domain
of COL3A1, removing about 7.5 kb and 1,026 nucleotides of coding
sequence from the message. The deleted segment extended from the 13th
nucleotide of exon 9 to within a DNA sequence of intron 24, which is
composed of a series of dinucleotide repeats. Using PCR, Lee et al.
(1991) tested the polymorphic nature of this dinucleotide repeat. At
least 4 distinct allelic forms were found.

.0010
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY910VAL
Richards et al. (1991) found a G-to-T mutation resulting in a
substitution of glycine-910 by valine. Nuytinck et al. (1992) described
the patient and laboratory findings in detail. A 54-year-old woman had a
lifetime history of easy bruising and recurrent bleeding and hematomas.
She had varicose veins of the legs and attacks of superficial phlebitis.
On 3 occasions her right shoulder had dislocated spontaneously. Family
history was negative. She was only 149 cm tall and had facial features
strongly suggestive of EDS IV, including prominent eyes with bluish
sclerae, a pinched nose, and hypoplastic earlobes. The skin was
generally thin and showed a prominent venous pattern but was not
hyperextensible. The knees and shins showed atrophic scars and
hemosiderin deposits at the sites of old hematomas. There was
hyperextensibility of large joints, especially the elbows and knees, but
mobility of small joints was within normal limits. At the age of 54
years she developed a perforation of the sigmoid colon for which a
sigmoidectomy was performed. The patient's skin fibroblasts produced
markedly diminished amounts of type III collagen. Cells obtained from
noncutaneous tissues showed 2 forms of type III chains, one normal and
one slow migrating. The type III collagen molecules containing mutant
alpha chains were overmodified, had a lower thermal stability, and were
poorly secreted into the extracellular medium. Nuytinck et al. (1992)
pointed out that the mutant molecules were preferentially retained
within cultured cells, presumably destined for degradation. By reducing
the incubation temperature of the cells, the secretion of type III
collagen was increased considerably. For this reason, cooler superficial
tissues, such as skin, may be less dramatically affected than internal
organs.

.0011
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS25DS, G-T, +5
In a sporadic case of EDS-IV, Lee et al. (1991) demonstrated a G-to-T
transversion at position +5 of the splice donor site of intron 25 in one
of the patient's COL3A1 genes. The splicing mutation resulted in
skipping of exon 25. As in previously characterized splicing mutations
in other collagen genes, lowering the temperature at which the patient's
fibroblasts were incubated nearly abolished exon skipping. The mutation
was first localized by amplifying the reverse transcribed product in
several overlapping fragments by use of PCR. Amplified products spanning
exon 24-26 sequences displayed 2 distinct fragments, one of normal size
and the other lacking the 99 basepairs of exon 25. As part of the study,
Lee et al. (1991) identified a highly polymorphic, intronic DNA sequence
whose different allelic forms could be easily detected by the PCR
technique.

The patient studied by Lee et al. (1991) (C.E., JHH 1538182, P13,719)
had suffered since boyhood from easy bruising and episodes of hemorrhage
occurring spontaneously or after trivial trauma. Physical examination at
age 31 years showed thin, delicate skin with hemosiderotic, atrophic
scars as well as paradoxically striking keloids. Superficial veins were
easily visible and flexion contractures of the thumb and third finger of
the right hand were found. He also had partial right bundle branch block
and pulmonary stenosis (confirmed by angiography at age 19 years). He
died at age 32 after falling from a bar stool.

.0012
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS41DS, G-A, +1
Sillence et al. (1991) described the clinical features in a patient with
E-D IV in whom Cole et al. (1990) found heterozygosity for a G-to-A
transition at the splice donor site of intron 41. The mutation resulted
in the splicing out of exon 41, which encoded 36 amino acids from
glycine-775 to lysine-810 of the triple helical domain of type III
collagen. The amount of type III collagen in the dermis was only about
11% of normal. The patient had typical features of the acrogeric form of
E-D IV: characteristic facies with pinched nose and thin lips, aesthenic
build, thin skin, prominent subcutaneous veins, and senile-appearing
hands. Spontaneous bruising, bleeding from the large bowel,
constipation, and delayed gastric emptying were other features.

.0013
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, 27-BP DEL
Matton et al. (1982) described a large Belgian family with E-D IV in
which Nicholls et al. (1988) showed that the abnormal phenotype was
linked to an AvaII polymorphism in the COL3A1. In contrast to most E-D
IV patients, fibroblasts from affected members of this family secreted
nearly normal amounts of an apparently normal collagen. Although the
level of type III collagen secreted was slightly lower than that
secreted by control cell lines, the level of COL3A1 mRNA was normal.
Richards et al. (1992) localized the mutation in this family to the CB5
peptide of type III collagen by use of both protein and cDNA mapping
techniques. Sequence analysis of cDNA demonstrated a 27-bp deletion
within exon 37, removing 9 amino acids and maintaining the gly-X-Y
repeat of the collagen helix. Further studies showed that the deletion
was present in all affected members and absent in all unaffected members
of the kindred. The deletion was flanked by 2 short direct repeats of
CTCC; it appeared to have arisen by slipped mispairing.

.0014
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY847GLU
In 3 affected members of the family of the patient with spontaneous
carotid-cavernous fistula reported by Fox et al. (1988), Richards et al.
(1992) demonstrated a G-to-A mutation converting glycine-847 to glutamic
acid. The spontaneous carotid-cavernous fistula was successfully
embolized and occluded. The mother and only sib had thin skin and joint
laxity. The mother died at the age of 50 years from postoperative
complications following ruptured bowel. Richards et al. (1992) showed
that the mutation must have arisen during embryogenesis of the proband's
maternal grandmother who was clinically unaffected but mosaic for the
mutation.

.0015
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY1018ASP
In a 41-year-old woman with arterial ruptures and skin changes
characteristic of type IV Ehlers-Danlos syndrome, Kontusaari et al.
(1992) found a single base substitution in the COL3A1 gene which
converted the codon for glycine at amino acid position 1018 to a codon
for aspartate. (Amino acid positions were numbered by the convention in
which the first glycine of the triple-helical domain of an alpha chain
is numbered 1. The number of positions in the mature collagen chain can
be converted to positions in the procollagen chain by adding 167.) The
glycine mutation markedly decreased the amount of type III procollagen
secreted into the medium by cultured skin fibroblasts. The same mutation
was found in about 94% of peripheral blood leukocytes of the proband's
asymptomatic 72-year-old mother. The mutation was present in 0.0-100% of
different samples of hair cells and in about 40% of cells from the oral
epithelium. Since the mutated allele was present in cells derived from
all 3 germ layers, the results indicated that the mutation arose by the
late blastocyst stage of development. The proband had been born
prematurely without obvious cause. Her case was reported by Morris
(1957) as one of acrogeria; her hands and feet were described as
'emaciated and fleshless with the veins showing through the thin and
wrinkled skin.' At the age of 24 years, she had spontaneous rupture of
the splenic artery. Two years later she developed recurrent
pneumothoraces. At age 28 she had a perinephric hematoma requiring left
nephrectomy for control of bleeding. At age 39 a large spontaneous
hematoma in her left thigh was thought to represent a venous rupture.
The mother had no history of easy bruisability or hemorrhaging and her
skin was normal on examination by Morris (1957) and by one of the
authors (F.M.P.) in the Kontusaari et al. (1992) report (Pope et al.,
1980).

.0016
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY1006GLU
Using denaturing gradient gel electrophoresis (DGGE), Johnson et al.
(1992) identified heterozygosity for a GGA-to-GAA transition in codon
1006 creating a new HinfI restriction site and substitution of glutamic
acid for glycine at residue 1006 of the COL3A1 chain. The patient had
typical acrogeric E-D IV and had been reported by Roberts et al. (1984)
as mimicking nonaccidental injury, i.e., child abuse.

.0017
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY1021GLU
Narcisi et al. (1993) described a 24-year-old woman with type IV
Ehlers-Danlos syndrome and sudden death due to 'massive' aortic
dissection arising about 0.5 cm above the aortic ring and extending to
the aortic bifurcation. The aneurysm had ruptured through the left
lateral wall of the abdominal aorta, producing a large retroperitoneal
hemorrhage. The presence of atrophy of all finger pulps with
acroosteolysis and loss of the first and second fingernails on the left
hand were commented on. Narcisi et al. (1993) found a single base
mutation in exon 49 of the COL3A1 gene which caused a gly-to-glu
substitution at amino acid residue 1021.

.0018
AORTIC ANEURYSM, DISSECTING, DUE TO FIBROMUSCULAR DYSPLASIA, GENERALIZED
COL3A1, GLY136ARG
In a large study involving sequencing of cDNA for the triple-helical
domain of type III procollagen in 54 patients with aortic aneurysms,
Tromp et al. (1993) found only one with a mutation of likely functional
significance: a substitution of arginine for an obligatory glycine at
amino acid position 136. The nucleotide change was a transition from GGG
to AGG at position 907. The patient was an 18-year-old black male
without any prior relevant medical history. He had suddenly developed
paraparesis and bilateral loss of pulses below the waist (Gatalica et
al., 1992). An aortogram disclosed a dissecting aneurysm of the entire
aorta and obstruction of blood flow below the renal arteries. Autopsy
demonstrated the dissecting aneurysm and generalized fibromuscular
dysplasia (135580). His father had died at the age of 36 years in a car
accident and no affected relatives were available for DNA testing. His
mother did not have the mutation, but 3 unaffected sibs were found to
have the same mutation. Ultrasound examination of the aorta in these
sibs, aged 21, 20, and 16 years, did not reveal any abnormalities.

.0019
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS7DS, T-C, +6
In a 32-year-old woman with type IV E-D, Lloyd et al. (1993) identified
a T-to-C transition at nucleotide +6 in the donor splice site of IVS7 of
the COL3A1 gene. This resulted in skipping of exon 7, which is the most
5-prime of the completely triple helix encoding exons, since exon 6 of
the COL3A1 gene codes partially for the N-peptidase cleavage site and
the first 9 amino acids of the triple helix. The patient, who suffered
from a de novo mutation, was classified as having a nonacrogeric form of
this disorder. She came to medical attention because of infection of the
right kidney and intermittent claudication of the left leg. Angiography
showed occlusion of the right renal artery and stenosis of the left
iliac artery with possible dissection. Four years previously she
suffered perforation of the bowel and had varicose veins since her
teens.

.0020
EHLERS-DANLOS SYNDROME, TYPE III
COL3A1, GLY637SER
Narcisi et al. (1994) characterized the first mutation identified in a
family with Ehlers-Danlos syndrome type III (130020). The proband was a
4-year-old boy with generalized joint laxity and minor skin
extensibility without scarring. Four other members of the family were
affected: his 36-year-old father, a younger brother, a 39-year-old
paternal uncle, and the 64-year-old paternal grandmother. The disorder
in the family was diagnosed as E-D III/articular hypermobility syndrome;
the latter, also called familial joint instability or Ehlers-Danlos
syndrome type XI (147900), is not clearly distinguished from E-D III.
Analysis of cultured fibroblasts from the affected members demonstrated
intracellular retention of type III collagen. This is usually a
biochemical characteristic of E-D IV, caused by mutations of COL3A1.
Analysis of the cDNA sequence in this family revealed a
glycine-to-serine mutation at amino acid residue 637 of the type III
collagen molecule. This was confirmed by allele-specific oligonucleotide
hybridization against amplified genomic DNA. There was no history of
vascular fragility in the family and there were no other clinical signs
usually associated with E-D VI such as thin skin and characteristic
facial features.

.0021
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, IVS27DS, G-A, +5
Thakker-Varia et al. (1995) identified a unique mutation in the COL3A1
gene in a 22-year-old woman who was the only 1 of 5 sibs affected by
type IV EDS. Her mother died at age 35 from a massive abdominal
hemorrhage after a minor car accident and was probably affected. During
delivery of a seemingly unaffected daughter, the proband experienced
protracted bleeding and significant tear damage of the pelvic tissues.
The skin was soft and hyperextensible around the elbows, but not on the
upper thorax, where it was thin and translucent. No evident joint
hypermobility was noted, while marked, diffuse bruising and pigmented
scars were present. The facies was characteristic, with a thin nose,
thin lips, and fine wrinkles around the mouth. The patient's fibroblasts
produced decreased amounts of type III procollagen despite normal levels
of translatable type III procollagen mRNA. S1 nuclease analysis of the
type III procollagen mRNA indicated a defect in the region encoding exon
27. Sequence analysis of cDNA clones and genomic fragments generated by
PCR amplification demonstrated that sequences representing exon 27 were
absent from 3 out of 5 cDNA clones and that a G at the +5 position of
the splice donor site in intron 27 was changed to an A in 1 allele of
their patient's COLA3A1 gene. Thakker-Varia et al. (1995) could
demonstrate that mRNA species containing and lacking exon 27 were
produced in a 1:1 ratio. However, pulse label and chase experiments in
the presence or absence of brefeldin A indicated that most of the type
III procollagen molecules synthesized by the patient's fibroblasts were
not secreted into the medium but were degraded in the endoplasmic
reticulum-Golgi compartment by a nonlysosomal mechanism.

.0022
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY499ASP
McGrory et al. (1996) found heterozygosity for a G-to-A transition at
nucleotide 1997, resulting in a G499D substitution in type III collagen
in a 48-year-old man with the acrogeric form of type IV EDS. The patient
had been reported by Pope et al. (1988). The age of onset of his
acrogeric appearance was uncertain, but with increasing age it had
become more severe. At 49 years of age, he died from massive pulmonary
emboli and acute myocardial infarction. The man had only 1 son who was
clinically normal at 15 years of age. However, he showed heterozygosity
for the same mutation.

.0023
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY793VAL
Tromp et al. (1995) found a G-to-T transition at position 2879 (exon 41)
in the COL3A1 gene that changed the codon for glycine-793 to a codon for
valine in a mother and her son with Ehlers-Danlos syndrome, type IV.
Clinical details of this family were reported by De Paepe et al. (1989).
This substitution most likely disrupted the triple-helical structure of
the protein and made it less stable.

.0024
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY415SER
Anderson et al. (1997) stated that more than 40 mutations in the type
III procollagen gene had been described in patients with EDS IV. These
mutations included missense mutations, splice site mutations, and
deletions. They reported a G-to-A transition that altered codon 415 from
GGT (glycine) to AGT (serine). They stated that the mutation results in
impaired secretion and decreased thermal stability type III procollagen.

.0025
EHLERS-DANLOS SYNDROME, TYPE IV
COL3A1, GLY934GLU
McGrory et al. (1996) found a 3302G-A transition in exon 46 of the
COL3A1 cDNA resulting in the amino acid change gly934glu. The change was
located in exon 46. It resulted in a severe deficiency of type III
collagen in fibroblast cultures and dermis. Dilatation of the
endoplasmic reticulum of the dermal fibroblast was probably due to
failure of these cells to secrete type III collagen molecules containing
one or more mutant alpha-1(III) chains. The dermal collagen fibrils were
narrow, but their constituent type III collagen molecules contained
predominantly normal alpha-1(III) chains. As a result, the major effect
of the mutation was to reduce severely the amount of normal type III
collagen available for the formation of collagen fibrils in the
extracellular matrix. The 50-year-old patient studied by McGrory et al.
(1996) had hypermobile joints with recurrent dislocations of the
shoulders, thumbs, and patellae, skin laxity, and easy bruising. At the
age of 28 she had an aortic thrombosis and at 50 she developed proptosis
and was shown to have carotico-cavernous fistulae and dilatations of the
internal carotid and vertebral arteries. Her sister had similar
cutaneous and joint anomalies, and had a myocardial infarction at 34
years of age. The proband's mother, aged 78 years, had joint
hypermobility and skin laxity suggestive of EDS-IV.

*FIELD* SA
Cutting et al. (1990); Dalgleish et al. (1985); Kontusaari et al.
(1990); Kontusaari et al. (1990); Lee et al. (1991); Richards et al.
(1992); Tromp et al. (1989)
*FIELD* RF
1. Anderson, D. W.; Thakker-Varia, S.; Tromp, G.; Kuivaniemi, H.;
Stolle, C. A.: A glycine (415)-to-serine substitution results in
impaired secretion and decreased thermal stability of type III procollagen
in a patient with Ehlers-Danlos syndrome type IV. Hum. Mutat. 9:
62-63, 1997.

2. Byers, P. H.: Personal Communication. Seattle, Wash.  9/23/1993.

3. Cole, W. G.; Chiodo, A. A.; Lamande, S. R.; Janeczko, R.; Ramirez,
F.; Dahl, H.-H. M.; Chan, D.; Bateman, J. F.: A base substitution
at a splice site in the COL3A1 gene causes exon skipping and generates
abnormal type III procollagen in a patient with Ehlers-Danlos syndrome
type IV. J. Biol. Chem. 265: 17070-17077, 1990.

4. Cutting, G. R.; McGinniss, M. J.; Kasch, I. M.; Tsipouras, P.;
Antonarakis, S. E.: Physical mapping by PFGE localizes the COL3A1
and COL5A2 genes to a 35 kb region on chromosome 2. (Abstract) Clin.
Res. 38: 266A, 1990.

5. Cutting, G. R.; McGinniss, M. J.; Kasch, L. M.; Tsipouras, P.;
Antonarakis, S. E.: Physical mapping by PFGE localizes the COL3A1
and COL5A2 genes to a 35 kb region on human chromosome 2. Genomics 8:
407-410, 1990.

6. Dalgleish, R.; Woodhouse, M.; Reeders, S.: An RFLP associated
with the human type III collagen gene (COL3A1). Nucleic Acids Res. 13:
4609, 1985.

7. De Paepe, A.; Thaler, B.; Van Gijsegem, M.; Van Hoecke, D.; Matton,
M.: Obstetrical problems in patients with Ehlers-Danlos syndrome
type IV: a case report. Europ. J. Obstet. Gynec. Reprod. Biol. 33:
189-193, 1989.

8. Emanuel, B. S.; Cannizzaro, L. A.; Seyer, J. M.; Myers, J. C.:
Human alpha-1(III) and alpha-2(V) procollagen genes are located on
the long arm of chromosome 2. Proc. Nat. Acad. Sci. 82: 3385-3389,
1985.

9. Fox, R.; Pope, F. M.; Narcisi, P.; Nicholls, A. C.; Kendall, B.
E.; Hourihan, M. D.; Compston, D. A. S.: Spontaneous carotid cavernous
fistula in Ehlers-Danlos syndrome. J. Neurol. Neurosurg. Psychiat. 51:
984-986, 1988.

10. Gatalica, Z.; Gibas, Z.; Martinez-Hernandez, A.: Dissecting aortic
aneurysm as a complication of generalized fibromuscular dysplasia. Hum.
Path. 23: 586-588, 1992.

11. Huerre-Jeanpierre, M.; Mattei, M.-G.; Weil, D.; Grzeschik, K.
H.; Chu, M.-L.; Sangiorgi, F. O.; Sobel, M. E.; Ramirez, F.; Junien,
C.: Further evidence for the dispersion of the human fibrillar collagen
genes. Am. J. Hum. Genet. 38: 26-37, 1986.

12. Janeczko, R. A.; Ramirez, F.: Nucleotide and amino acid sequences
of the entire human alpha-1(III) collagen. Nucleic Acids Res. 17:
6742, 1989.

13. Johnson, P. H.; Richards, A. J.; Pope, F. M.; Hopkinson, D. A.
: A COL3A1 glycine 1006 to glutamic acid substitution in a patient
with Ehlers-Danlos syndrome type IV detected by denaturing gradient
gel electrophoresis. J. Inherit. Metab. Dis. 15: 426-430, 1992.

14. Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Ladda, R. L.; Prockop,
D. J.: Inheritance of an RNA splicing mutation (G(+1) IVS20) in the
type III procollagen gene (COL3A1) in a family having aortic aneurysms
and easy bruisability: phenotypic overlap between familial arterial
aneurysms and Ehlers-Danlos syndrome type IV. Am. J. Hum. Genet. 47:
112-120, 1990.

15. Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Romanic, A.; Prockop,
D. J.: A mutation in the gene for the type III procollagen (COL3A1)
in a family with aortic aneurysms. (Abstract) Clin. Res. 38: 360A,
1990.

16. Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Romanic, A. M.; Prockop,
D. J.: A mutation in the gene for type III procollagen (COL3A1) in
a family with aortic aneurysms. J. Clin. Invest. 86: 1465-1473,
1990.

17. Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Stolle, C.; Pope, F.
M.; Prockop, D. J.: Substitution of aspartate for glycine 1018 in
the type III procollagen (COL3A1) gene causes type IV Ehlers-Danlos
syndrome: the mutated allele is present in most blood leukocytes of
the asymptomatic and mosaic mother. Am. J. Hum. Genet. 51: 497-507,
1992.

18. Kuivaniemi, H.; Kontusaari, S.; Tromp, G.; Zhao, M.; Sabol, C.;
Prockop, D. J.: Identical G(+1)-to-A mutations in three different
introns of the type III procollagen gene (COL3A1) produce different
patterns of RNA splicing in three variants of Ehlers-Danlos Syndrome
IV: an explanation for exon skipping with some mutations and not others. J.
Biol. Chem. 265: 12067-12074, 1990.

19. Kuivaniemi, H.; Tromp, G.; Prockop, D. J.: Genetic causes of
aortic aneurysms: unlearning at least part of what the textbooks say. J.
Clin. Invest. 88: 1441-1444, 1991.

20. Lee, B.; D'Alessio, M.; Vissing, H.; Ramirez, F.; Steinmann, B.;
Superti-Furga, A.: Characterization of a large deletion associated
with a polymorphic block of repeated dinucleotides in the type III
procollagen gene (COL3A1) of a patient with Ehlers-Danlos syndrome
type IV. Am. J. Hum. Genet. 48: 511-517, 1991.

21. Lee, B.; Vitale, E.; Superti-Furga, A.; Steinmann, B.; Ramirez,
F.: G to T transversion at position +5 of a splice donor site causes
skipping of the preceding exon in the type III procollagen transcripts
of a patient with Ehlers-Danlos syndrome type IV. J. Biol. Chem. 266:
5256-5259, 1991.

22. Liu, X.; Wu, H.; Byrne, M.; Krane, S.; Jaenisch, R.: Type III
collagen is crucial for collagen I fibrillogenenis and for normal
cardiovascular development. Proc. Nat. Acad. Sci. 94: 1852-1856,
1997.

23. Lloyd, J.; Narcisi, P.; Richards, A.; Pope, F. M.: A T(+6) to
C(+6) mutation in the donor splice site of COL3A1 IVS7 causes exon
skipping and results in Ehlers-Danlos syndrome type IV. J. Med. Genet. 30:
376-380, 1993.

24. Matton, M. T.; De Paepe, A.; De Keyser, F.; Francois, B.: Unusual
familial manifestation of Ehlers-Danlos syndrome.In: Papadatos, C.
J.; Bartsocas, C. H. S.: Skeletal Dysplasias.  New York: Alan R.
Liss (pub.)  1982. Pp. 243-257.

25. McGrory, J.; Costa, T.; Cole, W. G.: A novel G499D substitution
in the alpha-1(III) chain of type III collagen produces variable forms
of Ehlers-Danlos syndrome type IV. Hum. Mutat. 7: 59-60, 1996.

26. McGrory, J.; Weksberg, R.; Thorner, P.; Cole, W. G.: Abnormal
extracellular matrix in Ehlers-Danlos syndrome type IV due to the
substitution of glycine 934 by glutamic acid in the triple helical
domain of type III collagen. Clin. Genet. 50: 442-445, 1996.

27. Morris, D.: Acrogeria. J. Roy. Soc. Med. 50: 330-331, 1957.

28. Mudryj, M.; Merry, D. E.; de Crombrugghe, B.; McBride, O. W.:
Human collagen III (COL3A1) is on chromosome 2q. (Abstract) Cytogenet.
Cell Genet. 40: 704, 1985.

29. Narcisi, P.; Richards, A. J.; Ferguson, S. D.; Pope, F. M.: A
family with Ehlers-Danlos syndrome type III/articular hypermobility
syndrome has a glycine 637-to-serine substitution in type III collagen. Hum.
Molec. Genet. 3: 1617-1620, 1994.

30. Narcisi, P.; Wu, Y.; Tromp, G.; Earley, J. J.; Richards, A. J.;
Pope, F. M.; Kuivaniemi, H.: Single base mutation that substitutes
glutamic acid for glycine 1021 in the COL3A1 gene and causes Ehlers-Danlos
syndrome type IV. Am. J. Med. Genet. 46: 278-283, 1993.

31. Nicholls, A. C.; De Paepe, A.; Narcisi, P.; Dalgleish, R.; De
Keyser, F.; Matton, M.; Pope, F. M.: Linkage of a polymorphic marker
for the type III collagen gene (COL3A1) to atypical autosomal dominant
Ehlers-Danlos syndrome type IV in a large Belgian pedigree. Hum.
Genet. 78: 276-281, 1988.

32. Nuytinck, L.; Narcisi, P.; Nicholls, A.; Renard, J. P.; Pope,
F. M.; De Paepe, A.: Detection and characterisation of an overmodified
type III collagen by analysis of non-cutaneous connective tissues
in a patient with Ehlers-Danlos syndrome IV. J. Med. Genet. 29:
375-380, 1992.

33. Pope, F. M.; Nicholls, A. C.; Jones, P. M.; Wells, R. S.; Lawrence,
D.: EDS IV (acrogeria): new autosomal dominant and recessive types. J.
Roy. Soc. Med. 73: 180-186, 1980.

34. Pope, F. M.; Nicholls, A. C.; Narcisi, P.; Temple, A.; Chia, Y.;
Fryer, P.; De Paepe, A.; De Groote, W. P.; McEwan, J. R.; Compston,
D. A.; Oorthuys, H.; Davies, J.; Dinwoodie, D. L.: Type III collagen
mutations in Ehlers Danlos syndrome type IV and other related disorders. Clin.
Exp. Dermat. 13: 285-302, 1988.

35. Pyeritz, R. E.; Stolle, C. A.; Parfrey, N. A.; Myers, J. C.:
Ehlers-Danlos syndrome IV due to a novel defect in type III procollagen. Am.
J. Med. Genet. 19: 607-622, 1984.

36. Richards, A. J.; Lloyd, J. C.; Narcisi, P.; Ward, P. N.; Nicholls,
A. C.; De Paepe, A.; Pope, F. M.: A 27-bp deletion from one allele
of the type III collagen gene (COL3A1) in a large family with Ehlers-Danlos
syndrome type IV. Hum. Genet. 88: 325-330, 1992.

37. Richards, A. J.; Lloyd, J. C.; Ward, P. N.; De Paepe, A.; Narcisi,
P.; Pope, F. M.: Characterization of a glycine to valine substitution
at amino acid position 910 of the triple helical region of type III
collagen in a patient with Ehlers-Danlos syndrome type IV. J. Med.
Genet. 28: 458-463, 1991.

38. Richards, A. J.; Ward, P. N.; Narcisi, P.; Nicholls, A. C.; Lloyd,
J. C.; Pope, F. M.: A single base mutation in the gene for type III
collagen (COL3A1) converts glycine 847 to glutamic acid in a family
with Ehlers-Danlos syndrome type IV: an unaffected family member is
mosaic for the mutation. Hum. Genet. 89: 414-418, 1992.

39. Roberts, D. L. L.; Pope, F. M.; Nicholls, A. C.; Narcisi, P.:
Ehlers-Danlos syndrome type IV mimicking non-accidental injury in
a child. Brit. J. Derm. 111: 341-345, 1984.

40. Schurr, E.; Skamene, E.; Morgan, K.; Chu, M.-L.; Gros, P.: Mapping
of Col3a1 and Col6a3 to proximal murine chromosome 1 identifies conserved
linkage of structural protein genes between murine chromosome 1 and
human chromosome 2q. Genomics 8: 477-486, 1990.

41. Sillence, D. O.; Chiodo, A. A.; Campbell, P. E.; Cole, W. G.:
Ehlers-Danlos syndrome type IV: phenotypic consequences of a splicing
mutation in one COL3A1 allele. J. Med. Genet. 28: 840-845, 1991.

42. Solomon, E.; Hiorns, L. R.; Spurr, N.; Kurkinen, M.; Barlow, D.;
Hogan, B. L. M.; Dalgleish, R.: Chromosomal assignments of the genes
coding for human types II, III and IV collagen: a dispersed gene family. Proc.
Nat. Acad. Sci. 82: 3330-3334, 1985.

43. Stolle, C. A.; Pyeritz, R. E.; Myers, J. C.; Prockop, D. J.:
Synthesis of an altered type III procollagen in a patient with type
IV Ehlers-Danlos syndrome: a structural change in the alpha-1(III)
chain which makes the protein more susceptible to proteinases. J.
Biol. Chem. 260: 1937-1944, 1985.

44. Superti-Furga, A.; Gugler, E.; Gitzelmann, R.; Steinmann, B.:
Ehlers-Danlos syndrome type IV: a multi-exon deletion in one of the
two COL3A1 alleles affecting structure, stability, and processing
of type III procollagen. J. Biol. Chem. 263: 6226-6232, 1988.

45. Thakker-Varia, S.; Anderson, D. W.; Kuivaniemi, H.; Tromp, G.;
Shin, H.-G.; van der Rest, M.; Glorieux, F. H.; Ala-Kokko, L.; Stolle,
C. A.: Aberrant splicing of the type III procollagen mRNA leads to
intracellular degradation of the protein in a patient with Ehlers-Danlos
type IV. Hum. Mutat. 6: 116-125, 1995.

46. Tromp, G.; De Paepe, A.; Nuytinck, L.; Madhatheri, S.; Kuivaniemi,
H.: Substitution of valine for glycine 793 in type III procollagen
in Ehlers-Danlos syndrome type IV. Hum. Mutat. 5: 179-181, 1995.

47. Tromp, G.; Kuivaniemi, H.; Shikata, H.; Prockop, D. J.: A single
base mutation that substitutes serine for glycine 790 of the alpha-1(III)
chain of type III procollagen exposes an arginine and causes Ehlers-Danlos
syndrome IV. J. Biol. Chem. 264: 1349-1352, 1989.

48. Tromp, G.; Kuivaniemi, H.; Stolle, C.; Pope, F. M.; Prockop, D.
J.: Single base mutation in the type III procollagen gene that converts
the codon for glycine 883 to aspartate in a mild variant of Ehlers-Danlos
syndrome IV. J. Biol. Chem. 264: 19313-19317, 1989.

49. Tromp, G.; Wu, Y.; Prockop, D. J.; Madhatheri, S. L.; Kleinert,
C.; Earley, J. J.; Zhuang, J.; Norrgard, O.; Darling, R. C.; Abbott,
W. M.; Cole, C. W.; Jaakkola, P.; Ryynanen, M.; Pearce, W. H.; Yao,
J. S. T.; Majamaa, K.; Smullens, S. N.; Gatalica, Z.; Ferrell, R.
E.; Jimenez, S. A.; Jackson, C. E.; Michels, V. V.; Kaye, M.; Kuivaniemi,
H.: Sequencing of cDNA from 50 unrelated patients reveals that mutations
in the triple-helical domain of type III procollagen are an infrequent
cause of aortic aneurysms. J. Clin. Invest. 91: 2539-2545, 1993.

50. Tsipouras, P.; Schwartz, R. C.; Liddell, A. C.; Salkeld, C. S.;
Weil, D.; Ramirez, F.: Genetic distance of two fibrillar collagen
loci, COL3A1 and COL5A2, located on the long arm of human chromosome
2. Genomics 3: 275-277, 1988.

51. Wu, Y.; Tromp, G.; Kuivaniemi, H.; Prockop, D. J.:
G(+5) to T mutation in intron 37 of the type III procollagen gene
(COL3A1) causes aberrant RNA splicing in a proband with strokes and
a bleeding tendency.           (Series) Miami Short Reports. Advances
in Gene Technology: The Molecular Biology of Human Genetic Disease.
New York: IRL Press (pub.)  1: 1991. Pp. 39 only.

52. Zafarullah, K.; Kleinert, C.; Tromp, G.; Kuivaniemi, H.; Kontusaari,
S.; Wu, Y.; Ganguly, A.; Prockop, D. J.: G to A polymorphism in exon
31 of the COL3A1 gene. Nucleic Acids Res. 18: 6180, 1990.

*FIELD* CN
Victor A. McKusick - updated: 04/07/1997
Victor A. McKusick - updated: 3/12/1997
Victor A. McKusick - updated: 2/28/1997
Iosif W. Lurie - updated: 9/22/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 04/07/1997
terry: 4/1/1997
terry: 3/12/1997
terry: 3/6/1997
mark: 2/28/1997
terry: 2/26/1997
mark: 12/9/1996
carol: 9/22/1996
mark: 1/31/1996
terry: 1/25/1996
mark: 10/2/1995
terry: 11/16/1994
davew: 8/17/1994
carol: 4/12/1994
warfield: 4/8/1994
pfoster: 3/25/1994

*RECORD*
*FIELD* NO
120190
*FIELD* TI
*120190 COLLAGEN, TYPE V, ALPHA-2 CHAIN; COL5A2
AB COLLAGEN;;
COLLAGEN, FETAL MEMBRANE, A POLYPEPTIDE
*FIELD* TX
See 120215. Burgeson et al. (1976) identified in human fetal membranes
(placenta) 2 new genetically distinct collagen polypeptide chains, which
are subunits of new molecular species of collagen. They were tentatively
labeled alpha-A and alpha-B. The existence of a 'new' species of
collagen containing one A and two B alpha chains was suggested. This is
called collagen V and presumably is determined by 2 loci. Placental
collagen is sometimes referred to as AB collagen. Some have considered
it to consist of 2 separate molecules, one composed of 3 alpha-A chains
and one composed of 3 alpha-B chains. Others view it as a trimer of 1
alpha-A and 2 alpha-B chains. Brown and Weiss (1979) concluded that
these are 2 separate molecules (and perhaps a third consisting of 3
alpha-C chains), the first option, and that all 3 chains are derived
from one basic chain through posttranslational modification. Type V
collagen is usually found between the basement membrane and interstitial
space. Emanuel et al. (1985) concluded that both the alpha-1(III) and
the alpha-2(V) procollagen genes map to 2q24.3-q31. To the time of this
report, this was the only example of synteny of procollagen genes. Type
V collagen has 3 varieties of alpha chains. It has a specific
pericellular distribution and is not considered an interstitial
collagen. It is thought also to provide an inner core for large collagen
fibers. Thus, collagen V may aid in the orientation of large diameter
fibers. By in situ hybridization and analysis of DNA from somatic cell
hybrids, Huerre-Jeanpierre et al. (1986) obtained results consistent
with the assignment of COL5A2 to 2q24.3-q31 by Emanuel et al. (1985).
Tsipouras et al. (1988) demonstrated that the COL3A1 locus (120180) and
the COL5A2 locus are very close together; they found a maximum lod score
of 9.33 at a recombination fraction of 0.00.

The tissue-specific organization of collagen molecules into
tridimensional macroaggregates determines the physiomechanical
properties of most connective tissues. It had been postulated that
quantitatively minor types V and XI collagen regulate the growth of type
I and type II collagen fibrils, respectively. To test this hypothesis,
Andrikopoulos et al. (1995) created mice homozygous for deletion of the
Col5a2 gene. These mice survived poorly, possibly because of
complications from spinal deformities, and exhibited skin and eye
abnormalities caused by disorganized type I collagen fibrils.

*FIELD* SA
Huerre-Jeanpierre et al. (1985); Sage and Bornstein (1979); Tsipouras
et al. (1986); van der Rest et al. (1985)
*FIELD* RF
1. Andrikopoulos, K.; Liu, X.; Keene, D. R.; Jaenisch, R.; Ramirez,
F.: Targeted mutation in the col5a2 gene reveals a regulatory role
for type V collagen during matrix assembly. Nature Genet. 9: 31-36,
1995.

2. Brown, R. A.; Weiss, J. B.: Type V collagen: possible shared identity
of alpha-A, alpha-B and alpha-C chains. FEBS Lett. 106: 71-75, 1979.

3. Burgeson, R. E.; El Adli, F. A.; Kaitila, I. J.; Hollister, D.
W.: Fetal membrane collagens: identification of two new collagen
alpha chains. Proc. Nat. Acad. Sci. 73: 2579-2583, 1976.

4. Emanuel, B. S.; Cannizzaro, L. A.; Seyer, J. M.; Myers, J. C.:
Human alpha-1(III) and alpha-2(V) procollagen genes are located on
the long arm of chromosome 2. Proc. Nat. Acad. Sci. 82: 3385-3389,
1985.

5. Huerre-Jeanpierre, C.; Henry, I.; Bernard, M.; Gallano, P.; Weil,
D.; Grzeschik, K.-H.; Ramirez, F.; Junien, C.: The pro-alpha-2(V)
collagen gene (COL5A2) maps to 2q14-2q32, syntenic to the pro-alpha-1(III)
collagen locus (COL3A1). Hum. Genet. 73: 64-67, 1986.

6. Huerre-Jeanpierre, C.; Henry, I.; Mattei, M. G.; Weil, D.; Grzeschik,
K. H.; Chu, M. L.; Bernard, M.; Ramirez, F.; Junien, C.: The gene
for human alpha-1 type III collagen (COL3A1) is physically linked
to alpha-2 type V collagen COL5A2 on chromosome 2 (2q31-2q323). (Abstract) Cytogenet.
Cell Genet. 40: 657 only, 1985.

7. Sage, H.; Bornstein, P.: Characterization of a novel collagen
chain in human placenta and its relation to AB collagen. Biochemistry 18:
3815-3822, 1979.

8. Tsipouras, P.; Schwartz, R. C.; Liddell, A.; Weil, D.; Chu, M.-L.;
Ramirez, F.: Genetic distance of two collagen loci located on chromosome
2. (Abstract) 7th Int. Cong. Hum. Genet., Berlin 609-610, 1986.

9. Tsipouras, P.; Schwartz, R. C.; Liddell, A. C.; Salkeld, C. S.;
Weil, D.; Ramirez, F.: Genetic distance of two fibrillar collagen
loci, COL3A1 and COL5A2, located on the long arm of human chromosome
2. Genomics 3: 275-277, 1988.

10. van der Rest, M.; Niyibizi, C.; Fietzek, P. P.: Human placental
alpha-1(V)alpha-2(V)alpha-3(V) and [alpha-1(V)]-2-alpha-2(V) collagen
heterotrimers. Ann. N.Y. Acad. Sci. 460: 517-519, 1985.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
joanna: 11/12/1996
mark: 1/5/1996
terry: 1/3/1996
terry: 12/26/1995
supermim: 3/16/1992
carol: 10/1/1991
carol: 8/24/1990
supermim: 3/20/1990
ddp: 10/26/1989
root: 11/11/1988

*RECORD*
*FIELD* NO
120200
*FIELD* TI
*120200 COLOBOMA OF IRIS, CHOROID AND RETINA; COI
*FIELD* TX
Typical isolated ocular coloboma is a congenital abnormality caused by
defective closure of the embryonic fissure of the optic cup. The defect
is typically located in the lower part of the iris. Pedigrees supporting
dominant inheritance have been reported. Eldridge (1967) observed an
affected family with dominant pedigree pattern. Snell (1908) observed 12
cases in 5 generations. Optic nerve coloboma (120430) may be due to the
same mutation. Arias et al. (1984) studied a patient with de novo
deletion of 2p25.1-2pter. ACP1 (171500) and MDH1 (154200) levels were
normal, suggesting that these loci are proximal to 2p25.1. The child had
bilateral coloboma of the iris. Coloboma is a prime feature of the
CHARGE association (see 214800). Pagon et al. (1981) suggested autosomal
recessive inheritance. Barros-Nunez et al. (1995) described a 6-year-old
boy in whom bilateral iris coloboma had been observed at birth.
Psychomotor development was normal. He showed a typical inferonasal
bilateral coloboma of the iris and ciliary body without coloboma of the
choroid and retina or optic nerve. Retina, lens, corneal diameters, and
visual acuity were normal in both eyes and there were no malformations
elsewhere. A male and female first cousin of the proband related through
their fathers had iris coloboma and the son of a sister of the father of
the proband had unilateral coloboma. The parents in the case of all 3
sibships were normal as were the grandparents. Some unusual molecular
mechanism, such as trinucleotide expansion, was suggested, giving the
picture of 'delayed mutation' or 'premutation.'

*FIELD* SA
Francois  (1961)
*FIELD* RF
1. Arias, S.; Rolo, M.; Gonzalez, N.: Terminal deletion of the short
arm of chromosome 2, informative for acid phosphatase (ACP1), malate
dehydrogenase (MDH1), and coloboma of iris loci.  (Abstract) Cytogenet.
Cell Genet. 37: 401 only, 1984.

2. Barros-Nunez, P.; Medina, C.; Mendoza, R.; Sanchez-Corona, J.;
Garcia-Cruz, D.: Unexpected familial recurrence of iris coloboma:
a delayed mutation mechanism?. Clin. Genet. 48: 160-161, 1995.

3. Eldridge, R.: Personal Communication. Bethesda, Md.  1967.

4. Francois, J.: Heredity in Ophthalmology.  St. Louis: C. V. Mosby
(pub.)  1961. Pp. 149-152.

5. Pagon, R. A.; Kalina, R. E.; Lechner, D. J.: Possible autosomal-recessive
ocular coloboma. Am. J. Med. Genet. 9: 189-193, 1981.

6. Snell, S.: Carcinoma of orbit originating in a Meibomian gland.
Trans. Ophthal. Soc. U.K. 28: 144-147, 1908.

*FIELD* CS

Eyes:
   Coloboma of iris, choroid and retina

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 10/2/1995
davew: 8/15/1994
mimadm: 6/25/1994
carol: 4/28/1994
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120210
*FIELD* TI
*120210 COLLAGEN, TYPE IX, ALPHA-1; COL9A1
COLLAGEN, CARTILAGE-SPECIFIC SHORT;;
ALPHA-1(IX) COLLAGEN CHAIN;;
CARTILAGE-SPECIFIC SHORT COLLAGEN
*FIELD* TX
Type II collagen (120140) represents about 85% of the collagen of
hyaline cartilage. In addition to it, there are several minor collagens.
Using a cDNA library made from chick embryo sternal cartilage mRNA,
Ninomiya and Olsen (1984) isolated and characterized a cDNA that codes
for one of these. The unusual qualities of the molecule for which it
codes included a length of only about half that of pro-alpha-1 chains
and the presence of short, noncollagenous peptides containing cysteinyl
residues separating its 3 collagenous domains. The cartilage-specific
collagen is enumerated as type IX. Its function is unknown (Mayne et
al., 1985). The triple helix of type IX collagen is composed of 3
genetically distinct polypeptide subunits--alpha-1(IX), alpha-2(IX), and
alpha-3(IX). These are the products of genes whose exon structure is
different from that of fibrillar collagens. Type IX collagen is also a
proteoglycan. Chondroitin sulfate and dermatan sulfate chains are
covalently linked to the alpha-2(IX) chain. McCormick et al. (1987)
described the structure of the glycosaminoglycan attachment site. By a
combination of cDNA and peptide sequencing, they showed that the
attachment region contains the sequence gly-ser-ala-asp, located within
the noncollagenous domain of the alpha-2(IX) chain. The exon coding for
the attachment site in the alpha-2 gene is 48 bp long, whereas the
homologous alpha-1 exon is 33 bp long. The extra sequence in the alpha-2
molecule provides an explanation for the kink observed at that site in
type IX molecules when examined by electron microscopy. The inserted
block of amino acid residues also provides the alpha-2 chain with a
serine residue, not present in alpha-1 chains, that serves as attachment
site for a glycosaminoglycan side chain. Eyre et al. (1987) concluded
that type IX collagen molecules are covalently crosslinked in cartilage
to molecules of type II collagen.

Kimura et al. (1989) described the primary structure of type IX collagen
of rat and human based on cloning and sequencing of cDNA from cDNA
libraries. By in situ hybridization, they demonstrated that the COL9A1
gene is located in the proximal portion of the long arm of chromosome 6
(6q12-q14), probably at 6q13. By analysis of a panel of somatic cell
hybrids containing various parts of chromosome 6, Boyle et al. (1992)
confirmed the assignment to 6q12-q14. Muragaki et al. (1990)
demonstrated that mouse and human RNAs contain 2 types of COL9A1
transcripts based on the presence of 2 translation start codons located
within 2 alternative exons. Warman et al. (1993) confirmed the mapping
of COL9A1 to 6q12-q13 by fluorescence in situ hybridization and, using
an interspecific backcross panel, mapped murine Col9a1 to mouse
chromosome 1.

Nakata et al. (1993) generated transgenic mice expressing a truncated
alpha-1(IX) chain, which was expected to interfere with stable triple
helix formation and act as a trans-dominant mutation. Mice heterozygous
for the transgene developed osteoarthritis in the articular cartilage of
knee joints, while mice homozygous for the mutation developed mild
chondrodysplasia as well. The phenotypic severity correlated well with
the level of transgene expression. Jacenko et al. (1994) interpreted
these findings in mice with a dominant negative mutation in Col9a1, as
well as the observation that mice with a homozygous null mutation in the
gene have an unexpectedly mild phenotype, as indicating that type IX
collagen is not essential for the assembly of the cartilage
extracellular matrix, although it may be important in the maintenance of
structural integrity.

*FIELD* RF
1. Boyle, J. M.; Hey, Y.; Myers, K.; Stern, P. L.; Grzeschik, F.-H.;
Ikehara, Y.; Misumi, Y.; Fox, M.: Regional localization of a trophoblast
antigen-related sequence and 16 other sequences to human chromosome
6q using somatic cell hybrids. Genomics 12: 693-698, 1992.

2. Eyre, D. R.; Apon, S.; Wu, J.-J.; Ericsson, L. H.; Walsh, K. A.
: Collagen type IX: evidence for covalent linkages to type II collagen
in cartilage. FEBS Lett. 220: 337-341, 1987.

3. Jacenko, O.; Olsen, B. R.; Warman, M. L.: Of mice and men: heritable
skeletal disorders.  (Editorial) Am. J. Hum. Genet. 54: 163-168,
1994.

4. Kimura, T.; Mattei, M.-G.; Stevens, J. W.; Goldring, M. B.; Ninomiya,
Y.; Olsen, B. R.: Molecular cloning of rat and human type IX collagen
cDNA and localization of the alpha1(IX) gene on the human chromosome
6. Europ. J. Biochem. 179: 71-78, 1989.

5. Mayne, R.; van der Rest, M.; Ninomiya, Y.; Olsen, B. R.: The structure
of type IX collagen. Ann. N.Y. Acad. Sci. 460: 38-46, 1985.

6. McCormick, D.; van der Rest, M.; Goodship, J.; Lozano, G.; Ninomiya,
T.; Olsen, B. R.: Structure of the glycosaminoglycan domain in the
type IX collagen-proteoglycan. Proc. Nat. Acad. Sci. 84: 4044-4048,
1987.

7. Muragaki, Y.; Nishimura, I.; Henney, A.; Ninomiya, Y.; Olsen, B.
R.: The alpha-1(IX) collagen gene gives rise to two different transcripts
in both mouse embryonic and human fetal RNA. Proc. Nat. Acad. Sci. 87:
2400-2404, 1990.

8. Nakata, K.; Ono, K.; Miyazaki, J.; Olsen, B. R.; Muragaki, Y.;
Adachi, E.; Yamamura, K.; Kimura, T.: Osteoarthritis associated with
mild chondrodysplasia in transgenic mice expressing alpha-1(IX) collagen
chains with a central deletion. Proc. Nat. Acad. Sci. 90: 2870-2874,
1993.

9. Ninomiya, Y.; Olsen, B. R.: Synthesis and characterization of
cDNA encoding a cartilage-specific short collagen. Proc. Nat. Acad.
Sci. 81: 3014-3018, 1984.

10. Warman, M. L.; Tiller, G. E.; Polumbo, P. A.; Seldin, M. F.; Rochelle,
J. M.; Knoll, J. H. M.; Cheng, S.-D.; Olsen, B. R.: Physical and
linkage mapping of the human and murine genes for the alpha-1 chain
of type IX collagen (COL9A1). Genomics 17: 694-698, 1993.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
joanna: 04/18/1996
carol: 2/9/1995
jason: 6/7/1994
mimadm: 3/28/1994
carol: 9/21/1993
carol: 5/21/1993
carol: 6/2/1992

*RECORD*
*FIELD* NO
120215
*FIELD* TI
*120215 COLLAGEN, TYPE V, ALPHA-1 POLYPEPTIDE; COL5A1
*FIELD* TX
Type V collagen was first identified in human placenta and adult skin,
but later studies showed that it is present in many other tissues and
organs as a minor collagen component. Type V collagen occurs as
heterotrimers of 3 different polypeptide chains, alpha-1, alpha-2, and
alpha-3, or 2 copies of alpha-1 and 1 copy of alpha-2; or it occurs as a
homotrimer of alpha-1 polypeptides. Takahara et al. (1991) reported the
sequence of cDNA encoding the complete prepro-alpha-1(V) chain. The
collagenous region and COOH-terminal noncollagenous region closely
resembled that of the alpha-1(XI) (120280) chain; however, codon usage
differed, suggesting that the COL5A1 gene is evolutionarily distinct.

Using cDNA and genomic clones for the COL5A1 gene as probes, Greenspan
et al. (1992) determined in panels of human-mouse hybrid cell lines and
by in situ hybridization experiments that the COL5A1 gene is located in
the segment 9q34.2-q34.3. They noted that this is the area in which the
nail-patella syndrome (161200) maps. Studies of linkage between this
gene and the nail-patella gene, as well as searches for abnormalities in
the COL5A1 gene in nail-patella families, will be of interest. Caridi et
al. (1992) likewise assigned the COL5A1 gene to 9q34.3 by in situ
hybridization. Mattei et al. (1993) found that the homologous gene in
the mouse is located in the A2-B region of chromosome 2. They
independently confirmed the localization of the human gene to 9q34. Pilz
et al. (1994) likewise mapped the mouse gene to chromosome 2.

Takahara et al. (1995) determined the complete genomic structure of
COL5A1 and showed that the gene is more complex than other fibrillar
collagen genes, having 66 exons compared to 52. The gene spans at least
750 kb.

Fichard et al. (1994) reviewed collagens V and XI and commented on their
fundamental role in the control of fibrillogenesis, probably by forming
a core within the fibrils. Another characteristic of these collagens is
the partial retention of their N-propeptide extensions in tissue forms,
which is unusual for known fibrillar collagens. The tissue locations of
collagen V and XI are different, but their structural and biologic
properties seem to be closely related. Their primary structures are
highly conserved at both the gene and the protein level, and this
conservation is the basis of their similar biologic properties. In
particular, they are both resistant to mammalian collagenases, and
surprisingly sensitive to trypsin. Although they have both cell adhesion
and heparin binding sites that could be crucial in physiologic processes
such as development and wound healing, the 2 collagens are usually
buried within the major collagen fibrils. It had become evident that
several collagen-type molecules are, in fact, heterotypic associations
of chains from both collagens V and XI, demonstrating that these 2
collagens are not distinct types but a single type that can be called
collagen V/XI.

Nicholls et al. (1994) identified molecular abnormalities in type V
collagen in 2 patients with Ehlers-Danlos syndrome. The first patient,
with overlapping clinical features of both E-D I/II and E-D VII and
additional unusual corneal abnormalities, showed a G(+3)-to-T change in
the 5-prime splice site leading to deletion of the upstream exon
(120215.0001). The inframe 54-bp deletion eliminated 6 gly-X-Y triplets
from the triple helical domain. The second patient also showed clinical
features of E-D I/II and had, in addition, vascular weakness similar to
the E-D IV subtype. Both the alpha-1 and the alpha-2 chains of type V
collagen ran with lower mobility than normal on SDS-page gels,
indicative of excessive posttranslational modification of the protein
due to a point mutation in 1 of the protein chains.

Greenspan et al. (1995) used 3-prime-untranslated region RFLPs to
exclude the COL5A1 gene as a candidate in families with tuberous
sclerosis-1 (191100), Ehlers-Danlos syndrome type II (EDS II; 130010),
and the nail-patella syndrome (161200). In addition, they described a
polymorphic simple sequence repeat (SSR) within a COL5A1 intron. They
used this SSR to exclude COL5A1 as a candidate gene also in hereditary
hemorrhagic telangiectasia (187300), and to add COL5A1 to the index
markers of chromosome 9 by evaluation of the COL5A1 locus on the CEPH
40-family reference pedigree set. This genetic mapping placed COL5A1
between markers D9S66 and D9S67.

Using an intragenic simple sequence repeat polymorphism of the COL5A1
gene as a linkage marker, Loughlin et al. (1995) showed linkage to
Ehlers-Danlos syndrome, type II; maximum lod = 8.3 at theta = 0.00 in a
single large pedigree. The inconsistency of these results with those of
Greenspan et al. (1995) may be explained by the fundamental
heterogeneity of EDS II. It is possible, for example, that some forms of
the syndrome are due to mutation in the COL5A2 (120190) or COL5A3
(120216) gene.

Using a polymorphic intragenic simple sequence repeat at the COL5A1
locus, Burrows et al. (1996) demonstrated tight linkage to EDS I/II in a
3-generation family, giving a lod score of 4.07 at zero recombination.
The variation in expression in this family suggested that EDS types I
(EDS1; 130000) and II are allelic, and the linkage data supported the
hypothesis that mutation in COL5A1 can cause both phenotypes. That this
was indeed the case was demonstrated by Nicholls et al. (1996) who, in a
patient with clinical features of Ehlers-Danlos syndrome type I/II, and
VII, demonstrated an exon-skipping mutation in the COL5A1 gene
(120215.0001).

Wenstrup et al. (1996) reported 2 families in which EDS I cosegregated
with the COL5A1 gene. In 2 other families with EDS I, linkage was
excluded from both the COL5A1 and the COL5A2 loci. Wenstrup et al.
(1996) demonstrated that affected individuals in one of the EDS I
COL5A1-linked families were heterozygous for a 4-bp deletion in intron
65 (120215.0002). This deletion led to a 234-bp deletion of exon 65 in
the processed mRNA for pro-alpha-1(V) collagen.

De Paepe et al. (1997) likewise identified a mutation in COL5A1
segregating with EDS I in a 4-generation family (120215.0003). In
addition, they detected splicing defects in the COL5A1 gene in a patient
with EDS I and in a family with EDS II (120215.0005). Thus they proved
that EDS I and II are allelic disorders.

*FIELD* AV
.0001
EHLERS-DANLOS SYNDROME, MIXED TYPE
COL5A1, IVS49DS, G-T, +3
Nicholls et al. (1996) demonstrated a defect in COL5A1 in a 24-year-old
woman with many features of the Ehlers-Danlos syndrome. She showed
generalized skin fragility with extensive scarring of the forehead,
shins, and knees, and scattered bruising on the arms and legs. She had
marked generalized joint laxity with severe bilateral hallux valgus and
diamond-shaped feet. She was short (155 cm), with mild thoracic
kyphoscoliosis, pectus excavatum, and audible mitral valve prolapse. The
eyes were unusually prominent and ophthalmologic examination
demonstrated hypermetropia caused by flattened corneas. Because of the
short stature and scoliosis the differential diagnosis initially favored
EDS VII (225410), but the cutaneous fragility and other features were
also consistent with EDS types I and II. Electron microscopy of skin
tissue indicated abnormal collagen fibrillogenesis with longitudinal
sections showing a marked disruption of fibril packing, giving very
irregular outlines to transverse sections. Nicholls et al. (1996)
analyzed the collagens produced by cultured fibroblasts and found that
the type V collagen had a population of alpha-1(V) chains shorter than
normal. Peptide mapping suggested a deletion within the triple helical
domain. RT-PCR amplification of mRNA covering the whole of this domain
of COL5A1 showed a deletion of 54 bp. Takahara et al. (1995) had
reported that the forty-ninth exon is 54 bp in length. Nicholls et al.
(1996) stated that, although 6 gly-X-Y triplets were lost from the
domain, the essential triplet amino acid sequence and C-propeptide
structure were maintained, allowing mutant protein chains to be
incorporated into triple helices. Genomic DNA analysis identified a de
novo G-to-T transversion at position +3 in a 5-prime splice site of 1
COL5A allele. The authors noted that similar mutations causing exon
skipping in the major collagen genes, COL1A1, COL1A2, and COL3A1, have
been identified in several cases of osteogenesis imperfecta and EDS type
IV. These observations supported the hypothesis that type V, although
quantitatively a minor collagen, has a critical role in the formation of
fibrillar collagen matrix.

.0002
EHLERS-DANLOS SYNDROME, TYPE I
COL5A1, IVS65DS, 4-BP DEL, +3 TO +6
In 2 families with EDS type I linked to the COL5A1 gene, Wenstrup et al.
(1996) reported a 4-bp deletion of nucleotides +3 to +6 in intron 65.
The mutation caused a 234-bp deletion of exon 65 in the processed mRNA.
They reported that this inframe mutation predicts a pro-alpha-1(V) chain
in which the C-propeptide is shortened by 78 amino acids. They noted
that the deleted segment contains 2 of 8 highly conserved cysteine
residues that are thought to participate in disulfhydryl bonds and
facilitate chain association during molecular assembly.

.0003
EHLERS-DANLOS SYNDROME, TYPE I
COL5A1, CYS1181SER
De Paepe et al. (1997) identified a G-to-T transversion in the codon for
cysteine-1181 (TGC) to the codon for serine (TCC). This represented a
substitution of the most 5-prime cysteine residue within a highly
conserved sequence of the C-propeptide domain of the pro-alpha-1(V)
chain. The mutation thus caused reduction of collagen V by preventing
incorporation of the mutant chains in the collagen V trimers. The
patients were members of a family in which 7 members of 4 generations
were affected with typical changes of type I EDS.

.0004
EHLERS-DANLOS SYNDROME, TYPE I
COL5A1, EX42 DEL, SPLICE MUTATION
De Paepe et al. (1997) identified a splicing mutation in a 13-year-old
girl with classic features of EDS I occurring in her as a de novo
mutation. She was born prematurely after premature rupture of membranes
with an umbilical hernia and bilateral dislocation of the hips. A
deletion of exon 42 was demonstrated, resulting in the loss of
approximately 100 bp. The mutation causing the deletion of exon 42
remained to be defined, as no sequence abnormalities in exon 42 or in
the flanking 3-prime and 5-prime splice sites or the branch site were
found.

.0005
EHLERS-DANLOS SYNDROME, TYPE II
COL5A1, IVS64AS, T-A, -11
De Paepe et al. (1997) found a splicing mutation in the COL5A1 gene in a
man in whom type II EDS had been diagnosed at the age of 23 years
because of a history of easy bruising and abnormal scarring and several
luxations of the ankles while playing basketball. At age 32 years, he
presented with moderate skin hyperextensibility and joint laxity and
several pigmented paper scars on knees and shins. His 2 affected sons,
aged 9 and 16 years, showed mild skin hyperextensibility, hyperlaxity of
several joints, poor wound healing, and several ecchymoses and atrophic
scars on the lower legs. A T-to-A transversion was found at position -11
of the 3-prime splice site of exon 65. The mutation caused abnormal
splicing of the COL5A1 gene yielding 2 different mRNA products. One mRNA
contained a 9-bp insertion because of the use of a new 3-prime splice
site within IVS64. The second mRNA contained a deletion of 45
nucleotides at the 3-prime end of exon 65 because of the use of a
crytpic splice site within exon 65. The mutation created a BsrI
restriction site, which allowed De Paepe et al. (1997) to confirm the
presence of the mutation in the affected sons and absence of the
mutation in 30 control individuals.

*FIELD* RF
1. Burrows, N. P.; Nicholls, A. C.; Yates, J. R. W.; Gatward, G.;
Sarathachandra, P.; Richards, A.; Pope, F. M.: The gene encoding
collagen alpha-1(V) (COL5A1) is linked to mixed Ehlers-Danlos syndrome
type I/II. J. Invest. Derm. 106: 1273-1276, 1996.

2. Caridi, G.; Pezzolo, A.; Bertelli, R.; Gimelli, G.; Di Donato,
A.; Candiano, G.; Ghiggeri, G. M.: Mapping of the human COL5A1 gene
to chromosome 9q34.3. Hum. Genet. 90: 174-176, 1992.

3. De Paepe, A.; Nuytinck, L.; Hausser, I.; Anton-Lamprecht, I.; Naeyaert,
J.-M.: Mutations in the COL5A1 gene are causal in the Ehlers-Danlos
syndromes I and II. Am. J. Hum. Genet. 60: 547-554, 1997.

4. Fichard, A.; Kleman, J.-P.; Ruggiero, F.: Another look at collagen
V and XI molecules. Matrix Biol. 14: 515-531, 1994.

5. Greenspan, D. S.; Byers, M. G.; Eddy, R. L.; Cheng, W.; Jani-Sait,
S.; Shows, T. B.: Human collagen gene COL5A1 maps to the q34.2-q34.3
region of chromosome 9, near the locus for nail-patella syndrome. Genomics 12:
836-837, 1992.

6. Greenspan, D. S.; Northrup, H.; Au, K.-S.; McAllister, K. A.; Francomano,
C. A.; Wenstrup, R. J.; Marchuk, D. A.; Kwiatkowski, D. J.: COL5A1:
fine genetic mapping and exclusion as candidate gene in families with
nail-patella syndrome, tuberous sclerosis 1, hereditary hemorrhagic
telangiectasia, and Ehlers-Danlos syndrome type II. Genomics 25:
737-739, 1995.

7. Loughlin, J.; Irven, C.; Hardwick, L. J.; Butcher, S.; Walsh, S.;
Wordsworth, P.; Sykes, B.: Linkage of the gene that encodes the alpha-1
chain of type V collagen (COL5A1) to type II Ehlers-Danlos syndrome
(EDS II). Hum. Molec. Genet. 4: 1649-1651, 1995.

8. Mattei, M. G.; Bruce, B.; Karsenty, G.: Mouse alpha-1 type V collagen
gene maps to the [A2-B] region of chromosome 2. Genomics 16: 786-788,
1993.

9. Nicholls, A. C.; McCarron, S.; Narcisi, P.; Pope, F. M.: Molecular
abnormalities of type V collagen in Ehlers Danlos syndrome (Abstract) Am.
J. Hum. Genet. 55 (suppl.): A233, 1994.

10. Nicholls, A. C.; Oliver, J. E.; McCarron, S.; Harrison, J. B.;
Greenspan, D. S.; Pope, F. M.: An exon skipping mutation of a type
V collagen gene (COL5A1) in Ehlers-Danlos syndrome. J. Med. Genet. 33:
940-946, 1996.

11. Pilz, A.; Prohaska, R.; Peters, J.; Abbott, C.: Genetic linkage
analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notch1
genes in the region of mouse chromosome 2 homologous to human chromosome
9q. Genomics 21: 104-109, 1994.

12. Takahara, K.; Hoffman, G. G.; Greenspan, D. S.: Complete structural
organization of the human alpha-1(V) collagen gene (COL5A1): divergence
from the conserved organization of other characterized fibrillar collagen
genes. Genomics 29: 588-597, 1995.

13. Takahara, K.; Sato, Y.; Okazawa, K.; Okamoto, N.; Noda, A.; Yaoi,
Y.; Kato, I.: Complete primary structure of human collagen alpha-1(V)
chain. J. Biol. Chem. 266: 13124-13129, 1991.

14. Wenstrup, R. J.; Langland, G. T.; Willing, M. C.; D'Souza, V.
N.; Cole, W. G.: A splice-junction mutation in the region of COL5A1
that codes for the carboxyl propeptide of pro-alpha-1(V) chains results
in the gravis form of the Ehlers-Danlos syndrome (type I). Hum. Molec.
Genet. 5: 1733-1736, 1996.

*FIELD* CN
Victor A. McKusick - updated: 3/12/1997
Moyra Smith - updated: 1/29/1997
Alan F. Scott - updated: 11/8/1995

*FIELD* CD
Victor A. McKusick: 10/1/1991

*FIELD* ED
terry: 03/17/1997
terry: 3/12/1997
terry: 3/11/1997
mark: 1/29/1997
terry: 1/28/1997
mark: 1/28/1997
terry: 1/27/1997
jamie: 1/21/1997
terry: 1/14/1997
terry: 11/15/1996
terry: 11/6/1996
terry: 9/4/1996
terry: 4/22/1996
mark: 12/15/1995
terry: 12/6/1995
mark: 10/13/1995
terry: 11/18/1994
jason: 6/7/1994
carol: 7/13/1993
carol: 6/4/1993

*RECORD*
*FIELD* NO
120216
*FIELD* TI
*120216 COLLAGEN, TYPE V, ALPHA-3 POLYPEPTIDE; COL5A3
*FIELD* TX
See 120215.

*FIELD* CD
Victor A. McKusick: 10/1/1991
*FIELD* ED
supermim: 3/16/1992
carol: 10/1/1991
*RECORD*
*FIELD* NO
120220
*FIELD* TI
*120220 COLLAGEN, TYPE VI, ALPHA-1 CHAIN; COL6A1
COLLAGEN, INTIMAL;;
SHORT-CHAIN COLLAGEN
*FIELD* TX
Chung et al. (1976) isolated a collagen from the intima of human aorta
that differs from types IV and V collagen. Seemingly, the same collagen
was isolated from bovine placenta by Jander et al. (1981) and from human
placenta by Furuto and Miller (1981). It is cysteine-rich and appears to
have 3 peptides: a single relatively acidic peptide plus 2 more basic
peptides. Type VI collagen appears to be unusual among collagens in the
small size of its collagenous domains and in its supramolecular
structure. It has been called 'short-chain collagen.' It is relatively
resistant to bacterial collagenase and has a glycine content less than
one-third of the protein, suggesting interrupted helical regions.
Electron microscopy shows additional unique features. Collagen VI is a
component of microfibrillar structures in many tissues (Engel et al.,
1985). These microfibrils localize close to cells, nerves, blood
vessels, and large collagen fibrils and are considered to have an
anchoring function. Consistent with such a function are the biochemical
findings that type VI collagen binds cells and that its fusion protein
binds type I collagen. The binding activity also implies that, in
addition to a structural role, type VI collagen may be involved in cell
migration and differentiation and embryonic development.

Trueb and Winterhalter (1986) showed that type VI collagen consists of 2
different 140-kD subunits (alpha-1 and alpha-2) and a 200-kD subunit
(alpha-3). The alpha-3(VI) chain is synthesized by cells in culture as a
precursor of 260 kD, while no precursor forms of the other 2 chains
could be detected. Working with pepsin-solubilized collagen VI from
human placenta, Chu et al. (1987) characterized the 3 constituent chains
by peptide-sequences and cDNA clones.

By somatic cell hybrid analysis and in situ hybridization, Weil et al.
(1988) localized the alpha-1 and alpha-2 collagen VI genes to chromosome
21q22.3 and the alpha-3(VI) gene (120250) to chromosome 2q37. By
Southern hybridization analysis of DNA from Chinese hamster-human
somatic cell hybrids segregating different portions of human chromosome
21, Cutting et al. (1988) showed that COL6A1 and COL6A2 map distal to
the locus D21S3. Linkage analysis in 40 CEPH families showed 12.5%
recombination between COL6A1 and ETS2 (164740). No recombinants were
observed between COL6A1 and COL6A2. Recombinants between the Marfan
phenotype (154700) and COL6A1 markers in 3 families excluded mutation of
COL6A1 (and A2) as the cause of the Marfan syndrome. By pulsed field gel
electrophoresis (PFGE), Cutting et al. (1988) showed that COL6A1 and
COL6A2 hybridized to the same size restriction fragments, the smallest
of which was 205 kb. Petersen et al. (1991) presented a genetic linkage
map of chromosome 21 involving 27 markers (10 genes and 17 anonymous
sequences). The length of the male map was 132 cM and of the female map
161 cM. In both sexes, approximately one-half of the crossovers occurred
distally in terminal band 21q22.3, which also contained 16 of the
markers studied, including 8 of the 10 genes. Band 21q22.3 spans about
75 cM in the female map. The Petersen map illustrated the inhomogeneity
in the distribution of genes in the genome, with a concentration of
genes in Giemsa-light bands and near the ends of chromosomes. Francomano
et al. (1991) used PFEG and somatic cell hybrids to demonstrate that
COL6A1 and COL6A2 form a gene cluster on the most distal part of
chromosome 21. They detected several DNA polymorphisms (both restriction
site and VNTRs) associated with these loci. Using a slot-blot method for
the dosage of single copy sequences, Delabar et al. (1992) assessed the
copy number of 30 chromosome 21 markers in the blood DNA of 11 patients
with partial trisomy or monosomy 21. The physical order of the markers
on chromosome 21 was thereby determined. The results showed that COL6A1
and S100B (176990) were in the most terminal region, with CD18 (116920)
in the penultimate segment of 21q and PFKL (171860) in the next segment
toward the centromere. Using a single interspecific backcross, Justice
et al. (1990) mapped the homologous gene to mouse chromosome 10 and
determined its location relative to 17 other markers.

Murata et al. (1987) found predominant production of type VI collagen by
the tumors in a patient with 'multiple fibromatosis occurring at the
sites of multiple cartilaginous dysplasia.' They stated that the patient
had 'a hereditary disease, with regions of multiple articular dysplasia
surrounded by numerous protuberant tumors. Elastic globe-shaped tumors,
weighed (sic) about 100 g., were removed from his cervical regions at
operation.' The age of the patient was not given, and the nature of the
ailment is unclear.

Davies et al. (1995) studied genetic variation in the COL6A1/COL6A2 gene
cluster on chromosome 21 in 113 controls and 58 European families
(including control and family subgroups of British/Irish origin) having
a child with trisomy 21. They found statistically significant
differences among subgroups of trisomy children with and without
congenital heart defects in distributions of definitive, 3-RFLP
haplotype classes received from their nondisjoining and disjoining
parents. The haplotypes received by trisomy children with congenital
heart defects from the disjoining parents were not a random sample of
controls' haplotypes. Analysis of parental single-RFLP genotypes and
linkage disequilibrium patterns confirmed this parent subgroup differed
from a random sample of controls. There was no significant difference in
parent subgroup genotype distribution at any of 9 control loci
distributed along chromosome 21q. The study by Davies et al. (1995)
showed an association between genetic variation in the COL6A1 region and
congenital heart defects in trisomy 21.

By high-resolution fluorescence in situ hybridization (FISH) techniques,
Heiskanen et al. (1995) determined the distance separating the COL6A1
and COL6A2 genes (150 kb), the size of the COL6A1 gene (29 kb), and the
5-prime/3-prime orientation of these genes. By fiber-FISH, they showed
that the orientation is 5-prime COL6A1 3-prime/5-prime COL6A2 3-prime.
This appeared to be the first collagen gene pair found to be in a
head-to-tail configuration. Other closely located collagen gene pairs
are either in a head-to-head configuration (type IV collagen genes) with
a common promoter region or in a tail-to-tail configuration (COL3A1 and
COL5A2) on chromosome 2q.

In 9 kindreds with the Bethlem form of autosomal dominant myopathy with
contractures (158810), Jobsis et al. (1996) demonstrated genetic linkage
to the COL6A1-COL6A2 cluster on 21q22.3. By sequence analysis in 4
families Jobsis et al. (1996) identified a mutation in COL6A1
(120220.0001) in 1 and a COL6A2 mutation (120240.0001) in 2 other
kindreds. Both mutations disrupted the gly-X-Y motif of the triple
helical domain by substitution of gly for either val or ser. Analogous
to the putative perturbation of the anchoring function of the
dystrophin-associated complex in congenital muscular dystrophy with
mutations in the alpha-2-subunit of laminin (156225), the observation
suggested to the authors a similar mechanism in Bethlem myopathy.

*FIELD* AV
.0001
BETHLEM MYOPATHY
COL6A1, GLY286VAL
In a kindred with Bethlem myopathy, Jobsis et al. (1996) demonstrated
that affected members had a heterozygous missense mutation 962G-T
resulting in a G286V amino acid substitution in the triple helical
domain of COL6A1.

*FIELD* SA
Hessle and Engvall (1984); Jobsis et al. (1996)
*FIELD* RF
1. Chu, M.-L.; Mann, K.; Deutzmann, R.; Pribula-Conway, D.; Hsu-Chen,
C.-C.; Bernard, M. P.; Timpl, R.: Characterization of three constituent
chains of collagen type VI by peptide sequences and cDNA clones. Europ.
J. Biochem. 168: 309-317, 1987.

2. Chung, E.; Rhodes, R. K.; Miller, E. J.: Isolation of three collagenous
components of probable basement membrane origin from several tissues. Biochem.
Biophys. Res. Commun. 71: 1167-1174, 1976.

3. Cutting, G.; Francomano, C. A.; Chu, M. L.; Timpl, R.; McCormick,
M. K.; Warren, A. C.; Hong, H. K.; Pyeritz, R. E.; Antonarakis, S.
E.: Genetic linkage analysis and macrorestriction mapping of COL6A1
and COL6A2, structural genes of type VI collagen. (Abstract) Am.
J. Hum. Genet. 43: A141 only, 1988.

4. Davies, G. E.; Howard, C. M.; Farrer, M. J.; Coleman, M. M.; Bennett,
L. B.; Cullen, L. M.; Wyse, R. K. H.; Burn, J.; Williamson, R.; Kessling,
A. M.: Genetic variation in the COL6A1 region is associated with
congenital heart defects in trisomy 21 (Down's syndrome). Ann. Hum.
Genet. 59: 253-269, 1995.

5. Delabar, J.-M.; Chettouh, Z.; Rahmani, Z.; Theophile, D.; Blouin,
J.-L.; Bono, R.; Kraus, J.; Barton, J.; Patterson, D.; Sinet, P.-M.
: Gene-dosage mapping of 30 DNA markers on chromosome 21. Genomics 13:
887-889, 1992.

6. Engel, J.; Furthmayr, H.; Odermatt, E.; Von der Mark, H.; Aumailley,
M.; Fleishmajer, R.; Timpl, R.: Structure and macromolecular organization
of type VI collagen. Ann. N.Y. Acad. Sci. 460: 25-37, 1985.

7. Francomano, C. A.; Cutting, G. R.; McCormick, M. K.; Chu, M. L.;
Timpl, R.; Hong, H. K.; Antonarakis, S. E.: The COL6A1 and COL6A2
genes exist as a gene cluster and detect highly informative DNA polymorphisms
in the telomeric region of human chromosome 21q. Hum. Genet. 87:
162-166, 1991.

8. Furuto, D. K.; Miller, E. J.: Characterization of a unique collagenous
fraction from limited pepsin digests of human placental tissue: molecular
organization of the native aggregate. Biochemistry 20: 1635-1640,
1981.

9. Heiskanen, M.; Saitta, B.; Palotie, A.; Chu, M.-L.: Head to tail
organization of the human COL6A1 and COL6A2 genes by fiber-FISH. Genomics 29:
801-803, 1995.

10. Hessle, H.; Engvall, E.: Type VI collagen: studies on its localization,
structure, and biosynthetic form with monoclonal antibodies. J. Biol.
Chem. 259: 3955-3961, 1984.

11. Jander, R.; Rauterberg, J.; Voss, B.; von Bassewitz, D. B.: A
cysteine-rich collagenous protein from bovine placenta: isolation
of its constituent polypeptide chains and some properties of the non-denatured
protein. Europ. J. Biochem. 114: 17-25, 1981.

12. Jobsis, G. J.; Bolhuis, P. A.; Boers, J. M.; Baas, F.; Wolterman,
R. A.; Hensels, G. W.; de Visser, M.: Genetic localization of Bethlem
myopathy. Neurology 46: 779-782, 1996.

13. Jobsis, G. J.; Keizers, H.; Vreijling, J. P.; de Visser, M.; Speer,
M. C.; Wolterman, R. A.; Baas, F.; Bohlhuis, P. A.: Type VI collagen
mutations in Bethlem myopathy, an autosomal dominant myopathy with
contractures. Nature Genet. 14: 113-115, 1996.

14. Justice, M. J.; Siracusa, L. D.; Gilbert, D. J.; Heisterkamp,
N.; Groffen, J.; Chada, K.; Silan, C. M.; Copeland, N. G.; Jenkins,
N. A.: A genetic linkage map of mouse chromosome 10: localization
of eighteen molecular markers using a single interspecific backcross. Genetics 125:
855-866, 1990.

15. Murata, K.; Motoyama, T.; Suka, M.; Ohno, M.; Kuboki, Y.: High
production of type VI collagen in multiple fibromatosis with multiple
articular dysplasia. Biochem. Biophys. Res. Commun. 147: 275-281,
1987.

16. Petersen, M. B.; Slaugenhaupt, S. A.; Lewis, J. G.; Warren, A.
C.; Chakravarti, A.; Antonarakis, S. E.: A genetic linkage map of
27 markers on human chromosome 21. Genomics 9: 407-419, 1991.

17. Trueb, B.; Winterhalter, K. H.: Type VI collagen is composed
of a 200 kD subunit and two 140 kD subunits. EMBO J. 5: 2815-2819,
1986.

18. Weil, D.; Mattei, M.-G.; Passage, E.; Van Cong, N.; Pribula-Conway,
D.; Mann, K.; Deutzmann, R.; Timpl, R.; Chu, M.-L.: Cloning and chromosomal
localization of human genes encoding the three chains of type VI collagen. Am.
J. Hum. Genet. 42: 435-445, 1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 09/05/1996
terry: 9/3/1996
terry: 11/7/1995
mark: 10/19/1995
carol: 3/1/1993
carol: 12/23/1992
carol: 7/21/1992
carol: 6/17/1992

*RECORD*
*FIELD* NO
120240
*FIELD* TI
*120240 COLLAGEN, TYPE VI, ALPHA-2 CHAIN; COL6A2
*FIELD* TX
See 120220. Saitta et al. (1992) demonstrated that the COL6A2 gene is 36
kb long and contains 30 exons. By alternative processing, the human gene
produces multiple mRNAs differing in the 5-prime untranslated region as
well as in the 3-prime coding and noncoding sequences. COL6A2 is the
most telomeric gene on chromosome 21 (Antonarakis, 1993).

In 9 kindreds with the Bethlem form of autosomal dominant myopathy with
contractures (158810), Jobsis et al. (1996) demonstrated genetic linkage
to the COL6A1-COL6A2 cluster on 21q22.3. By sequence analysis in 4
families Jobsis et al. (1996) identified a mutation in COL6A1 in 1 and a
COL6A2 mutation in 2 other kindreds. Both mutations disrupted the
gly-X-Y motif of the triple helical domain by substitution of gly for
either val or ser. Analogous to the putative perturbation of the
anchoring function of the dystrophin-associated complex in congenital
muscular dystrophy with mutations in the alpha-2-subunit of laminin
(156225), the observation suggested a similar mechanism in Bethlem
myopathy.

*FIELD* AV
.0001
BETHLEM MYOPATHY
COL6A2, GLY250SER
In 2 kindreds with Bethlem myopathy, Jobsis et al. (1996) demonstrated
that affected members had a heterozygous missense mutation 898G-A
resulting in a G250S amino acid substitution in the triple helical
region.

*FIELD* RF
1. Antonarakis, C.: Personal Communication. Baltimore, Md. and Geneva,
Switzerland  3/27/1993.

2. Jobsis, G. J.; Bolhuis, P. A.; Boers, J. M.; Baas, F.; Wolterman,
R. A.; Hensels, G. W.; de Visser, M.: Genetic localization of Bethlem
myopathy. Neurology 46: 779-782, 1996.

3. Jobsis, G. J.; Keizers, H.; Vreijling, J. P.; de Visser, M.; Speer,
M. C.; Wolterman, R. A.; Baas, F.; Bohlhuis, P. A.: Type VI collagen
mutations in Bethlem myopathy, an autosomal dominant myopathy with
contractures. Nature Genet. 14: 113-115, 1996.

4. Saitta, B.; Timpl, R.; Chu, M.-L.: Human alpha-2(VI) collagen
gene: heterogeneity at the 5-prime-untranslated region generated by
an alternate exon. J. Biol. Chem. 267: 6188-6196, 1992.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 09/06/1996
terry: 9/5/1996
terry: 9/3/1996
mimadm: 4/18/1994
warfield: 4/8/1994
carol: 4/6/1993
carol: 6/17/1992
supermim: 3/16/1992
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120250
*FIELD* TI
*120250 COLLAGEN, TYPE VI, ALPHA-3 CHAIN; COL6A3
*FIELD* TX
See 120220. Weil et al. (1987, 1988) localized the COL6A3 gene to 2q37
by Southern blot analysis of somatic cell hybrids and by in situ
hybridization. It is of interest that at least 3 other extracellular
matrix genes are also located on 2q: 2 collagen genes (COL3A1 and
COL5A2) and the fibronectin gene (135600). Chu et al. (1990) isolated
and sequenced human cDNA clones corresponding to the COL6A3 gene. Stokes
et al. (1991) reported information on the exons for part of the gene.

Using fluorescence in situ hybridization, Speer et al. (1996) localized
the COL6A3 gene to 2q37 within a 17-cM region spanned by D2S336 and
D2S395. By linkage analysis, they mapped a candidate gene for Bethlem
myopathy (158810) to the same chromosomal region. It is likely that in
these families the members with Bethlem myopathy had a causative
mutation in the COL6A3 gene; Jobsis et al. (1996) found some families
without a mutation in the genes encoding the other chains of type VI
collagen, COL6A1 (120220) and COL6A2 (120240).

*FIELD* RF
1. Chu, M.-L.; Zhang, R.-Z.; Pan, T.-C.; Stokes, D.; Conway, D.; Kuo,
H.-J.; Glanville, R.; Mayer, U.; Mann, K.; Deutzmann, R.; Timpl, R.
: Mosaic structure of globular domains in the human type VI collagen
alpha-3 chain: similarity to von Willebrand factor, fibronectin, actin,
salivary proteins and apotinin type protease inhibitors. EMBO J. 9:
385-393, 1990.

2. Jobsis, G. J.; Keizers, H.; Vreijling, J. P.; de Visser, M.; Speer,
M. C.; Wolterman, R. A.; Baas, F.; Bohlhuis, P. A.: Type VI collagen
mutations in Bethlem myopathy, an autosomal dominant myopathy with
contractures. Nature Genet. 14: 113-115, 1996.

3. Speer, M. C.; Tandan, R.; Rao, P. N.; Fries, T.; Stajich, J. M.;
Bolhuis, P. A.; Jobsis, G. J.; Vance, J. M.; Viles, K. D.; Sheffield,
K.; James, C.; Kahler, S. G.; Pettenati, M.; Gilbert, J. R.; Denton,
P. H.; Yamaoka, L. H.; Pericak-Vance, M. A.: Evidence for locus heterogeneity
in the Bethlem myopathy and linkage to 2q37. Hum. Molec. Genet. 5:
1043-1046, 1996.

4. Stokes, D. G.; Saitta, B.; Timpl, R.; Chu, M.-L.: Human alpha-3(VI)
collagen gene: characterization of exons coding for the amino-terminal
globular domain and alternative splicing in normal and tumor cells. J.
Biol. Chem. 266: 8626-8633, 1991.

5. Weil, D.; Mattei, M.-G.; Passage, E.; Van Cong, N.; Pribula-Conway,
D.; Mann, K.; Deutzmann, R.; Timpl, R.; Chu, M.-L.: Assignment of
the three genes coding for the different chains of type VI collagen
(COL6A1, COL6A2, COL6A3). (Abstract) Cytogenet. Cell Genet. 46:
713 only, 1987.

6. Weil, D.; Mattei, M.-G.; Passage, E.; Van Cong, N.; Pribula-Conway,
D.; Mann, K.; Deutzmann, R.; Timpl, R.; Chu, M.-L.: Cloning and chromosomal
localization of human genes encoding the three chains of type VI collagen. Am.
J. Hum. Genet. 42: 435-445, 1988.

*FIELD* CN
Mark H. Paalman - updated: 8/15/1996

*FIELD* CD
Victor A. McKusick: 2/9/1987

*FIELD* ED
terry: 09/05/1996
terry: 9/3/1996
terry: 8/16/1996
mark: 8/15/1996
carol: 10/7/1994
supermim: 3/16/1992
carol: 7/24/1991
carol: 7/12/1991
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
120251
*FIELD* TI
*120251 COLLAGEN, TYPE VIII, ALPHA-1 POLYPEPTIDE; COL8A1
*FIELD* TX
Type VIII collagen may be unique among the collagens for its tissue
distribution and biosynthetic properties. It was first detected and
designated EC (endothelial cell) collagen in biosynthetic studies of
bovine aortic endothelial cells and rabbit corneal endothelial cells,
but not all endothelial cells synthesize type VIII collagen nor is the
protein restricted to vascular endothelium. Yamaguchi et al. (1989)
isolated 2 overlapping cDNA clones covering 2,425 basepairs encoding a
short type VIII collagen chain synthesized by rabbit corneal endothelial
cells. Because of similarities to parts of chicken alpha-1(X) collagen,
Yamaguchi et al. (1989) suggested that the triple-helix coding portions
and carboxyl three-quarters of the NC1 domains of the COL8A1 and COL10A1
(120110) genes have a common evolutionary origin. Type VIII collagen
molecules contain alpha-1 and alpha-2 (COL8A2; 120252) subunits in the
ratio of 2:1. In the rabbit, the COL8A1 gene consists of only 4 exons,
one of which is large and encodes the entire triple-helical and carboxyl
non-triple-helical domains. Muragaki et al. (1991) demonstrated that the
structure of the human COL8A1 gene is identical to that of the rabbit.
By in situ hybridization, they mapped the gene to 3q12-q13.1.

Using a gene fragment as a probe, Muragaki et al. (1992) performed
Northern blot hybridization analysis of RNA prepared from newborn mice
and demonstrated that COL8A1 mRNA is expressed in the calvarium, eye,
and skin. In situ hybridization demonstrated COL8A1 RNA in skin
keratinocytes, corneal epithelial and endothelial cells, lens epithelial
cells, as well as in mesenchymal cells surrounding cartilage and
calvarial bone and in the meninges surrounding the brain.

*FIELD* RF
1. Muragaki, Y.; Mattei, M.-G.; Yamaguchi, N.; Olsen, B. R.; Ninomiya,
Y.: The complete primary structure of the human alpha-1(VIII) chain
and assignment of its gene (COL8A1) to chromosome 3. Europ. J. Biochem. 197:
615-622, 1991.

2. Muragaki, Y.; Shiota, C.; Inoue, M.; Ooshima, A.; Olsen, B. R.;
Ninomiya, Y.: Alpha-1(VIII)-collagen gene transcripts encode a short-chain
collagen polypeptide and are expressed by various epithelial, endothelial
and mesenchymal cells in newborn mouse tissues. Europ. J. Biochem. 207:
895-902, 1992.

3. Yamaguchi, N.; Benya, P. D.; van der Rest, M.; Ninomiya, Y.: The
cloning and sequencing of alpha-1(VIII) collagen cDNAs demonstrate
that type VIII collagen is a short chain collagen and contains triple-helical
and carboxyl-terminal non-triple-helical domains similar to those
of type X collagen. J. Biol. Chem. 264: 16022-16029, 1989.

*FIELD* CD
Victor A. McKusick: 11/22/1989

*FIELD* ED
carol: 4/21/1994
carol: 1/5/1993
supermim: 3/16/1992
carol: 7/1/1991
carol: 6/18/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120252
*FIELD* TI
*120252 COLLAGEN, TYPE VIII, ALPHA-2 POLYPEPTIDE; COL8A2
*FIELD* TX
Type VIII collagen is a major component of Descemet membrane, the
basement membrane of corneal endothelial cells. These cells have been
shown to synthesize type VIII collagen in culture, and monoclonal
antibodies directed against epitopes in type VIII molecules have been
shown to label the characteristic hexagonal lattice structure of the
Descemet membrane. The sequence of the alpha-1 chain (120251) is
strikingly similar to that of the alpha-1 chain of type X collagen, a
product of hypertrophic chondrocytes. Because of the relatively small
size of the triple-helical domain, types VIII and X collagen have been
called 'short chain collagens.' Type VIII collagen molecules in the
Descemet membrane may be heterotrimers. The 2 polypeptides are
coexpressed in the Descemet membrane; the lengths of the triple-helical
regions of the 2 chains are almost identical and therefore compatible
with heterotrimer formation; and the proportion of alpha-1 and alpha-2
polypeptides suggests that the chain composition is two alpha-1 chains
to one alpha-2 chain. The alpha-2 chain of type VIII collagen contains a
triple-helical and a carboxyl non-triple-helical domain encoded by a
single, large exon, both in mice and humans (Muragaki et al., 1991).

By in situ hybridization, Muragaki et al. (1991) demonstrated that the
COL8A2 gene is located in the region 1p34.3-p32.3.

*FIELD* RF
1. Muragaki, Y.; Jacenko, O.; Apte, S.; Mattei, M.-G.; Ninomiya, Y.;
Olsen, B. R.: The alpha-2(VIII) collagen gene: a novel member of
the short chain collagen family located on the human chromosome 1.
J. Biol. Chem. 266: 7721-7727, 1991.

*FIELD* CD
Victor A. McKusick: 6/18/1991

*FIELD* ED
davew: 6/27/1994
warfield: 4/6/1994
carol: 4/10/1992
supermim: 3/16/1992
carol: 6/18/1991

*RECORD*
*FIELD* NO
120260
*FIELD* TI
*120260 COLLAGEN, TYPE IX, ALPHA-2 CHAIN; COL9A2
*FIELD* TX
See 120210. Type IX collagen, a heterotrimer of alpha-1, alpha-2, and
alpha-3 chains specific for this type of collagen, is a
cartilage-specific fibril-associated collagen. In the process of
characterizing genomic clones for the mouse COL9A2 gene, Perala et al.
(1993) also used 4 pairs of oligonucleotide primers designed for
amplification of murine exon sequences to construct cDNA clones for the
human gene spanning more than 90% of the coding region. The amino acid
and nucleotide sequence identities between human and chick are 78 and
71%, respectively. Perala et al. (1993) cloned COL9A2 cDNA and assigned
the gene to chromosome 1 by study of a panel of DNAs from human/rodent
somatic cell hybrids. Warman et al. (1994) used fluorescence in situ
hybridization to regionalize the COL9A2 gene to 1p33-p32.3. A
single-strand conformation polymorphism within the murine gene was used
to map Col9a2 to mouse chromosome 4. Since one form of multiple
epiphyseal dysplasia (600204) maps to the same region of chromosome 1,
COL9A2 is a candidate gene for that disorder. Hellsten et al. (1995)
demonstrated that the COL9A2 gene is in a 1-Mb contig, proximal to RLF
(180610) and MYCL1 (164850).

The usefulness of the candidate gene approach for identification of a
basic gene defect was illustrated by the finding of a mutation in the
COL9A2 gene in a Dutch EDM2 kindred showing linkage to DNA markers in
the region of 1p32 (Muragaki et al., 1996). The cartilage collagen
fibrils are formed from fibrular collagens II and XI (120280), while
collagen IX is located on the fibril surface (see Figure 2 in Muragaki
et al., 1996). The alpha-1 (IX) chain contains a large N-terminal
globular domain (NC4); a chondroitin sulfate chain is attached to the
alpha-2 (IX) chain. The authors stated that the results provided by the
EDM2 'experiment of nature' represent the first in vivo evidence for the
role of collagen IX in human articular cartilage.

*FIELD* AV
.0001
EPIPHYSEAL DYSPLASIA, MULTIPLE, TYPE 2
EDM2
COL9A2, IVS3DS, T-C, +2
Muragaki et al. (1996) demonstrated a mutation in affected members of a
family with multiple epiphyseal dysplasia that showed linkage to the
1p32 region. Affected members were heterozygous for a splice site
mutation causing exon skipping during RNA splicing and an inframe loss
of 12 amino acids within the alpha-2 (IX) collagen chain. The results
provided the first in vivo evidence for the role of collagen IX in human
articular cartilage. The clinical findings in the family were entirely
characteristic of MED although hip complaints were less conspicuous than
in many kindreds. The specific mutation was a gt-to-gc transition in the
consensus donor splice site of intron 3. The upstream exon 3 was
skipped.

*FIELD* RF
1. Hellsten, E.; Vesa, J.; Heiskanen, M.; Makela, T. P.; Jarvela,
I.; Cowell, J. K.; Mead, S.; Alitalo, K.; Palotie, A.; Peltonen, L.
: Identification of YAC clones for human chromosome 1p32 and physical
mapping of the infantile neuronal ceroid lipofuscinosis (INCL) locus.
Genomics 25: 404-412, 1995.

2. Muragaki, Y.; Mariman, E. C. M.; van Beersum, S. E. C.; Perala,
M.; van Mourik, J. B. A.; Warman, M. L.; Olsen, B. R.; Hamel, B. C.
J.: A mutation in the gene encoding the alpha-2 chain of the fibril-associated
collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nature
Genet. 12: 103-105, 1996.

3. Perala, M.; Hanninen, M.; Hastbacka, J.; Elima, K.; Vuorio, E.
: Molecular cloning of the human alpha-2(IX) collagen cDNA and assignment
of the human COL9A2 gene to chromosome 1. FEBS Lett. 319: 177-180,
1993.

4. Warman, M. L.; McCarthy, M. T.; Perala, M.; Vuorio, E.; Knoll,
J. H. M.; McDaniels, C. N.; Mayne, R.; Beier, D. R.; Olsen, B. R.
: The genes encoding alpha-2(IX) collagen (COL9A2) map to human chromosome
1p32.3-p33 and mouse chromosome 4. Genomics 23: 158-162, 1994.

*FIELD* CD
Victor A. McKusick: 6/26/1987

*FIELD* ED
mark: 01/08/1996
terry: 1/4/1996
terry: 3/7/1995
carol: 1/11/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
120270
*FIELD* TI
*120270 COLLAGEN, TYPE IX, ALPHA-3 CHAIN; COL9A3
*FIELD* TX
See 120210. Brewton et al. (1995) identified cDNA and genomic clones
that encode the entire alpha-3 chain of type IX collagen. Genomic
amplification identified a SSCP that was used to map COL9A3 to 20q13.3
by linkage analysis. Thus, patients with degenerative cartillage and eye
diseases can be screened for mutations in the COL9A3 gene.

*FIELD* RF
1. Brewton, R. G.; Wood, B. M.; Ren, Z.-X.; Gong, Y.; Tiller, G. E.;
Warman, M. L.; Lee, B.; Horton, W. A.; Olsen, B. R.; Baker, J. R.;
Mayne, R.: Molecular cloning of the alpha-3 chain of human type IX
collagen: linkage of the gene COL9A3 to chromosome 20q13.3. Genomics 30:
329-336, 1995.

*FIELD* CD
Victor A. McKusick: 6/26/1987

*FIELD* ED
mark: 01/15/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 6/26/1987

*RECORD*
*FIELD* NO
120280
*FIELD* TI
*120280 COLLAGEN, TYPE XI, ALPHA-1; COL11A1
*FIELD* TX
Cartilage and related tissues contain collagen molecules whose
structures are presumed to reflect the specialized functions of these
proteoglycan-rich extracellular matrices. Type II collagen (120140) is
arrayed in quarter-staggered fashion to form fibers similar to those of
type I collagen. Types IX (120210), X (120110) and XI are minor
cartilage constituents. Morris and Bachinger (1987) concluded that type
XI collagen is a trimer consisting of 3 different polypeptides--alpha-1,
alpha-2, and alpha-3. All 3 chains retain non-triple-helical domains.
The gene for at least one subunit of type XI collagen was assigned to
chromosome 1 by probing of DNA isolated from flow-sorted chromosomes
(Henry et al., 1988); by in situ hybridization, the gene was
regionalized to 1p21. Bernard et al. (1988) showed that the cDNA-derived
amino acid sequence of type XI collagen shows a variety of structural
features characteristic of fibril-forming collagens. In addition,
nucleotide sequence analysis of a selected portion of the human gene
showed the characteristic 54-bp exon motif. They concluded, therefore,
that type XI collagen belongs to the group of fibrillar collagens. They
also suggested that expression of this gene is not restricted to
cartilage, as previously thought, since the cDNA libraries from which
the clones were isolated originated from both cartilaginous and
noncartilaginous tissues.

Jacenko et al. (1994) pointed out the usefulness of studies of the more
than 40 well-characterized murine skeletal dysplasias as contributions
to the understanding of human osteochondrodysplasias. As one example,
they pointed to the work of Li et al. (1993), which demonstrated that
the mutation in the mouse autosomal recessive disease chondrodysplasia
(cho) maps to mouse chromosome 3 in the same region as the COL11A1 gene.
Li et al. (1995) demonstrated deletion of a cytidine residue about 570
nucleotides downstream of the translation initiation codon in COL11A1
mRNA from cho homozygotes. The deletion caused a reading frame shift and
introduced a premature stop codon. Limb bones of newborn cho/cho mice
are wider at the metaphyses than normal bones and only about half the
normal length. The findings demonstrate that collagen XI is essential
for normal formation of cartilage collagen fibrils and the cohesive
properties of cartilage. The results also suggest that the normal
differentiation and spatial organization of growth plate chondrocytes
are critically dependent on the presence of type XI collagen in
cartilage extracellular matrix. It is notable that Vikkula et al. (1995)
found mutation in the alpha-2 chain of type XI collagen (COL11A2;
120290) in an autosomal dominant form of Stickler syndrome as well as in
an autosomal recessive disorder with characteristics similar to the
Stickler syndrome but clinically more severe.

Yoshioka et al. (1995) reported 93% sequence identity between the
predicted amino acid sequence of mouse and human type XI collagen.
Cloning experiments also revealed alternative splicing of the sequence
coding for 85 residues located within the acidic region of the
amino-globular domain of alpha-1 (XI). Analysis of RNA samples from
different embryonic tissues suggested that alternative splicing may be
confined to tissue destined to become bone.

Fichard et al. (1994) reviewed collagens V and XI and commented on their
fundamental role in the control of fibrillogenesis, probably by forming
a core within the fibrils. Another characteristic of these collagens is
the partial retention of their N-propeptide extensions in tissue forms,
which is unusual for known fibrillar collagens. The tissue locations of
collagen V and XI are different, but their structural and biologic
properties seem to be closely related. Their primary structures are
highly conserved at both the gene and the protein level, and this
conservation is the basis of their similar biologic properties. In
particular, they are both resistant to mammalian collagenases, and
surprisingly sensitive to trypsin. Although they have both cell adhesion
and heparin binding sites that could be crucial in physiologic processes
such as development and wound healing, the 2 collagens are usually
buried within the major collagen fibrils. It had become evident that
several collagen-type molecules are, in fact, heterotypic associations
of chains from both collagens V and XI, demonstrating that these 2
collagens are not distinct types but a single type that can be called
collagen V/XI.

The Stickler syndrome (108300) has been shown to be caused by mutations
in type 2 collagen (COL2A1; 120140) in the so-called Stickler syndrome,
type I; and by mutation in the COL11A2 gene (120290) in the case of
Stickler syndrome, type II. Sirko-Osadsa et al. (1996) presented
evidence that a third form of Stickler syndrome is caused by a mutation
in the COL11A1 gene. They identified and used intragenic and highly
linked markers of COL11A1 to show that this locus is linked to Stickler
syndrome in which linkage to COL11A2 and COL2A1 had been excluded. The
data from this family, coupled with data from several smaller families,
suggested that COL11A1 is a third Stickler syndrome locus. The
polypeptide subunits of collagen XI also participate in the formation of
other collagen molecules. In addition, the genes encoding collagen XI
are subject to tissue-dependent alternative mRNA splicing. Comparison of
similarities and differences among families linked to each Stickler
syndrome locus can now be used to explore the basis of intrafamilial
variability as well as pleiotropy.

Richards et al. (1996) studied a 4-generation family in which 7
individuals were affected with Stickler syndrome type II with vitreous
and retinal abnormalities (184840) and 9 individuals were normal. The
authors demonstrated linkage to the COL11A1 gene region. Mutational
analysis of COL11A1 was performed on RT-PCR products using RNA extracted
from cultured dermal fibroblasts. Sequence analysis revealed that
affected individuals were heterozygous for a gly97-to-val substitution
(120280.0001) that disrupts the Gly-X-Y collagen sequence. SSCP analysis
of 100 chromosomes from 50 unrelated controls revealed only the pattern
of bands seen in normal family members. Richards et al. (1996) concluded
that collagen XI is an important structural component of human vitreous.

*FIELD* AV
.0001
STICKLER SYNDROME, TYPE II
COL11A1, GLY97VAL
In a 4-generation family with Stickler syndrome type II (184840),
Richards et al. (1996) found that affected individuals were heterozygous
for a single-bp change that led to a substitution of glycine-97 for
valine and disruption the Gly-X-Y collagen sequence.

*FIELD* RF
1. Bernard, M.; Yoshioka, H.; Rodriguez, E.; van der Rest, M.; Kimura,
T.; Ninomiya, Y.; Olsen, B. R.; Ramirez, F.: Cloning and sequencing
of pro-alpha1(XI) collagen cDNA demonstrated that type XI belongs
to the fibrillar class of collagens and reveals that the expression
of the gene is not restricted to cartilaginous tissue. J. Biol. Chem. 263:
17159-17166, 1988.

2. Fichard, A.; Kleman, J.-P.; Ruggiero, F.: Another look at collagen
V and XI molecules. Matrix Biol. 14: 515-531, 1994.

3. Henry, I.; Bernheim, A.; Bernard, M.; van der Rest, M.; Kimura,
T.; Jeanpierre, C.; Barichard, F.; Berger, R.; Olsen, B. R.; Ramirez,
F.; Junien, C.: Mapping of a human fibrillar collagen gene, pro alpha-1(XI)(COL11A1),
to the p21 region of chromosome 1. Genomics 3: 87-90, 1988.

4. Jacenko, O.; Olsen, B. R.; Warman, M. L.: Of mice and men: heritable
skeletal disorders. (Editorial) Am. J. Hum. Genet. 54: 163-168,
1994.

5. Li, Y.; Lacerda, D. A.; Warman, M.; Beier, D.; Oxford, J. T.; Morris,
N.; Andrikopoulos, K.; Ramirez, F.; Taylor, B.; Seegmiller, R.; Olsen,
B. R.: An abnormality in alpha-1(XI) collagen causes autosomal recessive
chondrodysplasia (cho) in mice. (Abstract) Molec. Biol. Cell 4 (suppl.
1): 7a, 1993.

6. Li, Y.; Lacerda, D. A.; Warman, M. L.; Beier, D. R.; Yoshioka,
H.; Ninomiya, Y.; Oxford, J. T.; Morris, N. P.; Andrikopoulos, K.;
Ramirez, F.; Wardell, B. B.; Lifferth, G. D.; Teuscher, C.; Woodward,
S. R.; Taylor, B. A.; Seegmiller, R. E.; Olsen, B. R.: A fibrillar
collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell 80:
423-430, 1995.

7. Morris, N. P.; Bachinger, H. P.: Type XI collagen is a heterotrimer
with the composition (1alpha,2alpha,3alpha) retaining non-triple-helical
domains. J. Biol. Chem. 262: 11345-11350, 1987.

8. Richards, A. J.; Yates, J. R. W.; Williams, R.; Payne, S. J.; Pope,
F. M.; Scott, J. D.; Snead, M. P.: A family with Stickler syndrome
type 2 has a mutation in the COL11A1 gene resulting in the substitution
of glycine 97 by valine in alpha-1(XI) collagen. Hum. Molec. Genet. 5:
1339-1343, 1996.

9. Sirko-Osadsa, D. A.; Zlotogora, J.; Tiller, G. E.; Knowlton, R.
G.; Warman, M. L.: A third Stickler syndrome locus is linked to COL11A1,
the gene encoding the alpha-1 subunit of collagen XI. (Abstract) Am.
J. Hum. Genet. 59 (suppl.): A17, 1996.

10. Vikkula, M.; Mariman, E. C. M.; Lui, V. C. H.; Zhidkova, N. I.;
Tiller, G. E.; Goldring, M. B.; van Beersum, S. E. C.; de Waal Malefijt,
M. C.; van den Hoogen, F. H. J.; Ropers, H.-H.; Mayne, R.; Cheah,
K. S. E.; Olsen, B. R.; Warman, M. L.; Brunner, H. G.: Autosomal
dominant and recessive osteochondrodysplasias associated with the
COL11A2 locus. Cell 80: 431-437, 1995.

11. Yoshioka, H.; Inoguchi, K.; Khaleduzzaman, M.; Ninomiya, Y.; Andrikopoulos,
K.; Ramirez, F.: Coding sequence and alternative splicing of the
mouse alpha-1(XI) collagen gene (Col11a1). Genomics 28: 337-340,
1995.

*FIELD* CN
Moyra Smith - updated: 10/18/1996

*FIELD* CD
Victor A. McKusick: 9/29/1987

*FIELD* ED
mark: 11/25/1996
mark: 11/24/1996
mark: 10/18/1996
joanna: 4/18/1996
mark: 10/13/1995
carol: 2/24/1995
jason: 6/7/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
120290
*FIELD* TI
*120290 COLLAGEN, TYPE XI, ALPHA-2; COL11A2
*FIELD* TX
See COL11A1 120280. Law et al. (1989, 1990) used a cosmid clone
containing the COL11A2 gene as a probe in the Southern blot analysis of
DNA from a panel of human/hamster somatic cell hybrids containing
different numbers and combinations of human chromosomes. They concluded
that the gene is located on chromosome 6, and study of a cell hybrid
containing only 6q indicated that the COL11A2 gene is on 6p. By a
combination of somatic cell hybrid mapping and in situ hybridization,
Hanson et al. (1989, 1991) localized the COL11A2 gene to 6p21.3. By
physical mapping of the class II HLA region using pulsed field gel
electrophoresis, Hanson et al. (1991) demonstrated that the COL11A2 gene
is about 45 kb centromeric to HLA-DPA1 (142880) and is transcribed in
the opposite (i.e., telomeric) direction. Kimura et al. (1989) assigned
the gene to 6p21.2 by in situ hybridization. By Northern blot analysis,
they showed that the gene is expressed in cartilage but not in adult
liver, skin, and tendon. The nucleotide sequence showed that although
type XI collagen belongs to the fibril-forming class of collagens, there
are substantial differences in exon sizes at the 3-prime end of the gene
when comparing the COL11A2 gene with the genes for types I, II, and III
collagens. It is thought that the alpha-3 chain of type XI collagen is a
posttranslational variant of the type II, or cartilage, collagen
subunit, i.e., is encoded by the COL2A1 gene (120140). Stubbs et al.
(1993) showed that the homologous gene in the mouse is also 'embedded'
within the major histocompatibility complex on chromosome 17.

Vuoristo et al. (1995) analyzed the COL11A2 gene from 2 overlapping
cosmid clones that had been previously isolated in the course of
searching the human major histocompatibility region. Nucleotide sequence
defined over 28,000 bp of the gene. It was shown to contain 66 exons. As
with most genes for fibrillar collagens, the first intron was among the
largest, and the introns at the 5-prime end of the gene were in general
larger than the introns at the 3-prime end. Analysis of the exons coding
for the major triple helical domain indicated that the gene structure
had not evolved with the genes for the major fibrillar collagen and that
there were marked differences in the number of exons, the exon sizes,
and codon usage. The gene was located close to the gene for the retinoid
X receptor beta (180246) in a head-to-tail arrangement similar to that
previously seen with the 2 mouse genes. Also, there was marked
interspecies homology in the intergenic sequences.

Type II collagen is closely associated with both type IX collagen
(120210) and type XI collagen in thin collagen fibrils of hyaline
cartilage. This prompted Brunner et al. (1994) to study linkage of a
Stickler syndrome phenotype (184840) to polymorphic markers within or
near genes encoding these cartilage collagens. In a large Dutch kindred,
Stickler syndrome was found to be linked to the 6p22-p21.3 region where
COL11A2 maps. Unlike the usual cases of Stickler syndrome which show
high myopia, vitreoretinal degeneration, and retinal detachment, ocular
features were lacking in all affected individuals in the Dutch family.
This may be explained by absence of the alpha-2 chain of type XI
collagen in the vitreous. The skeletal and otologic manifestations of
the Stickler syndrome were present in the family, however. Implication
of type XI collagen in human osteochondrodysplasias is supported by the
fact that in the mouse chondrodysplasia (cho), an autosomal recessive
disorder in which there is neonatal lethality, small mandible, cleft
palate, small thorax, disproportionate limbs, and fragile cartilage
(Seegmiller et al., 1971) was demonstrated to have abnormality in the
alpha-1 chain of type 11 collagen.

Vikkula et al. (1995) established that the affected members of the Dutch
kindred with Stickler syndrome reported by Brunner et al. (1994) had a
mutation in the COL11A2 gene (120290.0001). Furthermore, they found a
mutation in the COL11A2 gene in an autosomal recessive disorder
characterized by spondyloepiphyseal dysplasia and sensorineural hearing
loss, similar to the otospondylomegaepiphyseal dysplasia syndrome
(OSMED; 215150).

Lui et al. (1996) showed that COL11A2 contains at least 62 exons
spanning 30.5 kb. The gene differs from other collagens in that the
amino propeptide is encoded by 14 exons rather than the usual 5 to 8.
The promoter is GC-rich and lacks a TATA box. The authors believed that
the gene is likely to undergo alternative splicing. The gene lies within
the MHC region and is only 1.1-kb from the retinoid X receptor beta
(180246) and about 40 kb from DPB2 (142880).

*FIELD* AV
.0001
STICKLER SYNDROME, TYPE II
STL2
COL11A2, IVSDS, G-A, +1
In a large Dutch kindred with Stickler syndrome, which was found by
Brunner et al. (1994) to map to the same region of 6p as the COL11A2
gene, Vikkula et al. (1995) found heterozygosity for a 1-bp change at
the exon-intron boundary such that the intronic donor-site sequence,
GTGAG, was replaced by ATGAG. This change created a novel NlaIII
restriction site in the genomic sequence. The G-to-A transition resulted
in a 54-bp inframe deletion, which represented deletion of the exon
5-prime of the mutation. This exon sequence was located 108 nucleotides
upstream of the junction between sequences encoding the triple-helical
and C-propeptide domains of the alpha-2(XI) chain.

.0002
OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA
OSMED
COL11A2, GLY-ARG
Vikkula et al. (1995) studied a Dutch kindred in which 3 sibs had a
severe degenerative joint disease resembling osteoarthritis that
presented in early adulthood and affected predominantly the hips, knees,
elbows, and shoulders. The spine was less severely affected, and adult
height was only slightly below that of the unaffected sibs. There was
increased lumbar lordosis and prominent interphalangeal joints. Short
fifth metacarpals were found in all 3 sibs. The patients had distinctive
facial features with midface hypoplasia with a short upturned nose,
prominent eyes, depressed nasal bridge, and prominent supraorbital
ridges. Sensorineural hearing loss was present from birth and required
the use of hearing aids in all 3 affected sibs. None of the 3 had myopia
or vitreoretinal degeneration. The parents were fourth cousins. The
affected sibs were found to be homozygous for an extended haplotype of 7
CA dinucleotide repeat polymorphisms from 6p21 near the COL11A2 locus.
Using conservative estimates of 0.002 for the frequency of the abnormal
allele and 0.005 for the frequency of the marker haplotype, Vikkula et
al. (1995) obtained a lod score of 3.09 at theta = 0.0 for linkage of
the disease phenotype to 6p21. To find the mutation causing the
autosomal recessive disorder, they used RT-PCR with total RNA extracted
from EBV-transformed lymphoblasts, and the complete coding sequence of
the COL11A2 gene was determined for 1 individual. This identified a
G-to-A transition, converting a glycyl to an arginyl codon, within the
triple-helical domain of the alpha-2(XI) chain. The change in sequence
eliminated an MspI restriction site. Affected children were homozygous
for the arginyl codon, while unaffected children were homozygous for the
glycyl codon; both parents were heterozygous for the sequence change.
The mutation occurred in a gly-X-Y triplet.

*FIELD* SA
Hanson et al. (1989)
*FIELD* RF
1. Brunner, H. G.; van Beersum, S. E. C.; Warman, M. L.; Olsen, B.
R.; Ropers, H.-H.; Mariman, E. C. M.: A Stickler syndrome gene is
linked to chromosome 6 near the COL11A2 gene. Hum. Molec. Genet. 3:
1561-1564, 1994.

2. Hanson, I. M.; Cheah, K. S. E.; Gorman, P. A.; Solomon, E.; Trowsdale,
J.: The pro-alpha2(XI) collagen gene, COL11A2, maps to the centromeric
border of the major histocompatibility complex. (Abstract) Cytogenet.
Cell Genet. 51: 1010-1011, 1989.

3. Hanson, I. M.; Gorman, P.; Lui, V. C. H.; Cheah, K. S. E.; Solomon,
E.; Trowsdale, J.: The human alpha-2(XI) collagen gene (COL11A2)
maps to the centromeric border of the major histocompatibility complex
on chromosome 6. Genomics 5: 925-931, 1989.

4. Hanson, I. M.; Poustka, A.; Trowsdale, J.: New genes in the class
II region of the human major histocompatibility complex. Genomics 10:
417-424, 1991.

5. Kimura, T.; Cheah, K. S. E.; Chan, S. D. H.; Lui, V. C. H.; Mattei,
M.-G.; van der Rest, M.; Ono, K.; Solomon, E.; Ninomiya, Y.; Olsen,
B. R.: The human alpha-2(XI) collagen (COL11A2) chain: molecular
cloning of cDNA and genomic DNA reveals characteristics of a fibrillar
collagen with differences in genomic organization. J. Biol. Chem. 264:
13910-13916, 1989.

6. Law, M. L.; Chan, S. D. H.; Berger, R.; Jones, C.; Kao, F. T.;
Solomon, E.; Cheah, K. S. E.: The gene for the alpha-2 chain of the
human fibrillar collagen type XI (COL11A2) assigned to the short arm
of chromosome 6. Ann. Hum. Genet. 54: 23-29, 1990.

7. Law, M. L.; Chan, S. D. H.; Berger, R.; Jones, C. A.; Kao, F. T.;
Solomon, E.; Cheah, K. S. E.: The gene for the alpha2 chain of the
human fibrillar collagen, type XI (COL11A2) is on the short arm of
chromosome 6. (Abstract) Cytogenet. Cell Genet. 51: 1029-1030, 1989.

8. Lui, V. C. H.; Ng, L. J.; Sat, E. W. Y.; Cheah, K. S. E.: The
human alpha-2(XI) collagen gene (COL11A2): completion of coding information,
identification of the promoter sequence, and precise localization
within the major histocompatibility complex reveal overlap with the
KE5 gene. Genomics 32: 401-412, 1996.

9. Seegmiller, R.; Fraser, F. C.; Sheldon, H.: A new chondrodystrophic
mutant in mice: electron microscopy of normal and abnormal chondrogenesis. J.
Cell Biol. 48: 580-593, 1971.

10. Stubbs, L.; Lui, V. C. H.; Ng, L. J.; Cheah, K. S. E.: The alpha-2(XI)
collagen gene lies within 8 kb of Pb in the proximal portion of the
murine major histocompatibility complex. Mammalian Genome 4: 95-103,
1993.

11. Vikkula, M.; Mariman, E. C. M.; Lui, V. C. H.; Zhidkova, N. I.;
Tiller, G. E.; Goldring, M. B.; van Beersum, S. E. C.; de Waal Malefijt,
M. C.; van den Hoogen, F. H. J.; Ropers, H.-H.; Mayne, R.; Cheah,
K. S. E.; Olsen, B. R.; Warman, M. L.; Brunner, H. G.: Autosomal
dominant and recessive osteochondrodysplasias associated with the
COL11A2 locus. Cell 80: 431-437, 1995.

12. Vuoristo, M. M.; Pihlajamaa, T.; Vandenberg, P.; Prockop, D. J.;
Ala-Kokko, L.: The human COL11A2 gene structure indicates that the
gene has not evolved with the genes for the major fibrillar collagens. J.
Biol. Chem. 270: 22873-22881, 1995.

*FIELD* CN
Alan F. Scott - updated: 4/12/1996

*FIELD* CD
Victor A. McKusick: 9/29/1987

*FIELD* ED
mark: 10/18/1996
mark: 4/12/1996
terry: 4/11/1996
mark: 4/10/1996
joanna: 4/4/1996
mark: 2/19/1996
terry: 2/16/1996
carol: 2/24/1995
terry: 11/16/1994
carol: 2/25/1993
supermim: 3/16/1992
carol: 6/11/1991
carol: 5/22/1991

*RECORD*
*FIELD* NO
120300
*FIELD* TI
*120300 COLOBOMA OF MACULA
AGENESIS OF MACULA
*FIELD* TX
Clausen (1921) described affected brother and sister who had,
respectively, 2 affected sons and 2 affected daughters. Davenport (1927)
described mother and son. Phillips (1970) gave a review. This should be
considered agenesis, not coloboma (Maumenee, 1982).

*FIELD* RF
1. Clausen, (NI): Typisches, beiderseitiges hereditaeres Makulakolobom.
Klin. Mbl. Augenheilk. 67: 116 only, 1921.

2. Davenport, R. C.: Bilateral 'macular coloboma' in mother and son.
Proc. Roy. Soc. Med. 21: 109-110, 1927.

3. Maumenee, I. H.: Personal Communication. Baltimore, Md.  2/11/1982.

4. Phillips, C. I.: Hereditary macular coloboma. J. Med. Genet. 7:
224-226, 1970.

*FIELD* CS

Eyes:
   Agenesis of macula;
   Coloboma of macula

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
warfield: 4/8/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
120310
*FIELD* TI
*120310 COLLAGEN, TYPE XI, ALPHA-3 POLYPEPTIDE
COL11A3
*FIELD* TX
See 120280.

*FIELD* CD
Victor A. McKusick: 9/29/1987
*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 9/29/1987
*RECORD*
*FIELD* NO
120320
*FIELD* TI
*120320 COLLAGEN, TYPE XII, ALPHA-1 CHAIN; COL12A1
*FIELD* TX
In screening a cDNA library constructed from tendon fibroblast mRNA for
the presence of collagenous coding sequences, Gordon et al. (1987) found
a clone that encodes a polypeptide that is distinct but homologous to
type IX short-chain collagen polypeptides. The structure of the
conceptual translation product of the cDNA was also different from that
of other collagen types. They named the type IX-like collagen chain
alpha-1(XII). The exon/intron structure of the gene appeared to be
homologous to that of the alpha-1 (120210) and alpha-2 (120260) genes of
type IX collagen. Gordon et al. (1987) concluded that types IX and XII
collagen are 2 homologous members of a family of unique collagenous
proteins that show tissue-specific patterns of expression. Based on
their structure and the properties of their genes, this family of
collagen appears to be distinct from fibrillar collagens. This family,
which also includes collagen type XIV (120324), is referred to as the
FACIT (fibril-associated collagens with interrupted triple helices)
group. Members of this group show alternating triple-helical and
non-triple-helical domains.

*FIELD* RF
1. Gordon, M. K.; Gerecke, D. R.; Olsen, B. R.: Type XII collagen:
distinct extracellular matrix component discovered by cDNA cloning.
Proc. Nat. Acad. Sci. 84: 6040-6044, 1987.

*FIELD* CD
Victor A. McKusick: 10/1/1987

*FIELD* ED
mark: 03/07/1996
carol: 10/20/1992
carol: 10/14/1992
supermim: 3/16/1992
carol: 2/28/1992
carol: 8/24/1990
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120321
*FIELD* TI
*120321 COLLAGEN, TYPE XII, ALPHA 1-LIKE
COL12A1L
*FIELD* TX
Because of its structure, its association with collagen fibrils, and its
distribution in dense connective tissues, type XII is thought to act as
a crossbridge between fibrils and resist shear forces caused by tension.
By linkage analysis using DNA from interspecific backcrosses with Mus
spretus, Oh et al. (1992) demonstrated that the mouse gene Col12a1l is
located on chromosome 9. Screening of a human genomic library also
allowed the isolation of a human collagen XII-like gene, COL12A1L, which
was mapped to chromosome 6 by blot hybridization to DNA from
human/hamster hybrid cell lines. Four other collagen genes have been
mapped to chromosome 6: COL11A2 (120290) to 6p21.3; COL9A1 (120210) to
6q13; COL9A1L (120165), to 6q12-q14; and COL10A1 (120110) to 6q21-q22.
In the mouse the Col12a1 locus is tightly linked to the recessive short
ear (se) mutation, which is characterized by multiple skeletal
abnormalities and defective cartilage framework. However, preliminary
studies by Oh et al. (1992) failed to demonstrate deletion of the
Col12a1 gene in animals that probably contained a deletion of the se
gene.

*FIELD* RF
1. Oh, S. P.; Taylor, R. W.; Gerecke, D. R.; Rochelle, J. M.; Seldin,
M. F.; Olsen, B. R.: The mouse alpha-1(XII) and human alpha-1(XII)-like
collagen genes are localized on mouse chromosome 9 and human chromosome
6. Genomics 14: 225-231, 1992.

*FIELD* CD
Victor A. McKusick: 4/15/1993

*FIELD* ED
terry: 7/28/1994
carol: 4/15/1993

*RECORD*
*FIELD* NO
120324
*FIELD* TI
*120324 COLLAGEN, TYPE XIV
COL14A1
*FIELD* TX
Dublet and van der Rest (1991) extracted a homotrimeric collagen
molecule from fetal bovine skin and tendon. They demonstrated that it
has a triple helical disulfide-bonded domain homologous to type IX and
type XII collagens.

*FIELD* RF
1. Dublet, B.; van der Rest, M.: Type XIV collagen, a new homotrimeric
molecule extracted from fetal bovine skin and tendon, with a triple
helical disulfide-bonded domain homologous to type IX and type XII
collagens. J. Biol. Chem. 266: 6853-6858, 1991.

*FIELD* CD
Victor A. McKusick: 6/24/1991

*FIELD* ED
terry: 7/28/1994
carol: 6/29/1992
supermim: 3/16/1992
carol: 1/29/1992
carol: 6/24/1991

*RECORD*
*FIELD* NO
120325
*FIELD* TI
*120325 COLLAGEN, TYPE XV, ALPHA-1 POLYPEPTIDE; COL15A1
*FIELD* TX
Myers et al. (1992) isolated a 2.1-kb cDNA clone containing a derived
gly-X-Y sequence very different from those of collagen types I-XIV. The
protein partially encoded by this clone was named the alpha-1 chain of
type XV collagen. Kivirikko et al. (1994) and Muragaki et al. (1994)
obtained additional cDNA sequences and deduced the complete primary
structure of the polypeptide. The former group also partially
characterized the gene structure, while the latter noted strong amino
acid sequence similarity to mouse alpha-1(XVIII) collagen. The presence
of a predicted signal peptide suggests that the protein is secreted into
the extracellular matrix. Muragaki et al. (1994) also presented evidence
for predominant expression in embryonic internal organs such as the
adrenal glands, kidney, and pancreas.

By studying DNAs from rodent-human hybrid cells and by in situ
hybridization, Huebner et al. (1992) assigned the gene to 9q21-q22, a
region to which no other collagen genes had previously been assigned.
Huebner et al. (1992) stated that this was the 21st collagen gene to be
localized and that chromosome 9 was the 12th of the human chromosomes
found to contain at least one member of this unusual gene family.

Myers et al. (1996) stated that the collagen family of proteins consists
of 19 types encoded by 33 genes. Type XV collagen has a 577-amino acid,
highly interrupted, triple-helical region that is flanked by amino and
carboxyl noncollagenous domains of 555 and 256 residues, respectively.
Myers et al. (1996) produced a bacteria-expressed recombinant protein
representing the first half of the type XV collagen C-terminal domain in
order to generate highly specific polyclonal antisera. Northern blot
hybridization to human tissue RNAs indicated that type XV has a
widespread distribution. To determine the precise localization of type
XV collagen, immunohistochemical analyses were performed. A surprisingly
restricted and uniform presence was demonstrated in many tissues which
showed a strong association with vascular, neuronal, mesenchymal, and
some epithelial basement membrane zones. Myers et al. (1996) interpreted
their data as suggesting that type XV collagen may function in some
manner to adhere basement membrane to the underlying connective tissue
stroma.

*FIELD* RF
1. Huebner, K.; Cannizzaro, L. A.; Jabs, E. W.; Kivirikko, S.; Manzone,
H.; Pihlajaniemi, T.; Myers, J. C.: Chromosomal assignment of a gene
encoding a new collagen type (COL15A1) to 9q21-q22. Genomics 14:
220-224, 1992.

2. Kivirikko, S.; Heinamaki, P.; Rehn, M.; Honkanen, N.; Myers, J.
C.; Pihlajaniemi, T.: Primary structure of the alpha-1 chain of human
type XV collagen and exon-intron organization in the 3-prime region
of the corresponding gene. J. Biol. Chem. 269: 4773-4779, 1994.

3. Muragaki, Y.; Abe, N.; Ninomiya, Y.; Olsen, B. R.; Ooshima, A.
: The human alpha-1(XV) collagen chain contains a large amino-terminal
non-triple helical domain with a tandem repeat structure and homology
to alpha-1(XVIII) collagen. J. Biol. Chem. 269: 4042-4046, 1994.

4. Myers, J. C.; Dion, A. S.; Abraham, V.; Amenta, P. S.: Type XV
collagen exhibits a widespread distribution in human tissues but a
distinct localization in basement membrane zones. Cell Tissue Res. 286:
493-505, 1996.

5. Myers, J. C.; Kivirikko, S.; Gordon, M. K.; Dion, A. S.; Pihlajaniemi,
T.: Identification of a previously unknown human collagen chain,
alpha-1(XV), characterized by extensive interruptions in the triple-helical
region. Proc. Nat. Acad. Sci. 89: 10144-10148, 1992.

*FIELD* CN
Victor A. McKusick - updated: 4/21/1997

*FIELD* CD
Victor A. McKusick: 10/14/1992

*FIELD* ED
jenny: 04/21/1997
jenny: 4/21/1997
terry: 4/14/1997
carol: 2/7/1995
carol: 11/25/1992
carol: 10/14/1992

*RECORD*
*FIELD* NO
120326
*FIELD* TI
*120326 COLLAGEN, TYPE XVI, ALPHA-1; COL16A1
*FIELD* TX
The collagens fall into 2 major classes: the fibril-forming collagens
and the nonfibril-forming collagens. A long central triple-helical
domain, without gly-Xaa-Xaa interruptions, is the hallmark of the former
class; collagens type I, II, III, V, and XI, which form highly organized
fibrils in a quarter-staggered fashion, are members of this class. The
remaining collagens belong to the latter class with a common feature
being the presence of imperfections in the gly-Xaa-Xaa repeating
pattern. Within the latter class, collagens type IX, XII, and XIV form a
subgroup called the FACIT collagens (for 'fibril-associated collagens
with interrupted triple helices'). These collagens are associated with
type I or II collagen fibrils and play a role in interaction of these
fibrils with other matrix components.

Pan et al. (1992) cloned the gene for a new form of collagen with
features resembling those of members of the FACIT group. Northern blot
analyses showed hybridization of the cDNA to a 5.5-kb mRNA in human
fibroblasts and keratinocytes. By in situ hybridization, Pan et al.
(1992) localized the gene to 1p35-p34. They designated the collagen
chain encoded by the cDNA the alpha-1 chain of type XVI collagen.
Yamaguchi et al. (1992) also cloned and partially characterized the
COL16A1 gene. Furthermore, they also assigned the gene to chromosome 1
and regionalized it to 1p34-p13 by examination of somatic cell hybrids
containing spontaneous breaks or translocations. Combined with the in
situ hybridization data, the findings suggest that the COL16A1 gene lies
in the 1p34 band.

*FIELD* RF
1. Pan, T.-C.; Zhang, R.-Z.; Mattei, M.-G.; Timpl, R.; Chu, M.-L.
: Cloning and chromosomal location of human alpha-1(XVI) collagen.
Proc. Nat. Acad. Sci. 89: 6565-6569, 1992.

2. Yamaguchi, N.; Kimura, S.; McBride, O. W.; Hori, H.; Yamada, Y.;
Kanamori, T.; Yamakoshi, H.; Nagai, Y.: Molecular cloning and partial
characterization of a novel collagen chain, alpha-1(XVI), consisting
of repetitive collagenous domains and cysteine-containing non-collagenous
segments. J. Biochem. 112: 856-863, 1992.

*FIELD* CD
Victor A. McKusick: 8/18/1992

*FIELD* ED
joanna: 04/18/1996
carol: 3/10/1993
carol: 8/18/1992

*RECORD*
*FIELD* NO
^120327
*FIELD* TI
^120327 MOVED TO 113811
*FIELD* TX
This entry was incorporated into entry 113811 on 4 March 1996.

*FIELD* CD
Victor A. McKusick: 9/28/1993
*FIELD* ED
mark: 03/04/1996
mark: 2/20/1996
mark: 8/31/1995
carol: 9/28/1993
*RECORD*
*FIELD* NO
120328
*FIELD* TI
*120328 COLLAGEN, TYPE XVIII, ALPHA-1 POLYPEPTIDE; COL18A1
*FIELD* TX
Oh et al. (1994) isolated overlapping mouse cDNAs encoding a novel
collagenous polypeptide, alpha-1 (XVIII) collagen. Nucleotide sequence
analysis showed that the COL18A1 gene contains 10 triple-helical domains
separated and flanked by non-triple-helical regions. Within the
non-triple-helical regions, there are several ser-gly-containing
sequences that conform to the consensus sequences for glycosaminoglycan
attachment sites in proteoglycan core proteins. Northern blots showed
that COL18A1 transcripts are present in multiple organs, but the highest
levels were found in liver, lung, and kidney. Comparison of COL18A1
sequences with those of COL15A1 (120325) revealed a striking similarity
in the lengths of the 6 most carboxyl-terminal triple-helical domains.
In addition, within the carboxyl non-triple-helical domain NC1 of the 2
chains, a region of 177 amino acid residues showed about 60% identity at
the amino acid level. The similarities in structure suggested that the
collagens are functionally related, and their distinct structure pointed
to differences from other known collagen types. Oh et al. (1994)
concluded that they belonged to a novel subfamily of extracellular
matrix proteins with multiple triple-helical domains, and proposed to
designate these as multiplexins, for 'protein with multiple triple-helix
domains and interruptions.' Oh et al. (1994) reported the isolation of
human cDNAs and genomic DNAs representing the COL18A1 gene. Using a
genomic clone as a probe for fluorescence in situ hybridization, they
mapped the COL18A1 gene to 21q22.3. In addition, using an interspecific
backcross panel, they showed that the murine Col18a1 is on chromosome
10, close to the loci for Col6a1 and Col6a2.

Based on mouse cDNA clones, Rehn and Pihlajaniemi (1994) likewise
pointed out the homology between type XVIII and type XV collagens.
Northern blot hybridization analysis demonstrated a striking tissue
distribution for type XVIII collagen mRNAs, as the clones hybridized
strongly with mRNAs of 4.3 and 5.3 kilobases that were present only in
lung and liver of the 8 mouse tissues studied.

Rehn et al. (1996) showed that the mouse Col18a1 gene contains 43 exons
spanning over 100 kb and that 2 alternative promoters are used. Promoter
1, which is about 50 kb upstream and adjacent to exons 1 and 2, produces
a transcript that skips exon 3. Promoter 2, adjacent to exon 3, produces
2 types of transcripts depending on alternative splicing of that exon.
All 3 predicted proteins differ in their amino-terminal noncollagenous
domains.

*FIELD* SA
Oh et al. (1994)
*FIELD* RF
1. Oh, S. P.; Kamagata, Y.; Muragaki, Y.; Timmons, S.; Ooshima, A.;
Olsen, B. R.: Isolation and sequencing of cDNAs for proteins with
multiple domains of Gly-X-Y repeats identify a novel family of collagenous
proteins. Proc. Nat. Acad. Sci. 91: 4229-4233, 1994.

2. Oh, S. P.; Warman, M. L.; Seldin, M. F.; Cheng, S.-D.; Knoll, J.
H. M.; Timmons, S.; Olsen, B. R.: Cloning of cDNA and genomic DNA
encoding human type XVIII collagen and localization of the alpha-1(XVIII)
collagen gene to mouse chromosome 10 and human chromosome 21. Genomics 19:
494-499, 1994.

3. Rehn, M.; Hintikka, E.; Pihlajaniemi, T.: Characterization of
the mouse gene for the alpha-1 chain of type XVIII collagen (Col18a1)
reveals that the three variant N-terminal polypeptide forms are transcribed
from two widely separated promoters. Genomics 32: 436-446, 1996.

4. Rehn, M.; Pihlajaniemi, T.: Alpha-1(XVIII), a collagen chain with
frequent interruptions in the collagenous sequence, a distinct tissue
distribution, and homology with type XV collagen. Proc. Nat. Acad.
Sci. 91: 4234-4238, 1994.

*FIELD* CN
Alan F. Scott - updated: 04/12/1996

*FIELD* CD
Victor A. McKusick: 12/20/1993

*FIELD* ED
mark: 04/12/1996
terry: 4/12/1996
terry: 4/11/1996
mark: 4/10/1996
jason: 7/13/1994
mimadm: 4/14/1994
carol: 3/14/1994
carol: 12/20/1993

*RECORD*
*FIELD* NO
120330
*FIELD* TI
#120330 OPTIC NERVE COLOBOMA WITH RENAL DISEASE; ONCR
COLOBOMA OF OPTIC NERVE WITH RENAL DISEASE;;
OPTIC COLOBOMA, VESICOURETERAL REFLUX, AND RENAL ANOMALIES
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
phenotype can be caused by mutation in the PAX2 gene (167409).

Karcher (1979) described a father and son with the 'morning glory' optic
disc anomaly and renal disease. Weaver et al. (1988) reported on 2
brothers with optic nerve colobomas associated with renal disease. There
is uncertainty as to whether the 'morning glory' syndrome represents a
colobomatous defect or an abnormality of regression of mesodermal
structures of the embryonic optic disc (Kindler, 1970; Dempster et al.,
1983). Under the designation papillo-renal syndrome, Bron et al. (1989)
described the same disorder.

Coloboma of the optic nerve and renal disease was related to a mutation
in the PAX2 gene (167409.0001) by Sanyanusin et al. (1995). Schimmenti
et al. (1995) provided information on the family in which the mutation
was identified. A father and 3 sons had optic nerve colobomas,
vesicoureteral reflux, and renal anomalies. The youngest son had
congenital renal failure and ultimately underwent renal transplantation.
The father and 1 son had high frequency hearing loss.

Sanyanusin et al. (1995) demonstrated a PAX2 mutation in 2 brothers with
'typical renal-coloboma syndrome without associated vesicoureteric
reflux.' The younger brother had presented with severe progressive renal
failure leading to renal transplantation and had a bilateral visual
field defect with optic nerve colobomas. The older brother presented
with chronic mild renal failure, a visual field defect, and optic nerve
colobomas. The 2 brothers were the only affected family members and both
parents had normal ophthalmologic examinations. This was the family
reported by Weaver et al. (1988). The mutation was not present in the
mother; the father was not available for study. The mutation in both
sibs was an insertion of a G at position 619 (167409.0002) causing a
frameshift and predicted to result in a truncated protein due to the
introduction of a termination codon 26 amino acids downstream from the
mutation. The mutation probably resulted in haploinsufficiency of PAX2.
Eye and kidney abnormalities occurring together are not always
clinically apparent in the patients with renal-coloboma syndrome.

Rieger (1977) reported a family in which the father showed bilateral
optic disc anomalies and died of chronic nephritis; his son showed
macular and retinal abnormalities but renal function was normal, whereas
his daughter had normal eyes but suffered from renal failure. This is a
variability not unexpected for an autosomal dominant syndrome.

*FIELD* RF
1. Bron, A. J.; Burgess, S. E.; Awdry, P. N.; Oliver, D.; Arden, G.
: Papillo-renal syndrome: an inherited association of optic disc dysplasia
and renal disease. Report and review of the literature. Ophthal.
Paediat. Genet. 10: 185-198, 1989.

2. Dempster, A. G.; Lee, W. R.; Tornester, J. V.; McCreath, G. T.
: The morning glory syndrome: a mesodermal defect?. Ophthalmolgia 87:
222-230, 1983.

3. Karcher, H.: Zum 'morning glory' Syndrom. Klin. Mbl. Augenheilk. 175:
835-840, 1979.

4. Kindler, P.: Morning glory syndrome: unusual congenital optic
disk anomaly. Am. J. Ophthal. 69: 376-384, 1970.

5. Rieger, G.: Zum Krankheitsbild der Handmannschen Sehnerven-anomalie:
'Winderblum'-('Morning Glory') syndrom? Klin. Mbl. Augenheilk. 170:
697-706, 1977.

6. Sanyanusin, P.; McNoe, L. A.; Sullivan, M. J.; Weaver, R. G.; Eccles,
M. R.: Mutation of PAX2 in two siblings with renal-coloboma syndrome. Hum.
Molec. Genet. 4: 2183-2184, 1995.

7. Sanyanusin, P.; Schimmenti, L. A.; McNoe, L. A.; Ward, T. A.; Pierpont,
M. E. M.; Sullivan, M. J.; Dobyns, W. B.; Eccles, M. R.: Mutation
of the PAX2 gene in a family with optic nerve colobomas, renal anomalies
and vesicoureteral reflux. Nature Genet. 9: 358-364, 1995.

8. Schimmenti, L. A.; Pierpont, M. E.; Carpenter, B. L. M.; Kashtan,
C. E.; Johnson, M. R.; Dobyns, W. B.: Autosomal dominant optic nerve
colobomas, vesicoureteral reflux, and renal anomalies. Am. J. Med.
Genet. 59: 204-208, 1995.

9. Weaver, R. G.; Cashwell, L. F.; Lorentz, W.; Whiteman, D.; Geisinger,
K. R.; Ball, M.: Optic nerve coloboma associated with renal disease. Am.
J. Med. Genet. 29: 597-605, 1988.

*FIELD* CS

Eyes:
   Coloboma of optic disc

GU:
   Renal disease

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 4/25/1988

*FIELD* ED
alopez: 04/21/1997
alopez: 4/21/1997
alopez: 4/17/1997
terry: 4/11/1997
terry: 3/29/1996
mark: 1/18/1996
mark: 1/17/1996
terry: 1/17/1996
terry: 1/11/1996
terry: 4/18/1995
mimadm: 6/25/1994
carol: 3/31/1992
supermim: 3/16/1992
supermim: 3/20/1990
carol: 11/30/1989

*RECORD*
*FIELD* NO
120340
*FIELD* TI
*120340 COLLAGEN, TYPE I, ALPHA, RECEPTOR; COL1AR
COLLAGEN RECEPTOR; COLR
*FIELD* TX
Pignatelli and Bodmer (1988) studied the relationship of collagen
binding and epithelial differentiation in an in vitro system using a
human colon carcinoma cell line (SW1222). The synthetic peptide
arg-gly-asp-thr (RGDT), a cellular recognition site found in collagen,
inhibited the differentiation of cells in a 3-dimensional collagen gel
by as much as 66%. Human-mouse hybrid cells, created from a mouse rectal
carcinoma cell line and SW1222, bound collagen and would differentiate
in the collagen gel only if they contained human chromosome 15. The
authors, therefore, hypothesized that the ability of SW1222 cells to
express the differentiated phenotype is dependent upon an
arg-gly-asp-thr-directed collagen receptor controlled by a gene on
chromosome 15.

See 173510 for information on the collagen receptor of platelets.

*FIELD* RF
1. Pignatelli, M.; Bodmer, W. F.: Genetics and biochemistry of collagen
binding-triggered glandular differentiation in a human colon carcinoma
cell line. Proc. Nat. Acad. Sci. 85: 5561-5565, 1988.

*FIELD* CD
Victor A. McKusick: 9/14/1988

*FIELD* ED
joanna: 04/18/1996
carol: 9/22/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 5/18/1989
root: 9/27/1988

*RECORD*
*FIELD* NO
120350
*FIELD* TI
*120350 COLLAGEN, TYPE XIII, ALPHA-1; COL13A1
*FIELD* TX
Tikka et al. (1988) isolated and partially characterized the gene for
the alpha-1 chain of type XIII collagen. Some of the features resembled
those of genes for fibrillar collagens, but other features were
distinctly different. Analysis of overlapping cDNA clones and nuclease
S1 mapping of mRNAs indicated 1 alternative splicing site causing a
deletion of 36 bp from the mature mRNA. The 36 bp represented a single
exon. Furthermore, a 45-bp exon was also subject to alternative
splicing. Of the 3 major groups of collagens--the fibrillar collagens,
the large nonfibrillar collagens, and the short-chain collagens--type
XIII collagen belongs to the third group. Shows et al. (1989) mapped the
COL13A1 gene to 10q22 by a combination of somatic cell hybrid study and
in situ hybridization. Pajunen et al. (1989) assigned the COL13A1 gene
to 10q11-qter by Southern blot hybridization of DNA from human/rodent
somatic cell hybrids.

*FIELD* RF
1. Pajunen, L.; Tamminen, M.; Solomon, E.; Pihlajaniemi, T.: Assignment
of the gene coding for the alpha 1 chain of collagen type XIII (COL13A1)
to human chromosome region 10q11-qter. Cytogenet. Cell Genet. 52:
190-193, 1989.

2. Shows, T. B.; Tikka, L.; Byers, M. G.; Eddy, R. L.; Haley, L. L.;
Henry, W. M.; Prockop, D. J.; Tryggvason, K.: Assignment of the human
collagen alpha-1(XIII) chain gene (COL13A1) to the q22 region of chromosome
10. Genomics 5: 128-133, 1989.

3. Tikka, L.; Pihlajaniemi, T.; Henttu, P.; Prockop, D. J.; Tryggvason,
K.: Gene structure for the alpha-1 chain of a human short-chain collagen
(type XIII) with alternatively spliced transcripts and translation
termination codon at the 5-prime end of the last exon. Proc. Nat.
Acad. Sci. 85: 7491-7495, 1988.

*FIELD* CD
Victor A. McKusick: 12/9/1988

*FIELD* ED
mark: 04/18/1997
supermim: 3/16/1992
carol: 10/10/1990
supermim: 3/20/1990
supermim: 3/2/1990
ddp: 10/26/1989
root: 3/23/1989

*RECORD*
*FIELD* NO
120353
*FIELD* TI
*120353 COLLAGENASE, FIBROBLAST; CLG; CLGN
COLLAGENASE, INTERSTITIAL;;
MATRIX METALLOPROTEINASE-1; MMP1
*FIELD* TX
Brinckerhoff et al. (1987) identified a cDNA clone of human collagenase
(EC 3.4.23.7). The clone identified a single collagenase gene of about
17 kb from blots of human genomic DNA. Restriction enzyme analysis and
DNA sequence data indicated that the cDNA clone was full length and that
it was identical to that described for human skin fibroblast
collagenase. Collagenase is the only enzyme able to initiate breakdown
of the interstitial collagens, types I, II, and III. The fact that the
collagens are the most abundant proteins in the body means that
collagenase plays a key role in the remodeling that occurs constantly in
both normal and diseased conditions. The identity of human skin and
synovial cell collagenase and the ubiquity of this enzyme and of its
substrates, collagens I, II, and III, imply that the common mechanism
controlling collagenolysis throughout the body may be operative in both
normal and disease states. Gerhard et al. (1987) confirmed the
assignment of the collagenase gene to chromosome 11 by the use of a DNA
probe for Southern analysis of somatic cell hybrids. Analysis of cell
lines with rearrangements involving chromosome 11 indicated that the
gene is in the region 11q11-q23. Church et al. (1983) had used somatic
cell hybrids between mouse cells and human normal skin and corneal
fibroblasts and recessive dystrophic epidermolysis bullosa (RDEB;
226600) skin fibroblasts to assign the human structural gene for
collagenase to chromosome 11. Production of collagenase was measured by
a specific radioimmunoassay. It appeared that both the normal and the
RDEB collagenase gene mapped to chromosome 11. This was earlier taken to
indicate that the abnormal collagenase produced by RDEB cells
represented a mutation of the structural gene. Later work indicated that
both the autosomal dominant (131750) and autosomal recessive forms of
dystrophic epidermolysis bullosa are due to mutations in the type VII
collagen gene (COL7A1; 120120). The excessive formation of collagenase
must represent a secondary phenomenon, not the primary defect. It should
be noted that fibroblasts from patients with the Werner syndrome
(277700) also express high constitutive levels of collagenase in vitro
(Bauer et al., 1986).

Note on nomenclature: In reporting on the nomenclature of the matrix
metalloproteinases, Nagase et al. (1992) referred to interstitial
collagenase as MMP1.

*FIELD* RF
1. Bauer, E. A.; Silverman, N.; Busiek, D. F.; Kronberger, A.; Deuel,
T. F.: Diminished response of Werner's syndrome fibroblasts to growth
factors PDGF and FGF. Science 234: 1240-1243, 1986.

2. Brinckerhoff, C. E.; Ruby, P. L.; Austin, S. D.; Fini, M. E.; White,
H. D.: Molecular cloning of human synovial cell collagenase and selection
of a single gene from genomic DNA. J. Clin. Invest. 79: 542-546,
1987.

3. Church, R. L.; Bauer, E. A.; Eisen, A. Z.: Human skin collagenase:
assignment of the structural gene to chromosome 11 in both normal
and recessive dystrophic epidermolysis bullosa cells using human-mouse
somatic cell hybrids. Collagen Rel. Res. 3: 115-124, 1983.

4. Gerhard, D. S.; Jones, C.; Bauer, E. A.; Eisen, A. Z.; Goldberg,
G. I.: Human collagenase gene is localized to 11q.  (Abstract) Cytogenet.
Cell Genet. 46: 619 only, 1987.

5. Nagase, H.; Barrett, A. J.; Woessner, J. F., Jr.: Nomenclature
and glossary of the matrix metalloproteinases. Matrix Suppl. 1:
421-424, 1992.

*FIELD* CD
Victor A. McKusick: 5/28/1992

*FIELD* ED
carol: 4/7/1994
carol: 9/21/1992
carol: 9/18/1992
carol: 5/28/1992

*RECORD*
*FIELD* NO
120355
*FIELD* TI
*120355 MATRIX METALLOPROTEINASE-8; MMP8
COLLAGENASE I, NEUTROPHIL; CLG1
*FIELD* TX
Neutrophil collagenase, a member of the family of matrix
metalloproteinases, is distinct from the collagenase of skin fibroblasts
and synovial cells in substrate specificity and immunologic
crossreactivity. Hasty et al. (1990) cloned and sequenced a cDNA
encoding human neutrophil collagenase using a gamma-gt11 cDNA library
constructed from mRNA extracted from the peripheral leukocytes of a
patient with chronic granulocytic leukemia. The coding sequence
predicted a 467-amino acid protein. It hybridized to a 3.3-kb mRNA from
human bone marrow. Other features of the primary structure confirmed
that neutrophil collagenase is a member of the family of matrix
metalloproteinases but distinct from other members of the family.
Neutrophil collagenase shows a preference for type I collagen in
contrast with the greater susceptibility of type III collagen to
digestion by fibroblast collagenase. Yang-Feng et al. (1991) mapped the
CLG1 gene to 11q21-q22 by in situ hybridization. The expression of
neutrophil collagenase is closely linked to that of transcobalamin I in
the secondary 'specific' granules of the granulocyte. Interestingly, the
genes for both are located on the long arm of chromosome 11. Devarajan
et al. (1991) isolated a 2.4-kb cDNA clone encoding human neutrophil
collagenase. From its sequence, it was shown to encode a 467-residue
protein which exhibited 58% homology to human fibroblast collagenase and
had the same domain structure.

Nagase et al. (1992) provided a nomenclature and glossary of the matrix
metalloproteinases, indicating neutrophil collagenase as matrix
metalloproteinase 8 (MMP8).

*FIELD* RF
1. Devarajan, P.; Mookhtiar, K.; Van Wart, H.; Berliner, N.: Structure
and expression of the cDNA encoding human neutrophil collagenase. Blood 77:
2731-2738, 1991.

2. Hasty, K. A.; Pourmotabbed, T. F.; Goldberg, G. I.; Thompson, J.
P.; Spinella, D. G.; Stevens, R. M.; Mainardi, C. L.: Human neutrophil
collagenase: a distinct gene product with homology to other matrix
metalloproteinases. J. Biol. Chem. 265: 11421-11424, 1990.

3. Nagase, H.; Barrett, A. J.; Woessner, J. F., Jr.: Nomenclature
and glossary of the matrix metalloproteinases. Matrix Suppl. 1:
421-424, 1992.

4. Yang-Feng, T. L.; Berliner, N.; Deverajan, P.; Johnston, J.: Assignment
of two human neutrophil secondary granule protein genes, transcobalamin
I and neutrophil collagenase to chromosome 11. (Abstract) Cytogenet.
Cell Genet. 58: 1974 only, 1991.

*FIELD* CD
Victor A. McKusick: 12/21/1990

*FIELD* ED
joanna: 02/28/1997
carol: 4/7/1994
supermim: 3/16/1992
carol: 2/21/1992
carol: 10/3/1991
carol: 9/17/1991
carol: 9/13/1991

*RECORD*
*FIELD* NO
120360
*FIELD* TI
*120360 MATRIX METALLOPROTEINASE-2; MMP2
COLLAGENASE TYPE IV-A; CLG4A;;
COLLAGENASE TYPE IV, 72-KD;;
GELATINASE, 72-KD;;
GELATINASE, NEUTROPHIL
*FIELD* TX
Type IV collagenase is a metalloproteinase that specifically cleaves
type IV collagen, the major structural component of basement membranes
(120090, 120130). The metastatic potential of tumor cells has been found
to correlate with the activity of this enzyme. By hybridization to a
panel of DNAs from human-mouse cell hybrids and by in situ hybridization
using a gene probe, Fan et al. (1989) assigned the CLG4 gene to 16q21;
see Huhtala et al. (1990). Huhtala et al. (1990) determined that the
gene is 17 kb long with 13 exons varying in size from 110 to 901 bp and
12 introns ranging from 175 to 4,350 bp. Alignment of introns showed
that introns 1 to 4 and 8 to 12 of the type IV collagenase gene coincide
with intron locations in the interstitial collagenase (226600) and
stromelysin (185250) genes, indicating a close structural relationship
of these metalloproteinase genes. Devarajan et al. (1992) reported on
the structure and expression of 78-kD gelatinase, which they referred to
as neutrophil gelatinase.

By hybridization to somatic cell hybrid DNAs, Collier et al. (1991)
assigned both CLG4A and CLG4B (120361) to chromosome 16. Chen et al.
(1991) mapped 12 genes on the long arm of chromosome 16 by the use of 14
mouse/human hybrid cell lines and the fragile site FRA16B. The
breakpoints in the hybrids, in conjunction with the fragile site,
divided the long arm into 14 regions. They concluded that CLG4 is in
band 16q13.

Irwin et al. (1996) presented evidence that matrix metalloproteinase-2
is a likely effector of endometrial menstrual breakdown. They cultured
human endometrial stromal cells in the presence of progesterone and
found an augmentation of proteinase production after withdrawal of
proteinase: the same results were achieved by the addition of the P
receptor antagonist RU486. Characterization of the enzyme by Western
blotting revealed it to be MMP2. Northern blot analysis showed
differential expression of MMP2 mRNA in late secretory phase
endometrium.

Type IV collagenase, 72-kD, is officially designated matrix
metalloproteinase-2 (MMP2). It is also known as gelatinase, 72-kD
(Nagase et al., 1992).

Becker-Follmann et al. (1997) created a high-resolution map of the
linkage group on mouse chromosome 8 that is conserved on human 16q. The
map extended from the homolog of the MMP2 locus on 16q13 (the most
centromeric locus) to CTRB (118890) on 16q23.2-q23.3.

*FIELD* SA
Huhtala et al. (1990)
*FIELD* RF
1. Becker-Follmann, J.; Gaa, A.; Bausch, E.; Natt, E.; Scherer, G.;
von Deimling, O.: High-resolution mapping of a linkage group on mouse
chromosome 8 conserved on human chromosome 16Q. Mammalian Genome 8:
172-177, 1997.

2. Chen, L. Z.; Harris, P. C.; Apostolou, S.; Baker, E.; Holman, K.;
Lane, S. A.; Nancarrow, J. K.; Whitmore, S. A.; Stallings, R. L.;
Hildebrand, C. E.; Richards, R. I.; Sutherland, G. R.; Callen, D.
F.: A refined physical map of the long arm of human chromosome 16. Genomics 10:
308-312, 1991.

3. Collier, I. E.; Bruns, G. A. P.; Goldberg, G. I.; Gerhard, D. S.
: On the structure and chromosome location of the 72- and 92-kDa human
type IV collagenase genes. Genomics 9: 429-434, 1991.

4. Devarajan, P.; Johnston, J. J.; Ginsberg, S. S.; Van Wart, H. E.;
Berliner, N.: Structure and expression of neutrophil gelatinase cDNA:
identity with type IV collagenase from HT1080 cells. J. Biol. Chem. 267:
25228-25232, 1992.

5. Fan, Y.-S.; Eddy, R. L.; Huhtala, P.; Byers, M. G.; Haley, L. L.;
Henry, W. M.; Tryggvason, K.; Shows, T. B.: Collagenase type IV (CLG4)
is mapped to human chromosome 16q21. (Abstract) Cytogenet. Cell Genet. 51:
996, 1989.

6. Huhtala, P.; Chow, L. T.; Tryggvason, K.: Structure of the human
type IV collagenase gene. J. Biol. Chem. 265: 11077-11082, 1990.

7. Huhtala, P.; Eddy, R. L.; Fan, Y. S.; Byers, M. G.; Shows, T. B.;
Tryggvason, K.: Completion of the primary structure of the human
type IV collagenase preproenzyme and assignment of the gene (CLG4)
to the q21 region of chromosome 16. Genomics 6: 554-559, 1990.

8. Irwin, J. C.; Kirk, D.; Gwatkin, R. B. L.; Navre, M.; Cannon, P.;
Giudice, L. C.: Human endometrial matrix metalloproteinase-2, a putative
menstrual proteinase: hormonal regulation in cultured stromal cells
and messenger RNA expression during the menstrual cycle. J. Clin.
Invest. 97: 438-447, 1996.

9. Nagase, H.; Barrett, A. J.; Woessner, J. F., Jr.: Nomenclature
and glossary of the matrix metalloproteinases. Matrix Suppl. 1:
421-424, 1992.

*FIELD* CN
Victor A. McKusick - updated: 04/15/1997

*FIELD* CD
Victor A. McKusick: 6/2/1989

*FIELD* ED
jenny: 04/15/1997
terry: 4/10/1997
mark: 3/22/1996
terry: 3/19/1996
carol: 1/23/1995
supermim: 3/16/1992
carol: 5/21/1991
carol: 3/6/1991
carol: 9/8/1990
carol: 9/7/1990

*RECORD*
*FIELD* NO
120361
*FIELD* TI
*120361 MATRIX METALLOPROTEINASE 9; MMP9
COLLAGENASE TYPE IV-B; CLG4B;;
COLLAGENASE TYPE IV, 92-KD;;
COLLAGENASE TYPE V;;
GELATINASE, 92-KD
*FIELD* TX
The 72- and 92-kD type IV collagenases are members of a group of
secreted zinc metalloproteases which, in mammals, degrade the collagens
of the extracellular matrix. Other members of this group include
interstitial collagenase (120353) and stromelysin (185250). The 72-kD
type IV collagenase (120360) is secreted from normal skin fibroblasts,
whereas the 92-kD collagenase (CLG4B) is produced by normal alveolar
macrophages and granulocytes. Both CLG and STMY have 10 exons of
virtually identical length, are located on 11q, and are regulated in a
coordinate fashion. By hybridization to somatic cell hybrid DNAs,
Collier et al. (1991) demonstrated that both CLG4A and CLG4B are
situated on chromosome 16. However, St Jean et al. (1995) assigned CLG4B
to chromosome 20. They did linkage mapping of the CLG4B locus in 10 CEPH
reference pedigrees using a polymorphic dinucleotide repeat in the
5-prime flanking region of the gene. St Jean et al. (1995) observed lod
scores of between 10.45 and 20.29 with markers spanning chromosome
region 20q11.2-q13.1. Further support for assignment of CLG4B to
chromosome 20 was provided by analysis of human/rodent somatic cell
hybrids. Both CLG4A and CLG4B have 13 exons and similar intron locations
(Huhtala et al., 1991). Due to these similarities, the CLG4B cDNA clone
used in the mapping to chromosome 16 may have hybridized to CLG4A rather
than to CLG4B on chromosome 20.

The 13 exons of both CLG4A and CLG4B are 3 more than have been found in
other members of this gene family. The extra exons encode the amino
acids of the fibronectin-like domain which has been found only in the
72- and 92-kD type IV collagenases. The 92-kD type IV collagenase is
also known as 92-kD gelatinase, type V collagenase, or matrix
metalloproteinase 9 (MMP9); see the glossary of matrix
metalloproteinases provided by Nagase et al. (1992).

Linn et al. (1996) reassigned MMP9 (referred to as CLG4B by them) to
chromosome 20 based on 3 different lines of evidence: screening of a
somatic cell hybrid mapping panel, fluorescence in situ hybridization,
and linkage analysis using a newly identified polymorphism. They also
mapped mouse Clg4b to mouse chromosome 2, which has no known homology to
human chromosome 16 but large regions of homology with human chromosome
20.

*FIELD* RF
1. Collier, I. E.; Bruns, G. A. P.; Goldberg, G. I.; Gerhard, D. S.
: On the structure and chromosome location of the 72- and 92-kDa human
type IV collagenase genes. Genomics 9: 429-434, 1991.

2. Huhtala, P.; Tuuttila, A.; Chow, L. T.; Lohi, J.; Keski-Oja, J.;
Tryggvason, K.: Complete structure of the human gene for 92-kDa type
IV collagenase: divergent regulation of expression for the 92- and
72-kilodalton enzyme genes in HT-1080 cells. J. Biol. Chem. 266:
16485-16490, 1991.

3. Linn, R.; DuPont, B. R.; Knight, C. B.; Plaetke, R.; Leach, R.
J.: Reassignment of the 92-kDa type IV collagenase gene (CLG4B) to
human chromosome 20. Cytogent. Cell Genet. 72: 159-161, 1996.

4. Nagase, H.; Barrett, A. J.; Woessner, J. F., Jr.: Nomenclature
and glossary of the matrix metalloproteinases. Matrix Suppl. 1:
421-424, 1992.

5. St Jean, P. L.; Zhang, X. C.; Hart, B. K.; Lamlum, H.; Webster,
M. W.; Steed, D. L.; Henney, A. M.; Ferrell, R. E.: Characterization
of a dinucleotide repeat in the 92 kDa type IV collagenase gene (CLG4B),
localization of CLG4B to chromosome 20 and the role of CLG4B in aortic
aneurysmal disease. Ann. Hum. Genet. 59: 17-24, 1995.

*FIELD* CD
Victor A. McKusick: 3/6/1991

*FIELD* ED
terry: 06/13/1996
terry: 6/7/1996
terry: 4/19/1995
carol: 4/7/1994
supermim: 3/16/1992
carol: 3/6/1991

*RECORD*
*FIELD* NO
120400
*FIELD* TI
120400 COLOBOMA OF MACULA WITH TYPE B BRACHYDACTYLY
APICAL DYSTROPHY
*FIELD* TX
Sorsby (1935) described a mother and 5 children with bilateral pigmented
macular coloboma and brachydactyly. One of the patients had unilateral
absent kidney. Two other children and the father were unaffected. The
skeletal defect was of the type described by MacArthur and McCullough
(1932) as apical dystrophy with macular dystrophy and classified here as
brachydactyly, type B (113000). Abnormalities are confined to the distal
two phalanges. The distal phalanx may be completely absent. The distal
phalanx of the thumb is usually broad or bifid. The brother and sister
reported by Phillips and Griffiths (1969) in some ways resemble the
patients of Sorsby. Smith et al. (1980) described a patient with severe
short-limbed dwarfism and macular coloboma. Histologic changes in
cartilage resembled somewhat those of diastrophic dwarfism; the
chondrocytes were surrounded by a corona of densely staining material.
However, some other histologic and clinical features of diastrophic
dwarfism were not present.

Thompson and Baraitser (1988) reported a further generation of Sorsby's
original family. The proband was a 7-year-old boy referred to the
genetics clinic because of deafness. The thumbs were bifid, there was
aplasia or hypoplasia of the nails, and partial syndactyly between
digits 3 and 4 on the left hand. The feet showed large halluces,
abnormal nails, and syndactyly between the fourth and fifth toes
bilaterally. Ears were protuberant, more marked on the right side. His
8-year-old brother had nearly identical anomalies of the hands and feet.
Both children had congenital pigmented colobomas of both maculars
associated with nystagmus and reduced visual acuity. The 7-year-old had
no renal anomaly; no kidney was demonstrated on the left by intravenous
pyelogram in the older brother. The younger brother had bilateral
sensorineural hearing loss of 70 to 80 dB, worse at high frequencies;
the older brother had normal hearing. The mother had absent right kidney
and ureter, as well as uterus didelphys (double uterus) and double
vagina. (The authors stated that the duplication of the uterus and
vagina in the mother may or may not be part of the syndrome.) With the
information added by Thompson and Baraitser (1988), the total number of
affected members of the family, in 4 generations, was 9.

*FIELD* RF
1. MacArthur, J. W.; McCullough, E.: Apical dystrophy, an inherited
defect of hands and feet. Hum. Biol. 4: 179-207, 1932.

2. Phillips, C. I.; Griffiths, D. L.: Macular coloboma and skeletal
abnormality. Brit. J. Ophthal. 53: 346-349, 1969.

3. Smith, R. D.; Fineman, R. M.; Sillence, D. O.; Lester, P. D.; Nixon,
G. W.; Rimoin, D. L.; Lachman, R. S.: Congenital macular colobomas
and short-limb skeletal dysplasia. Am. J. Med. Genet. 5: 365-371,
1980.

4. Sorsby, A.: Congenital coloboma of the macula, together with an
account of the familial occurrence of bilateral macular coloboma in
association with apical dystrophy of hands and feet. Brit. J. Ophthal. 19:
65-90, 1935.

5. Thompson, E. M.; Baraitser, M.: Sorsby syndrome: a report on further
generations of the original family. J. Med. Genet. 25: 313-321,
1988.

*FIELD* CS

Eyes:
   Coloboma of macula

Limbs:
   Type B brachydactyly;
   Absent distal phalanx;
   Broad or bifid thumb distal phalanx

GU:
   Renal agenesis

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 03/04/1996
terry: 2/21/1996
terry: 12/22/1994
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
120420
*FIELD* TI
*120420 COLONY-STIMULATING FACTOR-1; CSF1
COLONY-STIMULATING FACTOR, MACROPHAGE-SPECIFIC; MCSF
*FIELD* TX
Kawasaki et al. (1985) isolated cDNA clones encoding human
macrophage-specific colony-stimulating factor (CSF1). Although it is a
single copy gene, its expression results in the synthesis of several
mRNAs, ranging in size from about 1.5 to 4.5 kb. Ladner et al. (1987)
showed that the CSF1 gene contains 10 exons and 9 introns spanning 20
kb. There are two forms of CSF1, with 224 and 522 amino acids, resulting
from alternative splicing. Pollard et al. (1987) presented evidence that
CSF1 has a role in development of the placenta. Uterine CSF1
concentration is regulated by a synergistic action of estradiol and
progesterone. CSF1 is produced by uterine glandular epithelial cells. It
had been found that FMS, the CSF1 receptor, is expressed in placenta and
choriocarcinoma cell lines.

Pettenati et al. (1987) used a CSF1 cDNA probe to map the gene to 5q33.1
by somatic cell hybridization and in situ hybridization in normal
chromosomes and in chromosomes with various rearrangements of neoplasia.
Morris et al. (1991) demonstrated that the previous assignment to
chromosome 5 was in error. They reassigned the gene to 1p21-p13 by in
situ hybridization and confirmed the localization by hybridizing a CSF1
cDNA probe to filters containing flow-sorted chromosomes and by
identifying CSF1 sequences in DNAs extracted from human/rodent somatic
cell hybrids that contained human chromosome 1 but not human chromosome
5. The findings are consistent with studies that have shown tight
linkage between the murine CSF1 and amylase genes, as part of a
conserved linkage group on mouse chromosome 3 and human 1p. Saltman et
al. (1992) likewise localized CSF1 to 1p21-p13 by fluorescence in situ
hybridization. (The product of the oncogene FMS (164770) is the CSF1
receptor (CSF1R), which maps to 5q33.2-q33.3. Granulocyte-macrophage
colony-stimulating factor (138960) maps to 5q.) Buchberg et al. (1989)
localized the murine equivalent gene, Csfm, to chromosome 3 by linkage
analysis of interspecific backcrosses. Yoshida et al. (1990) showed that
the murine Csfm gene is the site of the mutation in a form of
osteopetrosis (op/op). (Strictly speaking, 'murine' refers to the rodent
family Muridae, which includes both rats and mice. By common practice,
however, the term is used almost exclusively for mice.)

Blevins and Fedoroff (1995) noted that cell cultures established from
the brain of op/op mice required exogenous CSF-1 for the development of
microglia. In contrast, the brains of adult op/op mice contained normal
levels of microglia, suggesting that there exists another activity
present in vivo that can substitute for the effect of CSF-1 on this cell
type.

*FIELD* SA
Boosman et al. (1987); Le Beau et al. (1986); Wong et al. (1987)
*FIELD* RF
1. Blevins, G.; Fedoroff, S.: Microglia in colony-stimulating factor
1-deficient op/op mice. J. Neurosci. Res. 40: 535-544, 1995.

2. Boosman, A.; Strickler, J. E.; Wilson, K. J.; Stanley, E. R.:
Partial primary structures of human and murine macrophage colony stimulating
factor (CSF-1). Biochem. Biophys. Res. Commun. 144: 74-80, 1987.

3. Buchberg, A. M.; Jenkins, N. A.; Copeland, N. G.: Localization
of the murine macrophage colony-stimulating factor gene to chromosome
3 using interspecific backcross analysis. Genomics 5: 363-367,
1989.

4. Kawasaki, E. S.; Ladner, M. B.; Wang, A. M.; Van Arsdell, J.; Warren,
M. K.; Coyne, M. Y.; Schweickart, V. L.; Lee, M.-T.; Wilson, K. J.;
Boosman, A.; Stanley, E. R.; Ralph, P.; Mark, D. F.: Molecular cloning
of a complementary DNA encoding human macrophage-specific colony-stimulating
factor (CSF-1). Science 230: 291-296, 1985.

5. Ladner, M. B.; Martin, G. A.; Noble, J. A.; Nikoloff, D. M.; Tal,
R.; Kawasaki, E. S.; White, T. J.: Human CSF-1: gene structure and
alternative splicing of mRNA precursors. EMBO J. 6: 2693-2698,
1987.

6. Le Beau, M. M.; Pettenati, M. J.; Lemons, R. S.; Diaz, M. O.; Westbrook,
C. A.; Larson, R. A.; Sherr, C. J.; Rowley, J. D.: Assignment of
the GM-CSF, CSF-1, and FMS genes to human chromosome 5 provides evidence
for linkage of a family of genes regulating hematopoiesis and for
their involvement in the deletion (5q) in myeloid disorders. Cold
Spring Harbor Symp. Quant. Biol. 51: 899-909, 1986.

7. Morris, S. W.; Valentine, M. B.; Shapiro, D. N.; Sublett, J. E.;
Deaven, L. L.; Foust, J. T.; Roberts, W. M.; Cerretti, D. P.; Look,
A. T.: Reassignment of the human CSF1 gene to chromosome 1p13-p21.
Blood 78: 2013-2020, 1991.

8. Pettenati, M. J.; Le Beau, M. M.; Lemons, R. S.; Shima, E. A.;
Kawasaki, E. S.; Larson, R. A.; Sherr, C. J.; Diaz, M. O.; Rowley,
J. D.: Assignment of CSF-1 to 5q33.1: evidence for clustering of
genes regulating hematopoiesis and for their involvement in the deletion
of the long arm of chromosome 5 in myeloid disorders. Proc. Nat.
Acad. Sci. 84: 2970-2974, 1987.

9. Pollard, J. W.; Bartocci, A.; Arceci, R.; Orlofsky, A.; Ladner,
M. B.; Stanley, E. R.: Apparent role of the macrophage growth factor,
CSF-1, in placental development. Nature 330: 484-486, 1987.

10. Saltman, D. L.; Dolganov, G. M.; Hinton, L. M.; Lovett, M.: Reassignment
of the human macrophage colony stimulating factor gene to chromosome
1p13-21. Biochem. Biophys. Res. Commun. 182: 1139-1143, 1992.

11. Wong, G. G.; Temple, P. A.; Leary, A. C.; Witek-Giannotti, J.
S.; Yang, Y.-C.; Ciarletta, A. B.; Chung, M.; Murtha, P.; Kriz, R.;
Kaufman, R. J.; Ferenz, C. R.; Sibley, B. S.; Turner, K. J.; Hewick,
R. M.; Clark, S. C.; Yanai, N.; Yokota, H.; Yamada, M.; Saito, M.;
Motoyoshi, K.; Takaku, F.: Human CSF-1: molecular cloning and expression
of 4-kb cDNA encoding the human urinary protein. Science 235: 1504-1508,
1987.

12. Yoshida, H.; Hayashi, S.-I.; Kunisada, T.; Ogawa, M.; Nishikawa,
S.; Okamura, H.; Sudo, T.; Shultz, L. D.; Nishikawa, S.-I.: The murine
mutation osteopetrosis is in the coding region of the macrophage colony
stimulating factor gene. Nature 345: 442-444, 1990.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/26/1996
mark: 2/26/1996
mark: 10/18/1995
O.: 8/15/1995
carol: 5/22/1992
supermim: 3/16/1992
carol: 3/2/1992
carol: 2/23/1992

*RECORD*
*FIELD* NO
120430
*FIELD* TI
120430 COLOBOMA OF OPTIC NERVE
*FIELD* TX
Congenital coloboma of the optic nerve is often associated with serious
detachment of the macula. Savell and Cook (1976) observed 15 affected
persons in 1 kindred. In 21 of the 30 eyes, present or past detachment
of the retina was found. The coloboma was bilateral in all. It appeared
as enlargement of the physiologic cup with severely affected eyes
showing huge cavities at the site of the disc. A variable amount of
glial tissue was present in the coloboma. No male-to-male transmission
was observed. It is not certain that this entity is separate from that
discussed in 120200.

*FIELD* RF
1. Savell, J.; Cook, J. R.: Optic nerve colobomas of autosomal-dominant
heredity. Arch. Ophthal. 94: 395-400, 1976.

*FIELD* CS

Eyes:
   Bilateral coloboma of optic nerve;
   Retinal detachment

Inheritance:
   Autosomal dominant;
   ? same as 120200

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/15/1986

*RECORD*
*FIELD* NO
120433
*FIELD* TI
120433 COLOBOMA, UVEAL, WITH CLEFT LIP AND PALATE AND MENTAL RETARDATION
*FIELD* TX
Collum (1971) described uveal colobomata with other anomalies in 3
generations of a family. The features, both ocular and nonocular, were
variable, but uveal coloboma was the most consistent feature. Kingston
et al. (1982) studied the same family and concluded that cleft
lip/palate and mental retardation of variable degree were manifestations
of the same single gene defect. The affected members of the family were
described as having typical iris coloboma with involvement of the
choroid or extending to the disc and macula. Whereas 11 members had
uveal coloboma, 4 of the 11 had cleft lip and palate. In an addendum,
the authors noted the birth of another affected baby with bilateral
cleft lip/palate and bilateral severe microphthalmos.

*FIELD* RF
1. Collum, L. M. T.: Uveal colobomata and other anomalies in three
generations of one family. Brit. J. Ophthal. 55: 458-461, 1971.

2. Kingston, H. M.; Harper, P. S.; Jones, P. W.: An autosomal dominant
syndrome of uveal colobomata, cleft lip and palate, and mental retardation.
J. Med. Genet. 19: 444-446, 1982.

*FIELD* CD
Victor A. McKusick: 3/28/1994

*FIELD* ED
carol: 3/28/1994

*RECORD*
*FIELD* NO
120435
*FIELD* TI
*120435 COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1; FCC1
COCA1;;
HNPCC
mutS (E. COLI) HOMOLOG 2; MSH2, INCLUDED
*FIELD* TX
See also familial nonpolyposis colon cancer type 2 120436. Although one
of the earliest descriptions of 'inherited cancer' involved
adenocarcinoma of the colon in a large family described by Warthin
(1913), no definitive proof that the cancers in these families were due
primarily to hereditary factors has been forthcoming. One problem in
establishing such proof is that colon cancers are so common that it is
difficult to rule out chance clustering and other nonhereditary factors.
Moreover, the environment, notably diet, has been shown to play a
substantial role in colon cancer; members of families are likely to
share similar environments, thus complicating definitive analysis.
Peltomaki et al. (1993) and Aaltonen et al. (1993) searched for evidence
of a genetic component through linkage analysis. In studies of 2 large
kindreds, many individuals who had colon cancer with or without
endometrial cancer were found to show linkage to an anonymous
microsatellite marker on chromosome 2, D2S123, which means that a gene
is in the region of 2p16-p15. The residence of the 2 kindreds on 2
different continents made an environmental explanation unlikely.

Aaltonen et al. (1993) studied an additional 14 smaller kindreds.
Linkage could be excluded in 3 families by lod scores less than -2.0,
whereas the remaining 11 smaller families displayed varying degrees of
positive and negative lod scores, suggesting genetic heterogeneity.
Aaltonen et al. (1993) found, furthermore, no loss of heterozygosity for
the D2S123 or other chromosome 2 markers in either familial or sporadic
cases of FCC and the incidence of mutations in KRAS, P53, and APC was
similar in the 2 groups of tumors. They found, however, that most of the
familial cancers had widespread alteration in short repeated DNA
sequences, (CA)n dinucleotide repeat fragments, suggesting that numerous
replication errors had occurred in the sequences during tumor
development. In 13% of sporadic cancers, identical abnormalities were
found and these cancers shared biologic properties with the familial
cases, namely, location on the right side of the colon and preservation
of diploidy or near-diploidy. Aaltonen et al. (1993) proposed that these
findings reflect the existence on chromosome 2 of a gene which is
neither an oncogene nor a tumor suppressor gene but rather a gene
leading to genomic instability. Thibodeau et al. (1993) examined
colorectal tumor DNA for somatic instability at (CA)n repeats on 5q,
15q, 17p, and 18q. Differences between tumor and normal DNA were
detected in 25 of the 90 tumors studied. The instability appeared as
either a substantial change in repeat length (often heterogeneous in
nature) or a minor change (typically 2 bp). There was a significant
correlation between microsatellite instability and location of the tumor
in the proximal colon, i.e., the right colon, and with increased patient
survival; instability was correlated inversely with loss of
heterozygosity for 5q, 17p, and 18q.

Ionov et al. (1993) found that 12% of colorectal carcinomas carry
somatic deletions in poly(dA/dT) sequences and other simple repeats.
They estimated that cells from these tumors can carry more than 100,000
such mutations. They concluded that these mutations reflect a previously
undescribed form of carcinogenesis in the colon mediated by a mutation
in a DNA replication factor resulting in reduced fidelity for
replication or repair--a 'mutator mutation.'

The subset of sporadic colorectal tumors and most tumors developing in
hereditary nonpolyposis colorectal cancer (HNPCC) patients, containing
alterations in microsatellite sequences, are thought to manifest
replication errors and are referred to as RER(+). Using genetic
criteria, Parsons et al. (1993) demonstrated that the mutation rate of
(CA)n repeats in RER(+) tumor cells is at least 100-fold that in RER(-)
tumor cells and affects extrachromosomal as well as endogenous genomic
sequences. Moreover, using in vitro assays, they showed that the
mutability of RER(+) cells is associated with a profound defect in
strand-specific mismatch repair. This deficiency was observed with
microsatellite heteroduplexes as well as with heteroduplexes containing
single base-base mismatches and affected an early step in the repair
pathway. Thus, a true mutator phenotype exists in a subset of human
tumors. The responsible defect is likely to cause transitions and
transversions in addition to microsatellite alterations.

Fishel et al. (1993) studied human homologs of the mismatch repair
system in Escherichia coli referred to as the MutHLS pathway. The
pathway promotes a long patch (approximately 2 kb) excision repair
reaction that is dependent on the products of the MutH, MutL, MutS, and
MutU genes. Genetic analysis suggested that Saccharomyces cerevisiae has
a mismatch repair system similar to the bacterial MutHLS system. The S.
cerevisiae pathway has a MutS homolog, MSH2. In both bacteria and S.
cerevisiae, mismatch repair plays a role in maintaining the genetic
stability of DNA. In S. cerevisiae, Msh2 mutants exhibit increased rates
of expansion and contraction of dinucleotide repeat sequences. Fishel et
al. (1993) cloned and characterized a human MutS homolog, MSH2, and
demonstrated that the gene maps to 2p22-p21 by study of a mapping panel
of somatic cell hybrid DNAs using PCR. A T-to-C transition mutation was
detected in the -6 position of a splice acceptor site in sporadic colon
tumors and as a constitutional change in affected members of 2 small
families with HNPCC. Fishel et al. (1993) were prompted to study the
human homolog MSH2 following the report by Aaltonen et al. (1993) that
the mutation in nonpolyposis colon cancer that maps to 2p behaves like a
defect in DNA repair of the MutHLS type which they had previously been
studying.

Leach et al. (1993) used chromosome microdissection to obtain highly
polymorphic markers from 2p16. These and other markers were ordered in a
panel of somatic cell hybrids and used to define a 0.8-Mb interval
containing the locus for HNPCC. Candidate genes were mapped with respect
to this locus, and one gene was found to lie within the 0.8-Mb interval.
This gene was homologous to a prokaryotic gene, MutS, that participates
in mismatch repair. (Disruption of the MutL and MutS mismatch repair
genes produces microsatellite instability in bacteria and yeast
(Levinson and Gutman, 1987; Strand et al., 1993).) Using the sequence of
cDNA clones of the gene, they demonstrated the existence of germline
mutations that substantially altered the predicted gene product and
cosegregated with disease in the HNPCC kindreds. The highest homology
was to the yeast Msh-2 gene in the helix-turn-helix domain, perhaps
responsible for MutS binding to DNA. The yeast and human Msh-2 proteins
were 77% identical between codons 615 and 788. There were 10 other
blocks of similar amino acids distributed throughout the length of the 2
proteins. Furthermore, Leach et al. (1993) succeeded in identifying
specific germline mutations in each of the 2 kindreds that originally
established linkage to chromosome 2 (Peltomaki et al., 1993). It is
noteworthy that both the candidate gene approach and positional cloning,
the 2 main methods of map-based cloning, were used in identifying the
MSH2 gene.

Lishanski et al. (1994) developed an experimental strategy for detecting
heterozygosity in genomic DNA based on preferential binding of
Escherichia coli MutS protein to DNA molecules containing mismatched
bases. The binding was detected by a gel mobility-shift assay. The
approach was tested by using as a model the most commonly occurring
mutations within the cystic fibrosis gene (CFTR; 219700).

Using a panel of microsatellite polymorphisms in the vicinity of D2S123,
Green et al. (1994) tested 7 Canadian HNPCC families. Whereas 1 family
was clearly linked to the COCA1 locus (lod = 4.21) and a second family
was probably linked (lod = 0.92), linkage was excluded in 3 families. In
the remaining 2 families, the data were inconclusive. In the definitely
linked family, individuals with cancer of the endometrium or ureter
shared a common haplotype with 12 family members with colorectal cancer.
This supported the suspected association between these extracolonic
neoplasms and the HNPCC syndrome. In addition, 5 of the 6 persons with
adenomatous polyps, but no colorectal cancer, had the same haplotype as
the affected persons, while the sixth carried a recombination. One
individual with colorectal cancer carried a recombination that placed
the COCA1 locus telomeric to D2S123.

Aquilina et al. (1994) detected a mismatch binding defect leading to a
mutator phenotype in LoVo, a human colorectal carcinoma cell line. Umar
et al. (1994) described a deletion in the MSH2 gene in LoVo cells
together with a defect in mismatch repair by LoVo cell extracts.

The microsatellite DNA instability that is associated with alteration in
the MSH2 gene in hereditary nonpolyposis colon cancer and several forms
of sporadic cancer is thought to arise from defective repair of DNA
replication errors that create insertion-deletion loop-type (IDL)
mismatched nucleotides. Fishel et al. (1994) showed that purified MSH2
protein efficiently and specifically binds DNA containing IDL mismatches
of up to 14 nucleotides. The findings supported a direct role for MSH2
in mutation avoidance and microsatellite stability in human cells.

Kolodner et al. (1994) found that the genomic MSH2 locus covers
approximately 73 kb and contains 16 exons. The sequence of all the
intron-exon junctions was determined and used to develop methods for
analyzing each MSH2 exon for mutations. These methods were used to
analyze 2 large HNPCC kindreds exhibiting features of the Muir-Torre
syndrome (158320) and to demonstrate that cancer susceptibility was due
to the inheritance of a frameshift mutation in the MSH2 gene in 1 family
and a nonsense mutation in the MSH2 gene in the other family. Linkage of
the cancer phenotype to chromosome 2p had been described in these
families by Hall et al. (1994).

Orth et al. (1994) found that 5 of 10 ovarian tumor cell lines were
genetically unstable at most microsatellite loci analyzed. In clones and
subclones derived serially from 1 of these cell lines (serous
cystadenocarcinoma), a very high proportion of microsatellites
distributed in many different regions of the genome changed their size
in a mercurial fashion. In 1 ovarian tumor, they identified the source
of the genetic instability as a point mutation (R524P) in the MSH2 gene.
The patient was a 38-year-old heterozygote for this mutation and her
normal tissue carried both mutant and wildtype alleles of the MSH2 gene.
However, the wildtype allele was lost at some point early during
tumorigenesis so that DNA isolated either from the patients ovarian
tumor or from the cell line carried only the mutant MSH2 allele. The
genetic instability observed in the tumor and cell line DNA, together
with the germline mutation in a mismatch-repair gene, suggested that
MSH2 is involved in the onset and/or progression in a subset of ovarian
cancer.

Using denaturing gradient gel electrophoresis (DGGE) to screen for
mutations in all 16 exons of the MSH2 gene in 34 unrelated HNPCC
kindreds, Wijnen et al. (1995) found 7 novel pathogenic germline
mutations resulting in stop codons, either directly or through
frameshifts. Four nonpathogenic variations, including 1 useful
polymorphism, were also identified. MSH2 mutations were found in 21% of
the families. They could not establish any correlation between the site
of the individual mutations and the spectrum of tumor types.

To investigate the role of the MSH2 gene in genome stability and
tumorigenesis, de Wind et al. (1995) generated cells and mice deficient
for the gene. Msh2-deficient mouse embryonic stem cell lines were found
to have lost mismatch binding and acquired microsatellite instability, a
mutator phenotype, and tolerance to methylation agents. Moreover, in
these cells, homologous recombination had lost dependence on complete
identity between interacting DNA sequences, suggesting that Msh2 is
involved in safeguarding the genome from promiscuous recombination.
MSH2-deficient mice displayed no major abnormalities, but a significant
fraction developed lymphomas at an early age.

Reitmair et al. (1995) described a mouse strain homozygous for a
'knockout' mutation at the MSH2 locus. Surprisingly, these mice were
found to be viable, produced offspring in a mendelian ratio, and bred
through at least 2 generations. Starting at 2 months of age, homozygous
MSH2-deficient mice began to develop lymphoid tumors with high frequency
that contained microsatellite instabilities. These data established a
direct link between MSH2 deficiency and the pathogenesis of cancer.

Maliaka et al. (1996) identified 6 different new mutations in the MLH1
and MSH2 genes in Russian and Moldavian HNPCC families. Three of these
mutations occurred in CpG dinucleotides and led to a premature stop
codon, splicing defect, or an amino-acid substitution in evolutionarily
conserved residues. Analysis of a compilation of published mutations
including the new data suggested to the authors that CpG dinucleotides
within the coding regions of the MSH2 and MLH1 genes are hotspots for
single basepair substitutions.

The penetrance of mutations in the DNA mismatch repair (MMR) genes is
unknown except in classical HNPCC kindreds because the families studied
to date have been specifically selected for research purposes. Using a
population-based strategy, Dunlop et al. (1997) calculated the lifetime
cancer risk associated with germline MMR gene mutations, irrespective of
their family history. They identified 67 gene carriers whose risk to age
70 for all cancers was 91% for males and 69% for females. Risk of
developing colorectal cancer was significantly greater for males than
for females (74% versus 30%, P = 0.006). The risk of uterine cancer
(42%) exceeded that for colorectal cancer in females, emphasizing the
need for uterine screening. Their findings gave further insight into the
biologic effect of defective DNA MMR. Dunlop et al. (1997) demonstrated
a systematic approach to identifying individuals with high risk of
cancer who may not be part of classical HNPCC families. The risk
estimates derived from these analyses provided a rational basis on which
to guide genetic counseling and tailor clinical surveillance.

*FIELD* AV
.0001
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1
MSH2, PRO622LEU
In family J living in New Zealand and studied by Peltomaki et al. (1993)
for demonstration of linkage of colorectal cancer to chromosome 2, Leach
et al. (1993) demonstrated a CCA-to-CTA transition in codon 622,
resulting in substitution of leucine for proline. The mutation was
present in 1 allele of individual J-42, who was afflicted with colon and
endometrial cancer at ages 42 and 44, respectively. All 11 affected
individuals in the family had the mutation, while all 10 unaffected
members and 20 unrelated individuals had proline at codon 622.

.0002
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1
MSH2, DEL 50 CODONS
In studies of DNA from family C, a North American family studied by
Peltomaki et al. (1993), Leach et al. (1993) found no mutations of the
conserved region of MSH2. A presumptive splicing defect was found that
removed codons 265 to 314 from the MSH2 transcript.

.0003
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1
MSH2, ARG406TER
In a kindred with hereditary nonpolyposis colorectal cancer and linkage
to 2p, Leach et al. (1993) demonstrated a CGA-to-TGA transition in codon
406, resulting in change of arginine to a stop.

.0004
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1
MSH2, HIS639TYR
In a family with hereditary nonpolyposis colorectal cancer, linked to
2p, Leach et al. (1993) demonstrated a CAT-to-TAT transition in codon
639, resulting in substitution of tyrosine for histidine. Of interest
was the finding that, in addition to the germline mutation, an RER(+)
tumor had a somatic mutation: substitution of TG for A in codon 663
(ATG), resulting in a frameshift.

.0005
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1
MSH2, 3-BP DEL, ASN596DEL
In a family in which 3 first-degree relatives developed colon cancer
under the age of 45 years, with all neoplasms being mucinous
adenocarcinomas, Mary et al. (1994) found deletion of codon 596 (AAT)
resulting in the deletion of an asparagine residue from the protein.

.0006
MUIR-TORRE FAMILY CANCER SYNDROME
MSH2, GLN601TER
In a kindred with characteristics of the Muir-Torre syndrome, Kolodner
et al. (1994) found a C-to-T transition at nucleotide 1801 converting
codon 601 from gln to stop. Thus, a truncated MSH2 protein was
predicted. The affected members were heterozygous. This was 1 of 2
families in which all individuals in whom colorectal or endometrial
cancers occurred were found to carry the mutant allele. Many of those
carrying MSH2 mutations had tumors outside the colorectum, e.g., stomach
cancer and small bowel cancer, and there were skin lesions
characteristic of Muir-Torre syndrome.

.0007
OVARIAN CANCER
MSH2, ARG524PRO
In a 38-year-old woman with serous cystadenocarcinoma of the ovary, Orth
et al. (1994) found constitutional heterozygosity for an arg524-to-pro
mutation of the MSH2 gene. Whereas normal tissue carried both mutant and
wildtype alleles, the DNA isolated either from the patient's ovarian
tumor or from the derived cell line carried only the mutant allele of
the MSH2 gene.

.0008
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 1
MSH2, 1-BP DEL, CODON 705, TGT-TT, FS
In 2 apparently unrelated families with familial nonpolyposis colon
cancer type 1, Jeon et al. (1996) found the same mutation in exon 13 of
the MSH2 gene: deletion of a single nucleotide from codon 705, changing
TGT to TT. Exon 13 of the MSH2 gene was chosen for screening because it
is in the middle of the most conserved region of the gene. The 2
families did not fulfill the strict Amsterdam criteria for HNPCC because
each had an unaffected individual over the age of 50 with the mutation.

*FIELD* RF
1. Aaltonen, L. A.; Peltomaki, P.; Leach, F. S.; Sistonen, P.; Pylkkanen,
L.; Mecklin, J.-P.; Jarvinen, H.; Powell, S. M.; Jen, J.; Hamilton,
S. R.; Petersen, G. M.; Kinzler, K. W.; Vogelstein, B.; de la Chapelle,
A.: Clues to the pathogenesis of familial colorectal cancer. Science 260:
812-816, 1993.

2. Aquilina, G.; Hess, P.; Branch, P.; MacGeoch, C.; Casciano, I.;
Karran, P.; Bignami, M.: A mismatch recognition defect in colon carcinoma
confers DNA microsatellite instability and a mutator phenotype. Proc.
Nat. Acad. Sci. 91: 8905-8909, 1994.

3. de Wind, N.; Dekker, M.; Berns, A.; Radman, M.; te Riele, H.:
Inactivation of the mouse Msh2 gene results in mismatch repair deficiency,
methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82:
321-330, 1995.

4. Dunlop, M. G.; Farrington, S. M.; Carothers, A. D.; Wyllie, A.
H.; Sharp, L.; Burn, J.; Liu, B.; Kinzler, K. W.; Vogelstein, B.:
Cancer risk associated with germline DNA mismatch repair gene mutations. Hum.
Molec. Genet. 6: 105-110, 1997.

5. Fishel, R.; Ewel, A.; Lee, S.; Lescoe, M. K.; Griffith, J.: Binding
of mismatched microsatellite DNA sequences by the human MSH2 protein. Science 266:
1403-1405, 1994.

6. Fishel, R.; Lescoe, M. K.; Rao, M. R. S.; Copeland, N. G.; Jenkins,
N. A.; Garber, J.; Kane, M.; Kolodner, R.: The human mutator gene
homolog MSH2 and its association with hereditary nonpolyposis colon
cancer. Cell 75: 1027-1038, 1993.

7. Green, R. C.; Narod, S. A.; Morasse, J.; Young, T.-L.; Cox, J.;
Fitzgerald, G. W. N.; Tonin, P.; Ginsburg, O.; Miller, S.; Jothy,
S.; Poitras, P.; Laframboise, R.; Routhier, G.; Plante, M.; Morissette,
J.; Weissenbach, J.; Khandjian, E. W.; Rousseau, F.: Hereditary nonpolyposis
colon cancer: analysis of linkage to 2p15-16 places the COCA1 locus
telomeric to D2S123 and reveals genetic heterogeneity in seven Canadian
families. Am. J. Hum. Genet. 54: 1067-1077, 1994.

8. Hall, N. R.; Murday, V. A.; Chapman, P.; Williams, M. A.; Burn,
J.; Finan, P. J.; Bishop, D. T.: Genetic linkage in Muir-Torre syndrome
to the same chromosomal site as cancer family syndrome. Europ. J.
Cancer 30A: 180-182, 1994.

9. Ionov, Y.; Peinado, M. A.; Malkhosyan, S.; Shibata, D.; Perucho,
M.: Ubiquitous somatic mutations in simple repeated sequences reveal
a new mechanism for colonic carcinogenesis. Nature 363: 558-561,
1993.

10. Jeon, H. M.; Lynch, P. M.; Howard, L.; Ajani, J.; Levin, B.; Frazier,
M. L.: Mutation of the hMSH2 gene in two families with hereditary
nonpolyposis colorectal cancer. Hum. Mutat. 7: 327-333, 1996.

11. Kolodner, R. D.; Hall, N. R.; Lipford, J.; Kane, M. F.; Rao, M.
R. S.; Morrison, P.; Wirth, L.; Finan, P. J.; Burn, J.; Chapman, P.;
Earabino, C.; Merchant, E.; Bishops, D. T.: Structure of the human
MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics 24:
516-526, 1994.

12. Leach, F. S.; Nicolaides, N. C.; Papadopoulos, N.; Liu, B.; Jen,
J.; Parsons, R.; Peltomaki, P.; Sistonen, P.; Aaltonen, L. A.; Nystrom-Lahti,
M.; Guan, X.-Y.; Zhang, J.; Meltzer, P. S.; Yu, J.-W.; Kao, F.-T.;
Chen, D. J.; Cerosaletti, K. M.; Fournier, R. E. K.; Todd, S.; Lewis,
T.; Leach, R. J.; Naylor, S. L.; Weissenbach, J.; Mecklin, J.-P.;
Jarvinen, H.; Petersen, G. M.; Hamilton, S. R.; Green, J.; Jass, J.;
Watson, P.; Lynch, H. T.; Trent, J. M.; de la Chapelle, A.; Kinzler,
K. W.; Vogelstein, B.: Mutations of a MutS homolog in hereditary
non-polyposis colorectal cancer. Cell 75: 1215-1225, 1993.

13. Levinson, G.; Gutman, G. A.: High frequencies of short frameshifts
in poly-CA/TG tandem repeats borne by bacteriophage M13 in Escherichia
coli K-12. Nucleic Acids Res. 15: 5323-5338, 1987.

14. Lishanski, A.; Ostrander, E. A.; Rine, J.: Mutation detection
by mismatch binding protein, MutS, in amplified DNA: application to
the cystic fibrosis gene. Proc. Nat. Acad. Sci. 91: 2674-2678, 1994.

15. Maliaka, Y. K.; Chudina, A. P.; Belev, N. F.; Alday, P.; Bochkov,
N. P.; Buerstedde, J.-M.: CpG dinucleotides in the hMSH2 and hMLH1
genes are hotspots for HNPCC mutations. Hum. Genet. 97: 251-255,
1996.

16. Mary, J.-L.; Bishop, T.; Kolodner, R.; Lipford, J. R.; Kane, M.;
Weber, W.; Torhorst, J.; Muller, H.; Spycher, M.; Scott, R. J.: Mutational
analysis of the hMSH2 gene reveals a three base pair deletion in a
family predisposed to colorectal cancer development. Hum. Molec.
Genet. 3: 2067-2069, 1994.

17. Orth, K.; Hung, J.; Gazdar, A.; Bowcock, A.; Mathis, J. M.; Sambrook,
J.: Genetic instability in human ovarian cancer cell lines. Proc.
Nat. Acad. Sci. 91: 9495-9499, 1994.

18. Parsons, R.; Li, G.-M.; Longley, M. J.; Fang, W. H.; Papadopoulos,
N.; Jen, J.; de la Chapelle, A.; Kinzler, K. W.; Vogelstein, B.; Modrich,
P.: Hypermutability and mismatch repair deficiency in RER(+) tumor
cells. Cell 75: 1227-1236, 1993.

19. Peltomaki, P.; Aaltonen, L. A.; Sistonen, P.; Pylkkanen, L.; Mecklin,
J.-P.; Jarvinen, H.; Green, J. S.; Jass, J. R.; Weber, J. L.; Leach,
F. S.; Petersen, G. M.; Hamilton, S. R.; de la Chapelle, A.; Vogelstein,
B.: Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:
810-812, 1993.

20. Reitmair, A. H.; Schmits, R.; Ewel, A.; Bapat, B.; Redston, M.;
Mitri, A.; Waterhouse, P.; Mittrucker, H.-W.; Wakeham, A.; Liu, B.;
Thomason, A.; Griesser, H.; Gallinger, S.; Ballhausen, W. G.; Fishel,
R.; Mak, T. W.: MSH2 deficient mice are viable and susceptible to
lymphoid tumours. Nature Genet. 11: 64-70, 1995.

21. Strand, M.; Prolla, T. A.; Liskay, R. M.; Petes, T. D.: Destabilization
of tracts of simple repetitive DNA in yeast by mutations affecting
DNA mismatch repair. Nature 365: 274-276, 1993.

22. Thibodeau, S. N.; Bren, G.; Schaid, D.: Microsatellite instability
in cancer of the proximal colon. Lancet 260: 816-819, 1993.

23. Umar, A.; Boyer, J. C.; Thomas, D. C.; Nguyen, D. C.; Risinger,
J. I.; Boyd, J.; Ionov, Y.; Perucho, M.; Kunkel, T. A.: Defective
mismatch repair in extracts of colorectal and endometrial cancer cell
lines exhibiting microsatellite instability. J. Biol. Chem. 269:
14367-14370, 1994.

24. Warthin, A. S.: Heredity with reference to carcinoma. Arch.
Intern. Med. 12: 546-555, 1913.

25. Wijnen, J.; Vasen, H.; Khan, P. M.; Menko, F. H.; van der Klift,
H.; van Leeuwen, C.; van den Broek, M.; van Leeuwen-Cornelisse, I.;
Nagengast, F.; Meijers-Heijboer, A.; Lindhout, D.; Griffioen, G.;
Cats, A.; Kleibeuker, J.; Varesco, L.; Bertario, L.; Bisgaard, M.
L.; Mohr, J.; Fodde, R.: Seven new mutations in hMSH2, an HNPCC gene,
identified by denaturing gradient-gel electrophoresis. Am. J. Hum.
Genet. 56: 1060-1066, 1995.

*FIELD* CS

Oncology:
   Nonpolyposis colon cancer

Misc:
   Up to 60% of cases

Inheritance:
   Autosomal dominant (2p16)

*FIELD* CN
Victor A. McKusick - updated: 02/28/1997

*FIELD* CD
Victor A. McKusick: 5/6/1993

*FIELD* ED
mark: 02/28/1997
terry: 2/26/1997
terry: 6/7/1996
terry: 5/30/1996
mark: 3/27/1996
mark: 2/16/1996
mark: 2/13/1996
mark: 2/10/1996
terry: 11/13/1995
mark: 9/27/1995
carol: 2/2/1995
mimadm: 9/24/1994
jason: 7/15/1994
carol: 12/17/1993

*RECORD*
*FIELD* NO
120436
*FIELD* TI
*120436 COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 2
FCC2;;
COCA2;;
HNPCC
MutL (E. COLI) HOMOLOG 1; MLH1, INCLUDED
*FIELD* TX
Using RFLPs and microsatellite markers for linkage analysis in 3
hereditary nonpolyposis colon cancer families, Lindblom et al. (1993)
demonstrated linkage to 3p23-p21. Tumor DNA from 1 tumor in each family
was included in the study to look for rearrangements related to tumor
development. None of the colon tumors showed loss of heterozygosity
(LOH) for any of the informative markers used on 20 different
chromosomes. However, after they had detected linkage to 3p, Lindblom et
al. (1993) observed a gain of bands for several dinucleotide markers
located on 3p. A gain of bands was observed with markers on many
chromosomes.

After human homologs of the mutS gene of bacteria and yeast were found
to have mutations responsible for hereditary nonpolyposis colorectal
cancer (120435), Papadopoulos et al. (1994) searched for other human
mismatch repair genes. A survey of a large database of expressed
sequenced tags (ESTs) derived from random cDNA clones revealed 3
additional human mismatch repair genes, all related to the bacterial
mutL gene. Papadopoulos et al. (1994) mapped one of these genes (MLH1)
to 3p21.3 by fluorescence in situ hybridization. (The other 2 genes had
a slightly greater similarity to the yeast mutL homolog PMS1 and were
therefore denoted PMS1 and PMS2, respectively.) The mapping of MLH1 to
3p21 was of interest because markers in that area had been linked to
hereditary nonpolyposis colon cancer in several families (Lindblom et
al., 1993). Searching for mutations in the MLH1 gene, Papadopoulos et
al. (1994) performed RT-PCR analyses of lymphoblastoid cell RNA and
directly sequenced the coding region of the gene in 10 HNPCC kindreds
linked to 3p markers. Remarkably, all affected individuals from 7
Finnish kindreds exhibited a heterozygous deletion of codons 578 to 632.
The derivation of 5 of these 7 kindreds could be traced to a common
ancestor, and the presence of the same presumptive defect in 2 other
kindreds supported a 'founder effect' for many cases of HNPCC in the
Finnish population. Codons 578 to 632 were found to constitute a single
exon that was deleted from 1 allele in the 7 kindreds. This exon encodes
several highly conserved amino acids found at identical positions in
yeast MLH1. In another 3p-linked family, Papadopoulos et al. (1994)
observed a 4-nucleotide deletion beginning at the first position of
codon 727 and producing a frameshift with a new stop codon located 166
nucleotides downstream. As a result, the COOH-terminal 19 amino acids of
MLH1 were substituted with 53 different amino acids, some encoded by
nucleotides normally in the 3-prime untranslated region. Another kindred
displayed a 4-nucleotide insertion between codons 755 and 756. This
insertion resulted in a frameshift and extension of the open reading
frame to include 99 nucleotides downstream of the normal stop codon. One
cell line showed a transversion from TCA to TAA in codon 252, resulting
in conversion of a serine to a stop (120436.0001).

Simultaneously and independently, Bronner et al. (1994) likewise
implicated the human MutL homolog, MLH1, in the form of HNPCC that maps
to 3p. They mapped the MLH1 gene to the same region, 3p23-p21.3, by
fluorescence in situ hybridization. Furthermore, in 1 chromosome
3-linked HNPCC family, they demonstrated a missense mutation in affected
individuals (120436.0002). Using 19 dinucleotide markers and haplotype
analysis in 2 families in which the disease was linked to 3p23-p21,
Tannergard et al. (1994) also localized the gene specifically to
3p23-p21.3.

Since defects in the MSH2 gene (120435) on chromosome 2 may account for
as many as 60% of cases of hereditary nonpolyposis colon cancer and the
MLH1 gene on chromosome 3 may play a role in up to 30%, defects in these
2 genes can account for the vast majority of cases.

Between 1984 and 1994, extensive clinical and genealogic studies in
Finland had identified approximately 40 hereditary nonpolyposis
colorectal families that met the internationally accepted criteria for
the disorder. Nystrom-Lahti et al. (1994) focused on 18 of these
families. Since convincing evidence of 2p linkage had not been found in
Finnish families, the role of the proposed locus on 3p was investigated.
Of 18 apparently unrelated families living in different parts of
Finland, 11 could be traced genealogically to a common ancestry dating
at least 13 generations back in a small geographic area. Linkage studies
were possible in 9 families, revealing conclusive or probable linkage to
markers on 3p in 8. Of the 8, 5 were among those having shared ancestry.
By analysis of recombinations in the 'linked' families, this second
HNPCC locus was assigned to the 1-cM interval between marker loci
D3S1561 and D3S1298. A haplotype encompassing 10 cM around the HNPCC
locus was conserved in 5 of the pedigrees with shared ancestry and was
present in 2 further families in which linkage analysis was not
possible. The results suggested the presence of widespread single
ancestral founding mutation. Studies in vitro indicate that
heterozygosity of mutations in DNA mismatch repair genes, unlike
homozygosity, does not affect mismatch repair. Hemminki et al. (1994)
demonstrated that loss of heterozygosity of markers within or adjacent
to the MLH1 gene on 3p occurs nonrandomly in tumors from members of
families in which the disease phenotype cosegregates with MLH1. In every
informative case, the loss affected the wildtype allele. These results
suggested that DNA mismatch repair genes resemble tumor suppressor genes
in that 2 hits are required to cause a phenotypic effect.

Han et al. (1995) reported that the human MLH1 gene consists of 19
coding exons spanning approximately 100 kb, and that exons 1 to 7
contain a region that is highly conserved in the MLH1 and PMS1 (600258)
genes of yeast. Using PCR-SSCP analysis and DNA sequencing to examine
the entire coding region of the MLH1 gene in DNAs of 34 unrelated cancer
patients from HNPCC pedigrees, they found germline mutations in 8 (24%):
4 missense mutations, 1 intron mutation that would affect splicing, and
3 frameshift mutations resulting in truncation of the gene product
downstream of the mutation site.

Hypermutable H6 colorectal tumor cells are defective in strand-specific
mismatch repair and bear defects in both alleles of the human MLH1 gene.
Li and Modrich (1995) purified to near homogeneity an activity from HeLa
cells that complemented H6 nuclear extracts to restore repair
proficiency on a set of heteroduplex DNAs representing the 8 base-base
mismatches as well as a number of slipped-strand, insertion/deletion
mispairs. The activity behaved as a single species during fractionation
and copurified with proteins of 85 and 100 kD. Microsequence analysis
demonstrated both of these proteins to be homologs of bacterial MutL,
with the former corresponding to the human MLH1 product and the latter
to the product of human PMS2 (600259) or a closely related gene. The 1:1
molar stoichiometry of the 2 polypeptides and their hydrodynamic
behavior indicated formation of a heterodimer. These observations
indicated that interactions between members of the family of the human
MutL homologs may be restricted.

The Turcot syndrome (276300) is the association of colonic polyposis
with brain tumor. Hamilton et al. (1995) demonstrated that a majority of
such cases (at least 10 out of 15) have mutations in the APC gene
(175100) and that the brain tumor is usually medulloblastoma. Some of
the families with Turcot syndrome have mutations in the mismatch-repair
genes MLH1 or PMS2; in these cases, the type of brain tumor is
glioblastoma multiforme.

Liu et al. (1996) evaluated tumors from 74 HNPCC kindreds for genomic
instability characteristic of a mismatch repair deficiency and found
such instability in 68 (92%) of the kindreds. The entire coding regions
of the 5 known human mismatch repair genes were evaluated in 48 kindreds
with instability, and mutations were identified in 70%: mutations in the
MSH2 gene in 15 (31%), in the MLH1 gene in 16 (33%), in the PMS1 gene in
1 (2%), in the PMS2 gene, in 2 (4%), and in the GTBP gene (600678) in
none. The study was interpreted as demonstrating that a combination of
techniques can be used for genetic diagnosis of tumor susceptibility in
most HNPCC kindreds and lays the foundation for genetic testing of this
relatively common disease. Plummer and Casey (1996) pointed out that one
of challenges of genetic testing for HNPCC is the development of a
standard set of protocols that can be applied to the analysis of
multiple candidate genes. In families meeting the strict International
Collaborative Group (ICG) definition of HNPCC, the youngest living
affected family member should initially be screened for germline
mutations in the 2 most commonly mutated mismatch repair genes (MSH2 and
MLH1). In individuals who do not meet the strict ICG definition but
appear to have a familial predisposition to colon cancer reminiscent of
HNPCC, Liu et al. (1996) proposed that mutation analysis be performed
only if RER indicating genomic instability characteristic of a mismatch
repair deficiency is identified in the tumor of an affected individual.
They noted that difficulty is that it is often impossible to obtain
blood samples from living affected relatives. In fact, in the study by
Liu et al. (1996), blood samples for germline analysis could be obtained
from only 48 of the 68 kindreds showing the RER phenotype. Maliaka et
al. (1996) identified 6 different new mutations in the MLH1 and MSH2
genes in Russian and Moldavian HNPCC families. Three of these mutations
occurred in CpG dinucleotides and led to a premature stop codon,
splicing defect, or an amino-acid substitution in evolutionarily
conserved residues. Analysis of a compilation of published mutations
including the new data suggested to the authors that CpG dinucleotides
within the coding regions of the MSH2 and MLH1 genes are hot spots for
single basepair substitutions.

From a study of unrelated HNPCC families, Wijnen et al. (1996) commented
that, whereas the spectrum of mutations at the MSH2 gene is
heterogeneous, a cluster of MLH1 mutations were found in the region
encompassing exons 15 and 16, which accounts for 50% of all the
independent MLH1 mutations described to date. They stated that their
finding has great practical value in the design of clinical genetic
services.

By screening members of Finnish families displaying HNPCC for
predisposing germline mutations in MSH2 and MLH1, Nystrom-Lahti et al.
(1995) showed that 2 mutations in MLH1 together account for 63% (19/30)
of kindreds meeting international diagnostic criteria. One mutation,
originally detected as a 165-bp deletion in MLH1 cDNA comprising exon
16, was shown to represent a 3.5-kb genomic deletion most likely
resulting from Alu-mediated recombination (120436.0004). The second
mutation destroyed the splice acceptor site of exon 6 (120436.0005).
They commented that this was the first report of Alu-mediated
recombination causing a prevalent, dominantly inherited predisposition
to cancer. Nystrom-Lahti et al. (1995) designed a simple diagnostic test
based on PCR for both mutations. Thus 2 ancestral founding mutations
account for most Finnish HNPCC kindreds.

Sasaki et al. (1996) studied 43 tumors and corresponding normal tissues
from 23 Japanese patients with multiple primary cancers. They found no
germline mutations of the MLH1 gene and detected only 2 somatic missense
mutations among the 43 tumors examined. These 2 tumors had each shown
increased replication error (RER(+)) at more than 1 of the 5
microsatellite loci examined. Only the second of these 2 mutations
occurred in an evolutionarily conserved domain of the protein.

Baker et al. (1996) generated mice with a null mutation of the Mlh1
gene. They reported that in addition to compromising replication
fidelity, Mlh1 deficiency appeared to cause both male and female
sterility associated with reduced levels of chiasmata. Mlh1-deficient
spermatocytes exhibited high levels of prematurely separated chromosomes
and cell-cycle arrest occurred in the first division of meiosis. Baker
et al. (1996) also carried out analysis of the Mlh1 protein in
spermatocytes and oocytes using immunostaining. They demonstrated that
Mlh1 localizes at chiasma sites on meiotic chromosomes. They concluded
that Mlh1 in the mouse is involved in both DNA mismatch repair and
meiotic crossing over.

Bellacosa et al. (1996) reviewed genetic counseling aspects of HNPCC
against the background of the clinical and molecular genetics.

*FIELD* AV
.0001
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 2
MLH1, SER252TER
In a colorectal tumor cell line (H6) manifesting microsatellite
instability, Papadopoulos et al. (1994) used a technique that involves
the transcription and translation in vitro of PCR products to
demonstrate that only a truncated polypeptide was produced. Sequence
analysis of the cDNA revealed a C-to-A transversion at codon 252,
resulting in the substitution of a stop codon for serine. No band at the
normal C position was identified in the cDNA or genomic DNA from the H6
cells, indicating that these cells were devoid of a wildtype MLH1
allele.

.0002
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 2
MLH1, SER44PHE
In a family with hereditary nonpolyposis colon cancer, Bronner et al.
(1994) found that 4 affected individuals were heterozygous for a C-to-T
substitution in an exon encoding amino acids 41 to 69, which corresponds
to a highly conserved region of the protein. The nucleotide substitution
resulted in a ser44-to-phe amino acid change.

.0003
TURCOT SYNDROME WITH GLIOBLASTOMA
MLH1, 3BP DEL, LYS618DEL
Hamilton et al. (1995) described a man in family 14 who had
adenocarcinomas of the ascending and transverse colon at the age of 30,
adenomas of the descending and sigmoid colon at the ages of 32 and 33,
and an ileal adenocarcinoma and a glioblastoma multiforme at the age of
33. They found loss of 1 amino acid (lysine) in the MLH1 protein due to
a 3-nucleotide deletion (AAG) of codon 618. The patient was also
reported to have a transitional cell carcinoma of the ureter.

.0004
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 2
MLH1, 3.5-KB DEL
Nystrom-Lahti et al. (1995) found that a 3.5-kb genomic deletion in the
MLH1 gene was responsible for almost half of 30 Finnish kindreds meeting
international diagnostic criteria for HNPCC (14/30). The origins of the
families were clustered in the south-central region of Finland. The
mutation consisted of exon 15 and the proximal 2.4 kb of intron 15
joined to a distal half of intron 16 followed by intron 17. Introns 15
and 16 were found to be rich in Alu repetitive sequences. Sequence
analysis of the deletion breakpoint region in both mutant and normal
alleles suggested to Nystrom-Lahti et al. (1995) that the deletion may
have been due to recombination between 2 Alu repeat elements, 1 in
intron 15 and another in intron 16.

This large deletion mutation and the splice site mutation leading to
deletion of exon 6 (120436.0005), referred to by Moisio et al. (1996) as
mutations 1 and 2 respectively, are frequent among Finnish kindreds with
HNPCC. In order to assess the ages and origins of these mutations,
Moisio et al. (1996) constructed a map of 15 microsatellite markers
around MLH1 and used this information and haplotype analyses of 19
kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds
with mutation 1 showed a single allele for the intragenic marker D3S1611
that was not observed on any unaffected chromosome. They also shared
portions of a haplotype of markers encompassing 2.0 to 19.0 cM around
MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and
a conserved haplotype of 5 to 14 markers spanning 2.0 to 15.0 cM around
MLH1. The degree of haplotype conservation was used to estimate the ages
of these 2 mutations. The analyses suggested to the authors that the
spread of mutation 1 started 16 to 43 generations (400 to 1,075 years)
ago and that of mutation 2 started 5 to 21 generations (125 to 525
years) ago. These datings were compatible with genealogic results
identifying a common ancestor born in the 16th and 18th century,
respectively. The results indicated to Moisio et al. (1996) that all
Finnish kindreds studied to date showing either mutation 1 or mutation 2
were the result of single ancestral founding mutations relatively recent
in origin in the population. Alternatively, it is possible that the
mutations arose elsewhere and were introduced into Finland more
recently.

.0005
COLON CANCER, FAMILIAL, NONPOLYPOSIS TYPE 2
MLH1, IVS5AS, G-A, -1, EX6 DEL, FS, TER
In 5 Finnish families with HNPCC, Nystrom-Lahti et al. (1995) found that
a splice site mutation in the MLH1 gene was responsible. The mutation
consisted of a G-to-A transition in the -1 position of the splice
acceptor site in intron 5. This resulted in deletion of the 92-bp
segment corresponding to exon 6 and caused a frameshift that led to a
premature stop codon 24-bp downstream.

See also Moisio et al. (1996) and 120436.0004.

.0006
MUIR-TORRE SYNDROME
MTS
MLH1, 370-BP DEL, FS, TER
Muir-Torre syndrome (MTS; 158320) is an autosomal dominant disorder
characterized by development of sebaceous gland tumors and skin cancers,
including keratoacanthomas and basal cell carcinomas. Affected family
members may manifest a wide spectrum of internal malignancies, which
include colorectal, endometrial, urologic, and upper gastrointestinal
neoplasms. Sebaceous gland tumors, which are rare in the general
population, are considered to be the hallmark of MTS, and may arise
prior to the development of other visceral cancers. Hereditary
nonpolyposis colorectal cancer shares many features in common with MTS,
leading Lynch et al. (1985) to propose that these 2 syndromes have a
common genetic basis. Bapat et al. (1996) found a mutation in MLH1 locus
in a large, well-characterized kindred in which 17 affected family
members had colorectal and endometrial cancers, sebaceous gland tumors,
and hematopoietic malignancies. The family was originally reported by
Green et al. (1994) who excluded linkage to the MSH2 locus (120435).
Paraf et al. (1995) also described this family. Bapat et al. (1996)
studied 2 affected sibs and found by a protein-truncation test (PTT) a
truncated gene product of approximately 41 kD in addition to the
expected wildtype MLH1 protein of 53.9 kD. Further analysis discovered a
deletion of 370 bp (codons 346-467) corresponding to exon 12 of MLH1
cDNA. An examination of the MLH1 sequence indicated that deletion
generated a frameshift resulting in a stop codon at nucleotides
1472-1474 in exon 13 and a truncated protein of 40.8 kD. Linkage
analysis with an intragenic marker indicated that the affected parent
was heterozygous and the unaffected parent homozygous for the wildtype
allele.

*FIELD* RF
1. Baker, S. M.; Plug, A. W.; Prolla, T. A.; Bronner, C. E.; Harris,
A. C.; Yao, X.; Christie, D.-M.; Monell, C.; Arnheim, N.; Bradley,
A.; Ashley, T.; Liskay, R. M.: Involvement of mouse Mlh1 in DNA mismatch
repair and meiotic crossing over. Nature Genet. 336-342, 1996.

2. Bapat, B.; Xia, L.; Madlensky, L.; Mitri, A.; Tonin, P.; Narod,
S. A.; Gallinger, S.: The genetic basis of Muir-Torre syndrome includes
the hMLH1 locus. (Letter) Am. J. Hum. Genet. 59: 736-739, 1996.

3. Bellacosa, A.; Genuardi, M.; Anti, M.; Viel, A.; Ponz de Leon,
M.: Hereditary nonpolyposis colorectal cancer: review of clinical,
molecular genetics, and counseling aspects. Am. J. Med. Genet. 62:
353-364, 1996.

4. Bronner, C. E.; Baker, S. M.; Morrison, P. T.; Warren, G.; Smith,
L. G.; Lescoe, M. K.; Kane, M.; Earabino, C.; Lipford, J.; Lindblom,
A.; Tannergard, P.; Bollag, R. J.; Godwin, A. R.; Ward, D. C.; Nordenskjold,
M.; Fishel, R.; Kolodner, R.; Liskay, R. M.: Mutation in the DNA
mismatch repair gene homologue hMLH1 is associated with hereditary
non-polyposis colon cancer. Nature 368: 258-261, 1994.

5. Green, R. C.; Narod, S. A.; Morasse, J.; Young, T. L.; Cox, J.;
Fitzgerald, G. W. N.; Tonin, P.; Ginsburg, O.; Miller, S.; Poitras,
P.; Laframboise, R.; Routhier, G.; Plante, M.; Morissette, J.; Weissenbach,
J.: Khandjian, E. W.; Rousseau, F.: Hereditary nonpolyposis colon
cancer: analysis of linkage to 2p15-16 places the COCA1 locus telomeric
to D2S123 and reveals genetic heterogeneity in seven Canadian families. Am.
J. Hum. Genet. 54: 1067-1077, 1994.

6. Hamilton, S. R.; Liu, B.; Parsons, R. E.; Papadopoulos, N.; Jen,
J.; Powell, S. M.; Krush, A. J.; Berk, T.; Cohen, Z.; Tetu, B.; Burger,
P. C.; Wood, P. A.; Taqi, F.; Booker, S. V.; Petersen, G. M.; Offerhaus,
G. J. A.; Tersmette, A. C.; Giardiello, F. M.; Vogelstein, B.; Kinzler,
K. W.: The molecular basis of Turcot's syndrome. New Eng. J. Med. 332:
839-847, 1995.

7. Han, H.-J.; Maruyama, M.; Baba, S.; Park, J.-G.; Nakamura, Y.:
Genomic structure of human mismatch repair gene, hMLH1, and its mutation
analysis in patients with hereditary non-polyposis colorectal cancer
(HNPCC). Hum. Molec. Genet. 4: 237-242, 1995.

8. Hemminki, A.; Peltomaki, P.; Mecklin, J.-P.; Jarvinen, H.; Salovaara,
R.; Nystrom-Lahti, M.; de la Chapelle, A.; Aaltonen, L. A.: Loss
of the wild type MLH1 gene is a feature of hereditary nonpolyposis
colorectal cancer. Nature Genet. 8: 405-410, 1994.

9. Li, G.-M.; Modrich, P.: Restoration of mismatch repair to nuclear
extracts of H6 colorectal tumor cells by a heterodimer of human MutL
homologs. Proc. Nat. Acad. Sci. 92: 1950-1954, 1995.

10. Lindblom, A.; Tannergard, P.; Werelius, B.; Nordenskjold, M.:
Genetic mapping of a second locus predisposing to hereditary non-polyposis
colon cancer. Nature Genet. 5: 279-282, 1993.

11. Liu, B.; Parsons, R.; Papadopoulos, N.; Nicolaides, N. C.; Lynch,
H. T.; Watson, P.; Jass, J. R.; Dunlop, M.; Wyllie, A.; Peltomaki,
P.; de la Chapelle, A.; Hamilton, S. R.; Vogelstein, B.; Kinzler,
K. W.: Analysis of mismatch repair genes in hereditary non-polyposis
colorectal cancer patients. Nature Med. 2: 169-174, 1996.

12. Lynch, H. T.; Fusaro, R. M.; Roberts, L.; Voorhees, G. J.; Lynch,
J. F.: Muir-Torre syndrome in several members of a family with a
variant of the cancer family syndrome. Brit. J. Derm. 113: 295-301,
1985.

13. Maliaka, Y. K.; Chudina, A. P.; Belev, N. F.; Alday, P.; Bochkov,
N. P.; Buerstedde, J.-M.: CpG dinucleotides in the hMSH2 and hMLH1
genes are hotspots for HNPCC mutations. Hum. Genet. 97: 251-255,
1996.

14. Moisio, A.-L.; Sistonen, P.; Weissenbach, J.; de la Chapelle,
A.; Peltomaki, P.: Age and origin of two common MLH1 mutations predisposing
to hereditary colon cancer. Am. J. Hum. Genet. 59: 1243-1251, 1996.

15. Nystrom-Lahti, M.; Kristo, P.; Nicolaides, N. C.; Chang, S.-Y.;
Aaltonen, L. A.; Moisio, A.-L.; Jarvinen, H. J.; Mecklin, J.-P.; Kinzler,
K. W.; Vogelstein, B.; de la Chapelle, A.; Peltomaki, P.: Founding
mutations and Alu-mediated recombination in hereditary colon cancer. Nature
Med. 1: 1203-1206, 1995.

16. Nystrom-Lahti, M.; Sistonen, P.; Mecklin, J.-P.; Pylkkanen, L.;
Aaltonen, L. A.; Jarvinen, H.; Weissenbach, J.; de la Chapelle, A.;
Peltomaki, P.: Close linkage to chromosome 3p and conservation of
ancestral founding haplotype in hereditary nonpolyposis colorectal
cancer families. Proc. Nat. Acad. Sci. 91: 6054-6058, 1994.

17. Papadopoulos, N.; Nicolaides, N. C.; Wei, Y.-F.; Ruben, S. M.;
Carter, K. C.; Rosen, C. A.; Haseltine, W. A.; Fleischmann, R. D.;
Fraser, C. M.; Adams, M. D.; Venter, J. C.; Hamilton, S. R.; Petersen,
G. M.; Watson, P.; Lynch, H. T.; Peltomaki, P.; Mecklin, J.-P.; de
la Chapelle, A.; Kinzler, K. W.; Vogelstein, B.: Mutation of a mutL
homolog in hereditary colon cancer. Science 263: 1625-1629, 1994.

18. Paraf, F.; Sasseville, D.; Watters, A. K.; Narod, S.; Ginsburg,
O.; Shibata, H.; Jothy, S.: Clinicopathological relevance of the
association between gastrointestinal and sebaceous neoplasms: the
Muir-Torre syndrome. Hum. Pathol. 26: 422-427, 1995.

19. Plummer, S. J.; Casey, G.: Are we any closer to genetic testing
for common malignancies? Nature Med. 2: 156-158, 1996.

20. Sasaki, S.; Horii, A.; Shimada, M.; Han, H.-J.; Yanagisawa, A.;
Muto, T.; Nakamura, Y.: Somatic mutations of a human mismatch repair
gene, hMLH1, in tumors from patients with multiple primary cancers. Hum.
Mutat. 7: 275-278, 1996.

21. Tannergard, P.; Zabarovsky, E.; Stanbridge, E.; Nordenskjold,
M.; Lindblom, A.: Sublocalization of a locus at 3p21.3-23 predisposing
to hereditary nonpolyposis colon cancer. Hum. Genet. 94: 210-214,
1994.

22. Wijnen, J.; Khan, P. M.; Vasen, H.; Menko, F.; van der Klift,
H.; van den Broek, M.; van Leeuwen-Cornelisse, I.; Nagengast, F.;
Meijers-Heijboer, E. J.; Lindhout, D.; Griffioen, G.; Cats, A.; Kleibeuker,
J.; Varesco, L.; Bertario, L.; Bisgaard, M.-L.; Mohr, J.; Kolodner,
R.; Fodde, R.: Majority of hMLH1 mutations responsible for hereditary
nonpolyposis colorectal cancer cluster at the exonic region 15-16. Am.
J. Hum. Genet. 58: 300-307, 1996.

*FIELD* CS

Oncology:
   Nonpolyposis colon cancer

Misc:
   Up to 30% of cases

Inheritance:
   Autosomal dominant (3p23-p21.3)

*FIELD* CN
Moyra Smith - updated: 7/1/1996

*FIELD* CD
Victor A. McKusick: 12/9/1993

*FIELD* ED
alopez: 03/19/1997
terry: 1/16/1997
jamie: 1/15/1997
terry: 1/7/1997
jamie: 11/15/1996
terry: 11/14/1996
terry: 10/8/1996
terry: 8/19/1996
terry: 7/29/1996
terry: 7/2/1996
mark: 7/1/1996
terry: 7/1/1996
mark: 7/1/1996
terry: 6/27/1996
mark: 5/15/1996
terry: 5/13/1996
mark: 2/23/1996
terry: 2/19/1996
mark: 2/16/1996
mark: 2/13/1996
mark: 2/10/1996
terry: 2/5/1996
terry: 6/3/1995
mark: 5/14/1995
carol: 12/30/1994
jason: 7/13/1994
mimadm: 6/25/1994
carol: 12/9/1993

*RECORD*
*FIELD* NO
120440
*FIELD* TI
120440 COLONIC VARICES WITHOUT PORTAL HYPERTENSION
*FIELD* TX
Hawkey et al. (1985) reported lower bowel bleeding from colonic varices
in adult brother and sister and the daughter of one of them. No evidence
of liver disease or portal hypertension was found in any. The authors
sited two other instances of familial colonic varices with normal portal
pressure and concluded that the disorder represents one of venous
dysplasia.

*FIELD* RF
1. Hawkey, C. J.; Amar, S. S.; Daintith, H. A. M.; Toghill, P. J.
: Familial varices of the colon occurring without evidence of portal
hypertension. Brit. J. Radiol. 58: 677-679, 1985.

*FIELD* CS

GI:
   Lower bowel bleeding;
   Colonic varices;
   No liver disease;
   Normal portal pressure

Vascular:
   Venous dysplasia

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
120450
*FIELD* TI
120450 COMEDONES, FAMILIAL DYSKERATOTIC
*FIELD* TX
Carneiro et al. (1972) described a family in which 4 members had
disseminated comedo-like lesions which histologically showed distinctive
dyskeratotic changes. Rodin et al. (1967) described widespread comedones
in multiple family members. Dyskeratosis was not mentioned. No
male-to-male transmission has been observed.

*FIELD* RF
1. Carneiro, S. J.; Dickson, J. E.; Knox, J. M.: Familial dyskeratotic
comedones. Arch. Derm. 105: 249-251, 1972.

2. Rodin, H. H.; Blankenship, M. L.; Bernstein, G.: Diffuse familial
comedones. Arch. Derm. 95: 145-146, 1967.

*FIELD* CS

Skin:
   Dyskeratotic comedones

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 12/30/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
120460
*FIELD* TI
120460 COLORECTAL CANCER-RELATED CHROMOSOME SEQUENCE-17; CRCR2; CRC17
*FIELD* TX
Fearon et al. (1987) used X-linked RFLPs to examine the pattern of
X-chromosome inactivation in colorectal tumors of females. All 50
examined showed monoclonal patterns of X-chromosome inactivation; these
tumors included 20 carcinomas and 30 adenomas of either familial or
spontaneous type. Fearon et al. (1987) also used RFLPs of autosomes as
clonal markers to detect somatic loss or gain of specific chromosomal
sequences in colorectal tumors. They found that somatic loss of
chromosome 17p sequences occurred in over 75% of the carcinomas
examined, but that such loss was rare in adenomas. Monpezat et al.
(1988) also found loss of alleles located on 17p, loss of alleles from
chromosome 18 (120470), or both. By the study of 20 chromosome 17p
markers, Baker et al. (1989) localized the common region of deletion in
colorectal carcinomas to 17p13.3-p12. This region contains the gene for
the transformation-associated protein p53 (TP53; 191170). In 2 tumors in
which the TP53 gene was deleted on 1 chromosome, they could show that
the remaining allele was mutant; alanine substituted for valine at codon
143 in 1 tumor and histidine substituted for arginine at codon 175 of
the second tumor. Both mutations were in a highly conserved region of
the TP53 gene that had previously been found to be mutated in murine p53
oncogenes. Baker et al. (1989) concluded that TP53 mutations may be
involved in colorectal cancer (114500), perhaps through inactivation of
a tumor suppressor function of the wildtype gene. Evidence suggests that
the p53 gene is usually the relevant target in cases of 17p deletion
(Vogelstein, 1990).

*FIELD* RF
1. Baker, S. J.; Fearon, E. R.; Nigro, J. M.; Hamilton, S. R.; Preisinger,
A. C.; Jessup, J. M.; vanTuinen, P.; Ledbetter, D. H.; Barker, D.
F.; Nakamura, Y.; White, R.; Vogelstein, B.: Chromosome 17 deletions
and p53 gene mutations in colorectal carcinomas. Science 244: 217-221,
1989.

2. Fearon, E. R.; Hamilton, S. R.; Vogelstein, B.: Clonal analysis
of human colorectal tumors. Science 238: 193-197, 1987.

3. Monpezat, J. P.; Delattre, O.; Bernard, A.; Grunwald, D.; Remvikos,
Y.; Muleris, M.; Salmon, R. J.; Frelat, G.; Dutrillaux, B.; Thomas,
G.: Loss of alleles on chromosome 18 and on the short arm of chromosome
17 in polyploid colorectal carcinomas. Int. J. Cancer 41: 404-408,
1988.

4. Vogelstein, B.: Personal Communication. Baltimore, Md.  7/12/1990.

*FIELD* CD
Victor A. McKusick: 2/2/1988

*FIELD* ED
warfield: 4/8/1994
carol: 9/30/1992
supermim: 3/16/1992
carol: 7/12/1990
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
120470
*FIELD* TI
*120470 DELETED IN COLORECTAL CARCINOMA; DCC
COLORECTAL CANCER-RELATED CHROMOSOME SEQUENCE-18; CRC18;;
CRCR1
*FIELD* TX
Vogelstein et al. (1988) found that chromosome 18 sequences were lost
frequently in colorectal carcinomas (73%) and in advanced adenomas
(47%), but only occasionally in earlier stage adenomas (11-13%). Taken
in connection with other findings of changes in chromosome 17, as well
as chromosome 5, these findings suggest a model wherein the steps
required for malignancy often involve the activation of a dominantly
acting oncogene coupled with the loss of several genes that normally
suppress tumorigenesis. The critical area in chromosome 18 appeared to
reside between 18q21.3 and the telomere. It is of interest that Lynch et
al. (1985) found a lod score of 3.19 for linkage between a familial
cancer syndrome (Lynch syndrome II; 114400) and Kidd blood group (JK;
111000); the Kidd blood group has been assigned to 18q11-q12. Boman et
al. (1988) found tumor-specific allele loss at the D18S6 locus on
chromosome 18 in 2 patients with familial adenomatous polyposis and in 2
patients with sporadic colon cancer. D18S6 is closely linked to LCFS2
and JK. Fearon et al. (1990) cloned a contiguous stretch of DNA,
comprising 370 kb, from the region of 18q suspected to contain the tumor
suppressor gene. Potential exons in the 370-kb region were defined by
human-rodent sequence identities, and the expression of potential exons
was assessed by an 'exon-connection' strategy based on the polymerase
chain reaction. Expressed exons were used as probes for screening of
cDNA to obtain clones that encoded a gene the authors termed DCC
('deleted in colorectal carcinomas'). This cDNA was encoded by at least
8 exons. The predicted amino acid sequence specified a protein with
sequence similarity to neural cell adhesion molecules (116930) and
related cell surface glycoproteins. While the DCC gene was expressed in
most normal tissues, including colonic mucosa, its expression was
greatly reduced or absent in most colorectal carcinomas tested. Somatic
mutations within the DCC gene observed in colorectal cancers included a
homozygous deletion of the 5-prime end, a point mutation within one of
the introns, and 10 examples of DNA insertions within a 0.17-kb fragment
immediately downstream of one of the exons.

Thiagalingam et al. (1996) evaluated sporadic colon cancer tumors for
allelic deletions. They defined a minimally lost region (MLR) on
chromosome 18q21 which extended between markers D18S535 and D18S858. It
encompassed 16 cM between D18S535 and 20CO3 and included 2 candidate
tumor suppressor genes: DPC4 (600993) and DCC. DPC4 was deleted in up to
one-third of cases and DCC or a neighboring gene was deleted in the
remaining tumors.

Tanaka et al. (1991) demonstrated that transfer of a normal human
chromosome 18 into a colon carcinoma cell line through microcell
hybridization severely reduced the cloning efficiency of the hybrid
cells in soft agar and completely suppressed tumorigenicity in athymic
nude mice. Similar results were obtained when a normal chromosome 5,
which carries the locus for adenomatous polyposis coli (175100), was
transferred into the cells, but the growth properties of the hybrid
cells were unchanged when chromosome 11 was introduced. Nigro et al.
(1991) observed a curious phenomenon of scrambled exons in the DCC gene
in a variety of normal and neoplastic cells of rodent and human origin.
Abnormally spliced transcripts showed that exons were joined accurately
at consensus splice sites, but in an order different from that present
in the primary transcript. Thus, a novel type of RNA product resulted.
Using molecular markers in an interspecific backcross between C57BL/6J
and Mus spretus, Justice et al. (1992) mapped the corresponding gene to
mouse chromosome 18. In a study of 28 cases of surgically resected
gastric cancer, excluding the diffuse type, Uchino et al. (1992)
concluded that loss of heterozygosity (LOH) on chromosome 18q occurs at
an earlier stage than LOH on chromosome 17p and that tumor suppressor
genes located on these 2 chromosome arms is critically involved in the
development of most gastric cancers. Involvement of DCC may be rather
selective for gastrointestinal cancers. Hohne et al. (1992) presented
evidence that loss of DCC gene expression is an important factor in the
development or progress of pancreatic adenocarcinoma. In 8 of 11
pancreatic carcinoma cell lines and in 4 of 8 primary ductal
adenocarcinomas of the pancreas, a complete extinction of DCC gene
expression was observed, whereas the KRAS gene (190070) was mutated at
codon 12 in 7 of the 8 primary tumors. Reduced or absent DCC expression
tended to be associated with undifferentiated pancreatic tumor cell
lines, whereas in the more differentiated ones, DCC expression was
conserved.

Cho et al. (1994) commented that the DCC gene encodes a protein with
sequence similarity to cell adhesion molecules such as N-CAM (116930).
Studying a YAC contig containing the entire DCC coding region, they
showed that the DCC gene spans approximately 1.4 Mb. They used lambda
phage clones to demonstrate the existence of 29 DCC exons, and the
sequences of the exon-intron boundaries were determined. In a panel of
primary colorectal tumors, they found that most had lost the region
containing DCC.

The DCC protein has structural features in common with certain types of
cell-adhesion molecules and may participate with other proteins in
cell-cell and cell-matrix interactions. Zetter (1993) found that
expression of the DCC gene was absent in most colorectal cancers that
were metastatic to the liver, but was lost only in a minority of
nonmetastatic cancers. Furthermore, Jen et al. (1994) found that allelic
loss of 18q in the region occupied by the DCC gene carried a worse
prognosis than that in cases with no loss of chromosome 18q. They
developed procedures to examine the status of 18q with microsatellite
markers and PCR-amplified DNA from formalin-fixed, paraffin-embedded
tumors. Normal tissue and tumor tissue could be examined on the same
microscopic slide. Allelic loss of 18q was assessed in 145 consecutively
resected stage II or III colorectal carcinomas. The prognosis in
patients with stage II cancer (Dukes stage B; tumor extending through
the bowel wall, without lymph-node metastasis) was similar to that in
patients with stage III cancer, who were thought to benefit from
adjuvant therapy. In contrast, patients with stage II disease who did
not have chromosome 18q allelic loss in their tumor had a survival rate
similar to that of patients with stage I disease and might not require
additional therapy.

Shibata et al. (1996) reported findings that extended the observations
of Jen et al. (1994), who had found that allelic loss of 18q predicted a
poor outcome in patients with stage II colorectal cancer. They studied
the DCC gene as a possible specific prognostic marker. Expression of DCC
was evaluated immunohistochemically in 132 paraffin-embedded samples
from patients with curatively resected stage II or stage III colorectal
carcinomas. They found that expression of DCC was a strong positive
predictive factor for survival in both stage II and stage III colorectal
carcinomas. In patients with stage II disease whose tumors expressed
DCC, the 5-year survival rate was 94.3%, whereas in patients with
DCC-negative tumors, the survival rate was 61.6%. In patients with stage
III disease, the respective survival rates were 59.3% and 33.2%.

Vogelstein (1995) stated that the precise location of the DCC gene was
thought to be 18q21.3.

Maesawa et al. (1996) screened tumor specimens from 111 patients with
esophageal squamous cell carcinoma for LOH at the DCC locus and observed
LOH in 10 of 61 informative cases (16%). No statistically significant
correlation was observed between DCC-LOH and lymph node metastasis,
histopathologic grade, or tumor stage. Survivorship of DCC-LOH patients
was not statistically different from that of patients without LOH. These
results suggested to Maesawa et al. (1996) that LOH at the DCC locus is
not related to the acquisition of metastatic potential or the state of
tumor cell differentiation in esophageal squamous cell carcinoma.

Keino-Masu et al. (1996) noted that the establishment of neuronal
connections involves the accurate guidance of developing axons to their
targets through the combined actions of attractive and repulsive
guidance cues in the extracellular environment. Diffusible
chemoattractants secreted by target cells are involved, as well as
diffusible chemorepellents secreted by nontarget cells which generate
exclusion zones that axons avoid (Keynes and Cook, 1995). Two recently
identified families of guidance molecules, the netrins and semaphorins
(see for example 601281 and 601124), comprise members that can function
as diffusible attractants or repellents for developing neurons, but the
receptors and signal transduction mechanisms through which they produce
their effects are poorly understood. Netrins are chemoattractants for
commissural axons in the vertebral spinal cord. Keino-Masu et al. (1996)
showed that DCC, a transmembrane protein of the immunoglobulin
superfamily, is expressed on spinal commissural axons and possesses
netrin-1-binding activity. Moreover, an antibody to DCC selectively
blocked the netrin-1-dependent outgrowth of commissural axons in vitro.
These results indicated that DCC is a receptor or a component of a
receptor that mediates the effects of netrin-1 on commissural axons, and
they complement genetic evidence for interactions between DCC and netrin
homologs in C. elegans (UNC-40; see Chan et al., 1996) and Drosophila
(frazzled; see Kolodziej et al., 1996).

*FIELD* AV
.0001
COLORECTAL CANCER
DCC, PRO-HIS, 4124C-A
To look for structural alterations of the DCC gene, Cho et al. (1994)
analyzed 60 colorectal cancers matched with normal DNA samples from the
same individual, using Southern blot hybridization to DCC cDNA probes.
In 1 tumor, an altered pattern of EcoRI fragments was found and shown to
have its basis in a somatically acquired point mutation in intron 13.
The sequences flanking the mutation had features suggestive of an exon,
including a short open reading frame and consensus splice acceptor and
donor sites. These findings suggested that the tumor contained a
mutation in an alternatively utilized exon. To search for more subtle
alterations, Cho et al. (1994) evaluated several exons and their
flanking intron sequences for the presence of mutations in 30 colorectal
cancers by an RNase protection assay. A C-to-A transversion at position
4124 in exon 28 was identified in 1 tumor. This mutation was predicted
to result in a nonconservative amino acid change from proline to
histidine. It was absent from the DNA of normal lymphocytes from the
same patient.

.0002
ESOPHAGEAL CARCINOMA
DCC, MET168THR
Since the tumor suppressor gene DCC shows amino acid sequence homology
to the neural cell adhesion molecule (116930), Miyake et al. (1994)
considered the possibility that DCC might be related to tumor
metastasis. They examined 51 cases of primary esophageal carcinoma for
point mutations and loss of the gene. By screening using PCR-single
strand conformation polymorphism analysis, they found point mutations in
2 cases. One case with lymph node metastasis showed an ATG (met) to ACC
(thr) missense mutation in codon 168. Another case showed a CGA (arg) to
GGA (gly) mutation in codon 201, which might be a polymorphic change,
and 2 other mutations resulting in no amino acid change. Forty-four of
the 51 cases (86%) were informative for loss of heterozygosity of the
DCC gene; of these, 10 (23%) showed allelic deletion. The further away
the lymph node metastasis was from the primary tumor, the higher the
frequency of allelic deletions. They also found allelic deletions in
moderately and poorly differentiated squamous cell carcinomas but not in
well-differentiated ones. They interpreted these findings to indicate
that alterations in the DCC gene are related to the degree of lymph node
metastasis and the degree of differentiation.

*FIELD* RF
1. Boman, B. M.; Wildrick, D. M.; Alfaro, S. R.: Chromosome 18 allele
loss at the D18S6 locus in human colorectal carcinomas. Biochem.
Biophys. Res. Commun. 155: 463-469, 1988.

2. Chan, S. S.-Y.; Zheng, H.; Su, M.-W.; Wilk, R.; Killeen, M. T.;
Hedgecock, E. M.; Culotti, J. G.: UNC-40, a C. elegans homolog of
the DCC (deleted in colorectal cancer), is required in motile cells
responding to UNC-6 netrin cues. Cell 87: 187-195, 1996.

3. Cho, K. R.; Oliner, J. D.; Simons, J. W.; Hedrick, L.; Fearon,
E. R.; Preisinger, A. C.; Hedge, P.; Silverman, G. A.; Vogelstein,
B.: The DCC gene: structural analysis and mutations in colorectal
carcinomas. Genomics 19: 525-531, 1994.

4. Fearon, E. R.; Cho, K. R.; Nigro, J. M.; Kern, S. E.; Simons, J.
W.; Ruppert, J. M.; Hamilton, S. R.; Preisinger, A. C.; Thomas, G.;
Kinzler, K. W.; Vogelstein, B.: Identification of a chromosome 18q
gene that is altered in colorectal cancers. Science 247: 49-56,
1990.

5. Hohne, M. W.; Halatsch, M.-E.; Kahl, G. F.; Weinel, R. J.: Frequent
loss of expression of the potential tumor suppressor gene DCC in ductal
pancreatic adenocarcinoma. Cancer Res. 52: 2616-2619, 1992.

6. Jen, J.; Kim, H.; Piantadosi, S.; Liu, Z.-F.; Levitt, R. C.; Sistonen,
P.; Kinzler, K. W.; Vogelstein, B.; Hamilton, S. R.: Allelic loss
of chromosome 18q and prognosis in colorectal cancer. New Eng. J.
Med. 331: 213-221, 1994.

7. Justice, M. J.; Gilbert, D. J.; Kinzler, K. W.; Vogelstein, B.;
Buchberg, A. M.; Ceci, J. D.; Matsuda, Y.; Chapman, V. M.; Patriotis,
C.; Makris, A.; Tsichlis, P. N.; Jenkins, N. A.; Copeland, N. G.:
A molecular genetic linkage map of mouse chromosome 18 reveals extensive
linkage conservation with human chromosomes 5 and 18. Genomics 13:
1281-1288, 1992.

8. Keino-Masu, K.; Masu, M.; Hinck, L.; Leonardo, E. D.; Chan, S.
S.-Y.; Culotti, J. G.; Tessier-Lavigne, M.: Deleted in colorectal
cancer (DCC) encodes a netrin receptor. Cell 87: 175-185, 1996.

9. Keynes, R.; Cook, G. M. W.: Axon guidance molecules. Cell 83:
161-169, 1995.

10. Kolodziej, P. A.; Timpe, L. C.; Mitchell, K. J.; Fried, S. R.;
Goodman, C. S.; Jan, L. Y.; Jan, Y. N.: Frazzled encodes a Drosophila
member of the DCC immunoglobulin subfamily and is required for CNS
and motor axon guidance. Cell 87: 197-204, 1996.

11. Lynch, H. T.; Schuelke, G. S.; Kimberling, W. J.; Albano, W. A.;
Lynch, J. F.; Biscone, K. A.; Lipkin, M. L.; Deschner, E. E.; Mikol,
Y. B.; Sandberg, A. A.; Elston, R. C.; Bailey-Wilson, J. E.; Danes,
B. S.: Hereditary nonpolyposis colorectal cancer (Lynch syndromes
I and II). II. Biomarker studies. Cancer 56: 939-951, 1985.

12. Maesawa, C.; Tamura, G.; Ogasawara, S.; Suzuki, Y.; Sakata, K.;
Sugimura, J.; Nishizuka, S.; Sato, N.; Ishida, K.; Saito, K.; Satodate,
R.: Loss of heterozygosity at the DCC gene locus is not crucial for
the acquisition of metastatic potential in oesophageal squamous cell
carcinoma. Europ. J. Cancer. 32A: 896-898, 1996.

13. Miyake, S.; Nagai, K.; Yoshino, K.; Oto, M.; Endo, M.; Yuasa,
Y.: Point mutations and allelic deletion of tumor suppressor gene
DCC in human esophageal squamous cell carcinomas and their relation
to metastasis. Cancer Res. 54: 3007-3010, 1994.

14. Nigro, J. M.; Cho, K. R.; Fearon, E. R.; Kern, S. E.; Ruppert,
J. M.; Oliner, J. D.; Kinzler, K. W.; Vogelstein, B.: Scrambled exons. Cell 64:
607-613, 1991.

15. Shibata, D.; Reale, M. A.; Lavin, P.; Silverman, M.; Fearon, E.
R.; Steele, G., Jr.; Jessup, J. M.; Loda, M.; Summerhayes, I. C.:
The DCC protein and prognosis in colorectal cancer. New Eng. J. Med. 335:
1727-1732, 1996.

16. Tanaka, K.; Oshimura, M.; Kikuchi, R.; Seki, M.; Hayashi, T.;
Miyaki, M.: Suppression of tumorigenicity in human colon carcinoma
cells by introduction of normal chromosome 5 or 18. Nature 349:
340-342, 1991.

17. Thiagalingam, S.; Lengauer, C.; Leach, F. S.; Schutte, M.; Hahn,
S. A.; Overhauser, J.; Willson, J. K. V.; Markowitz, S.; Hamilton,
S. R.; Kern, S. E.; Kinzler, K. W.; Vogelstein, B.: Evaluation of
candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nature
Genet. 13: 343-346, 1996.

18. Uchino, S.; Tsuda, H.; Noguchi, M.; Yokota, J.; Terada, M.; Saito,
T.; Kobayashi, M.; Sugimura, T.; Hirohashi, S.: Frequent loss of
heterozygosity at the DCC locus in gastric cancer. Cancer Res. 52:
3099-3102, 1992.

19. Vogelstein, B.: Personal Communication. Baltimore, Md.  11/30/1995.

20. Vogelstein, B.; Fearon, E. R.; Hamilton, S. R.; Kern, S. E.; Preisinger,
A. C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A. M. M.; Bos,
J. L.: Genetic alterations during colorectal-tumor development. New
Eng. J. Med. 319: 525-532, 1988.

21. Zetter, B. R.: Adhesion molecules in tumor metastasis. Semin.
Cancer Biol. 4: 219-229, 1993.

*FIELD* CN
Moyra Smith - updated: 7/4/1996

*FIELD* CD
Victor A. McKusick: 2/26/1988

*FIELD* ED
mark: 01/06/1997
terry: 1/3/1997
mark: 12/20/1996
terry: 12/10/1996
terry: 12/9/1996
terry: 9/17/1996
marlene: 8/15/1996
mark: 7/5/1996
mark: 7/4/1996
mark: 12/18/1995
mark: 12/15/1995
terry: 12/6/1995
carol: 11/18/1994
terry: 8/25/1994
carol: 12/22/1993
carol: 12/17/1993
carol: 3/29/1993
carol: 11/3/1992

*RECORD*
*FIELD* NO
120500
*FIELD* TI
120500 COMMISSURAL LIP PITS
*FIELD* TX
These occur at the corners of the mouth. They are frequently of
pencil-lead size, from 1 to 4 mm deep and may be filled with cellular
debris. Preauricular pits may be associated. Everett and Wescott (1961)
found 2 cases among 1000 school children of Portland, Oregon. Witkop
(1965) and these authors found evidence of dominant inheritance but
could not distinguish between autosomal and X-linked dominance. Baker
(1966) found lip pits in 12% of Caucasoids and 20% of blacks. Congenital
preauricular sinuses occurred more frequently in persons with pits than
in those without pits.

*FIELD* RF
1. Baker, B. R.: Pits of the lip commissures in Caucasoid males.
Oral Surg. 21: 56-60, 1966.

2. Everett, F. G.; Wescott, W. B.: Commissural lip pits. Oral Surg. 14:
202-209, 1961.

3. Witkop, C. J., Jr.: Genetic disease of the oral cavity. In: Tiecke,
R. W.: Oral Pathology.  New York: McGraw-Hill (pub.)  1965.

*FIELD* CS

Mouth:
   Commissural lip pits

Ears:
   Preauricular pits

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 1/7/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
120502
*FIELD* TI
120502 COMMISSURAL LIP PITS WITH CONGENITAL CONDUCTIVE OR MIXED DEAFNESS,
PREAURICULAR SINUS, AND EXTERNAL EAR ANOMALY
*FIELD* TX
Marres and Cremers (1991) described a kindred in which 20 of 74 persons
in 3 generations had external ear anomalies, preauricular sinuses (or
cysts), and commissural lip pits, either in combination or separately.
The external ear anomaly was relatively minor and was found in 12
persons. Eleven persons had unilateral or bilateral preauricular sinus.
Two individuals without sinus or ear pit had a palpable preauricular
cyst. Eight persons had one or more commissural lip pits, which had not
been noticed before the study. Although several of the features form
part of the BOR syndrome (113650), Marres and Cremers (1991) considered
this a distinct entity because of the absence of cervical fistulae and
renal abnormalities and the presence of commissural lip pits. Baker
(1966) found commissural lip pits in 12% of Caucasoids and 20% of
blacks. Congenital preauricular sinuses occurred more frequently in
persons with pits than in those without pits.

*FIELD* RF
1. Baker, B. R.: Pits of the lip commissures in Caucasoid males.
Oral Surg. 21: 56-60, 1966.

2. Marres, H. A. M.; Cremers, C. W. R. J.: Congenital conductive
or mixed deafness, preauricular sinus, external ear anomaly, and commissural
lips pits: an autosomal dominant inherited syndrome. Ann. Otol.
Rhinol. Laryng. 100: 928-932, 1991.

*FIELD* CS

Ears:
   External ear anomaly;
   Preauricular sinuses (or cysts);
   Congenital hearing loss

Mouth:
   Commissural lip pits

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 1/9/1992

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 1/9/1992

*RECORD*
*FIELD* NO
120520
*FIELD* TI
*120520 COMMON ACUTE LYMPHOCYTIC LEUKEMIA ANTIGEN; CALLA; CD10
MEMBRANE METALLOENDOPEPTIDASE; MME
MEMBRANE-ASSOCIATED NEUTRAL ENDOPEPTIDASE, INCLUDED;;
NEP, INCLUDED;;
ENKEPHALINASE, INCLUDED
*FIELD* TX
Common acute lymphocytic leukemia antigen is an important cell surface
marker in the diagnosis of human acute lymphocytic leukemia (ALL). It is
present on leukemic cells of pre-B phenotype, which represent 85% of
cases of ALL. CALLA is not restricted to leukemic cells, however, and is
found on a variety of normal tissues. CALLA is a glycoprotein that is
particularly abundant in kidney, where it is present on the brush border
of proximal tubules and on glomerular epithelium. Letarte et al. (1988)
cloned a cDNA coding for CALLA and showed that the amino acid sequence
deduced from the cDNA sequence is identical to that of human
membrane-associated neutral endopeptidase (NEP; EC 3.4.24.11), also
known as enkephalinase. NEP cleaves peptides at the amino side of
hydrophobic residues and inactivates several peptide hormones including
glucagon, enkephalins, substance P, neurotensin, oxytocin, and
bradykinin. By cDNA transfection analysis, Shipp et al. (1989) confirmed
that CALLA is a functional neutral endopeptidase of the type that has
previously been called enkephalinase. Barker et al. (1989) demonstrated
that the CALLA gene, which encodes a 100-kD type II transmembrane
glycoprotein, exists in a single copy of greater than 45 kb which is not
rearranged in malignancies expressing cell surface CALLA. The gene was
located to human chromosome 3 by study of somatic cell hybrids and in
situ hybridization regionalized the location to 3q21-q27. Tran-Paterson
et al. (1989) also assigned the gene to chromosome 3 by Southern blot
analysis of DNA from human-rodent somatic cell hybrids. D'Adamio et al.
(1989) demonstrated that the CALLA gene spans more than 80 kb and is
composed of 24 exons.

*FIELD* RF
1. Barker, P. E.; Shipp, M. A.; D'Adamio, L.; Masteller, E. L.; Reinherz,
E. L.: The common acute lymphoblastic leukemia antigen gene maps
to chromosomal region 3(q21-q27). J. Immun. 142: 283-287, 1989.

2. D'Adamio, L.; Shipp, M. A.; Masteller, E. L.; Reinherz, E. L.:
Organization of the gene encoding common acute lymphoblastic leukemia
antigen (neutral endopeptidase 24.11): multiple miniexons and separate
5-prime untranslated regions. Proc. Nat. Acad. Sci. 86: 7103-7107,
1989.

3. Letarte, M.; Vera, S.; Tran, R.; Addis, J. B. L.; Onizuka, R. J.;
Quackenbush, E. J.; Jongeneel, C. V.; McInnes, R. R.: Common acute
lymphocytic leukemia antigen is identical to neutral endopeptidase.
J. Exp. Med. 168: 1247-1253, 1988.

4. Shipp, M. A.; Vijayaraghavan, J.; Schmidt, E. V.; Masteller, E.
L.; D'Adamio, L.; Hersh, L. B.; Reinherz, E. L.: Common acute lymphoblastic
leukemia antigen (CALLA) is active neutral endopeptidase 24.11 ('enkephalinase'):
direct evidence by cDNA transfection analysis. Proc. Nat. Acad.
Sci. 86: 297-301, 1989.

5. Tran-Paterson, R.; Willard, H. F.; Letarte, M.: The common acute
lymphoblastic leukemia antigen (neutral endopeptidase--3.4.24.11)
gene is located on human chromosome 3. Cancer Genet. Cytogenet. 42:
129-134, 1989.

*FIELD* CD
Victor A. McKusick: 12/1/1988

*FIELD* ED
carol: 11/17/1995
carol: 6/8/1992
carol: 4/3/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 1/7/1990

*RECORD*
*FIELD* NO
120550
*FIELD* TI
*120550 COMPLEMENT COMPONENT 1, q SUBCOMPONENT, ALPHA POLYPEPTIDE; C1QA
COMPLEMENT COMPONENT-C1q, A CHAIN;;
SERUM C1q
*FIELD* TX
The first component of complement is a calcium-dependent complex of the
3 subcomponents C1q, C1r, and C1s. Subcomponent C1q binds to
immunoglobulin complexes with resulting serial activation of C1r
(enzyme), C1s (proenzyme) and the other 8 components of complement. C1q
is composed of 3 different species of chains, called A, B (120570), and
C (120575). Fragments of the A chain of C1q have been sequenced. The
total A chain contains 190 amino acids. C1q shares with collagen the
presence of hydroxyproline in its amino acid sequence. Bing et al.
(1982) showed that fibronectin binds to C1q in the same manner that it
binds collagen. A major function of the fibronectins is in the adhesion
of cells to extracellular materials such as solid substrata and
matrices. Because fibronectin stimulates endocytosis and promotes the
clearance of particulate material from the circulation, the results of
Bing et al. (1982) suggest that fibronectin functions in the clearance
of C1q-coated material such as immune complexes or cellular debris.
Rother (1986) gave a summary of reported deficiencies of components of
complement. Many examples of deficiencies of C1q were listed, most of
them associated with systemic lupus erythematosus or glomerulonephritis.
Three instances of deficiency of C1r alone and several of C1r and C1s in
combination were also listed. Hedge et al. (1987) isolated a cDNA clone
for the A chain of C1q from a human monocyte cDNA library using a
variety of synthetic oligonucleotides as probes. They used this clone on
a panel of somatic cell hybrids to assign the gene for the A chain to
chromosome 1p, where the gene for the B chain had been assigned
previously. The genes for the A, B, and C chains of C1q are tandemly
arranged 5-prime to 3-prime in the order A-C-B on a 24-kb stretch of DNA
(Sellar et al., 1991). A and C are separated by 4 kb and B and C are
separated by 11 kb. Hybridization of cDNA probes to a hybrid cell line
containing the derived X chromosome from an X;1(q21.2;p34) translocation
described in a female patient with Duchenne muscular dystrophy
(Lindenbaum et al., 1979; Boyd et al., 1988) showed that the A and B
genes are located in the region 1p36.3-p34.1.

*FIELD* AV
.0001
C1Q DEFICIENCY, TYPE A
C1QA, GLN186TER
Topaloglu et al. (1996) described 2 sibs with homozygous C1q deficiency.
Both presented with a photosensitive rash and during follow-up 1
developed SLE with proteinuria in the nephrotic range. The other sib had
microscopic hematuria with a history of macroscopic hematuria. Renal
biopsies revealed mesangioproliferative glomerulonephritis in 1 and IgA
nephropathy in the other. Antibody response to hepatitis B vaccine was
normal in affected and unaffected members of the family. The sibs were
found to be homozygous for a C-to-T transition in codon 186 of the A
chain that resulted in a premature stop codon (gln186ter). The mutation
was present in heterozygous state in both parents and in 2 unaffected
sibs. The same mutation had been previously described in a Slovakian
family with C1q deficiency. The change in codon 186 was CAG (gln) to TAG
(stop).

*FIELD* SA
Gilmour et al. (1980); Reid  (1974); Sellar et al. (1992)
*FIELD* RF
1. Bing, D. H.; Almeda, S.; Isliker, H.; Lahav, J.; Hynes, R. O.:
Fibronectin binds to the C1q component of complement. Proc. Nat.
Acad. Sci. 79: 4198-4201, 1982.

2. Boyd, Y.; Cockburn, D.; Holt, S.; Munro, E.; van Ommen, G. J.;
Gillard, B.; Affara, N.; Ferguson-Smith, M.; Craig, I.: Mapping of
12 translocation breakpoints in the Xp21 region with respect to the
locus for Duchenne muscular dystrophy. Cytogenet. Cell Genet. 48:
28-34, 1988.

3. Gilmour, S.; Randall, J. T.; Willan, K. J.; Dwek, R. A.; Torbet,
J.: The confirmation of subcomponent C1q of the first component of
human complement. Nature 285: 512-514, 1980.

4. Hedge, P. J.; Seller, G. C.; Reid, K. B. M.; Solomon, E.: Assignment
of the A chain of C1q (C1QA) to the short arm of chromosome 1. (Abstract) Cytogenet.
Cell Genet. 46: 627 only, 1987.

5. Lindenbaum, R. H.; Clarke, G.; Patel, C.; Moncrieff, M.; Hughes,
J. T.: Muscular dystrophy in an X;1 translocation female suggests
that Duchenne locus is on X chromosome short arm. J. Med. Genet. 16:
389-392, 1979.

6. Reid, K. B. M.: A collagen-like amino acid sequence in a polypeptide
chain of human C1q (a subcomponent of the first component of complement). Biochem.
J. 141: 189-203, 1974.

7. Rother, K.: Hereditary deficiencies in man: summary of reported
deficiencies. Prog. Allergy 39: 202-211, 1986.

8. Sellar, G. C.; Blake, D. J.; Reid, K. B.: Characterization and
organization of the genes encoding the A-, B-, and C-chains of human
complement subcomponent C1q: the complete derived amino acid sequence
of human C1q. Biochem. J. 274: 481-490, 1991.

9. Sellar, G. C.; Cockburn, D.; Reid, K. B. M.: Localization of the
gene cluster encoding the A, B, and C chains of human C1q to 1p34.1-1p36.3. Immunogenetics 35:
214-216, 1992.

10. Topaloglu, R.; Bakkaloglu, A.; Slingsby, J. H.; Mihatsch, M. J.;
Pascual, M.; Norsworthy, P.; Morley, B. J.; Saatci, U.; Schifferli,
J. A.; Walport, M. J.: Molecular basis of hereditary C1q deficiency
associated with SLE and IgA nephropathy in a Turkish family. Kidney
Int. 50: 635-642, 1996.

*FIELD* CS

Immune:
   Autoimmune disease

Lab:
   C1q deficiency

Gene:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/14/1996
terry: 11/11/1996
jason: 6/29/1994
mimadm: 4/14/1994
carol: 10/13/1992
carol: 5/12/1992
supermim: 3/16/1992
carol: 9/9/1991

*RECORD*
*FIELD* NO
120560
*FIELD* TI
*120560 COMPLEMENT COMPONENT-C1q, FIBROBLAST TYPE
*FIELD* TX
Skok et al. (1981) identified a genetic defect of serum C1q. Homozygotes
produced no functional serum C1q, but normal fibroblast C1q.
Heterozygotes produced both normal and defective serum C1q. These
observations indicate the distinctness of the genetic determination of
serum and fibroblast C1q.

*FIELD* RF
1. Skok, J.; Solomon, E.; Reid, K. B. M.; Thompson, R. A.: Distinct
genes for fibroblast and serum C1q. Nature 292: 549-551, 1981.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

*RECORD*
*FIELD* NO
120570
*FIELD* TI
*120570 COMPLEMENT COMPONENT 1, q SUBCOMPONENT, BETA POLYPEPTIDE; C1QB
COMPLEMENT COMPONENT-C1q, B CHAIN
C1q DEFICIENCY, INCLUDED
*FIELD* TX
C1q, the first subcomponent of C1, has a complicated 18-chain structure:
6 A, 6 B, and 6 C chains. Each chain has a stretch of about 80 amino
acids with the collagenous triplet Gly-X-Y where X and Y can include
hydroxyproline and hydroxylysine. The A (120550), B (120575), and C
chains combine to form 6 heteromeric triple helices in the collagenous
regions of the chains. Using a cDNA probe to the B chain of C1q, Solomon
et al. (1985) assigned the gene to chromosome 1 in somatic cell hybrids.
A hybrid containing 1p, but no 1q, allowed them to localize the gene to
1p.

Thompson et al. (1980) reported C1q deficiency in a 4-year-old son of
first-cousin Pakistani parents, who presented with a lupus-like illness
and later developed glomerulonephritis. A younger sister, as yet
clinically unaffected, had the same complement profile and a younger
brother had half-normal functional C1 levels. The heterozygous status of
both parents, the younger brother and an older sister was suggested by
the presence of double lines on immunochemical analysis of serum from
these persons using anti-C1q antiserum; one line showed a reaction of
identity with the abnormal C1q of the proband, whereas the other showed
a reaction of identity with normal C1q. Hannema et al. (1984) found
deficiency of C1q in 2 sisters and a brother. In these persons a
dysfunctional C1q molecule was characterized by low molecular weight and
antigenic deficiency. In the 2 sisters a systemic lupus
erythematosus-like disease began at ages 20 and 23, respectively,
resulting in death of 1 of them. All 3 sibs suffered from
glomerulonephritis during childhood. The brother was apparently healthy
but showed membranous glomerulopathy, stage 1, on renal biopsy. It is
unclear whether the mutation responsible for C1q deficiency is in the
C1QA, C1QB, or C1QC gene (or perhaps in none of these). The genes for
the A, B, and C chains of C1q are tandemly arranged 5-prime to 3-prime
in the order A-C-B on a 24-kb stretch of DNA (Sellar et al., 1991). A
and C are separated by 4 kb and B and C are separated by 11 kb.
Hybridization of cDNA probes to a hybrid cell line containing the
derived X chromosome from an X;1(q21.2;p34) translocation described in a
female patient with Duchenne muscular dystrophy (Lindenbaum et al.,
1979; Boyd et al., 1988) showed that the A and B genes are located in
the region 1p36.3-p34.1.

Topaloglu et al. (1996) reported on the molecular basis of C1q
deficiency in a Turkish family (see 120550.0001) and reviewed the
literature on mutations in C1q chains A, B, and C.

*FIELD* AV
.0001
C1Q DEFICIENCY, TYPE B
C1QB, 150G-A
The first molecular lesion in C1q deficiency was reported by McAdam et
al. (1988). A homozygous G-to-A transition at nucleotide 150 in the
B-chain resulted in a premature stop codon.

*FIELD* SA
Sellar et al. (1992)
*FIELD* RF
1. Boyd, Y.; Cockburn, D.; Holt, S.; Munro, E.; van Ommen, G. J.;
Gillard, B.; Affara, N.; Ferguson-Smith, M.; Craig, I.: Mapping of
12 translocation breakpoints in the Xp21 region with respect to the
locus for Duchenne muscular dystrophy. Cytogenet. Cell Genet. 48:
28-34, 1988.

2. Hannema, A. J.; Kluin-Nelemans, J. C.; Hack, C. E.; Eerenberg-Belmer,
A. J. M.; Mallee, C.; van Helden, H. P. T.: SLE like syndrome and
functional deficiency of C1q in members of a large family. Clin.
Exp. Immun. 55: 106-114, 1984.

3. Lindenbaum, R. H.; Clarke, G.; Patel, C.; Moncrieff, M.; Hughes,
J. T.: Muscular dystrophy in an X;1 translocation female suggests
that Duchenne locus is on X chromosome short arm. J. Med. Genet. 16:
389-392, 1979.

4. McAdam, R. A.; Goundis, D.; Reid, K. B. M.: A homozygous point
mutation results in a stop codon in the C1q deficient individual. Immunogenetics 27:
259-264, 1988.

5. Sellar, G. C.; Blake, D. J.; Reid, K. B.: Characterization and
organization of the genes encoding the A-, B-, and C-chains of human
complement subcomponent C1q: the complete derived amino acid sequence
of human C1q. Biochem. J. 274: 481-490, 1991.

6. Sellar, G. C.; Cockburn, D.; Reid, K. B. M.: Localization of the
gene cluster encoding the A, B, and C chains of human C1q to 1p34.1-1p36.3. Immunogenetics 35:
214-216, 1992.

7. Solomon, E.; Skok, J.; Griffin, J.; Reid, K. B. M.: Human C1q
B chain (C1QB) is on chromosome 1p. (Abstract) Cytogenet. Cell Genet. 40:
749 only, 1985.

8. Thompson, R. A.; Haeney, M.; Reid, K. B. M.; Davis, J. G.; White,
R. H.; Cameron, A. H.: A genetic defect of the C1q subcomponent of
complement associated with childhood (immune complex) nephritis. New
Eng. J. Med. 303: 22-24, 1980.

9. Topaloglu, R.; Bakkaloglu, A.; Slingsby, J. H.; Mihatsch, M. J.;
Pascual, M.; Norsworthy, P.; Morley, B. J.; Saatci, U.; Schifferli,
J. A.; Walport, M. J.: Molecular basis of hereditary C1q deficiency
associated with SLE and IgA nephropathy in a Turkish family. Kidney
Int. 50: 635-642, 1996.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/14/1996
terry: 11/11/1996
jason: 6/29/1994
carol: 10/13/1992
carol: 5/12/1992
supermim: 3/16/1992
carol: 9/9/1991
carol: 3/14/1991

*RECORD*
*FIELD* NO
120575
*FIELD* TI
*120575 COMPLEMENT COMPONENT 1, q SUBCOMPONENT, GAMMA POLYPEPTIDE; C1QG
COMPLEMENT COMPONENT-C1q, C CHAIN
*FIELD* TX
Sellar et al. (1991) found that the genes encoding the A, B, and C
chains of human C1q are aligned, 5-prime to 3-prime, in the same
orientation in the order A-C-B on a 24-kb stretch of DNA on chromosome
1p. The A- (120550), B- (120570), and C-chain genes are approximately
2.5, 2.6 and 3.2 kb long, respectively, and each contains 1 intron
located within a codon for a glycine residue found halfway along the
collagen-like region present in each chain. These glycine residues are
located just before the point where the triple-helical portions of the
C1q molecule appear to bend when viewed by electron microscopy. Southern
blot analysis showed that there is only one gene per chain and
preliminary analysis in C1q-deficient patients showed no evidence for
major deletions or insertions within any of the 3 genes. The globular
C-terminal regions of the C1q chains show a strong similarity in amino
acid sequence to the noncollagen-like, C-terminal regions of type VIII
and type X collagens, indicating evolutionary relationships between
these 3 molecules. The genes for the A, B, and C chains of C1q are
tandemly arranged 5-prime to 3-prime in the order A-C-B on a 24-kb
stretch of DNA (Sellar et al., 1991). A and C are separated by 4 kb and
B and C are separated by 11 kb. Hybridization of cDNA probes to a hybrid
cell line containing the derived X chromosome from an X;1(q21.2;p34)
translocation described in a female patient with Duchenne muscular
dystrophy (Lindenbaum et al., 1979; Boyd et al., 1988) showed that the A
and B genes are located in the region 1p36.3-p34.1.

*FIELD* AV
.0001
C1Q DEFICIENCY, TYPE C
C1QG, 1-BP, DEL, 43C DEL, FS108TER
Topaloglu et al. (1996) stated that the molecular basis of C1q
deficiency had been characterized in 6 cases. In 4 of them a defect
resulted in absent C1q protein: 1 of these was in the A chain, 1 was in
the B chain, and 2 were in the C chain. Two others resulted in a
dysfunctional C1q molecule and were both in the C chain. Slingsby et al.
(1996) described a patient with a homozygous deletion of a C nucleotide
at position 43 of the C chain, resulting in a frameshift with a
premature stop codon inframe at position 108.

.0002
C1Q DEFICIENCY, TYPE C
C1QG, 41C-T
Slingsby et al. (1996) described absent C1q protein in a patient
homozygous for a C-to-T transition at position 41 of the C chain,
resulting in a premature stop codon.

.0003
C1Q DEFICIENCY, TYPE C
C1QG, 6G-A
In patients from 2 racially distinct groups, Slingsby et al. (1996) and
Kirschfink et al. (1993) described the same homozygous point mutation as
the cause of dysfunctional C1q deficiency: a G-to-A transition at
position 6 of the C chain.

*FIELD* SA
Sellar et al. (1992)
*FIELD* RF
1. Boyd, Y.; Cockburn, D.; Holt, S.; Munro, E.; van Ommen, G. J.;
Gillard, B.; Affara, N.; Ferguson-Smith, M.; Craig, I.: Mapping of
12 translocation breakpoints in the Xp21 region with respect to the
locus for Duchenne muscular dystrophy. Cytogenet. Cell Genet. 48:
28-34, 1988.

2. Kirschfink, M.; Petry, F.; Khirwadkar, K.; Wigand, R.; Kaltwasser,
J. P.; Loos, M.: Complete functional C1q deficiency associated with
systemic lupus erythematosus (SLE). Clin. Exp. Immun. 94: 267-272,
1993.

3. Lindenbaum, R. H.; Clarke, G.; Patel, C.; Moncrieff, M.; Hughes,
J. T.: Muscular dystrophy in an X;1 translocation female suggests
that Duchenne locus is on X chromosome short arm. J. Med. Genet. 16:
389-392, 1979.

4. Sellar, G. C.; Blake, D. J.; Reid, K. B.: Characterization and
organization of the genes encoding the A-, B- and C-chains of human
complement subcomponent C1q: the complete derived amino acid sequence
of human C1q. Biochem. J. 274: 481-490, 1991.

5. Sellar, G. C.; Cockburn, D.; Reid, K. B. M.: Localization of the
gene cluster encoding the A, B, and C chains of human C1q to 1p34.1-1p36.3. Immunogenetics 35:
214-216, 1992.

6. Slingsby, J. H.; Norsworthy, P.; Pearce, G.; Vaishnaw, A. K.; Issler,
H.; Morley, B. J.; Walport, M. J.: Homozygous hereditary C1q deficiency
and systemic lupus erythematosus: a new family and the molecular basis
of C1q deficiency in three families. Arthritis Rheum. 39: 663-670,
1996.

7. Topaloglu, R.; Bakkaloglu, A.; Slingsby, J. H.; Mihatsch, M. J.;
Pascual, M.; Norsworthy, P.; Morley, B. J.; Saatci, U.; Schifferli,
J. A.; Walport, M. J.: Molecular basis of hereditary C1q deficiency
associated with SLE and IgA nephropathy in a Turkish family. Kidney
Int. 50: 635-642, 1996.

*FIELD* CD
Victor A. McKusick: 9/9/1991

*FIELD* ED
jamie: 11/22/1996
terry: 11/14/1996
terry: 11/11/1996
jason: 6/17/1994
carol: 10/13/1992
carol: 5/12/1992
supermim: 3/16/1992
carol: 9/9/1991

*RECORD*
*FIELD* NO
120577
*FIELD* TI
*120577 COMPLEMENT COMPONENT-C1q RECEPTOR; C1QR
COLLECTIN RECEPTOR
*FIELD* TX
Malhotra et al. (1993) reported the partial amino acid sequence of the
C1q receptor. Similarities in sequence indicated a relationship to
calreticulin (109091), the Sjogren syndrome antigen; the two molecules
belong to the same protein superfamily.

*FIELD* RF
1. Malhotra, R.; Willis, A. C.; Jensenius, J.-C.; Jackson, J.; Sim,
R. B.: Structure and homology of human C1q receptor (collectin receptor).
Immunology 78: 341-348, 1993.

*FIELD* CD
Victor A. McKusick: 9/15/1993

*FIELD* ED
jason: 6/17/1994
carol: 10/21/1993
carol: 9/15/1993

*RECORD*
*FIELD* NO
120580
*FIELD* TI
*120580 COMPLEMENT COMPONENT-C1s; C1S
*FIELD* TX
See C1r (216950) for information on assignment to chromosome 12.
MacKinnon et al. (1987) derived the complete amino acid sequence from
molecular cloning of cDNA. Tosi et al. (1987) presented the complete
cDNA sequence of C1s. Hybridization of C1r and C1s probes to restriction
endonuclease fragments of genomic DNA demonstrated close physical
linkage of the genes. This finding is consistent with their evolution
through tandem gene duplication and is also consistent with the
previously observed combined hereditary deficiencies of C1r and C1s.
Their coordinate expression may depend on the close linkage. The 2 genes
lie in a DNA stretch no longer than 50 kb. In all recorded cases,
hereditary deficiencies of C1r and C1s have occurred in combination
(Loos and Heinz, 1986). Kusumoto et al. (1988) found that the amino acid
sequence of C1s was 40.5% identical to that of C1r, with excellent
matches of tentative disulfide bond locations conserving the overall
domain structure of C1r. DNA blotting and sequencing analyses of genomic
DNA and of an isolated genomic DNA clone showed that the C1r and C1s
genes are closely located in a 'tail-to-tail' arrangement at a distance
of about 9.5 kb.

*FIELD* RF
1. Kusumoto, H.; Hirosawa, S.; Salier, J. P.; Hagen, F. S.; Kurachi,
K.: Human genes for complement components C1r and C1s in a close
tail-to-tail arrangement. Proc. Nat. Acad. Sci. 85: 7307-7311,
1988.

2. Loos, M.; Heinz, H. P.: Component deficiencies. I. The first component:
C1q, C1r, C1s. Prog. Allergy 39: 212-231, 1986.

3. MacKinnon, C. M.; Carter, P. E.; Smyth, S. J.; Dunbar, B.; Fothergill,
J. E.: Molecular cloning of cDNA for human complement component C1s:
the complete amino acid sequence. Europ. J. Biochem. 169: 547-553,
1987.

4. Tosi, M.; Duponchel, C.; Meo, T.; Julier, C.: Complete cDNA sequence
of human complement C1s and close physical linkage of the homologous
genes C1s and C1r. Biochemistry 26: 8516-8524, 1987.

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 10/17/1988
root: 10/12/1988
root: 4/29/1988

*RECORD*
*FIELD* NO
120620
*FIELD* TI
*120620 COMPLEMENT COMPONENT-C3b, RECEPTOR FOR; CR1; C3BR
C3 BINDING PROTEIN; CD35
*FIELD* TX
In studying Treponema pallidum, Nelson (1953) observed the phenomenon he
called immune adherence. The phenomenon is the specific attachment of
primate red cells to antigen-antibody complexes in the presence of
complement and involves the binding of complement-fixing immune
complexes to the immune-adherence receptor (receptor for C3b) normally
present on human red cells. The receptor for Epstein-Barr virus on
lymphocytes is identical to C3DR (120650). The occurrence of excessive
amounts of antigen-antibody complexes in systemic lupus erythematosus
could be the consequence of either overproduction of autoantibodies (as
through polyclonal B-cell activation or altered suppressor T-cell
function) or impaired catabolism. A defect in cellular receptors for the
Fc fragment of IgG that promote removal of immune complexes by
reticuloendothelial cells has been described. A defect in cellular C3b
receptors involved in the clearance of immune complexes that have
activated the immune system and are coated with C3b has been found also,
and has been thought to be inherited (Miyakawa et al., 1981). Both
Miyakawa et al. (1981) and Iida et al. (1982) found CR1 deficiency in
systemic lupus erythematosus. Wilson et al. (1982) showed that the
number of C3b receptors on erythrocytes is genetically regulated.
Receptor sites on red cells were decreased in SLE patients and their
relatives; spouses of SLE patients had normal values. Three phenotypes
were demonstrated in the normal population: HH (5500-8500 sites per
cell), HL (3000-5499 sites per cell) and LL (less than 3000 sites per
cell). Among normal subjects, the 3 phenotypes were present in a
frequency of 34, 54, and 12%, respectively; the figures were 5, 42, and
53% for SLE patients. Hardy-Weinberg and pedigree analyses were
consistent with codominant inheritance of high and low alleles. Wilson
(1982) concluded that the locus for the C3b receptor numerical phenotype
is separate from the structural locus for C3b receptor; of 6 pairs of
HLA-identical sibs, 4 were discordant for the numerical phenotype.

Nowak (1987) demonstrated polymorphism of CR1 using the hemagglutination
assay with human aggregated IgG and guinea pig complement. Among normal
men, 3 phenotypes were distinguished: a high phenotype corresponding to
strong agglutination, an intermediate phenotype producing weak
agglutination, and a low phenotype that gave no agglutination. In a
group of 517 normal men in Poland, these 3 phenotypes occurred in 63.8,
30.6, and 5.6%, respectively. These findings gave an estimated gene
frequency of 0.791 and 0.209 for the high and low CR1 alleles,
respectively. CR1 is a single-chain glycoprotein with 4 allotypic
variants that differ in molecular weight by increments of 40-50 kD. The
2 most common variants are termed F and S (or A and B) allotypes and are
250 and 290 kD, respectively. The corresponding CR1 transcripts from
various allotypes show incremental differences of 1.3 to 1.5 kD. Wong et
al. (1989) described the organization of the S and F alleles of CR1.
Wilson et al. (1985) implicated autoantibodies to the C3b/C4b receptor
and absence of this receptor in the clinical manifestations of SLE.
Using monoclonal antibodies, Dykman et al. (1983) demonstrated
polymorphism of C3BR of red cells. In U.S. whites, the frequency of the
A and B alleles was found to be 0.83 and 0.17, respectively.
Heterozygotes showed differential expression of the 2 gene products in
different cell types. The A allele determines a 190,000 MW protein,
whereas the B allele determines a 220,000 MW protein. In red cells of
heterozygotes, the latter is preferentially expressed. The Bgb blood
group, which was raised in a multiparous woman, is an expression of this
same protein. Its genetics was always confusing because of the anomalous
expression in red cells in heterozygotes. There is cross-reactivity with
HLA-B17.

Although C3BR was assigned to chromosome 6 by somatic cell hybrid
studies (Curry et al., 1976), the immunoelectrophoretic polymorphism
does not show linkage to HLA. Atkinson (1983) counseled caution in
interpretation of the studies of Curry et al. (1976) because the ligands
used were no longer considered acceptable reagents for identifying the
receptors, the C3bi receptor (unknown in 1976) may account for all or
part of the rosette data, and the Raji cell does not have the CR1
C3b/C4b receptor. Rodriguez de Cordoba et al. (1985) concluded that
factor H (HF; 134370), C4BP (120830), C3BR, and C3DR represent a linked
cluster of genes for proteins regulating the activation of C3. They
called the cluster RCA for regulators of complement activation. They
showed, furthermore, that RCA segregates independently of HLA, the C2,
C4, Bf cluster (on 6p), and C3 (on 19p). Weis et al. (1987) mapped both
CR1 and CR2 (120650) to 1q32 by use of partial cDNA clones in in situ
hybridization and in Southern analysis of DNA from somatic cell hybrids.
Using cDNA probes, Hing et al. (1988) assigned the genes for HF and C3
binding protein to chromosome 1q. Weis et al. (1987) indicated that C3b
receptor is the same as C4b receptor (see 120830); it may be, however,
that the 2 are closely related proteins determined by closely linked
genes on chromosome 1. Holers et al. (1987) identified an mRNA size
polymorphism that correlated with the molecular weight polymorphism of
the gene product. This finding, in addition to the report of several
homologous repeats in CR1, is consistent with the hypothesis that the
molecular weight polymorphism is determined at the genomic level and was
generated by unequal crossingover.

Ohi et al. (1986) found CR1 deficiency in 2 cases of mesangiocapillary
glomerulonephritis. Moldenhauer et al. (1987) concluded that inherited
deficiency of CR1 does not cause susceptibility to SLE. Deficiency of
CR1 is found on red cells of patients with SLE; however, the 2 alleles
defined by the RFLP identified using a cDNA probe for CR1 showed the
same frequency in normals and in patients with SLE. Wilson et al. (1987)
reviewed the topic of CR1 and the other cell membrane proteins that bind
C3 and C4. They discussed the mechanism by which inherited and acquired
abnormalities of CR1 might participate in the pathogenesis of SLE.

*FIELD* SA
Dykman et al. (1983); Dykman et al. (1984); Gerdes et al. (1982);
Wong et al. (1985)
*FIELD* RF
1. Atkinson, J. P.: Personal Communication. St. Louis, Mo.  3/7/1983.

2. Curry, R. A.; Dierich, M. P.; Pellegrino, M. A.; Hoch, H. A.:
Evidence for linkage between HLA antigens and receptors for complement
components C3b and C3d in human-mouse hybrids. Immunogenetics 3:
465-471, 1976.

3. Dykman, T. R.; Cole, J. L.; Iida, K.; Atkinson, J. P.: Polymorphism
of human erythrocyte C3b/C4b receptor. Proc. Nat. Acad. Sci. 80:
1698-1702, 1983.

4. Dykman, T. R.; Cole, J. L.; Iida, K.; Atkinson, J. P.: Structural
heterogeneity of the C3b/C4b receptor (CR1) on human peripheral blood
cells. J. Exp. Med. 157: 2160-2165, 1983.

5. Dykman, T. R.; Hatch, J. A.; Atkinson, J. P.: Polymorphism of
the human C3b/C4b receptor: identification of a third allele and analysis
of receptor phenotypes in families and patients with systemic lupus
erythematosus. J. Exp. Med. 159: 691-703, 1984.

6. Gerdes, J.; Hansmann, M.-L.; Stein, H.; Naiem, M.; Mason, D. Y.
: Ultrastructural localization of human complement C3b receptors in
the human kidney as determined by immunoperoxidase staining with the
monoclonal antibody C3RTo5. Virchows Arch. B 40: 1-7, 1982.

7. Hing, S.; Day, A. J.; Linton, S. J.; Ripoche, J.; Sim, R. B.; Reid,
K. B.; Solomon, E.: Assignment of complement components C4 binding
protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA
probes. Ann. Hum. Genet. 52: 117-122, 1988.

8. Holers, V. M.; Chaplin, D. D.; Leykam, J. F.; Gruner, B. A.; Kumar,
V.; Atkinson, J. P.: Human complement C3b/C4b receptor (CR1) mRNA
polymorphism that correlates with the CR1 allelic molecular weight
polymorphism. Proc. Nat. Acad. Sci. 84: 2459-2463, 1987.

9. Iida, K.; Momaghi, R.; Nussenzweig, V.: Complement receptor (CR1)
deficiency in erythrocytes from patients with systemic lupus erythematosus.
J. Exp. Med. 155: 1427-1438, 1982.

10. Miyakawa, Y.; Yamada, A.; Kosaka, K.; Tsuda, F.; Kosugi, E.; Mayumi,
M.: Defective immune-adherence (C3b) receptor on erythrocytes from
patients with systemic lupus erythematosus. Lancet II: 493-497,
1981.

11. Moldenhauer, F.; David, J.; Fielder, A. H. L.; Lachmann, P. J.;
Walport, M. J.: Inherited deficiency of erythrocyte complement receptor
type 1 does not cause susceptibility to systemic lupus erythematosus.
Arthritis Rheum. 30: 961-966, 1987.

12. Nelson, R. A.: The immune-adherence phenomenon: an immunologically
specific reaction between microorganisms and erythrocytes leading
to enhanced phagocytosis. Science 118: 733-737, 1953.

13. Nowak, J. S.: Genetic variability of complement receptor on human
erythrocytes. J. Genet. 66: 133-138, 1987.

14. Ohi, H.; Ikezawa, T.; Watanabe, S.; Seki, M.; Mizutani, Y.; Nawa,
N.; Hatano, M.: Two cases of mesangiocapillary glomerulonephritis
with CR1 deficiency.  (Letter) Nephron 43: 307 only, 1986.

15. Rodriguez de Cordoba, S.; Lublin, D. M.; Rubinstein, P.; Atkinson,
J. P.: Human genes for three complement components that regulate
the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195,
1985.

16. Weis, J. H.; Morton, C. C.; Bruns, G. A. P.; Weis, J. J.; Klickstein,
L. B.; Wong, W. W.; Fearon, D. T.: A complement receptor locus: genes
encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map
to 1q32. J. Immun. 138: 312-315, 1987.

17. Wilson, J. G.: Personal Communication. Boston, Mass.  10/25/1982.

18. Wilson, J. G.; Andriopoulos, N. A.; Fearon, D. T.: CR1 and the
cell membrane proteins that bind C3 and C4: a basic and clinical review.
Immun. Res. 6: 192-209, 1987.

19. Wilson, J. G.; Jack, R. M.; Wong, W. W.; Schur, P. H.; Fearon,
D. T.: Autoantibody to the C3b/C4b receptor and absence of this receptor
from erythrocytes of a patient with systemic lupus erythematosus.
J. Clin. Invest. 76: 182-190, 1985.

20. Wilson, J. G.; Wong, W. W.; Schur, P. H.; Fearon, D. T.: Mode
of inheritance of decreased C3b receptors on erythrocytes of patients
with systemic lupus erythematosus. New Eng. J. Med. 307: 981-986,
1982.

21. Wong, W. W.; Cahill, J. M.; Rosen, M. D.; Kennedy, C. A.; Bonaccio,
E. T.; Morris, M. J.; Wilson, J. G.; Klickstein, L. B.; Fearon, D.
T.: Structure of the human CR1 gene: molecular basis of the structural
and quantitative polymorphisms and identification of a new CR1-like
allele. J. Exp. Med. 169: 847-863, 1989.

22. Wong, W. W.; Klickstein, L. B.; Smith, J. A.; Weis, J. H.; Fearon,
D. T.: Identification of a partial cDNA clone for the human receptor
for complement fragments C3b/C4b. Proc. Nat. Acad. Sci. 82: 7711-7715,
1985.

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
davew: 6/27/1994
mimadm: 4/14/1994
warfield: 4/8/1994
supermim: 3/16/1992
carol: 3/2/1992
carol: 1/21/1992

*RECORD*
*FIELD* NO
120650
*FIELD* TI
*120650 COMPLEMENT COMPONENT-C3d, RECEPTOR FOR; C3DR; CR2
EPSTEIN-BARR VIRUS RECEPTOR;;
EBV RECEPTOR
*FIELD* TX
See 120620. Yefenof et al. (1976) found complete overlapping of EBV
receptors and C3 receptors on human B-lymphocytes. CR2 is the membrane
protein on B lymphocytes to which the Epstein-Barr virus binds during
infection of these cells. Weis et al. (1987) demonstrated by Southern
analysis of DNA from somatic cell hybrids and by in situ hybridization
using partial cDNA clones that the CR2 gene is located on band 1q32.
Rodriguez de Cordoba and Rubinstein (1986) demonstrated that
quantitative variations of the C3b/C4b receptor (CR1) in human
erythrocytes are controlled by genes within the regulator of complement
activation (RCA) gene cluster. Rodriguez de Cordoba and Rubinstein
(1986) symbolized this gene as C3bRQ. Moore et al. (1987) presented the
nucleotide and derived amino acid sequence of the CR2 gene. They pointed
out the close similarity to CR1 and to factor H, which are closely
linked loci in 1q32.

*FIELD* SA
Rodriguez de Cordoba et al. (1985); Weis et al. (1984)
*FIELD* RF
1. Moore, M. D.; Cooper, N. R.; Tack, B. F.; Nemerow, G. R.: Molecular
cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement
receptor type 2) of human B lymphocytes. Proc. Nat. Acad. Sci. 84:
9194-9198, 1987.

2. Rodriguez de Cordoba, S.; Lublin, D. M.; Rubinstein, P.; Atkinson,
J. P.: Human genes for three complement components that regulate
the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195,
1985.

3. Rodriguez de Cordoba, S.; Rubinstein, P.: Quantitative variations
of the C3b/C4b receptor (CR1) in human erythrocyte are controlled
by genes within the regulator of complement activation (RCA) gene
cluster. J. Exp. Med. 164: 1274-1283, 1986.

4. Weis, J. H.; Morton, C. C.; Bruns, G. A. P.; Weis, J. J.; Klickstein,
L. B.; Wong, W. W.; Fearon, D. T.: A complement receptor locus: genes
encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map
to 1q32. J. Immun. 138: 312-315, 1987.

5. Weis, J. J.; Tedder, T. F.; Fearon, D. T.: Identification of a
145,000 M(r) membrane protein as the C3d receptor (CR2) of human B
lymphocytes. Proc. Nat. Acad. Sci. 81: 881-885, 1984.

6. Yefenof, E.; Klein, G.; Jondal, M.; Oldstone, M. B. A.: Surface
markers on human B- and T-lymphocytes. IX. Two color immunofluorescence
studies on the association between EBV receptors and complement receptors
on the surface of lymphoid cell lines. Int. J. Cancer 17: 693-700,
1976.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 10/18/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 2/7/1988

*RECORD*
*FIELD* NO
120700
*FIELD* TI
*120700 COMPLEMENT COMPONENT-3; C3
C3 DEFICIENCY, AUTOSOMAL RECESSIVE, INCLUDED
*FIELD* TX
In grandmother, mother, and 2 sons, Wieme and Demeulenaere (1967) found
a double electrophoretic band corresponding apparently to complement
component C-prime-3 (as it was then called). By means of high voltage
starch gel electrophoresis, Azen and Smithies (1968) also found
electrophoretic polymorphism of the third component of complement. This
component has many important functions in immune mechanisms. Alper and
Propp (1968) independently found polymorphism of C3. Alper et al. (1972)
described a patient with striking susceptibility to pyogenic infection
who was apparently homozygous for C3 deficiency. Her C3 levels were
one-thousandth or less of normal. Many relatives, including both
parents, had approximately half-normal levels. Pussell et al. (1980)
described a family in which 3 children had homozygous C3 deficiency and
both parents and 2 other children were heterozygous for a C3 null gene.
A heterozygous child had membranoproliferative glomerulonephritis.
Proteinuria and/or microscopic hematuria were present in all 3
homozygous children. The homozygous and heterozygous children were
susceptible to infection. The only child with normal complement had
neither nephritis nor increased susceptibility to infection. The family
was of Palestinian-Lebanese origin, living in Kuwait. The parents were
thought to be cousins. Nilsson et al. (1992) described 3 sisters who
were compound heterozygotes for a null allele inherited from the father
and a dysfunctional C3 allele inherited from the mother. Alternative
pathway complement function was absent, but classical pathway complement
function was partially intact. One of the sisters, the proband, had an
SLE-like syndrome. The proband's C3 proved normally susceptible to
trypsin proteolysis and partially resistant to classical pathways, but
completely resistant to alternative pathway, convertase-dependent
cleavage.

Johnson et al. (1986) described C3 deficiency in Brittany spaniel dogs.
Like the human disorder, this appears to be due to a null gene which
apparently is not closely linked to the canine major histocompatibility
complex.

McLean and Hoefnagel (1980) observed partial lipodystrophy (affecting
the face, arms and upper torso) in a 16-year-old girl with familial C3
deficiency. Berger et al. (1983) and Borzy et al. (1988) observed
C3-deficient homozygotes who developed mesangiocapillary
glomerulonephritis. The association of C3 deficiency with nephritis is
probably due to failure of a second physiologic activity of the
complement system, that of promoting the disposal of immune complexes to
the mononuclear phagocytic system. This may be an indication of an
immunologic basis of a form of lipodystrophy. Partial lipodystrophy
affects predominantly the face and trunk, often with excess accumulation
of fat in the lower part of the body (legs and hips). It occurs
predominantly in females and usually begins between ages 5 and 10.
Further evidence of an immunologic basis is the association with partial
lipodystrophy of nephritis of a mesangiocapillary
(membranoproliferative) type. C3 nephritic factor, an IgG antibody
against complement components, is demonstrable in some cases. Sissons et
al. (1976) studied 25 patients with lipodystrophy. Partial lipodystrophy
was present in 21, total lipodystrophy in 3, and a variant form
affecting arms, legs, and buttocks with normal facial and truncal fat in
1. Insulin resistance is found in many of the patients. Familial
lipodystrophy must be very rare. Bauer (1932-33) reported 3 affected
sisters from a consanguineous marriage in Holland. The sisters were said
to have mental and growth deficiency, otosclerosis, and multiple cysts
in different parts of the skeleton. One of the girls died from bone
sarcoma. Power et al. (1990) described a family in which 3 members had
partial lipodystrophy. Two of the 3, a mother and a son, also had C3
nephritic factor and membranoproliferative glomerulonephritis. Both the
mother and the son had end-stage renal disease.

Weitkamp et al. (1974) presented evidence that the Lewis blood group
locus and the C3 locus are linked. Three independent studies, by Ott et
al. (1974), Berg and Heiberg (1976) and Elston et al. (1976), strongly
suggested loose linkage between familial hypercholesterolemia and C3. By
the method of somatic cell hybridization, Whitehead et al. (1982)
assigned the gene for fibroblast-derived C3 to chromosome 19. It was at
first unclear whether fibroblast and serum C3 were identical; it was
known that fibroblast C1q (120560) and serum C1q (120550) are different
(Skok et al., 1981). Studies with a C3 probe (Davies et al., 1984)
suggested that there was only one C3 gene per haploid chromosome set; no
other hybridization was observed with relaxed stringency. Furthermore,
no recombination was observed between probe and serum C3 (Williamson,
1983). Thus, serum and fibroblast C3 almost certainly have the same
genetic basis. A specific antihuman C3 monoclonal antibody was used by
Whitehead et al. (1982) in their mapping studies. The assignment to
chromosome 19 was confirmed by use of a unique-sequence human genomic C3
DNA clone as a probe in DNA hybridization experiments with DNA prepared
from appropriate human-mouse somatic cell hybrids (Whitehead et al.,
1982). Because C3, C4 (120810) and C5 are strikingly similar, a common
evolutionary origin has been supposed. C4 is in the major
histocompatibility complex on chromosome 6, but C3 and C5 are not. (In
the mouse, C3 is on the same chromosome, no. 17, as H2, but is remote
from H2. In the chimpanzee, as in man, C2 and Bf are closely linked to
the MHC and neither C3 nor C8 is closely linked to MHC. C6 deficiency
was observed in the chimpanzee.) The protease alpha-2-macroglobulin
(103950) also shows considerable homology to C3, suggesting a common
evolutionary origin. Sanders et al. (1984) studied the linkage of
polymorphic serum C3 to Lewis and secretor and found low positive lod
scores for all 3 linkages. They favored the order: SE--C3--LE. Eiberg et
al. (1983) found linkage of secretor with the serum C3 polymorphism
(male lod = 4.35, theta = 0.12). There was suggestive evidence of
linkage of secretor with PEPD (male and female lod = 2.41, theta = 0.00)
and of C3 with PEPD (male lod = 0.95, theta = 0.17)--independent
confirmation of assignment to chromosome 19 where PEPD is known to be by
somatic cell studies. What they termed Lewis secretion (LES) was also
linked to C3 (male lod = 3.63, theta = 0.04). They suggested that the
most likely sequence is LES--C3--DM--(Se-PEPD)--Lu. Ball et al. (1984)
regionalized C3 to 19pter-p13.2. Brook et al. (1984) assigned the gene
to 19pter-p13 and concluded that familial hypercholesterolemia is
probably distal to C3 in the p13-pter segment. New data of Brook et al.
(1985) suggested that the LDL receptor is proximal to C3. Lusis et al.
(1986) used a reciprocal whole arm translocation between the long arm of
19 and the short arm of chromosome 1 to map APOC1, APOC2, APOE and GPI
to the long arm and LDLR, C3 and PEPD to the short arm. Furthermore,
they isolated a single lambda phage that carried both APOC1 and APOE
separated by about 6 kb of genomic DNA. Since family studies indicate
close linkage of APOE and APOC2, the 3 must be in a cluster on 19q.
Judging by the sequence of loci suggested by linkage data
(pter--FHC--C3--APOE/APOC2), the location of FHC (LDLR) is probably
19p13.2-p13.12 and of C3, 19p13.2-p13.11.

Fong et al. (1990) reported that the complete C3 gene is 41 kb long,
comprising 41 exons. The beta-gene spans 13 kb from exon 1 to exon 16.
Exon 16 encodes both alpha and beta chains. The alpha chain is 28 kb
long, with 26 exons, including exon 16. De Bruijn and Fey (1985)
presented the complete coding sequence of the C3 gene and the derived
amino acid sequence. C3 is an acute phase reactant; increased synthesis
of C3 is induced during acute inflammation. The liver is the main site
of synthesis, although small amounts are also produced by activated
monocytes and macrophages. A single chain precursor (pro-C3) of
approximately 200 kD is found intracellularly; the cDNA shows that it
comprises 1,663 amino acids. This is processed by proteolytic cleavage
into alpha and beta subunits which in the mature protein are linked by
disulfide bonds. Pro-C3 contains a signal peptide of 22 amino acid
residues, the beta chain (645 residues) and the alpha chain (992
residues). The 2 chains are joined by 4 arginine residues that are not
present in the mature protein. Human C3 has 79% identity to mouse C3 at
the nucleotide level and 77% at the amino acid level.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
C3S/C3F POLYMORPHISM
C3, ARG102GLY
Botto et al. (1990) studied the molecular basis of the C3F vs C3S
polymorphism. The less common variant, C3F, occurs with appreciable
frequencies (gene frequency = 0.20) only in the Caucasoid populations.
Botto et al. (1990) found a single nucleotide change, C-to-G, at
position 364 in exon 3, distinguishing C3S and C3F. This led to a
substitution of an arginine residue in C3S for a glycine residue in C3F.
The substitution resulted in a polymorphic restriction site for the
enzyme HhaI.

.0002
C3 POLYMORPHISM, HAV 4-1 PLUS/MINUS TYPE
C3, LEU314PRO
Botto et al. (1990) identified the molecular basis of a structural
polymorphism of C3, identified by the monoclonal antibody HAV 4-1: codon
314 in exon 9 of the beta chain showed a change of a proline residue in
the HAV 4-1(-) form to a leucine residue in the HAV 4-1(+) form.

.0003
C3 DEFICIENCY
C3, 61-BP DEL, EX18
Botto et al. (1990) studied the DNA from a 10-year-old boy who had
suffered from recurrent attacks of otitis media during the first 3 years
of life. Between 5 and 8 years of age, he suffered from more than 20
episodes of rash which affected his face, forearms, and hands and
resembled the target lesions of erythema multiforme. Attacks were
normally preceded by an upper respiratory infection, and a group A
beta-hemolytic Streptococcus was isolated from his throat during 2
episodes. The parents were consanguineous ('share a common
great-grandparent'). C3 could not be detected by RIA of serum from the
patient. Segregation of C3S and C3F allotypes within the family
confirmed the presence of a null allele, for which the patient was
homozygous. DNA studies showed a GT-to-AT mutation at the 5-prime donor
splice site of intron 18 of the C3 gene. Exons 17-21 were amplified by
PCR from first-strand cDNA synthesized from mRNA obtained from
peripheral blood monocytes. This revealed a 61-bp deletion in exon 18,
resulting from splicing of a cryptic 5-prime donor splice site in exon
18 with the normal 3-prime splice site in exon 19. The deletion led to a
disturbance of the reading frame of the mRNA with a stop codon 17 bp
downstream from the abnormal splice in exon 18. Both parents were
heterozygous for the C3*Q0 allele (Q0 = quantity zero, i.e., null
allele).

.0004
C3 DEFICIENCY
C3, 800-BP DEL
Botto et al. (1992) demonstrated partial gene deletion as the molecular
basis of C3 deficiency in an Afrikaans patient previously described by
Alper et al. (1972) as homozygous C3 deficient. By Southern blot
analysis, they demonstrated that the C3 null gene had an 800-bp deletion
in exons 22 and 23, resulting in a frameshift and a stop codon 19 bp
downstream from the deletion. DNA sequence analysis showed that the
deletion probably arose from homologous recombination between 2 ALU
repeats flanking the deletion. This mutant allele was found to have a
gene frequency of 0.0057 in the South African Afrikaans-speaking
population.

*FIELD* SA
Alper et al. (1970); Alper et al. (1970); Alper et al. (1976); Alper
et al. (1969); Alper and Rosen (1971); Arvilommi et al. (1973); Ballow
et al. (1975); Berg and Heiberg (1978); Botto et al. (1990); Donald
and Ball (1984); Einstein et al. (1977); Gedde-Dahl et al. (1974);
Goedde et al. (1970); Grace et al. (1976); Hoppe et al. (1978); Koch
and Behrendt (1986); McLean et al. (1985); McLean et al. (1980); McLean
et al. (1980); Muller-Eberhard  (1968); Osofsky et al. (1977); Osofsky
et al. (1977); Raum et al. (1980); Raum et al. (1980); Sano et al.
(1981); Teisberg  (1970); Teisberg  (1971); Whitehead et al. (1981);
Whitehead et al. (1982); Winkelstein et al. (1981)
*FIELD* RF
1. Alper, C. A.; Abramson, N.; Johnston, R. B., Jr.; Jandl, J. H.;
Rosen, F. S.: Increased susceptibility to infection associated with
abnormalities of complement-mediated functions and of the third component
of complement (C3). New Eng. J. Med. 282: 349-354, 1970.

2. Alper, C. A.; Abramson, N.; Johnston, R. B., Jr.; Jandl, J. H.;
Rosen, F. S.: Studies in vivo and in vitro on an abnormality in the
metabolism of C3 in a patient with increased susceptibility to infection.
J. Clin. Invest. 49: 1975-1985, 1970.

3. Alper, C. A.; Colten, H. R.; Gear, J. S. S.; Rabson, A. R.; Rosen,
F. S.: Homozygous human C3 deficiency: the role of C3 in antibody
production, C1s-induced vasopermeability, and cobra venom-induced
passive hemolysis. J. Clin. Invest. 57: 222-229, 1976.

4. Alper, C. A.; Colten, H. R.; Rosen, S. F.; Rabson, A. R.; MacNab,
G. M.; Gear, J. S. S.: Homozygous deficiency of C3 in a patient with
repeated infections. Lancet II: 1179-1181, 1972.

5. Alper, C. A.; Propp, R. P.: Genetic polymorphism of the third
component of human complement (C-prime-3). J. Clin. Invest. 47:
2181-2192, 1968.

6. Alper, C. A.; Propp, R. P.; Klemperer, M. R.; Rosen, F. S.: Inherited
deficiency of the third component of human complement (C-prime-3).
J. Clin. Invest. 48: 553-557, 1969.

7. Alper, C. A.; Rosen, F. S.: Studies of a hypomorphic variant of
human C3. J. Clin. Invest. 50: 324-326, 1971.

8. Arvilommi, H.; Berg, K.; Eriksson, A. W.: C3 types and their inheritance
in Finnish Lapps, Maris (Cheremisses) and Greenland Eskimos. Humangenetik 18:
253-259, 1973.

9. Azen, E. A.; Smithies, O.: Genetic polymorphism of C-prime-3 (beta-1C-globulin)
in human serum. Science 162: 905-907, 1968.

10. Ball, S.; Buckton, K. E.; Corney, G.; Fey, G.; Monteiro, M.; Noades,
J. E.; Pym, B.; Robson, E. B.; Tippett, P.: Mapping studies with
peptidase D (PEPD).  (Abstract) Cytogenet. Cell Genet. 37: 411 only,
1984.

11. Ballow, M.; Shira, J. E.; Harden, L.; Yang, S. Y.; Day, N. K.
: Complete absence of the third component of complement in man. J.
Clin. Invest. 56: 703-710, 1975.

12. Bauer, J.: Constitutional principles in clinical medicine. Harvey
Lect. 28: 37-55, 1932.

13. Berg, K.; Heiberg, A.: Linkage studies on familial hypercholesterolemia
with xanthomatosis: normal lipoprotein markers and the C3 polymorphism.
Cytogenet. Cell Genet. 16: 266-270, 1976.

14. Berg, K.; Heiberg, A.: Linkage between familial hypercholesterolemia
with xanthomatosis and the C3 polymorphism confirmed. Cytogenet.
Cell Genet. 22: 621-623, 1978.

15. Berger, M.; Balow, J. E.; Wilson, C. B.; Frank, M. M.: Circulating
immune complexes and glomerulonephritis in a patient with congenital
absence of the third component of complement. New Eng. J. Med. 308:
1009-1012, 1983.

16. Borzy, M. S.; Gewurz, A.; Wolff, L.; Houghton, D.; Lovrien, E.
: Inherited C3 deficiency with recurrent infections and glomerulonephritis.
Am. J. Dis. Child. 142: 79-83, 1988.

17. Botto, M.; Fong, K. Y.; So, A. K.; Barlow, R.; Routier, R.; Morley,
B. J.; Walport, M. J.: Homozygous hereditary C3 deficiency due to
a partial gene deletion. Proc. Nat. Acad. Sci. 89: 1957-1961, 1992.

18. Botto, M.; Fong, K. Y.; So, A. K.; Koch, C.; Walport, M. J.:
Molecular basis of polymorphisms of human complement component C3.
J. Exp. Med. 172: 1011-1017, 1990.

19. Botto, M.; Fong, K. Y.; So, A. K.; Rudge, A.; Walport, M. J.:
Molecular basis of hereditary C3 deficiency. J. Clin. Invest. 86:
1158-1163, 1990.

20. Brook, J. D.; Shaw, D. J.; Meredith, A. L.; Worwood, M.; Cowell,
J.; Scott, J.; Knott, T. J.; Litt, M.; Bufton, L.; Harper, P. S.:
A somatic cell hybrid panel for chromosome 19: localization of known
genes and RFLPs and orientation of the linkage group.  (Abstract) Cytogenet.
Cell Genet. 40: 590-591, 1985.

21. Brook, J. D.; Shaw, D. J.; Meredith, L.; Bruns, G. A. P.; Harper,
P. S.: Localisation of genetic markers and orientation of the linkage
group on chromosome 19. Hum. Genet. 68: 282-285, 1984.

22. Davies, K. E.; Williamson, R.; Ball, S.; Sarfarazi, M.; Meredith,
L.; Fey, G.; Harper, P. S.: C3 DNA sequence and protein polymorphisms
in linkage analysis of myotonic dystrophy.  (Abstract) Cytogenet.
Cell Genet. 37: 447 only, 1984.

23. de Bruijn, M. H. L.; Fey, G. H.: Human complement component C3:
cDNA coding sequence and derived primary structure. Proc. Nat. Acad.
Sci. 82: 708-712, 1985.

24. Donald, J. A.; Ball, S. P.: Approximate linkage equilibrium between
two polymorphic sites within the gene for human complement component
3. Ann. Hum. Genet. 48: 269-273, 1984.

25. Eiberg, H.; Mohr, J.; Nielsen, L. S.; Simonsen, N.: Genetics
and linkage relationships of the C3 polymorphism: discovery of C3-Se
linkage and assignment of LES-C3-DM-Se-PEPD-Lu synteny to chromosome
19. Clin. Genet. 24: 159-170, 1983.

26. Einstein, L. P.; Hansen, P. J.; Ballow, M.; Davis, A. E., III;
Davis, J. S., IV; Alper, C. A.; Rosen, F. S.; Colten, H. R.: Biosynthesis
of the third component of complement (C3) in vitro by monocytes from
both normal and homozygous C3-deficient humans. J. Clin. Invest. 60:
963-969, 1977.

27. Elston, R. C.; Namboodiri, K. K.; Go, R. C. P.; Siervogel, R.
M.; Glueck, C. J.: Probable linkage between essential familial hypercholesterolemia
and third complement component (C3). Cytogenet. Cell Genet. 16:
294-297, 1976.

28. Fong, K. Y.; Botto, M.; Walport, M. J.; So, A. K.: Genomic organization
of human complement component C3. Genomics 7: 579-586, 1990.

29. Gedde-Dahl, T., Jr.; Teisberg, P.; Thorsby, E.: C(3) polymorphism:
genetic linkage relations. Clin. Genet. 6: 66-72, 1974.

30. Goedde, H. W.; Benkmann, H.-G.; Hirth, L.: Genetic polymorphism
of C-prime-3(beta-1C-globulin) component of complement in a German
and a Spanish population. Humangenetik 10: 231-234, 1970.

31. Grace, H. J.; Brereton-Stiles, G. G.; Vos, G. H.; Schonland, M.
: A family with partial and total deficiency of complement C3. S.
Afr. Med. J. 50: 139-140, 1976.

32. Hoppe, H. H.; Goedde, H. W.; Agarwal, D. P.; Benkmann, H.-G.;
Hirth, L.; Janssen, W.: A silent (C-prime-3) producing partial deficiency
of the third component of human complement. Hum. Hered. 28: 141-146,
1978.

33. Johnson, J. P.; McLean, R. H.; Cork, L. C.; Winkelstein, J. A.
: Genetic analysis of an inherited deficiency of the third component
of complement in Brittany spaniel dogs. Am. J. Med. Genet. 25:
557-562, 1986.

34. Koch, C.; Behrendt, N.: A novel polymorphism of human complement
component C3 detected by means of a monoclonal antibody. Immunogenetics 23:
322-325, 1986.

35. Lusis, A. J.; Heinzmann, C.; Sparkes, R. S.; Scott, J.; Knott,
T. J.; Geller, R.; Sparkes, M. C.; Mohandas, T.: Regional mapping
of human chromosome 19: organization of genes for plasma lipid transport
(APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI. Proc.
Nat. Acad. Sci. 83: 3929-3933, 1986.

36. McLean, R. H.; Bryan, R. K.; Winkelstein, J.: Hypomorphic variant
of the slow allele of C3 associated with hypocomplementemia and hematuria.
Am. J. Med. 78: 865-868, 1985.

37. McLean, R. H.; Hoefnagel, D.: Partial lipodystrophy and familial
C3 deficiency. Hum. Hered. 30: 149-154, 1980.

38. McLean, R. H.; Siegel, N. J.; Kashgarian, M.: Activation of the
classic complement pathway in patients with the C3 nephritic factors.
Nephron 25: 57-64, 1980.

39. McLean, R. H.; Wienstein, A.; Chapitis, J.; Lowenstein, M.; Rothfield,
N. F.: Familial partial deficiency of the third component of complement
(C3) and the hypocomplementemic cutaneous vasculitis syndrome. Am.
J. Med. 68: 549-558, 1980.

40. Muller-Eberhard, H. J.: Chemistry and reaction mechanisms of
complement. Adv. Immun. 8: 1-80, 1968.

41. Nilsson, U. R.; Nilsson, B.; Storm, K.-E.; Sjolin-Forsberg, G.;
Hallgren, R.: Hereditary dysfunction of the third component of complement
associated with a systemic lupus erythematosus-like syndrome and meningococcal
meningitis. Arthritis Rheum. 35: 580-586, 1992.

42. Osofsky, S. G.; Thompson, B. H.; Gewurz, H.; Schmid, F. R.; Mittal,
K. K.: Evidence for lack of linkage between HLA and C3 deficiency
in man. Immunogenetics 4: 195-198, 1977.

43. Osofsky, S. G.; Thompson, B. H.; Lint, T. F.; Gewurz, H.: Hereditary
deficiency of 3rd component of complement in a child with fever, skin
rash, and arthralgias--response to transfusion of whole blood. J.
Pediat. 90: 180-186, 1977.

44. Ott, J.; Schrott, H. G.; Goldstein, J. L.; Hazzard, W. R.; Allen,
F. H.; Falk, C. T.; Motulsky, A. G.: Linkage studies in a large kindred
with familial hypercholesterolemia. Am. J. Hum. Genet. 26: 598-603,
1974.

45. Power, D. A.; Ng, Y. C.; Simpson, J. G.: Familial incidence of
C3 nephritic factor, partial lipodystrophy and membranoproliferative
glomerulonephritis. Quart. J. Med. 75: 387-398, 1990.

46. Pussell, B. A.; Bourke, E.; Nayef, M.; Morris, S.; Peters, D.
K.: Complement deficiency and nephritis: a report of a family. Lancet I:
675-677, 1980.

47. Raum, D.; Balner, H.; Petersen, B. H.; Alper, C. A.: Genetic
polymorphism of serum complement components in the chimpanzee. Immunogenetics 10:
455-468, 1980.

48. Raum, D.; Donaldson, V. H.; Rosen, F. S.; Alper, C. A.: Genetics
of complement. Curr. Top. Hemat. 3: 111-174, 1980.

49. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

50. Sanders, M. F.; Crandall, J.; Huey, B.; Leung, R.; King, M. C.
: Possible synteny of LE, SE, and C3.  (Abstract) Cytogenet. Cell
Genet. 37: 575 only, 1984.

51. Sano, Y.; Nishimukai, H.; Kitamura, H.; Nagaki, K.; Inai, S.;
Hamasaki, Y.; Maruyama, I.; Igata, A.: Hereditary deficiency of the
third component of complement in two sisters with systemic lupus erythematosus-like
symptoms. Arthritis Rheum. 24: 1255-1260, 1981.

52. Sissons, J. G. P.; West, R. J.; Fallows, J.; Williams, D. G.;
Boucher, B. J.; Amos, N.; Peters, D. K.: The complement abnormalities
of lipodystrophy. New Eng. J. Med. 294: 461-465, 1976.

53. Skok, J.; Solomon, E.; Reid, K. B. M.; Thompson, R. A.: Distinct
genes for fibroblast and serum C1q. Nature 292: 549-551, 1981.

54. Teisberg, P.: New variants in the C3 system. Hum. Hered. 20:
631-637, 1970.

55. Teisberg, P.: Another variant in the C3 system. Clin. Genet. 2:
298-302, 1971.

56. Weitkamp, L. R.; Johnston, E.; Guttormsen, S. A.: Probable genetic
linkage between the loci for the Lewis blood group and complement
C3. Cytogenet. Cell Genet. 13: 183-184, 1974.

57. Whitehead, A. S.; Sim, R. B.; Bodmer, W. F.: A monoclonal antibody
against human complement component C3: the production of C3 by human
cells in vitro. Europ. J. Immun. 11: 140-146, 1981.

58. Whitehead, A. S.; Solomon, E.; Chambers, S.; Bodmer, W. F.; Povey,
S.; Fey, G.: Assignment of the structural gene for the third component
of human complement to chromosome 19. Proc. Nat. Acad. Sci. 79:
5021-5025, 1982.

59. Whitehead, A. S.; Solomon, E.; Chambers, S. P.; Povey, S.; Bodmer,
W. F.: Assignment of the gene for the third component of human complement
(C3) to chromosome 19 using human-mouse somatic cell hybrids.  (Abstract) Cytogenet.
Cell Genet. 32: 326-327, 1982.

60. Wieme, R. J.; Demeulenaere, L.: Genetically determined electrophoretic
variant of the human complement component C-prime-3. Nature 214:
1042-1043, 1967.

61. Williamson, R.: Personal Communication. London, England  8/25/1983.

62. Winkelstein, J. A.; Cork, L. C.; Griffin, D. E.; Griffin, J. W.;
Adams, R. J.; Price, D. L.: Genetically determined deficiency of
the third component of complement in the dog. Science 212: 1169-1170,
1981.

*FIELD* CS

Immunology:
   C3 deficiency;
   Susceptibility to pyogenic infection

GU:
   Membranoproliferative glomerulonephritis

Skin:
   Partial lipodystrophy (face, arms and upper torso);
   Erythema multiforme-like rash of face, forearms, and hands

Lab:
   C3 nephritic factor, IgG antibody against complement components;
   Proteinuria and/or microscopic hematuria

Inheritance:
   Autosomal dominant (19p13.2-p13.11)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 7/30/1995
davew: 7/5/1994
mimadm: 6/25/1994
warfield: 4/8/1994
carol: 10/28/1992
carol: 8/17/1992

*RECORD*
*FIELD* NO
120790
*FIELD* TI
#120790 COMPLEMENT COMPONENT-4, PARTIAL DEFICIENCY OF
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
mutation resides in the gene for the C1 inhibitor (C1NH; 106100).

Muir et al. (1984) described a partial deficiency of C4 in a kindred
ascertained through a 26-year-old woman with systemic lupus
erythematosus. Six healthy members of the family also had partial
deficiency of C4. The inheritance pattern was autosomal dominant with
involved persons in 4 sibships of 2 generations (and by inference in a
third earlier generation) and with male-to-male transmission. This form
of C4 deficiency differs from that in previously reported families in
the mode of inheritance, in the marked reduction of C4 levels (2-5% of
normal in the proband; 2.4-24.1% of normal in healthy relatives), and in
the lack of linkage to HLA, BF and the C4 structural loci.

Wisnieski et al. (1987) found no evidence of hypercatabolism of C4 in
metabolic turnover studies which appeared to be compatible with C4
hyposynthesis, even though C4 structural alleles were intact in affected
members. In kindred members with decreased C4 levels, Wisnieski et al.
(1994) found that after a 15-minute incubation, approximately 50% of
serum C1 inhibitor did not complex with and inhibit C1r. However, C1
inhibitor function, as measured by both inhibition of C1s and the
ability to form an SDS-stable complex with C1s, was normal in affected
kindred members' sera. In addition, approximately half of the C1
inhibitor molecules in affected members' sera appeared to be relatively
resistant to cleavage by trypsin. No member of this kindred had ever had
angioedema. Zahedi et al. (1995) demonstrated that affected members of
this kindred were heterozygous for an ala443-to-val mutation in the C1
inhibitor gene (see 106100.0012).

*FIELD* RF
1. Muir, W. A.; Hedrick, S.; Alper, C. A.; Ratnoff, O. D.; Schacter,
B.; Wisnieski, J. J.: Inherited incomplete deficiency of the fourth
component of complement (C4) determined by a gene not linked to human
histocompatibility leukocyte antigens. J. Clin. Invest. 74: 1509-1514,
1984.

2. Wisnieski, J. J.; Knauss, T. C.; Yike, I.; Dearborn, D. G.; Narvy,
R. L.; Naff, G. B.: Unique C1 inhibitor dysfunction in a kindred
without angioedema. I. A mutant C1 INH that inhibits C1s but not Clr1.
J. Immunol. 152: 3199-3209, 1994.

3. Wisnieski, J. J.; Nathanson, M. H.; Anderson, J. E.; Davis, A.
E., III; Alper, C. A.; Naff, G. B.: Metabolism of C4 and linkage
analysis in a kindred with hereditary incomplete C4 deficiency. Arthritis
Rheum. 30: 919-926, 1987.

4. Zahedi, R.; Bissler, J. J.; Davis, A. E., III; Andreadis, C.; Wisnieski,
J. J.: Unique C1 inhibitor dysfunction in a kindred without angioedema.
II. Identification of an ala443-to-val substitution and functional
analysis of the recombinant mutant protein. J. Clin. Invest. 95:
1299-1305, 1995.

*FIELD* CS

Immunology:
   Partial C4 deficiency;
   Systemic lupus erythematosus

Inheritance:
   Autosomal dominant

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 4/10/1995
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

*RECORD*
*FIELD* NO
120810
*FIELD* TI
*120810 COMPLEMENT COMPONENT 4A; C4A
COMPLEMENT COMPONENT-4S; C4S;;
ACIDIC C4;;
RODGERS FORM OF C4
RODGERS BLOOD GROUP, INCLUDED
*FIELD* TX
O'Neill et al. (1978) described an electrophoretic polymorphism of C4.
Using immunofixation electrophoresis, they found three clusters of bands
in EDTA plasma: four fast-moving anodal bands (F), four slow-moving
cathodal bands (S), or a combination of F and S bands (FS). Family data,
including HLA haplotyping, were compatible with the existence of two
loci, one controlling the presence or absence of the four anodal (F)
bands and a second serving the same role for the S bands. C4F and C4S
were closely linked to HLA-B. These findings were also consistent with
those suggesting that the Chido and the Rodgers blood groups are
antigenic characteristics of C4, but are not allelic. Like Chido,
Rodgers has a low frequency of negatives (about 3%) and is closely
linked to HLA (Giles et al., 1976). Polymorphism was thought to exist,
i.e., some persons have two C4 loci and others one. Teisberg et al.
(1988) studied RFLP patterns in the C4 gene region, determining C4
haplotype pattern and C4 gene number. Among 76 haplotypes, 12 had one C4
gene, 58 had two C4 genes, and 6 had three C4 genes. The finding fitted
satisfactorily with the hypothesis that the 1-gene and 3-gene haplotypes
originated through unequal crossingover between chromosomes carrying
duplicated C4 genes. In the mouse, Ss and Slp are separate antigenic
specificities corresponding to human C4; they map within the major
histocompatibility complex in the mouse also. The symbol Slp for the
mouse locus comes from 'sex-limited protein.' Slp expression in many
strains is limited to males and is androgen-dependent. However, female
expression is also observed in rare strains, due to 1 or more unlinked
genes termed 'regulator of sex limitation' (rsl). Jiang et al. (1996)
demonstrated that female expression of Slp results from homozygous
recessive alleles at a single autosomal locus that maps to a 2.2-cM
interval on mouse chromosome 13. The locus Rsl was found not only to
enable expression in females but also to increase expression in males.
The findings suggested that the expression of Slp and perhaps other
sexually dimorphic proteins is regulated by 2 pathways, 1 that is
dependent upon RSL but not androgens and another that is Rsl-independent
but requires androgens.

Awdeh and Alper (1980) used new designations, C4A and C4B (120820), for
C4S and C4F, respectively: C4A = acidic or Rodgers; C4B = basic or
Chido. They counted at least 6 structural variants and a deletion allele
at the C4A locus and 2 structural variants and a deletion allele at the
C4B locus. No crossovers were found between the two C4 loci. An
important technical advance critical in the unraveling of the C4 protein
genetic puzzle was the introduction of desialation before
electrophoresis to achieve maximal separation of the products of the two
C4 loci (Awdeh and Alper, 1980). Yu et al. (1986) demonstrated that C4A
and C4B differ by only 4 amino acids at position 1101-1106. Over this
region C4A has the sequence PCPVLD while C4B has the sequence LSPVIH.
Palsdottir et al. (1987) showed that the 2 human C4 genes differ in
length because of the presence or absence of a 6.5-kb intron near the
5-prime end of the gene. The large intron was present in all C4A genes
but only some C4B genes. In a review of the molecular genetics of C4,
Carroll and Alper (1987) stated that C4A and C4B differ by 14
nucleotides. Allotypic and serologic differences appear to result from
single amino acid substitutions. About half of C4 null genes are the
result of DNA deletions, some of which also involve nearby steroid
21-hydroxylase genes. The C4B isotype of C4 displays 3- to 4-fold
greater hemolytic activity than does the C4A isotype. Carroll et al.
(1990) demonstrated that a conversion of residue 1106 from histidine to
aspartic acid in C4B changed the functional activity to that of C4A.
Palsdottir et al. (1983) identified a different genomic variant of C4
using the restriction enzyme BglII. Of 26 patients with autoimmune
chronic active hepatitis beginning in childhood, Vergani et al. (1985)
found low C4 in 18 (69%) and low C3 serum levels in 5 (19%). Associated
characteristics indicated a defect in synthesis of C4 and a genetic
basis thereof was indicated by the fact that C4 phenotyping in 20
patients and in 26 parents showed that 90% and 81%, respectively, had
null allotypes at either the C4A or C4B locus compared with 59% in
controls.

Bruun-Petersen et al. (1981) found 1 recombinant between C4 and HLA-B in
154 meioses, giving a map distance of 0.6 cM. Another recombinant
between C4 and HLA-D was found in 101 meioses, giving a map distance of
1.0 cM. They found marked linkage disequilibrium with both HLA-B and
HLA-D/DR, especially with the former. The findings are consistent with
the previous estimate of 1.8 cM for the HLA-B--HLA-D map distance (Lamm
et al., 1977). The authors stated a preference of C4F and C4S, because
of the possibility of confusion of C4A and C4B with HLA-A and HLA-B.
Olaisen et al. (1983) studied gene order and relative distance in the
HLA-A to HLA-B segment of MHC by a method based on allelic association
(linkage disequilibrium). A total of 701 haplotypes based on typing of
HLA-A, HLA-B, HLA-C, HLA-D/DR, C4, C2 and BF were studied. The study
confirmed localization of the complement loci between HLA-D and HLA-B;
suggested the order HLA-D--BF--C4--C2--HLA-B (perhaps with C4A on the
HLA-B side of C4B) and suggested the following relative distances (given
a length of 0.8 cM for the HLA-A to HLA-B segment):
D--0.44--BF--0.04--C4--0.11--C2--0.12--B. Wilton and Charlton (1986)
used the haplotype method to determine the sequence of class III genes
in relation to MHC genes: C4 is closest to HLA-B and BF is closest to
HLA-DR. HLA-B is telomeric to 21B. C4B, 21A, C4A, BF, and C2 then follow
21B in that order covering 120 kb. Whitehead et al. (1984) used a cDNA
probe for C4 to demonstrate DNA polymorphism of the C4 genes.
Furthermore, they validated its potential for the study of
21-hydroxylase deficiency (201910) through linkage. Robinson et al.
(1985) gave mapping information on the C4 genes derived from family
studies using RFLPs. By molecular studies at the DNA level, Schneider et
al. (1986) found that about half of the C4 genes typed as C4 null were
deleted. Several unrecognized homoduplication genes were detected. Null
alleles at either the C4A locus or the C4B locus, designated C4AQ0 and
C4BQ0, respectively, are relatively common, occurring at the C4A locus
in about 10% of normal persons and at the C4B locus in about 16% of
normal persons. The double null haplotype is very rare. Fasano et al.
(1992) studied a 7-year-old patient with recurrent sinopulmonary
infections in whom the C4A*Q0,B*Q0 double null haplotype was shown to be
due to a recombination event within the C4B locus in the mother, who
possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype.

In C4 deficiency of the guinea pig, Whitehead et al. (1983) observed a
C4 precursor RNA but no mature mRNA, suggesting that the defect lies in
RNA processing.

Homozygous deficiency of C4A is associated with systemic lupus
erythematosus (152700) and with type I diabetes mellitus; homozygous
deficiency of C4B is associated with susceptibility to bacterial
meningitis (Winkelstein, 1987). Huang et al. (1995) found a strong
association between C4A deletion and systemic lupus erythematosus in 14
multiplex SLE families.

Ranford et al. (1987) found an extraordinarily high frequency of C4
deficiency in the Australian aboriginal population of Darwin: 29% as
compared with 12% in aborigines in Alice Springs and 17% in Canberra
blood donors. Partial C4B deficiency was also higher in Darwin
aborigines than in the other populations. Nerl et al. (1984) reported an
increase in the frequency of the C4B allele C4B2 in patients with
Alzheimer disease (AD), but Eikelenboom et al. (1988) failed to find a
significant association between C4B2 allelic frequency and AD.

Lhotta et al. (1990) stated that only 17 cases of complete deficiency of
C4 had been described. They described a patient with complete deficiency
and renal disease, first presenting as severe Henoch-Schonlein purpura
with renal involvement at the age of 17. Six years later, he developed
hypertension and nephrotic syndrome, requiring hemodialysis followed by
cadaveric kidney graft. After 2 years of uncomplicated course, the
patient suffered a recurrence of his primary disease in the grafted
kidney.

The C4 molecule has 3 polypeptide chains, alpha, beta and gamma, all
encoded by a single gene. This is true for the gene product(s) of both
C4A and C4B. Ebanks et al. (1992) demonstrated the amino acid
substitution at residue 458 of the beta chain, which accounts for the
defect in classical pathway C5 convertase activity of allotype C4A6.
Their findings suggested that arg458 of the beta chain of C4 contributes
to the C5-binding site of the molecule.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988). The C4A and C4B proteins differ in their
amino acid sequences by less than 1%. The C4A and C4B genes are tandemly
arranged with the CYP21A and CYP21B genes (see 201910), each located
3-prime to the C4A and C4B genes, respectively (Carroll et al., 1985;
White et al., 1985). The C4A gene is usually approximately 22 kb long,
whereas the C4B gene is polymorphic in size, either 22 or 16 kb. This
size variation is due to the presence of a 7-kb intron located
approximately 2.5 kb from the 5-prime end of the C4 genes (Prentice et
al., 1986; Yu, 1991).

Suto et al. (1996) demonstrated that the MHC class III region can be
examined directly and visually by multicolor fluorescence in situ
hybridization using stretched DNA preparations. By varying the time of
treatment with SDS solution, the extent of the DNA stretching could be
varied. The authors thus determined the organization of the human C4A,
C4B, 210HA (CYP21A), and 210HB (CYP21B) genes. The authors stated that
the method should be useful for rapid screening of gene deletions and
duplications and analysis of gene organization.

The WHO-IUIS Nomenclature Sub-Committee (1993) made recommendations for
C4 nomenclature.

*FIELD* AV
.0001
C4A DEFICIENCY
C4A, 2BP INS, EX29, FSTER
In a study of the molecular basis of C4 null alleles, Braun et al.
(1990) found evidence for defective genes at the C4A locus and for gene
conversion at the C4B locus as demonstrated by the presence of
C4A-specific sequences. To characterize further the molecular basis of
these nonexpressed C4A genes, Barba et al. (1993) selected 9 pairs of
PCR primers from flanking genomic intron sequences to amplify all 41
exons from individuals with a defective C4A gene. The amplified products
were subjected to single-strand conformation polymorphism (SSCP)
analysis to detect possible mutations. PCR products exhibiting a
variation in the SSCP pattern were sequenced directly. In 10 of 12
individuals, a 2-bp insertion in exon 29, leading to nonexpression due
to creation of a termination codon, was detected. The insertion was
linked to the haplotype HLA-B60-DR6 in 7 cases. In 1 of the other 2
individuals without this mutation, evidence was obtained for gene
conversion to the C4B isotype. They suggested that the insertion was due
to slipped mispairing mediated by a direct repeat or run of identical
bases since the original sequence of the insertion site CTC was changed
to CTCTC by addition of a CT or a TC dinucleotide. Since the reading
frame was shifted, a complete change in the amino acid sequence
resulted, followed by a termination codon at the beginning of exon 30.

*FIELD* SA
Awdeh et al. (1979); Belt et al. (1985); Bruun-Petersen et al. (1982);
Jackson et al. (1979); Kjellman et al. (1982); Lundwall et al. (1981);
Mascart-Lemone et al. (1983); Mauff et al. (1984); Mauff et al. (1983);
Raum et al. (1984); Rittner et al. (1984); Sjoholm et al. (1985);
Teisberg et al. (1976)
*FIELD* RF
1. Awdeh, Z. L.; Alper, C. A.: Inherited structural polymorphism
of the fourth component of human complement. Proc. Nat. Acad. Sci. 77:
3576-3580, 1980.

2. Awdeh, Z. L.; Raum, D.; Alper, C. A.: Genetic polymorphism of
human complement C4 and detection of heterozygotes. Nature 282:
205-207, 1979.

3. Barba, G.; Rittner, C.; Schneider, P. M.: Genetic basis of human
complement C4A deficiency: detection of a point mutation leading to
nonexpression. J. Clin. Invest. 91: 1681-1686, 1993.

4. Belt, K. T.; Yu, C. Y.; Carroll, M. C.; Porter, R. R.: Polymorphism
of human complement component C4. Immunogenetics 21: 173-180, 1985.

5. Braun, L.; Schneider, P. M.; Giles, C. M.; Bertrams, J.; Rittner,
C.: Null alleles of human complement C4: evidence for pseudogenes
at the C4A locus and for gene conversion at the C4B locus. J. Exp.
Med. 171: 129-140, 1990.

6. Bruun-Petersen, G.; Lamm, L. U.; Jacobsen, B. K.; Kristensen, T.
: Genetics of complement C4: two homoduplication haplotypes C4S-C4S
and C4F-C4F in a family. Hum. Genet. 61: 36-38, 1982.

7. Bruun-Petersen, G.; Lamm, L. U.; Sorensen, I. J.; Buskjaer, L.;
Mortensen, J. P.: Family studies of complement C4 and HLA in man. Hum.
Genet. 58: 260-267, 1981.

8. Carroll, M. C.; Alper, C. A.: Polymorphism and molecular genetics
of human C4. Brit. Med. Bull. 43: 50-65, 1987.

9. Carroll, M. C.; Campbell, R. D.; Porter, R. R.: Mapping of steroid
21-hydroxylase genes adjacent to the complement component C4 genes
in HLA, the major histocompatibility complex in man. Proc. Nat. Acad.
Sci. 82: 521-525, 1985.

10. Carroll, M. C.; Fathallah, D. M.; Bergamaschini, L.; Alicot, E.
M.; Isenman, D. E.: Substitution of a single amino acid (aspartic
acid for histidine) converts the functional activity of human complement
C4B to C4A. Proc. Nat. Acad. Sci. 87: 6868-6872, 1990.

11. Ebanks, R. O.; Jaikaran, A. S. I.; Carroll, M. C.; Anderson, M.
J.; Campbell, R. D.; Isenman, D. E.: A single arginine to tryptophan
interchange at beta-chain residue 458 of human complement component
C4 accounts for the defect in classical pathway C5 convertase activity
of allotype C4A6: implications for the location of a C5 binding site
in C4. J. Immun. 148: 2803-2811, 1992.

12. Eikelenboom, P.; Goetz, J.; Pronk, J. C.; Hauptmann, G.: Complement
C4 phenotypes in dementia of the Alzheimer type. Hum. Hered. 38:
48-51, 1988.

13. Fasano, M. B.; Winkelstein, J. A.; LaRosa, T.; Bias, W. B.; McLean,
R. H.: A unique recombination event resulting in a C4A*Q0,C4B*Q0
double null haplotype. J. Clin. Invest. 90: 1180-1184, 1992.

14. Giles, C. M.; Gedde-Dahl, T., Jr.; Robson, E. B.; Thorsby, E.;
Olaisen, B.; Arnason, A.; Kissmeyer-Nielsen, F.; Schreuder, I.: Rg(a)
(Rodgers) and the HLA region: linkage and associations. Tissue Antigens 8:
143-149, 1976.

15. Huang, D.-F.; Siminovitch, K. A.; Liu, X.-Y.; Olee, T.; Olsen,
N. J.; Berry, C.; Carson, D. A.; Chen, P. P.: Population and family
studies of three disease-related polymorphic genes in systemic lupus
erythematosus. J. Clin. Invest. 95: 1766-1772, 1995.

16. Jackson, C. G.; Ochs, H. D.; Wedgwood, R. J.: Immune response
of a patient with deficiency of the fourth component of complement
and systemic lupus erythematosus. New Eng. J. Med. 300: 1124-1129,
1979.

17. Jiang, P. P.; Frederick, K.; Hansen, T. H.; Miller, R. D.: Localization
of the mouse gene releasing sex-limited expression of Slp. Proc.
Nat. Acad. Sci. 93: 913-917, 1996.

18. Kjellman, M.; Laurell, A.-B.; Low, B.; Sjoholm, A. G.: Homozygous
deficiency of C4 in a child with a lupus erythematosus syndrome. Clin.
Genet. 22: 331-339, 1982.

19. Lamm, L. U.; Kristensen, T.; Kissmeyer-Nielsen, F.; Jorgensen,
F.: On the HLA-B, -D map distance. Tissue Antigens 10: 394-398,
1977.

20. Lhotta, K.; Konig, P.; Hintner, H.; Spielberger, M.; Dittrich,
P.: Renal disease in a patient with hereditary complete deficiency
of the fourth component of complement. Nephron 56: 206-211, 1990.

21. Lundwall, A.; Malmheden, I.; Stalenheim, G.; Sjoquist, J.: Isolation
of component C4 of human complement and its polypeptide chains. Europ.
J. Biochem. 117: 141-146, 1981.

22. Mascart-Lemone, F.; Hauptmann, G.; Goetz, J.; Duchateau, J.; Delespesse,
G.; Vray, B.; Dab, I.: Genetic deficiency of C4 presenting with recurrent
infections and a SLE-like disease: genetic and immunologic studies. Am.
J. Med. 75: 295-304, 1983.

23. Mauff, G.; Bender, K.; Giles, C. M.; Goldmann, S.; Opferkuch,
W.; Wachauf, B.: Human C4 polymorphism: pedigree analysis of qualitative,
quantitative, and functional parameters as a basis for phenotype interpretations. Hum.
Genet. 65: 362-372, 1984.

24. Mauff, G.; Steuer, M.; Weck, M.; Bender, K.: The C4 beta-chain:
evidence for a genetically determined polymorphism. Hum. Genet. 64:
186-188, 1983.

25. Nerl, C.; Mayeux, R.; O'Neill, G. J.: HLA-linked complement markers
in Alzheimer's and Parkinson's disease C4 variant (C4B2)--a possible
marker for senile dementia of the Alzheimer type. Neurology 34:
310-314, 1984.

26. O'Neill, G. J.; Yang, S. Y.; Dupont, B.: Two HLA-linked loci
controlling the fourth component of human complement. Proc. Nat.
Acad. Sci. 75: 5165-5169, 1978.

27. Olaisen, B.; Teisberg, P.; Jonassen, R.; Thorsby, E.; Gedde-Dahl,
T., Jr.: Gene order and gene distances in the HLA region studied
by the haplotype method. Ann. Hum. Genet. 47: 285-292, 1983.

28. Palsdottir, A.; Cross, S. J.; Edwards, J. H.; Carroll, M. C.:
Correlation between a DNA restriction fragment length polymorphism
and C4A6 protein. Nature 306: 615-616, 1983.

29. Palsdottir, A.; Fossdal, R.; Arnason, A.; Edwards, J. H.; Jensson,
O.: Heterogeneity of human C4 gene size: a large intron (6.5 kb)
is present in all C4A genes and some C4B genes. Immunogenetics 25:
299-304, 1987.

30. Prentice, H. L.; Schneider, P. M.; Strominger, J. L.: C4B gene
polymorphism detected in a human cosmid clone. Immunogenetics 23:
274-276, 1986.

31. Ranford, P.; Serjeantson, S. W.; Hay, J.; Dunckley, H.: A high
frequency of inherited deficiency of complement component C4 in Darwin
aborigines. Aust. New Zeal. J. Med. 17: 420-423, 1987.

32. Raum, D.; Awdeh, Z.; Anderson, J.; Strong, L.; Granados, J.; Teran,
L.; Giblett, E.; Yunis, E. J.; Alper, C. A.: Human C4 haplotypes
with duplicated C4A or C4B. Am. J. Hum. Genet. 36: 72-79, 1984.

33. Rittner, C.; Tippett, P.; Giles, C. M.; Mollenhauer, E.; Berger,
R.; Nordhagen, R.; Buskjaer, L.; Bruun-Petersen, G.; Lamm, L.; Roos,
M. H.: An international reference typing for Ch and Rg determinants
on rare human C4 allotypes. Vox Sang. 46: 224-234, 1984.

34. Robinson, M. A.; Carroll, M. C.; Johnson, A. H.; Hartzman, R.
J.; Belt, K. T.; Kindt, T. J.: Localization of C4 genes within the
HLA complex by molecular genotyping. Immunogenetics 21: 143-152,
1985.

35. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

36. Schneider, P. M.; Carroll, M. C.; Alper, C. A.; Rittner, C.; Whitehead,
A. S.; Yunis, E. J.; Colten, H. R.: Polymorphism of the human complement
C4 and steroid 21-hydroxylase genes: restriction fragment length polymorphisms
revealing structural deletions, homoduplications, and size variants. J.
Clin. Invest. 78: 650-657, 1986.

37. Sjoholm, A. G.; Kjellman, N.-I. M.; Low, B.: C4 allotypes and
HLA-DR antigens in the family of a patient with C4 deficiency. Clin.
Genet. 28: 385-393, 1985.

38. Suto, Y.; Tokunaga, K.; Watanabe, Y.; Hirai, M.: Visual demonstration
of the organization of the human complement C4 and 21-hydroxylase
genes by high-resolution fluorescence in situ hybridization. Genomics 33:
321-324, 1996.

39. Teisberg, P.; Akesson, I.; Olaisen, B.; Gedde-Dahl, T., Jr.; Thorsby,
E.: Genetic polymorphism of C4 in man and localization of a structural
C4 locus to the HLA gene complex of chromosome 6. Nature 264: 253-254,
1976.

40. Teisberg, P.; Jonassen, R.; Mevag, B.; Gedde-Dahl, T., Jr.; Olaisen,
B.: Restriction fragment length polymorphisms of the complement component
C4 loci on chromosome 6: studies with emphasis on the determination
of gene number. Ann. Hum. Genet. 52: 77-84, 1988.

41. Vergani, D.; Wells, L.; Larcher, V. F.; Nasaruddin, B. A.; Davies,
E. T.; Mieli-Vergani, G.; Mowat, A. P.: Genetically determined low
C4: a predisposing factor to autoimmune chronic active hepatitis. Lancet II:
294-298, 1985.

42. White, P. C.; Grossberger, D.; Onufer, B. J.; Chaplin, D. D.;
New, M. I.; Dupont, B.; Strominger, J. L.: Two genes encoding steroid
21-hydroxylase are located near the genes encoding the fourth component
of complement in man. Proc. Nat. Acad. Sci. 82: 1089-1093, 1985.

43. Whitehead, A. S.; Goldberger, G.; Woods, D. E.; Markham, A. F.;
Colten, H. R.: Use of a cDNA clone for the fourth component of human
complement (C4) for analysis of a genetic deficiency of C4 in guinea
pig. Proc. Nat. Acad. Sci. 80: 5387-5391, 1983.

44. Whitehead, A. S.; Woods, D. E.; Fleischnick, E.; Chin, J. E.;
Yunis, E. J.; Katz, A. J.; Gerald, P. S.; Alper, C. A.; Colten, H.
R.: DNA polymorphism of the C4 genes: a new marker for analysis of
the major histocompatibility complex. New Eng. J. Med. 310: 88-91,
1984.

45. WHO-IUIS Nomenclature Sub-Committee: Revised nomenclature for
human complement component C4*2. Europ. J. Immunogenet. 20: 301-305,
1993.

46. Wilton, A. N.; Charlton, B.: Order of class III genes relative
to HLA genes determined by the haplotype method. Immunogenetics 24:
79-83, 1986.

47. Winkelstein, J. A.: Personal Communication. Baltimore, Md.
9/15/1987.

48. Yu, C. Y.: The complete exon-intron structure of a human complement
component C4A gene: DNA sequences, polymorphism, and linkage to the
21-hydroxylase gene. J. Immun. 146: 1057-1066, 1991.

49. Yu, C. Y.; Belt, K. T.; Giles, C. M.; Campbell, R. D.; Porter,
R. R.: Structural basis of the polymorphism of human complement components
C4A and C4B: gene size, reactivity and antigenicity. EMBO J. 5:
2873-2881, 1986.

*FIELD* CS
Inheritance:
   Autosomal dominant;

Immunology:
   Homozygous C4A deficiency;
   Autoimmune chronic active hepatitis;
   Systemic lupus erythematosus;
   Type I diabetes mellitus;
   Henoch-Schonlein purpura

Endo:
   Hypertension

GU:
   Nephrotic syndrome

Inheritance:
   Autosomal recessive

*FIELD* ED
joanna: 10/17/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/26/1997
mark: 5/9/1996
terry: 5/7/1996
terry: 4/30/1996
mark: 2/9/1996
terry: 2/8/1996
mark: 5/10/1995
mimadm: 6/25/1994
warfield: 4/21/1994
carol: 3/28/1994
carol: 5/12/1993
carol: 11/13/1992

*RECORD*
*FIELD* NO
120820
*FIELD* TI
*120820 COMPLEMENT COMPONENT 4B; C4B
COMPLEMENT COMPONENT-4F; C4F;;
BASIC C4;;
CHIDO FORM OF C4
*FIELD* TX
By the process of antigen-antibody crossed electrophoresis, Rosenfeld et
al. (1969) demonstrated heterogeneity in the fourth component of
complement. Subtypes A and A(1) seem to be inherited as codominant
traits independent of subtype C. Partial deficiency of C4 was found in 3
persons during a screening of 42,000 healthy Japanese (Torisu et al.,
1970). Ellman et al. (1970) found a deficiency of C4 in the guinea pig,
where total deficiency was recessive. Hall and Colten (1978) showed that
C4 deficiency in the guinea pig is due to a defect in translation of
specific C4 messenger RNA on polysomes. Fontaine et al. (1980) found a
common antigenic determinant on human C4b and C3b. This supports a
common ancestral origin for C3 and C4. However, C3 is located on
chromosome 19. Both C3 and C4 are synthesized as single polypeptide
chains (Brade et al., 1977; Hall and Colten, 1977). In the serum,
however, C3 consists of 2 polypeptide chains and C4 consists of 3
(Porter and Reid, 1978). 'Half null' haplotypes (deletion on one or the
other but not both C4 loci on any given chromosome) are common in
Caucasians (O'Neill et al., 1978). Awdeh et al. (1981) analyzed C4 types
in relatives of a C4-deficient proband and provided evidence that the
deficiency results from homozygosity for a rare, double null haplotype.
The family contained persons with 1, 2, 3 or 4 expressed C4 genes
(rather like alpha hemoglobin genes in alpha-thalassemic states), and
the mean serum C4 levels roughly reflected the number of structural
genes present. Kramer et al. (1991) demonstrated a marked drop in the
frequency of the C4 null allele (C4B*Q0) in elderly subjects: in 'young'
and 'old' men the frequency was 17.6 and 3.4%, respectively. This
suggested that the allele is a negative selection factor for survival.
Whether this is a direct effect of the gene or the result of linkage
disequilibrium with neighboring genes such as HLA or CYP21 was
discussed. To evaluate the molecular basis of the C4 null phenotypes,
Partanen et al. (1988) used Southern blotting techniques to analyze
genomic DNA from 23 patients with systemic lupus erythematosus (SLE;
152700) and from healthy controls. They confirmed the earlier findings
of high frequencies of C4 null phenotypes and of HLA-B8,DR3 antigens. In
addition, they found that among the patients most of both the C4A
(120810) and C4B null phenotypes resulted from gene deletions. Among the
controls, only the C4A null phenotypes were predominantly the result of
gene deletions. In all SLE cases the C4 gene deletions extended also to
a closely linked pseudogene, CYP21A (see 201910). Altogether, 52% of the
patients and 26% of the controls carried a C4/CYP21A deletion. Partanen
et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci
fell within the range of 30-38 kb, as determined by pulsed field gel
electrophoresis. Because the deletion sizes in most other gene clusters
are more heterogeneous, the results suggested to Partanen et al. (1989)
the involvement of a specific mechanism in the generation of C4+CYP21
deletions. Roos et al. (1982) showed that the alpha chains of C4A and
C4B differ in molecular weight, being 96,000 and 94,000, respectively.
Each C4 molecule consists of beta-alpha-gamma subunits, in that sequence
in the pro-C4. The secreted form of C4 is larger than the major plasma
form by a molecular weight of about 5000 (Chan et al., 1983).
Presumably, the extra piece is removed extracellularly by proteolytic
cleavage. Wank et al. (1984) found a particular rare C4B allele in 25%
of 59 unselected patients with primary glomerulonephritis but in only 2%
of the normal population--a relative risk of 22.1 for persons with the
variant C4B*2.9. The association with the membranoproliferative type was
especially strong. In 3 black-American patients with SLE, Wilson and
Perez (1988) found complete deficiency of plasma C4B. In a 9-year-old
girl with SLE and complete C4 deficiency, Welch et al. (1990) found
uniparental isodisomy 6. The girl had 2 identical chromosome 6
haplotypes from the father and none from the mother.

The C4 locus in the guinea pig is linked to the major histocompatibility
complex (Shevach et al., 1976) and to Bf (Kronke et al., 1977). The
locus in man is in the major histocompatibility region on chromosome 6
(Teisberg et al., 1976; Ochs et al., 1977). The Ss protein of the mouse,
determined by a gene that is part of the MHC complex, is homologous to
C4 in man (Lachmann et al., 1975; Meo et al., 1975). Thus, linkage
homology is maintained in 3 species. Pollack et al. (1980) used the
linkage principle (and the tight linkage to HLA) for the prenatal
diagnosis of C4 deficiency. On the basis of 4 overlapping cosmid clones,
Carroll et al. (1984) aligned 4 human complement genes which are known
to map between HLA-D and HLA-B. The C2 and BF genes, less than 2 kb
apart, are about 30 kb from the two C4 genes, which are separated from
each other by about 10 kb. Using a chromosome-specific C4 DNA pattern
relative to the loss or retention of other MHC genes on the same
chromosome, in subclones of a cell line with gamma-ray-induced lesions
of the MHC region, Whitehead et al. (1985) could document the location
of C4 between HLA-B and HLA-DR.

Awdeh and Alper (1980) introduced a typing system that allowed them to
detect 6 common structural alleles at the Rodgers (C4A) locus or 2 or 3
at the Chido (C4B) locus in whites. The Chido blood group, which was
discovered by Harris et al. (1967), is an antigenic characteristic of
C4B. Chido has a low frequency of negatives (2%) and is tightly linked
to HLA (Middleton and Crookston, 1972), closer to HLA-B than to HLA-A.
The Chido antigen resembles the HLA antigens in molecular structure.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

Suto et al. (1996) demonstrated that the MHC class III region can be
examined directly and visually by multicolor fluorescence in situ
hybridization using stretched DNA preparations. By varying the time of
treatment with SDS solution, the extent of the DNA stretching could be
varied. The authors thus determined the organization of the human C4A,
C4B, 210HA (CYP21A), and 210HB (CYP21B) genes. The authors stated that
the method should be useful for rapid screening of gene deletions and
duplications and analysis of gene organization.

*FIELD* SA
Carroll and Porter (1983); Cream et al. (1979); Cunningham-Rundles
et al. (1977); Cunningham-Rundles et al. (1977); Curman et al. (1975);
Giles  (1984); Hobart and Lachmann (1976); Mascart-Lemone et al. (1983);
Middleton et al. (1974); O'Neill  (1981); O'Neill et al. (1978); O'Neill
et al. (1978); Olaisen et al. (1979); Petersen et al. (1979); Rittner
and Bertrams (1981); Rittner et al. (1976); Schaller et al. (1977);
Shreffler  (1976)
*FIELD* RF
1. Awdeh, Z. L.; Alper, C. A.: Inherited structural polymorphism
of the fourth component of human complement. Proc. Nat. Acad. Sci. 77:
3576-3580, 1980.

2. Awdeh, Z. L.; Ochs, H. D.; Alper, C. A.: Genetic analysis of C4
deficiency. J. Clin. Invest. 67: 260-263, 1981.

3. Brade, V.; Hall, R. E.; Colten, H. R.: Biosynthesis of pro-C3,
a precursor of the third component of complement. J. Exp. Med. 146:
759-765, 1977.

4. Carroll, M. C.; Campbell, R. D.; Bentley, D. R.; Porter, R. R.
: A molecular map of the human major histocompatibility complex class
III region linking complement genes C4, C2 and factor B. Nature 307:
237-241, 1984.

5. Carroll, M. C.; Porter, R. R.: Cloning of a human complement component
C4 gene. Proc. Nat. Acad. Sci. 80: 264-267, 1983.

6. Chan, A. C.; Mitchell, K. R.; Munns, T. W.; Karp, D. R.; Atkinson,
J. P.: Identification and partial characterization of the secreted
form of the fourth component of human complement: evidence that it
is different from major plasma form. Proc. Nat. Acad. Sci. 80:
268-272, 1983.

7. Cream, J. J.; Olaisen, B.; Teisberg, P.; Soler, A. V.; Thompson,
R. A.: Genetic basis of acquired C4 deficiency. Clin. Genet. 16:
297-300, 1979.

8. Cunningham-Rundles, C.; Dupont, B.; Jersild, C.; Tegoli, C.; Whitsett,
C.; Good, R. A.: Are HLA and Chido related antigenic groups?. Transplant.
Proc. 9: 33-38, 1977.

9. Cunningham-Rundles, C.; Tegoli, J.; Dupont, B.; Whitsett, C.; Good,
R. A.: Chemical studies on the Chido antigen. Transplant. Proc. 9:
647-652, 1977.

10. Curman, B.; Ostberg, L.; Sandberg, L.; Malmheden-Erikkson, I.;
Stalenheim, G.; Rask, L.; Peterson, P. A.: H-2 linked Ss protein
is C-4 component of complement. Nature 258: 243-245, 1975.

11. Ellman, L.; Green, I.; Frank, M.: Genetically controlled total
deficiency of the fourth component of complement in the guinea pig.
Science 170: 74-75, 1970.

12. Fontaine, M.; Daveau, M.; Lebreton, J. P.: A common antigenic
determinant on human C4b and C3b. Molec. Immun. 17: 1075-1078,
1980.

13. Giles, C. M.: A new genetic variant for Chido. Vox Sang. 46:
149-156, 1984.

14. Hall, R. E.; Colten, H. R.: Genetic defect in biosynthesis of
the precursor form of the fourth component of complement. Science 199:
69-70, 1978.

15. Hall, R. E.; Colten, H. R.: Cell-free synthesis of the fourth
component of guinea pig complement (C4): identification of a precursor
of serum C4 (pro-C4). Proc. Nat. Acad. Sci. 74: 1707-1710, 1977.

16. Harris, J. P.; Tegoli, J.; Swanson, J.; Fisher, N.; Gavin, J.;
Noades, J.: A nebulous antibody responsible for cross-matching difficulties
(Chido). Vox Sang. 12: 140-142, 1967.

17. Hobart, M. J.; Lachmann, P. J.: Allotypes of complement components
in man. Transplant. Rev. 32: 26-42, 1976.

18. Kramer, J.; Fulop, T.; Rajczy, K.; Ahn Tuan, N.; Fust, G.: A
marked drop in the incidence of the null allele of the B gene of the
fourth component of complement (C4B*Q0) in elderly subjects: C4B*Q0
as a probable negative selection factor for survival. Hum. Genet. 86:
595-598, 1991.

19. Kronke, M.; Geezy, A. F.; Hadding, U.; Bitter-Suermann, D.: Linkage
of C4 and C4 deficiency to Bf and GPLA. Immunogenetics 5: 461-466,
1977.

20. Lachmann, P. J.; Grennan, D.; Martin, A.; Demant, P.: Identification
of Ss protein as murine C4. Nature 258: 242-243, 1975.

21. Mascart-Lemone, F.; Hauptmann, G.; Goetz, J.; Duchateau, J.; Delespesse,
G.; Vray, B.; Dab, I.: Genetic deficiency of C4 presenting with recurrent
infections and a SLE-like disease: genetic and immunologic studies.
Am. J. Med. 75: 295-304, 1983.

22. Meo, T.; Krasteff, T.; Shreffler, D. C.: Immunochemical characterization
of murine H-2 controlled Ss (serum substance) protein through identification
of its human homologue as the fourth component of complement. Proc.
Nat. Acad. Sci. 72: 4536-4540, 1975.

23. Middleton, J.; Crookston, M. C.: Chido-substance in plasma. Vox
Sang. 23: 256-261, 1972.

24. Middleton, J.; Crookston, M. C.; Falk, J. A.; Robson, E. B.; Cook,
P. J. L.; Batchelor, J. R.; Bodmer, J.; Ferrara, G. B.; Festenstein,
J.; Harris, H.; Kissmeyer-Nielsen, F.; Lawler, S. D.; Sachs, J. A.;
Wolf, E.: Linkage of Chido and HL-A. Tissue Antigens 4: 366-373,
1974.

25. O'Neill, G. J.: The genetic control of Chido and Rodgers blood
group substances. Seminars Hemat. 18: 32-38, 1981.

26. O'Neill, G. J.; Yang, S. Y.; Dupont, B.: Two HLA-linked loci
controlling the fourth component of human complement. Proc. Nat.
Acad. Sci. 75: 5165-5169, 1978.

27. O'Neill, G. J.; Yang, S. Y.; Dupont, B.: Chido and Rodgers blood
groups: relationships to C4 and HLA. Transplant. Proc. 10: 749-751,
1978.

28. O'Neill, G. J.; Yang, S. Y.; Tegoli, J.; Berger, R.; Dupont, B.
: Chido and Rodgers blood groups are distinct antigenic components
of human C4. Nature 273: 668-670, 1978.

29. Ochs, H. D.; Rosenfeld, S. I.; Thomas, E. D.; Giblett, E. R.;
Alper, C. A.; Dupont, B.; Schaller, J. G.; Gilliland, B. C.; Hansen,
J. A.; Wedgwood, R. J.: Linkage between the gene (or genes) controlling
synthesis of the fourth component of complement and the major histocompatibility
complex. New Eng. J. Med. 296: 470-475, 1977.

30. Olaisen, B.; Teisberg, P.; Nordhagen, R.; Michaelsen, T.; Gedde-Dahl,
T., Jr.: Human complement C4 locus is duplicated on some chromosomes.
Nature 279: 736-737, 1979.

31. Partanen, J.; Kere, J.; Wessberg, S.; Koskimies, S.: Determination
of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase
genes by pulsed-field gel electrophoresis. Genomics 5: 345-349,
1989.

32. Partanen, J.; Koskimies, S.; Johansson, E.: C4 null phenotypes
among lupus erythematosus patients are predominantly the result of
deletions covering C4 and closely linked 21-hydroxylase A genes. J.
Med. Genet. 25: 387-391, 1988.

33. Petersen, G. B.; Sorensen, I. J.; Buskjaer, L.; Lamm, L. U.:
Genetic studies of complement C4 in man. Hum. Genet. 53: 31-36,
1979.

34. Pollack, M. S.; Ochs, H. D.; Dupont, B.: HLA typing of cultured
amniotic cells for the prenatal diagnosis of complement C4 deficiency.
Clin. Genet. 18: 197-200, 1980.

35. Porter, R. R.; Reid, K. B. M.: The biochemistry of complement.
Nature 275: 699-704, 1978.

36. Rittner, C.; Bertrams, J.: On the significance of C2, C4, and
factor B polymorphisms in disease. Hum. Genet. 56: 235-247, 1981.

37. Rittner, C.; Hauptmann, G.; Grosse-Wilde, H.; Grosshans, E.; Tongio,
M. M.; Mayer, S.: Linkage between HL-A (major histocompatibility
complex) and genes controlling the fourth component of complement.
In: Histocompatibility Testing 1975.  Copenhagen: Munksgaard (pub.)
1976. Pp. 945-953.

38. Roos, M. H.; Mollenhauer, E.; Demant, P.; Rittner, C.: A molecular
basis for the two locus model of human complement component C4. Nature 298:
854-856, 1982.

39. Rosenfeld, S. I.; Ruddy, S.; Austen, K. F.: Structural polymorphism
of the fourth component of human complement. J. Clin. Invest. 48:
2283-2292, 1969.

40. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

41. Schaller, J. G.; Gilliland, B. G.; Ochs, H. D.; Leddy, J. P.;
Agodoa, L. C. Y.; Rosenfeld, S. I.: Severe systemic lupus erythematosus
with nephritis in a boy with deficiency of the fourth component of
complement. Arthritis Rheum. 20: 1519-1525, 1977.

42. Shevach, E. M.; Frank, M. M.; Green, I.: Linkage of gene controlling
the synthesis of the fourth component of complement to the major histocompatibility
complex of the guinea pig. Immunogenetics 3: 595-602, 1976.

43. Shreffler, D. C.: The S region of the mouse major histocompatibility
complex (H-2): genetic variation and functional role in complement
system. Transplant. Rev. 32: 140-167, 1976.

44. Suto, Y.; Tokunaga, K.; Watanabe, Y.; Hirai, M.: Visual demonstration
of the organization of the human complement C4 and 21-hydroxylase
genes by high-resolution fluorescence in situ hybridization. Genomics 33:
321-324, 1996.

45. Teisberg, P.; Akesson, I.; Olaisen, B.; Gedde-Dahl, T., Jr.; Thorsby,
E.: Genetic polymorphism of C4 in man and localization of a structural
C4 locus to the HLA gene complex of chromosome 6. Nature 264: 253-254,
1976.

46. Torisu, M.; Sonozaki, H.; Inai, S.; Arata, M.: Deficiency of
the fourth component of complement in man. J. Immunogenet. 104:
728-737, 1970.

47. Wank, R.; Schendel, D. J.; O'Neill, G. J.; Riethmuller, G.; Held,
E.; Feucht, H. E.: Rare variant of complement C4 is seen in high
frequency in patients with primary glomerulonephritis. Lancet I:
872-874, 1984.

48. Welch, T. R.; Beischel, L. S.; Choi, E.; Balakrishnan, K.; Bishof,
N. A.: Uniparental isodisomy 6 associated with deficiency of the
fourth component of complement. J. Clin. Invest. 86: 675-678, 1990.

49. Whitehead, A. S.; Colten, H. R.; Chang, C. C.; Demars, R.: Localization
of the human MHC-linked complement genes between HLA-B and HLA-DR
by using HLA mutant cell lines. J. Immun. 134: 641-643, 1985.

50. Wilson, W. A.; Perez, M. C.: Complete C4B deficiency in black
Americans with systemic lupus erythematosus. J. Rheum. 15: 1855-1858,
1988.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 05/09/1996
terry: 5/7/1996
mark: 5/7/1996
mimadm: 4/29/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 8/7/1991
carol: 7/2/1991
carol: 1/11/1991

*RECORD*
*FIELD* NO
120830
*FIELD* TI
*120830 COMPLEMENT COMPONENT-4 BINDING PROTEIN, ALPHA; C4BPA
C4b RECEPTOR; C4BP
*FIELD* TX
The C4b-binding protein is involved in the regulation of the complement
system. It is a multimeric protein comprising 7 identical alpha chains
and a single beta chain. The alpha and beta chains have molecular
weights 70 kD and 45 kD, respectively. Both subunits belong to a
superfamily of proteins composed predominantly of tandemly arranged
short consensus repeats (SCR) approximately 60 amino acid residues in
length. Kaidoh et al. (1981) showed that the C4 binding protein is
determined by a gene in the major histocompatibility complex in the
mouse. C4BP is a macromolecular serum protein with the electrophoretic
mobility of beta-globulin. In both the classical and the alternative
pathways of activation of complement proteins, a unique enzyme complex,
C3 convertase, is assembled. The C3 convertase of the classical pathway
consists of C2 and C4; that of the alternative pathway of factor B and
C3. Each C3 convertase plays a key role in the amplification process of
complement activation. C4BP is an essential cofactor for C3b inactivator
in the proteolytic cleavage of C4b and, to a lesser extent, of C3b, and
functions as the regulator of C3 convertase of the classical pathway.
C4BP is polymorphic in the mouse. C4BP of man has been studied by Gigli
et al. (1979) and Nagasawa and Stroud (1980). By isoelectric focusing
under completely denaturing conditions, Rodriguez de Cordoba et al.
(1983, 1984) identified 2 allelic variants of C4BP. Rodriguez de Cordoba
et al. (1984) studied 3 pedigrees informative for segregation of C4BP
and the C3b receptor (C3BR; 120620). Three distinct forms of C3BR have
been identified by NaDod-SO4/polyacrylamide gel electrophoresis on human
red cells and white cells. The 3 forms vary in molecular weights by
relatively large amounts--160,000, 190,000 and 220,000. Matsuguchi et
al. (1989) showed that proline-rich protein (PRP), a glycoprotein
present in chylomicrons, is identical to C4BP. Obviously, it is not to
be confused with salivary proline-rich protein (168790).

Neither C4BP nor C3BR is closely linked to HLA (Rodriguez de Cordoba et
al., 1983; Hatch et al., 1984); however, segregation in the 3 kindreds
indicated that the 2 loci are closely linked in man. There were 10
informative meioses with no recombinants--maximum lod score = 2.4 at
theta 0.0. The cosegregation of 2 common alleles supported close linkage
by the principle of linkage disequilibrium. These 2 closely linked genes
determine functionally related proteins. Rodriguez de Cordoba et al.
(1985) concluded that HF, C4BP, C3BR, and C3DR represent a cluster of
linked genes encoding complement components regulating the activation of
C3. They called the cluster RCA for regulators of complement activation.
They showed, furthermore, that the RCA cluster segregates independently
of HLA, the C2, BF, C4 cluster (on 6p), and C3 (on 19p). Using
pulsed-field gel electrophoresis, Rey-Campos et al. (1988) showed that
the RCA cluster is physically linked and aligned as CR1--CR2--DAF--C4BP
in an 800-kb DNA segment. The very tight linkage between CR1 and C4BP
revealed by family linkage studies contrasts with the relatively long
DNA distance between these genes, suggesting that there may be
mechanisms interfering with recombination within the RCA gene cluster.
The probe for factor H (HF; 134370) did not hybridize to any of the
fragments recognized by the CR1, CR2, DAF, or C4BP probes. Rey-Campos et
al. (1988) estimated that the RCA cluster may exceed 1 Mb in length and,
given the recombination data, may be as long as 7 Mb. By Southern
analysis of hybrid cell DNA, Hing et al. (1988) assigned C4BP and HF to
1q. Barnum et al. (1989) assigned the murine equivalent to chromosome 1.

Aso et al. (1991) found that the C4BPA gene comprises 12 exons and spans
about 40 kb. Each of the 8 SCRs that constitute the N-terminal 491
residues is encoded by a single exon, except for the second, which is
encoded by 2 separate exons.

*FIELD* SA
Andersson et al. (1990); Rodriguez de Cordoba et al. (1984)
*FIELD* RF
1. Andersson, A.; Dahlback, B.; Hanson, C.; Hillarp, A.; Levan, G.;
Szpirer, J.; Szpirer, C.: Genes for C4b-binding protein alpha- and
beta-chains (C4BPA and C4BPB) are located on chromosome 1, band 1q32,
in humans and on chromosome 13 in rats. Somat. Cell Molec. Genet. 16:
493-500, 1990.

2. Aso, T.; Okamura, S.; Matsuguchi, T.; Sakamoto, N.; Sata, T.; Niho,
Y.: Genomic organization of the alpha chain of the human C4b-binding
protein gene. Biochem. Biophys. Res. Commun. 174: 222-227, 1991.

3. Barnum, S. R.; Kristensen, T.; Chaplin, D. D.; Seldin, M. F.; Tack,
B. F.: Molecular analysis of the murine C4b-binding protein gene:
chromosome assignment and partial gene organization. Biochemistry 28:
8312-8317, 1989.

4. Gigli, I.; Fujita, T.; Nussenzweig, V.: Modulation of the classical
pathway C3 convertase by plasma proteins C4 binding protein and C3b
inactivator. Proc. Nat. Acad. Sci. 76: 6596-6600, 1979.

5. Hatch, J. A.; Atkinson, J. P.; Suarez, B. K.; Dykman, T. R.: Evaluation
of linkage of the human C3b/C4b receptor to HLA. J. Immun. 132:
2168-2169, 1984.

6. Hing, S.; Day, A. J.; Linton, S. J.; Ripoche, J.; Sim, R. B.; Reid,
K. B. M.; Solomon, E.: Assignment of complement components C4 binding
protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA
probes. Ann. Hum. Genet. 52: 117-122, 1988.

7. Kaidoh, T.; Natsuume-Sakai, S.; Takahashi, M.: Murine binding
protein of the fourth component of complement: structural polymorphism
and its linkage to the major histocompatibility complex. Proc. Nat.
Acad. Sci. 78: 3794-3798, 1981.

8. Matsuguchi, T.; Okamura, S.; Aso, T.; Sata, T.; Niho, Y.: Molecular
cloning of the cDNA coding for proline-rich protein (PRP): identity
of PRP as C4b-binding protein. Biochem. Biophys. Res. Commun. 165:
138-144, 1989.

9. Nagasawa, S.; Stroud, R. M.: Purification and characterization
of a macromolecular weight cofactor for C3b-inactivator, C4bC3bINA-cofactor,
of human plasma. Molec. Immun. 17: 1365-1372, 1980.

10. Rey-Campos, J.; Rubinstein, P.; Rodriguez de Cordoba, S.: A physical
map of the human regulator of complement activation gene cluster linking
the complement genes CR1, CR2, DAF, and C4BP. J. Exp. Med. 167:
664-669, 1988.

11. Rodriguez de Cordoba, S.; Dykman, T. R.; Ginsberg-Fellner, F.;
Ercilla, G.; Aqua, M.; Atkinson, J. P.; Rubinstein, P.: Evidence
for linkage between the loci coding for the binding protein for the
fourth component of human complement (C4BP) and for the C3b/C4b receptor. Proc.
Nat. Acad. Sci. 81: 7890-7892, 1984.

12. Rodriguez de Cordoba, S.; Ferreira, A.; Nussenzweig, V.; Rubinstein,
P.: Genetic polymorphism of human C4-binding protein. J. Immun. 131:
1565-1569, 1983.

13. Rodriguez de Cordoba, S.; Lublin, D. M.; Rubinstein, P.; Atkinson,
J. P.: Human genes for three complement components that regulate
the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195,
1985.

14. Rodriguez de Cordoba, S.; Rubinstein, P.; Ferreira, A.: High
resolution isoelectric focusing of immunoprecipitated proteins under
denaturing conditions: a simple analytical method applied to the study
of complement component polymorphisms. J. Immun. Methods 69: 165-172,
1984.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 02/21/1997
supermim: 3/16/1992
carol: 3/2/1992
carol: 3/1/1991
carol: 2/25/1991
carol: 1/2/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120831
*FIELD* TI
*120831 COMPLEMENT COMPONENT-4 BINDING PROTEIN, BETA CHAIN; C4BPB
*FIELD* TX
The complement component C4b-binding protein is composed of 7 identical
70-kD alpha chains, each containing a binding site for the complement
protein C4b. Hillarp and Dahlback (1988) showed the presence in C4BP of
a single copy of a unique 45-kD subunit. Called the beta chain, it binds
protein S. The subunit composition of C4BP in plasma is heterogeneous; a
subform lacks the beta chain and does not bind protein S. The alpha
chain is composed of 549 amino acid residues, and the 491 terminal
residues can be divided into 8 short consensus repeats (SCRs). Hillarp
and Dahlback (1990) isolated and characterized full-length cDNA clones
encoding the beta chain of human C4BP. The deduced amino acid sequence
contained 3 SCRs homologous to those found in the alpha chain and a
60-amino acid nonrepeat region that is similar to the corresponding
portion of the alpha chain. Pardo-Manuel et al. (1990) showed by pulsed
field gel electrophoresis that the alpha and beta chains of C4BP are
closely situated in the same 420-kb SalI restriction fragment in a
head-to-tail orientation. Presumably, they share regulatory sequences
for coordinate regulation. Thus, there are 7 genes in the regulator of
complement activation (RCA) gene cluster: C4BPA, C4BPB, MCP, CR1, CR2,
DAF, and CFH. Hillarp et al. (1993) provided further information on the
structure of the C4BPB gene.

Andersson et al. (1990) used cDNA probes for both the alpha- and
beta-chains of human C4b-binding protein to localize their genes with an
in situ hybridization technique to 1q32. The probes were also used to
screen mouse-rat somatic cell hybrids using Southern blotting to
localize the genes in the rat. Both genes were shown to be on chromosome
13 in the rat. These 2 genes and the gene for coagulation factor V
represent a conserved chromosomal region in rat and man.

Rodriguez de Cordoba et al. (1994) used a human C4BPB cDNA probe to
isolate and characterize a genomic DNA fragment that included the murine
C4BPB gene. They found that it is present in single copy and maps close
to the murine homolog of C4BPA on chromosome 1. However, in several
inbred strains of Mus musculus and in Mus spretus, they demonstrated 2
inphase stop codons that are incompatible with the expression of a
functional C4BPB polypeptide. It appeared that the loss of a functional
C4BPB gene was a relatively recent event in the evolution of the mouse.
Since the genetic change had become fixed, the mice lacking the C4BPB
polypeptide may have enjoyed some kind of selective advantage.

*FIELD* RF
1. Andersson, A.; Dahlback, B.; Hanson, C.; Hillarp, A.; Levan, G.;
Szpirer, J.; Szpirer, C.: Genes for C4b-binding protein alpha- and
beta-chains (C4BPA and C4BPB) are located on chromosome 1, band 1q32,
in humans and on chromosome 13 in rats. Somat. Cell Molec. Genet. 16:
493-500, 1990.

2. Hillarp, A.; Dahlback, B.: Novel subunit in C4b-binding protein
required for protein S binding. J. Biol. Chem. 263: 12759-12764,
1988.

3. Hillarp, A.; Dahlback, B.: Cloning of cDNA coding for the beta-chain
of human complement component C4b-binding protein: sequence homology
with the alpha chain. Proc. Nat. Acad. Sci. 87: 1183-1187, 1990.

4. Hillarp, A.; Pardo-Manuel, F.; Ramos Ruiz, R.; Rodriguez de Cordoba,
R.; Dahlback, B.: The human C4b-binding protein beta-chain gene.
J. Biol. Chem. 268: 15017-15023, 1993.

5. Pardo-Manuel, F.; Rey-Campos, J.; Hillarp, A.; Dahlback, B.; Rodriguez
de Cordoba, S.: Human genes for the alpha and beta chains of complement
C4b-binding protein are closely linked in a head-to-tail arrangement.
Proc. Nat. Acad. Sci. 87: 4529-4532, 1990.

6. Rodriguez de Cordoba, S.; Perez-Blas, M.; Ramos-Ruiz, R.; Sanchez-Corral,
P.; Pardo-Manuel de Villena, F.; Rey-Campos, J.: The gene coding
for the beta-chain of C4b-binding protein (C4BPB) has become a pseudogene
in the mouse. Genomics 21: 501-509, 1994.

*FIELD* CD
Victor A. McKusick: 3/1/1990

*FIELD* ED
jason: 7/1/1994
carol: 10/18/1993
carol: 10/1/1993
supermim: 3/16/1992
carol: 1/10/1991
carol: 1/2/1991

*RECORD*
*FIELD* NO
120832
*FIELD* TI
#120832 COMPLEMENT COMPONENT-4 BINDING PROTEIN, ALPHA-LIKE 1
C4BPAL1
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
gene is a pseudogene.

C4BPAL1 is a member of the human RCA gene cluster that arose from
duplication of the C4BPA gene (120830) and is in the same 5-prime to
3-prime orientation found in all RCA genes. It was found to include 9
exon-like regions homologous to several exons of the C4BPA gene.
Analysis of its sequence suggested that it is currently a pseudogene in
humans. However, comparisons between C4BPAL1 and the human and murine
C4BPA genes showed sequence conservation which strongly suggested that,
for a long period of time, the gene was functional.

*FIELD* SA
Sanchez-Corral et al. (1993)
*FIELD* RF
1. Sanchez-Corral, P.; Pardo-Manuel de Villena, F.; Rey-Campos, J.;
Rodriguez de Cordoba, S.: C4BPAL1, a member of the human regulator
of complement activation (RCA) gene cluster that resulted from the
duplication of the gene coding for the alpha-chain of C4b-binding
protein. Genomics 17: 185-193, 1993.

*FIELD* CD
Victor A. McKusick: 7/13/1993

*FIELD* ED
carol: 7/13/1993

*RECORD*
*FIELD* NO
120900
*FIELD* TI
*120900 COMPLEMENT COMPONENT-5, DEFICIENCY OF
C5 DEFICIENCY
*FIELD* TX
Dysfunction of the fifth component of complement (C5) was found to be
the basis for the deficiency in phagocytosis-enhancing activity of serum
present in the proband, her mother and 15 other relatives (Miller and
Nilsson, 1970). Genetic deficiency of C5 in mice was studied also.
Jacobs and Miller (1972) reported a second family with deficiency of C5.
However, in this family 2 brothers were affected and the laboratory
characteristics of the deficiency were different. The presence of low
opsonic indices in relatives through each parent supported autosomal
recessive inheritance. The clinical picture of affected children in both
families was that described by Leiner (1908). The 4 cardinal features
are: (1) generalized seborrheic dermatitis, (2) intractable diarrhea,
(3) recurrent local and systemic infections, usually of gram-negative
etiology, and (4) marked wasting. The diagnostic test is for uptake of
particles (baker's yeast) by leukocytes, since C5 is required for full
opsonization. Immunochemical assays of C5 are normal. Recognition of
this disorder is important because effective therapy is available. Fresh
plasma contains opsonically active C5, which is absent in 5-day-old
stored bank blood. The pedigree of the first family, as presented by
Miller et al. (1968), is probably as consistent with recessive
inheritance as with dominant. Rosenfeld and Leddy (1974) found a kindred
with C5 deficiency through studies of a black woman with systemic lupus
erythematosus, frequent bacterial infections, and absent serum hemolytic
complement activity. A healthy half-sister had almost no C5 and 4
relatives had about half normal levels. The ability of the proband's
serum to promote phagocytosis of baker's yeast by normal or self
neutrophils was unimpaired--an apparent conflict with other studies
cited above. Asghar et al. (1991) described C5 deficiency in association
with discoid lupus erythematosus. Snyderman et al. (1979) demonstrated
that repeated disseminated gonococcal infection can be associated with
C5 deficiency. They excluded linkage with HLA-A and HLA-B, as did
Rosenfeld et al. (1976).

By study of somatic cell hybrids using a cDNA probe and by in situ
hybridization using the same probe, Jeremiah et al. (1987, 1988)
assigned C5 to 9q22-q34. Wetsel et al. (1988) employed in situ
hybridization methods to localize the genes to band 9q32-q34. In their
studies, the largest cluster of grains was found at 9q34.1.

Schifferli and Hirschel (1985) suggested that deficiency of a late
component of complement (C5 to C8) was present in G. D. Heist of
Philadelphia, a scientist who gave the first description of complement
deficiency and who himself died of meningococcal meningitis. The paper
of Heist et al. (1922) stated: 'The subsequent history of man 'H'
illustrates the lack of resistance to meningococcal infection that
accompanies absence of bactericidal power against the meningococcus. Man
'H' was no other than Dr. George D. Heist, the chief author of this
paper. With no known contact with patient or cancer, in the absence of
any known cases in the city, Dr. Heist in August, 1920, developed
epidemic cerebrospinal meningitis, and although the diagnosis was made
early, the patient succumbed--a loss beyond measure to science and to
his friends. The unique interest attaching to the case suggests the
publication of certain particulars. Dr. Heist was 36 years of age. His
father had died at the age of 24 of typhoid fever, the course of which
presented many points of similarity to the fatal illness of the son.
Four paternal uncles had died of acute illnesses that were said to have
'gone to the head.'' The work reported by Heist et al. (1922) concerned
bactericidal properties of whole blood against strains of meningococcus.
Control blood without bactericidal activity came from Dr. Heist.
Schifferli and Hirschel (1985) excluded deficiency of an early component
of complement because of the absence of recurrent pyogenic infection or
features of lupus. They excluded properdin deficiency, which can be
accompanied by susceptibility to meningococcal meningitis, because of
its X-linked inheritance (312060).

In C5 deficiency in the mouse, Wetsel et al. (1990) found a deletion of
2 basepairs, TA, near the 5-prime end of the cDNA. The deletion shifted
the reading frame with the creation of a termination codon, UGA, 4
basepairs downstream from the deletion. The same deletion was found in 6
C5-deficient strains but in none of 4 C5-sufficient strains.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
McLean et al. (1981); Ooi and Colten (1979); Rosenfeld et al. (1976);
Rosenfeld et al. (1978); Tack et al. (1979); Weitkamp et al. (1978)
*FIELD* RF
1. Asghar, S. S.; Venneker, G. T.; van Meegen, M.; Meinardi, M. M.
H. M.; Hulsmans, R.-F. H. J.; de Waal, L. P.: Hereditary deficiency
of C5 in association with discoid lupus erythematosus. J. Am. Acad.
Derm. 24: 376-378, 1991.

2. Heist, D. G.; Solis-Cohen, S.; Solis-Cohen, M.: A study of the
virulence of meningococci for man and human susceptibility to meningococcic
infection. J. Immun. 7: 1-33, 1922.

3. Jacobs, J. C.; Miller, M. E.: Fatal familial Leiner's disease:
a deficiency of the opsonic activity of serum complement. Pediatrics 49:
225-232, 1972.

4. Jeremiah, S. J.; West, L. F.; Davis, M.; Povey, S.; Carritt, B.;
Fey, G. H.: The assignment of the human gene coding for complement
C5 to chromosome 9q22-9q33. Ann. Hum. Genet. 52: 111-116, 1988.

5. Jeremiah, S. J.; West, L. F.; Davis, M. B.; Povey, S.; Carritt,
B.; Fey, G.: Assignment of human complement component C5 to chromosome
9.  (Abstract) Cytogenet. Cell Genet. 46: 634 only, 1987.

6. McLean, R. H.; Peter, G.; Gold, R.; Guerra, L.; Yunis, E. J.; Kreutzer,
D. L.: Familial deficiency of C5 in humans: intact but deficient
alternative complement pathway activity. Clin. Immun. Immunopath. 21:
62-76, 1981.

7. Miller, M. E.; Nilsson, U. R.: A familial deficiency of the phagocytosis-enhancing
activity of serum related to a dysfunction of the fifth component
of complement (C5). New Eng. J. Med. 282: 354-358, 1970.

8. Miller, M. E.; Seals, J.; Kaye, R.; Levitsky, L. C.: A familial,
plasma-associated defect of phagocytosis: a new cause of recurrent
bacterial infections. Lancet II: 60-63, 1968.

9. Ooi, Y. M.; Colten, H. R.: Genetic defect in secretion of complement
C5 in mice. Nature 282: 207-208, 1979.

10. Rosenfeld, S. I.; Baum, J.; Steigbigel, R. T.; Leddy, J. P.:
Hereditary deficiency of the fifth component of complement in man.
II. Biological properties of C5-deficient human serum. J. Clin.
Invest. 57: 1635-1643, 1976.

11. Rosenfeld, S. I.; Kelly, M. E.; Leddy, J. P.: Hereditary deficiency
of the fifth component of complement in man. I. Clinical, immunochemical,
and family studies. J. Clin. Invest. 57: 1626-1634, 1976.

12. Rosenfeld, S. I.; Leddy, J. P.: Hereditary deficiency of fifth
component of complement (C5) in man.  (Abstract) J. Clin. Invest. 53:
67A only, 1974.

13. Rosenfeld, S. I.; Weitkamp, L. R.; Countryman, J. K.: Non-linkage
for a locus of human complement C5 deficiency to the complement C6
structural locus. Immunogenetics 7: 95-97, 1978.

14. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

15. Schifferli, J. A.; Hirschel, B.: Meningococcal meningitis in
the first case of complement deficiency.  (Letter) Lancet II: 1240
only, 1985.

16. Snyderman, R.; Durack, D. T.; McCarty, G. A.; Ward, F. E.; Meadows,
L.: Deficiency of the fifth component of complement in human subjects:
clinical, genetic and immunologic studies in a large kindred. Am.
J. Med. 67: 638-645, 1979.

17. Tack, B. F.; Morris, S. C.; Prahl, J. W.: Fifth component of
human complement: purification from plasma and polypeptide chain structure.
Biochemistry 18: 1490-1497, 1979.

18. Weitkamp, L. R.; Rosenfeld, S.; Johnston, E.: Complement C5:
immunofixation electrophoresis, quantitative variants, and nonlinkage
to HLA. Cytogenet. Cell Genet. 22: 651-654, 1978.

19. Wetsel, R. A.; Fleischer, D. T.; Haviland, D. L.: Deficiency
of the murine fifth complement component (C5): a 2-base pair gene
deletion in a 5-prime-exon. J. Biol. Chem. 265: 2435-2440, 1990.

20. Wetsel, R. A.; Lemons, R. S.; Le Beau, M. M.; Barnum, S. R.; Noack,
D.; Tack, B. F.: Molecular analysis of human complement component
C5: localization of the structural gene to chromosome 9. Biochemistry 27:
1474-1482, 1988.

*FIELD* CS

Imunology:
   C5 deficiency;
   Recurrent local and systemic infections, esp. gram-negative;
   Systemic lupus erythematosus;
   Discoid lupus erythematosus

Skin:
   Generalized seborrheic dermatitis

GI:
   Intractable diarrhea

Growth:
   Marked wasting

Lab:
   Defective phagocytosis-enhancing activity of serum;
   Defective opsonization corrected by fresh plasma;
   Absent serum hemolytic complement activity

Inheritance:
   Autosomal dominant vs. recessive (9q32-q34)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
davew: 7/20/1994
mimadm: 6/25/1994
supermim: 3/16/1992
carol: 4/23/1991
carol: 3/27/1991
carol: 1/11/1991

*RECORD*
*FIELD* NO
120920
*FIELD* TI
*120920 COMPLEMENT MEMBRANE COFACTOR PROTEIN; MCP; CD46
MEASLES VIRUS RECEPTOR
MEASLES, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
Membrane cofactor protein, a C3B/C4B binding molecule of the complement
system with cofactor activity for the I-dependent cleavage of C3B and
C4B, is widely distributed in white blood cells, platelets, epithelial
cells, and fibroblasts. Lublin et al. (1988) purified MCP from a human
T-cell line and determined the sequence of the N-terminal 24 amino
acids. An oligonucleotide probe was used to identify a clone from a
human monocyte cDNA library. The deduced full-length MCP consisted of a
34-amino acid signal peptide and a 350-amino acid mature protein. The
protein had, beginning at the N-terminus, 4 repeating units of about 60
amino acids each that matched the consensus sequence found in a
multigene family of complement regulatory proteins: CR1 (120620), CR2
(120650), C4BP (120830), FH (134370), and DAF (125240). Lublin et al.
(1988) localized MCP to 1q31-q41 by Southern analysis of human-rodent
somatic cell hybrid DNA and by in situ hybridization. This is the sixth
member of this multigene family that has been assigned to this region of
the genome. Bora et al. (1989) demonstrated that the MCP gene is on the
same 1,250-kb NotI fragment that contains CR1, CR2, DAF, and C4BP and
maps within 100 kb of the 3-prime end of the CR1 gene. The order of the
genes appears to be that just indicated, with MCP preceding the other 4
genes. Purcell et al. (1991) identified isoforms.

Measles virus normally causes disease in the human, and the host range
of the virus might be determined by a specific receptor on the surface
of primate cells, comparable to the poliovirus receptor (PVR; 173850).
Dorig et al. (1993) used a genetic approach to identify the receptor for
measles virus. Human/rodent somatic cell hybrids were tested for their
ability to bind measles virus; only cells that contained human
chromosome 1 were capable of binding virus. Rodent cells do not bind
measles virus. A study of lymphocyte markers suggested that CD46 is the
measles virus receptor. Dorig et al. (1993) proved this hypothesis by
demonstrating that hamster cell lines that expressed human CD46 could
bind virus. Furthermore, infected CD46+ cells produced syncytia and
viral proteins. Finally, polyclonal antisera against CD46 inhibited
virus binding and infection. These results proved that human CD46
permits cells both to bind measles virus and to support infection.

*FIELD* RF
1. Bora, N. S.; Lublin, D. M.; Kumar, B. V.; Hockett, R. D.; Holers,
V. M.; Atkinson, J. P.: Structural gene for human membrane cofactor
protein (MCP) of complement maps to within 100 kb of the 3-prime end
of the C3b/C4b receptor gene. J. Exp. Med. 169: 597-602, 1989.

2. Dorig, R. E.; Marcil, A.; Chopra, A.; Richardson, C. D.: The human
CD46 molecule is a receptor for measles virus (Edmonston strain).
Cell 75: 295-305, 1993.

3. Lublin, D. M.; Liszewski, M. K.; Post, T. W.; Arce, M. A.; LeBeau,
M. M.; Lemons, R. S.; Seya, T.; Atkinson, J. P.: Molecular cloning
and chromosomal localization of human complement membrane cofactor
protein (MCP).  (Abstract) FASEB J. 2: A1643 only, 1988.

4. Purcell, D. F. J.; Johnstone, R. W.; McKenzie, I. F. C.: Identification
of four different CD46 (MCP) molecules with anti-peptide antibodies.
Biochem. Biophys. Res. Commun. 180: 1091-1097, 1991.

*FIELD* CD
Victor A. McKusick: 6/29/1988

*FIELD* ED
carol: 11/2/1993
supermim: 3/16/1992
carol: 1/21/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/13/1989

*RECORD*
*FIELD* NO
120930
*FIELD* TI
*120930 COMPLEMENT COMPONENT-8, GAMMA SUBUNIT; C8C; C8G
*FIELD* TX
The eighth component of complement (C8) consists of 3 nonidentical
subunits arranged asymmetrically as a disulfide-linked alpha-gamma dimer
and a noncovalently associated beta chain. Genetic studies of C8
polymorphisms established that alpha-gamma and beta are encoded at
different loci (see 120950, 120960). Implicit in this finding was the
existence of 2 different genes and the likelihood that alpha-gamma is
synthesized as a single-chain precursor. Ng et al. (1987), however,
presented evidence that the C8 molecule is assembled from 3 different
gene products, alpha, beta, and gamma, that undergo both covalent and
noncovalent association to yield the mature protein. The linkage
relationships of the gamma locus to the others are unknown. Ng et al.
(1987) identified a cDNA clone containing the entire coding region for
the human gamma polypeptide, and its sequence supported the existence of
a separate gamma mRNA. Whereas the alpha chain and beta chain of C8 show
an overall sequence homology to C6, C7, and C9 (which like C8 are
involved in the membrane-attack complex that leads to lysis of target
cells), the gamma chain was found by Haefliger et al. (1987) to show
structural homology to protein HC (alpha-1-microglobulin/bikunin
precursor; AMBP; 176870). This suggested a similar 3-dimensional
structure of the 2 proteins and a possible functional relationship. Hunt
et al. (1987) also pointed out the close sequence homology of C8G to
alpha-1-microglobulin.

The C8G gene and its protein product belong to the lipocalin
superfamily, a group of distantly related and similarly folded proteins
that are able to carry small lipophilic molecules such as retinol,
odorants, and steroids. The lipocalin superfamily has a very ancient
origin since lipocalins are found in arthropods as well as in
vertebrates.

Kaufman et al. (1989) assigned the C8G locus to chromosome 9q by probing
a panel of hybrid DNAs with a C8-gamma probe clone. C5 (120900) and 2
genes from the same family, alpha-1-microglobulin (inter-alpha-trypsin
inhibitor, light chain; ITIL) and alpha-1-acid-glycoprotein
(orosomucoid-1; ORM1; 138600), map to the same area. This indicated a
common evolutionary origin of these genes. In the mouse, the lipocalin
genes coding for orosomucoid, the alpha-1-microglobulin/bikunin
precursor, and the major urinary protein (MUP) map to chromosome 4,
while their human counterparts map to the homologous 9q34 area where 3
other lipocalin genes, those for C8G, progestagen-associated endometrial
protein (PAEP; 173310) and prostaglandin D synthase (PTGDS; 176803), are
also located (Chan et al., 1994).

*FIELD* RF
1. Chan, P.; Simon-Chazottes, D.; Mattei, M. G.; Guenet, J. L.; Salier,
J. P.: Comparative mapping of lipocalin genes in human and mouse:
the four genes for complement C8 gamma chain, prostaglandin-D-synthase,
oncogene-24P3, and progestagen-associated endometrial protein map
to HSA9 and MMU2. Genomics 23: 145-150, 1994.

2. Haefliger, J.-A.; Jenne, D.; Stanley, K. K.; Tschopp, J.: Structural
homology of human complement component C8-gamma and plasma protein
HC: identity of the cysteine bond pattern. Biochem. Biophys. Res.
Commun. 149: 750-754, 1987.

3. Hunt, L. T.; Elzanowski, A.; Barker, W. C.: The homology of complement
factor C8 gamma chain and alpha-1-microglobulin. Biochem. Biophys.
Res. Commun. 149: 282-288, 1987.

4. Kaufman, K. M.; Snider, J. V.; Spurr, N. K.; Schwartz, C. E.; Sodetz,
J. M.: Chromosomal assignment of genes encoding the alpha, beta,
and gamma subunits of human complement protein C8: identification
of a close physical linkage between the alpha and the beta loci. Genomics 5:
475-480, 1989.

5. Ng, S. C.; Rao, A. G.; Howard, O. M. Z.; Sodetz, J. M.: The eighth
component of human complement: evidence that it is an oligomeric serum
protein assembled from products of three different genes. Biochemistry 26:
5229-5233, 1987.

*FIELD* CD
Victor A. McKusick: 10/19/1987

*FIELD* ED
carol: 11/8/1994
terry: 11/7/1994
supermim: 3/16/1992
carol: 3/27/1991
carol: 3/14/1991
supermim: 3/20/1990

*RECORD*
*FIELD* NO
120940
*FIELD* TI
*120940 COMPLEMENT COMPONENT-9; C9
*FIELD* TX
Activation of the complement system results in formation of the membrane
attack complex (MAC) on the membranes of target cells. The complex is
assembled by sequential addition of 1 molecule each of C5b, C6, C7, and
C8 and 6 to 16 molecules of the ninth component, C9. DiScipio et al.
(1984) screened a human liver cDNA library by the colony-hybridization
technique using 2 radiolabelled oligonucleotide probes that correspond
to known regions of the C9 amino acid sequence. The cDNA coding for C9
was sequenced and the protein sequence--537 amino acids in a single
polypeptide chain--was derived. The amino-terminal half of C9 is
predominantly hydrophilic and the carboxyl-terminal half is more
hydrophobic. The amphipathic organization of the primary structure is
consistent with the known potential of polymerized C9 to penetrate lipid
bilayers and cause the formation of transmembrane channels as part of
the lytic action of MAC. Marazziti et al. (1988) compared gene and
protein structure of C9 and compared both with low-density lipoprotein
receptor (143890).

Kusaba et al. (1983) reported a large family with hereditary deficiency
of C9. The proposita was a 64-year-old Japanese woman with gastric
cancer. C9 was not detectable by either rocket immunoelectrophoresis or
hemolytic assay. C9 was also undetectable in 2 healthy sisters. Levels
presumably indicative of heterozygosity (22-46% of normal) were found in
8 males and 7 females from 3 generations of the family. One instance of
male-to-male transmission was found and all offspring of homozygotes
tested had heterozygous levels. No liability to specific disease was
detected in any. This is, it seems, the ninth family with C9 deficiency
reported from Japan. Lint et al. (1980) reported C9 deficiency in a
Caucasian family. They found no linkage with HLA. Yonemura et al. (1990)
found that deficiency of C9 tempered the clinical manifestations,
specifically hemolysis, in a woman who also had paroxysmal nocturnal
hemoglobinuria.

Kusaba et al. (1983) referred to studies excluding close linkage with
HLA, ABO, Rh, Lutheran, Kell, MNS, P, Duffy, Kidd, Diego, and Xg. By
hybridizing a cloned cDNA coding for human complement factor C9 to
hybrid cells containing subsets of human chromosomes on a rodent
background, Rogne et al. (1989) localized the gene for C9 to chromosome
5. Abbott et al. (1989) used a novel application of PCR to amplify
specifically the human C9 gene on a background of rodent DNA in somatic
cell hybrids. The assignment of the gene to 5p13 was confirmed and
regionalized by in situ hybridization. Coto et al. (1991) identified
RFLPs for the C6, C7, and C9 loci and showed that these 3 loci are
tightly linked. When examining the haplotypes of unrelated parents in
their family study, they found significant linkage disequilibrium
between C6 and C7 and between C7 and C9. Thus, the so-called terminal
complement components are encoded by a cluster of genes. Coto et al.
(1991) suggested that this cluster be referred to as MACII, MACI being
the C8A (120950) and C8B (120960) cluster. Rogne et al. (1991) used DNA
polymorphism of C9 and protein variants of C6 to show that the 2 genes
are closely linked (maximum lod = 9.28 at theta = 0.00). They found no
indication of allelic association. Setien et al. (1993) found that,
although the C6 and C7 genes are contained in the same NotI fragment of
500 kb, no evidence of physical linkage between C9 and C6 or C7 could be
found in a range 50 kb to 2.5 megabases.

Alvarez et al. (1995) analyzed RFLPs at the closely linked C6, C7, and
C9 loci in a family with brothers who had recurrent Neisseria
meningitidis. The haplotype carrying a 'silent' C9*Q0 allele was
defined, allowing for detection of carriers among asymptomatic
relatives.

*FIELD* SA
Shiver et al. (1986)
*FIELD* RF
1. Abbott, C.; West, L.; Povey, S.; Jeremiah, S.; Murad, Z.; DiScipio,
R.; Fey, G.: The gene for human complement component C9 mapped to
chromosome 5 by polymerase chain reaction. Genomics 4: 606-609,
1989.

2. Alvarez, V.; Coto, E.; Setien, F.; Spath, P. J.; Lopez-Larrea,
C.: Genetic detection of the silent allele (*Q0) in hereditary deficiencies
of the human complement C6, C7, and C9 components. Am. J. Med. Genet. 55:
408-413, 1995.

3. Coto, E.; Martinez-Naves, E.; Dominguez, O.; DiScipio, R. G.; Urra,
J. M.; Lopez-Larrea, C.: DNA polymorphism and linkage relationship
of the human complement component C6, C7, and C9 genes. Immunogenetics 33:
184-187, 1991.

4. DiScipio, R. G.; Gehring, M. R.; Podack, E. R.; Kan, C. C.; Hugli,
T. E.; Fey, G. H.: Nucleotide sequence of cDNA and derived amino
acid sequence of human complement component C9. Proc. Nat. Acad.
Sci. 81: 7298-7302, 1984.

5. Kusaba, T.; Kisu, T.; Inaba, S.; Sakai, K.; Okochi, K.; Yanase,
T.: A pedigree of deficiency of the ninth component of complement
(C9). Jpn. J. Hum. Genet. 28: 239-248, 1983.

6. Lint, T. F.; Zeitz, H. J.; Gewurz, H.: Inherited deficiency of
the ninth component of complement in man. J. Immun. 125: 2252-2257,
1980.

7. Marazziti, D.; Eggertsen, G.; Fey, G. H.; Stanley, K. K.: Relationships
between the gene and protein structure in human complement component
C9. Biochemistry 27: 6529-6534, 1988.

8. Rogne, S.; Myklebost, O.; Olving, J. H.; Tomter Kyrkjebo, H.; Jonassen,
R.; Olaisen, B.; Gedde-Dahl, T., Jr.: The human genes for complement
components 6 (C6) and 9 (C9) are closely linked on chromosome 5. J.
Med. Genet. 28: 587-590, 1991.

9. Rogne, S.; Myklebost, O.; Stanley, K.; Geurts van Kessel, A.:
The gene for human complement C9 is on chromosome 5. Genomics 5:
149-152, 1989.

10. Setien, F.; Alvarez, V.; Coto, E.; DiScipio, R. G.; Lopez-Larrea,
C.: A physical map of the human complement component C6, C7, and
C9 genes. Immunogenetics 38: 341-344, 1993.

11. Shiver, J. W.; Dankert, J. R.; Donovan, J. J.; Esser, A. F.:
The ninth component of human complement (C9): functional activity
of the b fragment. J. Biol. Chem. 261: 9629-9636, 1986.

12. Yonemura, Y.; Kawakita, M.; Koito, A.; Kawaguchi, T.; Nakakuma,
H.; Kagimoto, T.; Shichishima, T.; Terasawa, T.; Akagaki, Y.; Inai,
S.; Takatsuki, K.: Paroxysmal nocturnal haemoglobinuria with coexisting
deficiency of the ninth component of complement: lack of massive haemolytic
attack. Brit. J. Haemat. 74: 108-113, 1990.

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 11/27/1996
carol: 3/19/1995
carol: 11/9/1993
supermim: 3/16/1992
carol: 3/3/1992
carol: 11/8/1991
carol: 6/24/1991

*RECORD*
*FIELD* NO
120950
*FIELD* TI
*120950 COMPLEMENT COMPONENT-8, DEFICIENCY OF
C8 DEFICIENCY, TYPE I;;
C8 ALPHA-GAMMA DEFICIENCY;;
C81 DEFICIENCY
C8 ALPHA SUBUNIT, INCLUDED;;
C8A, INCLUDED
*FIELD* TX
Petersen et al. (1976) described a 24-year-old black woman with 3
episodes of disseminated gonococcal infection. Severe deficiency of C8
was found. The proband's parents and children had about half-normal
levels of C8. Merritt et al. (1976) concluded, through family linkage
studies, that a gene for C8 is in the HLA region. Other studies failed
to confirm linkage with HLA. Jasin (1977) reported the case of a
56-year-old black woman with absence of C8 and a disease compatible with
SLE. One of 2 brothers had serum levels of C8 approaching 50% of normal.
A normal brother was HLA-identical to the proband, whereas the
heterozygous brother shared only 1 haplotype with the proband. Thus the
C8 gene appeared to be unlinked to HLA. Giraldo et al. (1977) concluded
that C6 and C8 are not in the HLA complex and probably not on chromosome
6. Pericak-Vance et al. (1982) found a suggestion of linkage of C8
deficiency to 1p markers: lod score of 1.44 for UMPK at male theta of
0.14 and female theta of 0.17; lod score of 1.65 for PGM1 at male theta
of 0.0 and female theta of 0.22. The family in which linkage was studied
by Pericak-Vance et al. (1982) had deficiency of C8 beta (C8B; 120960).

Two kinds of inherited C8 deficiency have been reported in man. Type I,
in which no C8 antigen is detected, was thought to represent deficiency
of the whole molecule, whereas in type II, antigenically deficient C8,
which apparently lacks only the beta chain, is found. In studies of 2
families with type II deficiency, 1 family with type I deficiency, and
several normal families, Marcus et al. (1982) showed that beta chains
are present in type I deficiency and produce a normal pattern on
isoelectric focusing; that alpha-gamma chains are present in type II
deficiency and exhibit genetic polymorphism; that beta and alpha-gamma
alleles segregate independently in families; and that C8 alpha-gamma and
C8 beta are not only unlinked but that neither is closely linked to HLA.
Tedesco et al. (1983) studied restoration of hemolytic activity in sera
from 7 unrelated persons with C8 deficiency. The sera fell into 2
groups, depending on whether hemolytic activity was restored by addition
of the beta-chain (group 1) or the alpha-gamma subunit (group 2)
purified from normal human C8. A dysfunctional C8 was demonstrated by
antigenic analysis in all 4 sera of group 1. A different dysfunctional
C8 was found in one of the group 2 cases. Chromatographic analysis
demonstrated that the generation of hemolytic activity in the mixture of
2 sera resulted from reconstitution of the C8 molecule rather than the
sequential action of the two C8 subunits. By the technique used by Rogde
et al. (1984), 2 different protein patterns, each with polymorphism,
were demonstrated: A for acidic; B for basic. The B pattern, which was
absent from a serum with known beta-chain deficiency, reflected the
presence of 4 or 5 frequently occurring alleles in the Norwegian
population. Tedesco et al. (1990) detected a small amount of
dysfunctional C8-alpha-gamma in the sera of C8-alpha-gamma deficient
patients.

Rogde et al. (1984) found that the polymorphism detected by anti-C8 was
determined by a locus linked to PGM1 on 1p (maximal lod score, sexes
combined, of 8.0 at theta = 0.10). They interpreted their evidence as
suggesting that this polymorphism is in the alpha-gamma subunit. By
2-dimensional electrophoresis, Rogde et al. (1985) showed that the C81
polymorphism resides in the structural gene for the alpha chain. Alper
et al. (1983) demonstrated a second C8 polymorphism by isoelectric
focusing of serum in polyacrylamide gel and development of specific
patterns of hemolysis in an overlay gel containing C8 beta-chain
deficiency. Alper et al. (1983) proposed renaming the alpha-gamma C8
locus C81 and the beta C8 locus C82. They ruled out close linkage of the
2 loci with each other and with those for MHC and C6. Nakamura et al.
(1986) reported on C81 polymorphism in the Japanese. The alpha and gamma
subunits are bound covalently through a disulfide linkage whereas the
beta subunit is associated with the others via weaker, noncovalent
bonds. (In fact, alpha-gamma C8 does not constitute a 'locus' since, as
detailed later, the gamma subunit is encoded by a gene on chromosome 9
and the alpha subunit is encoded by a gene on chromosome 1. Furthermore,
locus symbols with 2 digits in sequence, such as C81 and C82, are
unacceptable because of confusion. To avoid such confusion, C8A and C8B
are the accepted conventions.)

Contrary to the findings of Alper et al. (1983), Rodge et al. (1985),
and Rodge et al. (1986), using separation by isoelectric focusing
followed by immunoblotting, concluded that C8A and C8B are closely
linked to each other (lod = 3.01, theta 0.0) and to PGM1 (171900): C8A,
lod = 16.5 at theta 0.09; C8B, lod = 3.54 at theta 0.11, sexes combined.
Both C8 loci are linked to Rh (maximum lod = 3.56 at theta 0.23 in males
and 0.36 at theta 0.37 in females). The C8 loci must lie between Rh and
PGM1. Rittner et al. (1986) showed that the C81 gene and PGM1 were
linked with male theta of 0.18 and female theta of 0.26. The sum of the
lods for 9 families was 1.822. The genetic distances between the two C8
loci and PGM1 appeared to be identical in males and females (Rogde et
al., 1986). As noted, a female/male ratio of 1.6 was observed between
the two C8 loci and Rh. No evidence of linkage of the C8 loci to Fy was
found. Using cDNA clones for the C8-alpha and C8-beta genes for
nonradioactive in situ hybridization, Theriault et al. (1991, 1992)
mapped the 2 genes to 1p32. For both subunits the results were confirmed
by hybridization to metaphase chromosomes derived from a person with the
balanced reciprocal translocation t(1;5)(p32;q35), the hybridization
signal being observed on the derivative chromosome 5. Using BamHI RFLPs
of the C8A and C8B genes, Rogde et al. (1992) obtained a peak lod score
of 4.52 at recombination fraction of 0.0 between C8A and C8B. Combined
with data from a previous study, a maximum lod score of 22.02 at
recombination fraction 0.11, with no sex difference, was compiled for
the C8-PGM1 linkage. No evidence of allelic association between the C8A
and C8B BamHI RFLPs was found.

See 120930 for evidence that the alpha and gamma polypeptides of C8 are
encoded by separate genes located on chromosomes 1 and 9, respectively.
Michelotti et al. (1995) isolated overlapping genomic clones and used
them to decipher the organization of the human C8A gene. The gene
contains at least 11 exons and spans approximately 70 kb of DNA. C8A
genomic organization was found to be remarkably similar to that of C6,
C8B, and C9. Although the C8A and C8B loci were previously reported to
be less than 2.5-kb apart, Michelotti et al. (1995) obtained results
using exon-specific probes, indicating that the loci are not as closely
linked as initially believed.

Komatsu et al. (1985) and Komatsu et al. (1990) described hereditary
C8-alpha-gamma deficiency in the rabbit where it was associated with
dwarfism, small thymus, small litter size, and low survival rate.
Komatsu et al. (1990) showed that the C8 deficiency was not linked to
the dw-2 locus which causes dwarfism in rabbits. Whether the dwarfism
was due to a separate locus closely linked to the C8 locus or was a
pleiotropic effect of the C8 locus was unclear.

Michelotti et al. (1995) demonstrated that the C8A gene is approximately
70 kb in length and contains 11 exons.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
COMPLEMENT COMPONENT-8, ALPHA-CHAIN, A/B POLYMORPHISM
C8A, GLN-LYS
Using an exon-specific PCR followed by direct DNA sequence analysis,
Zhang et al. (1995) demonstrated that the 2 common alleles, C8A*A and
C8A*B, are characterized by the substitution of lys for gln as the
result of a C-to-A transversion of nucleotide 187 in exon 3 in their
mature C8A cDNA sequence. (Presumably, the amino acid change in this
case is at residue 63, the codon being changed from CAA (gln) to AAA
(lys).) Zhang et al. (1995) designed an allele-specific PCR for
detecting the 2 alleles. Comparison of the data from DNA samples of a
Chinese Han population with data protein typing of the same samples
proved that the DNA method is efficient and reliable.

*FIELD* SA
Densen et al. (1983); Kolb and Muller-Eberhard (1976); Matthews et
al. (1980); Pickering et al. (1982); Rittner et al. (1984); Rogde
et al. (1985)
*FIELD* RF
1. Alper, C. A.; Marcus, D.; Raum, D.; Petersen, B. H.; Spira, T.
J.: Genetic polymorphism in C8 beta-chains: evidence for two unlinked
genetic loci for the eighth component of human complement (C8). J.
Clin. Invest. 72: 1526-1531, 1983.

2. Densen, P.; Brown, E. J.; O'Neill, G. J.; Tedesco, F.; Clark, R.
A.; Frank, M. M.; Webb, D.; Myers, J.: Inherited deficiency of C8
in a patient with recurrent meningococcal infections: further evidence
for a dysfunctional C8 molecule and nonlinkage to the HLA system.
J. Clin. Immun. 3: 90-99, 1983.

3. Giraldo, G.; Degos, L.; Beth, E.; Sasportes, M.; Marcelli, A.;
Gharbi, R.; Day, N. K.: C8 deficiency in a family with xeroderma
pigmentosum: lack of linkage to HLA region. Clin. Immun. Immunopath. 8:
377-384, 1977.

4. Jasin, H. E.: Absence of the eighth component of complement in
association with systemic lupus erythematosus-like disease. J. Clin.
Invest. 60: 709-715, 1977.

5. Kolb, W. P.; Muller-Eberhard, H. J.: The membrane attack mechanism
of complement: the three polypeptide chain structure of the eighth
component (C8). J. Exp. Med. 143: 1131-1139, 1976.

6. Komatsu, M.; Imaoka, K.; Satoh, M.; Mikami, H.: Hereditary C8-alpha-gamma
deficiency associated with dwarfism in the rabbit. J. Hered. 81:
413-417, 1990.

7. Komatsu, M.; Yamamoto, K.; Kawashima, T.; Migita, S.: Genetic
deficiency of the alpha-gamma-subunit of the eighth complement component
in the rabbit. J. Immun. 134: 2607-2609, 1985.

8. Marcus, D.; Spira, T. J.; Petersen, B. H.; Raum, D.; Alper, C.
A.: There are two unlinked genetic loci for human C8.  (Abstract) Molec.
Immun. 19: 1385 only, 1982.

9. Matthews, N.; Stark, J. M.; Harper, P. S.; Doran, J.; Jones, D.
M.: Recurrent meningococcal infections associated with a functional
deficiency of the C8 component of human complement. Clin. Exp. Immun. 39:
53-59, 1980.

10. Merritt, A. D.; Petersen, B. H.; Biegel, A. A.; Meyers, D. A.;
Brooks, G. F.; Hodes, M. E.: Chromosome 6: linkage of the eighth
component of complement (C8) to the histocompatibility region (HLA).
Cytogenet. Cell Genet. 16: 331-334, 1976.

11. Michelotti, G. A.; Snider, J. V.; Sodetz, J. M.: Genomic organization
of human complement protein C8-alpha and further examination of its
linkage to C8-beta. Hum. Genet. 95: 513-518, 1995.

12. Nakamura, S.; Ohue, O.; Abe, K.: Genetic polymorphism of human
complement component C81 in the Japanese population. Hum. Genet. 72:
344-347, 1986.

13. Pericak-Vance, M. A.; Elston, R. C.; Spira, T. J.; Band, J.:
Segregation and linkage analysis of immunochemical C8 levels in a
family with C8 beta-chain deficiency.  (Abstract) Am. J. Hum. Genet. 34:
109A only, 1982.

14. Petersen, B. H.; Graham, J. A.; Brooks, G. F.: Human deficiency
of the eighth component of complement: the requirement of C8 for serum
Neisseria gonorrhoeae bactericidal activity. J. Clin. Invest. 57:
283-290, 1976.

15. Pickering, R. J.; Rynes, R. I.; LoCascio, N.; Monahan, J. B.;
Sodetz, J. M.: Identification of the alpha-gamma subunit of the eighth
component of complement (C8) in a patient with systemic lupus erythematosus
and absent C8 activity: patient and family studies. Clin. Immun.
Immunopath. 23: 323-334, 1982.

16. Rittner, C.; Hargesheimer, W.; Mollenhauer, E.: Population and
formal genetics of the human C81(alpha-gamma) polymorphism. Hum.
Genet. 67: 166-169, 1984.

17. Rittner, C.; Hargesheimer, W.; Stradmann, B.; Bertrams, J.; Baur,
M. P.; Petersen, B. H.: Human C81 (alpha-gamma) polymorphism: detection
in the alpha-gamma subunit on SDS-PAGE, formal genetics and linkage
relationship. Am. J. Hum. Genet. 38: 482-491, 1986.

18. Rogde, S.; Gedde-Dahl, T., Jr.; Teisberg, P.; Jonassen, R.; Hoyheim,
B.; Olaisen, B.: Linkage and association studies with C8A and C8B
RFLPs on chromosome 1. Ann. Hum. Genet. 56: 233-242, 1992.

19. Rogde, S.; Mevag, B.; Olaisen, B.; Gedde-Dahl, T., Jr.; Teisberg,
P.: Structural genes for complement factor C8 on chromosome 1.  (Abstract) Cytogenet.
Cell Genet. 37: 571 only, 1984.

20. Rogde, S.; Mevag, B.; Teisberg, P.; Gedde-Dahl, T., Jr.; Tedesco,
F.; Olaisen, B.: Genetic polymorphism of complement component C8.
Hum. Genet. 70: 211-216, 1985.

21. Rogde, S.; Olaisen, B.; Gedde-Dahl, T., Jr.; Teisberg, P.: Two
complement component C8 loci are localized between PGM1 and Rh on
chromosome 1.  (Abstract) Cytogenet. Cell Genet. 40: 734-735, 1985.

22. Rogde, S.; Olaisen, B.; Gedde-Dahl, T., Jr.; Teisberg, P.: The
C8A and C8B loci are closely linked on chromosome 1. Ann. Hum. Genet. 50:
139-144, 1986.

23. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution.  New York: Oxford Univ. Press (pub.)  1988.

24. Tedesco, F.; Densen, P.; Villa, M. A.; Petersen, B. H.; Sirchia,
G.: Two types of dysfunctional eighth component of complement (C8)
molecules in C8 deficiency in man: reconstitution of normal C8 from
the mixture of two abnormal C8 molecules. J. Clin. Invest. 71:
183-191, 1983.

25. Tedesco, F.; Roncelli, L.; Petersen, B. H.; Agnello, V.; Sodetz,
J. M.: Two distinct abnormalities in patients with C8-alpha-gamma
deficiency: low level of C8-beta chain and presence of dysfunctional
C8-alpha-gamma subunit. J. Clin. Invest. 86: 884-888, 1990.

26. Theriault, A.; Boyd, E.; Whaley, K.; Sodetz, J. M.; Connor, J.
M.: Regional chromosomal assignment of genes encoding the alpha and
beta subunits of human complement protein c8 to 1p32.  (Abstract) Cytogenet.
Cell Genet. 58: 1864 only, 1991.

27. Theriault, A.; Boyd, E.; Whaley, K.; Sodetz, J. M.; Connor, J.
M.: Regional chromosomal assignment of genes encoding the alpha and
beta subunits of human complement protein C8 to 1p32. Hum. Genet. 88:
703-704, 1992.

28. Zhang, L.; Rittner, C.; Sodetz, J. M.; Schneider, P. M.; Kaufmann,
T.: The eighth component of human complement: molecular basis of
C8A (C81) polymorphism. Hum. Genet. 96: 281-284, 1995.

*FIELD* CS

Immunology:
   C8 deficiency;
   Episodes of neisserial infection;
   Systemic lupus erythematosus

Neuro:
   Meningitis

Lab:
   No C8 antigen detected

Inheritance:
   Autosomal dominant (1p32);
   complete deficiency recessive

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 9/12/1995
terry: 5/25/1995
mimadm: 6/25/1994
carol: 12/16/1993
carol: 12/17/1992
carol: 11/20/1992

*RECORD*
*FIELD* NO
120960
*FIELD* TI
*120960 COMPLEMENT COMPONENT-8, DEFICIENCY OF, TYPE II
C8 BETA DEFICIENCY
C8B, INCLUDED;;
C8 BETA SUBUNIT, INCLUDED
*FIELD* TX
See 120950. Raum et al. (1979) used serum from patients with complete or
type I deficiency (which lacks alpha-gamma chains but has normal beta
chains) to raise antisera against beta C8 and to demonstrate
polymorphism thereof. Herrmann et al. (1989) estimated the size of the
C8B gene to be 32 to 36 kb. Tanaka et al. (1991) studied deficient
activity of the beta subunit of C8 in mice and demonstrated by linkage
studies that this form of C8 deficiency is controlled by a single
recessive gene, designated C8b, located on mouse chromosome 4, near
Pgm-2 (172000). Bahary et al. (1991) also mapped the murine homolog of
C8B to chromosome 4.

Patients with deficiency of C8 suffer from recurrent neisserial
infections, predominantly with meningococcus infection of rare
serotypes. Most such patients are discovered among those having their
first episode of meningitis at ages older than 10 years. C8 deficiency
of the alpha and gamma subunits was found in 4 black families and no
Caucasian families by Ross and Densen (1984), whereas C8B deficiency was
reported in 12 Caucasian kindreds and no black kindreds. Wulffraat et
al. (1994) described a family in which a 13-year-old boy was found to be
homozygous for C8B deficiency and to have juvenile chronic arthritis of
6 months' duration. Antinuclear antibodies, anti-double-stranded DNA
antibodies, and rheumatoid factor were not detected. The same deficiency
was present in the patient's sister, and both parents were heterozygous.
There was no history of meningococcal disease in the family.

By direct sequence analysis of all exon-specific PCR products from
normal and C8B-deficient persons, Kaufmann et al. (1993) found a single
C-T change in exon 9 leading to a stop codon. An allele-specific PCR
system was designed to detect the normal and the deficiency allele
simultaneously. Using this approach as well as PCR typing of the TaqI
polymorphism located in intron 11, 5 families with 7 C8B-deficient
members were investigated. The mutant allele was observed in all
families investigated and could therefore be regarded as a major cause
of C8B deficiency in Caucasians. In 2 C8B-deficient patients, only 1
chromosome carried the C-T change; the molecular nature of the other
allele had not been determined. By using PCR primers located in the
adjacent intron sequences, Kaufmann et al. (1993) could amplify all 12
exons of the C8B gene from genomic DNA. These analyses and the insert
sizes of the genomic lambda clones indicated that the C8B gene has a
total size of approximately 40 kb.

*FIELD* AV
.0001
COMPLEMENT C8B DEFICIENCY
C8B, ARG374TER
In all 7 C8-deficient members of 5 Caucasian families, Kaufmann et al.
(1993) found a C-to-T transversion in exon 9 leading to the creation of
a stop codon; CGA (arg) was changed to TGA (stop) at nucleotide position
1309; the codon involved was 374 (Kaufmann, 1993). The authors noted
that the mutation occurred at a CpG dinucleotide.

*FIELD* SA
Kaufmann et al. (1993)
*FIELD* RF
1. Bahary, N.; Zorich, G.; Pachter, J. E.; Leibel, R. L.; Friedman,
J. M.: Molecular genetic linkage maps of mouse chromosomes 4 and
6. Genomics 11: 33-47, 1991.

2. Herrmann, D.; Sodetz, J. M.; Rittner, C.; Schneider, P. M.: DNA
polymorphism of the human complement C8B gene: formal genetics and
intragenic localization. Immunogenetics 30: 291-295, 1989.

3. Kaufmann, T.: Personal Communication. Mainz, Germany  7/14/1993.

4. Kaufmann, T.; Hansch, G.; Rittner, C.; Spath, P.; Tedesco, F.;
Schneider, P. M.: Genetic basis of human complement C8-beta deficiency.
J. Immun. 150: 4943-4947, 1993.

5. Kaufmann, T.; Rittner, C.; Schneider, P. M.: The human complement
component C8B gene: structure and phylogenetic relationship. Hum.
Genet. 92: 69-75, 1993.

6. Raum, D.; Spence, M. A.; Balavitch, D.; Tideman, S.; Merritt, A.
D.; Taggart, R. T.; Petersen, B. H.; Day, N. K.; Alper, C. A.: Genetic
control of the eighth component of complement. J. Clin. Invest. 64:
858-865, 1979.

7. Ross, S. C.; Densen, P.: Complement deficiency states and infection:
epidemiology, pathogenesis and consequences of neisserial and other
infections in an immune deficiency. Medicine 63: 243-273, 1984.

8. Tanaka, S.; Suzuki, T.; Sakaizumi, M.; Harada, Y.; Matsushima,
Y.; Miyashita, N.; Fukumori, Y.; Inai, S.; Moriwaki, K.; Yonekawa,
H.: Gene responsible for deficient activity of the beta subunit of
C8, the eighth component of complement, is located on mouse chromosome
4. Immunogenetics 33: 18-23, 1991.

9. Wulffraat, N. M.; Sanders, E. A. M.; Fijen, C. A. P.; Hannema,
A.; Kuis, W.; Zegers, B. J. M.: Deficiency of the beta subunit of
the eighth component of complement presenting as arthritis and exanthem.
Arthritis Rheum. 37: 1704-1706, 1994.

*FIELD* CS

Immunology:
   C8 deficiency;
   Recurrent neisserial infections

Neuro:
   Meningitis

Lab:
   Antigenically defective C8 detected

Inheritance:
   Autosomal dominant (1p32);
   complete deficiency recessive

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 1/3/1995
mimadm: 6/25/1994
carol: 11/4/1993
carol: 9/2/1993
carol: 6/28/1993
supermim: 3/16/1992

*RECORD*
*FIELD* NO
120970
*FIELD* TI
*120970 CONE-ROD DYSTROPHY; CORD
CONE-ROD DYSTROPHY-2;;
CORD2;;
CONE-ROD RETINAL DYSTROPHY; CRD; CRD2;;
RETINAL CONE-ROD DYSTROPHY; RCRD2
*FIELD* TX
Cone-rod retinal dystrophy (CRD) characteristically leads to early
blindness. An initial loss of color vision and of visual acuity is
followed by nyctalopia (night blindness) and loss of peripheral visual
fields. These progressive symptoms are accompanied by widespread,
advancing retinal pigmentation and chorioretinal atrophy of the central
and peripheral retina (Moore, 1992).

Hittner et al. (1975) described an extensively affected kindred with an
autosomal dominant dystrophy of the retinal photoreceptors and pigment
epithelium that is characterized by simultaneous abiotrophic
degeneration of rods and cones. The onset of decreased central vision
with concurrent progressive constriction of peripheral visual fields
occurs prior to age 10. Unlike previously described cone dystrophies,
there is an inexorable progression to no light perception. Ferrell et
al. (1981) provided follow-up. In all, 25 persons had been identified as
affected in the family. Linkage with 17 marker loci was tested, with
negative results. Specifically, a large negative lod score with Rh
argued against location of the CRD gene on 1p, a large negative lod
score with acid phosphatase-1 argued against its location on 2p, and a
large negative lod score with ABO and transcobalamin II argued against
its location on 9q. Warburg et al. (1991) described a 20-year-old man
with mental retardation and electrophysiologically demonstrated cone-rod
dystrophy present since childhood. He had hypogonadism and a central
postsynaptic hearing impairment. Particularly noteworthy was the finding
of deletion of the 18q21.1-qter segment. Three patients with more distal
deletions on chromosome 18 did not present retinal dystrophies. This led
Warburg et al. (1991) to suggest that a locus for cone-rod dystrophy may
be located in the segment 18q21.1-q21.3. The form of cone-rod dystrophy
which may be determined by mutation in the gene on chromosome 18 has
been designated here as CORD1; see 600624.

Kylstra and Aylsworth (1993) reported a case of cone-rod retinal
dystrophy in association with neurofibromatosis type 1 (NF1; 162200),
suggesting a localization for CRD close to NF1 on 17q. Although there
may be genetic heterogeneity as well as the recognized phenotypic
heterogeneity in the group called cone-rod retinal dystrophy, the most
definitive mapping, using DNA markers, is that of Evans et al. (1994) to
19q13.1-q13.2.

In the large kindred with autosomal dominant cone-rod dystrophy studied
by Evans et al. (1994), it appeared that inheritance was influenced by
meiotic drive, resulting in segregation distortion. Affected fathers (N
= 25) produced 71 children of whom 31 (44%) were affected, a value
approximating the expected 1:1 ratio; however, 63 of 101 children (63%)
born to 26 affected mothers inherited the CRD gene. The cumulative
binomial distribution calculation for this finding in the progeny of
affected mothers gave p = 0.008. Evans et al. (1995) reported on the
clinical features of 34 affected members in 4 generations. Loss of
visual acuity occurred in the first decade of life, onset of night
blindness occurred after 20 years of age, and little visual function
remained after the age of 50 years. Central and, later, peripheral
retinal fundus changes were associated with central scotoma,
pseudoaltitudinal field defects, and finally, global loss of function.
Psychophysical and electrophysiologic testing before the age of 26 years
showed more marked loss of cone than of rod function.

*FIELD* SA
Heckenlively et al. (1981)
*FIELD* RF
1. Evans, K.; Duvall-Young, J.; Fitzke, F. W.; Arden, G. B.; Bhattacharya,
S. S.; Bird, A. C.: Chromosome 19q cone-rod retinal dystrophy: ocular
phenotype. Arch. Ophthal. 113: 195-201, 1995.

2. Evans, K.; Fryer, A.; Inglehearn, C.; Duvall-Young, J.; Whittaker,
J. L.; Gregory, C. Y.; Butler, R.; Ebenezer, N.; Hunt, D. M.; Bhattacharya,
S.: Genetic linkage of cone-rod retinal dystrophy to chromosome 19q
and evidence for segregation distortion. Nature Genet. 6: 210-213,
1994.

3. Ferrell, R. E.; Hittner, H. M.; Chakravarti, A.: Autosomal dominant
cone-rod dystrophy: a linkage study with 17 biochemical and serological
markers. Am. J. Med. Genet. 8: 363-369, 1981.

4. Heckenlively, J. R.; Rosales, T.; Martin, D.: Optic nerve changes
in dominant cone-rod dystrophy. Docum. Ophthal. Proc. Ser. 27:
183-192, 1981.

5. Hittner, H. M.; Murphree, A. L.; Garcia, C. A.; Justice, J., Jr.;
Chokshi, D. B.: Dominant cone-rod dystrophy. Docum. Ophthal. 39:
29-52, 1975.

6. Kylstra, J. A.; Aylsworth, A. S.: Cone-rod retinal dystrophy in
a patient with neurofibromatosis type 1. Canad. J. Ophthal. 28:
79-80, 1993.

7. Moore, A. T.: Cone and cone-rod dystrophies. J. Med. Genet. 29:
289-290, 1992.

8. Warburg, M.; Sjo, O.; Tranebjaerg, L.; Fledelius, H. C.: Deletion
mapping of a retinal cone-rod dystrophy: assignment to 18q211. Am.
J. Med. Genet. 39: 288-293, 1991.

*FIELD* CS

Eyes:
   Cone-rod retinal dystrophy;
   Initial color vision and visual acuity loss;
   Night blindness;
   Peripheral visual field loss;
   Widespread retinal pigmentation;
   Chorioretinal atrophy;
   Early blindness

Inheritance:
   Autosomal dominant (19q13.1-q13.2)

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mark: 7/18/1995
terry: 4/19/1995
mimadm: 6/25/1994
carol: 6/24/1994
carol: 3/31/1992
supermim: 3/16/1992

*RECORD*
*FIELD* NO
120980
*FIELD* TI
*120980 COMPLEMENT RECEPTOR TYPE 3, ALPHA SUBUNIT; CR3A
Mac-1, ALPHA SUBUNIT; MAC1A;;
Mo1, ALPHA SUBUNIT; MO1A; CD11B;;
INTEGRIN, ALPHA-M; ITGAM
*FIELD* TX
A major surface antigen family on human leukocytes includes complement
receptor type 3 (CR3A; also called Mac-1 or Mo1), lymphocyte
function-associated antigen type 1 (LFA-1; 153370), and p150,95 (Leu M5;
151510). These antigens share a common beta chain (116920) of 94 kD,
linked noncovalently to 1 of 3 alpha chains distinctive to each. They
promote adhesion of granulocytes to each other and to endothelial cell
monolayers. The apparent molecular weight of the Mo1 alpha chain is
155-165 kD, that of the LFA1 alpha subunit is 180 kD, and and that of
the Leu M5 subunit is 130-150 kD. Pierce et al. (1986) purified human
Mo1 to homogeneity from normal granulocytes by affinity chromatography
and high performance liquid chromatography (HPLC) and determined the
N-terminal amino acid sequence of its alpha subunit. The obtained
sequence was identical, except for 2 conservative substitutions, to that
of the alpha subunit of Mac-1 antigen (Springer et al., 1985).
Furthermore, Pierce et al. (1986) found that the N-terminal amino acid
sequence of the alpha subunit of Mo1 was homologous to the alpha subunit
of IIb/IIIa, a glycoprotein that serves similar adhesive functions on
platelets and is deficient or defective in Glanzmann thrombasthenia
(273800). Patients with a history of recurrent bacterial infections and
an inherited deficiency of all 3 leukocyte membrane surface antigens are
thought to have reduced or absent synthesis of the common beta subunit
of the antigen family; see 116920. Arnaout et al. (1988) described the
isolation and analysis of 2 partial cDNA clones encoding the alpha
subunit of Mo1 in humans and guinea pigs. Southern analysis of DNA from
hamster-human hybrids localized the human MO1A gene to chromosome 16,
which has been shown to contain the gene LFA1A (153370). A comparison of
the coding region of the MO1A gene revealed significant homology with
the carboxyl-terminal portions of the alpha subunits of fibronectin,
vitronectin, and platelet IIb/IIIa receptors. By in situ hybridization,
Corbi et al. (1988) demonstrated that the alpha subunits of LFA-1, Mac-1
and p150,95 constitute a cluster that might be called leukocyte
adhesion, alpha, cluster (LAAC) located on 16p13.1-p11. Callen et al.
(1991) narrowed the assignment to 16p11.2. Corbi et al. (1988) described
full-length cDNA clones for the alpha subunit of Mac-1. Arnaout et al.
(1988) reported the complete amino acid sequence as deduced from cDNA
for the human alpha subunit. The protein consists of 1,136 amino acids
with a long amino-terminal extracytoplasmic domain, a 26-amino acid
hydrophobic transmembrane segment, and a 19-carboxyl-terminal
cytoplasmic domain. The alpha subunit is highly similar in sequence to
the alpha subunit of leukocyte p150,95.

*FIELD* SA
Arnaout et al. (1988); Corbi et al. (1988)
*FIELD* RF
1. Arnaout, M. A.; Gupta, S. K.; Pierce, M. W.; Tenen, D. G.: Amino
acid sequence of the alpha subunit of human leukocyte adhesion receptor
Mo1 (complement receptor type 3). J. Cell Biol. 106: 2153-2158,
1988.

2. Arnaout, M. A.; Remold-O'Donnell, E.; Pierce, M. W.; Harris, P.;
Tenen, D. G.: Molecular cloning of the alpha-subunit of human and
guinea pig leukocyte adhesion glycoprotein Mo1: chromosomal localization
and homology to the alpha-subunits of integrins. Proc. Nat. Acad.
Sci. 85: 2776-2780, 1988.

3. Callen, D. F.; Chen, L. Z.; Nancarrow, J.; Whitmore, S. A.; Apostolou,
S.; Thompson, A. D.; Lane, S. A.; Stallings, R. L.; Hildebrand, C.
E.; Harris, P. G.; Sutherland, G. R.: Current state of the physical
map of human chromosome 16.  (Abstract) Cytogenet. Cell Genet. 58:
1998 only, 1991.

4. Corbi, A. L.; Kishimoto, T. K.; Miller, L. J.; Springer, T. A.
: The human leukocyte adhesion glycoprotein Mac-1 (complement receptor
type 3, CD11b) alpha subunit: cloning, primary structure, and relation
to the integrins, von Willebrand factor and factor B. J. Biol. Chem. 263:
12403-12411, 1988.

5. Corbi, A. L.; Larson, R. S.; Kishimoto, T. K.; Springer, T. A.;
Morton, C. C.: Chromosomal location of the genes encoding the leukocyte
adhesion receptors LFA-1, Mac-1 and p150,95: identification of a gene
cluster involved in cell adhesion. J. Exp. Med. 167: 1597-1607,
1988.

6. Pierce, M. W.; Remold-O'Donnell, E.; Todd, R. F., III; Arnaout,
M. A.: N-terminal sequence of human leukocyte glycoprotein Mo1: conservation
across species and homology to platelet IIb/IIIa. Biochim. Biophys.
Acta 874: 368-371, 1986.

7. Springer, T. A.; Teplow, D. B.; Dreyer, W. J.: Sequence homology
of the LFA-1 and Mac-1 leukocyte adhesion glycoproteins and unexpected
relation to leukocyte interferon. Nature 314: 540-542, 1985.

*FIELD* CD
Victor A. McKusick: 6/24/1986

*FIELD* ED
carol: 7/2/1992
carol: 5/4/1992
carol: 3/26/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

*RECORD*
*FIELD* NO
121000
*FIELD* TI
#121000 CONGENITAL HEART DISEASE
*FIELD* TX
A number sign (#) is used with this entry because it relates to a
presumably heterogeneous category of malformations. Most cases are of
multifactorial etiology. Occasional instances of parent-child
involvement are to be expected. When successively affected generations
are observed in the case of a rare malformation such as supravalvar
aortic stenosis (185500) or when 3 or more generations are affected,
especially through several lines, simple autosomal dominant inheritance
is likely. See the families reported by Kahler et al. (1966). Tiller et
al. (1988) reviewed the types of defects that have been observed with 7q
deletion and concluded that about 20% of patients have a congenital
heart defect. Because material is deleted from the 22q11 region in most
individuals with DiGeorge syndrome (188400) and Shprintzen syndrome
(192430)--both conditions in which heart anomalies are an important
feature--Wilson et al. (1992) looked for deletions in 9 families with 2
or more cases of outflow-tract heart defects. In 5 of the families,
chromosome 22 deletions were detected in all living affected persons
studied and also in the clinically normal father of 3 affected children.
The deletion was transmitted from parents to offspring and was
associated with an increase in the severity of cardiac defects. No
deletions were found in 4 families in which the parents were normal and
affected sibs had anatomically identical defects.

*FIELD* SA
Carleton et al. (1958); Chelius et al. (1962); Nora et al. (1969);
Pitt  (1962)
*FIELD* RF
1. Carleton, R. A.; Abelmann, W. H.; Hancock, E. W.: Familial occurrence
of congenital heart disease: report of three families and review of
the literature. New Eng. J. Med. 259: 1237-1245, 1958.

2. Chelius, C. J.; Rowe, G. G.; Crumpton, C. W.: Familial aspects
of congenital heart disease. Am. J. Cardiol. 9: 508-514, 1962.

3. Kahler, R. L.; Braunwald, E.; Plauth, W. H., Jr.; Morrow, A. G.
: Familial congenital heart disease. Familial occurrence of atrial
septal defect with A-V conduction abnormalities, supravalvular aortic
and pulmonic stenosis, and ventricular septal defect. Am. J. Med. 40:
384-399, 1966.

4. Nora, J. J.; Dodd, P. F.; McNamara, D. G.; Hattwick, M. A. W.;
Leachman, R. D.; Cooley, D. A.: Risk to offspring of parents with
congenital heart defects. J.A.M.A. 209: 2052-2053, 1969.

5. Pitt, D. B.: A family study of Fallot's tetrad. Aust. Ann. Med. 11:
179-183, 1962.

6. Tiller, G. E.; Watson, M. S.; Duncan, L. M.; Dowton, S. B.: Congenital
heart defect in a patient with deletion of chromosome 7q. Am. J.
Med. Genet. 29: 283-287, 1988.

7. Wilson, D. I.; Goodship, J. A.; Burn, J.; Cross, I. E.; Scambler,
P. J.: Deletions within chromosome 22q11 in familial congenital heart
disease. Lancet 340: 573-575, 1992.

*FIELD* CS

Cardiac:
   Congenital heart defect

Inheritance:
   Autosomal dominant form occurs;
   most are multifactorial

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mimadm: 6/25/1994
carol: 10/7/1992
carol: 9/14/1992
supermim: 3/16/1992
carol: 3/5/1992
carol: 3/4/1992

*RECORD*
*FIELD* NO
121009
*FIELD* TI
*121009 CONNECTIVE TISSUE GROWTH FACTOR; CTGF
*FIELD* TX
Bradham et al. (1991) described a new mitogen produced by human
umbilical vein endothelial cells, which they termed connective tissue
growth factor. Related to platelet-derived growth factor, the protein
was predicted from its cDNA to be a 38-kD cysteine-rich secreted
protein. Martinerie et al. (1992) identified a locus sharing homology
with the nov protooncogene overexpressed in avian nephroblastoma and
corresponding to the CTGF gene. They assigned the CTGF gene to 6q23.1 by
a combination of study of mouse/human somatic cell hybrids and
fluorescence in situ hybridization. They showed that CTGF is situated
proximal to MYB (189990).

*FIELD* RF
1. Bradham, D. M.; Igarashi, A.; Potter, R. L.; Grotendorst, G. R.
: Connective tissue growth factor: a cysteine-rich mitogen secreted
by human vascular endothelial cells is related to the SRC-induced
immediate early gene product CEF-10. J. Cell Biol. 114: 1285-1294,
1991.

2. Martinerie, C.; Viegas-Pequignot, E.; Guenard, I.; Dutrillaux,
B.; Nguyen, V. C.; Bernheim, A.; Perbal, B.: Physical mapping of
human loci homologous to the chicken nov proto-oncogene. Oncogene 7:
2529-2534, 1992.

*FIELD* CD
Victor A. McKusick: 5/14/1993

*FIELD* ED
carol: 5/14/1993

*RECORD*
*FIELD* NO
121010
*FIELD* TI
*121010 CONNECTIVE TISSUE-ACTIVATING PEPTIDE III; CTAP3
PRO-PLATELET BASIC PROTEIN; PPBP;;
PRO-PBP;;
LOW-AFFINITY PF4
BETA-THROMBOGLOBULIN, INCLUDED;;
TGB, INCLUDED;;
THROMBOGLOBULIN, BETA-1, INCLUDED;;
TGB1, INCLUDED;;
NEUTROPHIL-ACTIVATING PEPTIDE-2; NAP2
*FIELD* TX
Connective tissue-activating peptide-III is a platelet-derived growth
factor that stimulates a variety of specific metabolic and cellular
activities including mitogenesis, extracellular matrix synthesis,
glucose metabolism, and plasminogen activator synthesis in human
fibroblast cultures (Castor et al., 1983; Castor et al., 1985).
Pro-platelet basic protein is the precursor of the 2 platelet
alpha-granule proteins, platelet basic protein (PBP) and connective
tissue activating peptide-III. Upon platelet activation they are
released and further processed in plasma to beta-thromboglobulin and
neutrophil-activating peptide-2. Majumdar et al. (1991) compared
beta-thromboglobulin with platelet factor 4 (PF4; 173460). The TGB gene
is 1,139 bp long and, like other members of the small inducible gene
(SIG) family, it is divided into 3 exons. Southern blot analysis of
genomic DNA suggested that, as with the PF4 gene, there are multiple
copies of the beta-thromboglobulin gene in the human genome. Chromosomal
localization using PCR analysis of human/hamster somatic cell hybrids
demonstrated that the TGB gene, like the PF4 gene, is located on
chromosome 4. Possibly these genes are coordinately activated during
megakaryocyte differentiation. Wenger et al. (1991) mapped the CTAP3
gene to 4q12-q13 by in situ hybridization.

There are 2 branches of the family of small inducible genes which encode
related proteins that are involved in the overlapping processes of
coagulation, inflammation, immune response, and wound repair. Termed CXC
and CC, the 2 branches are distinguished by whether or not the first 2
of 4 conserved cysteine residues are separated by an additional amino
acid residue. All of the CXC SIGs map to chromosome 4. By pulsed field
gel electrophoresis (PFGE), Tunnacliffe et al. (1992) demonstrated that
the TGB genes (which are duplicate) are closely linked to the duplicated
PF4 genes and to other previously mapped CXC SIGs, namely, IL8 (146930),
GRO1 (155730), GRO2 (139110), and GRO3 (139111), on a single 700-kb
restriction fragment located in bands 4q12-q13. The only CXC SIG not
linked to this cluster is that encoding gamma-interferon-induced 10-kD
protein (INP10; 147310), which is located in band 4q21. By analysis of
lambda genomic clones, Tunnacliffe et al. (1992) demonstrated that the
TGB1 and PF4 genes are separated by less than 7 kb, and the TGB2 and
PF4-alternate (PF4V1; 173461) genes by approximately 5 kb. Within each
TGB/PF4 duplication, the TGB-like gene is upstream of its linked
PF4-like gene. The genes in this closely linked complex are expressed in
a megakaryocyte-specific fashion.

*FIELD* RF
1. Castor, C. W.; Furlong, A. M.; Carter-Su, C.: Connective tissue
activation. XXIX. Stimulation of glucose transport by connective tissue
activating peptide-III. Biochemistry 24: 1762-1767, 1985.

2. Castor, C. W.; Miller, J. W.; Walz, D. A.: Structural and biological
characteristics of connective tissue activating peptide (CTAP-III),
a major human platelet derived growth factor. Proc. Nat. Acad. Sci. 80:
765-769, 1983.

3. Majumdar, S.; Gonder, D.; Koutsis, B.; Poncz, M.: Characterization
of the human beta-thromboglobulin gene: comparison with the gene for
platelet factor 4. J. Biol. Chem. 266: 5785-5789, 1991.

4. Tunnacliffe, A.; Majumdar, S.; Yan, B.; Poncz, M.: Genes for beta-thromboglobulin
and platelet factor 4 are closely linked and form part of a cluster
of related genes on chromosome 4. Blood 79: 2896-2900, 1992.

5. Wenger, R. H.; Hameister, H.; Clemetson, K. J.: Human platelet
basic protein/connective tissue activating peptide-III maps in a gene
cluster on chromosome 4q12-q13 along with other genes of the beta-thromboglobulin
superfamily. Hum. Genet. 87: 367-368, 1991.

*FIELD* CD
Victor A. McKusick: 10/26/1990

*FIELD* ED
carol: 11/5/1992
carol: 9/14/1992
supermim: 3/16/1992
carol: 10/14/1991
carol: 10/4/1991
carol: 9/24/1991

*RECORD*
*FIELD* NO
121011
*FIELD* TI
*121011 GAP JUNCTION PROTEIN, BETA-2, 26 KD; GJB2
CONNEXIN 26 GAP JUNCTION PROTEIN; CX26
*FIELD* TX
Gap junctions were first characterized by electron microscopy as
regionally specialized structures on plasma membranes of contacting
adherent cells. These structures were shown to consist of cell-to-cell
channels. Proteins, called connexins, purified from fractions of
enriched gap junctions from different tissues differ. The connexins are
designated by their molecular mass. Another system of nomenclature
divides gap junction proteins into 2 categories, alpha and beta,
according to sequence similarities at the nucleotide and amino acid
levels. For example, CX43 (121014) is designated alpha-1 gap junction
protein, whereas CX32 (304040) and CX26 are called beta-1 and beta-2 gap
junction proteins, respectively. This nomenclature emphasizes that CX32
and CX26 are more homologous to each other than either of them is to
CX43. Willecke et al. (1990) used rat connexin gene probes in Southern
blot analysis of human-mouse somatic cell hybrids to map the CX26 gene
to chromosome 13. By means of somatic cell hybrids, Hsieh et al. (1991)
assigned the GJB2 gene to chromosome 13 in man and chromosome 14 in the
mouse. Haefliger et al. (1992) showed that the rat homologs of the CX26
and CX46 genes are tightly linked on chromosome 14.

By isotopic in situ hybridization, Mignon et al. (1996) mapped GJB2 to
13q11-q12 and confirmed the assignment to mouse chromosome 14.

Kelsell et al. (1997) studied a pedigree containing individuals with
autosomal dominant deafness (DFNA3; 601544) and identified a mutation in
the CX26 gene. CX26 mutations resulting in premature stop codons were
also found in 3 autosomal recessive nonsyndromic sensorineural deafness
pedigrees, genetically linked to 13q11-q12, where the CX26 gene is
localized (DFNB1; 220290). Immunohistochemical staining of human
cochlear cells for CX26 demonstrated high levels of expression.

*FIELD* AV
.0001
DEAFNESS, AUTOSOMAL DOMINANT, 3
DFNA3
GJB2, MET34THR
In a family in which both Clouston syndrome (129500) and deafness were
segregating as probably independent autosomal dominant traits, Kelsell
et al. (1997) found a T-to-C substitution in codon 34 (exon 1) of the
GJB2 gene. The substitution resulted in a change in codon 34 from ATG
(met) to ACG (thr). The M34T mutation segregated with the profound
deafness phenotype but not with the skin disorder in the family studied,
which was originally reported by Verbov (1987) (see 148350).

.0002
DEAFNESS, AUTOSOMAL RECESSIVE, 1
DFNB1
GJB2, TRP77TER
In a large consanguineous family of Pakistani origin with recessive
nonsyndromic profound deafness (DFNB1; 220290) that mapped to 13q11-q12
(Brown et al., 1996), Kelsell et al. (1997) found that 2 affected
individuals were homozygous for a G-to-A substitution in codon 77, which
resulted in a premature stop codon (Trp to Opal; W77X). The parents were
heterozygous for the mutation and had no noticeable hearing impairment.

.0003
DEAFNESS, AUTOSOMAL RECESSIVE, 1
DFNB1
GJB2, TRP24TER
In 2 consanguineous Pakistani families with nonsyndromic profound
deafness, Kelsell et al. (1997) found evidence for linkage to 13q11-q12
and showed that 2 affected individuals from each pedigree were
homozygous for a G-to-A substitution in codon 24 that resulted in a
premature stop codon (Trp-to-Amber; W24X). Haplotype comparisons
indicated that these 2 identical mutations arose independently.

*FIELD* RF
1. Brown, K. A.; Janjua, A. H.; Karbani, G.; Parry, G.; Noble, A.;
Crockford, G.; Bishop, D. T.; Newton, V. E.; Markham, A. F.; Mueller,
R. F.: Linkage studies of non-syndromic recessive deafness (NSRD)
in a family originating from the Mirpur region of Pakistan maps DFNB1
centromeric to D13S175. Hum. Molec. Genet. 5: 169-173, 1996.

2. Haefliger, J.-A.; Bruzzone, R.; Jenkins, N. A.; Gilbert, D. J.;
Copeland, N. G.; Paul, D. L.: Four novel members of the connexin
family of gap junction proteins: molecular cloning, expression, and
chromosome mapping. J. Biol. Chem. 267: 2057-2064, 1992.

3. Hsieh, C.-L.; Kumar, N. M.; Gilula, N. B.; Francke, U.: Distribution
of genes for gap junction membrane channel proteins on human and mouse
chromosomes. Somat. Cell Molec. Genet. 17: 191-200, 1991.

4. Kelsell, D. P.; Dunlop, J.; Stevens, H. P.; Lench, N. J.; Liang,
J. N.; Parry, G.; Mueller, R. F.; Leigh, I. M.: Connexin 26 mutations
in hereditary non-syndromic sensorineural deafness. Nature 387:
80-83, 1997.

5. Mignon, C.; Fromaget, C.; Mattei, M.-G.; Gros, D.; Yamasaki, H.;
Mesnil, M.: Assignment of connexin 26 (GJB2) and 46 (GJA3) genes
to human chromosome 13q11-q12 and mouse chromosome 14D1-E1 by in situ
hybridization. Cytogenet. Cell Genet. 72: 185-186, 1996.

6. Verbov, J.: Palmoplantar keratoderma, deafness and atopy.(Letter) Brit.
J. Derm. 116: 881-882, 1987.

7. Willecke, K.; Jungbluth, S.; Dahl, E.; Hennemann, H.; Heynkes,
R.; Grzeschik, K.-H.: Six genes of the human connexin gene family
coding for gap junctional proteins are assigned to four different
human chromosomes. Europ. J. Cell Biol. 53: 275-280, 1990.

*FIELD* CD
Victor A. McKusick: 3/18/1991

*FIELD* ED
alopez: 04/30/1997
terry: 4/29/1997
mark: 8/15/1996
terry: 6/13/1996
terry: 6/12/1996
terry: 6/6/1996
carol: 3/14/1994
carol: 2/17/1993
carol: 1/6/1993
supermim: 3/16/1992
carol: 5/10/1991
carol: 3/18/1991

*RECORD*
*FIELD* NO
121012
*FIELD* TI
*121012 GAP JUNCTION PROTEIN, ALPHA-4; GJA4
CONNEXIN 37 GAP JUNCTION PROTEIN; CX37
*FIELD* TX
See 121011. Reed et al. (1993) used PCR amplification and cDNA library
screening to clone DNA encoding the connexin 37 gap junction protein.
The derived polypeptide contained 333 amino acids, with a predicted
molecular mass of about 37 kD. RNA blots demonstrated that CX37 is
expressed in multiple organs and tissues, including heart, uterus,
ovary, and blood vessel endothelium, and in primary cultures of vascular
endothelial cells. Reed et al. (1993) demonstrated that CX37 can form
functional cell-to-cell channels that have unique voltage-dependence and
unitary conductance properties.

Willecke et al. (1990) used a mouse cDNA probe in Southern analysis of
human-mouse somatic cell hybrids to map the human CX37 gene to
1pter-q12. CX40 (121013) was assigned to the same region of chromosome
1. Haefliger et al. (1992) showed that the homologs of CX37 and one
other connexin gene are located on rat chromosome 4.

Van Camp et al. (1995) used the human GJA4 cDNA sequence to design PCR
primers that amplified the complete coding sequence of the gene. Using a
cosmid probe isolated from a chromosome 1-specifice cosmid library, they
assigned the gene to 1p35.1 by fluorescence in situ hybridization.
Furthermore, they screened the CEPH megaYAC library by PCR and
demonstrated that the GJA4 gene and D1S195 colocalized to a region of
1.1 Mb.

*FIELD* RF
1. Haefliger, J.-A.; Bruzzone, R.; Jenkins, N. A.; Gilbert, D. J.;
Copeland, N. G.; Paul, D. L.: Four novel members of the connexin
family of gap junction proteins: molecular cloning, expression, and
chromosome mapping. J. Biol. Chem. 267: 2057-2064, 1992.

2. Reed, K. E.; Westphale, E. M.; Larson, D. M.; Wang, H.-Z.; Veenstra,
R. D.; Beyer, E. C.: Molecular cloning and functional expression
of human connexin37, an endothelial cell gap junction protein. J.
Clin. Invest. 91: 997-1004, 1993.

3. Van Camp, G.; Coucke, P.; Speleman, F.; Van Roy, N.; Beyer, E.
C.; Oostra, B. A.; Willems, P. J.: The gene for human gap junction
protein connexin37 (GJA4) maps to chromosome 1p35.1, in the vicinity
of D1S195. Genomics 30: 402-403, 1995.

4. Willecke, K.; Jungbluth, S.; Dahl, E.; Hennemann, H.; Heynkes,
R.; Grzeschik, K.-H.: Six genes of the human connexin gene family
coding for gap junctional proteins are assigned to four different
human chromosomes. Europ. J. Cell Biol. 53: 275-280, 1990.

*FIELD* CD
Victor A. McKusick: 3/18/1991

*FIELD* ED
mark: 01/09/1996
carol: 3/14/1994
carol: 5/7/1993
supermim: 3/16/1992
carol: 8/19/1991
carol: 3/18/1991

*RECORD*
*FIELD* NO
121013
*FIELD* TI
*121013 CONNEXIN 40 GAP JUNCTION PROTEIN; CX40
GAP JUNCTION PROTEIN, ALPHA-5; GJA5
*FIELD* TX
See 121011. Willecke et al. (1990) used a mouse cDNA probe in Southern
analysis of mouse-human somatic cell hybrids to map the CX40 and CX37
(121012) genes to 1pter-q12.

*FIELD* RF
1. Willecke, K.; Jungbluth, S.; Dahl, E.; Hennemann, H.; Heynkes,
R.; Grzeschik, K.-H.: Six genes of the human connexin gene family
coding for gap junctional proteins are assigned to four different
human chromosomes. Europ. J. Cell Biol. 53: 275-280, 1990.

*FIELD* CD
Victor A. McKusick: 3/18/1991

*FIELD* ED
supermim: 3/16/1992
carol: 8/19/1991
carol: 3/18/1991

*RECORD*
*FIELD* NO
121014
*FIELD* TI
*121014 GAP JUNCTION PROTEIN, ALPHA-1, 43 KD; GJA1
CONNEXIN 43 GAP JUNCTION PROTEIN; CX43;;
HEART CONNEXIN
VISCEROATRIAL HETEROTAXIA, AUTOSOMAL RECESSIVE, INCLUDED;;
VAH, AUTOSOMAL RECESSIVE, INCLUDED
*FIELD* TX
See 121011. Two members of the connexin gene family, connexins 43 (Cx43)
and 32, or GJB1 (304040), are abundantly expressed in the heart and
liver, respectively. Li et al. (1995) demonstrated that GAP43-like
immunoreactivity in rat is mainly present in sympathetic and sensory
nerve fibers as well as in perivascular nerve terminals. This peptide is
axonally transported mainly in sensory and adrenergic axons.

Using a rat cDNA probe in Southern analysis of a panel of human-mouse
somatic cell hybrids, Willecke et al. (1990) assigned the CX43 gene
(symbol = GJA1) to 6q14-qter. A pseudogene of connexin 43, which lacks
an intron, was located on human chromosome 5. Through analysis of
somatic cell hybrids by PCR and hybridization, Fishman et al. (1991)
mapped the gene for heart connexin 43 (GJA1) to chromosome 6. A
pseudogene, symbolized GJA1P, was assigned to chromosome 5. The
structures of GJA1 and the liver connexin gene, GJB1, are sufficiently
similar to suggest that they arose from a single progenitor. By study of
somatic cell hybrids, Hsieh et al. (1991) mapped GJA1 to 6p21.1-q24.1.
Taken in connection with the findings of Willecke et al. (1990), one can
conclude that the location of GJA1 is 6q14-q24.1. Also by study of
rat/mouse somatic cell hybrids, Hsieh et al. (1991) assigned the
corresponding gene to mouse chromosome 10. Corcos et al. (1993) narrowed
the assignment to 6q21-q23.2 by study of a human/rodent somatic cell
hybrid mapping panel.

To identify the molecular basis for the function of connexin 43, Fishman
et al. (1991) used site-directed mutagenesis to generate mutant cDNAs of
human connexin 43 with shortened cytoplasmic tail domains. Results
suggested that the cytoplasmic tail domain is an important determinant
of the unitary conductance event of gap junction channels but not their
voltage dependence.

By targeted mutagenesis of connexin 43, Reaume et al. (1995) showed that
its absence was compatible with survival of mouse embryos to term, even
though cell lines mutant in Cx43 showed reduced dye coupling in vitro as
assessed by injection of carboxyfluorescein. The latter test indicated a
reduction, but not complete absence, of junctional communication.
However, mutant embryos died at birth as a result of a failure in
pulmonary gas exchange caused by a swelling and blockage of the right
ventricular outflow tract from the heart. Reaume et al. (1995)
interpreted this finding as indicating that Cx43 plays an essential role
in heart development but that there is functional compensation among
connexins in other parts of the developing fetus.

Connexin 43 is the major protein of gap junctions in the heart, and gap
junctions are thought to have a crucial role in the synchronized
contraction of the heart and in embryonic development. CX43 is targeted
by several protein kinases that regulate myocardial cell-cell coupling.
Britz-Cunningham et al. (1995) hypothesized that mutations altering
sites critical to this regulation would lead to functional or
developmental abnormalities of the heart. In 25 normal subjects and in
23 of 30 children with various forms of congenital heart disease, they
found no amino acid substitutions in connexin 43. All 6 children with
syndromes that included complex heart malformations had substitutions of
one or more phosphorylatable serine or threonine residues. In 4 of these
children, Britz-Cunningham et al. (1995) found 2 independent mutations,
suggesting an autosomal recessive disorder. Five of the children had
substitutions of proline for serine at position 364.

In 15 patients with sporadic defects of laterality and 3 with familial
defects of laterality, Casey and Ballabio (1995) amplified and sequenced
the region of CX43 that codes for the cytoplasmic tail. They stated that
all of the nucleotides reported by Britz-Cunningham et al. (1995) were
contained within this portion of the gene. The patients with familial
defects of laterality were from kindreds with apparent autosomal
dominant transmission of the trait. Casey and Ballabio (1995) detected
no base changes in the coding sequence in any of the patients studied.
Specifically, none