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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