Hum Mol Genet 1998 Sep;7(9):1363-9

Mutational analysis of the Jagged 1 gene in Alagille syndrome families

Yuan ZR, Kohsaka T, Ikegaya T, Suzuki T, Okano S, Abe J, Kobayashi N, Yamada M

National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku,
Tokyo 154, Japan and National Children's Hospital, Tokyo, Japan.

Abstract

Alagille syndrome (AGS) is an autosomal dominant disease characterized by five
major abnormalities in the liver, heart, face, vertebrae and eye. The
responsible gene has been recently identified as the human Jagged 1 (JAG1) gene,
which encodes a ligand for the Notch receptor. We analyzed the JAG1 gene in
eight AGS families, including affected and unaffected individuals, at the
genomic DNA level, mainly by single-strand conformational polymorphism (SSCP)
and DNA sequencing analysis. Four categories of mutations were identified: (i)
four frameshift mutations in exons 9, 22, 24 and 26 were exhibited respectively
in affected individuals of four AGS families, which resulted in moving the
translational frame of JAG1; (ii) one nonsense mutation, a 1 bp substitution in
exon 5 of the EGF-like repeat domain, was detected in two unrelated AGS
families, which altered codon 235 from arginine to stop; (iii) one acceptor
splice site mutation of exon 5 was revealed in a sporadic patient; and (iv) a
1.3 Mb deletion, which included the entire JAG1 gene, was found in another
patient. Our results further demonstrate that AGS is a dominant disease and
suggest that the JAG1 gene exerts a fundamental role in regulating genes
involved in development.