MUTATIONAL ANALYSIS OF THE JAGGED-1 GENE IN ALAGILLE-SYNDROME FAMILIES

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 Ja gged 1(JAG1) gene, which encodes a ligand for the Notch receptor, We a nalyzed the JAG1 gene in eight AGS families, including affected and un affected individuals, at the genomic DNA level, mainly by single-stran d conformational polymorphism (SSCP) and DNA sequencing analysis, Four categories of mutations were identified: (i) four frameshift mutation s in exons 9, 22, 24 and 26 were exhibited respectively in affected in dividuals of four AGS families, which resulted in moving the translati onal 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 A GS families, which altered codon 235 from arginine to stop; (iii) one acceptor splice site mutation of exon 5 was revealed in a sporadic pat ient; and (iv) a 1.3 Mb deletion, which included the entire JAG1 gene, was found in another patient. Our results further demonstrate that AG S is a dominant disease and suggest that the JAG1 gene exerts a fundam ental role in regulating genes involved in development.