Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal develop ment of the liver, heart, skeleton, eye, and face. Mutatio ns in the Jagged1 gene (JAG1) have been found to result in the AGS phenotyp e and both protein truncating mutations and missense mutations have been id entified. Using single stranded conformational polymorphism analysis we hav e screened 22 AGS affected individuals from 19 families for mutations withi n Jagged1. Twelve distinct Jagged1 mutations were identified in 15 (68.2%) of the 22 AGS cases, seven of which are novel. The mutations include three small deletions (25%), two small insertions (16.6%), three missense mutatio ns (25%), two nonsense mutations (16.6%), and two splice-site mutations (16 .6%). These mutations are spread across the entire coding sequence of the g ene and most are localized to highly conserved motifs of the protein predic ted to be important for Jagged 1 function. One-half of the mutations found in this study are located between exons 9 and 12, a region constituting onl y 12% of the coding sequence. A splice donor site mutation in intron 11 was shown to cause aberrant splicing of Jagged1 mRNA, consequently terminating translation prematurely in exon 12, The results of this study are consiste nt with the proposal that either haploinsufficiency for wild type Jagged1 a nd/or dominant negative effects produced by mutated Jagged1 are responsible for the AGS phenotype, Hum Mutat 16:408-416, 2000. (C) 2000 Wiley-Liss, In c.