Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal development of the liver, heart, skeleton, eye, and face. Mutations in the Jagged1 gene have been found to result in the AGS phenotype. Using denaturing high performance liquid chromatography (DHPLC) mutation analysis we have screened 20 individuals with symptoms of AGS from 14 families for mutations within Jagged1. Eleven distinct Jagged1 mutations, six of which are novel, were identified in the 14 probands and affected family members. The mutations include four small deletions (36.6%), one small insertion (9.1%), three missense mutations (27.3%), one nonsense mutation (9.1%) and two splice donor site mutations (18.2%). The two newly identified splice site mutations were shown to cause the aberrant splicing of Jagged1 mRNA resulting in premature truncation of JAG1. A splice acceptor site mutation previously identified by our group in intron 13 was also shown to cause multiple splicing abnormalities of Jagged1 mRNA, consequently removing exons 14 and 15. The results of this study are consistent with the proposal that either haploinsufficiency for wild-type JAG1 and/or dominant negative effects produced by mutated JAG1 are responsible for the AGS phenotype.
Copyright 2002 Wiley-Liss, Inc.