We have summarized data on 233 Alagille syndrome patients reported with mutations in Jagged1 (JAG1). This data has been published by seven different laboratories in Europe, the United States, Australia, and Japan. Mutations have been demonstrated in 60-75% of patients with a clinically confirmed diagnosis of Alagille syndrome. Total gene deletions have been reported in 3-7% of patients, and the remainder have intragenic mutations. Seventy two percent (168/233) of the reported mutations lead to frameshifts that cause a premature termination codon. These mutations will either lead to a prematurely truncated protein, or alternatively, nonsense mediated decay might lead to lack of a product from that allele. Twenty three unique missense mutations were identified (13% of mutations). These were clustered in conserved regions at the 5' end of the gene, or in the EGF repeats. Splicing consensus sequence changes were identified in 15% of patients. A high frequency of de novo mutations (60-70%) has been reported. The spectrum of mutations identified is consistent with haploinsufficiency for JAG1 being a mechanism for Alagille syndrome.
Copyright 2001 Wiley-Liss, Inc.