Jagged1 mutations in Alagille syndrome

We have summarized data on 233 Alagille syndrome patients reported with mut ations in Jagged1 (JAG1). This data has been published by seven different l aboratories in Europe, the United States, Australia, and Japan, Mutations h ave been demonstrated in 60-75% of patients with a clinically confirmed dia gnosis of Alagille syndrome. Total gene deletions have been reported in 3-7 % of patients, and the remainder have intragenic mutations. Seventy two per cent (168/233) of the reported mutations lead to frameshifts that cause a p remature termination codon. These mutations will either lead to a premature ly truncated protein, or alternatively, nonsense mediated decay might lead to lack of a product from that allele. Twenty three unique missense mutatio ns were identified ( 13% of mutations). These were clustered in conserved r egions 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 d e novo mutations (60-70%) has been reported. The spectrum of mutations iden tified is consistent with haploinsufficiency for JAG1 being a mechanism for Alagille syndrome. Hum Mutat 17:18-33, 2001. (C) 2001 Wiley Liss, Inc.