Jagged-1 mutation analysis in Italian Alagille syndrome patients

Alagille syndrome (AGS) is an autosomal dominant disorder with developmenta l abnormalities affecting the liver, heart, eyes, vertebrae, and craniofaci al region, The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has r ecently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of IS different JAGI mutations, including a large deletion of the 20p12 regio n, six frameshift, three nonsense, three splice site, and two missense muta tions. The two novel missense mutations were clustered in the 5' region, wh ile the remaining mutations were scattered throughout the gene. The spectru m of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dup18bp, whi ch was shown to lead to an abnormal JAG1 mRNA, resulting in a premature sto p codon, With the exception of the missense mutations, the majority of the JAGI mutations are therefore likely to produce truncated proteins, Since th e phenotype of the patient with a complete deletion of the JAG1 gene is ind istinguishable from that of patients with intragenic mutations, our study f urther supports the hypothesis that haploinsufficiency is the most common m echanism involved in AGS pathogenesis, Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype. Hum Mutat 14:394-400, 1999, (C) 1999 Wiley Liss, Inc.