Molecular analysis of human Jaggedl gene in an Indian family with Alagille syndrome

Abstract

Alagille syndrome (AGS), a multisystem developmental disorder, is characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae and a characteristic facial appearance. The AGS phenotype has been associated with mutations in the Jaggedl gene (JAGI) which encodes a ligand in the Notch signalling pathway that is important in cell-fate determination in a number of tissues.We report an Indian family with a two year old male proband presenting severe AGS with marked hypercholesterolemia while the mother presented only characteristic facial phenotype but normal liver and kidney function. Mutation screening of all 26 exons of JAGI identified a 2841insA mutation in exon 21 (codon 824) in the patient. This mutation is predicted to cause a premature termination of translation of protein within the same codon. The mutated termination codon occurs within the EGF-like repeats domain of the JAGI protein. This domain is highly conserved between Drosophila, rat and human, and is thought to be one of the regions which play a critical role in ligand-receptor interactions. Direct sequencing of genomic DNA from the mother of the patient failed to reveal the presence of the 2841insA mutation. As the 2841insA mutation abolishes a cutting site for Bsm1, this restriction enzyme was also used to confirm the absence of this mutation in the mother. Our data show that that factors not attributable to the specific 2841insA mutation must play a role in determination of the subclinical AGS phenotype seen in the mother.