SPECTRUM AND FREQUENCY OF JAGGED1 (JAG1) MUTATIONS IN ALAGILLE-SYNDROME PATIENTS AND THEIR FAMILIES

Alagille syndrome (AGS) is a dominantly inherited disorder characteriz ed by liver disease in combination with heart, skeletal, ocular, facia l, renal, and pancreatic abnormalities. We have recently demonstrated that Jagged1 (JAG1) is the AGS gene. JAG1 encodes a ligand in the Notc h intercellular signaling pathway. AGS is the first developmental diso rder to be associated with this pathway and the first human disorder c aused by a Notch ligand. We have screened 54 AGS probands and family m embers to determine the frequency of mutations in JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (63%) had mutations within JAG1, identified by SSCP analysis. Of th e 35 identified intragenic mutations, all were unique, with the except ions of a 5-bp deletion in exon 16, seen in two unrelated patients, an d a C insertion at base 1618 in exon 3, also seen in two unrelated pat ients. The 35 intragenic mutations included 3 nonsense mutations (26%) ; 2 missense mutations (6%); 11 small deletions (31%), 8 small inserti ons (23%), and 1 complex rearrangement (3%), all leading to frameshift s; and 4 splice-site mutations (11%). The mutations are spread across the coding sequence of the gene within the evolutionarily conserved mo tifs of the JAG1 protein. There is no phenotypic difference between pa tients with deletions of the entire JAG1 gene and those with intrageni c mutations, which suggests that one mechanism involved in AGS is hapl oinsufficiency. The two missense mutations occur at the same amino aci d residue. The mechanism by which these missense mutations lead to the disease is not yet understood; however, they suggest that mechanisms other than haploinsufficiency may result in the AGS phenotype.