Alagille syndrome (AGS) is a dominantly inherited disorder characterized by 
liver disease in combination with heart, skeletal, ocular, facial, renal, and 
pancreatic abnormalities. We have recently demonstrated that Jagged1 (JAG1) is 
the AGS gene. JAG1 encodes a ligand in the Notch intercellular signaling 
pathway. AGS is the first developmental disorder to be associated with this 
pathway and the first human disorder caused by a Notch ligand. We have screened 
54 AGS probands and family members to determine the frequency of mutations in 
JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 
patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis. Of 
the 35 identified intragenic mutations, all were unique, with the exceptions of 
a 5-bp deletion in exon 16, seen in two unrelated patients, and a C insertion at 
base 1618 in exon 9, also seen in two unrelated patients. The 35 intragenic 
mutations included 9 nonsense mutations (26%); 2 missense mutations (6%); 11 
small deletions (31%), 8 small insertions (23%), and 1 complex rearrangement 
(3%), all leading to frameshifts; and 4 splice-site mutations (11%). The 
mutations are spread across the coding sequence of the gene within the 
evolutionarily conserved motifs of the JAG1 protein. There is no phenotypic 
difference between patients with deletions of the entire JAG1 gene and those 
with intragenic mutations, which suggests that one mechanism involved in AGS is 
haploinsufficiency. The two missense mutations occur at the same amino acid 
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.