Alagille syndrome is an autosomal dominant disorder characterized by abnormal 
development of liver, heart, skeleton, eye, face and, less frequently, kidney. 
Analyses of many patients with cytogenetic deletions or rearrangements have 
mapped the gene to chromosome 20p12, although deletions are found in a 
relatively small proportion of patients (< 7%). We have mapped the human Jagged1 
gene (JAG1), encoding a ligand for the developmentally important Notch 
transmembrane receptor, to the Alagille syndrome critical region within 20p12. 
The Notch intercellular signalling pathway has been shown to mediate cell fate 
decisions during development in invertebrates and vertebrates. We demonstrate 
four distinct coding mutations in JAG1 from four Alagille syndrome families, 
providing evidence that it is the causal gene for Alagille syndrome. All four 
mutations lie within conserved regions of the gene and cause translational 
frameshifts, resulting in gross alterations of the protein product Patients with 
cytogenetically detectable deletions including JAG1 have Alagille syndrome, 
supporting the hypothesis that haploinsufficiency for this gene is one of the 
mechanisms causing the Alagille syndrome phenotype.