IDENTIFICATION OF THE GENE(S) RESPONSIBLE FOR ALAGILLE SYNDROME

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Alagille syndrome (AGS) is an autosomal dominant condition characterized by intrahepatic cholestasis and abnormalities of heart, eye, and vertebrae, as well as a characteristic facial appearance. Previous identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene to 20p12. We have generated a bacterial artificial clone (BAC) contig of the critical region and used fluorescent in situ hybridization (FISH) on cells from patients with submicroscopic deletions to narrow the candidate region to 250 kb. Within this region we have identified JAG1, the human homolog of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frameshift mutations, two splice donor mutations, and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.