Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for notch1

Linheng Li, Ian D. Krantz, Yu Deng, Anna Genin, Amy B. Banta, Colin C. Collins, Ming Qi, Barbara J. Trask, Wen Lin Kuo, Joanne Cochran, Teresa Costa, Mary Ella M. Pierpont, Elizabeth B. Rand, David A. Piccoli, Leroy Hood, Nancy B. Spinner

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960 Scopus citations

Abstract

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 20p 12, 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 20p 12. 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.

Original languageEnglish (US)
Pages (from-to)243-251
Number of pages9
JournalNature Genetics
Volume16
Issue number3
DOIs
StatePublished - 1997

Bibliographical note

Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.

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