volume 16 number 3 page 243 


Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1

Linheng Li^1,6, Ian D. Krantz², Yu Deng^3,6, Anna Genin², Amy B. Banta^1,6 , Colin C. Collins⁴, Ming Qi⁵, Barbara J. Trask⁶, Wen Lin Kuo⁷, Joanne Cochran⁴, Teresa Costa⁸, Mary Ella M. Pierpont⁹, Elizabeth B. Rand¹⁰, David A. Piccoli¹⁰, Leroy Hood^1,6 & Nancy B. Spinner²

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.

¹Stowers Institute for Medical Research, ⁶Department of Molecular Biotechnology, University of Washington, Seattle, Washington 98195, USA. ²Division of Human Genetics, ¹⁰Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 324 S 34th Street, Philadelphia, Pennsylvania 19104, USA. ³Institute of Genetics, Fudan University, Shanghai, 200433, China. ⁴Resource for Molecular Cytogenetics, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ⁵Division of Medical Genetics, Departments of Medicine & Pathology, University of Washington, Seattle, WA 98195, USA. ⁷University of California San Francisco Cancer Center, Cancer Genetics Program, San Francisco California 941413, USA. ⁸The Hospital for Sick Children, Department of Genetics, 555 University Avenue Toronto, Ontario M5G 1X8, Canada. ⁹Department of Pediatrics and Institute of Human Genetics, University of Minnesota, Minneapolis MN, USA. Correspondence should be addressed to N.B.S. (spinner@mail.med.upenn.edu) or L.H. (lee@nirvana.MBT.Washington.edu)