title: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.
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 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.
authors.affiliation: Stowers Institute for Medical Research, Department of Molecular Biotechnology, University of Washington, Seattle 98195 USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: I D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Y
authors.initials: Y
authors.lastname: Deng
authors.forename: A
authors.initials: A
authors.lastname: Genin
authors.forename: A B
authors.initials: AB
authors.lastname: Banta
authors.forename: C C
authors.initials: CC
authors.lastname: Collins
authors.forename: M
authors.initials: M
authors.lastname: Qi
authors.forename: B J
authors.initials: BJ
authors.lastname: Trask
authors.forename: W L
authors.initials: WL
authors.lastname: Kuo
authors.forename: J
authors.initials: J
authors.lastname: Cochran
authors.forename: T
authors.initials: T
authors.lastname: Costa
authors.forename: M E
authors.initials: ME
authors.lastname: Pierpont
authors.forename: E B
authors.initials: EB
authors.lastname: Rand
authors.forename: D A
authors.initials: DA
authors.lastname: Piccoli
authors.forename: L
authors.initials: L
authors.lastname: Hood
authors.forename: N B
authors.initials: NB
authors.lastname: Spinner
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics*; D002135:Calcium-Binding Proteins; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003001:Cloning, Molecular; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007438:Introns / Q000235:genetics; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors