title: Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population.
abstract: Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal development of the liver, heart, skeleton, eye, and face. Mutations in the Jagged1 gene (JAG1) have been found to result in the AGS phenotype and both protein truncating mutations and missense mutations have been identified. Using single stranded conformational polymorphism analysis we have screened 22 AGS affected individuals from 19 families for mutations within Jagged1. Twelve distinct Jagged1 mutations were identified in 15 (68.2%) of the 22 AGS cases, seven of which are novel. The mutations include three small deletions (25%), two small insertions (16.6%), three missense mutations (25%), two nonsense mutations (16.6%), and two splice-site mutations (16.6%). These mutations are spread across the entire coding sequence of the gene and most are localized to highly conserved motifs of the protein predicted to be important for Jagged1 function. One-half of the mutations found in this study are located between exons 9 and 12, a region constituting only 12% of the coding sequence. A splice-donor site mutation in intron 11 was shown to cause aberrant splicing of Jagged1 mRNA, consequently terminating translation prematurely in exon 12. The results of this study are consistent with the proposal that either haploinsufficiency for wild type Jagged1 and/or dominant negative effects produced by mutated Jagged1 are responsible for the AGS phenotype.
authors.affiliation: Joint Clinical Sciences Program, Queensland Institute of Medical Research and University of Queensland, Brisbane, Queensland, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Heritage
authors.forename: J C
authors.initials: JC
authors.lastname: MacMillan
authors.forename: R P
authors.initials: RP
authors.lastname: Colliton
authors.forename: A
authors.initials: A
authors.lastname: Genin
authors.forename: N B
authors.initials: NB
authors.lastname: Spinner
authors.forename: G J
authors.initials: GJ
authors.lastname: Anderson
mesh_terms: D016738:Alagille Syndrome / Q000453:epidemiology* / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D001315:Australia / Q000453:epidemiology; D002135:Calcium-Binding Proteins; D002461:Cell Line, Transformed; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011159:Population Surveillance; D011506:Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D022821:RNA Splice Sites; D000072099:Serrate-Jagged Proteins