title: Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome.
abstract: Alagille syndrome (AGS) is an autosomal dominant disorder characterized by five major symptoms: cholestasis, vertebral deformity, heart malformations, ocular defects and peculiar facial appearance. The previously described Jagged1 (JAG1) gene on chromosome 20p12 has been identified as being responsible for AGS. JAG1 encodes a transmembrane protein acting as ligand for the evolutionarily conserved Notch signaling pathway. Here we report 36 novel mutations in the JAG1 gene. We identified 12 novel deletions, 4 insertions, 8 missense, 7 nonsense and 5 splice site mutations. All mutations map to the sequence encoding the extracellular part of the Jagged1 protein. The mutations spread over the entire gene with slightly increased rates in exons 2 to 6 and exon 23 and 24. Eight novel missense mutations map to the Delta-Serrate-Lag2 (DSL) domain and adjacent sequences which are important for ligand-receptor interaction. Inheritance was determined in 27 families. Sixteen mutations (55%) were de novo and eleven mutations (45%) were transmitted. Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations. AGS variants are spread over the entire gene with only a few mutations in exon 26. A relatively high number of mutations are clustered in exons 2 to 6. This sequence region shows high interspecies conservation and encodes the Notch receptor-binding region (DSL domain).
authors.affiliation: Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany. albrecht.roepke@medizin.uni-magedburg.de
authors.forename: Albrecht
authors.initials: A
authors.lastname: Röpke
authors.forename: Annegret
authors.initials: A
authors.lastname: Kujat
authors.forename: Mechthild
authors.initials: M
authors.lastname: Gräber
authors.forename: Joannis
authors.initials: J
authors.lastname: Giannakudis
authors.forename: Ingo
authors.initials: I
authors.lastname: Hansmann
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics*; D002135:Calcium-Binding Proteins; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009154:Mutation; D011506:Proteins / 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; D000072099:Serrate-Jagged Proteins