title: Expression of mutant JAGGED1 alleles in patients with Alagille syndrome.
abstract: Heterozygous mutations in JAGGED1 (JAG1), encoding a ligand for Notch receptors, have been identified in patients with Alagille syndrome (AGS). These mutations map to the extracellular and transmembrane domains of JAG1, giving rise in 70% cases to a premature termination codon (PTC). Although haploinsufficiency has been hypothesised as the main mechanism of AGS, a dominant negative effect of truncated forms of Serrate/Jagged has been suggested. Only few studies of the mutant mRNAs and proteins from AGS patients have been performed to elucidate the molecular mechanisms of the disease. To gain insight into the stability of mutant mRNAs, we studied transcripts from five livers and 24 lymphoblastoid cell lines (LCLs) of AGS patients. Mutant JAG1 transcripts were recovered (albeit in different relative amounts) from RNAs with missense mutations (five) or in-frame deletions (two), and from all but two of the 21 with PTCs. In addition, results from LCL RNAs correlated well with results from liver RNAs. Mutant transcripts were also recovered from tissues of a 23-week-old AGS foetus with a PTC mutation. This suggests that most mutant transcripts with PTCs escape nonsense-mediated mRNA decay (NMD) and could lead to the synthesis of soluble forms of JAG1. Production of a truncated protein was indeed observed after transfection of COS cells with a mutant JAG1 cDNA. In conclusion, mutant JAG1 transcripts are present in LCLs, livers and tissues of AGS patients, whatever the mutation type, and mutant proteins can be produced, suggesting a dominant negative effect of some mutant proteins as another molecular mechanism of AGS.
authors.affiliation: INSERM E00-20, Bâtiment Gregory Pincus, 80 rue du Général Leclerc, 94276, Le Kremlin-Bicêtre cedex, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Boyer
authors.forename: Cécile
authors.initials: C
authors.lastname: Crosnier
authors.forename: Catherine
authors.initials: C
authors.lastname: Driancourt
authors.forename: Nicole
authors.initials: N
authors.lastname: Raynaud
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Michelle
authors.initials: M
authors.lastname: Hadchouel
authors.forename: Michèle
authors.initials: M
authors.lastname: Meunier-Rotival
mesh_terms: D016738:Alagille Syndrome / Q000196:embryology / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002135:Calcium-Binding Proteins; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008214:Lymphocytes; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D000072099:Serrate-Jagged Proteins; D014162:Transfection
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins