title: Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome.
abstract: Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations.
authors.affiliation: Department of Genetics, INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades (AP-HP), Paris, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Bacrot
authors.forename: Mathilde
authors.initials: M
authors.lastname: Doyard
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Olivier
authors.initials: O
authors.lastname: Alibeu
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Daphné
authors.initials: D
authors.lastname: Lehalle
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Vazquez
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008844:Micrognathism / Q000235:genetics*; D020125:Mutation, Missense; D012272:Ribs / Q000002:abnormalities*; D055815:Young Adult; D055517:snRNP Core Proteins / Q000235:genetics*
chemical_list: C526407:SNRPB protein, human; D055517:snRNP Core Proteins
keywords: NMD; SNRPB; alternative splicing; cerebro-costo-mandibular syndrome; spliceosome