Mutations inSNRPB, 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.

A review of craniofacial disorders caused by spliceosomal defects

“…In 2014, Lynch et al employed exome sequencing to identify dominant, heterozygous mutations in SNRPB, encoding small nuclear ribonucleoprotein polypeptides B and B1, as a cause of CCMS (9). In an independent exome sequencing study, Bacrot et al recently identified de novo mutations in the same alternative exon of SNRPB as Lynch et al, in five CCMS patients (10). Each snRNP contains specific protein and RNA components plus a core of seven proteins, known as the Sm proteins, common to all snRNPs.…”

“…Besides the classic features of CCMS, scoliosis, decreased height, conductive hearing loss and down-slanting palpebral fissures were occasionally present in the SNRPB mutation-positive patients (9,10), and neurological and cognitive defects were reported in a small proportion of the cohort reported by Lynch et al Although it had previously been suggested that psychomotor retardation in CCMS may be a secondary effect linked to hypoxia due to respiratory distress at birth, it is also plausible that when present, this phenotype is due to a primary defect in splicing of neurodevelopmental genes.…”

“…Cerebrocostomandibular syndrome (CCMS; MIM 117650)-affected individuals exhibit Robin sequence and characteristic rib defects and harbor mutations in SNRPB (9,10), while Richieri-Costa-Pereira syndrome (RCPS; MIM 268305) is characterized by midline mandibular cleft, Robin sequence, radial and tibial abnormalities, and often intellectual disability, and is associated with mutations in EIF4A3 (11) (Fig. Along the same lines, defects in mRNA processing have recently been established as the basis of two syndromes in which the mandible is severely affected.…”

Structural basis for the recognition of spliceosomal SmN/B/B’ proteins by the RBM5 OCRE domain in splicing regulation

“…Recently, mutations in SmB were linked to cerebro-costo-mandibular syndrome (Bacrot et al, 2015). The multi-domain protein RBM5 promotes FAS exon 6 skipping and it has been proposed that for this activity the protein modulates splice site pairing after the competing 5’ and 3’ splice sites have been recognized by U1 and U2 snRNPs, respectively (Bonnal et al, 2008).…”

The ontogeny of Robin sequence

“…The identification of CDG type II with a mutation in COG1 (component of oligomeric golgi complex 1, involved in glycosylation) in patients with RS and features resembling CCMS revealed that a metabolic disorder might also be the underlying cause of RS (Zeevaert et al, ). Curiously, CCMS is also caused by mutation in SNRPB , encoding the small nuclear ribonucleoprotein polypeptides B and B1 and a core component of the spliceosome required for processing of pre‐mRNA into the mature mRNA form in all cells (Bacrot et al, ).…”