Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome

Lynch, Danielle; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth; Innes, A. Micheil; Lamont, Ryan E.; Lemire, Edmond G.; Chodirker, Bernard N.; Taylor, Juliet; Zackai, Elaine H.; McLeod, David; Kirk, Edwin P.; Hoover‐Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Boycott, Kym M.; MacKenzie, Alex; Brudno, Michael; Bulman, Dennis E.; Dyment, David A.; Majewski, Jacek; Jerome-Majewska, Loydie A.; Bernier, François P.

doi:10.1038/ncomms5483

Cited by 64 publications

(86 citation statements)

References 36 publications

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“…Interestingly, five mutations in the same region have recently been identified in another series of CCMS patients [Lynch et al, 2014] and three of them are identical to our patients variants (P1, P2, P4).…”

supporting

confidence: 84%

“…Interestingly, Saltzman et al [] demonstrated that 12‐base segments deletion including these two regions leads to an increase in inclusion of the alternative exon. Moreover, Lynch et al [] reported increased expression of the PTC‐containing transcript associated with decreased overall expression of SNRPB in CCMS case fibroblasts. Transcript 3 is essential for SmB autoregulation.…”

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confidence: 99%

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Mutations inSNRPB, Encoding Components of the Core Splicing Machinery, Cause Cerebro-Costo-Mandibular Syndrome

et al. 2014

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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.

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confidence: 84%

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confidence: 99%

Mutations inSNRPB, Encoding Components of the Core Splicing Machinery, Cause Cerebro-Costo-Mandibular Syndrome

et al. 2014

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“…Interestingly, mutations in genes encoding other components of the spliceosome have been linked to craniofacial disorders. They include mutations in EFTUD2 (Lines et al, 2012), SNRPB (Lynch et al, 2014) and TXNL4A (Wieczorek et al, 2014), which cause related but distinct syndromes known as MFD with microcephaly (OMIM #610536), cerebro-costo-mandibular syndrome (OMIM #117650), and Burn-McKeown syndrome (OMIM #608572) respectively, suggesting that spliceosomopathies may underlie the etiology of some forms of MFD (Lehalle et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…During assembly of the U2 pre-spliceosomal complex, SAP49 binds to the pre-mRNA just upstream of the branch point sequence and plays a crucial role in tethering the U2 snRNP to the branch site during the splicing process (Champion-Arnaud and Reed, 1994). Mutations in genes encoding other components of the spliceosome, such as EFTUD2 (Lines et al, 2012), SNRPB (Lynch et al, 2014) and TXNL4A (Wieczorek et al, 2014) also cause craniofacial disorders, suggesting that defects in mRNA processing may underlie the etiology of some forms of MFD (Lehalle et al, 2015). …”

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confidence: 99%

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

Devotta

Juraver-Geslin

González

et al. 2016

Developmental Biology

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Mandibulofacial dysostosis (MFD) is a human developmental disorder characterized by defects of the facial bones. It is the second most frequent craniofacial malformation after cleft lip and palate. Nager syndrome combines many features of MFD with a variety of limb defects. Mutations in SF3B4 (splicing factor 3b, subunit 4) gene, which encodes a component of the pre-mRNA spliceosomal complex, were recently identified as a cause for Nager syndrome, accounting for 60% of affected individuals. Nothing is known about the cellular pathogenesis underlying Nager type MFD. Here we describe the first animal model for Nager syndrome, generated by knocking down Sf3b4 function in Xenopus laevis embryos, using morpholino antisense oligonucleotides. Our results indicate that Sf3b4-depleted embryos show reduced expression of the neural crest genes sox10, snail2 and twist at the neural plate border, associated with a broadening of the neural plate. This phenotype can be rescued by injection of wild-type human SF3B4 mRNA but not by mRNAs carrying mutations that cause Nager syndrome. At the tailbud stage, morphant embryos had decreased sox10 and tfap2a expression in the pharyngeal arches, indicative of a reduced number of neural crest cells. Later in development, Sf3b4-depleted tadpoles exhibited hypoplasia of neural crest-derived craniofacial cartilages, phenocopying aspects of the craniofacial skeletal defects seen in Nager syndrome patients. With this animal model we are now poised to gain important insights into the etiology and pathogenesis of Nager type MFD, and to identify the molecular targets of Sf3b4.

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“…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.…”

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confidence: 99%

A review of craniofacial disorders caused by spliceosomal defects

et al. 2015

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The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders.

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Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome

Cited by 64 publications

References 36 publications

Mutations inSNRPB, Encoding Components of the Core Splicing Machinery, Cause Cerebro-Costo-Mandibular Syndrome

Mutations inSNRPB, Encoding Components of the Core Splicing Machinery, Cause Cerebro-Costo-Mandibular Syndrome

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

A review of craniofacial disorders caused by spliceosomal defects

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