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

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro–costo–mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development. Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPBdisrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.

• Publication year

  2014

• Venue

  Nature Communications

• Publication date

  2014-07-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms5483PMID 25047197PMCID 4109005
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Evolutionary growth process of highly conserved sequences in vertebrate genomes.

  2012cited by this paper
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  2012cited by this paper
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  2011cited by this paper
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  2011cited by this paper
• Regulation of alternative splicing by the core spliceosomal machinery.

  2011cited by this paper
• Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++

  2010cited by this paper
• Promiscuity of enhancer, coding and non-coding transcription functions in ultraconserved elements

  2010cited by this paper
• The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.

  2010cited by this paper
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  2010cited by this paper
• ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

  2010cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2008cited by this paper
• Alternative Isoform Regulation in Human Tissue Transcriptomes

  2008cited by this paper
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  2008cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2006cited by this paper
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  2005cited by this paper
• Use of minigene systems to dissect alternative splicing elements.

  2005cited by this paper
• Conserved non-genic sequences — an unexpected feature of mammalian genomes

  2005cited by this paper
• Identification of alternative splicing regulators by RNA interference in Drosophila.

  2004cited by this paper
• Ultraconserved Elements in the Human Genome

  2004cited by this paper
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  2004cited by this paper
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  2004cited by this paper
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  2002cited by this paper
• Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs.

  1999cited by this paper
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  1997cited by this paper
• Smith's Recognizable Patterns of Human Malformation

  1996cited by this paper
• RIB GAP DEFECTS WITH MICROGNATHIA

  1972cited by this paper
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  1972cited by this paper

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• Modeling craniofacial spliceosomopathies: a pathway toward deciphering disease mechanisms

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• PTBP3 Associated With 9q32 Locus Is a Candidate Gene for Nager Syndrome

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• [Clinical case analysis and literature review of mandibulofacial dysostosis with microcephaly syndrome].

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  2020cites this paper
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  2019cites this paper
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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
• Variant snRNPs: New players within the spliceosome system

  2017cites this paper
• Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

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• Cerebro–costo–mandibular syndrome: Clinical, radiological, and genetic findings

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  2015cites this paper
• A review of craniofacial disorders caused by spliceosomal defects

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• New insights into craniofacial malformations.

  2015cites this paper