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

Author

Listed:
  • Danielle C. Lynch

    (University of Calgary)

  • Timothée Revil

    (McGill University)

  • Jeremy Schwartzentruber

    (McGill University and Génome Québec Innovation Centre)

  • Elizabeth J. Bhoj

    (The Children’s Hospital of Philadelphia)

  • A. Micheil Innes

    (University of Calgary
    Alberta Children’s Hospital Research Institute for Child and Maternal Health)

  • Ryan E. Lamont

    (University of Calgary
    Alberta Children’s Hospital Research Institute for Child and Maternal Health)

  • Edmond G. Lemire

    (University of Saskatchewan)

  • Bernard N. Chodirker

    (University of Manitoba
    Faculty of Medicine, University of Manitoba)

  • Juliet P. Taylor

    (Genetic Health Service)

  • Elaine H. Zackai

    (The Children’s Hospital of Philadelphia)

  • D. Ross McLeod

    (University of Calgary
    Alberta Children’s Hospital Research Institute for Child and Maternal Health)

  • Edwin P. Kirk

    (Sydney Children’s Hospital
    School of Women’s and Children’s Health, University of New South Wales)

  • Julie Hoover-Fong

    (Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University)

  • Leah Fleming

    (National Human Genome Research Institute, National Institutes of Health)

  • Ravi Savarirayan

    (McGill University Health Centre)

  • Jacek Majewski

    (McGill University
    McGill University and Génome Québec Innovation Centre)

  • Loydie A. Jerome-Majewska

    (McGill University
    McGill University, Montreal Children’s Hospital)

  • Jillian S. Parboosingh

    (University of Calgary
    Alberta Children’s Hospital Research Institute for Child and Maternal Health
    University of Toronto)

  • Francois P. Bernier

    (University of Calgary
    Alberta Children’s Hospital Research Institute for Child and Maternal Health
    University of Toronto)

Abstract

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.

Suggested Citation

  • Danielle C. Lynch & Timothée Revil & Jeremy Schwartzentruber & Elizabeth J. Bhoj & A. Micheil Innes & Ryan E. Lamont & Edmond G. Lemire & Bernard N. Chodirker & Juliet P. Taylor & Elaine H. Zackai & D, 2014. "Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome," Nature Communications, Nature, vol. 5(1), pages 1-6, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5483
    DOI: 10.1038/ncomms5483
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