2. Academic Validation
  3. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome

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

  • Nat Commun. 2014 Jul 22;5:4483. doi: 10.1038/ncomms5483.
Danielle C Lynch 1,  Timothée Revil 2,  Jeremy Schwartzentruber 3,  Elizabeth J Bhoj 4,  A Micheil Innes 5,  Ryan E Lamont 5,  Edmond G Lemire 6,  Bernard N Chodirker 7,  Juliet P Taylor 8,  Elaine H Zackai 4,  D Ross McLeod 5,  Edwin P Kirk 9,  Julie Hoover-Fong 10,  Leah Fleming 11,  Ravi Savarirayan 12,  Care4Rare Canada,  Jacek Majewski 13,  Loydie A Jerome-Majewska 14,  Jillian S Parboosingh 15,  Francois P Bernier 15
Affiliations

Affiliations

  • 1 Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
  • 2 Department of Human Genetics, McGill University, Montréal, Quebec, Canada H3A 1B1.
  • 3 McGill University and Génome Québec Innovation Centre, Montréal, Quebec, Canada H3A 0G1.
  • 4 Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
  • 5 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8.
  • 6 Division of Medical Genetics, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W8.
  • 7 1] Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1S1 [2] Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1S1.
  • 8 Genetic Health Service, Auckland 1142, New Zealand.
  • 9 1] Sydney Children's Hospital, Randwick, New South Wales 2031, Australia [2] School of Women's and Children's Health, University of New South Wales, Randwick, New South Wales 2031, Australia.
  • 10 Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.
  • 11 National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 12 Department of Pediatrics, McGill University Health Centre, Montreal, Quebec H3Z 2Z3, Canada.
  • 13 1] Department of Human Genetics, McGill University, Montréal, Quebec, Canada H3A 1B1 [2] McGill University and Génome Québec Innovation Centre, Montréal, Quebec, Canada H3A 0G1.
  • 14 1] Department of Human Genetics, McGill University, Montréal, Quebec, Canada H3A 1B1 [2] Department of Pediatrics, McGill University, Montreal Children's Hospital, Montreal, Quebec, Canada H3H 1P3.
  • 15 1] Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 [2] Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada T3B 6A8 [3] Department of Computer Science, University of Toronto, Ontario, Canada. [4].
PMID: 25047197 DOI: 10.1038/ncomms5483
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.

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