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

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. Ross McLeod, Edwin P. Kirk, Julie Hoover-Fong, Leah Fleming, Ravi Savarirayan, Jacek Majewski, Loydie A. Jerome-Majewska, Jillian S. Parboosingh and Francois P. Bernier ()
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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
Ryan E. Lamont: University of Calgary
Edmond G. Lemire: University of Saskatchewan
Bernard N. Chodirker: University of Manitoba
Juliet P. Taylor: Genetic Health Service
Elaine H. Zackai: The Children’s Hospital of Philadelphia
D. Ross McLeod: University of Calgary
Edwin P. Kirk: Sydney Children’s Hospital
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
Loydie A. Jerome-Majewska: McGill University
Jillian S. Parboosingh: University of Calgary
Francois P. Bernier: University of Calgary

Nature Communications, 2014, vol. 5, issue 1, 1-6

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5483

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