Journal article
Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome
DC Lynch, T Revil, J Schwartzentruber, EJ Bhoj, AM Innes, RE Lamont, EG Lemire, BN Chodirker, JP Taylor, EH Zackai, DR McLeod, EP Kirk, J Hoover-Fong, L Fleming, R Savarirayan, K Boycott, A MacKenzie, J Majewski, M Brudno, D Bulman Show all
Nature Communications | NATURE PUBLISHING GROUP | Published : 2014
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 impo..
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Funding Acknowledgements
Supporting information can be found in the online Supplementary Material. We thank the patients and their families who participated in this study. Cell culture for the qRT-PCR experiments was performed by Nadine Gamache. The miniSmB construct was a gift from Dr Benjamin Blencowe. Drs Roy Gravel, Kym Boycott and Benedikt Hallgrimsson provided critical review of the manuscript. This work was performed under the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec and Children's Hospital of Eastern Ontario Research Foundation. We acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada. We would like to thank Taila Hartley (Clinical Coordinator) and Chandree Beaulieu (Project Manager) at the Children's Hospital of Eastern Ontario Research Institute for their contribution to the infrastructure of Care4Rare. D.C.L. is supported by a graduate studentship from Alberta Innovates-Health Solutions. T.R. is supported in part by a fellowship from the RI MUHC-Foundation of Stars at the Montreal Children's Hospital. L.A.J.-M. is a member of the Research Institute of the McGill University Health Centre, which is supported in part by the Fonds de recherche du Quebec-Sante.