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; Kym Boycott; Alex MacKenzie; Jacek Majewski; Michael Brudno; Dennis Bulman; David Dyment; Loydie A. Jerome-Majewska; Jillian S. Parboosingh; Francois P. Bernier

doi:10.1038/ncomms5483

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, Kym Boycott, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis BulmanDavid Dyment, Loydie A. Jerome-Majewska, Jillian S. Parboosingh, Francois P. Bernier

School of Medicine

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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.

Original language	English (US)
Article number	4483
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5483
State	Published - Jul 22 2014

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Lynch, D. C., Revil, T., Schwartzentruber, J., Bhoj, E. J., Innes, A. M., Lamont, R. E., Lemire, E. G., Chodirker, B. N., Taylor, J. P., Zackai, E. H., McLeod, D. R., Kirk, E. P., Hoover-Fong, J., Fleming, L., Savarirayan, R., Boycott, K., MacKenzie, A., Majewski, J., Brudno, M., ... Bernier, F. P. (2014). Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome. Nature communications, 5, Article 4483. https://doi.org/10.1038/ncomms5483

Lynch, DC, Revil, T, Schwartzentruber, J, Bhoj, EJ, Innes, AM, Lamont, RE, Lemire, EG, Chodirker, BN, Taylor, JP, Zackai, EH, McLeod, DR, Kirk, EP, Hoover-Fong, J, Fleming, L, Savarirayan, R, Boycott, K, MacKenzie, A, Majewski, J, Brudno, M, Bulman, D, Dyment, D, Jerome-Majewska, LA, Parboosingh, JS & Bernier, FP 2014, 'Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome', Nature communications, vol. 5, 4483. https://doi.org/10.1038/ncomms5483

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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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AU - Lynch, Danielle C.

AU - Revil, Timothée

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AU - Bhoj, Elizabeth J.

AU - Innes, A. Micheil

AU - Lamont, Ryan E.

AU - Lemire, Edmond G.

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AU - Taylor, Juliet P.

AU - Zackai, Elaine H.

AU - McLeod, D. Ross

AU - Kirk, Edwin P.

AU - Hoover-Fong, Julie

AU - Fleming, Leah

AU - Savarirayan, Ravi

AU - Boycott, Kym

AU - MacKenzie, Alex

AU - Majewski, Jacek

AU - Brudno, Michael

AU - Bulman, Dennis

AU - Dyment, David

AU - Jerome-Majewska, Loydie A.

AU - Parboosingh, Jillian S.

AU - Bernier, Francois P.

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

Abstract

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