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

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, Care4Rare CanadaMajewski J, Jerome-Majewska LA, Parboosingh JS, Bernier FP - Nat Commun (2014)

Bottom Line: Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.

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.

No MeSH data available.


Related in: MedlinePlus

CCMS mutations overlap with highly conserved ESSs.The bar height shows mammalian PhyloP conservation scores within and flanking the alternative PTC-containing exon. The colours represent the strength of exonic splicing enhancers (ESEs) and silencers (ESSs) identified by deletion mutagenesis of miniSmB (17).
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f3: CCMS mutations overlap with highly conserved ESSs.The bar height shows mammalian PhyloP conservation scores within and flanking the alternative PTC-containing exon. The colours represent the strength of exonic splicing enhancers (ESEs) and silencers (ESSs) identified by deletion mutagenesis of miniSmB (17).

Mentions: Collectively, these results implicate the deregulation of SNRPB expression as the main disease mechanism for CCMS. Mutations in the alternative PTC-containing exon cluster at two sites, which overlap with known exonic splicing silencers (ESSs)22. In an experiment by Saltzman et al.18, deletion of both of these regions resulted in increased inclusion of the alternative exon in HeLa cells. Our results support the functional significance of these ESSs, which are perfectly conserved across placental mammals (Fig. 3 and Supplementary Fig. 3), and suggest that the identified mutations weaken their silencing function. This would lead to the observed increase in the inclusion of this exon in CCMS, which is presumably the cause of the decreased overall SNRPB expression seen in patient cells (Fig. 4).


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

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, Care4Rare CanadaMajewski J, Jerome-Majewska LA, Parboosingh JS, Bernier FP - Nat Commun (2014)

CCMS mutations overlap with highly conserved ESSs.The bar height shows mammalian PhyloP conservation scores within and flanking the alternative PTC-containing exon. The colours represent the strength of exonic splicing enhancers (ESEs) and silencers (ESSs) identified by deletion mutagenesis of miniSmB (17).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109005&req=5

f3: CCMS mutations overlap with highly conserved ESSs.The bar height shows mammalian PhyloP conservation scores within and flanking the alternative PTC-containing exon. The colours represent the strength of exonic splicing enhancers (ESEs) and silencers (ESSs) identified by deletion mutagenesis of miniSmB (17).
Mentions: Collectively, these results implicate the deregulation of SNRPB expression as the main disease mechanism for CCMS. Mutations in the alternative PTC-containing exon cluster at two sites, which overlap with known exonic splicing silencers (ESSs)22. In an experiment by Saltzman et al.18, deletion of both of these regions resulted in increased inclusion of the alternative exon in HeLa cells. Our results support the functional significance of these ESSs, which are perfectly conserved across placental mammals (Fig. 3 and Supplementary Fig. 3), and suggest that the identified mutations weaken their silencing function. This would lead to the observed increase in the inclusion of this exon in CCMS, which is presumably the cause of the decreased overall SNRPB expression seen in patient cells (Fig. 4).

Bottom Line: Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.

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.

No MeSH data available.


Related in: MedlinePlus