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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

SNRPB mutations in CCMS.(a) The transcript isoforms encoding SmB (NM_003091), SmB′ (NM_198216), and the alternative PTC-containing transcript. (b) One patient (D II-1) had a mutation in the 5′ UTR predicted to introduce an upstream out-of-frame TIS, leading to a PTC after 25 amino acids (SOM text). The green boxes represent translation initiation codons, and the red box and asterisk represents a translation termination codon. (c) Five mutations within the alternative PTC-containing exon were identified in CCMS patients. These cluster at four nucleotides at the 5′ and 3′ ends of the exon within blocks of high conservation. WT, wild type.
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f1: SNRPB mutations in CCMS.(a) The transcript isoforms encoding SmB (NM_003091), SmB′ (NM_198216), and the alternative PTC-containing transcript. (b) One patient (D II-1) had a mutation in the 5′ UTR predicted to introduce an upstream out-of-frame TIS, leading to a PTC after 25 amino acids (SOM text). The green boxes represent translation initiation codons, and the red box and asterisk represents a translation termination codon. (c) Five mutations within the alternative PTC-containing exon were identified in CCMS patients. These cluster at four nucleotides at the 5′ and 3′ ends of the exon within blocks of high conservation. WT, wild type.

Mentions: Here we present mutations in a highly conserved, alternative PTC-containing exon of the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene (Fig. 1) as the cause of cerebro–costo–mandibular syndrome (CCMS), a human multiple malformation disorder characterized by posterior rib gaps and Pierre Robin sequence (micrognathia, glossoptosis and cleft palate). This finding provides biological evidence of a direct link between conserved genomic elements, regulation of AS and human development, and therefore novel insight in the regulatory and developmental role of NCEs.


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)

SNRPB mutations in CCMS.(a) The transcript isoforms encoding SmB (NM_003091), SmB′ (NM_198216), and the alternative PTC-containing transcript. (b) One patient (D II-1) had a mutation in the 5′ UTR predicted to introduce an upstream out-of-frame TIS, leading to a PTC after 25 amino acids (SOM text). The green boxes represent translation initiation codons, and the red box and asterisk represents a translation termination codon. (c) Five mutations within the alternative PTC-containing exon were identified in CCMS patients. These cluster at four nucleotides at the 5′ and 3′ ends of the exon within blocks of high conservation. WT, wild type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: SNRPB mutations in CCMS.(a) The transcript isoforms encoding SmB (NM_003091), SmB′ (NM_198216), and the alternative PTC-containing transcript. (b) One patient (D II-1) had a mutation in the 5′ UTR predicted to introduce an upstream out-of-frame TIS, leading to a PTC after 25 amino acids (SOM text). The green boxes represent translation initiation codons, and the red box and asterisk represents a translation termination codon. (c) Five mutations within the alternative PTC-containing exon were identified in CCMS patients. These cluster at four nucleotides at the 5′ and 3′ ends of the exon within blocks of high conservation. WT, wild type.
Mentions: Here we present mutations in a highly conserved, alternative PTC-containing exon of the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene (Fig. 1) as the cause of cerebro–costo–mandibular syndrome (CCMS), a human multiple malformation disorder characterized by posterior rib gaps and Pierre Robin sequence (micrognathia, glossoptosis and cleft palate). This finding provides biological evidence of a direct link between conserved genomic elements, regulation of AS and human development, and therefore novel insight in the regulatory and developmental role of NCEs.

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