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Article: Characterization of disease-associated mutations affecting an exonic splicing enhancer and two cryptic splice sites in exon 13 of the cystic fibrosis transmembrane conductance regulator gene
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TitleCharacterization of disease-associated mutations affecting an exonic splicing enhancer and two cryptic splice sites in exon 13 of the cystic fibrosis transmembrane conductance regulator gene
 
AuthorsAznarez, I2 3
Chan, EM2 3
Zielenski, J3
Blencowe, BJ2
Tsui, LC3 2 1
 
Issue Date2003
 
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
CitationHuman Molecular Genetics, 2003, v. 12 n. 16, p. 2031-2040 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddg215
 
AbstractSequences in exons can play an important role in constitutive and regulated pre-mRNA splicing. Since exonic splicing regulatory sequences are generally poorly conserved and their mechanism of action is not well understood, the consequence of exonic mutations on splicing can only be determined empirically. In this study, we have investigated the consequence of two cystic fibrosis (CF) disease-causing mutations, E656X and 2108delA, on the function of a putative exonic splicing enhancer (ESE) in exon 13 of the CFTR gene. We have also determined whether five other CF mutations D648V, D651N, G654S, E664X and T665S located near this putative ESE could lead to aberrant splicing of exon 13. Using minigene constructs, we have demonstrated that the E656X and 2108delA mutations could indeed cause aberrant splicing in a predicted manner, supporting a role for the putative ESE sequence in pre-mRNA splicing. In addition, we have shown that D648V, E664X and T665S mutations could cause aberrant splicing of exon 13 by improving the polypyrimidine tracts of two cryptic 3′ splice sites. We also provide evidence that the relative levels of two splicing factors, hTra2α and SF2/ASF, could alter the effect on splicing of some of the exon 13 disease mutations. Taken together, our results suggest that the severity of CF disease could be modulated by changes in the fidelity of CFTR pre-mRNA splicing.
 
ISSN0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
DOIhttp://dx.doi.org/10.1093/hmg/ddg215
 
ISI Accession Number IDWOS:000185064000009
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorAznarez, I
 
dc.contributor.authorChan, EM
 
dc.contributor.authorZielenski, J
 
dc.contributor.authorBlencowe, BJ
 
dc.contributor.authorTsui, LC
 
dc.date.accessioned2007-09-12T03:52:31Z
 
dc.date.available2007-09-12T03:52:31Z
 
dc.date.issued2003
 
dc.description.abstractSequences in exons can play an important role in constitutive and regulated pre-mRNA splicing. Since exonic splicing regulatory sequences are generally poorly conserved and their mechanism of action is not well understood, the consequence of exonic mutations on splicing can only be determined empirically. In this study, we have investigated the consequence of two cystic fibrosis (CF) disease-causing mutations, E656X and 2108delA, on the function of a putative exonic splicing enhancer (ESE) in exon 13 of the CFTR gene. We have also determined whether five other CF mutations D648V, D651N, G654S, E664X and T665S located near this putative ESE could lead to aberrant splicing of exon 13. Using minigene constructs, we have demonstrated that the E656X and 2108delA mutations could indeed cause aberrant splicing in a predicted manner, supporting a role for the putative ESE sequence in pre-mRNA splicing. In addition, we have shown that D648V, E664X and T665S mutations could cause aberrant splicing of exon 13 by improving the polypyrimidine tracts of two cryptic 3′ splice sites. We also provide evidence that the relative levels of two splicing factors, hTra2α and SF2/ASF, could alter the effect on splicing of some of the exon 13 disease mutations. Taken together, our results suggest that the severity of CF disease could be modulated by changes in the fidelity of CFTR pre-mRNA splicing.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationHuman Molecular Genetics, 2003, v. 12 n. 16, p. 2031-2040 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddg215
 
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddg215
 
dc.identifier.epage2040
 
dc.identifier.isiWOS:000185064000009
 
dc.identifier.issn0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
dc.identifier.issue16
 
dc.identifier.openurl
 
dc.identifier.pmid12913074
 
dc.identifier.scopuseid_2-s2.0-0042420388
 
dc.identifier.spage2031
 
dc.identifier.urihttp://hdl.handle.net/10722/44385
 
dc.identifier.volume12
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofHuman Molecular Genetics
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshCystic fibrosis transmembrane conductance regulator - genetics
 
dc.subject.meshEnhancer elements (genetics) - physiology
 
dc.subject.meshExons
 
dc.subject.meshMutation
 
dc.subject.meshRna splicing
 
dc.titleCharacterization of disease-associated mutations affecting an exonic splicing enhancer and two cryptic splice sites in exon 13 of the cystic fibrosis transmembrane conductance regulator gene
 
dc.typeArticle
 
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<description.abstract>Sequences in exons can play an important role in constitutive and regulated pre-mRNA splicing. Since exonic splicing regulatory sequences are generally poorly conserved and their mechanism of action is not well understood, the consequence of exonic mutations on splicing can only be determined empirically. In this study, we have investigated the consequence of two cystic fibrosis (CF) disease-causing mutations, E656X and 2108delA, on the function of a putative exonic splicing enhancer (ESE) in exon 13 of the CFTR gene. We have also determined whether five other CF mutations D648V, D651N, G654S, E664X and T665S located near this putative ESE could lead to aberrant splicing of exon 13. Using minigene constructs, we have demonstrated that the E656X and 2108delA mutations could indeed cause aberrant splicing in a predicted manner, supporting a role for the putative ESE sequence in pre-mRNA splicing. In addition, we have shown that D648V, E664X and T665S mutations could cause aberrant splicing of exon 13 by improving the polypyrimidine tracts of two cryptic 3&#8242; splice sites. We also provide evidence that the relative levels of two splicing factors, hTra2&#945; and SF2/ASF, could alter the effect on splicing of some of the exon 13 disease mutations. Taken together, our results suggest that the severity of CF disease could be modulated by changes in the fidelity of CFTR pre-mRNA splicing.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong
  2. University of Toronto
  3. Hospital for Sick Children University of Toronto