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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

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
Authors
Issue Date2003
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2003, v. 12 n. 16, p. 2031-2040 How to Cite?
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′ 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.
Persistent Identifierhttp://hdl.handle.net/10722/44385
ISSN
2013 Impact Factor: 6.677
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorAznarez, Ien_HK
dc.contributor.authorChan, EMen_HK
dc.contributor.authorZielenski, Jen_HK
dc.contributor.authorBlencowe, BJen_HK
dc.contributor.authorTsui, LCen_HK
dc.date.accessioned2007-09-12T03:52:31Z-
dc.date.available2007-09-12T03:52:31Z-
dc.date.issued2003en_HK
dc.identifier.citationHuman Molecular Genetics, 2003, v. 12 n. 16, p. 2031-2040en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/44385-
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.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.subject.meshCystic fibrosis transmembrane conductance regulator - geneticsen_HK
dc.subject.meshEnhancer elements (genetics) - physiologyen_HK
dc.subject.meshExonsen_HK
dc.subject.meshMutationen_HK
dc.subject.meshRna splicingen_HK
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 geneen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=12&issue=16&spage=2031&epage=2040&date=2003&atitle=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+geneen_HK
dc.identifier.emailTsui, LC: tsuilc@hkucc.hku.hken_HK
dc.identifier.authorityTsui, LC=rp00058en_HK
dc.description.naturelink_to_OA_fulltexten_HK
dc.identifier.doi10.1093/hmg/ddg215en_HK
dc.identifier.pmid12913074en_HK
dc.identifier.scopuseid_2-s2.0-0042420388en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0042420388&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume12en_HK
dc.identifier.issue16en_HK
dc.identifier.spage2031en_HK
dc.identifier.epage2040en_HK
dc.identifier.isiWOS:000185064000009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridAznarez, I=6506570199en_HK
dc.identifier.scopusauthoridChan, EM=7401993847en_HK
dc.identifier.scopusauthoridZielenski, J=7003732699en_HK
dc.identifier.scopusauthoridBlencowe, BJ=7003332002en_HK
dc.identifier.scopusauthoridTsui, LC=7102754167en_HK

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