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• W1550716623 abstract "HomeCirculationVol. 99, No. 18Splice Mutations in KVLQT1? Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBSplice Mutations in KVLQT1? Jessica Tyson, Sue Malcolm and Maria Bitner-Glindzicz Jessica TysonJessica Tyson Molecular Genetics Unit, Institute of Child Health, London, UK Search for more papers by this author , Sue MalcolmSue Malcolm Molecular Genetics Unit, Institute of Child Health, London, UK Search for more papers by this author and Maria Bitner-GlindziczMaria Bitner-Glindzicz Molecular Genetics Unit, Institute of Child Health, London, UK Search for more papers by this author Originally published11 May 1999https://doi.org/10.1161/circ.99.18.2476/aCirculation. 1999;99:2476a–2479To The Editor:Li et al1 propose that 2 new mutations in KVLQT1 in Romano-Ward syndrome (RWS) disrupt splicing, leading to frameshift and premature protein truncation, acting through a loss-of-function mechanism. This is surprising because missense mutations in KVLQT1, acting in a dominant-negative manner, predominate in RWS. In Table 2 of the article by Li et al, 24 of the 26 mutations are missense (the 2 remaining being discussed here). We suggest alternative interpretations.The SP/A249/g-a mutation is a substitution G to A at the third position of codon 249, in which GCG is altered to GCA, occurring at the donor splice junction of exon 6. Mutation of splice sites can cause skipping of the affected exon, activation of cryptic splice sites, or retention of the intron.2 Exon skipping is common. If this occurs in SP/A249/g-a, the predicted protein will lack part of the pore and S6 transmembrane domain but may still multimerise, because if exon 6 is skipped, the resulting mRNA would still read “in frame.” In-frame but deleted transcripts may be stable and translated into protein, as shown for the dystrophin gene.3 The effect of the mutation should be confirmed in RNA, because frameshift and premature truncation of the KVLQT1 protein, as suggested by Li et al, would be a truly novel type of KVLQT1 mutation in RWS.The second mutation is the 3-bp deletion across an exon/intron boundary (denoted SP/V212/ΔGGT), disrupting the 5′ donor site of exon 5. A donor consensus splice site consists of CAG.gtaagt.4 In the patient in the study by Li et al, the wild-type exonic sequence GGG.GTG.gtaagt is mutated to GGG.GTaagt by deletion of 3 nucleotides, Ggt. The authors propose that the mutation SP/V212/ΔGGT alters splicing, leading to a 1-bp deletion in the coding region, causing frameshift and premature truncation of the predicted protein (see Figure ).However, a potential splice sequence, GGG.gtaagt, remains.4 Splicing here would delete a single valine,5 causing a mutant protein capable of dominant-negative action.Missense mutations in KVLQT1 predominate in RWS, whereas nonsense and frameshift mutations predominate in Jervell and Lange-Nielsen syndrome (Tyson, 1998, unpublished data). Carriers of nonsense mutations rarely manifest RWS clinically. The gene product of the null allele should not interfere with the wild-type allele in a dominant-negative manner.Download figureDownload PowerPoint References 1 Li H, Chen Q, Moss AJ, Robinson J, Goytia V, Perry JC, Vincent GM, Priori SG, Lehmann MH, Denfield SW, Duff D, Kaine S, Shimizu W, Schwartz PJ, Wang Q, Towbin JA. New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation.1998; 97:1264–1269.CrossrefMedlineGoogle Scholar2 Maquat LE. Defects in RNA splicing and the consequence of shortened translational reading frames. Am J Hum Genet.1996; 59:279–286.MedlineGoogle Scholar3 Dunckley MG, Manoharan M, Villiet P, Eperon IC, Dickson G. Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Hum Mol Genet.1998; 7:1083–1090.CrossrefMedlineGoogle Scholar4 Shapiro M, Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res.1987; 15:7155–7174.CrossrefMedlineGoogle Scholar5 Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J.1997; 16:5472–5479.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 11, 1999Vol 99, Issue 18 Advertisement Article InformationMetrics Copyright © 1999 by American Heart Associationhttps://doi.org/10.1161/circ.99.18.2476/aPMID: 10318740 Originally publishedMay 11, 1999 PDF download Advertisement" @default.
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• W1550716623 title "Splice Mutations in KVLQT1 ?" @default.
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