title: Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias.
abstract: BACKGROUND
  Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers.
  
  
  RESULTS
  We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in approximately 11% of the Japanese population. This 1727G>A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in approximately 30% reduction in the slow delayed rectifier K+ current I(Ks) without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes.
  
  
  CONCLUSIONS
  We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I(Ks) dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kubota
authors.forename: M
authors.initials: M
authors.lastname: Horie
authors.forename: M
authors.initials: M
authors.lastname: Takano
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Takenaka
authors.forename: E
authors.initials: E
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: H
authors.initials: H
authors.lastname: Otani
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004562:Electrocardiography; D019317:Evidence-Based Medicine; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D016387:Women's Health
chemical_list: D018076:DNA, Complementary; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated