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- Title
Evidence for a Single Nucleotide Polymorphism in the KCNQ1 Potassium Channel that Underlies Susceptibility to Life-Threatening Arrhythmias.
- Authors
Kubota, Tomoyuki; Horie, Minoru; Takano, Makoto; Yoshida, Hidetada; Takenaka, Kotoe; Watanabe, Eiichi; Tsuchiya, Takeshi; Otani, Hideo; Sasayama, Shigetake
- Abstract
Introduction: 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. Methods and 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 <em>KCNQ1</em> that is found in ∼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-<em>KCNQ1</em> forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-<em>KCNQ1</em> and G643S-<em>KCNQ1</em> with <em>KCNE1</em> resulted in ∼30% reduction in the slow delayed rectifier K+ current IKs 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. Conclusion: We demonstrate that a common polymorphism in the <em>KCNQ1</em> potassium channel could be a molecular basis for mild IKs dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.
- Subjects
ARRHYTHMIA; HEART disease susceptibility; CHROMOSOME polymorphism; NUCLEOTIDES; POTASSIUM channels; ETIOLOGY of diseases
- Publication
Journal of Cardiovascular Electrophysiology, 2001, Vol 12, Issue 11, p1223
- ISSN
1045-3873
- Publication type
Article
- DOI
10.1046/j.1540-8167.2001.01223.x