Evidence for a Single Nucleotide Polymorphism in the KCNQ1 Potassium Channel that Underlies Susceptibility to Life‐Threatening Arrhythmias

Ion Channel Polymorphism and Cardiac Arrhythmia.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 KCNQ1 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‐ 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 ˜ 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. Conclusion: 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.