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 l ong QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disord er caused by mutations in at least five different genes encoding cardiac io n channels. It was suggested recently that common polymorphisms of LQTS-ass ociated genes might modify arrhythmia susceptibility in potential gene carr iers. Methods and Results: We examined the known LQTS genes in 95 patients with d efinitive or suspected LQTS. Exon-specific polymerase chain reaction single -strand conformation polymorphism and direct sequence analyses identified s ix patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in similar to 11% of the Japanese population. This 1727G>A substi tution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, oft en precipitated by hypokalemia and bradyarrhythmias. When heterologously ex amined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms func tional homomultimeric channels, producing a significantly smaller current t han that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S -KCNQ1 with KCNE1 resulted in similar to 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 ha d a weaker dominant-negative effect on the heteromultimeric channel complex es. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassiu m 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.