Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias
Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias
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DOI：
10.1046/j.1540-8167.2001.01223.x
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发表时间：
2001-11-01
影响因子：
2.7
通讯作者：
Sasayama, S
中科院分区：
文献类型：
--
作者：
Kubota, T;Horie, M;Sasayama, S
离子通道多态性与心律失常。简介：先天性长QT综合征（LQTS）是一种遗传异质性的致心律失常疾病，由至少5种不同的心脏离子通道编码基因突变引起。最近有人提出，lqts相关基因的常见多态性可能会改变潜在基因携带者的心律失常易感性。方法和结果：我们检测了95例确诊或疑似LQTS患者的已知LQTS基因。外显子特异性聚合酶链反应单链构象多态性和直接序列分析确定了6例仅携带KCNQ1单核苷酸多态性的患者，这与11%的日本人口相似。这种1727G>A取代将其编码序列的意义从643位的甘氨酸变为丝氨酸（G643S），主要与较轻的表型相关，通常由低钾血症和慢性心律失常引起。通过电压钳实验进行异源检测，单核苷酸多态性引起的体外细胞表型显示G643S-KCNQ1形成功能性同源通道，产生的电流明显小于野生型（WT）通道。WT-KCNQ1和G643S- kcnq1与KCNE1共表达可使慢延迟整流器K+电流I-Ks降低30%，但除了失活过程外，动力学性质没有太大变化，表明G643S取代对异聚通道复合物具有较弱的显性-负性影响。结论：我们证明KCNQ1钾通道的常见多态性可能是轻度i - k功能障碍的分子基础，在适当的诱发因素存在下，可能使特定人群中潜在的基因携带者易患危及生命的心律失常。
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 similar to 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 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 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.