A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
复制标题
与早期复极综合征相关的杂合错义 hERG 突变。
DOI：
10.1159/000495549
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Wu, Su-Hua
中科院分区：
文献类型：
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作者：
Cheng, Yun-Jiu;Yao, Hao;Wu, Su-Hua
背景/目的：早期复极综合征(ERS)是近年来公认的伴有特发性室颤的早期复极模式。然而，ERS的遗传背景还没有完全被了解。方法：对一家系合并ERS的心脏性猝死患者进行调查。对先证者和家系成员进行ERS易感基因直接测序。采用全细胞膜片钳技术对HEK 293细胞表达的突变通道进行鉴定。结果：候选基因直接测序发现HERG(KCNH2基因)有1个错义突变(p.K801T)。对HEK 293细胞K801T突变的全细胞电压钳研究表明，与野生型通道相比，最大稳态电流(37.2+/-7.3vs20.3+/-4.4pA/pF)增加了1.5倍，该电流的正电位为20 mV。失活的电压依赖性向正电压方向移动(WT-59.5+/-1.4vsK801T-44.3+/-1.2 mV)。动力学分析表明，K801T的失活速度较慢，但激活和失活速度较快。受试的HERG通道阻滞剂在浓度反应中抑制K801T-HERG通道，这些药物的效力顺序如下：奎尼丁；异丙吡胺；索他洛尔；氟卡胺。结论：K801T突变导致HERG通道功能增强，可能与ERS的临床表型有关。奎尼丁和异丙吡胺可改善K801T HERG突变通道的功能，有可能成为K801T HERG突变患者的治疗选择。(C)2018年作者(S)由S.Karger AG，巴塞尔出版
Background/Aims: Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic background of ERS has not been fully understood. Methods: A Chinese family with sudden cardiac death associated with ERS was investigated. Direct sequencing of ERS susceptibility genes was performed on the proband and family members. Whole-cell patch-clamp methods were used to characterize the mutant channel expressed in HEK 293 cells. Results: One missense mutation (p. K801T) was found in the hERG (KCNH2 gene) by the direct sequencing of candidate genes. Whole cell voltage clamp studies of the K801T mutation in HEK 293 cells demonstrated a 1.5-fold increase in maximum steady state current (37.2 +/- 7.3 vs 20.3 +/- 4.4 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -59.5 +/- 1.4 vs K801T -44.3 +/- 1.2 mV). Kinetic analysis revealed slower inactivation rates of K801T, but faster rates of activation and deactivation. The hERG channel blockers tested inhibited K801T-hERG channel in concentration response, and the potencies of these drugs can be rank-ordered as follows: quinidine > disopyramide> sotalol> flecainide. Conclusion: Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation. (C) 2018 The Author(s) Published by S. Karger AG, Basel