A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome

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 wa...

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Main Authors: Yun-Jiu Cheng, Hao Yao, Cheng-Cheng Ji, Xu-Miao Chen, Jun Fan, Li-Juan Liu, Su-Hua Wu
Format: Article
Language:English
Published: Cell Physiol Biochem Press GmbH & Co KG 2018-11-01
Series:Cellular Physiology and Biochemistry
Subjects:
Online Access:https://www.karger.com/Article/FullText/495549
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author Yun-Jiu Cheng
Hao Yao
Cheng-Cheng Ji
Xu-Miao Chen
Jun Fan
Li-Juan Liu
Su-Hua Wu
author_facet Yun-Jiu Cheng
Hao Yao
Cheng-Cheng Ji
Xu-Miao Chen
Jun Fan
Li-Juan Liu
Su-Hua Wu
author_sort Yun-Jiu Cheng
collection DOAJ
description 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.
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spelling doaj.art-298881f54dc1459a9fa2e91841ab756b2022-12-22T02:20:47ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782018-11-015131301131210.1159/000495549495549A Heterozygous Missense hERG Mutation Associated with Early Repolarization SyndromeYun-Jiu ChengHao YaoCheng-Cheng JiXu-Miao ChenJun FanLi-Juan LiuSu-Hua WuBackground/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.https://www.karger.com/Article/FullText/495549Early repolarization syndrome Early repolarization patternKCNH2Gene mutationSudden cardiac death
spellingShingle Yun-Jiu Cheng
Hao Yao
Cheng-Cheng Ji
Xu-Miao Chen
Jun Fan
Li-Juan Liu
Su-Hua Wu
A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
Cellular Physiology and Biochemistry
Early repolarization syndrome
Early repolarization pattern
KCNH2
Gene mutation
Sudden cardiac death
title A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
title_full A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
title_fullStr A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
title_full_unstemmed A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
title_short A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome
title_sort heterozygous missense herg mutation associated with early repolarization syndrome
topic Early repolarization syndrome
Early repolarization pattern
KCNH2
Gene mutation
Sudden cardiac death
url https://www.karger.com/Article/FullText/495549
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