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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Format: | Article |
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Cell Physiol Biochem Press GmbH & Co KG
2018-11-01
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Series: | Cellular Physiology and Biochemistry |
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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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language | English |
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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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