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A novel mutation in the KCNH2 gene associated with short QT syndrome
Sun, Yaxun3,7; Quan, Xiao-Qing1,2,4; Fromme, Samantha1,2; Cox, Robert H.1,2; Zhang, Ping3,6; Zhang, Li1,2; Guo, Donglin1,2; Guo, Jihong3,6; Patel, Chinmay1,2; Kowey, Peter R.1,2,5; Yan, Gan-Xin1,2,4,5
关键词Short Qt Syndrome Sudden Death Qt Tp-e/qt Genetics Channelopathy Herg I-kr
刊名JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
2011-03-01
DOI10.1016/j.yjmcc.2010.11.017
50期:3页:433-441
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cardiac & Cardiovascular Systems ; Cell Biology
研究领域[WOS]Cardiovascular System & Cardiology ; Cell Biology
关键词[WOS]SUDDEN CARDIAC DEATH ; CELLULAR-BASIS ; TRANSMURAL DISPERSION ; XENOPUS-OOCYTES ; LONG-QT ; HERG ; ARRHYTHMOGENESIS ; REPOLARIZATION ; INACTIVATION ; CHANNEL
英文摘要

A gain of function mutation N588K in the KCNH2 gene that encodes HERG channels has been shown to underlie the SQT1 form of short QT syndrome (SQTS). We describe a different mutation in the KCNH2 gene in a Chinese family with clinical evidence of SQTS. A Chinese family with a markedly short QT interval (QTc = 316 +/- 9 ms, n = 4) and a strong family history of sudden death was investigated. Analysis of candidate genes contributing to ventricular repolarization identified a C1853T mutation in the KCNH2 gene coding for the HERG channel, resulting in an amino acid change (T6181) that was found to 100% co-segregate with the SQTS phenotype (n = 4). Whole cell voltage clamp studies of the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady state current (146.1 +/- 16.7 vs 23.8 +/- 5.5 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 -78.6 +/- 6.8 vs T618I -29.3 +/- 1.7 mV). Kinetic analysis revealed slower inactivation rates of T6181 but faster rates of recovery from inactivation. Quinidine (5 mu M) and sotalol (500 mu M) had similar inhibitory effects on steady currents measured at +20 mV in WT and T618I but were less effective in inhibiting tail currents of mutant channels. The altered function of T618I-HERG channels suggests that this mutation in the KCNH2 gene is responsible for the SQTS phenotype in this family. Both quinidine and sotalol may be therapeutic options for patients with the 16181 HERG mutation. (C) 2010 Elsevier Ltd. All rights reserved.

语种英语
WOS记录号WOS:000287469400008
项目编号81070162 ; 30700297 ; 30973601 ; 2007CB512008 ; R01 HL28476
资助机构National Natural Science Foundation of China ; Sharpe-Strumia Foundation ; China Scholarship Council ; National Key Basic Research Program (NKBRP) of China ; American Heart Association ; W. W. Smith Charitable Trust ; NIH
引用统计
被引频次:31[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/53113
专题北京大学第二临床医学院_心血管内科
作者单位1.Lankenau Inst Med Res, Wynnewood, PA USA
2.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
3.Main Line Hlth Heart Ctr, Wynnewood, PA 19096 USA
4.Peking Univ, Peoples Hosp, Div Cardiol, Beijing 100044, Peoples R China
5.Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Wuhan 430074, Peoples R China
6.Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA
7.Zhejiang Univ, Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China
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Sun, Yaxun,Quan, Xiao-Qing,Fromme, Samantha,et al. A novel mutation in the KCNH2 gene associated with short QT syndrome[J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY,2011,50(3):433-441.
APA Sun, Yaxun.,Quan, Xiao-Qing.,Fromme, Samantha.,Cox, Robert H..,Zhang, Ping.,...&Yan, Gan-Xin.(2011).A novel mutation in the KCNH2 gene associated with short QT syndrome.JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY,50(3),433-441.
MLA Sun, Yaxun,et al."A novel mutation in the KCNH2 gene associated with short QT syndrome".JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 50.3(2011):433-441.
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