Functional effects of a KCNQ1 mutation associated with the long QT syndrome
Functional effects of a KCNQ1 mutation associated with the long QT syndrome
复制标题
DOI：
10.1016/j.cardiores.2006.02.006
复制
发表时间：
2006-06-01
影响因子：
10.8
通讯作者：
Snyders, Dirk J.
中科院分区：
文献类型：
--
作者：
Boulet, Inge R.;Raes, Adam L.;Snyders, Dirk J.
目的：长QT综合征（LQTS）是一种遗传性心室复极障碍，由心脏离子通道基因（包括KCNQ 1）突变引起。在这项研究中，KCNQ 1（Q357 R）的LQTS相关突变的电生理特性进行了表征。这种突变位于附近的C-末端的S6，一个区域，这是重要的门structure.Methods和结果：共组装KCNE 1与突变体Q357 R引起的电流显示较慢的激活相比，野生型KCNQ 1/KCNE 1通道。Q357 R的激活电压依赖性向更正的电位移动。此外，观察到电流密度的强烈降低，这部分归因于改变的电压依赖性和活化动力学。通过共聚焦显微镜观察发现，Q357 R/KCNE 1通道的胞内滞留也导致了电流幅度的降低。这表明Q357 R突变通过Q357 R/KCNE 1复合物的运输或组装问题干扰蛋白质表达。为了模拟病人的状态KCNQ 1，Q357 R和KCNE 1共表达，这揭示了一个显性的负效应电流密度和activationkinetic.Conclusion：的影响Q357 R突变的激活的通道连同减少在膜上的表达将导致减少在I-Ks，从而在“复极储备”在生理情况下。因此，它解释了在这些患者中观察到的长QT综合征。(c)2006年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Long QT syndrome (LQTS) is an inherited disorder of ventricular repolarization caused by mutations in cardiac ion channel genes, including KCNQ1. In this study the electrophysiological properties of a LQTS-associated mutation in KCNQ1 (Q357R) were characterized. This mutation is located near the C-terminus of S6, a region that is important for the gate structure.Methods and results: Co-assembly of KCNE1 with the mutant Q357R elicited a current displaying slower activation compared to the wildtype KCNQ1/KCNE1 channels. The voltage dependence of activation of Q357R was shifted to more positive potentials. Moreover, a strong reduction in current density was observed that was partially attributed to the altered voltage dependence and kinetics of activation. The reduced current amplitude was also caused by intracellular retention of Q357R/KCNE1 channels as was shown by confocal microscopy. It indicated that the Q357R mutation disturbed protein expression by a trafficking or assembly problem of the Q357R/KCNE1 complex. To mimic the patient status KCNQ1, Q357R and KCNE1 were co-expressed, which revealed a dominant negative effect on current density and activation kinetics.Conclusion: The effects of the Q357R mutation on the activation of the channel together with a reduced expression at the membrane would lead to a reduction in I-Ks and thus in "repolarization reserve" under physiological circumstances. As such it explains the long QT syndrome observed in these patients. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.