A trafficking defective, Brugada syndrome-causing SCN5A in mutation rescued by drugs
A trafficking defective, Brugada syndrome-causing SCN5A in mutation rescued by drugs
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DOI：
10.1016/j.cardiores.2004.01.022
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发表时间：
2004-04-01
影响因子：
10.8
通讯作者：
Ackerman, MJ
中科院分区：
文献类型：
--
作者：
Valdivia, CR;Tester, DJ;Ackerman, MJ
背景：人类心脏SCN5A基因编码人类心脏电压依赖性钠通道hNav1.5的α亚基[Neuron 28(2)(2000) 365]，并向内携带钠电流（I-Na）。SCN5A突变可引起心律失常综合征，包括Brugada综合征（BrS）和先天性长QT综合征亚型3 （LQT3）。在这里，我们报告了一种药物拯救的贩运缺陷brs引起的SCN5A突变。方法与结果：1例14岁白人男性被诊断为BrS，具有典型的BrS心电图型，易诱发心室颤动。他也有明显的HV间期延迟（类似于65 ms）和高（31 J）除颤阈值（DFTs）。基因组分析显示SCN5A突变（G1743R）。我们将G1743R植入心脏Na通道，并转染HEK-293细胞进行功能研究。突变通道产生了几乎无法检测到的钠通道电流。与β(1)亚基共表达或低温孵育均未增加电流密度。然而，钠通道阻滞剂美西汀在G1743R中使电流密度增加93倍，而在WT中仅增加2倍。结论：本研究确定了SCN5A中表达缺陷的BrS突变，具有药理拯救作用。与G1743R相关的钠电流的显著降低提示先证者His-Purkinje传导延迟和dft升高的分子基础。美西汀是否可以在体内挽救突变通道，并使患者的电生理参数正常化，仍有待检验。(C) 2004欧洲心脏病学会。Elsevier B.V.版权所有。
Background: The human cardiac SCN5A gene encodes for the alpha subunit of the human cardiac voltage-dependent sodium channel hNav1.5 [Neuron 28 (2) (2000) 365] and carries inward Na current (I-Na). Mutations in SCN5A cause arrhythmia syndromes including Brugada syndrome (BrS) and congenital long QT syndrome subtype 3 (LQT3). Here, we report a trafficking defective BrS-causing SCN5A mutation that was drug-rescued. Methods and Results: A 14-year-old Caucasian male was diagnosed with BrS with typical ECG pattern for BrS and ventricular fibrillation was easily induced. He also had significant HV interval delay ( similar to 65 ms) and high (31 J) defibrillation thresholds (DFTs). Genomic analysis revealed the SCN5A mutation (G1743R). We engineered G1743R into the cardiac Na channel and transfected HEK-293 cells for functional studies. The mutant channel yielded nearly undetectable sodium channel currents. Coexpression with the beta(1) subunit, or incubation at low temperature did not increase current density. However, mexiletine, a sodium channel blocker, increased current density 93-fold in G1743R, but only twofold in WT. Conclusions: This study identifies an expression-defective BrS mutation in SCN5A with pharmacological rescue. The profoundly decreased sodium current associated with the G1743R suggests a molecular basis for the delayed His-Purkinje conduction and elevated DFTs observed in the proband. Whether the mutant channel may be rescued in vivo by mexiletine and normalize the patient's electrophysiologic parameters remains to be tested. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.