Brugada syndrome and fever:: Genetic and molecular characterization of patients carrying SCN5A mutations
Brugada syndrome and fever:: Genetic and molecular characterization of patients carrying SCN5A mutations
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DOI：
10.1016/j.cardiores.2005.03.024
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发表时间：
2005-08-15
影响因子：
10.8
通讯作者：
Abriel, H
中科院分区：
文献类型：
--
作者：
Keller, DI;Rougier, JS;Abriel, H
目的：Brugada综合征（BrS）以室性心动过速导致心源性猝死为特征，部分由编码钠通道Na(v)1.5的SCN5A基因突变引起。发烧可引发或加重BrS的临床表现。这项工作的目的是表征发烧依赖性BrS的遗传和分子决定因素。方法：筛选4例具有典型BrS st段V1-V3抬高或发热时室性心律失常的男性患者，检测SCN5A基因突变。野生型（WT）和突变型Na(v)1.5通道在HEK293细胞中表达。利用全细胞膜片钳技术分析了不同温度下的钠电流（I-Na）。Western blot实验研究WT和突变体通道的蛋白表达。结果：在SCN5A中发现了两个突变，L325R和R535X。HEK293细胞中两个突变Na(v)1.5通道的表达在每种情况下都显示出严重的功能丧失。当温度升高到42℃时，我们观察到Na(v)1.5活化的明显加速和快速失活动力学。心脏动作电位模拟实验表明，在I-Na降低的患者中，发热可通过其对WT通道的影响过早缩短动作电位。进一步的实验表明L325R通道可能是错误折叠的，因为它们的功能可以被美西汀或姜黄素部分恢复。在共表达实验中，L325R通道干扰了WT通道的正常功能，表明发烧引发的BrS可能存在显性负性现象。结论：BrS发热敏感患者的遗传背景具有异质性。我们的实验数据表明，发热加重的BrS的临床表现可能不是突变特异性的。(C) 2005年欧洲心脏病学会。Elsevier B.V.版权所有。
Objective: Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and is caused, in part, by mutations in the SCN5A gene encoding the sodium channel Na(v)1.5. Fever can trigger or exacerbate the clinical manifestations of BrS. The aim of this work was to characterize the genetic and molecular determinants of fever-dependent BrS.Methods: Four male patients with typical BrS ST-segment elevation in V1-V3 or ventricular arrhythmias during fever were screened for mutations in the SCN5A gene. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. The sodium currents (I-Na) were analysed using the whole-cell patch clamp technique at various temperatures. Protein expression of WT and mutant channels was studied by Western blot experiments.Results: Two mutations in SCN5A, L325R and R535X, were identified. Expression of the two mutant Na(v)1.5 channels in HEK293 cells revealed in each case a severe loss-of-function. Upon the increase of temperature up to 42 degrees C, we observed a pronounced acceleration of Na(v)1.5 activation and fast inactivation kinetics. Cardiac action potential modelling experiments suggest that in patients with reduced I-Na, fever could prematurely shorten the action potential by virtue of its effect on WT channels. Further experiments revealed that L325R channels are likely misfolded, since their function could be partially rescued by mexiletine or curcumin. In co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever.Conclusions: The genetic background of BrS patients sensitive to fever is heterogeneous. Our experimental data suggest that the clinical manifestations of fever-exacerbated BrS may not be mutation specific. (C) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.