Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
J Am Coll Cardiol. 2012 Oct 16;60(16):1566-73. doi: 10.1016/j.jacc.2012.05.050. Epub 2012 Sep 19.
The goal of this study was to characterize a variant in the SCN5A gene that encodes the alpha-subunit of the cardiac sodium channel, Nav1.5, which was identified in 1 large kindred with dilated cardiomyopathy (DCM) and multiple arrhythmias, including premature ventricular complexes (PVCs).
Treatment guidelines for familial DCM are based on conventional heart failure therapies, and no gene-based interventions have been established.
Family members underwent clinical evaluation and screening of the SCN5A and LMNA genes. Cellular electrophysiology and computational modeling were used to determine the functional consequences of the mutant Nav1.5 protein.
An R222Q missense variant located in a Nav1.5 voltage-sensing domain was identified in affected family members. Patch-clamp studies showed that R222Q Nav1.5 did not alter sodium channel current density, but did left shift steady-state parameters of activation and inactivation. Using a voltage ramp protocol, normalized current responses of R222Q channels were of earlier onset and greater magnitude than wild-type channels. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant and a potential cause of DCM. In R222Q carriers, there were only modest responses to heart failure therapies, but PVCs and DCM were substantially reduced by amiodarone or flecainide, which are drugs that have sodium channel-blocking properties.
The R222Q SCN5A variant has an activating effect on sodium channel function and is associated with reversible ventricular ectopy and DCM. Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented.
本研究旨在对编码心脏钠离子通道α亚基（Nav1.5）的 SCN5A 基因突变进行特征描述，该突变是在一个患有扩张型心肌病（DCM）和多种心律失常（包括室性早搏[PVCs]）的大型家系中发现的。
家族性 DCM 的治疗指南基于常规心力衰竭治疗，尚未建立基于基因的干预措施。
对家系成员进行临床评估和 SCN5A 和 LMNA 基因筛查。采用细胞电生理学和计算模型来确定突变 Nav1.5 蛋白的功能后果。
在受影响的家系成员中发现了位于 Nav1.5 电压感应结构域的 R222Q 错义突变。膜片钳研究表明，R222Q Nav1.5 并未改变钠离子通道电流密度，但确实使激活和失活的稳态参数左移。使用电压斜坡方案，R222Q 通道的归一化电流响应比野生型通道更早出现且幅度更大。使用浦肯野纤维和心室细胞模型的动作电位建模表明，浦肯野纤维起源的速率依赖性异位是 R222Q 变体的主要心室效应，也是 DCM 的潜在原因。在 R222Q 携带者中，心力衰竭治疗的反应仅适度，但胺碘酮或氟卡尼可显著减少 PVCs 和 DCM，这些药物具有钠通道阻断特性。
R222Q SCN5A 变体对钠通道功能具有激活作用，与可逆性室性心律失常和 DCM 相关。阐明家族性 DCM 的遗传基础可以实现有效的基因靶向治疗。
