Mutations in SCN5A encoding the principal Na+ channel alpha-subunit expressed in human heart (Na(V)1.5) have recently been linked to an inherited form of dilated cardiomyopathy with atrial and ventricular arrhythmia. We compared the biophysical properties of 2 novel Na(V)1.5 mutations associated with this syndrome (D2/S4--R814W; D4/S3--D1595H) with the wild-type (WT) channel using heterologous expression in cultured tsA201 cells and whole-cell patch-clamp recording. Expression levels were similar among WT and mutant channels, and neither mutation affected persistent sodium current. R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased "window current." This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies. By contrast, D1595H channels exhibited impaired fast inactivation characterized by slower entry into the inactivated state and a hyperpolarized steady-state inactivation curve. Our findings illustrate the divergent biophysical defects caused by 2 different SCN5A mutations associated with familial dilated cardiomyopathy. Retrospective review of the published clinical data suggested that cardiomyopathy was not common in the family with D1595H, but rather sinus bradycardia was the predominant clinical finding. However, for R814W, we speculate that an increased window current coupled with enhanced slow inactivation and rate-dependent loss of channel availability provided a unique substrate predisposing myocytes to disordered Na+ and Ca2+ homeostasis leading to myocardial dysfunction.

中文翻译：

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扩张型心肌病伴心律失常中由钠通道突变引起的不同生物物理缺陷。

SCN5A 中编码人类心脏中表达的主要 Na+ 通道 α 亚基 (Na(V)1.5) 的突变最近与一种遗传性扩张型心肌病伴房性和室性心律失常有关。我们使用在培养的 tsA201 细胞和全细胞膜片钳记录。WT 和突变通道之间的表达水平相似，并且两种突变都不影响持续的钠电流。R814W 通道在激活的动力学和电压依赖性方面表现出突出和新颖的缺陷，其特征是上升时间较慢和超极化电导-电压关系导致“窗口电流”增加。该突变体还显示出增强的缓慢失活和快速脉冲频率下峰值电流的更大使用依赖性降低。相比之下，D1595H 通道表现出受损的快速失活，其特征是进入失活状态的速度较慢和超极化的稳态失活曲线。我们的研究结果说明了由与家族性扩张型心肌病相关的 2 种不同 SCN5A 突变引起的不同生物物理缺陷。对已发表临床数据的回顾性审查表明，心肌病在 D1595H 家族中并不常见，但窦性心动过缓是主要的临床发现。但是，对于 R814W，