SCN5A基因突变致右束支传导阻滞并室性心律失常的分子机制研究

Currently, right bundle brunch block (RBBB) has been demonstrated to be associated with increased cardiovascular risk and all-cause mortality. RBBB in asymptomatic individuals should alert clinicians to cardiovascular risk. However, the underlying molecular mechanism of RBBB combined with malignant arrhythmia remains to be illustrated. In our early stage genetic study, a novel SCN5A gene mutation T285I has been identified in an individual presenting RBBB and ventricular arrhythmia without structural heart disease, we speculated that the pathogenesis of RBBB and malignant arrhythmia is related with ion channel gene SCN5A variation, which can lead to loss-of-function of cardiac sodium channel. Consequently, the molecular genetic basis will be illustrated in the present study by using the methods of site-directed mutagenesis, gene cloning, gene transfection, the whole cell patch technique, immunofluorescence, and cell protein fraction, etc. The electrophysiological characteristics and transferring function of mutated sodium channels, which will be further confirmed in vivo, can be demonstrated to disclosure the potential relationship between RBBB and sodium ion channel gene. Additionally, it will provide rationale and reasonable evidence to illustrate the relationship between RBBB and the development of malignant arrhythmia.

研究发现，右束支传导阻滞（RBBB）尤其是完全性RBBB与心血管疾病风险以及全因死亡率增加有着密切的联系，但其发生的分子机制尚不明确。本课题前期研究对无结构性心脏病但心电图显示完全性RBBB且合并室性心律失常患者的基因筛查发现SCN5A-p.T285I突变，我们推测其发病与SCN5A基因变异相关，机制可能为该突变影响钠通道蛋白表达和/或转运，进而引起钠通道功能异常。我们通过定点突变诱导、全细胞膜片钳技术、免疫荧光共聚焦检测等技术，分析其对钠离子通道的细胞电生理特性或通道蛋白表达及分布的影响，并利用在体动物实验进一步验证，阐明SCN5A基因突变通过影响钠通道功能引起RBBB并室性心律失常表型的作用机制，为揭示RBBB与室性心律失常发生的相关性提供理论基础和科学依据。

研究发现，右束支传导阻滞（RBBB）尤其是完全性RBBB与心血管疾病风险以及全因死亡率增加有着密切的联系，但其发生的分子机制尚不明确。本研究对无结构性心脏病但心电图显示完全性RBBB且合并室性心律失常患者的基因筛查发现SCN5A-p.T285I突变，推测其发病与SCN5A基因变异相关，机制可能为该突变影响钠通道蛋白表达和/或转运，进而引起钠通道功能异常。我们通过定点突变诱导、全细胞膜片钳技术、免疫荧光共聚焦检测等技术，分析其对钠离子通道的细胞电生理特性或通道蛋白表达及分布的影响，并利用在体动物实验进一步验证，结果提示SCN5A基因p.T285I 突变导致 Nav1.5 通道功能完全丧失，通过影响钠通道功能引起RBBB并室性心律失常表型，为揭示RBBB与室性心律失常发生的相关性提供理论基础和科学依据。为今后基因检测及个体化治疗提供理论基础。