国人冠心病发生VT/VF的首个致病基因SCN5A的发现及突变功能分析

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目的心源性猝死(SCD)高危患者常见于两大类人群,一类为心脏结构正常的患者,另一类为心脏结构异常的患者。心脏结构异常患者发生SCD以冠心病患者多见,国际上曾报道SCN5A基因突变与心梗后电风暴有关。本研究将对国人冠心病并发恶性室性心律失常患者进行SCN5A基因筛查,以探索是否SCN5A与国人缺血性心律失常相关,并揭示其细胞电生理致病机制。方法临床收集冠心病发生恶性心律失常患DNA标本31份,使用DNA直接测序技术对选基因SCN5A进行筛查,寻找基因突变,使用细胞膜片钳技术进行突变通道功能分析。结果本研究对31例国人冠心病发生VT/VF患者进行已知致病基因SCN5A筛查,发现2个SCN5A基因新突变,即L1469S和R812C突变。通过细胞膜片钳技术,分别对转染R812C突变和L1469S突变的HEK293细胞进行功能分析,观察峰值电流,I-V曲线,电流密度,电流失活等特性。结果与正常对照组相比,发现突变通道明显增加SCN5A峰值电流密度,I-V曲线电流失活没有明显差异。结论首次揭示SCN5A基因是国人冠心病发生恶性心律失常的致病基因,其突变通道功能获得是发生冠心病发生恶性心律失常的细胞电生理机制。 Purpose High-risk patients with sudden cardiac death (SCD) are common in two broad categories of patients, one with normal cardiac structures and the other with abnormal cardiac structures. SCD in patients with abnormal cardiac structure in patients with coronary heart disease more common, SCN5A gene mutations have been reported in the world and myocardial infarction related to electrical storm. In this study, SCN5A gene screening will be performed in patients with coronary heart disease complicated with malignant ventricular arrhythmia to explore whether SCN5A is associated with ischemic arrhythmia in Chinese and to reveal its electrophysiological pathogenesis. Methods Thirty-one DNA samples were collected from patients with malignant arrhythmia in coronary heart disease. The SCN5A gene was screened by DNA direct sequencing to find the gene mutation. The functional analysis of the mutant channel was performed using the cell patch clamp technique. Results In this study, SCN5A, a known causative gene, was screened in 31 Chinese patients with coronary heart disease (VT / VF). Two new mutations in SCN5A gene were found, namely L1469S and R812C mutations. The cell patch clamp technique was used to analyze the function of HEK293 cells transfected with R812C mutation and L1469S mutation respectively. The peak current, I-V curve, current density and current inactivation were observed. Results Compared with the normal control group, it was found that the mutant channel significantly increased the peak current density of SCN5A, and there was no significant difference in the inactivation of I-V curve current. Conclusion It is the first time to reveal that SCN5A gene is the causative gene of malignant arrhythmia in coronary heart disease in China. The function of mutation channel is the cellular electrophysiological mechanism of malignant arrhythmia in coronary heart disease.
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