心律失常中HCN4突变与功能改变和表型的相关研究  

Functional changes and phenotypes are associated with HCN4 mutations in patients with arrythmia

作　　者：王红蕊 崔冰[1] 周建业[1] 汪一波[1] WANG Hong-Rui;CUI Bing;ZHOUJian-Ye;WANG Yi-Bo(State Key Laboratory of Cardiovascular Diseases,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100037,China)

机构地区：[1]中国医学科学院北京协和医学院国家心血管病中心阜外医院心血管疾病国家重点实验室

出　　处：《中国分子心脏病学杂志》2019年第4期3015-3019,共5页Molecular Cardiology of China

基　　金：国家重点研发计划资助(2017YFC0909400);心血管疾病国家重点实验室自主研究课题(2019-10);西安交通大学第一附属医院陕西省分子心脏病重点实验室开放课题(KLMC-2018-01)

摘　　要：目的HCN通道(超极化激活的环核昔酸门控通道)激活起搏电流(If),促进并调节心脏节律。在人类窦房结中,HC7V4功能缺失与窦房结功能障碍相关。假设体外电生理功能参数及预测软件分值可以作为突变是否致病的参考项。方法根据检索的文献可知,对于心律失常家系的调查,确定多个特异性〃C7V4通道突变与窦性心动过缓、病态窦房结综合征、房室传导阻滞等相关。在COS-7、CHO和HEK-293细胞中,全细胞膜片钳实验表明,HCN4突变通道的表达和动力学发生变化。使用不同软件在线预测并整理突变的致病性,比较不同预测软件之间的准确率。结果通过比较电生理参数发现,半数激活电压数与电流密度可以作为HGV4突变通道功能缺失的电生理指标。对于截短突变适合使用PROVEAN进行预测,对于点突变需要结合多种预测软件的结果。结论HCN4突变与病态窦房结综合征、房室传导阻滞及房颤的发病风险密切相关。半数激活电压数与电流密度两个电生理参数与HCN4突变通道功能缺失密切相关。另外,比较不同预测软件之间的准确率,为预测HUV4突变的功能提供一定的参考。Objective Hyperpolarized activated cyclic nucleotide gated channel activates the pacemaker current (If), which promotes and regulates the heart rhythm. In human sinus node, loss of HCN4 function is associated with sinus node dysfunction. It is hypothesized that in vitro electrophysiological function parameters and predictive software scores can be used as reference for whether the mutation is pathogenic. Methods According to the searched literature, for the investigation of arrhythmia family, it is determined that HCN4 mutation is associated with sinus bradycardia, sick sinus syndrome, and atrioventricular block. In COS-7, CHO, and HEK-293 cells, whole-cell patch-clamp experiments showed changes in the expression and kinetics of HCN4 mutant channels. Different software was used to predict and organize the pathogenicity of mutations online, and to compare the accuracy between different prediction software. Results By comparing the electrophysiological parameters, it was found that half of the activation voltage and current density can be used as electrophysiological indicators for the loss of HCN4 mutation channel function. For truncation mutations, it is suitable to use PROVEAN for prediction, and point mutations need to combine the results of multiple prediction software. Conclusions HCN4 mutation is closely related to the risk of sick sinus syndrome, atrioventricular block and atrial fibrillation. The two electrophysiological parameters of hairactivation voltage and current density are closely related to the loss of HCN4 mutation channel function. In addition, comparing the accuracy between different prediction software provides a reference for predicting the function of HCN4 mutation.

关 键 词：HCN4 IF 心律失常 全细胞膜片钳 预测软件 

分 类 号：R541.7[医药卫生—心血管疾病]