孤立性心房颤动致病基因TBX20新突变的发现及功能研究  

Identification and functional investigation of a new TBX20 mutation contributing to lone atrial fibrillation

作　　者：张道良 李宁 姜伟峰[3] 吴绍辉[3] 仇兴标[3] 杨奕清 ZHANG Daoliang;LI Ning;JIANG Weifeng;WU Shaohui;QIU Xingbiao;YANG Yiqing(Cardiac Arrhythmia Center,Shenzhen Hospital of Fuwai Hospital,Chinese Academy of Medical Sciences,Shenzhen 518057;Department of Cardiology,Putuo Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200062;Department of Cardiology,Shanghai Chest Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200030;Department of Cardiology,Cardiovascular Research Laboratory,and Central Laboratory,Shanghai Fifth People′s Hospital,Fudan University,Shanghai 200240,China)

机构地区：[1]中国医学科学院阜外医院深圳医院心律失常中心,518057 [2]上海中医药大学附属普陀医院心内科,200062 [3]上海交通大学医学院附属胸科医院心内科,200030 [4]复旦大学附属上海市第五人民医院心内科、心血管研究室、中心实验室,200240

出　　处：《国际心血管病杂志》2024年第2期114-117,122,共5页International Journal of Cardiovascular Disease

基　　金：国家自然科学基金(82070331);广东省引进创新创业团队项目(2019ZT08Y481)。

摘　　要：目的:寻找孤立性心房颤动(房颤)致病基因TBX20新突变并研究其功能。方法:测序分析182例孤立性房颤患者和236名无房颤对照者的TBX20基因,以发现新的致房颤突变。克隆人TBX20基因,构建野生型TBX20表达质粒,通过定点诱变制备突变型TBX20表达质粒,借助脂质体将表达质粒转染HeLa细胞,应用双荧光素酶报告基因分析系统研究突变体的功能特性。结果:在1例散发性孤立性房颤患者中发现TBX20基因新突变,即NM_001077653.2:c.706A>T;p(.Lys236*)突变。该突变不存在于其他孤立性房颤患者和对照者。功能研究显示突变型TBX20对靶基因KCNH2的转录激活作用丧失。结论:TBX20基因功能障碍可能是部分房颤患者的分子病因,这对房颤的精准防治有潜在临床意义。Objective:To identify and functionally investigate a new TBX20 mutation underlying lone atrial fibrillation.Methods:Sequencing assay of TBX20 was performed in 182 patients with lone atrial fibrillation and 236 control individuals without atrial fibrillation to identify a new mutation accountable for atrial fibrillation.The human TBX20 gene was cloned with its wild-type expression plasmid constructed.The mutant-type TBX20 expression plasmid was produced through site-directed mutagenesis.Hela cells were transfected using multiple expression plasmids with the help of lipofectamine and the functional characteristics of the mutant-type TBX20 were explored by utilizing a dual-reporter assay system.Results:In one patient suffering from sporadic lone atrial fibrillation,a new TBX20 mutation,NM_001077653.2:c.706A>T;p.(Lys236*),was found,which was neither observed in the other patients with lone atrial fibrillation nor detected in the control subjects.Further functional investigation revealed that the mutant-type TBX20 lost the transactivation effect on its target gene KCNH2.Conclusion:Dysfunctional TBX20 is likely to be a molecular cause of atrial fibrillation in a minority of cases,implying its potential clinical significance for the precise prophylaxis and therapy of atrial fibrillation.

关 键 词：心房颤动 分子遗传学 转录因子 TBX20基因 报告基因分析 

分 类 号：R541.75[医药卫生—心血管疾病]