导致J波综合征的CACNA1C基因的热点突变  

Hot spot mutation of CACNA1C gene causing J-wave syndrome

作　　者：张想 黄燕[1] 曾彬[1] 胡丹[1] ZHANG Xiang;HUANG Yan;ZENG Bin;HU Dan(Dept.of Cardiology,Renmin Hospital of Wuhan University/Cardiovascular Research Institute of Wuhan University/&Hubei Key Laboratory of Cardiology,Wuhan 430060,Hubei,China)

机构地区：[1]武汉大学人民医院心血管内科/心血管病湖北省重点实验室/武汉大学心血管病研究所,湖北武汉430060

出　　处：《武汉大学学报（医学版）》2023年第4期387-392,共6页Medical Journal of Wuhan University

基　　金：国家自然科学基金资助项目(编号:82270332,81670304);中央高校基本科研业务费专项资金资助项目(编号:2042020kf1014)。

摘　　要：目的:探讨心脏钙通道α亚单位(CACNA1C)热点突变对J波综合征(JWS)的影响及其电生理机制。方法:对377例确诊为JWS患者的血液标本进行二代基因测序,评估该基因突变在人群中出现的频率及危险性。在野生型(WT)质粒的基础上,利用定点突变技术构建突变体(MUT)质粒,采用全细胞膜片钳技术在转染WT或MUT质粒的HEK293细胞上记录钙通道电流(ICa),研究相应通道的电生理功能。结果:基因测序发现5例携带CACNA1C-G37R突变(c.109 G>A;p.37 G>R),该突变位于第2个外显子上,而在420例正常对照者中均未出现。临床分析发现携带者均为男性,年龄为23.0~47.0(33.6±10.8)岁,主要临床表现为晕厥、室性期前收缩、心室颤动和心源性猝死。5例患者的心电图有3例为ERS,2例为BrS,其中3例家族史为阳性。与正常对照组相比,钙突变患者心率减慢[(72.7±8.9)次/min vs.(69.8±4.6)次/min],QTc间期缩短[(408.2±21.4)ms vs.(378.7±9.2)ms],Tp-e/QT延长[(0.22±0.05)ms vs.(0.26±0.01)ms]。全细胞膜片钳结果显示MUT组ICa密度较WT组降低了约90%[WT vs.G37R:(-25.4±4.4)pA/pF vs.(-2.5±1.7)pA/pF;n=12和n=13;P<0.001]。结论:CACNA1C-G37R是目前发现与J波综合征密切相关的钙通道中频率较高的罕见突变,其致病性主要源于钙通道功能的丧失。Objective:To explore the effects of hotspot mutations in theαsubunit of the cardiac calcium channel(CACNA1C)on J-wave syndrome(JWS)and its electrophysiological mechanisms.Methods:Second-generation sequencing were adopted on the blood specimens from 377 JWS cases to assess the frequency and risk of the mutation in the population.On the basis of wild-type(WT)plasmids,mutant(MUT)plasmids were constructed and transfected into HEK293 cells by site-directed mutagenesis.Calcium channel currents(I_(Ca))were recorded in HEK293 cells transfected with WT or MUT plasmids by whole-cell membrane clamp technique to study the electrophysiological functions of the calcium channels.Results:Gene sequencing identified 5 cases carrying the CACNA1C-G37R mutation(c.109 G>A;p.37 G>R),which was located in exon 2 and was absent in 420 reference control alleles.The clinical analysis revealed that all carriers were male,with a mean age of 23.0-47.0(33.6±10.8)years.The main signs were syncope,premature ventricular contraction,ventricular fibrillation,and sudden cardiac death.Three JWS cases had a positive family history.Among the 5 patients,3showed ERS and 2 showed BrS.Compared with normal controls,the patients with this calcium mutation had a slower heart rate,as(72.7±8.9)beats/min vs.(69.8±4.6)beats/min,shorter QTc interval,as(408.2±21.4)ms vs.(378.7±9.2)ms,and prolonged Tp-e/QT,as(0.22±0.05)vs.(0.26±0.01)ms.Whole-cell membrane clamp results showed that the I_(Ca)density was reduced by approximately 90%in the MUT group as compared with that in the WT group,as(-25.4±4.4 pA/pF)vs.(-2.5±1.7)pA/pF(n=12 and n=13,P<0.001).Conclusion:CACNA1C-G37R is a rare mutation with a high frequency in the calcium channel found to be closely associated with J-wave syndrome,and its pathogenicity stems mainly from the loss of calcium channel function.

关 键 词：J波综合征 CACNA1C L型钙通道 心源性猝死 离子通道病 

分 类 号：R541.7[医药卫生—心血管疾病]