L型钙离子通道α亚基R1950K突变致Brugada综合征心电图的电生理机制  

Electrophysiological mechanism of CACNAIC（R1950K）causing L type calcium channel dysfunction in Brugada syndrome

作　　者：冯莉[1] 马克娟[1] 李新[1] 刘彤[1] 董建增[1] 马长生[1] 

机构地区：[1]首都医科大学附属北京安贞医院心内科,100029

出　　处：《中华心律失常学杂志》2016年第1期64-68,共5页Chinese Journal of Cardiac Arrhythmias

摘　　要：目的通过对1例Brugada综合征患者疑似致病突变CACNAIC（R1950K）细胞电生理学研究，探究其细胞电生理学发病机制。方法采用目标区域捕获高深度测序技术进行候选基因突变筛查；以脂质体转染技术通过HEK293细胞表达可疑致病突变。应用全细胞膜片钳技术记录L型钙离子通道（LCa）电流。结果候选基因测序发现CACNAIC基因第5849核苷酸位点G〉A杂合子错义突变，导致第1950位密码子由精氨酸利用变为赖氨酸R1950K，进一步细胞膜片钳研究发现R1950K突变型LCa电流密度显著减小，峰值电流约为野生型的0．37。两者稳态激活曲线差异无统计学意[（V1/2：WT（-12．22±0．41）mV；R1950K（-12．23±0．28）mV；k：WT（6．11±0．38）；R1950K（6．82±0．26），P〉0．05）。结论本例国人CACNAlC突变致Brugada综合征，通过细胞电生理学研究证实其发生机制为CACNAIC（P1950K）导致LCa功能减弱。Objective The purpose of this study was to identify the electrophysiological mechanisms of a mutation fund in α subunit of L type calcium channel （ LTCC, Car 1.2） of a proband with Brugada syndrome. Methods Candidate genes were screened by direct sequencing. Whole cell patch clamp analysis of the HEK293 cell with express the mutant channel was used to investigate the molecular and electrophysiological mechanism.Results Sequence analysis of the coding region of the CACNA 1C gene,identified a G to A hetero- zygous missense mutation at nucleotide site 5 849 that resulted in an amino acid substitution of arginine to 1y- sine at amino acid site 1 950 （R1950K）.Patch clamp analysis showed that the R1950K significantly reduced the current of LTCC in transfected HEK293 cell, the reduction rate was almost 37%.The activation curve analy- sis between CACNA1C （R1950K）and wile type CACNA1C showed no difference in both the half-maximal acti- vation （ VI/2 ） and the slope value [ V1/2 ： WT ： （ - 12.22 ±0.41 ） mV ; R 1950K ： （ - 12.23 ± 0.28 ） mV ;k ： WT ： 6.11 ± 0.38;R1950K：6.82±0.26;P〉0.003.Conclusion We reported a case of CACNA1C mutation related to Bruga- da syndrome in Chinese population, and the electrophysiological mechanism was LTCC function reduced.

关 键 词：BRUGADA综合征 L型钙离子通道 CACNA1C基因 

分 类 号：R541.78[医药卫生—心血管疾病]