心房颤动(AF)是最常见的临床心律失常,并大大增加了脑卒中的风险。心力衰竭,和死亡。尽管已经确定了房颤的致病基因,房颤的遗传决定因素仍不清楚.
本研究旨在探讨中国家族房颤的分子基础。
患有常染色体显性房颤和其他心律失常(房室传导阻滞,窦性心动过缓,和室性早搏)被招募。使用微卫星标记进行全基因组扫描和连锁分析以及全外显子组测序分析。使用双全细胞膜片钳和共聚焦显微镜分析了AF连锁突变体的电生理特性和亚细胞定位,分别。
将AF的新遗传基因座定位于染色体17q21.3,标记D17S951和D17S931之间的间隔为3.23cM,标记D17S1868的最大2点对数赔率评分为4.2144。测序分析显示作图区域有杂合突变,NM_005497.4:c.703A>T;p。(M235L),在GJC1基因中编码连接蛋白45(Cx45)。该突变在家族中与AF共分离,在632个对照个体中不存在。该突变降低了细胞对中的耦合电导(M235L/M235L,M235L/Cx45、M235L/Cx43和M235L/Cx40),可能是因为亚细胞定位受损。
本研究在染色体17q21.3上定义了AF的新基因位点,并揭示了GJC1(Cx45)功能缺失突变导致AF和其他心律失常。
Atrial fibrillation (AF) represents the most common clinical cardiac arrhythmia and substantially increases the risk of cerebral stroke, heart failure, and death. Although causative genes for AF have been identified, the genetic determinants for AF remain largely unclear.
This study aimed to investigate the molecular basis of AF in a Chinese kindred.
A 4-generation family with autosomal-dominant AF and other arrhythmias (atrioventricular block, sinus bradycardia, and premature ventricular contractions) was recruited. Genome-wide scan with microsatellite markers and linkage analysis as well as whole-exome sequencing analysis were performed. Electrophysiological characteristics and subcellular localization of the AF-linked mutant were analyzed using dual whole-cell patch clamps and confocal microscopy, respectively.
A novel genetic locus for AF was mapped to chromosome 17q21.3, a 3.23-cM interval between markers D17S951 and D17S931, with a maximum 2-point logarithm of odds score of 4.2144 at marker D17S1868. Sequencing analysis revealed a heterozygous mutation in the mapping region, NM_005497.4:c.703A>T;p.(M235L), in the GJC1 gene encoding connexin45 (Cx45). The mutation cosegregated with AF in the family and was absent in 632 control individuals. The mutation decreased the coupling conductance in cell pairs (M235L/M235L, M235L/Cx45, M235L/Cx43, and M235L/Cx40), likely because of impaired subcellular localization.
This study defines a novel genetic locus for AF on chromosome 17q21.3 and reveals a loss-of-function mutation in GJC1 (Cx45) contributing to AF and other cardiac arrhythmias.