Gollob Michael H, Jones Douglas L, Krahn Andrew D, Danis Lynne, Gong Xiang-Qun, Shao Qing, Liu Xiaoqin, Veinot John P, Tang Anthony S L, Stewart Alexandre F R, Tesson Frederique, Klein George J, Yee Raymond, Skanes Allan C, Guiraudon Gerard M, Ebihara Lisa, Bai Donglin
Arrhythmia Research Laboratory and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada.
N Engl J Med. 2006 Jun 22;354(25):2677-88. doi: 10.1056/NEJMoa052800.
Atrial fibrillation is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity, particularly stroke. The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. We hypothesized that idiopathic atrial fibrillation has a genetic basis and that tissue-specific mutations in GJA5, the gene encoding connexin 40, may predispose the atria to fibrillation.
We sequenced GJA5 from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation. Identified GJA5 mutations were transfected into a gap-junction-deficient cell line to assess their functional effects on protein transport and intercellular electrical coupling.
Four novel heterozygous missense mutations were identified in 4 of the 15 patients. In three patients, the mutations were found in the cardiac-tissue specimens but not in the lymphocytes, indicating a somatic source of the genetic defects. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germ-line origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling.
Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. Our data suggest that common diseases traditionally considered to be idiopathic may have a genetic basis, with mutations confined to the diseased tissue.
心房颤动是最常见的心律失常类型，也是心血管疾病发病，尤其是中风的主要原因。心脏缝隙连接蛋白连接蛋白40在心房肌细胞中选择性表达，并介导心房的协调电激活。我们推测特发性心房颤动有遗传基础，编码连接蛋白40的基因GJA5中的组织特异性突变可能使心房易发生颤动。
我们对从15例特发性心房颤动患者切除的心脏组织和外周淋巴细胞中分离的基因组DNA进行了GJA5测序。将鉴定出的GJA5突变转染到缺乏缝隙连接的细胞系中，以评估它们对蛋白质转运和细胞间电偶联的功能影响。
在15例患者中的4例中鉴定出4种新的杂合错义突变。在3例患者中，突变存在于心脏组织标本中，但不存在于淋巴细胞中，表明遗传缺陷的体细胞来源。在第4例患者中，在心脏组织和淋巴细胞中均检测到序列变异，提示种系起源。对突变蛋白表达的分析显示细胞内转运受损或细胞间电偶联减少。
GJA5突变可能通过损害缝隙连接组装或电偶联使患者易患特发性心房颤动。我们的数据表明，传统上被认为是特发性的常见疾病可能有遗传基础，突变局限于患病组织。
