• Michael H Gollob, Douglas L Jones, Andrew D Krahn, Lynne Danis, Xiang-Qun Gong, Qing Shao, Xiaoqin Liu, John P Veinot, Anthony S L Tang, StewartAlexandre F RAF, Frederique Tesson, George J Klein, Raymond Yee, Allan C Skanes, Gerard M Guiraudon, Lisa Ebihara, and Donglin Bai.
• Arrhythmia Research Laboratory and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada. mgollob@ottawaheart.ca
• N. Engl. J. Med. 2006 Jun 22; 354 (25): 267726882677-88.

BackgroundAtrial 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.MethodsWe 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.ResultsFour 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.ConclusionsMutations 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.Copyright 2006 Massachusetts Medical Society.

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