Somatic Mutations in the Connexin 40 Gene (GJA5) in Atrial Fibrillation

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.

From the Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.H.G., L.D., J.P.V., A.S.L.T., A.F.R.S., F.T.), and the Departments of Medicine (M.H.G., D.L.J., A.D.K., G.J.K., R.Y., A.C.S.), Physiology and Pharmacology (D.L.J., X.-Q.G., D.B.), Anatomy and Cell Biology (Q.S.), and Surgery (G.M.G.), University of Western Ontario, London, Ont. - both in Canada; and the Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Ill. (X.L., L.E.). Address reprint requests to Dr. Gollob at the Arrhythmia Research Laboratory and Division of Cardiology, University of Ottawa Heart Institute, Rm. H350, 40 Ruskin St., Ottawa, ON K1Y 4W7, Canada, or at [email protected].

New England Journal of Medicine 354(25):p 2677-2688, June 22, 2006.

Background

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.

Methods

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.

Results

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.

Conclusions

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.

N Engl J Med 2006;354

2677-88.