FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 354:2677-2688 June 22, 2006 Number 25 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Saffitz, J. E. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

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.

Source Information

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 mgollob{at}ottawaheart.ca.

Full Text of this Article

This article has been cited by other articles:

• Tsai, C.-T., Lai, L.-P., Hwang, J.-J., Lin, J.-L., Chiang, F.-T. (2008). Molecular Genetics of Atrial Fibrillation. J Am Coll Cardiol 52: 241-250 [Abstract] [Full Text]  
• Hodgson-Zingman, D. M., Karst, M. L., Zingman, L. V., Heublein, D. M., Darbar, D., Herron, K. J., Ballew, J. D., de Andrade, M., Burnett, J. C. Jr., Olson, T. M. (2008). Atrial Natriuretic Peptide Frameshift Mutation in Familial Atrial Fibrillation. NEJM 359: 158-165 [Abstract] [Full Text]  
• Severs, N. J., Bruce, A. F., Dupont, E., Rothery, S. (2008). Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 0: cvn133v2-11 [Abstract] [Full Text]  
• Schoonderwoerd, B. A., Smit, M. D., Pen, L., Van Gelder, I. C. (2008). New risk factors for atrial fibrillation: causes of 'not-so-lone atrial fibrillation'. Europace 10: 668-673 [Abstract] [Full Text]  
• Nattel, S., Burstein, B., Dobrev, D. (2008). Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications. Circ Arrhythmia Electrophysiol 1: 62-73 [Full Text]  
• Sinner, M. F., Pfeufer, A., Akyol, M., Beckmann, B.-M., Hinterseer, M., Wacker, A., Perz, S., Sauter, W., Illig, T., Nabauer, M., Schmitt, C., Wichmann, H.-E., Schomig, A., Steinbeck, G., Meitinger, T., Kaab, S. (2008). The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG). Eur Heart J 29: 907-914 [Abstract] [Full Text]  
• Kanaporis, G., Mese, G., Valiuniene, L., White, T. W., Brink, P. R., Valiunas, V. (2008). Gap Junction Channels Exhibit Connexin-specific Permeability to Cyclic Nucleotides. J. Gen. Physiol. 131: 293-305 [Abstract] [Full Text]  
• Hatcher, C. J., Basson, C. T. (2008). Disrupted Intercalated Discs: Is Kindlin-2 Required?. Circ. Res. 102: 392-394 [Full Text]  
• Ehrlich, J. R., Biliczki, P., Hohnloser, S. H., Nattel, S. (2008). Atrial-Selective Approaches for the Treatment of Atrial Fibrillation. J Am Coll Cardiol 51: 787-792 [Abstract] [Full Text]  
• Laird, D. W. (2008). Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease. J. Biol. Chem. 283: 2997-3001 [Abstract] [Full Text]  
• Lehnart, S. E., Ackerman, M. J., Benson, D. W. Jr, Brugada, R., Clancy, C. E., Donahue, J. K., George, A. L. Jr, Grant, A. O., Groft, S. C., January, C. T., Lathrop, D. A., Lederer, W. J., Makielski, J. C., Mohler, P. J., Moss, A., Nerbonne, J. M., Olson, T. M., Przywara, D. A., Towbin, J. A., Wang, L.-H., Marks, A. R. (2007). Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function. Circulation 116: 2325-2345 [Abstract] [Full Text]  
• Fatkin, D., Otway, R., Vandenberg, J. I. (2007). Genes and Atrial Fibrillation: A New Look at an Old Problem. Circulation 116: 782-792 [Full Text]  
• Gong, X.-Q., Shao, Q., Langlois, S., Bai, D., Laird, D. W. (2007). Differential Potency of Dominant Negative Connexin43 Mutants in Oculodentodigital Dysplasia. J. Biol. Chem. 282: 19190-19202 [Abstract] [Full Text]  
• Scheinman, M. M., Keung, E. (2007). The Year in Clinical Cardiac Electrophysiology. J Am Coll Cardiol 49: 2061-2069 [Full Text]  
• Sawaya, S. E., Rajawat, Y. S., Rami, T. G., Szalai, G., Price, R. L., Sivasubramanian, N., Mann, D. L., Khoury, D. S. (2007). Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor. Am. J. Physiol. Heart Circ. Physiol. 292: H1561-H1567 [Abstract] [Full Text]  
• Peters, N. S. (2006). Gap Junctions: Clarifying the Complexities of Connexins and Conduction. Circ. Res. 99: 1156-1158 [Full Text]  
• Saffitz, J. E. (2006). Connexins, conduction, and atrial fibrillation.. NEJM 354: 2712-2714 [Full Text]