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Mutations in the Connexin 40 Gene, GJA5, Predisposes Patients to Idiopathic Atrial Fibrillation

July 3, 2006

By Sahar Bedrood B.S. and Asher Kimchi M.D.

Ottawa, Canada- Atrial Fibrillation is the most common type of cardiac arrhythmia characterized by erratic electrical activation of the atrial myocardium, resulting in loss of effective contractility and an increase in clot formation. Michael H. Gollob et al from the University of Ottawa Heart Institute studied the genetic basis of atrial fibrillation as it relates to mutations in the connexin 40 gene, GJA5. Their results, published in the June 22, 2006 issue of The New England Journal of Medicine, found that mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling.

The study focused on the GJA5 gene, which encodes connexin 40, a gap-junction protein with gene _expression restricted principally to atrial tissue in humans. Connexin 40 is thought to play a role in mediating atrial conduction through electrical coupling between cells. The study obtained archival tissue specimens from 15 patients with idiopathic atrial fibrillation. The GJA5 gene from genomic DNA from these cardiac tissues was sequenced. Identified GJA5 mutations were transfected into a gap-junction-deficient cell line to assess their effects on protein transport and intercellular electrical coupling.

In 4 of 15 patients, four heterozygous missense mutations were identified. In three patients, the mutations were found in the cardiac-tissue specimens, but not in the lymphocytes, indicating a somatic mutation rather than a germ line mutation. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germ-line origin. The mutations were in the highly conserved regions of the transmembrane spanning domains of connexin 40 protein. Confocal microscopic analysis of cells expressing mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling.

It can be concluded from this study that mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling.

Co-authors: Michael H. Gollob, M.D., Douglas L. Jones, Ph.D., Andrew D. Krahn, M.D., Lynne Danis, M.L.T., Xiang-Qun Gong, Ph.D., Qing Shao, Ph.D., Xiaoqin Liu, M.D., John P. Veinot, M.D., Anthony S.L. Tang, M.D., Alexandre F.R. Stewart, Ph.D., Frederique Tesson, Ph.D., George J. Klein, M.D., Raymond Yee, M.D., Allan C. Skanes, M.D., Gerard M. Guiraudon, M.D., Lisa Ebihara, M.D., Ph.D., and Donglin Bai, Ph.D.

 


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