July 3, 2006|
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
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.