Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.
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.
Gollob
Michael H
MH
Arrhythmia Research Laboratory and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada. mgollob@ottawaheart.ca
Jones
Douglas L
DL
Krahn
Andrew D
AD
Danis
Lynne
L
Gong
Xiang-Qun
XQ
Shao
Qing
Q
Liu
Xiaoqin
X
Veinot
John P
JP
Tang
Anthony S L
AS
Stewart
Alexandre F R
AF
Tesson
Frederique
F
Klein
George J
GJ
Yee
Raymond
R
Skanes
Allan C
AC
Guiraudon
Gerard M
GM
Ebihara
Lisa
L
Bai
Donglin
D
D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D006325:Heart Atria / Q000473:pathology; D006801:Humans; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D017385:Sequence Homology; D014162:Transfection; D000097003:Gap Junction alpha-5 Protein
D017630:Connexins; D000097003:Gap Junction alpha-5 Protein