title: Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.
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.
authors.affiliation: Arrhythmia Research Laboratory and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada. mgollob@ottawaheart.ca
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Jones
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
authors.forename: Lynne
authors.initials: L
authors.lastname: Danis
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Gong
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.forename: John P
authors.initials: JP
authors.lastname: Veinot
authors.forename: Anthony S L
authors.initials: AS
authors.lastname: Tang
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Frederique
authors.initials: F
authors.lastname: Tesson
authors.forename: George J
authors.initials: GJ
authors.lastname: Klein
authors.forename: Raymond
authors.initials: R
authors.lastname: Yee
authors.forename: Allan C
authors.initials: AC
authors.lastname: Skanes
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Guiraudon
authors.forename: Lisa
authors.initials: L
authors.lastname: Ebihara
authors.forename: Donglin
authors.initials: D
authors.lastname: Bai
mesh_terms: 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
chemical_list: D017630:Connexins; D000097003:Gap Junction alpha-5 Protein