title: Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF.
  
  
  RESULTS
  We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins.
  
  
  CONCLUSIONS
  This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.
authors.affiliation: Department of Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Isabelle L
authors.initials: IL
authors.lastname: Thibodeau
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Li
authors.forename: Gele
authors.initials: G
authors.lastname: Liu
authors.forename: Khanh
authors.initials: K
authors.lastname: Lam
authors.forename: John P
authors.initials: JP
authors.lastname: Veinot
authors.forename: David H
authors.initials: DH
authors.lastname: Birnie
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Jones
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
authors.forename: Robert
authors.initials: R
authors.lastname: Lemery
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Nicholson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
mesh_terms: D000818:Animals; D020517:Atrial Appendage / Q000502:physiology; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D017629:Gap Junctions / Q000502:physiology*; D017353:Gene Deletion; D006325:Heart Atria; D006801:Humans; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000502:physiology; D009030:Mosaicism; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D021381:Protein Transport / Q000502:physiology; D014981:Xenopus
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human