Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation

N Engl J Med. 2006 Jun 22;354(25):2677-88. doi: 10.1056/NEJMoa052800.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Amino Acid Sequence
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / pathology
  • Base Sequence
  • Cell Line, Tumor
  • Connexins / genetics*
  • Connexins / metabolism
  • DNA Mutational Analysis
  • Female
  • Gap Junctions / metabolism
  • Heart Atria / pathology
  • Humans
  • Lymphocytes
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation, Missense*
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Sequence Homology
  • Transfection


  • Connexins
  • connexin 40