Sequencing of atrial tissue and lymphocytes from 10 patients with lone atrial fibrillation identified a novel somatic frameshift mutation in the Cx43 gene in 1 patient, indicating genetic mosaicism.
Observational (n=10)
Are atrial tissue-specific genetic defects in Cx43 associated with sporadic cases of lone atrial fibrillation?
Somatic genetic defects in Cx43 (genetic mosaicism) may be a potential cause of sporadic, nonfamilial lone atrial fibrillation by creating heterogeneous coupling patterns.
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. METHODS AND 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.
Thibodeau et al. (Wed,) conducted a observational in Nonfamilial, lone atrial fibrillation (n=10). Atrial tissue-specific genetic defects (Cx43 mutation) was evaluated on Identification of genetic mutations in the Cx43 gene (GJA1) from atrial tissue vs lymphocytes. Sequencing of atrial tissue and lymphocytes from 10 patients with lone atrial fibrillation identified a novel somatic frameshift mutation in the Cx43 gene in 1 patient, indicating genetic mosaicism.