Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia observed in clinical practice and a major contributor to cardiovascular morbidity and mortality. Accumulating evidence indicates a substantial genetic basis for AF. However, AF is genetically heterogeneous and the hereditary components responsible for AF remain to be identified in the majority of patients. The cardiac gap junction proteinα5(GJA5) is specifically expressed in atrial myocytes and is associated with the coordinated electrical activation of the atria, providing a rationale to screen GJA5 as a logical candidate gene for AF. A cohort of 310unrelated patients with lone AF and their available relatives were included in this study. A group of 200unrelated healthy individuals matched for age, gender and race were also included as controls. The entire coding region and splice sites of the GJA5 gene were initially sequenced in 310unrelated AF patients. The relatives of mutation carriers and 200controls were subsequently genotyped for the presence of identified mutations. As a result, 4novel heterozygous GJA5 mutations, p.K107R, p.L223M, p.Q236H and p.I257L, were identified in 4 of 310unrelated AF patients, respectively, with a prevalence of ~1.29%. Genetic analysis of the carriers' families showed that in each family the missense mutation was present in all the affected family members. Absent in the 400reference alleles, these mutations altered the amino acids highly conserved among various species, with the exception of p.I257L. In conclusion, this study expands the spectrum of GJA5 mutations associated with AF and provides novel insights into the molecular basis of AF, suggesting potential implications for the improved, gene-specific rhythm control strategies.