GATA6 loss-of-function mutation in atrial fibrillation.

Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia and is associated with substantial morbidity and mortality. Increasing evidence demonstrates that hereditary defects are involved in the pathogenesis of AF. However, AF is of remarkable genetic heterogeneity, and the heritable components responsible for AF in the majority of patients remain unclear. In this study, the entire coding region of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, was sequenced in 138 unrelated patients with lone AF, and a novel heterozygous GATA6 mutation, c.704A > C equivalent to p.Y235S, was identified in a patient. The detected substitution, which altered the amino acid highly conserved evolutionarily across species, was absent in 200 unrelated ethnically matched healthy individuals, and was predicted to be disease-causing by MutationTaster. Genetic analysis of the available relatives of the mutation carrier showed that in the family the variation co-segregated with the disease transmitted as an autosomal dominant trait, with complete penetrance. The functional analysis performed using a luciferase reporter assay system revealed that the mutant GATA6 protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. These findings provide novel insight into the molecular pathophysiology implicated in AF, suggesting the potential implications in the prophylactic strategy and effective therapy for this common arrhythmia.