TASK-1 potassium channel mutations in atrial fibrillation

Abstract

Purpose: Genetic factors contribute significantly to the pathogenesis of atrial fibrillation (AF) but molecular defects in the majority of patients with AF are unknown The two-pore domain potassium channel, K2P3.1 (TASK-1) has atrial-specific expression and has been recently shown to be a major determinant of resting membrane potential in human atrial cardiomyocytes. We hypothesized that mutations in the KCNK3 gene that encodes TASK-1 might predispose to AF Methods: We performed genetic screening of two independent AF cohorts (373 subjects) using Sanger sequencing. Results: We identified three novel KCNK3 mutations. Two of these variants were located at adjacent nucleotides in the Kozak sequence and were both present in one proband with familial AF. Analysis of the double Kozak variants by reporter gene assays revealed reduced TASK-1 translation efficiency. A third missense V123L variant was found in a patient with lone AF. Structural modeling predicted a role for residue V123 in pore formation and integrity. Electrophysiological characterization of V123L-TASK-1 in heterologous expression systems showed a loss-of-function effect with reduced resting membrane potential and altered pH sensitivity. Cardiac action potential modeling suggested that loss-of-function of TASK-1 is associated with a prolongation of atrial action potential duration. These effects on the atrial action potential were potentiated by genetic variants in other cardiac potassium channels. Conclusions: Here we demonstrate for the first time an association of TASK-1 channel variants with human disease. Our data suggest that TASK-1 loss-of-function can promote AF and open a new avenue of investigation into the role of K2P channels in atrial arrhythmogenesis.