Gain‐of‐function mutation in TASK‐4 channels and severe cardiac conduction disorder

Abstract

Abstract Analyzing a patient with progressive and severe cardiac conduction disorder combined with idiopathic ventricular fibrillation (IVF), we identified a splice site mutation in the sodium channel gene SCN5A. Due to the severe phenotype, we performed whole‐exome sequencing (WES) and identified an additional mutation in the KCNK17 gene encoding the K2P potassium channel TASK‐4. The heterozygous change (c.262G>A) resulted in the p.Gly88Arg mutation in the first extracellular pore loop. Mutant TASK‐4 channels generated threefold increased currents, while surface expression was unchanged, indicating enhanced conductivity. When co‐expressed with wild‐type channels, the gain‐of‐function by G88R was conferred in a dominant‐active manner. We demonstrate that KCNK17 is strongly expressed in human Purkinje cells and that overexpression of G88R leads to a hyperpolarization and strong slowing of the upstroke velocity of spontaneously beating HL‐1 cells. Thus, we propose that a gain‐of‐function by TASK‐4 in the conduction system might aggravate slowed conductivity by the loss of sodium channel function. Moreover, WES supports a second hit‐hypothesis in severe arrhythmia cases and identified KCNK17 as a novel arrhythmia gene.

Keywords

• arrhythmia
• K2P channels
• progressive cardiac conduction disorder
• SCN5A