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

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.

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

“…NaCl, 5 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 0.33 mM NaH 2 PO 4 , 10 mM glucose, 2 mM sodium pyruvate, and 5 mM HEPES (pH 7.4 with NaOH) as previously described (49,50). Patch-clamp experiments were performed in the whole-cell configuration using pipettes pulled from borosilicate glass capillaries.…”

“…Data analysis of action potentials was done using Fitmaster software (HEKA). For each cell measured, the action potential parameters were averaged by analyzing 10 subsequent action potentials, as previously described (49).…”

Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity

“…Furthermore, classic efforts to link genes to Mendelian disease are gradually being displaced by next-generation sequencing platforms (23)(24)(25), and exome sequencing has proved itself as an indispensable technology to identify disease-causing coding variants in congenital arrhythmia syndromes (26,27). Thus, we used a strategy seeking to identify gene variants affecting either ion channels, associated channel proteins, or loci associated with QT interval variability that could explain variable expressivity in an LQT2 family.…”

“…However, a wealth of transgenic animal studies support the notion that TASK family K 2p channels also strongly contribute to cardiac repolarization (30)(31)(32). Recently, Friedrich et al (27) used exome sequencing to identify a gain-of-function mutation in KCNK17 that in tandem with an SCN5A mutation underpinned the molecular mechanism of a severely affected arrhythmia phenotype. Furthermore, work by Schmidt et al (33) showed that pharmacological inhibition of a K 2p (TASK-1) is a novel potential pharmacological strategy for treatment of chronic atrial fibrillation.…”

Stress-Kinase Regulation of TASK-1 and TASK-3

“…WIK-related cid-ensitive + (TASK) channels belonging to the K 2P family of potassium channels are relevant for the pathogenesis of many different cardiovascular diseases [1, 2], including pulmonary hypertension [3], obstructive sleep apnea [4] and arrhythmias like atrial fibrillation (AFib) [4-6] or conduction disorders [7, 8]. …”