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

EMBO Molecular Medicine

Corinna Friedrich¹  Susanne Rinné²  Sven Zumhagen¹  Aytug K Kiper²  Nicole Silbernagel²  Michael F Netter²  Birgit Stallmeyer¹  Eric Schulze-Bahr¹ 

[1] Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany;Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany

关键词: arrhythmia;    K2P channels;    progressive cardiac conduction disorder;    SCN5A;   

DOI  :  10.15252/emmm.201303783

来源: Wiley

【 摘 要 】

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 K_2P 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.

Synopsis

A novel exonic mutation in the K_2P potassium channel TASK-4 is found in a patient with severe progressive cardiac conduction disorder (PCCD), resulting in a gain-of-function that could explain the severe progressive conduction disorder compared to isolated loss-of-function mutations in SCN5A channels.

• A splice site mutation in the sodium channel gene SCN5A was identified in a patient with progressive and severe cardiac conduction disorder combined with IVF.
• Whole-exome sequencing (WES) revealed for the first time a heterozygous mutation in the KCNK17 gene encoding the two-pore domain potassium (K_2P) channel TASK-4.
• The resulting amino acid exchange, G88R, in the first extracellular pore loop resulted in a dominant-active increase of the current amplitude, while surface expression of the channel protein was unchanged.
• KCNK17 was found to be strongly expressed in human Purkinje cells, and overexpression of G88R led to a hyperpolarization and strong slowing of the upstroke velocity of the action potentials of spontaneously beating HL-1 cells.
• A gain-of-function of TASK-4 in the conduction system might aggravate slowed conductivity by the loss of sodium channel function, linking a TASK-4 channel mutation to arrhythmogenesis for the first time.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.