title: 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.
authors: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors: Corinna
authors: C
authors: Friedrich
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
authors: Susanne
authors: S
authors: Rinné
authors: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors: Sven
authors: S
authors: Zumhagen
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
authors: Aytug K
authors: AK
authors: Kiper
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
authors: Nicole
authors: N
authors: Silbernagel
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
authors: Michael F
authors: MF
authors: Netter
authors: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors: Birgit
authors: B
authors: Stallmeyer
authors: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors: Eric
authors: E
authors: Schulze-Bahr
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany decher@staff.uni-marburg.de.
authors: Niels
authors: N
authors: Decher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002460:Cell Line; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006329:Heart Conduction System / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014981:Xenopus
chemical_list: C423407:KCNK17 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024683:Potassium Channels, Tandem Pore Domain; C568320:SCN5A protein, human
keywords: K2P channels; SCN5A; arrhythmia; progressive cardiac conduction disorder