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Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder
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 additio...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119356/ https://www.ncbi.nlm.nih.gov/pubmed/24972929 http://dx.doi.org/10.15252/emmm.201303783 |
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author | Friedrich, Corinna Rinné, Susanne Zumhagen, Sven Kiper, Aytug K Silbernagel, Nicole Netter, Michael F Stallmeyer, Birgit Schulze-Bahr, Eric Decher, Niels |
author_facet | Friedrich, Corinna Rinné, Susanne Zumhagen, Sven Kiper, Aytug K Silbernagel, Nicole Netter, Michael F Stallmeyer, Birgit Schulze-Bahr, Eric Decher, Niels |
author_sort | Friedrich, Corinna |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4119356 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-41193562014-08-18 Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder Friedrich, Corinna Rinné, Susanne Zumhagen, Sven Kiper, Aytug K Silbernagel, Nicole Netter, Michael F Stallmeyer, Birgit Schulze-Bahr, Eric Decher, Niels EMBO Mol Med Research Articles 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. BlackWell Publishing Ltd 2014-07 2014-06-27 /pmc/articles/PMC4119356/ /pubmed/24972929 http://dx.doi.org/10.15252/emmm.201303783 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Friedrich, Corinna Rinné, Susanne Zumhagen, Sven Kiper, Aytug K Silbernagel, Nicole Netter, Michael F Stallmeyer, Birgit Schulze-Bahr, Eric Decher, Niels Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder |
title | Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder |
title_full | Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder |
title_fullStr | Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder |
title_full_unstemmed | Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder |
title_short | Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder |
title_sort | gain-of-function mutation in task-4 channels and severe cardiac conduction disorder |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119356/ https://www.ncbi.nlm.nih.gov/pubmed/24972929 http://dx.doi.org/10.15252/emmm.201303783 |
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