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- Title
Biophysical Characterization of the Short QT Mutation hERG-N588K Reveals a Mixed Gain-and Loss-of-Function.
- Authors
Grunnet, Morten; Diness, Thomas Goldin; Hansen, Rie Schultz; Olesen, Søren-Peter
- Abstract
The short QT syndrome is a newly discovered pro-arrhythmic condition, which may cause ventricular fibrillation and sudden death. Short QT can originate from the apparent gain-of-function mutation N588K in the hERG potassium channel that conducts repolarising IKr current. The present study describes a profound biophysical characterization of HERG-N588K revealing both loss-of-function and gain-of-function properties of the mutant. Experiments were conducted after heterologous expression in both Xenopus laevis oocytes and mammalian cells and at both room temperature and at 37 °C. Also the impact of the β-subunits KCNE2 was investigated. The most prominent loss-of-function property of HERG-N588K was reduced tail currents but also the activation properties was compromised. Based on these biophysical results we suggest that the general view of HERG-N588K being a gain-of-function is modified to a mixed gain- and loss-of-function mutation. This might also have impact on the pathological picture of the HERG-N588K channels ability to trigger arrhythmic events. Copyright © 2008 S. Karger AG, Basel
- Subjects
SUDDEN death; ARRHYTHMIA; POTASSIUM channels; XENOPUS laevis; GENETIC mutation
- Publication
Cellular Physiology & Biochemistry (Karger AG), 2008, Vol 22, Issue 5/6, p611
- ISSN
1015-8987
- Publication type
Article
- DOI
10.1159/000185545