@article{b827b155d1254844b5ac0c99e1334e64,
title = "Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.",
abstract = "BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 beta-subunit, has been shown to reduce IKs. OBJECTIVE: The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF. METHODS: One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5. RESULTS: A missense mutation involving substitution of a phenylalanine for leucine at position 65 (L65F) was identified in one patient. This patient did not have a history of familial AF, and neither KCNQ1 nor KCNE2 mutations were found. Transient transfection of Chinese hamster ovary (CHO) cells expressing IKs(KCNQ1+KCNE1) with KCNE5 suppressed the developing and tail currents of IKs in a concentration-dependent manner. Transient transfection with KCNE5-L65F failed to suppress IKs, yielding a current indistinguishable from that recorded in the absence of KCNE5. Developing currents recorded during a test pulse to +60 mV and tail currents recorded upon repolarization to -40 mV both showed a significant concentration-dependent gain of function in IKs with expression of KCNE5-L65F vs KCNE5-WT. CONCLUSION: The results of this study suggest that a missense mutation in KCNE5 may be associated with nonfamilial or acquired forms of AF. The arrhythmogenic mechanism most likely is a gain of function of IKs.",
keywords = "Adult, Aged, Aged, 80 and over, Analysis of Variance, Atrial Fibrillation, Denmark, Electrocardiography, Electrophysiologic Techniques, Cardiac, Female, Humans, Male, Middle Aged, Mutation, Missense, Potassium Channels, Voltage-Gated",
author = "Ravn, {Lasse S} and Yoshiyasu Aizawa and Pollevick, {Guido D} and Jacob Hofman-Bang and Cordeiro, {Jonathan M} and Ulrik Dixen and Gorm Jensen and Yuesheng Wu and Elena Burashnikov and Stig Haunso and Alejandra Guerchicoff and Dan Hu and Svendsen, {Jesper Hastrup} and Michael Christiansen and Charles Antzelevitch",
year = "2008",
doi = "10.1016/j.hrthm.2007.12.019",
language = "English",
volume = "5",
pages = "427--35",
journal = "Heart rhythm : the official journal of the Heart Rhythm Society",
issn = "1547-5271",
publisher = "Elsevier Inc",
number = "3",
}