PubMed 18313602

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNQ1 , Kv2.1 , Kv7.1 , Slo1

Title: Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.

Authors: Lasse S Ravn, Yoshiyasu Aizawa, Guido D Pollevick, Jacob Hofman-Bang, Jonathan M Cordeiro, Ulrik Dixen, Gorm Jensen, Yuesheng Wu, Elena Burashnikov, Stig Haunso, Alejandra Guerchicoff, Dan Hu, Jesper H Svendsen, Michael Christiansen, Charles Antzelevitch

Journal, date & volume: Heart Rhythm, 2008 Mar , 5, 427-35

PubMed link:

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.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.One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5.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.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.