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


CONCLUSIONS
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.
Ravn
Lasse S
LS
Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark.
Aizawa
Yoshiyasu
Y
Pollevick
Guido D
GD
Hofman-Bang
Jacob
J
Cordeiro
Jonathan M
JM
Dixen
Ulrik
U
Jensen
Gorm
G
Wu
Yuesheng
Y
Burashnikov
Elena
E
Haunso
Stig
S
Guerchicoff
Alejandra
A
Hu
Dan
D
Svendsen
Jesper H
JH
Christiansen
Michael
M
Antzelevitch
Charles
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology; D003718:Denmark; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*
C502068:KCNE5 protein, human; D024642:Potassium Channels, Voltage-Gated