TY - JOUR

T1 - Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.

AU - Ravn, Lasse S

AU - Aizawa, Yoshiyasu

AU - Pollevick, Guido D

AU - Hofman-Bang, Jacob

AU - Cordeiro, Jonathan M

AU - Dixen, Ulrik

AU - Jensen, Gorm

AU - Wu, Yuesheng

AU - Burashnikov, Elena

AU - Haunso, Stig

AU - Guerchicoff, Alejandra

AU - Hu, Dan

AU - Svendsen, Jesper H

AU - Christiansen, Michael

AU - Antzelevitch, Charles

AU - Ravn, Lasse S

AU - Aizawa, Yoshiyasu

AU - Pollevick, Guido D

AU - Hofman-Bang, Jacob

AU - Cordeiro, Jonathan M

AU - Dixen, Ulrik

AU - Jensen, Gorm

AU - Wu, Yuesheng

AU - Burashnikov, Elena

AU - Haunso, Stig

AU - Guerchicoff, Alejandra

AU - Hu, Dan

AU - Svendsen, Jesper H

AU - Christiansen, Michael

AU - Antzelevitch, Charles

N1 - 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

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1016/j.hrthm.2007.12.019

DO - 10.1016/j.hrthm.2007.12.019

M3 - Journal article

C2 - 18313602

VL - 5

SP - 427

EP - 435

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 3

ER -