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

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; 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

doi:10.1016/j.hrthm.2007.12.019

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

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

103 Citations (Scopus)

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.

Original language	English
Journal	Heart Rhythm
Volume	5
Issue number	3
Pages (from-to)	427-35
Number of pages	8
ISSN	1547-5271
DOIs	https://doi.org/10.1016/j.hrthm.2007.12.019 https://doi.org/10.1016/j.hrthm.2007.12.019
Publication status	Published - 2008

Access to Document

Cite this

Ravn, L. S., Aizawa, Y., Pollevick, G. D., Hofman-Bang, J., Cordeiro, J. M., Dixen, U., Jensen, G., Wu, Y., Burashnikov, E., Haunso, S., Guerchicoff, A., Hu, D., Svendsen, J. H., Christiansen, M., Antzelevitch, C., Ravn, L. S., Aizawa, Y., Pollevick, G. D., Hofman-Bang, J., ... Antzelevitch, C. (2008). Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation. Heart Rhythm, 5(3), 427-35. https://doi.org/10.1016/j.hrthm.2007.12.019, https://doi.org/10.1016/j.hrthm.2007.12.019

Ravn, LS, Aizawa, Y, Pollevick, GD, Hofman-Bang, J, Cordeiro, JM, Dixen, U, Jensen, G, Wu, Y, Burashnikov, E, Haunso, S, Guerchicoff, A, Hu, D, Svendsen, JH, Christiansen, M, Antzelevitch, C, Ravn, LS, Aizawa, Y, Pollevick, GD, Hofman-Bang, J, Cordeiro, JM, Dixen, U, Jensen, G, Wu, Y, Burashnikov, E, Haunso, S, Guerchicoff, A, Hu, D, Svendsen, JH, Christiansen, M & Antzelevitch, C 2008, 'Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.', Heart Rhythm, vol. 5, no. 3, pp. 427-35. https://doi.org/10.1016/j.hrthm.2007.12.019, https://doi.org/10.1016/j.hrthm.2007.12.019

@article{e73e85f0f77d11ddbf70000ea68e967b,

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.",

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 H} and Michael Christiansen and Charles Antzelevitch and 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 H} and Michael Christiansen and Charles Antzelevitch",

note = "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",

year = "2008",

doi = "10.1016/j.hrthm.2007.12.019",

language = "English",

volume = "5",

pages = "427--35",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier",

number = "3",

}

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

SN - 1547-5271

VL - 5

SP - 427

EP - 435

JO - Heart Rhythm

JF - Heart Rhythm

IS - 3

ER -

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

Abstract

Access to Document

Fingerprint

Cite this