Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation
| Autor: | Jonathan M. Cordeiro, Guido D. Pollevick, Charles Antzelevitch, Yoshiyasu Aizawa, Dan Hu, Alejandra Guerchicoff, Jacob Hofman-Bang, Stig Haunsø, Gorm B. Jensen, Lasse Steen Ravn, Jesper Hastrup Svendsen, Michael Christiansen, Yuesheng Wu, Elena Burashnikov, Ulrik Dixen |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Mutation biology business.industry Chinese hamster ovary cell KCNE2 Atrial fibrillation medicine.disease medicine.disease_cause Electrophysiology Endocrinology Physiology (medical) Internal medicine medicine Cardiology biology.protein Missense mutation Repolarization Cardiology and Cardiovascular Medicine business Gene |
| Zdroj: | Heart Rhythm. 5:427-435 |
| ISSN: | 1547-5271 |
| DOI: | 10.1016/j.hrthm.2007.12.019 |
| Popis: | 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 β-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. |
| Databáze: | OpenAIRE |
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