A Novel Missense Mutation Causing a G487R Substitution in the S2–S3 Loop of Human ether‐à‐go‐go‐Related Gene Channel |
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Authors: | KOSHI KINOSHITA Ph.D. KATSUYA KIMOTO B.E. YUKI NONOBE B.E. AKIRA FUJITA B.E. KENTA ASANO B.E. TOSHIHIDE TABATA Ph.D. HISASHI MORI Ph.D. HIROSHI INOUE M.D. Ph.D. YUKIKO HATA Ph.D. KENKICHI FUKUROTANI Ph.D. NAOKI NISHIDA M.D. Ph.D. |
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Affiliation: | 1. Department of Legal Medicine;2. Laboratory for Neural Information Technology, Graduate School of Sciences and Engineering, University of Toyama, Toyama, Japan;3. Department of Molecular Neurosciences, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Japan;4. Second Department of Internal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Japan |
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Abstract: | hERG(G487R) Channel . Introduction: Mutations of human ether‐à‐go‐go‐related gene (hERG), which encodes a cardiac K+ channel responsible for the acceleration of the repolarizing phase of an action potential and the prevention of premature action potential regeneration, often cause severe arrhythmic disorders. We found a novel missense mutation of hERG that results in a G487R substitution in the S2–S3 loop of the channel subunit [hERG(G487R)] from a family and determined whether this mutant gene could induce an abnormality in channel function. Methods and Results: We made whole‐cell voltage‐clamp recordings from HEK‐293T cells transfected with wild‐type hERG [hERG(WT)], hERG(G487R), or both. We measured hERG channel‐mediated current as the “tail” of a depolarization‐elicited current. The current density of the tail current and its voltage‐ and time‐dependences were not different among all the cell groups. The time‐courses of deactivation, inactivation, and recovery from inactivation and their voltage‐dependences were not different among all the cell groups. Furthermore, we performed immunocytochemical analysis using an anti‐hERG subunit antibody. The ratio of the immunoreactivity of the plasma membrane to that of the cytoplasm was not different between cells transfected with hERG(WT), hERG(G487R), or both. Conclusion: hERG(G487R) can produce functional channels with normal gating kinetics and cell‐surface expression efficiency with or without the aid of hERG(WT). Therefore, neither the heterozygous nor homozygous inheritance of hERG(G487R) is thought to cause severe cardiac disorders. hERG(G487R) would be a candidate for a rare variant or polymorphism of hERG with an amino acid substitution in the unusual region of the channel subunit. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1246–1253, November 2012) |
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Keywords: | arrhythmia HEK‐293T cell hERG(G487R) KCNH2 Kv11.1 patch‐clamp sudden death |
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