Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome

doi:10.1016/S0008-6363(02)00240-7

Cardiovascular Research 2002 54(1):67-76; doi:10.1016/S0008-6363(02)00240-7
© 2002 by European Society of Cardiology

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Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome

Kenshi Hayashi^a^,*, Masami Shimizu^a, Hidekazu Ino^a, Masato Yamaguchi^a, Hiroshi Mabuchi^a, Naoto Hoshi^b and Haruhiro Higashida^b

^aMolecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University 13-1, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan
^bBiophysical Genetics, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University 13-1, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan

kenshi{at}im2.m.kanazawa-u.ac.jp

^* Corresponding author. Tel.: +81-76-265-2254; fax: +81-76-234-4251

Objective: In a 32-year-old woman with marked QT prolongation(QTc=0.61 s) and repeated episodes of syncope, we identifieda single pertinent base substitution (G to A at 1909) in HERGby genetic analysis. This novel missense mutation is predictedto cause an amino acid substitution of lysine for glutamic acidat position 637 (E637K) in the pore-S6 loop. Therefore, we investigatedthe role of a glutamic acid at the vicinity of the pore in HERGchannels by mutating it to a lysine. Methods: We characterizedthe electrophysiological properties of the E637K mutation usinga Xenopus oocyte heterologous expression system. Results: Injectionof the E637K mutant cRNA alone into Xenopus oocytes did notresult in any expression of detectable currents. Coexpressionof wild-type (WT) and E637K (E637K/WT) elicited only about 30%of the control peak tail current that was expected from expressionof WT alone. Kinetic analyses revealed that E637K/WT deceleratedthe rate of channel activation and enhanced steady-state inactivation.Furthermore, the reversal potentials at low concentrations ofK⁺ showed a positive shift in oocytes injected with E637K/WTcompared with WT alone. Conclusions: These results indicatedthat the E637K mutation causes apparent dominant negative suppressionof WT HERG channel function and suggest that E637 at the Pore-S6is a crucial component of the activation and inactivation gateof HERG channels.

KEYWORDS Arrhythmia (mechanisms); K-channel; Long QT syndrome

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