Patients with LQTS (long QT syndrome) with a mutation in a cardiac ion channel gene, leading to mild-to-moderate channel dysfunction, may manifest marked QT prolongation or torsade de pointes only upon an additional stressor. A 59-year-old woman had marked QT prolongation and repeated torsade de pointes 3 months after initiation of probucol, a cholesterol-lowering drug. We identified a single base substitution in the HERG gene by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of Met124→Thr (M124T) in the N-terminus. Three other relatives with this mutation also had QT prolongation and one of them had a prolonged QT interval and torsade de pointes accompanied by syncope after taking probucol. We expressed wild-type HERG and HERG with M124T in Xenopus oocytes and characterized the electrophysiological properties of these HERG channels and the action of probucol on the channels. Injection of the M124T mutant cRNA into Xenopus oocytes resulted in expression of functional channels with markedly smaller amplitude. In both HERG channels, probucol decreased the amplitude of the HERG tail current, decelerated the rate of channel activation, accelerated the rate of channel deactivation and shifted the reversal potential to a more positive value. The electrophysiological study indicated that QT lengthening and cardiac arrhythmia in the two present patients were due to inhibition of IKr (rapidly activating delayed rectifier K+ current) by probucol, in addition to the significant suppression of HERG current in HERG channels with the M124T mutation.
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Research Article|
July 27 2004
Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG
Kenshi HAYASHI;
*Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
Correspondence: Dr Kenshi Hayashi (email kenshi@yd6.so-net.ne.jp).
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Masami SHIMIZU;
Masami SHIMIZU
*Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Hidekazu INO;
Hidekazu INO
*Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Masato YAMAGUCHI;
Masato YAMAGUCHI
*Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Hidenobu TERAI;
Hidenobu TERAI
*Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Naoto HOSHI;
Naoto HOSHI
†Biophysical Genetics, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Haruhiro HIGASHIDA;
Haruhiro HIGASHIDA
†Biophysical Genetics, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Nariaki TERASHIMA;
Nariaki TERASHIMA
‡Division of Cardiology, Ishikawa Prefectural Hospital, Kanazawa, Japan
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Yoshihide UNO;
Yoshihide UNO
‡Division of Cardiology, Ishikawa Prefectural Hospital, Kanazawa, Japan
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Honin KANAYA;
Honin KANAYA
‡Division of Cardiology, Ishikawa Prefectural Hospital, Kanazawa, Japan
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Hiroshi MABUCHI
Hiroshi MABUCHI
*Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Publisher: Portland Press Ltd
Received:
October 27 2003
Revision Received:
March 22 2004
Accepted:
March 25 2004
Accepted Manuscript online:
March 25 2004
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society
2004
Clin Sci (Lond) (2004) 107 (2): 175–182.
Article history
Received:
October 27 2003
Revision Received:
March 22 2004
Accepted:
March 25 2004
Accepted Manuscript online:
March 25 2004
Citation
Kenshi HAYASHI, Masami SHIMIZU, Hidekazu INO, Masato YAMAGUCHI, Hidenobu TERAI, Naoto HOSHI, Haruhiro HIGASHIDA, Nariaki TERASHIMA, Yoshihide UNO, Honin KANAYA, Hiroshi MABUCHI; Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG. Clin Sci (Lond) 1 August 2004; 107 (2): 175–182. doi: https://doi.org/10.1042/CS20030351
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