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(Circulation. 2002;106:1269.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation

Naomasa Makita, MD, PhD^*; Minoru Horie, MD, PhD^*; Takeshi Nakamura, MD; Tomohiko Ai, MD, PhD; Koji Sasaki, MD; Hisataka Yokoi, MD; Masayuki Sakurai, MD; Ichiro Sakuma, MD, PhD; Hideo Otani, MD, PhD; Hirofumi Sawa, MD, PhD; Akira Kitabatake, MD, PhD

From the Department of Cardiovascular Medicine (N.M., K.S., H.Y., I.S., S.K.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Cardiology (M.H., T.A., H.O.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Kyoto Saiseikai Hospital (T.N.), Kyoto, Japan; Hokko Memorial Hospital (M.S.), Sapporo, Japan; and Laboratory of Molecular and Cellular Pathology (H.S.), Hokkaido University Graduate School of Medicine, Sapporo, CREST, Japan Science and Technology, Japan.

Correspondence to Naomasa Makita, MD, PhD, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-8638, Japan. E-mail makitan{at}med.hokudai.ac.jp

Background— Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K⁺ channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na⁺ channel mutation in an individual who exhibited drug-induced LQTS.

Methods and Results— An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na⁺ channel (SCN5A). The L1825P channel heterologously expressed in tsA-201 cells showed Na⁺ current with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A-associated congenital LQTS (LQT3). In addition, L1825P exhibited loss of function Na⁺ channel features characteristic of Brugada syndrome. Peak Na⁺ current density observed in cells expressing L1825P was significantly diminished, and the voltage dependence of activation and inactivation was shifted toward more positive and negative potentials, respectively.

Conclusions— This study demonstrates that subclinical mutations in the LQTS-related gene SCN5A may predispose certain individuals to drug-induced cardiac arrhythmias.

Key Words: long-QT syndrome • drugs • genetics • torsade de pointes • ion channels

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