Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation.
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.


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.
Makita
Naomasa
N
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. makitan@med.hokudai.ac.jp
Horie
Minoru
M
Nakamura
Takeshi
T
Ai
Tomohiko
T
Sasaki
Koji
K
Yokoi
Hisataka
H
Sakurai
Masayuki
M
Sakuma
Ichiro
I
Otani
Hideo
H
Sawa
Hirofumi
H
Kitabatake
Akira
A
D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D020117:Cisapride / Q000009:adverse effects; D004553:Electric Conductivity; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; C568320:SCN5A protein, human; D015222:Sodium Channels; D020117:Cisapride