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.

These functional abnormalities may be responsible for the overlapping clinical phenotypes associated with Brugada syndrome and the cardiac conduction defect, a novel cardiac Na(+) channelopathy.

Background-Mutations in the gene encoding the human cardiac Na ϩ channel ␣-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary ␤ 1 -subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na ϩ channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human ␤ 1 -subunit (h␤ 1 ) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF. Methods and Results-When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V 1/2 ) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of h␤ 1 did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V 1/2 and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal. Conclusions-It is suggested that coexpression of h␤ 1 exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered ␣-/␤ 1 -subunit association in the mutant. (Circulation. 2000;101:54-60.)

OBJECTIVES:The purpose of the study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation identified in a family with atrial standstill. BACKGROUND:Congenital atrial standstill has been linked to SCN5A. Incomplete