Circulation Research. 2001;88:740-745
Published online before print March 30, 2001, doi: 10.1161/hh0701.089668
Published online before print March 30, 2001, doi: 10.1161/hh0701.089668
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© 2001 American Heart Association, Inc.
Clinical Research |
Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel
From the Department of Pharmacology (H.A., C.C., X.H.T.W., I.R., H.K.M., R.S.K.), College of Physicians & Surgeons of Columbia University, New York, NY; Molecular Cardiology Laboratory (M.M., C.N., S.G.P.), Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy.
Correspondence to R.S. Kass, PhD, Department of Pharmacology, College of Physicians & Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032. E-mail rsk20{at}columbia.edu
Abstract—Variant
3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in
the gene encoding the 
subunit of the cardiac
Na+ channel. In the present study, we
report a novel LQTS-3 mutation, E1295K (EK), and describe its
functional consequences when expressed in HEK293 cells. The clinical
phenotype of the proband indicated QT interval prolongation in
the absence of T-wave morphological abnormalities and a steep QT/R-R
relationship, consistent with an LQTS-3 lesion. However,
biophysical analysis of mutant channels indicates that the EK
mutation changes channel activity in a manner that is distinct from
previously investigated LQTS-3 mutations. The EK mutation causes
significant positive shifts in the half-maximal voltage
(V1/2) of steady-state inactivation and
activation (+5.2 and +3.4 mV, respectively). These gating changes shift
the window of voltages over which Na+
channels do not completely inactivate without altering the
magnitude of these currents. The change in voltage dependence of window
currents suggests that this alteration in the voltage dependence of
Na+ channel gating may cause marked changes
in action potential duration because of the unique voltage-dependent
rectifying properties of cardiac K+ channels
that underlie the plateau and terminal repolarization phases of the
action potential. Na+ channel window current
is likely to have a greater effect on net membrane current at more
positive potentials (EK channels) where total
K+ channel conductance is low than at more
negative potentials (wild-type channels), where total
K+ channel conductance is high. These
findings suggest a fundamentally distinct mechanism of arrhythmogenesis
for congenital LQTS-3.
Key Words: long-QT syndrome • Na+ channel • genetics • arrhythmias
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