Novel arrhythmogenic mechanism revealed by a Long-QT syndrome mutation in the cardiac Na+ channel

Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutation s in the gene encoding the alpha subunit of the cardiac Na+ channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describ e 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, cons istent with an LQTS-3 lesion. However, biophysical analysis of mutant chann els indicates that the EK mutation changes channel activity in a manner tha t is distinct from previously investigated LQTS-3 mutations. The EK mutatio n causes significant positive shifts in the half-maximal voltage (V-1/2) 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 curren ts. 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-depende nt rectifying properties of cardiac K+ channels that underlie the plateau a nd terminal repolarization phases of the action potential. Na+ channel wind ow current is likely to have a greater effect on net membrane current at mo re positive potentials (EK channels) where total K+ channel conductance is low than at more negative potentials (wild-type channels), where total K+ c hannel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.