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SCN5A mutations that cause a gain of function in the cardiac voltage-gated sodium channel (Nav1.5) lead to long QT syndrome and a higher risk for sudden cardiac death.

Here we functionally characterize the biophysical properties of the LQT3 variant, V411M, found in a newborn with a QT interval of 640 ms and 2:1 atrioventricular block.

Whole cell patch clamp was performed on wild-type and V411M Nav1.5 channels stably expressed in human embryonic kidney cells.

V411M channels showed hyperpolarizing shifts in both the conductance-voltage (V_1/2 = −48.5 ± 2.2 mV vs. −40.4 ± 1.6 mV for wild-type) and inactivation-voltage (−95.6 ± 1.9 mV vs. −87.7 ± 1.7 mV) relationships, and a two-fold increase in late (sustained) sodium current during voltage ramp repolarizations. While neither mexiletine nor lidocaine exhibited potency differences between WT and …