Background: Nav1.5, which is encoded by theSCN5A gene, is the predominant voltage-gated
Na+ channel in the heart. Several mutations of this
gene have been identified and have been reported to be involved in
several cardiac rhythm disorders, including type 3 long QT syndrome
(LQT3), that can cause sudden cardiac death. We analyzed the biophysical
properties of two novel variants of the Nav1.5 channel
(Q1491H and G1481V) detected in 5- and 12-week-old infants diagnosed
with a prolonged QT interval.
Methods: The Nav1.5 wild-type (WT) and the
Q1491H and G1481V mutant channels were reproduced in vivo . WT or
the mutant channels were co-transfected in HEK 293 cells with the beta 1
regulatory subunit. Na+ currents were recorded using
the whole-cell configuration of the patch-clamp technique.
Results: The Q1491H mutant channel exhibited a lower current
density, a persistent Na+ current, an enhanced window
current due to a +20-mV shift of steady-state inactivation, a +10-mV
shift of steady-state activation, a faster onset of slow inactivation,
and a recovery from fast inactivation with fast and a slow time
constants of recovery. The G1481V mutant channel exhibited an increase
in current density and a +7-mV shift of steady-state inactivation. The
observed defects are characteristic of gain-of-function mutations
typical of LQT3.
Discussion and Conclusion: The 5- and 12-week-old infants
displayed prolonged QT intervals. Our analyses of the Q1491H and G1481V
mutations correlated with the clinical diagnosis. The observed
biophysical dysfunctions associated with both mutations were most likely
responsible for the sudden deaths of the two infants.
Key words: SCN5A, Nav1.5, Voltage-gated sodium
channels, Long QT syndrome, Variant, LQT3, Electrophysiology, Sudden
cardiac death, Heart