Abstract
BACKGROUND: Na(v)1.5, which is encoded by the SCN5A gene, is the predominant voltage-gated Na(+) channel in the heart. Several mutations of this gene have been identified and reported to be involved in several cardiac rhythm disorders, including type 3 long QT interval syndrome, that can cause sudden cardiac death. We analyzed the biophysical properties of 2 novel variants of the Na(v)1.5 channel (Q1491H and G1481V) detected in 5- and 12-week-old infants diagnosed with a prolonged QT interval. METHODS: The Na(v)1.5 wild-type and the Q1491H and G1481V mutant channels were reproduced in vi tr o. Wild-type or mutant channels were cotransfected in human embryonic kidney (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 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 type 3 long QT interval syndrome. CONCLUSIONS: 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 2 infants.