Key result
The novel Q1491H and G1481V SCN5A mutations exhibited gain-of-function biophysical defects characteristic of LQT3, likely responsible for the sudden deaths of the two infants.
Why the study?
SCN5A mutations are linked to cardiac rhythm disorders including LQT3, prompting analysis of the biophysical properties of two novel Nav1.5 variants detected in infants with prolonged QT intervals.
Do the novel Q1491H and G1481V SCN5A mutations alter the biophysical properties of Nav1.5 channels in a manner consistent with long QT syndrome type 3?
Do the novel Q1491H and G1481V SCN5A mutations alter the biophysical properties of Nav1.5 channels in a manner consistent with long QT syndrome type 3?
Answers are grounded in this paper and cite their sources.
The novel Q1491H and G1481V SCN5A mutations cause gain-of-function biophysical defects in Nav1.5 channels characteristic of LQT3, providing a mechanistic explanation for the sudden cardiac death observed in the affected infants.
BACKGROUND: Nav1.5, 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 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.
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Plumereau et al. (2020) studied Type 3 long QT syndrome (LQT3) (n=2). Q1491H and G1481V SCN5A mutations vs. Nav1.5 wild-type (WT) channel was evaluated on Biophysical properties of the Nav1.5 channel (Na+ currents). The novel Q1491H and G1481V SCN5A mutations exhibited gain-of-function biophysical defects characteristic of LQT3, likely responsible for the sudden deaths of the two infants.
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