A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias

Abstract

Background Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. Methods and Results We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the “late” Na+ current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current. Conclusions The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism.

More Severe Loss-of-Function Sodium Channel induced by Compound SCN5A R965C and R1309H Mutants lead to Complex Familial Arrhythmia Syndrome

“…Those results were basically consistent with previous studies (16,17). As for R965C-R1309H mutations, compared to R1309H mutation, it induced more significant depolarization shift of activation curve, V 1/2 and slope factor, suggesting that Na v 1.5 R965C-R1309H channel was activated at the much more depolarized membrane potential and displayed slower activation (Supplement 3).…”

“…Consistent with previous literatures reported (16,17), as shown in the Figure 4A-C and Table 2, the R1309H mutation, but not R965C mutation, significantly reduced the Na + current density at a series of test potentials ranging from -45 mV to -15 mV when compared to the WT group (Supplement 1). More importantly, we found that R965C-R1309H mutations resulted in a more severe reduction in Na + current density ranging from -45 mV to 30 mV compared to the WT group.…”

“…And the slope factor (K) of R1309H mutation was significant amplified but not of R965C mutation when compared to the WT group. These above data were keeping with the previous studies (16,17). We were surprised to find that the inactivation curve of R965C-R1309H mutations most significantly shifted to the left with the increase of V 1/2 hyperpolarization and K value ( Figure 5C, Table 3).…”

“…The R1309H mutation significantly reduced the current density of I Na , hyperpolarized inactivation, slowed recovery from inactivation, and increased the I NaL. It was noted that the carriers with heterozygous R1309H mutation showed slightly abnormal ECGs without arrhythmia events (16).…”

Sulfur‐containing gaseous signal molecules, ion channels and cardiovascular diseases

“…Ion channels represent a family of important membrane proteins that conduct ions across the membrane, thereby controlling the intracellular ion content, membrane potential and action potentials. The abnormal function and structure of ion channels can lead to a variety of cardiovascular diseases (Ackerman, ; Navedo et al, ; Hsiao et al, ; George, ; Wang et al, ). More importantly, endogenous sulfur‐containing gaseous signal molecules play an important role in the pathogenesis of cardiovascular diseases by targeting ion channels (Wang, ; Brampton and Aaronson, ).…”