A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias. (March 2016)

• Record Type: Journal Article
• Authors: Wang, Hong-Gang; Zhu, Wandi; Kanter, Ronald J.; Silva, Jonathan R.; Honeywell, Christina; Gow, Robert M.; Pitt, Geoffrey S.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 92(2016:Mar.)
• Page Start: 52
• Page End: 62
• Publication Date: 2016-03
• Subjects: NaV1.5 sodium channels -- VCF voltage clamp fluorometry -- F-V voltage sensor movement -- VSD voltage sensing domain -- ECG electrocardiogram -- CPR cardiopulmonary resuscitation -- AED automated external defibrillators -- HEK human embryonic kidney -- EGFP enhanced green fluorescent protein -- WT wild type -- R arginine -- H histidine -- C cysteine -- Y tyrosine -- M methionine -- Q glutamine -- W tryptophan -- S serine; R1309H mutation -- S4 segment -- Voltage sensor -- NaV1.5 -- Gating pore current -- Ventricular arrhythmia -- Atrial arrhythmia; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.01.014
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: Inherited autosomal dominant mutations in cardiac sodium channels (NaV 1.5) 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 NaV 1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. Methods and results: We expressed the wild type or mutant NaV 1.5 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 NaV 1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV 1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism. Highlights: We identified a novel, homozygous, recessive p.R1309H mutation in NaV 1.5 associated with a complex arrhythmia syndrome. The mutation, within the domain III/S4 voltage sensor, induces a gating pore current. Biophysical analysis of the p.R1309H mutant also revealed several other features that likely contribute to arrhythmogenesis. Therapeutic success of lidocaine correlated with amelioration of the gating pore current for the p.R1309H mutant.