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

TitleA novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.
Publication TypeJournal Article
Year of Publication2016
AuthorsWang H-G, Zhu W, Kanter RJ, Silva JR, Honeywell C, Gow RM, Pitt GS
JournalJ Mol Cell Cardiol
Date Published2016 Mar
KeywordsArrhythmias, Cardiac, Brugada Syndrome, Heart Conduction System, Humans, Infant, Lidocaine, Male, Membrane Potentials, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques

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.

Alternate JournalJ. Mol. Cell. Cardiol.
PubMed ID26801742
PubMed Central IDPMC4789166
Grant ListR01 HL071165 / HL / NHLBI NIH HHS / United States
R01 HL112918 / HL / NHLBI NIH HHS / United States
R01 HL122967 / HL / NHLBI NIH HHS / United States
HL071165 / HL / NHLBI NIH HHS / United States