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http://purl.uniprot.org/citations/26801742http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
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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."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.org/dc/terms/identifier"doi:10.1016/j.yjmcc.2016.01.014"xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Zhu W."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Pitt G.S."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Kanter R.J."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Wang H.G."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Silva J.R."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Gow R.M."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/author"Honeywell C."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/name"J Mol Cell Cardiol"xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/pages"52-62"xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/title"A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias."xsd:string
http://purl.uniprot.org/citations/26801742http://purl.uniprot.org/core/volume"92"xsd:string
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