Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias

Sottas, Valentin; Rougier, Jean-Sébastien; Jousset, Florian; Kucera, Jan P.; Shestak, Anna; Makarov, Leonid M.; Zaklyazminskaya, Elena V.; Abriel, Hugues (2013). Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias. Journal of cardiovascular electrophysiology, 24(9), pp. 1037-1046. Wiley-Blackwell 10.1111/jce.12173

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Hundreds of genetic variants in SCN5A, the gene coding for the pore-forming subunit of the cardiac sodium channel, Na(v) 1.5, have been described in patients with cardiac channelopathies as well as in individuals from control cohorts. The aim of this study was to characterize the biophysical properties of 2 naturally occurring Na(v) 1.5 variants, p.R689H and p.R689C, found in patients with cardiac arrhythmias and in control individuals. In addition, this study was motivated by the finding of the variant p.R689H in a family with sudden cardiac death (SCD) in children. When expressed in HEK293 cells, most of the sodium current (I(Na)) biophysical properties of both variants were indistinguishable from the wild-type (WT) channels. In both cases, however, an ∼2-fold increase of the tetrodotoxin-sensitive late I(Na) was observed. Action potential simulations and reconstruction of pseudo-ECGs demonstrated that such a subtle increase in the late I(Na) may prolong the QT interval in a nonlinear fashion. In conclusion, despite the fact that the causality link between p.R689H and the phenotype of the studied family cannot be demonstrated, this study supports the notion that subtle alterations of Na(v) 1.5 variants may increase the risk for cardiac arrhythmias.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology

UniBE Contributor:

Sottas, Valentin; Rougier, Jean-Sébastien; Jousset, Florian; Kucera, Jan and Abriel, Hugues

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1045-3873

Publisher:

Wiley-Blackwell

Funders:

[4] Swiss National Science Foundation

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

18 Mar 2014 10:46

Last Modified:

10 Sep 2017 09:11

Publisher DOI:

10.1111/jce.12173

PubMed ID:

23692053

Uncontrolled Keywords:

Brugada syndrome, Nav1.5, cardiac sodium channel long-QT syndrome, sudden cardiac death

BORIS DOI:

10.7892/boris.43791

URI:

https://boris.unibe.ch/id/eprint/43791

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