title: Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias.
abstract: 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.
authors.affiliation: Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Valentin
authors.initials: V
authors.lastname: Sottas
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.forename: Florian
authors.initials: F
authors.lastname: Jousset
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kucera
authors.forename: Anna
authors.initials: A
authors.lastname: Shestak
authors.forename: Leonid M
authors.initials: LM
authors.lastname: Makarov
authors.forename: Elena V
authors.initials: EV
authors.lastname: Zaklyazminskaya
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
mesh_terms: D001120:Arginine / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D004562:Electrocardiography / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D001120:Arginine
keywords: Brugada syndrome; Nav1.5; cardiac sodium channel; long-QT syndrome; sudden cardiac death