Referenced in: none

Automatically associated channels: Nav1.5

Title: A novel nonsense variant in Nav1.5 cofactor MOG1 eliminates its sodium current increasing effect and may increase the risk of arrhythmias.

Authors: Morten S Olesen, Niels F Jensen, Anders G Holst, Jonas B Nielsen, Jacob Tfelt-Hansen, Thomas Jespersen, Ahmad Sajadieh, Stig Haunsø, Jens T Lund, Kirstine Calloe, Nicole Schmitt, Jesper Hastrup Svendsen

Journal, date & volume: Can J Cardiol, 2011 Jul-Aug , 27, 523.e17-23

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21621375

Abstract
The protein MOG1 is a cofactor of the cardiac sodium channel, Nav1.5. Overexpression of MOG1 in Nav1.5-expressing cells increases sodium current markedly. Mutations in the genes encoding Nav1.5 and its accessory proteins have been associated with cardiac arrhythmias of significant clinical impact. We sought to investigate whether MOG1 is implicated in cardiac arrhythmias.We performed a genetic screening of the MOG1-encoding gene (gene symbol RANGRF, alias MOG1) in 220 Danish patients with cardiac arrhythmia. Of the 220, 197 were young patients with lone atrial fibrillation and 23 were patients with Brugada syndrome. The effect of one variant was investigated functionally by patch-clamping CHO-K1 cells coexpressing Nav1.5 with MOG1.We uncovered a novel heterozygous nonsense variant, c.181G>T (p.E61X), that, however, was also present in control subjects, albeit at a lower frequency (1.8% vs 0.4%, P = 0.078). Electrophysiological investigation showed that the p.E61X variant completely eliminates the sodium current-increasing effect of MOG1 and thereby causes loss of function in the sodium current. When mimicking heterozygosity by coexpression of Nav1.5 with wild-type MOG1 and p.E61X-MOG1, no current decrease was seen.Our screening of Nav1.5 cofactor MOG1 uncovered a novel nonsense variant that appeared to be present at a higher frequency among patients than control subjects. This variant causes MOG1 loss of function and therefore might be disease causing or modifying under certain conditions.