PubMed 21447824

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1.5

Title: MOG1: a new susceptibility gene for Brugada syndrome.

Authors: Darouna Kattygnarath, Svetlana Maugenre, Nathalie Neyroud, Elise Balse, Carole Ichai, Isabelle Denjoy, Gilles Dilanian, Raphaël P Martins, Véronique Fressart, Myriam Berthet, Jean Jacques Schott, Antoine Leenhardt, Vincent Probst, Hervé Le Marec, Bernard Hainque, Alain Coulombe, Stéphane N Hatem, Pascale Guicheney

Journal, date & volume: Circ Cardiovasc Genet, 2011 Jun , 4, 261-8

PubMed link:

Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na(v)1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS.MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation. A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)- and mutant E83D-MOG1 were expressed in HEK Na(v)1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I(Na)) density compared to control conditions (P<0.01). In contrast, overexpression of mutant E83D alone or E83D+WT failed to increase I(Na) (P<0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na(v)1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I(Na) density.Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na(v)1.5 to the membrane, leading to I(Na) reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I(Na), demonstrating that MOG1 is likely to be important in the surface expression of Na(v)1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS.