title: MOG1: a new susceptibility gene for Brugada syndrome.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: INSERM, UMRS 956 and Université Pierre et Marie Curie, Paris, France.
authors: Darouna
authors: D
authors: Kattygnarath
authors: Svetlana
authors: S
authors: Maugenre
authors: Nathalie
authors: N
authors: Neyroud
authors: Elise
authors: E
authors: Balse
authors: Carole
authors: C
authors: Ichai
authors: Isabelle
authors: I
authors: Denjoy
authors: Gilles
authors: G
authors: Dilanian
authors: Raphaël P
authors: RP
authors: Martins
authors: Véronique
authors: V
authors: Fressart
authors: Myriam
authors: M
authors: Berthet
authors: Jean Jacques
authors: JJ
authors: Schott
authors: Antoine
authors: A
authors: Leenhardt
authors: Vincent
authors: V
authors: Probst
authors: Hervé
authors: H
authors: Le Marec
authors: Bernard
authors: B
authors: Hainque
authors: Alain
authors: A
authors: Coulombe
authors: Stéphane N
authors: SN
authors: Hatem
authors: Pascale
authors: P
authors: Guicheney
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D016415:Sequence Alignment; D015222:Sodium Channels / Q000235:genetics; D014162:Transfection; D020931:ran GTP-Binding Protein / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D015222:Sodium Channels; C498735:RANGNRF protein, human; D020931:ran GTP-Binding Protein