MOG1

Abstract

Background-Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the ␣-subunit of the cardiac sodium channel Na v 1.5. However, Ϸ20% 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. Methods and 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 (PϽ0.01). In contrast, overexpression of mutant E83D alone or E83DϩWT failed to increase I Na (PϽ0.05), 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. (Circ Cardiovasc Genet. 2011;4:261-268.)

Brugada Syndrome

“…37 Putative causal mutations were also found in calcium channel genes (CACNA1C, CACNB2b, CACNA2D1); sodium channel β-subunit genes (SCN1B, SCN3B); glycereol-3 phosphate dehydrogenase 1-like enzyme (GPD1L) and MOG1, which affects trafficking of sodium channels; and in genes that affect transient outward current (I to ) (KCNE3, KCND3, KCNE5) in single patients and families with BrS. [38][39][40][41][42][43][44][45][46] In basic electrophysiological studies, mutations in CACNA1C and CACNB2b showed loss of function of basal L-type calcium current (I Ca,L ); a mutation in SCN1B, SCN3B, GPD1L, or MOG1 led to loss of function of I Na ; and a mutation in KCNE3, KCND3, or KCNE5 to gain of function of I to . Mutations in CACNA1C and CACNB2b are reported to contribute to 11.5% of BrS, where patients generally present with shorter-thannormal QT intervals.…”

Brugada Syndrome 2012

“…18 Mutations in genes encoding the α1-(CACNA1c) and β2b-(CACNB2b) subunits of the L-type cardiac calcium (Ca 2+ ) channel leading to a decrease of the ICa current, result in a combined BS/short QT syndrome. 19 Other genes recently reported to be linked to the syndrome are: SCN1B (encoding for β1-and β1b-subunits, auxiliary function-modifying subunits of the cardiac Na + channel, resulting in a decrease of the INa current by affecting the Na + channel trafficking; 20 KCNE3 21 (encoding MiRP2, a protein that decreases the potassium (K + ) transient outward current (Ito) current by interacting with channel Kv4.3, resulting in an increase of Ito magnitude and density; 21 SCN3B (which encodes for the β3-subunit of the Na + cardiac channel, and leading to a loss of function of the Na + cardiac channel also cause B BERNE P et al 23 (mutations in this gene cause INa reduction by impairing the trafficking of the cardiac Na + channel to the cell membrane); KCNE5 24 and KCND3 25 (mutations in both genes leading to an increase of the Ito current have been linked to BS). Each of the these 9 genes is responsible for less than 1% of reported cases of BS.…”

Response to the Letter by Kattygnarath et al

“…To summarize, 3 different groups repeatedly demonstrated the ability of MOG1 to increase the sodium current in a heterologous system, after cotransfection with Na v 1.5 1 or in cells overexpressing Na v 1.5. 3,4 This observation was confirmed in neonatal rat cardiomyocytes. 3 Then, our study demonstrated that the p.E83D-MOG1 mutant abolishes the effect of MOG1 on the sodium current in Na v 1.5-stable human embryonic kidney (HEK) cells and has a dominant-negative effect on wild-type MOG1.…”