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Background— Loss-of-function mutations in Nav 1.5 cause sodium channelopathies, including Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome; however, no effective therapy exists. MOG1 increases plasma membrane (PM) expression of Nav 1.5 and sodium current (I Na ) density, thus we hypothesize that MOG1 can serve as a therapeutic target for sodium channelopathies.Methods and Results— Knockdown ofMOG1 expression using small interfering RNAs reduced Nav 1.5 PM expression, decreasedI Na densities by 2-fold in HEK/Nav 1.5 cells and nearly abolishedI Na in mouse cardiomyocytes. MOG1 did not affect Nav 1.5 PM turnover.MOG 1 small interfering RNAs caused retention of Nav 1.5 in endoplasmic reticulum, disrupted the distribution of Nav 1.5 into caveolin-3–enriched microdomains, and led to redistribution of Nav 1.5 to noncaveolin-rich domains. MOG1 fully rescued the reduced PM expression andI Na densities by Nav 1.5 trafficking–defective mutation D1275N associated with sick sinus syndrome/dilated cardiomyopathy/atrial arrhythmias. For Brugada syndrome mutation G1743R, MOG1 restored the impaired PM expression of the mutant protein and restoredI Na in a heterozygous state (mixture of wild type and mutant Nav 1.5) to a full level of a homozygous wild-type state.Conclusions— Use of MOG1 to enhance Nav 1.5 trafficking to PM may be a potential personalized therapeutic approach for some patients with Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome in the future.

MOG1 Rescues Defective Trafficking of Na v 1.5 Mutations in Brugada Syndrome and Sick Sinus Syndrome

MOG1 Rescues Defective Trafficking of Na _v 1.5 Mutations in Brugada Syndrome and Sick Sinus Syndrome