title: MOG1 rescues defective trafficking of Na(v)1.5 mutations in Brugada syndrome and sick sinus syndrome.
abstract: BACKGROUND
  Loss-of-function mutations in Na(v)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 Na(v)1.5 and sodium current (I(Na)) density, thus we hypothesize that MOG1 can serve as a therapeutic target for sodium channelopathies.
  
  
  RESULTS
  Knockdown of MOG1 expression using small interfering RNAs reduced Na(v)1.5 PM expression, decreased I(Na) densities by 2-fold in HEK/Na(v)1.5 cells and nearly abolished I(Na) in mouse cardiomyocytes. MOG1 did not affect Na(v)1.5 PM turnover. MOG1 small interfering RNAs caused retention of Na(v)1.5 in endoplasmic reticulum, disrupted the distribution of Na(v)1.5 into caveolin-3-enriched microdomains, and led to redistribution of Na(v)1.5 to noncaveolin-rich domains. MOG1 fully rescued the reduced PM expression and I(Na) densities by Na(v)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 restored I(Na) in a heterozygous state (mixture of wild type and mutant Na(v)1.5) to a full level of a homozygous wild-type state.
  
  
  CONCLUSIONS
  Use of MOG1 to enhance Na(v)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.
authors: Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Susmita
authors: S
authors: Chakrabarti
authors: Xiaofen
authors: X
authors: Wu
authors: Zhaogang
authors: Z
authors: Yang
authors: Ling
authors: L
authors: Wu
authors: Sandro L
authors: SL
authors: Yong
authors: Cuntai
authors: C
authors: Zhang
authors: Keli
authors: K
authors: Hu
authors: Qing K
authors: QK
authors: Wang
authors: Qiuyun
authors: Q
authors: Chen
mesh_terms: D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D012313:RNA