Cardiac arrhythmias cause more than 400,000 sudden deaths each year in the U.S. Mutations in the cardiac sodium channel gene SCN5A cause several inherited arrhythmias, including Brugada syndrome (BrS) and sick sinus syndrome (SSS). SCN5A encodes the cardiac sodium channel Nav1.5, which produces the cardiac sodium current (INa) responsible for generation and propagation of the cardiac action potential. BrS and SSS mutations in SCN5A act by a loss of function mechanism (i.e. loss or reduction of INa). Reduction of INa is associated with defective trafficking of Nav1.5 to the plasma membrane. However, the molecular mechanisms underlying trafficking of Nav1.5 to the plasma membrane are mostly unknown. To identify critical molecular determinants required for Nav1.5 trafficking, we performed a yeast two-hybrid screen and identified a small protein MOG1 that interacts directly with Nav1.5 and can facilitate trafficking of Nav1.5 to the plasma membrane and increase INa. One dominant negative mutation of MOG1 (E83D) was reported in BrS and also causes a trafficking defect of Nav1.5 and reduced INa. We have found that MOG1 is required for ER export of Nav1.5 during trafficking. Computer-based protein structural modeling followed by protein-protein interaction studies indicate that MOG1 interacts with Sar1-GTPase, one of the most important proteins regulating ER export. Based on these novel findings, we hypothesize that MOG1 regulates ER export of Nav1.5 by regulating the Sar1-GTP cycle. Interestingly, we have found that overexpression of MOG1 in HEK293/tsA201 cells can fully rescue the reduced INa caused by trafficking defects of BrS mutation G1743R and SSS mutation D1275N in SCN5A. We surmise that overexpression of MOG1 can rescue trafficking defects of Nav1.5 mutations causing BrS and SSS in animal models containing mutations G1743R and D1275N as well as heterozygous Scn5a+/- mice (an existing model for BrS). Thus, in this project we will first determine whether overexpression of MOG1 by adeno- associated virus-mediated gene transfer can rescue the trafficking defects of Nav1.5 mutations G1743R and D1275N and attenuate related disease phenotypes in mouse models for BrS and SSS (Aim 1). Currently, no effective therapies exist for BrS or SSS except for invasive implantation of ICDs (Implantable Cardioverter Defibrillators) or pacemakers, respectively. Due to the invasiveness and many side effects associated with ICDs and pacemakers, we believe that the development of a non-invasive therapy, i.e. a novel MOG1- based gene therapy, is highly valuable for human patients. Then, we will utilize a series of integrative biochemical, molecular biological and cellular approaches to identify the molecular mechanisms by which MOG1 controls trafficking of Nav1.5 to cell surface (Aim 2), which may be used to enhance the efficacy of MOG1 gene therapy for BrS and SSS.

Public Health Relevance

A decrease of cardiac sodium currents in the heart causes many significant cardiovascular disorders, including Brugada syndrome (a lethal arrhythmia), sick sinus syndrome, common heart failure, and myocardial ischemia (coronary artery disease and heart attacks). The proposed studies will identify the molecular mechanism by which a small protein MOG1 shuttles the cardiac sodium channel onto the cell surface to increase sodium currents as a driver. The project will then demonstrate that increasing the level of MOG1 in the heart can attenuate disease symptoms associated with reduced sodium currents. If successful, our strategy of MOG1 gene transfer could be translated into an effective, non-invasive therapy for human patients. These studies may lead to development of a novel gene therapy to treat lethal arrhythmias and sudden death associated not only with Brugada syndrome and sick sinus syndrome, but also with more common diseases like myocardial ischemia and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-TAG-Q (01))
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Krull, Holly
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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