Use of mutants

Abstract

The present invention relates to a mutant encoding small molecular chaperone MOG1 gene and its use, which belongs to the field of biomedicine technology. The present invention uses the mutant encoding small molecular chaperone MOG1 gene and the mutant of small molecular chaperone MOG1 in the preparation of a drug for treating diseases such as Brugada syndrome, arrhythmia, dilated cardiomyopathy or heart failure, and the mutant in the present invention can improve myocardial sodium current more effectively than wild-type MOG1.

Description

Technical Field

[0001] The present invention belongs to the field of biopharmaceutical technology, and more specifically ,Tsu it relates to a natural variant and its use.

Background Art

[0002] Arrhythmia causes millions of sudden deaths worldwide every year. Most anti-arrhythmic drugs cannot prevent arrhythmia and, conversely, may cause arrhythmia. Brugada syndrome (BrS) is a fatal ventricular arrhythmia syndrome characterized by ST elevation, ventricular tachycardia (VT) or ventricular fibrillation (VF) in the precordial leads of an electrocardiogram (ECG), causing syncope, epilepsy and sudden death. Brugada syndrome causes a large number of sudden cardiac deaths in relatively young and healthy people aged 30 to 40 years, especially causing 4% of sudden deaths in the population of Southeast Asia. However, the available treatments for this syndrome are limited. Implantable cardioverter defibrillators (ICDs) are commonly used but cannot prevent arrhythmia. Furthermore, ICDs often cause side effects including allergic reactions, infections, inappropriate discharges, etc. Therefore, finding an effective treatment for Brugada syndrome and the associated arrhythmia is extremely important.

[0003] In 1998, the first gene causing Brugada syndrome, SCN5A, was reported. This gene encodes the cardiac sodium channel Nav1.5. The cardiac sodium channel Nav1.5 is responsible for the initiation and conduction of action potentials in human cardiomyocytes. SCN5A mutations that cause arrhythmias like those in Brugada syndrome are loss-of-function mutations. To date, SCN5A mutations are the most common mutation causing Brugada syndrome, accounting for 25%–30% of BrS cases. In 2008, yeast two-hybrid screening identified MOG1, a small molecule chaperone of only 20 kDa that can interact with Nav1.5. Further studies showed that MOG1 facilitates the transport of Nav1.5 from the endoplasmic reticulum to the cell surface, but does not affect sodium channel dynamics or the conductance of individual sodium channels. In 2003, in HEK293 cells, it was discovered that the Brugada syndrome mutation p.G1743R prevents the cardiac sodium channel Nav1.5 from being properly transported to the cell membrane, resulting in a significant decrease in cardiac sodium current, while high expression of MOG1 can restore this defect. Furthermore, the SCN5A mutation p.D1275N causes arrhythmias such as sick sinus syndrome and atrial fibrillation, as well as dilated cardiomyopathy and heart failure. The SCN5A mutation p.D1275N also prevents the proper transport of the cardiac sodium channel Nav1.5 to the cell membrane, resulting in a significant decrease in cardiac sodium current, while high expression of MOG1 can restore this defect. Recently, the SCN5A mutant p.G1743R knock-in (KI) mouse (Scn5aG1746R / +) was established. Homozygous KI mice die before embryonic stage E12. On the other hand, heterozygous Scn5aG1746R / + KI mice reproduce the clinical features of Brugada syndrome, including ST abnormalities (prominent J waves) on the electrocardiogram, spontaneous ventricular tachyarrhythmias (VT), epileptic seizures, and sudden death. The fundamental mechanism of ventricular tachycardia involves a shortening of the cardiac action potential duration, late phase 3 early afterdepolarization (EAD), and a decrease in sodium current density.Furthermore, we discovered that AAV-MOG1 gene therapy using adeno-associated virus AAV as a vector enhances the expression of the exogenous MOG1 gene, increases the expression of the cell surface cardiac sodium channel Nav1.5, increases cardiac sodium current, normalizes cardiac action potential abnormalities, eliminates J waves, and resolves the arrhythmic pathology in SCN5aG1746R / + mice. Humanized KI mice with the SCN5A mutation p.D1275N have been previously reported. We found that p.D1275N humanized KI heterozygous mice exhibit features of arrhythmia, dilated cardiomyopathy, and heart failure. Decreased expression of the cell surface cardiac sodium channel Nav1.5 and decreased cardiac sodium current density are the main causes of this disease. AAV-MOG1 gene therapy also enhanced Nav1.5 expression on the cell surface, improved cardiac sodium current density, and restored the dilated cardiomyopathy and arrhythmic phenotype in humanized KI heterozygous mice. These studies have shown that the use of AAV-MOG1 gene therapy can treat arrhythmias caused by SCN5A mutations, Brugada syndrome, ventricular tachycardia, ventricular fibrillation, sick sinus syndrome, atrial fibrillation, dilated cardiomyopathy, and heart failure.

[0004] However, it has been found that only high doses of MOG1 can increase cardiac sodium current by approximately 1.6 times, which will make future clinical gene therapy more difficult. The main reason for this is that it is necessary to prepare ultra-high titer AAV-MOG1 virus preparations in order to inject ultra-high doses of the virus into patients. To solve this problem, we attempted to mutate the MOG1 protein and found an ultra-potent MOG1 mutant. We found that the E50K MOG1 mutant effectively increases Nav1.5 expression on the cell surface of HEK293 / Nav1.5 cells and increases cardiac sodium current density by 3.7 times. In rat cardiomyocytes, the E50K MOG1 mutant also significantly increased cardiac sodium current density. The main molecular mechanism is as follows. The E50K MOG1 mutant reduces its binding strength to the small GTPase Ran, decreasing the amount of MOG1 in the nucleus and enriching it in the cytoplasm, thereby making it more deeply involved in the transport of cardiac sodium channel Nav1.5 to the cell membrane. Furthermore, the E50K MOG1 mutant also exhibits improved protein stability. In addition, compared to wild-type MOG1, low-dose E50K MOG1 mutants can completely restore the decrease in cardiac sodium current density caused by the SCN5A mutation. Therefore, MOG1 mutants that affect Ran interaction and enhance MOG1 protein stability are considered more effective for use in AAV-MOG1-based gene therapy. [Overview of the project] [Problems that the invention aims to solve]

[0005] This invention solves the technical problem of wild-type MOG1 in the prior art, where high doses are required to improve cardiac sodium current and the effect is insufficient. This invention is a low molecular weight chaperone. protein MOG1 thrust Natural mutants and low-molecular-weight chaperones protein A mutant of MOG1, This is due to a decrease in sodium current.The mutant of this invention is used in the preparation of drugs to treat diseases such as Brugada syndrome, arrhythmias, dilated cardiomyopathy, or heart failure, and it effectively enhances myocardial sodium current compared to wild-type MOG1. [Means for solving the problem]

[0006] According to a first aspect of the present invention, A mutant of the small molecule chaperone protein MOG1, The base sequence is shown as SEQ ID NO:1 Ruko and are characterized by 、 To provide mutants.

[0007] According to a first aspect of the present invention, A mutant of the small molecule chaperone protein MOG1, The amino acid sequence is shown as SEQ ID NO:2. Ruko and are characterized by 、 To provide mutants.

[0008] According to a first aspect of the present invention, This is due to a decrease in sodium current. The low molecular weight chaperone in the preparation of drugs for the treatment of Brugada syndrome, arrhythmia, dilated cardiomyopathy, or heart failure. protein MOG1 thrust Natural mutant A mutant characterized by having a base sequence represented by SEQ ID NO:1 Provides the use of.

[0009] Preferably, the arrhythmia is This is due to a decrease in sodium current. This could be ventricular tachycardia, ventricular fibrillation, sick sinus syndrome, or atrial fibrillation.

[0010] Preferably, before Memorandum Natural mutants are used to improve the sodium current density of cardiomyocytes.

[0011] According to a first aspect of the present invention, This is due to a decrease in sodium current. The low molecular weight chaperone in the preparation of drugs for the treatment of Brugada syndrome, arrhythmia, dilated cardiomyopathy, or heart failure protein MOG1 thrust Natural mutant The amino acid sequence is characterized by being represented by SEQ ID NO:2. It provides the use of mutants.

[0012] Preferably, the arrhythmia is This is due to a decrease in sodium current.This could be ventricular tachycardia, ventricular fibrillation, sick sinus syndrome, or atrial fibrillation.

[0013] Preferably, before Memorandum Natural mutants are used to improve the sodium current density of cardiomyocytes. [Effects of the Invention]

[0014] In general, compared to conventional technology, the above-described technical solutions devised in the present invention have the following main technical advantages.

[0015] (1) Adeno-associated virus (AAV) vectors used in gene therapy can only package genes smaller than 4.3 kb, and the coding region of the SCN5A gene is 6048 bp, exceeding the packaging capacity of adeno-associated virus (AAV) vectors. To overcome this limitation, we have developed a gene therapy technology that treats diseases such as Brugada syndrome, ventricular tachycardia, ventricular fibrillation, sick sinus syndrome, atrial fibrillation, dilated cardiomyopathy, and heart failure by packaging the MOG1 gene, which is only 561 bp, via an adeno-associated virus (AAV) vector. The gene therapy technology of the present invention also has reference significance for other genes and diseases that cannot be used in gene therapy due to their excessive size.

[0016] (2) While AAV-MOG1 vectors packaging wild-type MOG1 can be used in related gene therapies, the highly functional mutants based on MOG1 developed by the present invention (including mutants with disrupted MOG1-Ran binding and mutants with improved MOG1 stability) are more effective, reduce the amount of virus injected into the patient, and are easier to use in clinical therapy.

[0017] (3) In the present invention, the molecular mechanism by which the E50K MOG1 mutant effectively improves the myocardial sodium current compared to wild-type MOG1 is as follows. In HEK293 / Nav1.5 cells, the E50K MOG1 mutant effectively improves the myocardial sodium current compared to wild-type MOG1. MOG1 is a small protein of approximately 22 kD and was first discovered to be a Ran-GTP release factor that regulates the Ran-GTP level in the nucleus and is involved in the nuclear transport of proteins. MOG1 is mainly localized in the nucleus, and its interaction with Ran is highly conserved evolutionarily. The mouse MOG1 mutant R30A is hyperactivated with respect to GTP release by strengthening its binding to Ran-GTP. Recently, as a result of combining nuclear magnetic resonance (NMR)-based structural analysis and biochemical characterization, it has been revealed that several salt bridges (RanR95-MOG150, RanR106-MOG1D27, RanK130-MOG1D70, RanK132-MOG153, and RanK134-MOG153) are involved in the interaction between Ran and MOG1. The human MOG1 mutants E50K and D70K significantly reduce their binding to Ran.

Brief Description of the Drawings

[0018] [Figure 1] It is a diagram showing the results of the improvement of the myocardial sodium current by the E50K MOG1 mutant and wild-type MOG1 in HEK293 / Nav1.5 cells. [Figure 2] It is a diagram showing the results of the myocardial sodium current density by the E50K MOG1 mutant and wild-type MOG1 in primary rat cardiomyocytes. [Figure 3] It is a diagram showing the results that half-dose of the E50K MOG1 super mutant and full-dose of wild-type MOG1 restored the sodium current density of the p.D1275N Nav1.5 mutant. [Figure 4] It is a diagram showing the results that half-dose of the E50K MOG1 super mutant and full-dose of wild-type MOG1 restored the sodium current density of the p.G1743R Nav1.5 mutant. [Figure 5]This figure shows the results of half-dose E50K MOG1 supermutant and full-dose wild-type MOG1 restoring the sodium current density of the p.T353I Nav1.5 mutant. [Figure 6] This figure shows the results of improving Nav1.5 cell surface expression in HEK293 / Nav1.5 cells using the E50K MOG1 mutant and wild-type MOG1. [Figure 7] This figure shows the results of the Ran-binding ability of the E50K MOG1 mutant. [Figure 8] This figure shows the results of the E50K MOG1 mutant, where its expression level in the nucleus is reduced and its expression level in the cytoplasm is increased. [Figure 9] This is a schematic diagram illustrating how the E50K MOG1 mutant of the present invention treats arrhythmias and heart failure caused by SCN5A loss-of-function mutations. [Modes for carrying out the invention]

[0019] To further clarify the object, technical solution, and advantages of the present invention, the present invention will be described in more detail below with reference to the drawings and examples. It should be understood that the specific examples described herein are used solely to illustrate the present invention and are not intended to limit it. Furthermore, the technical features of each embodiment of the present invention described below may be combined with each other, insofar as they do not conflict with each other.

[0020] The mutant in this invention is an E50K mutant in which codon GAA at position 50, which codes for glutamic acid (E), is mutated to codon AAA, which codes for lysine (K). The MOG1 gene has four transcripts, and this invention is based on type A transcript AF265206, which codes for the longest MOG1 protein with a total of 186 amino acids. MOG1 coded by type B transcript AF265205 has a total of 146 amino acids, MOG1 coded by the third transcript NM_001177802 has a total of 165 amino acids, and MOG1 coded by the fourth transcript NM_001330127 has a total of 118 amino acids. Glutamic acid is at position 50 in all transcripts.

[0021] Example 1 The E50K MOG1 mutant effectively enhances myocardial sodium current density compared to wild-type MOG1. MOG1 is a small protein of approximately 22 kD and was first discovered to be a Ran-GTP release factor that regulates Ran-GTP levels in the nucleus and is involved in the nuclear transport of proteins. MOG1 is mainly localized in the nucleus, and its interaction with Ran is highly evolutionarily conserved. The mouse MOG1 mutant R30A is overactivated for GTP release by enhancing binding to Ran-GTP. Recently, a combination of structural analysis based on nuclear magnetic resonance (NMR) and biochemical characterization revealed that several salt bridges (RanR95-MOG150, RanR106-MOG1D27, RanK130-MOG1D70, RanK132-MOG153, and RanK134-MOG153) are involved in the interaction between Ran and MOG1. In 2018, Bao et al. discovered that human MOG1 mutants E50K and D70K significantly reduced Ran binding.

[0022] Next, the present invention established three mutants of human MOG1, namely R29A, E50K, and D70K, and detected the effects of these mutants on cardiac sodium ion channel function and cardiac sodium current (INa) density, which may affect the MOG1-Ran interaction. The present invention transfected HEK293-Nav1.5 cells with the three mutants, a wild-type MOG1-positive control, and an empty plasmid-negative control, respectively, and recorded and analyzed changes in sodium current using whole-cell patch clamp. Compared with the control plasmid, all mutants of the present invention significantly improved the peak density of cardiac sodium current INa (Figure 1A, Figure 1B). Furthermore, compared to wild-type (WT) MOG1, the E50K-MOG1 mutant showed an improvement of approximately 2.14 times (-593.9±75.61 pA / pF VS -276.4±34.05, P<0.01, E50K-MOG1 VS wild-type MOG1). These results indicate that the E50K-MOG1 mutant can significantly improve the peak density of cardiac sodium current (INa) compared to the wild type. As can be seen in Figure 1, in HEK293 / Nav1.5 cells, the E50K MOG1 mutant effectively improved cardiac sodium current compared to wild-type MOG1. (A) Schematic diagram of sodium current, (B) Peak sodium current density, *: P<0.05, **: P<0.01, ns: not significant (n=15~34 cells per group). Therefore, the E50K-MOG1 mutant is more functional than wild-type MOG1. The same results were verified in primary rat cardiomyocytes (Figure 2A, Figure 2B, and Figure 2C). As can be seen in Figure 2, the E50K MOG1 mutant was found to effectively improve cardiac sodium current density compared to wild-type MOG1 in primary rat cardiomyocytes. A: Original schematic diagram of sodium current recorded by whole-cell patch clamp, B: Sodium current IV curve (current vs voltage; activated at -120mV to 100mV), C: Peak sodium current density (pA / pF). *: P<0.05, **: P<0.01, ns: not significant (n=13~19 cells per group).

[0023] Example 2 The E50K MOG1 mutant excessively functionally restores the sodium current abnormalities caused by the SCN5A mutant p.D1275N. Wild-type Nav1.5 and p.D1275N Nav1.5 mutants, as well as varying amounts of wild-type MOG1 p3XFLAG-CMV10-WT-MOG1 or mutant MOG1 p3XFLAG-CMV10-E50K-MOG1, were transmitted to the tsA-201 cell line, and sodium currents were then recorded by patch clamp. The p.D1275N SCN5A mutant reduced the sodium current peak density by approximately 32.48% (-132.8±19.76 vs -196.7±24.33, D1275N-Nav1.5 vs wild-type Nav1.5). 0.6 μg of wild-type MOG1 can restore the sodium current density of D1275N-Nav1.5, but 0.3 μg of wild-type MOG1 cannot improve the sodium current density of the p.D1275N mutant. Conversely, 0.3 μg of E50K MOG1 mutant can restore the sodium current density of D1275N-Nav1.5 to normal levels, showing the same efficacy as 0.6 μg of wild-type MOG1 (Figures 3A, 3B, and 3C). As can be seen from Figure 3, half-dose E50K MOG1 supermutant is equivalent to full-dose wild-type MOG1 in restoring the sodium current density of the p.D1275N Nav1.5 mutant. *:P<0.05, **:P<0.01, ns:not significant (n=25~31 cells per group).

[0024] Example 3 The E50K MOG1 mutant excessively and functionally restores the sodium current abnormality caused by the SCN5A mutant p.G1743R. Using the same experiments as with the p.D1275N Nav1.5 mutant described above, 0.3 μg of the E50K MOG1 mutant was able to restore the sodium current density of G1743R-Nav1.5 to normal, demonstrating the same efficacy as 0.6 μg of wild-type MOG1 (Figure 4A, Figure 4B, Figure 4C). As can be seen from Figure 4, half-dose of the E50K MOG1 supermutant is equivalent to full-dose wild-type MOG1 in restoring the sodium current density of the p.G1743R Nav1.5 mutant. *:P<0.05, **:P<0.01, ns:not significant (n=14~22 cells per group).

[0025] Example 4 The E50K MOG1 mutant excessively functionally restores the sodium current abnormalities caused by the SCN5A mutant p.T353I. The Nav1.5 mutant p.T353I causes Brugada syndrome. The sodium current was reduced by approximately 74% compared to the wild-type channel. In the same experiments as with the p.D1275N and p.G1743R Nav1.5 mutants described above, 0.3 μg of the E50K MOG1 mutant was demonstrated to restore the sodium current density of T353I-Nav1.5 to normal, demonstrating the same efficacy as 0.6 μg of wild-type MOG1 (Figures 5A, 5B, and 5C). As can be seen from Figure 5, half-dose of the E50K MOG1 supermutant is equivalent to full-dose wild-type MOG1 in restoring the sodium current density of the p.T353I Nav1.5 mutant. *:P<0.05, **:P<0.01, ns:not significant (n=14~22 cells per group).

[0026] Example 5 The E50K MOG1 mutant more effectively enhances Nav1.5 cell surface expression than wild-type MOG1. In HEK293 / Nav1.5 cells, neither the E50K nor the D70K MOG1 mutants affected total intracellular Nav1.5 protein expression, similar to wild-type MOG1 (Figure 6A, Figure 6B). However, regarding Nav1.5 on the cell membrane surface, wild-type MOG1 significantly increased the expression level of Nav1.5 on the cell surface compared to the control vector (Figure 6C, Figure 6D). Compared to wild-type MOG1, the E50K MOG1 mutant more strongly and significantly increased the expression level of Nav1.5 on the cell surface, while the D70K MOG1 mutant did not have this effect (Figure 6C, Figure 6D). As can be seen from Figure 6, in HEK293 / Nav1.5 cells, the E50K MOG1 mutant effectively increased Nav1.5 cell surface expression compared to wild-type MOG1. A: Schematic diagram of Western blotting (WB) of total intracellular Nav.15 expression. B: Quantitative statistical analysis similar to (A) Western blotting diagram. C: Schematic diagram of Western blotting of Nav.15 expression on the cell membrane surface. D: Quantitative statistical analysis similar to (C) Western blotting diagram. *: P<0.05, **: P<0.01, ns: not significant. Therefore, the molecular mechanism by which the E50K MOG1 mutant effectively increases myocardial sodium current compared to wild-type MOG1 is as follows: The E50K MOG1 mutant effectively transports Nav1.5 to the cell surface more effectively than wild-type MOG1.

[0027] Example 6 The E50K MOG1 mutant almost completely lost its ability to bind to Ran. To further elucidate the molecular mechanism by which the E50K MOG1 mutant enhances sodium current, this invention detected the binding ability of the E50K MOG1 mutant to Ran by glutathione-S-transferase (GST) pull-down experiment (GST pull-down). The ability to pull down MOG1 using GST-Ran as bait was detected. Compared to wild-type MOG1, the E50K MOG1 mutant reduced Ran binding by approximately 95%, while the D70K MOG1 mutant reduced this binding by only approximately 26% (Figure 7A, Figure 7B). Furthermore, this invention further verified the experimental results of the GST pull-down experiment by immunoprecipitation. In tsA-201 cells, there is an interaction between MOG1 and Ran (Figure 7C). Compared to wild-type MOG1, the E50K MOG1 mutant reduced Ran binding by approximately 92%, while the D70K MOG1 mutant reduced it by approximately 47% (Figure 7D, Figure 7E). A: GST pull-down experiment. GST-Ran or control GST protein was purified from E. coli using glutathione Sepharose as feed, and the results are shown by carmine staining (below). FLAG-labeled wild-type MOG1, E50K, or D70K MOG1 mutants were transmitted to human tsA201 cells for expression. Cell lysates were used as prey. GST pull-down analysis was performed by mixing feed and prey. Next, interactions were detected by Western blotting using anti-FLAG antibody. B: Quantitative statistical analysis similar to (A) Western blotting figure. C: Co-immunoprecipitation experiment. FLAG-labeled MOG1 and HA-labeled Ran were co-expressed in TSA-201 cells, lysed, incubated with HA antibody or control mouse IgG, and precipitated. The interaction between wild-type MOG1 and wild-type Ran was then detected by Western blotting using anti-FLAG antibody. D: Immunoprecipitation experiment to detect the effect of MOG1 mutants on interaction with Ran. E: Quantitative statistical analysis similar to (D) Western blotting figure. **: P<0.01 (n=3 per group).

[0028] Example 7 The E50K MOG1 mutant reduces nuclear expression and increases cytoplasmic expression. Because the E50K MOG1 mutant almost completely loses its ability to bind to Ran, it is thought that this mutation can reduce nuclear expression, thereby significantly increasing cytoplasmic expression. When wild-type and mutant MOG1, both possessing the FLAG tag, were expressed in tsA-201 cells, the total protein expression levels of wild-type and mutant MOG1 were found to be equivalent (Figure 8A, Figure 8B). However, upon separation of nuclear and cytoplasmic components, it was found that the nuclear expression levels of the E50K MOG1 mutant and the E70K MOG1 mutant were reduced by approximately 95.72% and 63.32%, respectively (Figure 8C, Figure 8D). Furthermore, the E50K MOG1 and E70K MOG1 mutants increased cytoplasmic expression by approximately 42.67% and 19.14%, respectively (Figure 8E, Figure 8F). On the other hand, the R29A, D33A, or D44A MOG1 mutants did not affect their expression in the nucleus or cytoplasm. Immunofluorescence was also used to detect the expression of the E50K MOG1 mutant in HEK293 cells. As shown in Figure 8G, wild-type MOG1 was uniformly distributed in the nucleus and cytoplasm, while the D70K MOG1 mutant showed decreased nuclear expression and increased cytoplasmic expression. The E50K MOG1 mutant, however, showed almost no nuclear expression and was highly expressed in the cytoplasm. As can be seen from Figure 8, the E50K MOG1 mutant reduced nuclear expression, resulting in increased cytoplasmic expression. A: Schematic diagram of Western blotting. FLAG-labeled wild-type and MOG1 mutants were transmitted to tsA-201 cells, and total MOG1 protein expression was detected using an anti-FLAG antibody. B: Quantitative statistical analysis similar to (A) Western blotting diagram. C: Schematic diagram of Western blotting of nucleoproteins. D: Quantitative statistical analysis similar to (C) Western blotting diagram. E: Schematic diagram of Western blotting of cytoplasmic proteins. F: Quantitative statistical analysis similar to (E) Western blotting diagram. G: Immunofluorescence staining shows the specific location of MOG1 protein in tsA-201 cells.FLAG-labeled MOG1 plasmid was transmitted to tsA-201 cells, and the MOG1 protein was incubated with anti-FLAG antibody, followed by a secondary antibody. Cell nuclei were then indicated by blue DAPI staining. Scale bar: 20 μm.

[0029] Figure 9 is a schematic diagram illustrating how the E50K MOG1 mutant of the present invention treats arrhythmias and heart failure caused by SCN5A loss-of-function mutations. Loss-of-function mutations such as p.G1743R, p.D1275N, and p.T353I reduce the sodium current density produced by the cardiac sodium ion channel Nav1.5, leading to diseases such as Brugada syndrome, dilated cardiomyopathy, heart failure, atrial fibrillation, and sick sinus syndrome. The E50K MOG1 mutant can restore the effects of these Nav1.5 mutants on cardiac sodium channel function and cardiac sodium current density, with a higher degree of restoration than the wild type. The molecular mechanism is as follows: The E50K MOG1 mutant inhibits the interaction between MOG1 and the nuclear protein Ran, thereby reducing the number of MOG1 entering the nucleus and thus significantly increasing the number of MOG1 in the cytoplasm. Therefore, the E50K MOG1 mutant can interact more effectively with Nav1.5, promote Nav1.5 upper membrane transport, and ultimately restore sodium current to normal levels, thereby achieving the goal of treating the disease.

[0030] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit it, and that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should all be within the scope of protection of the present invention.

Claims

1. Use of a mutant of the low molecular weight chaperone protein MOG1, whose amino acid sequence is shown as SEQ ID NO:2, in the preparation of a drug for treating Brugada syndrome, arrhythmia, dilated cardiomyopathy, or heart failure caused by a decrease in sodium current.

2. The use according to claim 1, characterized in that the arrhythmia is ventricular tachycardia, ventricular fibrillation, sick sinus syndrome, or atrial fibrillation caused by a decrease in sodium current.

3. The use according to claim 1 or 2, characterized in that the mutant is used to improve the sodium current density of cardiomyocytes.

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