Mutants encoding the small molecular chaperone MOG1 gene and uses thereof

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 relates to the field of biopharmaceutical technology, and more particularly to a mutant encoding the small molecule chaperone MOG1 gene and its uses. [Background technology]

[0002] Cardiac arrhythmias cause millions of sudden deaths worldwide every year. Most antiarrhythmic drugs cannot prevent arrhythmias and may instead induce arrhythmias. Brugada syndrome (BrS) is a fatal ventricular arrhythmia syndrome characterized by ST-segment elevation in the precordial leads of the electrocardiogram (ECG), ventricular tachycardia (VT) or ventricular fibrillation (VF), leading to syncope, epilepsy, and sudden death. Brugada syndrome causes a large number of sudden cardiac deaths in relatively young and healthy individuals aged 30-40 years, and is responsible for 4% of sudden deaths in the population of Southeast Asia in particular. However, there are limited treatments available for this syndrome. Although implantable cardioverter defibrillators (ICDs) are commonly used, they do not prevent arrhythmias. Furthermore, ICDs often cause side effects including allergic reactions, infections, and inappropriate discharges. Therefore, finding an effective treatment for Brugada syndrome and its associated arrhythmias is crucial.

[0003] In 1998, the first gene causing Brugada syndrome was reported, SCN5A, which 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 such as Brugada syndrome are loss-of-function mutations. To date, SCN5A mutations are the most common mutations causing Brugada syndrome, causing 25%–30% of BrS cases. In 2008, a yeast two-hybrid screen identified MOG1, a small molecular 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, we found that the Brugada syndrome mutation p.G1743R in HEK293 cells prevented cardiac sodium channel Nav1.5 from being properly transported to the cell membrane, resulting in a significant reduction in cardiac sodium current, while high expression of MOG1 could restore this defect. In addition, the SCN5A mutation p.D1275N causes arrhythmias such as sick sinus syndrome and atrial fibrillation, dilated cardiomyopathy, and heart failure. The SCN5A mutation p.D1275N also prevented cardiac sodium channel Nav1.5 from being properly transported to the cell membrane, resulting in a significant reduction in cardiac sodium current, while high expression of MOG1 could restore this defect. Recently, SCN5A mutant p.G1743R knock-in (KI) mice (Scn5aG1746R / +) were established. Homozygous KI mice die before embryonic stage E12. On the other hand, heterozygous Scn5aG1746R / + KI mice recapitulate the clinical features of Brugada syndrome, including ST abnormalities (prominent J waves) on electrocardiograms, spontaneous ventricular tachyarrhythmias (VT), epileptic seizures, and sudden death. The underlying mechanism of ventricular tachycardia is a shortened cardiac action potential duration, late phase 3 early afterdepolarizations (EADs), and reduced sodium current density.Furthermore, we found that AAV-MOG1 gene therapy using adeno-associated virus (AAV) as a vector improved the expression of exogenous MOG1 gene, increased the expression of cardiac sodium channel Nav1.5 on the cell surface, increased cardiac sodium current, normalized cardiac action potential abnormalities, eliminated J waves, and eliminated arrhythmia pathology in Scn5aG1746R / + mice. Humanized KI mice carrying the SCN5A mutation p.D1275N have been previously reported. We found that p.D1275N humanized KI heterozygous mice had characteristics of arrhythmia, dilated cardiomyopathy, and heart failure. The reduced expression of cardiac sodium channel Nav1.5 on the cell surface and reduced cardiac sodium current density are the main causes of the disease. AAV-MOG1 gene therapy also improved Nav1.5 expression on the cell surface, improved cardiac sodium current density, and rescued the dilated cardiomyopathy and arrhythmia phenotypes in humanized KI heterozygous mice. These studies demonstrated that AAV-MOG1 gene therapy can be used to 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 was found that only high doses of MOG1 could improve cardiac sodium current by about 1.6-fold, which makes future clinical gene therapy more difficult. The main reason is that ultra-high titer AAV-MOG1 virus preparations need to be prepared in order to inject ultra-high doses of virus into patients. To solve this problem, we tried to mutate the MOG1 protein and found an ultra-potent MOG1 mutant. We found that the E50K MOG1 mutant effectively improved Nav1.5 expression on the cell surface of HEK293 / Nav1.5 cells and improved cardiac sodium current density by 3.7-fold. In addition, in rat cardiomyocytes, the E50K MOG1 mutant also significantly improved cardiac sodium current density. The main molecular mechanisms are as follows: The E50K MOG1 mutant reduces the binding strength to the small GTPase Ran, reduces the amount of MOG1 in the nucleus and enriches MOG1 in the cytoplasm, making it more deeply involved in the transport of cardiac sodium channel Nav1.5 to the plasma membrane, and also improves the protein stability of the E50K MOG1 mutant. Moreover, compared with wild-type MOG1, low-dose E50K MOG1 mutant can fully restore the reduction in cardiac sodium current density caused by SCN5A mutation. Therefore, MOG1 mutants that affect the interaction with Ran and increase the stability of MOG1 protein may be more effectively used in AAV-MOG1-based gene therapy. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention solves the technical problem of wild-type MOG1 in the prior art, which is that the dose for improving cardiac sodium current is high and the effect is insufficient. The present invention uses a mutant encoding small molecular chaperone MOG1 gene and a 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 improves myocardial sodium current more effectively than wild-type MOG1. [Means for solving the problem]

[0006] According to a first aspect of the present invention, there is provided a mutant encoding the small molecule chaperone MOG1 gene, the nucleotide sequence of which is shown in SEQ ID NO:1.

[0007] According to a first aspect of the present invention there is provided a mutant of the small molecule chaperone MOG1, the amino acid sequence of which is shown in SEQ ID NO:2.

[0008] According to a first aspect of the present invention there is provided the use of a mutant encoding the small molecular chaperone MOG1 gene in the preparation of a medicament for the treatment of Brugada syndrome, arrhythmia, dilated cardiomyopathy or heart failure.

[0009] Preferably, the arrhythmia is ventricular tachycardia, ventricular fibrillation, sick sinus syndrome or atrial fibrillation.

[0010] Preferably, the mutant encoding the small molecular chaperone MOG1 gene is used to improve sodium current density in cardiomyocytes.

[0011] According to a first aspect of the invention there is provided the use of said mutant of the small molecular chaperone MOG1 in the preparation of a medicament for the treatment of Brugada syndrome, arrhythmia, dilated cardiomyopathy or heart failure.

[0012] Preferably, the arrhythmia is ventricular tachycardia, ventricular fibrillation, sick sinus syndrome or atrial fibrillation.

[0013] Preferably, the mutant of the small molecular chaperone MOG1 is used to increase sodium current density in cardiomyocytes. Effect of the Invention

[0014] Generally speaking, compared with the prior art, the above technical solutions devised in the present invention mainly have the following technical advantages:

[0015] (1) The adeno-associated virus (AAV) vector used in gene therapy can only package genes less than 4.3 kb in size, and the size of the coding region of the SCN5A gene is 6048 bp, which exceeds the packaging capacity of the adeno-associated virus (AAV) vector. To overcome this limitation, a gene therapy technique was developed to treat diseases such as Brugada syndrome, ventricular tachycardia, ventricular fibrillation, sick sinus syndrome, atrial fibrillation, dilated cardiomyopathy, and heart failure by packaging only 561 bp of MOG1 gene via the adeno-associated virus (AAV) vector. The gene therapy technique of the present invention also has reference significance for other genes and diseases that cannot be used in gene therapy because the genes are too large.

[0016] (2) Although AAV-MOG1 vectors packaging wild-type MOG1 can be used for related gene therapy, the hyperfunctional mutants based on MOG1 developed by the present invention (including mutants that disrupt MOG1-Ran binding and mutants that improve MOG1 stability) are more effective, reduce the amount of virus injected into patients, and are easier to use in clinical treatment.

[0017] (3) In the present invention, the molecular mechanism by which the E50K MOG1 mutant improves myocardial sodium current more effectively than wild-type MOG1 is as follows. In HEK293 / Nav1.5 cells, the E50K MOG1 mutant improves myocardial sodium current more effectively than wild-type MOG1. MOG1 is a small protein of about 22 kD, and was first discovered to be a Ran-GTP releasing 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. Mouse MOG1 mutant R30A is hyperactivated for GTP release by enhancing binding to Ran-GTP. Recently, nuclear magnetic resonance (NMR)-based structural analysis combined with biochemical characterization revealed that the interaction between Ran and MOG1 involves several salt bridges (RanR95-MOG150, RanR106-MOG1D27, RanK130-MOG1D70, RanK132-MOG153, and RanK134-MOG153). Human MOG1 mutants E50K and D70K show significantly reduced binding to Ran. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 shows the results of improving cardiac sodium current by E50K MOG1 mutant and wild-type MOG1 in HEK293 / Nav1.5 cells. [Diagram 2] FIG. 1 shows the results of myocardial sodium current density with E50K MOG1 mutant and wild-type MOG1 in rat primary cardiomyocytes. [Diagram 3] FIG. 1 shows that half the dose of the E50K MOG1 supermutant and full dose of wild-type MOG1 restored sodium current density in the p.D1275N Nav1.5 mutant. [Figure 4] FIG. 1 shows that half the dose of the E50K MOG1 supermutant and full dose of wild-type MOG1 restored sodium current density in the p.G1743R Nav1.5 mutant. [Diagram 5]FIG. 1 shows that half the dose of the E50K MOG1 supermutant and full dose of wild-type MOG1 restored sodium current density in the p.T353I Nav1.5 mutant. [Figure 6] FIG. 1 shows the results of enhanced cell surface expression of Nav1.5 by the E50K MOG1 mutant and wild-type MOG1 in HEK293 / Nav1.5 cells. [Figure 7] FIG. 1 shows the results of the binding ability of the E50K MOG1 mutant to Ran. [Figure 8] FIG. 1 shows that the E50K MOG1 mutant reduces expression in the nucleus and increases expression in the cytoplasm. [Figure 9] FIG. 1 is a schematic diagram of the E50K MOG1 mutant of the present invention treating arrhythmia and heart failure caused by SCN5A loss-of-function mutations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In order to make the objectives, technical solutions and advantages of the present invention clearer, 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 in this specification are only used to explain the present invention, and are not used to limit the present invention. Furthermore, the technical features according to each embodiment of the present invention described below may be combined with each other as long as they are not mutually inconsistent.

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

[0021] Example 1 The E50K MOG1 mutant enhances myocardial sodium current density more effectively than wild-type MOG1. MOG1 is a small protein of approximately 22 kD that was first discovered to be a Ran-GTP releasing 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 evolutionarily conserved. The mouse MOG1 mutant R30A is hyperactive for GTP release by enhancing its binding to Ran-GTP. Recently, a combination of nuclear magnetic resonance (NMR)-based structural analysis and biochemical characterization revealed that the interaction between Ran and MOG1 involves several salt bridges (RanR95-MOG150, RanR106-MOG1D27, RanK130-MOG1D70, RanK132-MOG153, and RanK134-MOG153). In 2018, Bao et al. found that human MOG1 mutants E50K and D70K significantly reduced binding to Ran.

[0022] Next, the present invention establishes three mutants of human MOG1, namely R29A, E50K and D70K, and detects the effects of these mutants on cardiac sodium ion channel function and cardiac sodium current (INa) density, which may affect MOG1-Ran interaction. The present invention transfects the three mutants, wild-type MOG1 positive control and empty plasmid negative control into HEK293-Nav1.5 cells, respectively, and uses whole-cell patch clamp to record and analyze the changes in sodium current. Compared with the control plasmid, all mutants of the present invention significantly improve the peak density of cardiac sodium current INa (Figure 1A, Figure 1B). Moreover, compared with wild-type (WT) MOG1, E50K-MOG1 mutant is improved by about 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 with the wild type. As can be seen from Figure 1, in HEK293 / Nav1.5 cells, the E50K MOG1 mutant improved myocardial sodium current more effectively than wild type MOG1. (A) Schematic diagram of sodium current, (B) Peak current density of sodium, *: P<0.05, **: P<0.01, ns: not significant (n=15~34 cells per group). Therefore, the E50K-MOG1 mutant has a higher function than the wild type MOG1. The same results were also verified in rat primary cardiomyocytes (Figure 2A, Figure 2B, and Figure 2C). As can be seen from Figure 2, the E50K MOG1 mutant was found to improve myocardial sodium current density more effectively than wild type MOG1 in rat primary 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~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 functionally restores the sodium current abnormality caused by the SCN5A mutation p.D1275N. Wild-type Nav1.5 and p.D1275N Nav1.5 mutant, as well as various amounts of wild-type MOG1 p3XFLAG-CMV10-WT-MOG1 or mutant MOG1 p3XFLAG-CMV10-E50K-MOG1, were transfected into tsA-201 cell lines, and then sodium currents were recorded by patch clamp. The p.D1275N SCN5A mutant reduced the sodium current peak density by about 32.48% (-132.8±19.76 vs -196.7±24.33, D1275N-Nav1.5 vs wild-type Nav1.5). 0.6μg wild-type MOG1 can restore the sodium current density of D1275N-Nav1.5, but 0.3μg wild-type MOG1 cannot improve the sodium current density of p.D1275N mutant. Conversely, 0.3μg E50K MOG1 mutant can restore the sodium current density of D1275N-Nav1.5 normally, with the same efficacy as 0.6μg wild-type MOG1 (Figure 3A, B, and C). As can be seen from Figure 3, half dose of E50K MOG1 super mutant is equivalent to full dose of wild-type MOG1 in restoring the sodium current density of 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 hyperfunctionally restores the sodium current abnormality caused by the SCN5A mutation p.G1743R. The same experiment as the p.D1275N Nav1.5 mutant above demonstrated that 0.3 μg of the E50K MOG1 mutant can restore the sodium current density of G1743R-Nav1.5 to normal, with the same efficacy as 0.6 μg of wild-type MOG1 (Figure 4A, B, C). As can be seen in Figure 4, a half dose of the E50K MOG1 super mutant is equivalent to a full dose of 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 hyperfunctionally restores the sodium current abnormality caused by the SCN5A mutation p.T353I. The Nav1.5 mutation p.T353I causes Brugada syndrome. The sodium current was reduced by about 74% compared to the wild-type channel. The same experiment as the p.D1275N and p.G1743R Nav1.5 mutants described above demonstrated that 0.3 μg of the E50K MOG1 mutant can restore the sodium current density of T353I-Nav1.5 to normal, with the same efficacy as 0.6 μg of wild-type MOG1 (FIG. 5A, FIG. 5B, and FIG. 5C). As can be seen in FIG. 5, a half dose of the E50K MOG1 super mutant is equivalent to a full dose of 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 enhances cell surface expression of Nav1.5 more effectively than wild-type MOG1. In HEK293 / Nav1.5 cells, similar to wild-type MOG1, neither the E50K nor the D70K MOG1 mutant affected the expression of total Nav1.5 protein in cells (Figure 6A, Figure 6B). However, for Nav1.5 on the cell membrane surface, wild-type MOG1 significantly increased the expression 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 enhanced the expression of Nav1.5 on the cell surface more strongly and significantly, whereas 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 enhanced the cell surface expression of Nav1.5 more effectively than wild-type MOG1. A: Schematic diagram of Western blotting (WB) of the total Nav.15 expression level in cells. B: Quantitative statistical analysis as in (A) Western blotting diagram. C: Schematic diagram of Western blotting of the Nav.15 expression level on the cell membrane surface. D: Quantitative statistical analysis as in (C) Western blotting diagram. *: P<0.05, **: P<0.01, ns: not significant. Therefore, the molecular mechanism by which the E50K MOG1 mutant enhances cardiac sodium current more effectively than wild-type MOG1 is as follows: The E50K MOG1 mutant transports Nav1.5 to the cell surface more effectively than wild-type MOG1.

[0027] Example 6 The E50K MOG1 mutant almost lost its binding to Ran. To further clarify the molecular mechanism by which the E50K MOG1 mutant improves sodium current, the present 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 was detected by using GST-Ran as bait. Compared with wild-type MOG1, the E50K MOG1 mutant reduced its binding to Ran by about 95%, while the D70K MOG1 mutant reduced this binding by only about 26% (Figure 7A, Figure 7B). Furthermore, the present invention further verified the results of the GST pull-down experiment by co-immunoprecipitation. In tsA-201 cells, there is an interaction between MOG1 and Ran (Figure 7C). Compared with wild-type MOG1, the E50K MOG1 mutant reduced the binding to Ran by about 92%, whereas the D70K MOG1 mutant reduced it by about 47% (Fig. 7D, Fig. 7E). A: GST pull-down experiment. GST-Ran or control GST protein was purified from E. coli by glutathione sepharose as bait, and the results are shown by carmine staining (bottom). FLAG-tagged wild-type MOG1, E50K, or D70K MOG1 mutant was transfected into human tsA201 cells for expression. Cell lysates were used as prey. The bait and prey were mixed to perform GST pull-down analysis. The interaction was then detected by Western blot using anti-FLAG antibody. B: Quantitative statistical analysis similar to (A) Western blotting figure. C: Co-immunoprecipitation experiment. FLAG-tagged MOG1 and HA-tagged Ran were co-expressed in TSA-201 cells, then lysed and precipitated by incubation with HA antibody or control mouse IgG, and the interaction between wild-type MOG1 and wild-type Ran was then detected by Western blot using anti-FLAG antibody. D: Co-immunoprecipitation experiment to detect the effect of MOG1 mutants on the interaction with Ran. E: Quantitative statistical analysis as in (D) Western blotting figure. **: P<0.01 (n=3 per group).

[0028] Example 7 The E50K MOG1 mutant leads to reduced nuclear expression and enhanced cytoplasmic expression. Because the E50K MOG1 mutant has almost completely lost its ability to bind Ran, this MOG1 mutant may be able to reduce nuclear expression, thereby significantly increasing cytoplasmic expression. When wild-type and mutant MOG1 carrying a 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 and Figure 8B). However, when the nuclear and cytoplasmic components were separated, the expression of the E50K MOG1 mutant and the E70K MOG1 mutant in the nucleus was found to be reduced by approximately 95.72% and approximately 63.32%, respectively (Figure 8C and Figure 8D). In addition, the E50K MOG1 and E70K MOG1 mutants enhanced cytoplasmic expression by approximately 42.67% and approximately 19.14%, respectively (Figure 8E and Figure 8F). Meanwhile, the R29A, D33A, or D44A MOG1 mutants did not affect their expression in the nucleus or cytoplasm. We also detected the expression of the E50K MOG1 mutant in HEK293 cells by immunofluorescence. As shown in Figure 8G, wild-type MOG1 is distributed uniformly in the nucleus and cytoplasm, while the D70K MOG1 mutant has reduced expression in the nucleus and increased expression in the cytoplasm, whereas the E50K MOG1 mutant is hardly expressed in the nucleus and highly expressed in the cytoplasm. As can be seen from Figure 8, the E50K MOG1 mutant reduces the expression level in the nucleus, resulting in increased expression in the cytoplasm. A: Schematic diagram of Western blotting. FLAG-tagged wild-type and MOG1 mutants were transfected into tsA-201 cells, and total MOG1 protein expression was detected by anti-FLAG antibody. B: Quantitative statistical analysis as in (A) Western blotting figure. C: Schematic diagram of Western blotting of nuclear proteins. D: Quantitative statistical analysis as in (C). E: Schematic diagram of Western blotting of cytoplasmic proteins. F: Quantitative statistical analysis as in (E). G: Immunofluorescence staining shows the specific location of MOG1 protein in tsA-201 cells.FLAG-tagged MOG1 plasmid was transfected into tsA-201 cells, and MOG1 protein was incubated with anti-FLAG antibody followed by secondary antibody, revealing cell nuclei with blue DAPI staining. Scale bar: 20 um.

[0029] FIG. 9 is a schematic diagram of the E50K MOG1 mutant of the present invention treating arrhythmia 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 generated by the cardiac sodium ion channel Nav1.5, causing 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 to normal, and the restoration strength is higher than that of the wild type. The molecular mechanism is as follows: The E50K MOG1 mutant inhibits the interaction of MOG1 with the nuclear protein Ran, thereby reducing the number of MOG1 entering the nucleus, and thus greatly increasing the number of MOG1 in the cytoplasm. Therefore, the E50K MOG1 mutant can interact with Nav1.5 more effectively, promote the epithelial transport of Nav1.5, and ultimately restore sodium current to normal levels, achieving the purpose of treating the disease.

[0030] Those skilled in the art will easily understand that the above description is merely a preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should all be included in the protection scope of the present invention.

Claims

1. A mutant encoding the small molecule chaperone MOG1 gene, characterized in that the base sequence is shown in SEQ ID NO:

1.

2. A mutant of the small molecule chaperone MOG1, characterized in that the amino acid sequence is shown in SEQ ID NO:

2.

3. Use of a mutant encoding the small molecular chaperone MOG1 gene according to claim 1 in the preparation of a drug for treating Brugada syndrome, arrhythmia, dilated cardiomyopathy or heart failure.

4. 4. The use according to claim 3, wherein the arrhythmia is ventricular tachycardia, ventricular fibrillation, sick sinus syndrome or atrial fibrillation.

5. The use according to claim 3 or 4, characterized in that the mutant encoding the small molecular chaperone MOG1 gene is used to improve sodium current density in cardiomyocytes.

6. Use of the mutant of small molecular chaperone MOG1 according to claim 2 in the preparation of a drug for treating Brugada syndrome, arrhythmia, dilated cardiomyopathy or heart failure.

7. 7. The use according to claim 6, wherein the arrhythmia is ventricular tachycardia, ventricular fibrillation, sick sinus syndrome or atrial fibrillation.

8. The use according to claim 6 or 7, characterized in that the mutant of the small molecular chaperone MOG1 is used to improve sodium current density in cardiomyocytes.

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