Genomics of SOX13 gene is dynamic in Type 1 Diabetes
Main Article Content
Abstract
Background: The SOX13 (SRY-box 13) genes belong to the high mobility group box (HMG-box) family and are primarily associated with testicular concern. This gene has an HMG-box domain that binds with DNA and plays a crucial role in growth and survival. Specifically, SOX13 is located on chromosome 1 and is an insulin-mediated gene. The presence of insulin is significant evidence of genomics variation in the SRY-box transcription factor 13, which is sensitive in type-1 diabetes (T1D). So, the SRY-box transcription factor 13 (ICA12) genes circulate in islets and the exocrine pancreas and are considered a powerful auto-antigen. Thus, beta-cell antigens trigger mechanisms of peripheral tolerance. The recognition of ICA12 as an auto-antigen is an effective marker for autoimmunity.
Aim: The study aims to in-silico analyze the SRY-box 13 gene from the family of SRY-related high mobility group box (HMG-box) genes (SOX gene family) in mammals. So, perform bioinformatics and computational pipelines and applications for experimentation and even upgradation of a particular gene and its family in two different organisms.
Results: The observation documented the total SOX13 and HMG-box domains in two mammalian genomes (i.e. Homo sapiens and Mus musculus). A computational and bioinformatics analysis demonstrated that SOX13 is an insulin-initiated gene. Also, the findings provided genomic variations of the SRY-box 13 gene response in T1D. Also, the study stated the molecular and immunologic mechanisms associated with autoimmune T1D.
Concluding Remarks: The series of data forwarded supreme future of autoimmune T1D are linked with SRY-related HMG-box 13 genes during the outgrowth of organisms. Also, the study justified that HMG-box genes reveal a significant nature during the growth in mammals. Thus, the high mobility group of ICA12 is an insulin-mediated gene that shows a preface in T1D. Also, auto-reactive CD4+ T cells and killer T cells play a fundamental role in autoimmune T1D.
Keywords:
SOX13, SOX family, T1D, Gene therapy, Immunotherapy
Article Details
How to Cite
CHOUDHURY, Shouhartha.
Genomics of SOX13 gene is dynamic in Type 1 Diabetes.
Medical Research Archives, [S.l.], v. 13, n. 7, july 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6716>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i7.6716.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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24. Corthay A. How do regulatory T cells work? Scand J Immunol. 2009. 70(4):326-336
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26. Askenasy N. Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity. Autoimmun Rev. 2013. 12(10): 972-975
27. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, and Howson JM. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes. 2004. 53(11):3020-3023
28. Gregersen PK and Behrens TW. Genetics of autoimmune diseases-disorders of immune homeostasis. Nat Rev Genet. 2006. 7(12):917-928
29. Guo D, Li M, Zhang Y, Yang P, Eckenrode S, and Hopkins D. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet. 2004. 36(8):837-841
30. Guo D, Han J, Adam BL, Colburn NH, Wang MH, and Dong Z. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun. 2005. 337(4):1308-1318
31. Caamano J and Hunter CA. NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev. 2002. 15(3):414-429
32. Lee HS, Park H, Yang S, Kim D, and Park Y. STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann N Y Acad Sci. 2008. 1150:93-98
33. Frucht DM, Aringer M, Galon J, Danning C, Brown M, Fan S. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol. 2000. 164(9):4659-4664
34. Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, and McDuffie M. Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun. 2004. 22(3):191-200
35. Trinchieri G. Interleukin-12: a cytokine produced by antigenpresenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994. 84(12):4008-4027
36. Lin J, Zhou ZG,Wang JP, Zhang C, Huang G. From Type 1, through LADA, to type 2 diabetes: a continuous spectrum? Ann N YAcad Sci. 2008. 1150:99-102
37. Organization, W.H., Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus. 1999, Geneva: World health organization.
38. SHTAUVERE‐BRAMEUS, A., et al., Antibodies to new beta cell antigen ICA12 in Latvian diabetes patients. Annals of the New York Academy of Sciences. 2002, 958(1):297-304.
39. Elkon, K. and P. Casali, Nature and functions of autoantibodies. Nature Reviews Rheumatology.2008, 4(9):491.
40. Bosi, E. and E. Bonifacio. Autoantibodies in insulin-dependent diabetes mellitus. Journal ofendocrinological investigation. 1994, 17(7):521-531.
41. Pi-Sunyer, F.X. Medical hazards of obesity. Annals of internal medicine, 1993, 119:655-660.
42. Willis J.A. et al. Islet cell antibodies and antibodies against glutamic acid decarboxylase in newly diagnosed adult-onset diabetes mellitus. Diabetes research and clinical practice. 1996,33(2):89-97.
43. Lernmark Å. Glutamic acid decarboxylase–gene to antigen to disease. Journal of internal medicine. 1996, 240(5):259-277.
44. Bonifacio E. et al. Identification of protein tyrosine phosphatase-like IA2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies. The Journal of Immunology, 1995. 155(11): 5419-5426.
45. Falorni, A. et al. Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM. Diabetologia, 1996. 39(9): 1091-1098.
46. Sanjeevi C. et al. Glutamic acid decarboxylase (GAD) in insulin-dependent diabetes mellitus. Diabetes Nutrition and Metabolism. 1996, 9:167-182.
47. Christgau S. et al. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. The Journal of cell biology. 1992, 118(2):309-320.
48. Solimena, M. et al. ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. The EMBO journal. 1996, 15(9):2102-2114.
49. Pevny, L.H. and R. Lovell-Badge. Sox genes find their feet. Current opinion in genetics & development. 1997, 7(3):338-344.
50. Hagopian W.A et al. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. The Journal of clinical investigation. 1993, 91(1):368-374.
51. Sanjeevi C et al. HLA and glutamic acid decarboxylase in human insulin‐dependent diabetes mellitus. Diabetic medicine, 1996. 13(3): p. 209-217.
52. Sanjeevi C. et al. Prevalence of GAD65 autoantibodies in South Indian patients with insulin-dependent diabetes mellitus, and in their parents. Diabetes, nutrition & metabolism. 1997, 10(2):60-64.
53. Hyoty H and Taylor KW, The role of viruses in human diabetes. Diabetologia. 2002, 45 (10):1353-1361
54. Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE et al. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes. Aug 2000, 49(8):1319-1324
55. Ramondetti F, Sacco S, Comelli M, Bruno G, Falorni A, Iannilli A et al. Type 1 diabetes and measles, mumps and rubella childhood infections within the Italian Insulindependent Diabetes Registry. Diabet Med J Br Diabet Assoc, Jun 2012, 29:761-766
56. Aarnisalo J, Veijola R, Vainionpaa R, Simell O, Knip M, Ilonen J, Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes. Diabetologia. May 2008, 51(5):769-772
57. Blank M, Barzilai O, Shoenfeld Y, Molecular mimicry and auto-immunity. Clin Rev Allergy Imunol. Feb 2007, 32(1):111-118
58. Coppieters KT, Wiberg A, von Herrath MG. Viral infections and molecular mimicry in type 1 diabetes. APMIS. 2012, 120(12):941-949
59. Delong T, Baker RL, He J, HaskinsK(2013)Novel autoantigens for diabetogenic CD4 Tcells in autoimmune diabetes. Immunol Res 55():167-172
2. Roose, J. et al. The Sox-13 Gene: Structure, Promoter Characterization, and Chromosomal Localization. Genomics. 1999, 57(2):301-305.
3. Kasimiotis H. et al. Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets. Diabetes. 2000, 49(4): 555-561.
4. Schepers, G.E., R.D. Teasdale, and P. Koopman. Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Developmental cell, 2002. 3(2): p. 167-170.
5. Graves, J.A.M. Two uses for old SOX. Nature genetics. 1997, 16(2):114.
6. Fida S et al. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. Journal of autoimmunity. 2002, 19(4):251-257.
7. Kasimiotis H et al. Antibodies to SOX13 (ICA12) are associated with type 1 diabetes. Autoimmunity. 2001, 33(2):95-101.
8. Argentaro A et al. Linkage studies of SOX13, the ICA12 autoantigen gene, in families with type 1 diabetes. Molecular genetics and metabolism. 2001, 72(4):356-359.
9. Bieg S, J. Seissler, and W.A. Scherbaum. Cytoplasmic islet cell antibodies and GAD antibodies in diagnosis of diabetes. Medizinische Klinik (Munich, Germany: 1983). 1995, 90(10):594-598.
10. Wilkin T.J. Autoantibodies as mechanisms, markers, and mediators of B‐cell disease. Diabetes/metabolism reviews. 1991, 7(2):105-120.
11. Lucassen A.M. et al. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nature genetics. 1993, 4(3):305.
12. Rabin D.U. et al. Cloning and expression of IDDM-specific human autoantigens. Diabetes. 1992, 41(2):183-186.
13. Wildner G, Kaufmann U. What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells. Autoimmun Rev. 2013, 12 (11):1070-1075
14. Sarikonda G, Pettus J, Phatak S, Sachithanantham S, Miller JF, Wesley JD et al. CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes. J Autoimmun. 2004, 50:77-82
15. Han S, Donelan W, Wang H, Reeves W, Yang LJ. Novel autoantigens in type 1 diabetes. AmJ Transl Res. 2013, 5(4):379-392
16. Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, Cilio M C, Groop. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes. 2008. 57(5):1433-1437
17. Ounissi-Benkalha H, Polychronakos C. The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends Mol Med. 2008. 14(6):268-275
18. van Belle TL, Coppieters K T, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011. 91(1):79-118
19. Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G. Nierras RC, Todd AJ, Rich SS, and Nerup J. Genetics of type 1 diabetes: what’s next? Diabetes. 2010. 59(7):1561-1571
20. Vafiadis P, Ounissi-BenkalhaH, PalumboM,Grabs R, Rousseau M, Goodyer CG. Polychronakos C. Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab. 2001. 86(8):3705-3710
21. Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E. Larrad TM, Rios SM, Chow CC, Cockram SC, Jacobs K, Mijovic C, Bain CS, Barnett HA, Vandewalle LS, Schuit F, Gorus KF, Tosi R, Pozzilli P, and Todd AJ. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet. 1996. 5(7):1075-1080
22. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003. 423(6939):506-511
23. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z. Nomura T, Sakaguchi S. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008. 322(5899):271-275
24. Corthay A. How do regulatory T cells work? Scand J Immunol. 2009. 70(4):326-336
25. Mehers KL, Gillespie KM. The genetic basis for type 1 diabetes. Br Med Bull. 2008. 88(1):115-129
26. Askenasy N. Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity. Autoimmun Rev. 2013. 12(10): 972-975
27. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, and Howson JM. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes. 2004. 53(11):3020-3023
28. Gregersen PK and Behrens TW. Genetics of autoimmune diseases-disorders of immune homeostasis. Nat Rev Genet. 2006. 7(12):917-928
29. Guo D, Li M, Zhang Y, Yang P, Eckenrode S, and Hopkins D. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet. 2004. 36(8):837-841
30. Guo D, Han J, Adam BL, Colburn NH, Wang MH, and Dong Z. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun. 2005. 337(4):1308-1318
31. Caamano J and Hunter CA. NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev. 2002. 15(3):414-429
32. Lee HS, Park H, Yang S, Kim D, and Park Y. STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann N Y Acad Sci. 2008. 1150:93-98
33. Frucht DM, Aringer M, Galon J, Danning C, Brown M, Fan S. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol. 2000. 164(9):4659-4664
34. Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, and McDuffie M. Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun. 2004. 22(3):191-200
35. Trinchieri G. Interleukin-12: a cytokine produced by antigenpresenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994. 84(12):4008-4027
36. Lin J, Zhou ZG,Wang JP, Zhang C, Huang G. From Type 1, through LADA, to type 2 diabetes: a continuous spectrum? Ann N YAcad Sci. 2008. 1150:99-102
37. Organization, W.H., Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus. 1999, Geneva: World health organization.
38. SHTAUVERE‐BRAMEUS, A., et al., Antibodies to new beta cell antigen ICA12 in Latvian diabetes patients. Annals of the New York Academy of Sciences. 2002, 958(1):297-304.
39. Elkon, K. and P. Casali, Nature and functions of autoantibodies. Nature Reviews Rheumatology.2008, 4(9):491.
40. Bosi, E. and E. Bonifacio. Autoantibodies in insulin-dependent diabetes mellitus. Journal ofendocrinological investigation. 1994, 17(7):521-531.
41. Pi-Sunyer, F.X. Medical hazards of obesity. Annals of internal medicine, 1993, 119:655-660.
42. Willis J.A. et al. Islet cell antibodies and antibodies against glutamic acid decarboxylase in newly diagnosed adult-onset diabetes mellitus. Diabetes research and clinical practice. 1996,33(2):89-97.
43. Lernmark Å. Glutamic acid decarboxylase–gene to antigen to disease. Journal of internal medicine. 1996, 240(5):259-277.
44. Bonifacio E. et al. Identification of protein tyrosine phosphatase-like IA2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies. The Journal of Immunology, 1995. 155(11): 5419-5426.
45. Falorni, A. et al. Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM. Diabetologia, 1996. 39(9): 1091-1098.
46. Sanjeevi C. et al. Glutamic acid decarboxylase (GAD) in insulin-dependent diabetes mellitus. Diabetes Nutrition and Metabolism. 1996, 9:167-182.
47. Christgau S. et al. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. The Journal of cell biology. 1992, 118(2):309-320.
48. Solimena, M. et al. ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. The EMBO journal. 1996, 15(9):2102-2114.
49. Pevny, L.H. and R. Lovell-Badge. Sox genes find their feet. Current opinion in genetics & development. 1997, 7(3):338-344.
50. Hagopian W.A et al. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. The Journal of clinical investigation. 1993, 91(1):368-374.
51. Sanjeevi C et al. HLA and glutamic acid decarboxylase in human insulin‐dependent diabetes mellitus. Diabetic medicine, 1996. 13(3): p. 209-217.
52. Sanjeevi C. et al. Prevalence of GAD65 autoantibodies in South Indian patients with insulin-dependent diabetes mellitus, and in their parents. Diabetes, nutrition & metabolism. 1997, 10(2):60-64.
53. Hyoty H and Taylor KW, The role of viruses in human diabetes. Diabetologia. 2002, 45 (10):1353-1361
54. Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE et al. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes. Aug 2000, 49(8):1319-1324
55. Ramondetti F, Sacco S, Comelli M, Bruno G, Falorni A, Iannilli A et al. Type 1 diabetes and measles, mumps and rubella childhood infections within the Italian Insulindependent Diabetes Registry. Diabet Med J Br Diabet Assoc, Jun 2012, 29:761-766
56. Aarnisalo J, Veijola R, Vainionpaa R, Simell O, Knip M, Ilonen J, Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes. Diabetologia. May 2008, 51(5):769-772
57. Blank M, Barzilai O, Shoenfeld Y, Molecular mimicry and auto-immunity. Clin Rev Allergy Imunol. Feb 2007, 32(1):111-118
58. Coppieters KT, Wiberg A, von Herrath MG. Viral infections and molecular mimicry in type 1 diabetes. APMIS. 2012, 120(12):941-949
59. Delong T, Baker RL, He J, HaskinsK(2013)Novel autoantigens for diabetogenic CD4 Tcells in autoimmune diabetes. Immunol Res 55():167-172