The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes

Nature Genetics

Volumn 15, Issue 3, 1997, Pages 293-297

  Pugliese, Alberto ^a   Zeller, Markus ^a   Fernandez Jr , Alarico ^a   Zalcberg, Laura J ^a   Bartlett, Richard J ^a   Ricordi, Camillo ^a   Pietropaolo, Massimo ^b   Eisenbarth, George S ^c   Bennett, Simon T ^d   Patel, Dhavalkumar D ^e  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

^c UNIVERSITY OF COLORADO   (United States)

^d UNIVERSITY OF OXFORD   (United Kingdom)

^e DUKE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GENE PRODUCT; GLUTAMATE DECARBOXYLASE; INSULIN; PHOSPHATASE; PROINSULIN; TYROSINE;

ADULT; ALLELE; ANIMAL CELL; ARTICLE; AUTOIMMUNITY; CHROMOSOME 11P; CONTROLLED STUDY; FETUS; GENE LOCUS; GENETIC SUSCEPTIBILITY; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HUMAN; HUMAN TISSUE; INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; RAT; T LYMPHOCYTE; THYMUS; VARIABLE NUMBER OF TANDEM REPEAT;

AGING; ALLELES; CHILD; CHILD, PRESCHOOL; CHROMOSOME MAPPING; CHROMOSOMES, HUMAN, PAIR 11; DIABETES MELLITUS, TYPE 1; DISEASE SUSCEPTIBILITY; DNA PRIMERS; EMBRYONIC AND FETAL DEVELOPMENT; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HUMANS; INFANT; INFANT, NEWBORN; INSULIN; MINISATELLITE REPEATS; ORGAN SPECIFICITY; POLYMERASE CHAIN REACTION; PROINSULIN; RNA, MESSENGER; THYMUS GLAND; TRANSCRIPTION, GENETIC; VARIATION (GENETICS);

ANIMALIA; RODENTIA;

EID: 18244421874     PISSN: 10614036     EISSN: None     Source Type: Journal    
DOI: 10.1038/ng0397-293     Document Type: Article

References (34)

1. Atkinson, M.A. & Maclaren, N.K. The pathogenesis of insulin-dependent diabetes mellitus. New Engl. J. Med. 331, 1428-1436 (1994).
2. Pietropaolo, M. et al. Islet cell autoantigen 69 kDa (ICA69): molecular cloning and characterization of a novel diabetes associated autoantigen. J. Clin. Invest. 92, 359-371 (1993).
3. Rabin, D.U. et al. Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases. J. Immunol. 152, 3183-3188 (1994).
4. Bell, G.I., Horita, S. & Karam, J.H. A polymorphic locus near the human insulin gene is associated with insulin dependent diabetes mellitus. Diabetes 33, 176-183 (1984).
5. Julier, C. et al. Insulin-IGF2 region encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155-159 (1991).
6. Lucassen, A. 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 Genet. 4, 305-310 (1993).
7. Owerbach, D. & Gabbay, K.H. Localization of a Type I diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes 42, 1708-1714 (1993).
8. Bennett, S.T. et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisalellite locus. Nature Genet. 9, 284-292 (1995).
9. Undlien, D.E. et al. Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene. Diabetes 44, 620-625 (1995).
10. Bennett, S.T. et al. IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J. Autoimmun. 9, 415-421 (1996).
11. Vafiadis, P. et al. Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J. Autoimmun. 9, 397-403 (1996).
12. Catignani Kennedy, G., German, M.S. & Rutter, W.J. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nature Genet. 9, 293-298 (1995).
13. Lucassen, A.M., Screaton, G.R., Julier, C., Elliott, T.J., Lathrop, M. & Bell, J.I. Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype. Hum. Mol. Genet. 4, 501-506 (1995).
14. Owerbach, D. & Gabbay, K.H. The search for IDDM susceptibility genes. Diabetes 45, 544-551 (1996).
15. Pugliese, A., Awdeh, Z.L., Alper, C.A., Jackson, R.A. & Eisenbarth, G.S. The paternally inherited insulin gene B allele (1,428 Fokl site) confers protection from insulin-dependent diabetes in families. J. Autoimmun. 7, 687-694 (1994).
16. Bell, G.I., Selby, M.J. & Rutter, W.J. The highly polymorphic region near the insulin gene is composed of simple tandemly repeating sequences. Nature 295, 31-35 (1982).
17. Jolicouer, C., Hanahan, D. & Smith, K.M. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc. Natl. Acad. Sci. USA 91, 6707-6711 (1994).
18. Oehen, S.U. et al. Escape of thymocytes and mature T cells from clonal deletion due to limiting tolerogen expression levels. Cell. Immunol. 158, 342-352 (1994).
19. Sebzda, E. et al. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263, 1615-1618 (1994).
20. Kuglin, B., Gries, F.A. & Kolb, H. Evidence for IgG autoantibodies against human proinsulin in patients with IDDM before insulin treatment. Diabetes 37, 130-132 (1988).
21. Castano, L., Ziegler, A., Ziegler, R., Shoelson, S. & Eisenbarth, G.S. Characterization of insulin autoantibodies in relatives of patients with insulin-dependent diabetes mellitus. Diabetes 42, 1202-1209 (1993).
22. Griffin, A.C., Zhao, W., Wegmann, K.W. & Hickey, W.F. Experimental autoimmune insulitis. Induction by T lymphocytes specific for a peptide of proinsulin. Am. J. Path. 147, 845-857 (1995).
23. Keilacker, H., Rjasanowski, I., Besch, W. & Kohnert, K.D. Autoantibodies to insulin and to proinsulin in type 1 diabetic patients and in at-risk probands differentiate only little between both antigens. Hormone Metab. Res. 27, 90-94 (1995).
24. French, M.B., et al. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 46, 34-39 (1997).
25. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alles at the IDDM2 locus. Nature Genet. 15, 289-292 (1997).
26. Bennett, S.T. & Todd, J.A. Human type 1 diabetes and the insulin gene: Principles of mapping polygenes. Ann. Rev. Genet. 30, 343-370 (1996).
27. Hoffman, A.R. & Vu, T.H. Genomic Imprinting. Sci. Am. 1, 52-61 (1996).
28. Polychronakos, C., Kukuvitis, A., Giannoukakis, N. & Colle, E. Parental imprinting effect at the INS-IGF2 diabetes susceptibility locus. Diabetologia 38, 715-719 (1995).
29. Bui, M.M. et al. Paternally transmitted IDDM2 influences diabetes susceptibility despite biallelic expression of the insulin gene in human pancreas. J. Autoimmun. 9, 97-103 (1996).
30. Vu, T.H., Hoffman, A.R. Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371, 714-717 (1994).
31. Xu, Y., Goodyear, C.G., Deal, C. & Polychronakos, C. Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem. Biophys. Res. Comm. 197, 747-754 (1993).
32. Mally, M.J., Cirulli, V., Hayek, A., Otonkoski, T. ICA69 is expressed equally in the human endocrine and exocrine pancreas. Diabetologia 39, 474-480 (1996).
33. Lan, M.S., Goto, J.L., Notkins, A.L. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol. 13, 505-514 (1994).
34. Devaskar, S.U., Singh, B.S., Carnaghi, L.R., Rajakumar, P.A., Giddings & S.J. Insulin II gene expression in rat central nervous system. Reg. Peptides 48, 55-63 (1993).