Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 Feb;56(2):528–534.

Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies.

G Y Deng 1, A Muir 1, N K Maclaren 1, J X She 1
PMCID: PMC1801142  PMID: 7847389

Abstract

LMP2 and LMP7, two subunits of the proteasomes encoded in the major histocompatibility complex, are speculated to play a role in the generation of endogenous peptides for presentation by class I molecules to cytotoxic T cells. Their possible role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) has not been documented. In this study of Caucasian subjects, we have analyzed the polymorphisms of four genes within the HLA class II region (LMP2, LMP7, and HLA-DRB1 and -DQB1) in 198 unrelated IDDM patients and 192 normal controls ascertained from the southeastern United States. A genomic polymorphism of LMP7 was found strongly associated with IDDM, and the Arg/His-60 polymorphism in LMP2 was found associated with IDDM only in subjects containing an HLA DR4-DQB1*0302 haplotype. To determine whether the apparent associations between LMP genes and IDDM resulted from the strong linkage disequilibria observed between LMP and HLA-DR/DQ genes, we compared LMP gene frequencies in extended LMP-HLA haplotypes derived from control and diabetic families. Our results suggest that LMP genes have independent effects on IDDM susceptibility.

Full text

PDF
528

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arnold D., Driscoll J., Androlewicz M., Hughes E., Cresswell P., Spies T. Proteasome subunits encoded in the MHC are not generally required for the processing of peptides bound by MHC class I molecules. Nature. 1992 Nov 12;360(6400):171–174. doi: 10.1038/360171a0. [DOI] [PubMed] [Google Scholar]
  2. Beck S., Kelly A., Radley E., Khurshid F., Alderton R. P., Trowsdale J. DNA sequence analysis of 66 kb of the human MHC class II region encoding a cluster of genes for antigen processing. J Mol Biol. 1992 Nov 20;228(2):433–441. doi: 10.1016/0022-2836(92)90832-5. [DOI] [PubMed] [Google Scholar]
  3. Brown M. G., Driscoll J., Monaco J. J. Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes. Nature. 1991 Sep 26;353(6342):355–357. doi: 10.1038/353355a0. [DOI] [PubMed] [Google Scholar]
  4. Bucher P. Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences. J Mol Biol. 1990 Apr 20;212(4):563–578. doi: 10.1016/0022-2836(90)90223-9. [DOI] [PubMed] [Google Scholar]
  5. Caillat-Zucman S., Bertin E., Timsit J., Boitard C., Assan R., Bach J. F. Protection from insulin-dependent diabetes mellitus is linked to a peptide transporter gene. Eur J Immunol. 1993 Aug;23(8):1784–1788. doi: 10.1002/eji.1830230808. [DOI] [PubMed] [Google Scholar]
  6. Cohen-Haguenauer O., Robbins E., Massart C., Busson M., Deschamps I., Hors J., Lalouel J. M., Dausset J., Cohen D. A systematic study of HLA class II-beta DNA restriction fragments in insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1985 May;82(10):3335–3339. doi: 10.1073/pnas.82.10.3335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Deverson E. V., Gow I. R., Coadwell W. J., Monaco J. J., Butcher G. W., Howard J. C. MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters. Nature. 1990 Dec 20;348(6303):738–741. doi: 10.1038/348738a0. [DOI] [PubMed] [Google Scholar]
  8. Dick L. R., Aldrich C., Jameson S. C., Moomaw C. R., Pramanik B. C., Doyle C. K., DeMartino G. N., Bevan M. J., Forman J. M., Slaughter C. A. Proteolytic processing of ovalbumin and beta-galactosidase by the proteasome to a yield antigenic peptides. J Immunol. 1994 Apr 15;152(8):3884–3894. [PMC free article] [PubMed] [Google Scholar]
  9. Driscoll J., Brown M. G., Finley D., Monaco J. J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature. 1993 Sep 16;365(6443):262–264. doi: 10.1038/365262a0. [DOI] [PubMed] [Google Scholar]
  10. Fehling H. J., Swat W., Laplace C., Kühn R., Rajewsky K., Müller U., von Boehmer H. MHC class I expression in mice lacking the proteasome subunit LMP-7. Science. 1994 Aug 26;265(5176):1234–1237. doi: 10.1126/science.8066463. [DOI] [PubMed] [Google Scholar]
  11. Festenstein H., Awad J., Hitman G. A., Cutbush S., Groves A. V., Cassell P., Ollier W., Sachs J. A. New HLA DNA polymorphisms associated with autoimmune diseases. Nature. 1986 Jul 3;322(6074):64–67. doi: 10.1038/322064a0. [DOI] [PubMed] [Google Scholar]
  12. Früh K., Yang Y., Arnold D., Chambers J., Wu L., Waters J. B., Spies T., Peterson P. A. Alternative exon usage and processing of the major histocompatibility complex-encoded proteasome subunits. J Biol Chem. 1992 Nov 5;267(31):22131–22140. [PubMed] [Google Scholar]
  13. Gaczynska M., Rock K. L., Goldberg A. L. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature. 1993 Sep 16;365(6443):264–267. doi: 10.1038/365264a0. [DOI] [PubMed] [Google Scholar]
  14. Kelly A., Powis S. H., Glynne R., Radley E., Beck S., Trowsdale J. Second proteasome-related gene in the human MHC class II region. Nature. 1991 Oct 17;353(6345):667–668. doi: 10.1038/353667a0. [DOI] [PubMed] [Google Scholar]
  15. Maity S. N., Sinha S., Ruteshouser E. C., de Crombrugghe B. Three different polypeptides are necessary for DNA binding of the mammalian heteromeric CCAAT binding factor. J Biol Chem. 1992 Aug 15;267(23):16574–16580. [PubMed] [Google Scholar]
  16. Monaco J. J., Cho S., Attaya M. Transport protein genes in the murine MHC: possible implications for antigen processing. Science. 1990 Dec 21;250(4988):1723–1726. doi: 10.1126/science.2270487. [DOI] [PubMed] [Google Scholar]
  17. Monaco J. J., McDevitt H. O. Identification of a fourth class of proteins linked to the murine major histocompatibility complex. Proc Natl Acad Sci U S A. 1982 May;79(9):3001–3005. doi: 10.1073/pnas.79.9.3001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nepom B. S., Palmer J., Kim S. J., Hansen J. A., Holbeck S. L., Nepom G. T. Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. J Exp Med. 1986 Jul 1;164(1):345–350. doi: 10.1084/jem.164.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ortiz-Navarrete V., Seelig A., Gernold M., Frentzel S., Kloetzel P. M., Hämmerling G. J. Subunit of the '20S' proteasome (multicatalytic proteinase) encoded by the major histocompatibility complex. Nature. 1991 Oct 17;353(6345):662–664. doi: 10.1038/353662a0. [DOI] [PubMed] [Google Scholar]
  20. Owerbach D., Lernmark A., Platz P., Ryder L. P., Rask L., Peterson P. A., Ludvigsson J. HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals. Nature. 1983 Jun 30;303(5920):815–817. doi: 10.1038/303815a0. [DOI] [PubMed] [Google Scholar]
  21. She J. X., Bui M. M., Tian X. H., Muir A., Wakeland E. K., Zorovich B., Zhang L. P., Liu M. C., Thomson G., Maclaren N. K. Additive susceptibility to insulin-dependent diabetes conferred by HLA-DQB1 and insulin genes. Autoimmunity. 1994;18(3):195–203. doi: 10.3109/08916939409007996. [DOI] [PubMed] [Google Scholar]
  22. Spies T., Bresnahan M., Bahram S., Arnold D., Blanck G., Mellins E., Pious D., DeMars R. A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. Nature. 1990 Dec 20;348(6303):744–747. doi: 10.1038/348744a0. [DOI] [PubMed] [Google Scholar]
  23. Svejgaard A., Hauge M., Jersild C., Platz P., Ryder L. P., Nielsen L. S., Thomsen M. The HLA system. An introductory survey. Monogr Hum Genet. 1975;7:1–100. [PubMed] [Google Scholar]
  24. Thorsby E., Rønningen K. S. Role of HLA genes in predisposition to develop insulin-dependent diabetes mellitus. Ann Med. 1992 Dec;24(6):523–531. doi: 10.3109/07853899209167006. [DOI] [PubMed] [Google Scholar]
  25. Trowsdale J., Hanson I., Mockridge I., Beck S., Townsend A., Kelly A. Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. Nature. 1990 Dec 20;348(6303):741–744. doi: 10.1038/348741a0. [DOI] [PubMed] [Google Scholar]
  26. Yewdell J., Lapham C., Bacik I., Spies T., Bennink J. MHC-encoded proteasome subunits LMP2 and LMP7 are not required for efficient antigen presentation. J Immunol. 1994 Feb 1;152(3):1163–1170. [PubMed] [Google Scholar]
  27. van Endert P. M., Liblau R. S., Patel S. D., Fugger L., Lopez T., Pociot F., Nerup J., McDevitt H. O. Major histocompatibility complex-encoded antigen processing gene polymorphism in IDDM. Diabetes. 1994 Jan;43(1):110–117. doi: 10.2337/diab.43.1.110. [DOI] [PubMed] [Google Scholar]
  28. van Endert P. M., Lopez M. T., Patel S. D., Monaco J. J., McDevitt H. O. Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11594–11597. doi: 10.1073/pnas.89.23.11594. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES