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A point mutation in PTPRC is associated with the development of multiple sclerosis

Nature Genetics volume 26, pages 495–499 (2000)Cite this article

Abstract

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis1,2,3,4. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown5,6,7. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.

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Figure 1: Characterization of variant CD45 expression pattern.
Figure 2: CD45 isoform expression pattern on TCLs.
Figure 3: Pedigrees, genotypes and clinical characteristics in four MS families with altered PTPRC expression caused by a mutation in exon 4 of PTPRC (a) and a mutation of unknown origin (b).

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References

  1. Martin, R., McFarland, H.F. & McFarlin, D.E. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 10, 153–187 (1992).

    Article  CAS  Google Scholar 

  2. Hafler, D.A. & Weiner, H.L. Immunologic mechanisms and therapy in multiple sclerosis. Immunol. Rev. 144, 75–107 (1995).

    Article  CAS  Google Scholar 

  3. Steinman, L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85, 299–302 (1996).

    Article  CAS  Google Scholar 

  4. Noseworthy, J.H. Progress in determining the causes and treatment of multiple sclerosis. Nature 399, 40–47 (1999).

    Article  Google Scholar 

  5. Sawcer, S., Goodfellow, P.N. & Compston, A. The genetic analysis of multiple sclerosis. Trends Genet. 13, 234–239 (1997).

    Article  CAS  Google Scholar 

  6. Oksenberg, J.R. & Hauser, S.L. New insights into the immunogenetics of multiple sclerosis. Curr. Opin. Neurol. 10, 181–185 (1997).

    Article  CAS  Google Scholar 

  7. Ebers, G.C. & Dyment, D.A. Genetics of multiple sclerosis. Semin. Neurol. 18, 295–299 (1998).

    Article  CAS  Google Scholar 

  8. Trowbridge, I.S. & Thomas, M.L. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu. Rev. Immunol. 12, 85–116 (1994).

    Article  CAS  Google Scholar 

  9. Shenoi, H., Seavitt, J., Zheleznyak, A., Thomas, M.L. & Brown, E.J. Regulation of integrin-mediated T cell adhesion by the transmembrane protein tyrosine phosphatase CD45. J. Immunol. 162, 7120–7127 (1999).

    CAS  PubMed  Google Scholar 

  10. Thomas, M.L. & Brown, E.J. Positive and negative regulation of Src-family membrane kinases by CD45. Immunol. Today 20, 406–411 (1999).

    Article  CAS  Google Scholar 

  11. Thomas, M.L. The leukocyte common antigen family. Annu. Rev. Immunol. 7, 339–369 (1989).

    Article  CAS  Google Scholar 

  12. Novak, T.J. et al. Isoforms of the transmembrane tyrosine phosphatase CD45 differentially affect T cell recognition. Immunity 1, 109–119 (1994).

    Article  CAS  Google Scholar 

  13. Leitenberg, D., Boutin, Y., Lu, D.D. & Bottomly, K. Biochemical association of CD45 with the T cell receptor complex: regulation by CD45 isoform and during T cell activation. Immunity 10, 701–711 (1999).

    Article  CAS  Google Scholar 

  14. Kishihara, K. et al. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74, 143–156 (1993).

    Article  CAS  Google Scholar 

  15. Kung, C. et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nature Med. 6, 343–345 (2000).

    Article  CAS  Google Scholar 

  16. Schwinzer, R. & Wonigeit, K. Genetically determined lack of CD45R-T cells in healthy individuals. Evidence for a regulatory polymorphism of CD45R antigen expression. J. Exp. Med. 171, 1803–1808 (1990).

    Article  CAS  Google Scholar 

  17. Thude, H., Hundrieser, J., Wonigeit, K. & Schwinzer, R. A point mutation in the human CD45 gene associated with defective splicing of exon A. Eur. J. Immunol. 25, 2101–2106 (1995).

    Article  CAS  Google Scholar 

  18. Zilch, C.F. et al. A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans. Eur. J. Immunol. 28, 22–29 (1998).

    Article  CAS  Google Scholar 

  19. Martin, E.R., Kaplan, N.L. & Weir, B.S. Tests for linkage and association of nuclear families. Am. J. Hum. Genet. 61, 439–448 (1997).

    Article  CAS  Google Scholar 

  20. Haines, J.L. et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nature Genet. 13, 469–471 (1996).

    Article  CAS  Google Scholar 

  21. Sawcer, S. et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nature Genet. 13, 464–468 (1996).

    Article  CAS  Google Scholar 

  22. Ebers, G.C. et al. A full genome search in multiple sclerosis. Nature Genet. 13, 472–476 (1996).

    Article  CAS  Google Scholar 

  23. Kuokkanen, S. et al. Genomewide scan of multiple sclerosis in Finnish multiplex families. Am. J. Hum. Genet. 61, 1379–1387 (1997).

    Article  CAS  Google Scholar 

  24. Poser, C.M. et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13, 227–231 (1983).

    Article  CAS  Google Scholar 

  25. Kantarci, O.H., Atkinson, E.J., Hebrink, D.D., McMurray, C.T. & Weinshenker, B.G. A population-based association study of two polymorphisms in the IL-1β and IL-1 receptor antagonist genes with susceptibility to and severity of multiple sclerosis. J. Neuroimmunol. 106, 220–227 (2000).

    Article  CAS  Google Scholar 

  26. Vergelli, M. et al. Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99). Eur. J Immunol. 26, 2624–2634 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Cepok, R. Dodel, A. Hehenkamp, M. Happel, R. Holzbach, J. Hundrieser, S. Schumacher, C. Schmid and B. Tackenberg for support, and A. Tzou for comments on the manuscript. The study was supported by the Gemeinnützige Hertie-Stiftung, the Deutsche Forschungsgemeinschaft (SFB 297-B6 and grant Schw437/2) and the Stiftung P.E. Kempkes. O.K., J.S.-K. and B.G.W. were supported by the National Multiple Sclerosis Society of the USA.

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Authors and Affiliations

  1. Department of Neurology, Philipps-University, Marburg, Germany

    Marc Jacobsen, Dorothee Schweer, Rami Gaber, Sabine Schock, Wolfgang H. Oertel, Norbert Sommer & Bernhard Hemmer

  2. Institute of Medical Biometry and Epidemiology, Philipps-University, Marburg, Germany

    Andreas Ziegler

  3. Transplantationslabor, Klinik für Viszeral- und Transplantationschirurgie, Hannover Medical School, Hannover, Germany

    Reinhard Schwinzer & Kurt Wonigeit

  4. Department of Neurology, Hannover Medical School, Hannover, Germany

    Ralf-Björn Lindert & Fedor Heidenreich

  5. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

    Orhun Kantarci, Janet Schaefer-Klein & Brian G. Weinshenker

  6. Schloßbergklinik Wittgenstein, Bad Laasphe, Germany

    Hayo I. Schipper

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Correspondence to Bernhard Hemmer.

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Jacobsen, M., Schweer, D., Ziegler, A. et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat Genet 26, 495–499 (2000). https://doi.org/10.1038/82659

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