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

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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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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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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