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Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant

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Abstract

A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.

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Figure 1: The disease-associated variant LYP-Trp620 inhibits T cell activation more potently than LYP-Arg620.
Figure 2: The disease-associated variant LYP-Trp620 is a more potent inhibitor of early TCR signaling and a more active PTP.

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Acknowledgements

We thank A. Cao for suggestions and P. Frongia, P. Pusceddu, M. Chessa and R. Riccardi for recruiting affected individuals and collecting blood samples. This work was supported by a fellowship from the Norwegian Cancer Society (to T.V.) and by grants from the Juvenile Diabetes Research Foundation (to N.B.), Telethon-JDRF (to F.C.) and the US National Institutes of Health (to T.M).

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Authors and Affiliations

  1. Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    Torkel Vang, Lucia Musumeci, Konstantina Nika, Lutz Tautz, Tomas Mustelin & Nunzio Bottini

  2. Dipartimento di Scienze Biomediche e Biotecnologie, Università degli Studi di Cagliari, Ospedale Microcitemico, Cagliari, 09121, Italy

    Mauro Congia, Maria Doloretta Macis, Valeria Orrú, Patrizia Zavattari & Francesco Cucca

  3. Department of Orthopaedic Surgery and Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, 90033, California, USA

    Valeria Orrú & Nunzio Bottini

  4. The Biotechnology Centre, University of Oslo, Box 1125, Blindern, Oslo, N-0317, Norway

    Kjetil Taskén

  5. Dipartimento di Scienze Biomediche, Cattedra di Genetica Medica, Università degli Studi di Sassari, 07100, Sassari, Italy

    Francesco Cucca

Authors
  1. Torkel Vang
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  2. Mauro Congia
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  3. Maria Doloretta Macis
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  4. Lucia Musumeci
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  5. Valeria Orrú
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  6. Patrizia Zavattari
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  7. Konstantina Nika
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  8. Lutz Tautz
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  9. Kjetil Taskén
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  10. Francesco Cucca
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  11. Tomas Mustelin
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  12. Nunzio Bottini
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Corresponding author

Correspondence to Nunzio Bottini.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Analysis of T cell lineages and subpopulations in T1D children of RW or RR genotype. (PDF 151 kb)

Supplementary Fig. 2

The disease-associated LYP*W620 is a more potent inhibitor of early TCR signaling. (PDF 111 kb)

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Vang, T., Congia, M., Macis, M. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 37, 1317–1319 (2005). https://doi.org/10.1038/ng1673

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