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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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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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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DOI: https://doi.org/10.1038/ng1673
