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Ptpn22 and Cd2 Variations Are Associated with Altered Protein Expression and Susceptibility to Type 1 Diabetes in Nonobese Diabetic Mice.

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Fraser, Heather I 
Howlett, Sarah 
Clark, Jan 
Rainbow, Daniel B 
Stanford, Stephanie M 


By congenic strain mapping using autoimmune NOD.C57BL/6J congenic mice, we demonstrated previously that the type 1 diabetes (T1D) protection associated with the insulin-dependent diabetes (Idd)10 locus on chromosome 3, originally identified by linkage analysis, was in fact due to three closely linked Idd loci: Idd10, Idd18.1, and Idd18.3. In this study, we define two additional Idd loci--Idd18.2 and Idd18.4--within the boundaries of this cluster of disease-associated genes. Idd18.2 is 1.31 Mb and contains 18 genes, including Ptpn22, which encodes a phosphatase that negatively regulates T and B cell signaling. The human ortholog of Ptpn22, PTPN22, is associated with numerous autoimmune diseases, including T1D. We, therefore, assessed Ptpn22 as a candidate for Idd18.2; resequencing of the NOD Ptpn22 allele revealed 183 single nucleotide polymorphisms with the C57BL/6J (B6) allele--6 exonic and 177 intronic. Functional studies showed higher expression of full-length Ptpn22 RNA and protein, and decreased TCR signaling in congenic strains with B6-derived Idd18.2 susceptibility alleles. The 953-kb Idd18.4 locus contains eight genes, including the candidate Cd2. The CD2 pathway is associated with the human autoimmune disease, multiple sclerosis, and mice with NOD-derived susceptibility alleles at Idd18.4 have lower CD2 expression on B cells. Furthermore, we observed that susceptibility alleles at Idd18.2 can mask the protection provided by Idd10/Cd101 or Idd18.1/Vav3 and Idd18.3. In summary, we describe two new T1D loci, Idd18.2 and Idd18.4, candidate genes within each region, and demonstrate the complex nature of genetic interactions underlying the development of T1D in the NOD mouse model.



Alleles, Animals, B-Lymphocytes, CD2 Antigens, Chromosomes, Mammalian, Diabetes Mellitus, Type 1, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Humans, Mice, Mice, Inbred NOD, Mice, Transgenic, Molecular Sequence Data, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Signal Transduction, T-Lymphocytes

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J Immunol

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The American Association of Immunologists
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (091157/Z/10/B)
HIF was funded by a Wellcome Trust 4-year studentship. This work was supported by Wellcome Trust Grant 091157 and JDRF International Grant 9-2011-253. Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140). This work was also supported by Awards P01AI039671 (L.S.W. and J.A.T.), R01AI070544 (N.B.) and U01AI070351 (L.A.S.) from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. S.M.S. was supported by a postdoctoral fellowship from JDRF. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The resequencing of Ptpn22 in the NOD mouse strain was performed at WTSI and was funded by the Immune Tolerance Network contract AI15416, which was sponsored by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation International.