Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN22
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:113,813,811-113,871,759 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.2 | {Diabetes, type 1, susceptibility to} | 222100 | Autosomal recessive | 3 |
| {Rheumatoid arthritis, susceptibility to} | 180300 | 3 | ||
| {Systemic lupus erythematosus susceptibility to} | 152700 | Autosomal dominant | 3 |
All protein tyrosine phosphatases contain a catalytic domain of approximately 200 to 300 amino acids and can be divided into membrane-bound receptors or cytoplasmic phosphatases. The intracellular location of cytoplasmic phosphatases depends on amino acid sequences outside the catalytic domain. PTPN22 is a lymphoid-specific intracellular phosphatase (Cohen et al., 1999).
Matthews et al. (1992) characterized 2 murine cDNAs of hematopoietic intracellular protein-tyrosine phosphatases. One was Ptpn6 (176883); the other was Ptpn8, which the authors called Pep. Pep was shown to contain a large C-terminal domain of approximately 500 amino acids that is rich in PEST (proline, glutamic acid, serine, and threonine) motifs. Such domains are characteristic of proteins that are rapidly degraded. The Pep cDNA was isolated by generating PCR products from mouse brain or spleen mRNA using degenerate primers designed on the basis of known phosphatase sequences. These PCR products were cloned, characterized, and used to isolate longer cDNAs from a 70Z/3 pre-B-cell-derived cDNA library. The Pep 2.7-kb cDNA was found to code for an 802-amino acid protein with a predicted molecular mass of 89.7 kD. The amino acid sequence of the phosphatase domain was about 35% similar to the phosphatase domains of other PTPases. Pep mRNA, detected by Northern blots, was most abundant in spleen and thymus, with lower amounts in lymph node and bone marrow. Pep protein, expressed both in vitro and in bacteria, was shown to have PTPase activity.
By PCR screening of a human thymocyte cDNA library to identify sequences containing the conserved PTPase catalytic domain, Cohen et al. (1999) obtained cDNAs encoding 2 isoforms of PTPN8, which they termed LYP1 and LYP2. The deduced 808-amino acid LYP1 protein shares 70% overall identity with the mouse Pep protein, including 89% identity in their catalytic domains. It contains an N-terminal phosphatase catalytic domain but no hydrophobic sequences, indicating that it is most likely a nonreceptor phosphatase. LYP2 has 692 amino acids. Northern blot analysis revealed expression of a 4.4-kb LYP1 transcript in all lymphoid tissues examined, but no expression was detected in other tissues. LYP2 was expressed as a 5.2-kb transcript in lymphoid tissues, with highest levels in fetal liver, where LYP1 was not expressed. Immunoprecipitation and immunoblot analysis showed expression of 105- and 85-kD proteins for LYP1 and LYP2, respectively. Immunofluorescence microscopy demonstrated that both proteins are cytoplasmic. Immunoblot analysis detected expression of LYP1 in both B- and T-cell lines. Resting T cells expressed both isoforms, with LYP1 and LYP2 being upregulated and downregulated, respectively, after T-cell activation.
Cloutier and Veillette (1996) used the yeast 2-hybrid system to identify proteins associated with CSK (124095). They found that the Src homology-3 (SH3) domain of CSK associates with a proline-rich region of PEP. Cloutier and Veillette (1996) showed that this association is highly specific and speculated that PEP may be an effector and/or regulator of CSK in T cells and other hematopoietic cells.
By functional analysis, Cohen et al. (1999) confirmed that LYP has phosphatase activity. Coprecipitation analysis identified a 116-kD protein, CBL (165360), with which LYP appears to be constitutively associated. Overexpression of LYP reduced CBL phosphorylation.
Using a phage display screen of an activated peripheral blood leukocyte cDNA library with a GRB2 (108355) fusion protein as bait, followed by immunoprecipitation analysis, Hill et al. (2002) found that LYP binds to the N-terminal SH3 domain of GRB2. Luciferase analysis showed that overexpression of LYP in a T-cell line inhibited transcriptional activity initiated by antibodies to the T-cell receptor (see 186830) and the CD28 (186760) costimulatory molecule.
By screening a library of compounds designed to bridge the PTP active site and an adjacent peripheral site, Yu et al. (2007) identified a bidentate inhibitor, I-C11, with activity against LYP, but little or no activity against other PTPs except PTP1B (PTPN1; 176885). The crystal structure of the LYP PTP domain in the presence or absence of inhibitor revealed that the WPD loop has a half-open conformation in the apo-LYP structure and a fully open one when bound to ligand. Protein kinase C (see 176960) phosphorylated LYP at ser35 in vitro and in vivo, and this phosphorylation impaired the ability of LYP to inactivate SRC family kinases and downregulate T-cell receptor signaling.
By database analysis. Ho et al. (2021) found evidence suggesting that PTPN22 is involved in negative regulation of anticancer immunity in human. They identified a germline variant in PTPN22, rs2476601, that was associated with a lower likelihood of cancer compared with controls. Ptpn22 knockout conferred protection against MC38 tumor growth in association with enhanced immune infiltration in mice. Treatment with a small molecule inhibitor of Ptpn22 phenocopied Ptpn22 -/- mice. The antitumor effects of Ptpn22 inhibition were mediated by Cd8 (see 186910)-positive T cells and by tumor-associated macrophage subpopulations. Targeting Ptpn22 was not redundant with checkpoint inhibition and enhanced tumor resistance in mice. Similarly, cancer patients with the PTPN22 rs2476601 variant showed significantly greater responses to checkpoint inhibitor immunotherapy.
Using FISH, Cohen et al. (1999) mapped the PTPN22 gene to chromosome 1p13, a region associated with rearrangements in solid and hematopoietic tumors.
Bottini et al. (2004) presented evidence suggesting that a SNP in the PTPN22 gene, a 1858C-T transition resulting in an arg620-to-trp (R620W; 600716.0001) substitution, is associated with insulin-dependent diabetes mellitus (IDDM; 222100). The authors suggested a mechanism that involves a modification in T-cell activation.
Rheumatoid arthritis (RA; 180300) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. Begovich et al. (2004) reported the association of RA susceptibility with the minor allele, 1858T, of the R620W SNP in PTPN22. They showed that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with CSK (124095), potentially altering these proteins' normal function as negative regulators of T cell activation. The minor allele of the R620W SNP of PTPN8 implicated by Begovich et al. (2004) was the same as that associated with type I diabetes mellitus by Bottini et al. (2004).
Smyth et al. (2004) reported a further association between PTPN22 1858T and Graves thyroiditis (275000) and also replicated the association between PTPN22 1858T and type I diabetes mellitus in 2 large type I diabetes mellitus cohorts. Siminovitch (2004) reviewed these data, which provided compelling evidence for the involvement of PTPN22 and susceptibility to both systemic and organ-specific autoimmune diseases, consistent with longstanding predictions regarding the existence of 'general' autoimmune disease susceptibility genes.
To determine whether other genetic variants in PTPN22 contribute to the development of rheumatoid arthritis, Carlton et al. (2005) sequenced the coding region of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. They then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls, and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls. Analyses of these results predicted 10 common (frequency more than 1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the W620 risk allele (600716.0001) was strongly associated with disease in both the sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, did not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified 2 SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least 1 additional variant in the PTPN22 gene region influence RA susceptibility.
Kawasaki et al. (2006) genotyped 1,698 Asian individuals, including 732 patients with type I diabetes and 141 patients with autoimmune thyroid disease, and found that all had the wildtype homozygous 1858C/C genotype. The authors identified a novel SNP in the promoter region of the PTPN22 gene, -1123C-G (rs2488457; 600716.0002), and observed a significant association with type I diabetes in Japanese and Korean patients. The affected family-based control association test and transmission disequilibrium analysis in 472 DNA samples from multiplex Caucasian families with type I diabetes indicated that the association with type I diabetes was stronger for -1123C-G than for 1858C-T. Kawasaki et al. (2006) concluded that association of the PTPN22 gene with type I diabetes could not be attributed solely to the 1858C-T variant, and that the -1123C-G promoter SNP was a more likely causative variant.
Orru et al. (2009) reported a 788G-A variant, resulting in an arg263-to-gln (R263Q; rs33996649) substitution within the catalytic domain of the PTPN22 gene, that leads to reduced phosphatase activity. They genotyped 881 SLE (152700) patients and 1,133 healthy controls from Spain and observed a significant protective effect (p = 0.006; OR, 0.58). Three replication cohorts of Italian, Argentinian, and Caucasian North American populations failed to reach significance; however, the combined analysis of 2,093 SLE patients and 2,348 controls confirmed the protective effect (p = 0.0017; OR, 0.63).
For discussion of a possible association between variation in the PTPN22 gene and psoriasis, see PSORS1 (177900).
Hasegawa et al. (2004) generated viable Pep -/- mice that did not express Pep protein. Thymocyte numbers and subsets were generally similar to wildtype mice, with a marginal increase in CD5 (153340) expression in CD4 (186940)/CD8 (see 186910) double-positive thymocytes, suggesting an inhibitory role of Pep in positive but not negative selection. Older Pep-deficient mice developed splenomegaly and lymphadenopathy with an accumulation of effector/memory phenotype CD8-positive T lymphocytes. After the first 2 days of in vitro stimulation, Pep-deficient T cells demonstrated a growth advantage over wildtype T lymphocytes, with increased proliferation, cytokine secretion, and dephosphorylation of the Lck (153390) autoregulatory catalytic cycle. Analysis of lymphocyte function in vivo also showed enhanced antigen-dependent proliferation and increased numbers of large, well-formed germinal centers and serum IgG1, IgG2a, and IgE, but not autoantibodies or autoimmunity.
Zhang et al. (2011) generated mice expressing the Lyp variant homolog Pep619W, which corresponds to the human arg620-to-trp mutation (600716.0001), and found that they manifest thymic and splenic enlargement accompanied by increases in T cell number, activation, and positive selection and in dendritic and B cell activation. Although Ptpn22(Pep) transcript levels were comparable in Pep619W and wildtype Pep619R mice, Pep protein levels were dramatically reduced in the mutant mice, with Pep619W protein being more rapidly degraded and showing greater association with and in vitro cleavage by calpain-1 (114220) than Pep619R. Similarly, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wildtype Lyp620R. Thus, calpain-mediated degradation with consequently reduced Lyp/Pep expression and lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby Lyp620W may increase risk for autoimmune disease.
Wang et al. (2022) showed that Ptpn22 knockout mice (Ptpn22 -/-) had shortened bleeding time and enhanced arterial thrombus formation, but normal venous thrombus formation. Protein phosphorylation studies in platelets from the Ptpn22 -/- mice demonstrated increased phosphorylation of Pde5a (603310) at ser92 and lower cGMP levels after collagen-related peptide stimulation compared to platelets from wildtype Ptpn22 mice. Further studies showed that Ptpn22 had intrinsic serine phosphatase activity and dephosphorylated and deactivated Pde5a at ser92 in activated platelets. Wang et al. (2022) concluded that PTPN22 negatively regulates platelet function and formation of arterial thrombi through the dephosphorylation of PDE5A.
Bottini et al. (2004) found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; 222100). Begovich et al. (2004) found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; 180300).
In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; 152700), Kyogoku et al. (2004) found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.
To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis (126200), Begovich et al. (2005) genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis.
Criswell et al. (2005) described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 (rs2476601) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis (140300). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus.
Qu et al. (2005) genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of Bottini et al. (2004). However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading Qu et al. (2005) to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W.
Vang et al. (2005) studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; 147680) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. Vang et al. (2005) concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant.
Kawasaki et al. (2006) genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing.
Kallberg et al. (2007) compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see 142857) and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W.
Huffmeier et al. (2006) excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see 177900).
The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that rs6679667, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP {dbSNP 2476601}, and that the effect size was consistent with previous estimates (Hinks et al., 2007).
Using flow cytometry, Rieck et al. (2007) found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 (186940)-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; 147730) expression, and IL10 (124092) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. Rieck et al. (2007) concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes.
Skinningsrud et al. (2008) presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease (240200). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele.
Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)).
Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis.
Arechiga et al. (2009) showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK (600085), and could be reversed by PTPN22 inhibition. Arechiga et al. (2009) proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity.
In human T and B cells carrying the R620W mutation, Zhang et al. (2011) showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease.
By sequencing both strands of genomic DNA from 35 healthy Japanese individuals, Kawasaki et al. (2006) identified a -1123C-G promoter SNP (rs2488457) in the PTPN22 gene. In a study of 484 Japanese patients with type I diabetes (IDDM; 222100), 317 of whom had acute-onset diabetes, and 492 healthy controls, the authors found that the heterozygous C/G genotype was associated with susceptibility to acute-onset but not slow-onset type I diabetes (OR = 1.42, p = 0.015). A similar tendency was observed in 69 Korean patients with acute-onset type I diabetes (p = 0.0105, combined OR = 1.41).
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