The PTPN Locus
The PTPN22 gene (lymphoid protein tyrosine phosphatase, nonreceptor type 22) was identified to be a DM1 locus by Bottini et al. in 2004 (9). The lymphoid phosphatase (Lyp) encoded by PTPN22 is a negative regulator of TCR signaling in T cells and a well-established suppressor of T-cell activation, acting alone or interacting with C-terminal Src kinase (Csk) or c-Cbl (an adaptor protein for receptor protein-tyrosine kinases) to inhibit Src family protein tyrosine kinases (PTKs, involved in TCR signal integration) (78, 79). Targeted disruption of PEP, the mouse ortholog of Lyp, results in increased expansion and function of the effector/memory T-cell pool, which was also associated with spontaneous development of germinal centers and elevated serum antibody levels (80).
The DM1 association is with a nsSNP R620W (Arg620Trp, rs2476601) (9) and has been confirmed by multiple studies (9, 81-89). The protein encoded by the Trp allele (DM1 predisposing) is unable to bind to its Csk partner (9). The association between Csk and PEP is highly specific. A previous study has shown that disruption of binding to Csk with an induced mutation that mimics the effect of R620W abolishes the inhibitory effect of PEP on TCR signaling (90). As shown by Hasegawa et al., Lyp plays an inhibitory role in positive but not negative selection (80). The predisposing Trp allele of the R620W may cause the loss of inhibition of thymus positive selection and lead to the increase of autoreactive T lymphocytes. Besides DM1, the R620W has also been shown to be associated with other autoimmune disorders, including RA (91) and SLE (92), Grave's disease, and juvenile idiopathic arthritis (JIA) (93), which suggests that the Lyp-Csk pathway is involved in a common mechanism of autoimmune diseases.
Although disruption of Lyp-Csk binding suggests that R620W is the causal variation of DM1 susceptibility, another SNP is also interesting. The SNP rs6679677 has the allele frequency identical to that of PTPN22-R620W (r2 = 1), which makes it impossible to dissect the effects of these two SNPs on the basis of genetic data alone. This SNP is located in the intergenic region between RSBN1 (round spermatid basic protein 1, also known as FLJ11220) and PHTF1 (putative homeodomain transcription factor 1). Through bioinformatic models, SNP rs6679677 is predicted to destroy a binding site of promoter CCAAT binding factors, or destroy a site of enhancer CCAAT binding factors, or generate a binding site of the transcription factor, Sox-5 (86). In addition, both R620W and rs6679677 are nonpolymorphic in Asian populations, as shown by both the HapMap data (94) and a large-scale study in East Asians (95). The DM1 predisposing Trp allele does not exist in the East Asian population. However, a promoter SNP -1123G-C (rs2488457) was found to be DM1-associated (95). This interesting finding suggests that R620W may not be the sole causative polymorphism.
Post a comment