PTPN22 two routes to discovery

As discussed below, the importance of kinases and phosphatases for regulating T-cell signaling, as well as a wide variety of biological functions, has been an area of rapidly expanding research [47]. In early 2004, Bottini et al. reported the association of the intracellular tyrosine phosphatase PTPN22 with type 1 diabetes [6]. This discovery resulted from a candidate gene approach, informed by a detailed knowledge of the importance of phosphatases for regulating T-cell function. The associated polymorphism (rs2476601, 1858C^T) was found to confer a relative risk (RR) of ~1.8 for carriers of the susceptible allele, and the disease-associated allele results in an amino acid substitution of tryptophane (W) for arginine (R) at position 620. This amino acid change was located in one of four proline rich SH3 binding sites (Fig. 1), and was shown to disrupt the binding of PTPN22 to the intracellular kinase, Csk.

The PTPN22 association with rheumatoid arthritis was found using an alternative experimental approach based on a broad 'functional' genome-wide association study [7], informed in part by knowledge of the linkage results from affected sibling pair analysis [36, 40]. Again, positive associations with the 620W allele were

Figure 1

Domain organization of the PTPN22 protein showing the catalytic site in the N-erminal region, followed by four proline rich SH3 binding sites. The R620W polymorphism is located in the first SH3 binding site. Splice variants as indicated in the figure have been described [54].

Figure 1

Domain organization of the PTPN22 protein showing the catalytic site in the N-erminal region, followed by four proline rich SH3 binding sites. The R620W polymorphism is located in the first SH3 binding site. Splice variants as indicated in the figure have been described [54].

observed in both a discovery and replication cohort of cases and controls, with RR ~1.7-2.0 overall. The effect of the risk allele on reducing binding of PTPN22 to Csk was also confirmed.

Thus, the finding of an association of PTPN22 with autoimmune disease resulted from two complementary approaches to gene discovery, one mainly hypothesis driven and the other largely discovery driven. It is likely that both of these experimental approaches will be successfully employed in the future to identify additional genes involved in autoimmunity.

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