The PTPRJ gene encodes a protein tyrosine phosphatase that is a master positive regulator of the activity of SFKs in platelets and megakaryocytes, and, as such, has a central role in controlling the transmission of signals in these cells.
PTPRJ was first reported in relation to thrombocytopenia-10 (Marconi et al., PMID:30591527) in a family with thrombocytopenia and small platelet volume inherited in an autosomal-recessive manner. 2 different variants (c.97-2A>G and c.1875del, both leading to frameshifts and premature stop) were identified in 2 members of the family. These are the only patients and the only variants described so far in thrombocytopenia-10.
The mechanism of disorder is loss of function.
Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (expression; functional alteration in patient cells and non-patient cells, non-human model organism).
Summary of Case Level Data: 3 POINTS Variants in this gene have been reported in 2 probands in 1 publication (PMID 30591527). Affected patients show thrombocytopenia, small platelet volume, bleeding, defective platelet activation in response to convulxin and TRAP-6, defective aggregation in response to collagen, convulxin and TRAP-6.
Summary of Experimental Data: 6.5 POINTS Senis et al. showed that PTPRJ is expressed in platelets by flow cytometry and Western blotting (PMID: 20345711) (Expression A). Marconi et al. showed that PTPRJ is less expressed on platelets of patients with variants in PTPRJ (PMID:30591527) (Expression B). They also showed evidence that megakaryocytes cultured from patients with PTPRJ variants show defective proplatelet formation and migration (functional alteration - Patient cells). DAMI cells knocked down for PTPRJ showed impaired migration as well (functional alteration - Patient cells). Finally, they knockdown ptprj in zebrafish and observe thrombocytopenia (Non-human model organism). Senis et al studied a murine model KO for ptprj, the mouse showed prolonged tail bleeding time, compatible with patients bleeding diathesis (PMID: 20345711) (Non-human model organism). In another mouse model, from Ellison et al, the same platelet aggregation defect of patients is shown (PMID: 20345711).
In summary, we obtained moderate association of PTPRJ with thrombocytopenia-10. However, due to the limited genetic data (only one family described), we will maintain the final classification as limited until more genetic evidence becomes available.
This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 11-04-2024 (SOP Version 11).
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