Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRJ
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,980,559-48,170,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Colon cancer, somatic | 114500 | 3 | |
| Thrombocytopenia 10 | 620484 | Autosomal recessive | 3 |
The PTPRJ gene encodes a receptor-type protein tyrosine phosphatase (RPTP) expressed in several cells types. PTPRJ activates Src family kinases (SFKs) by dephosphorylating inhibitory tyrosine residues; thus, PTPRJ is involved in the regulation of certain downstream signaling pathways (summary by Marconi et al., 2019).
Experimental evidence indicates that specific protein-tyrosine phosphatases (PTPases) interact with members of cascades to modulate biologic function differentiation and development. Experiments suggested that the PTPases PTP-beta (176882) and PTP-epsilon (600926) are involved in the early molecular events for in vitro differentiation of mouse erythroleukemia (MEL) as well as embryonic carcinoma (F9) cells (Watanabe et al., 1995).
A human homolog of mouse Ptprj, encoding PTP-beta-2, was identified by Ostman et al. (1994).
Honda et al. (1994) cloned and characterized the PTPRJ gene, which they designated HPTP-eta. The predicted protein has a molecular mass of approximately 220 to 250 kD and contains an extracellular region homologous to fibronectin type III repeats, a transmembrane region, and a cytoplasmic region containing a single PTPase-like domain.
Marconi et al. (2019) noted that PTPRJ is highly expressed in platelets and megakaryocytes.
Honda et al. (1994) mapped the PTPRJ gene to chromosome 11p11.2 by fluorescence in situ hybridization.
Using mouse cDNA for PTP-beta-2 and PTP-epsilon, Watanabe et al. (1995) assigned the genes, Ptprj and Ptpre, to chromosome 2 and chromosome 7, respectively.
Crystal Structure
Li et al. (2020) showed that a segment within the CTCF (604167) N terminus interacts with the SA2 (300826)-SCC1 subunits of human cohesin. They reported a crystal structure of SA2-SCC1 in complex with CTCF at a resolution of 2.7 angstroms, which revealed the molecular basis of the interaction. Li et al. (2020) demonstrated that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF binding sites. A similar motif is present in a number of established and newly identified cohesin ligands, including the cohesin release factor WAPL (610754). Li et al. (2020) concluded that their data suggested that CTCF enables the formation of chromatin loops by protecting cohesin against loop release.
Thrombocytopenia 10
In 2 sibs with thrombocytopenia-10 (THC10; 620484), Marconi et al. (2019) identified compound heterozygous mutations in the PTPRJ gene (600925.0003 and 600925.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations resulted in a loss of PTPRJ dephosphorylation activity, causing constitutive phosphorylation-mediated inhibition of Src family kinases (SFKs) and impaired activation of downstream signaling pathways important for the development and function of platelets.
Somatic Mutations
Nonfamilial, 'sporadic' cancers, which represent most cancer cases, have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals may help identify homologous genes in humans. For example, several cancer susceptibility QTLs were mapped in mouse and rat. One of these, the mouse gene Scc1 (susceptibility to colon cancer-1), was positionally cloned by Ruivenkamp et al. (2002) and identified as Ptprj, which encodes a receptor-type protein-tyrosine phosphatase. In human cancers of colon, lung, and breast, Ruivenkamp et al. (2002) found frequent deletions, loss of heterozygosity, and missense mutations in the PTPRJ gene (see, e.g., 600925.0001-600925.0002).
Lesueur et al. (2005) assessed common SNPs and haplotypes of the PTPRJ gene in 4,512 breast cancer (114480) patients and 4,554 controls from East Anglia, U.K. The authors observed a difference in the haplotype frequency distributions between patients and controls (P = 0.0023; OR = 0.81; range, 0.72-0.92). They concluded that carrying a specific PTPRJ haplotype may confer a protective effect on the risk of breast cancer.
Marconi et al. (2019) found that CRISPR/Cas9-mediated knockdown of the ptprj gene in zebrafish resulted in thrombocytopenia.
Ruivenkamp et al. (2002) identified 5 somatic missense mutations in the PTPRJ gene in colon cancer (see 114500). Sequence alignments, secondary structure prediction, and homology modeling predicted with high confidence levels that most of these in the extracellular portion of the gene product occur in exposed regions available for interactions with ligands or other proteins and could affect the signaling process. One of these missense mutations was an arg214-to-cys mutation (R214C) that resulted in loss of a positive charge.
In a colon cancer (see 114500), Ruivenkamp et al. (2002) found a gln276-to-pro (Q276P) mutation in exon 5 of the PTPRJ gene. The change was predicted to result in torsional stress.
In 2 sibs with thrombocytopenia-10 (THC10; 620484), Marconi et al. (2019) identified compound heterozygous mutations in the PTPRJ gene. Both mutations resulted in a frameshift and premature termination. One mutation was an A-to-G transition in intron 1 (c.97-2A-G, ENST00000418331.1), resulting in frameshift (Thr38ProfsTer9), and the other was a 1-bp deletion in exon 10 (c.1875delG; 600925.0004), resulting in a different frameshift (Ser626AlafsTer7). No homozygous PTPRJ-null variants are present in the gnomAD or ExAC databases. Patient cells showed severely depleted PTPRJ mRNA levels, suggesting nonsense-mediated mRNA decay, and no detectable protein, consistent with a complete loss of function. Patient-derived megakaryocytes showed impaired migration, defective maturation, and decreased and abnormal proplatelet formation. In vitro functional studies of patient platelets showed defective platelet aggregation in response to collagen and the GP6 (605546) agonist convulxin; aggregation was normal in response to ADP and ristocetin. Patient platelets also showed reduced P-selectin (173610) exposure and GPIIb/GPIIIa activation after stimulation. These findings were consistent with a GP6-mediated functional defect and impaired activation of the thrombin receptor (F2R; 187930). Normally, PTPRJ activates Src family kinases (SFKs), such as Syk (600085), by dephosphorylating inhibitory tyrosine residues. The loss of PTPRJ function resulted in a constitutive increase in phosphorylation of the inhibitory tyrosine of SFKs, which impaired the activation of downstream signaling pathways important for platelet development and function.
For discussion of the 1-bp deletion in exon 10 of the PTPRJ gene (c.1875delG, ENST00000418331.1), resulting in a frameshift and premature termination (Ser626AlafsTer7), that was found in compound heterozygous state in 2 sibs with thrombocytopenia-10 (THC10; 620484) by Marconi et al. (2019), see 600925.0003.
Honda, H., Inazawa, J., Nishida, J., Yazaki, Y., Hirai, H. Molecular cloning, characterization, and chromosomal localization of a novel protein-tyrosine phosphatase, HPTP eta. Blood 84: 4186-4194, 1994. [PubMed: 7994032]
Lesueur, F., Pharoah, P. D., Laing, S., Ahmed, S., Jordan, C., Smith, P. L., Luben, R., Wareham, N. J., Easton, D. F., Dunning, A. M., Ponder, B. A. J. Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer. Hum. Molec. Genet. 14: 2349-2356, 2005. [PubMed: 16000320] [Full Text: https://doi.org/10.1093/hmg/ddi237]
Li, Y., Haarhuis, J. H. I., Sedeno Cacciatore, A., Oldenkamp, R., van Ruiten, M. S., Willems, L., Teunissen, H., Muir, K. W., de Wit, E., Rowland, B. D., Panne, D. The structural basis for cohesin-CTCF-anchored loops. Nature 578: 472-476, 2020. [PubMed: 31905366] [Full Text: https://doi.org/10.1038/s41586-019-1910-z]
Marconi, C., Di Buduo, C. A., LeVine, K., Barozzi, S., Faleschini, M., Bozzi, V., Palombo, F., McKinstry, S., Lassandro, G., Giordano, P., Noris, P., Balduini, C. L., Savoia, A., Balduini, A., Pippucci, T., Seri, M., Katsanis, N., Pecci, A. Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia. Blood 133: 1346-1357, 2019. [PubMed: 30591527] [Full Text: https://doi.org/10.1182/blood-2018-07-859496]
Ostman, A., Yang, Q., Tonks, N. K. Expression of DEP-1, a receptor-like protein-tyrosine-phosphatase, is enhanced with increasing cell density. Proc. Nat. Acad. Sci. 91: 9680-9684, 1994. [PubMed: 7937872] [Full Text: https://doi.org/10.1073/pnas.91.21.9680]
Ruivenkamp, C. A. L., van Wezel, T., Zanon, C., Stassen, A. P. M., Vlcek, C., Csikos, T., Klous, A. M., Tripodis, N., Perrakis, A., Boerrigter, L., Groot, P. C., Lindeman, J., Mooi, W. J., Meijjer, G. A., Scholten, G., Dauwerse, H., Paces, V., van Zandwijk, N., van Ommen, G. J. B., Demant, P. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature Genet. 31: 295-300, 2002. [PubMed: 12089527] [Full Text: https://doi.org/10.1038/ng903]
Watanabe, T., Mukouyama, Y., Rhodes, M., Thomas, M., Kume, T., Oishi, M. Chromosomal location of murine protein tyrosine phosphatase (Ptprj and Ptpre) genes. Genomics 29: 793-795, 1995. [PubMed: 8575779] [Full Text: https://doi.org/10.1006/geno.1995.9932]