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HGNC Approved Gene Symbol: P2RY8
Cytogenetic location: Xp22.33 Genomic coordinates (GRCh38) : X:1,462,581-1,537,185 (from NCBI)
P2RY8 is a member of the purine nucleotide G protein-coupled receptor gene family and is located in the pseudoautosomal region of the X chromosome (Cantagrel et al., 2004).
While investigating a pericentric inversion on the X chromosome, inv(X)(p22.3)(q13.2), segregating in a family with mental retardation, Cantagrel et al. (2004) identified 2 genes disrupted by the breakpoint: P2RY8 and KIAA2022 (300524). P2RY8 encodes a deduced 359-amino acid protein. Using RT-PCR and Northern blot analysis, Cantagrel et al. (2004) found that P2RY8 is highly expressed in lymphocytes. Weaker expression was seen in heart, kidney, and lung.
Adrian et al. (2000) analyzed the expression of several purinergic receptors during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. Moderate P2Y8 expression was detected in undifferentiated cells, and expression was completely downregulated during granulocyte differentiation. P2Y8 transcription decreased until 24 hours of monocytic differentiation, then began to return to higher levels. P2Y8 expression was barely detectable in normal blood leukocytes.
Lu et al. (2019) searched for P2RY8 ligands and found P2RY8 bioactivity in bile and in culture supernatants of several mouse and human cell lines. Using a 7-step biochemical fractionation procedure and a drop-out mass spectrometry approach, they showed that a previously undescribed biomolecule, S-geranylgeranyl-L-glutathione (GGG), is a potent P2RY8 ligand that is detectable in lymphoid tissues at the nanomolar level. GGG inhibited the chemokine-mediated migration of human germinal-center B cells and T follicular helper cells, and antagonized the induction of phosphorylated AKT (164730) in germinal-center B cells. Lu et al. (2019) also found that the enzyme gamma-glutamyltransferase-5 (GGT5; 137168), which was highly expressed by follicular dendritic cells, metabolized GGG to a form that did not activate the receptor. Overexpression of GGT5 disrupted the ability of P2RY8 to promote B-cell confinement to germinal centers, which indicated that GGT5 establishes a GGG gradient in lymphoid tissues. This work defined GGG as an intercellular signaling molecule that is involved in organizing and controlling germinal-center responses. As the P2RY8 locus is modified in several other types of cancer in addition to germinal-center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) and Burkitt lymphoma, Lu et al. (2019) speculated that GGG might have organizing and growth-regulatory roles in multiple human tissues.
P2RY8/CRLF2 FUSION GENE
Mullighan et al. (2009) reported a recurring interstitial deletion of pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL (613035) that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2 (300357). They identified the P2RY8/CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8/CRLF2 together with mutated mouse Jak2 (147796) resulted in constitutive JAK-STAT activation and cytokine-independent growth of Ba/F3 cells overexpressing IL7 receptor-alpha (IL7R; 146661). Mullighan et al. (2009) concluded that rearrangement of CRLF2 and JAK mutations together contribute to leukemogenesis in B-progenitor ALL.
Cantagrel et al. (2004) determined that the P2RY8 gene contains 2 exons separated by a 70-kb intron.
Cantagrel et al. (2004) identified the P2RY8 gene at the Xp22.3 breakpoint of a pericentric inversion of the X chromosome.
In the family with the pericentric inversion inv(X)(q13;p22) studied by Cantagrel et al. (2004), 2 males related as first cousins once removed had severe mental retardation, whereas the carrier females who represented the genealogic connection between the 2 affected males were phenotypically unaffected. RT-PCR showed that the KIAA2022 transcript was not expressed in the patients' cells, whereas the P2RY8 transcript was expressed; the amount of P2RY8 was similar in the cells of the affected patients and a tested carrier female. Because haploinsufficiency of the P2RY8 gene in carrier mothers did not have a phenotypic consequence, Cantagrel et al. (2004) concluded that the severe mental retardation of the affected males was due to the absence of the KIAA2022 gene product. However, screening of 20 probands from X-linked mental retardation families revealed no mutation in the KIAA2022 gene.
Adrian, K., Bernhard, M. K., Breitinger, H.-G., Ogilvie, A. Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochim. Biophys. Acta 1492: 127-138, 2000. [PubMed: 11004484] [Full Text: https://doi.org/10.1016/s0167-4781(00)00094-4]
Cantagrel, V., Lossi, A.-M., Boulanger, S., Depetris, D., Mattei, M.-G., Gecz, J., Schwartz, C. E., Van Maldergem, L., Villard, L. Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males. J. Med. Genet. 41: 736-742, 2004. [PubMed: 15466006] [Full Text: https://doi.org/10.1136/jmg.2004.021626]
Lu, E., Wolfreys, F. D., Muppidi, J. R., Xu, Y., Cyster, J. G. S-Geranylgeranyl-L-glutathione is a ligand for human B cell-confinement receptor P2RY8. Nature 567: 244-248, 2019. [PubMed: 30842656] [Full Text: https://doi.org/10.1038/s41586-019-1003-z]
Mullighan, C. G., Collins-Underwood, J. R., Phillips, L. A. A., Loudin, M. G., Liu, W., Zhang, J., Ma, J., Coustan-Smith, E., Harvey, R. C., Willman, C. L., Mikhail, F. M., Meyer, J., and 12 others. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nature Genet. 41: 1243-1246, 2009. [PubMed: 19838194] [Full Text: https://doi.org/10.1038/ng.469]