Alternative titles; symbols
HGNC Approved Gene Symbol: PTGDS
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:136,977,504-136,981,742 (from NCBI)
Prostaglandin D2 (PGD2) functions as a neuromodulator and/or trophic factor in the central nervous system. Glutathione (GSH)-independent PGD synthase catalyzes the conversion of prostaglandin H2 (PGH2) to PGD2 in the presence of various sulfhydryl compounds. The enzyme is responsible for biosynthesis of PGD2 in the brain (Nagata et al., 1991).
Nagata et al. (1991) isolated cDNAs for GSH-independent PGD2 synthase from cDNA libraries of human brain. The longest insert contained a coding region of 570 basepairs corresponding to 190 amino acid residues with a calculated molecular mass of 21,016.
Tanaka et al. (1997) analyzed the binding of recombinant rat brain Ptgds to retinoids by measuring fluorescence, UV, and circular dichroism spectra after incubation of Ptgds with various isoforms of retinoid. They found that Ptgds binds all-trans-retinoic acid, 9-cis-retinoic acid, all-trans-retinal, and 13-cis-retinal, but not all-trans-retinol, with affinities sufficient for function as a retinoid transporter. All-trans-retinoic acid inhibited Ptgds activity in a noncompetitive manner, suggesting that it binds to the same hydrophobic pocket as PGH2, the substrate for Ptgds, but at a different site in this pocket. Tanaka et al. (1997) suggested that PTGDS is a bifunctional protein that acts as both a retinoid transporter and a PGD2-producing enzyme.
Kanekiyo et al. (2007) detected PTGDS within amyloid plaques in the brain of a human patient with late-onset Alzheimer disease (AD; 104300) and in mouse models of AD. In vitro studies showed that human PTGDS inhibited the aggregation of beta-amyloid (APP; 104760) fibrils in a dose-dependent manner. Ptgds-knockout mice showed acceleration of brain beta-amyloid deposition, and transgenic mice overexpressing human PTGDS showed decreased amyloid deposition, compared to wildtype. Since PTGDS is present in human cerebrospinal fluid (CSF), Kanekiyo et al. (2007) concluded that PTGDS acts as an endogenous beta-amyloid chaperone by binding to a particular area of APP and preventing a conformational shape change from soluble to insoluble peptides. The findings suggested that quantitative or qualitative changes in PTGDS may be involved in the pathogenesis of Alzheimer disease.
Both SRY (480000) and SOX9 (608160) are necessary for testis development in humans and mice. Prostaglandin D2 contributes to the development of the testis by recruiting cells of the supporting cell lineage to a Sertoli cell fate (Wilhelm et al., 2005). Wilhelm et al. (2007) found that Pgds was expressed in embryonic mouse Sertoli cells immediately after the onset of Sry and Sox9 expression. Pgds upregulation was mediated by Sox9, but not Sry, and required the binding of dimeric Sox9 to a paired SOX recognition site within the Pgds 5-prime flanking region.
White et al. (1992) isolated the PTGDS gene from a genomic library. It spans 3,600 bp and contains 7 exons. The transcriptional start site was mapped to a G residue 74 bp 5-prime of the ATG initiation codon. A TATA box-like element (ATAAATA) was situated 21 bp upstream of the mRNA start site. The gene for PGDS had a close structural resemblance to those for murine major urinary protein (MUP) and ovine beta-lactoglobulin.
By fluorescence in situ hybridization (FISH), White et al. (1992) localized the PGDS2 gene to 9q34.2-q34.3. By dual-color FISH, they demonstrated the following order: cen--HXB (187380)--ABL (189980)--PGDS--tel. Southern blot analysis indicated that there is a single copy of the gene in the haploid genome.
By linkage analyses in an interspecific backcross progeny in the mouse, Chan et al. (1994) mapped the Ptgds gene to chromosome 2 in a region of homology to human 9q34 and in the same region as other genes of the lipocalin family. By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Ptgds gene to mouse chromosome 2.
Miwa et al. (2004) identified 6 SNPs in the LPGDS gene in a Japanese population, including a common 4111A-C SNP in the 3-prime UTR. Serum levels of high density lipoprotein were significantly higher in individuals with the AA genotype of 4111A-C compared with those with the AC or CC genotypes. The maximum intima-media thickness in the common carotid artery (CIMT-max) was significantly smaller in subjects with the AA genotype than in those with AC or CC. Logistic regression analysis revealed that the presence of the AA genotype significantly reduced the risk for increased CIMT-max, even after adjustment for other risk factors. Miwa et al. (2004) concluded that the 4111A-C SNP in the LPGDS gene contributes to development of carotid atherosclerosis in Japanese hypertensive patients.
Pinzar et al. (2000) noted that PGD2 is the most abundant prostanoid produced in the central nervous system of mammals and one of the most potent sleep-inducing substances. It induces excess sleep in rats and monkeys after intracerebral ventricular infusion. Sleep induced by PGD2 is indistinguishable from physiologic sleep, as judged by electroencephalogram (EEG), electromyogram (EMG), brain temperature, locomotor activities, heart rate, and general behavior of animals (Onoe et al., 1988). PGD2 is produced in the arachidonic acid cascade from a common precursor of various prostanoids, PGH2, by the action of PTGDS. In the CNS, PGDS is produced mainly in the leptomeninges and choroid plexus and secreted into the cerebrospinal fluid as beta-trace, the second most abundant protein in CSF after albumin. To examine the function of PTGDS, as well as endogenously produced PGD2 in sleep regulation in vivo, Pinzar et al. (2000) generated transgenic mice that overexpressed the human PTGDS gene to study their sleep behavior. Although no differences were observed in the sleep/wake patterns between wildtype and transgenic mice, a striking time-dependent increase in nonrapid eye movement (NREM), but not in rapid eye movement (REM), sleep was observed in 2 independent lines of transgenic mice after stimulation by tail clipping. Concomitantly, the spontaneous locomotor activity of transgenic mice was drastically decreased in response to the tail clip. Induction of NREM sleep in transgenic mice was positively correlated with the PGD2 production in the brain. Sleep, locomotion, and PGD2 content were essentially unchanged in wildtype mice after tail clipping. The results demonstrated the involvement of the PTGDS gene in the regulation of NREM sleep. Thus, the PTGDS gene appears to be responsible for the regulation of NREM sleep, in contrast to the orexin/hypocretin gene (HCRT; 602358), which is involved in the pathogenesis of narcolepsy and possibly in the regulation of REM sleep.
Ragolia et al. (2005) found that Lpgds-knockout mice became glucose intolerant and insulin resistant at an accelerated rate compared with controls. Adipocytes were significantly larger in Lpgds-knockout mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated MAP kinase phosphatase-2 (DUSP4; 602747), protein tyrosine phosphatase-1D (PTPN21; 603271), and phosphorylated focal adhesion kinase (PTK2; 600758) expression levels in Lpgds-knockout vascular smooth muscle cells and controls. Only Lpgds-knockout mice developed nephropathy and an aortic thickening reminiscent of the early stages of atherosclerosis when fed a 'diabetogenic' diet.
Qu et al. (2006) found that selenium tetrachloride (SeCl4), an inhibitor of prostaglandin D synthase, inhibited sleep in wildtype mice dose-dependently and immediately after administration. SeCl4-induced insomnia was observed in hematopoietic Pgds (HPGDS; 602598)-knockout mice, but not in Lpgds-knockout mice, Lpgds/Hpgds double-knockout mice, or prostaglandin D receptor (PTGDR; 604687)-knockout mice. Administration of a Ptgdr antagonist reduced sleep of rats by 30%.
Philibert et al. (2013) found that 24% of Ptgds -/- mice and 16% of Ptgds +/- mice presented with random unilateral undescended testes. All other parts of the male reproductive system appeared normal. The undescended testis located cranially to the inguinal canal in a suprascrotal position. The phenotype was accompanied by decreased Rxfp2 (606655) mRNA expression in the gubernaculum and was similar to that observed in mice with conditional inactivation of androgen receptor (AR; 313700) in the gubernaculum.
Chan, P., Simon-Chazottes, D., Mattei, M. G., Guenet, J. L., Salier, J. P. Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 gamma chain, prostaglandin-D-synthase, oncogene-24P3, and progestagen-associated endometrial protein map to HSA9 and MMU2. Genomics 23: 145-150, 1994. [PubMed: 7829063] [Full Text: https://doi.org/10.1006/geno.1994.1470]
Kanekiyo, T., Ban, T., Aritake, K., Huang, Z.-L., Qu, W.-M., Okazaki, I., Mohri, I., Murayama, S., Ozono, K., Taniike, M., Goto, Y., Urade, Y. Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid. Proc. Nat. Acad. Sci. 104: 6412-6417, 2007. [PubMed: 17404210] [Full Text: https://doi.org/10.1073/pnas.0701585104]
Miwa, Y., Takiuchi, S., Kamide, K., Yoshii, M., Horio, T., Tanaka, C., Banno, M., Miyata, T., Sasaguri, T., Kawano, Y. Identification of gene polymorphism in lipocalin-type prostaglandin D synthase and its association with carotid atherosclerosis in Japanese hypertensive patients. Biochem. Biophys. Res. Commun. 322: 428-433, 2004. [PubMed: 15325247] [Full Text: https://doi.org/10.1016/j.bbrc.2004.07.143]
Nagata, A., Suzuki, Y., Igarashi, M., Eguchi, N., Toh, H., Urade, Y., Hayaishi, O. Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins. Proc. Nat. Acad. Sci. 88: 4020-4024, 1991. [PubMed: 1902577] [Full Text: https://doi.org/10.1073/pnas.88.9.4020]
Onoe, H., Ueno, R., Fujita, I., Nishino, H., Oomura, Y., Hayaishi, O. Prostaglandin D2, a cerebral sleep-inducing substance in monkeys. Proc. Nat. Acad. Sci. 85: 4082-4086, 1988. [PubMed: 3163802] [Full Text: https://doi.org/10.1073/pnas.85.11.4082]
Philibert, P., Boizet-Bonhoure, B., Bashamboo, A., Paris, F., Aritake, K., Urade, Y., Leger, J., Sultan, C., Poulat, F. Unilateral cryptorchidism in mice mutant for Ptgds. Hum. Mutat. 34: 278-282, 2013. [PubMed: 23076868] [Full Text: https://doi.org/10.1002/humu.22231]
Pilz, A., Woodward, K., Povey, S., Abbott, C. Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25: 139-149, 1995. [PubMed: 7774911] [Full Text: https://doi.org/10.1016/0888-7543(95)80119-7]
Pinzar, E., Kanaoka, Y., Inui, T., Eguchi, N., Urade, Y., Hayaishi, O. Prostaglandin D synthase gene is involved in the regulation of non-rapid eye movement sleep. Proc. Nat. Acad. Sci. 97: 4903-4907, 2000. [PubMed: 10781097] [Full Text: https://doi.org/10.1073/pnas.090093997]
Qu, W.-M., Huang, Z.-L., Xu, X.-H., Aritake, K., Eguchi, N., Nambu, F., Narumiya, S., Urade, Y., Hayaishi, O. Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep. Proc. Nat. Acad. Sci. 103: 17949-17954, 2006. [PubMed: 17093043] [Full Text: https://doi.org/10.1073/pnas.0608581103]
Ragolia, L., Palaia, T., Hall, C. E., Maesaka, J. K., Eguchi, N., Urade, Y. Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice. J. Biol. Chem. 280: 29946-29955, 2005. [PubMed: 15970590] [Full Text: https://doi.org/10.1074/jbc.M502927200]
Tanaka, T., Urade, Y., Kimura, H., Eguchi, N., Nishikawa, A., Hayaishi, O. Lipocalin-type prostaglandin D synthase (beta-trace) is a newly recognized type of retinoid transporter. J. Biol. Chem. 272: 15789-15795, 1997. [PubMed: 9188476] [Full Text: https://doi.org/10.1074/jbc.272.25.15789]
White, D. M., Mikol, D. D., Espinosa, R., Weimer, B., Le Beau, M. M., Stefansson, K. Structure and chromosomal localization of the human gene for a brain form of prostaglandin D-2 synthase. J. Biol. Chem. 267: 23202-23208, 1992. [PubMed: 1385416]
Wilhelm, D., Hiramatsu, R., Mizusaki, H., Widjaja, L., Combes, A. N., Kanai, Y., Koopman, P. SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J. Biol. Chem. 282: 10553-10560, 2007. [PubMed: 17277314] [Full Text: https://doi.org/10.1074/jbc.M609578200]
Wilhelm, D., Martinson, F., Bradford, S., Wilson, M. J., Combes, A. N., Beverdam, A., Bowles, J., Mizusaki, H., Koopman, P. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev. Biol. 287: 111-124, 2005. [PubMed: 16185683] [Full Text: https://doi.org/10.1016/j.ydbio.2005.08.039]