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HPMR

progesterone receptor membrane component 2

OKDB#: 3107

Symbols:	PGRMC2	Species:	human
Synonyms:	DG6, PMBP	Locus:	4q28.2 in Homo sapiens
HPMR

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
Mammalian Reproductive Genetics Endometrium Database Resource Orthologous Genes UCSC Genome Browser GEO Profiles ^new! Amazonia (transcriptome data) ^new!
R-L INTERACTIONS MGI

General Comment

This gene is the chaperone for heme. Responsible for transporting heme from mitochondrion to the nucleus nature 2019 ///////PGRMC2 is an intracellular haem chaperone critical for adipocyte function. Galmozzi A et al. (2019) Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes^1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown^3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined^3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.//////////////////Ligand and Target Discovery by Fragment-Based Screening in Human Cells. Parker CG et al. (2017) Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.//////////////////

General function

Receptor

Comment

Cellular localization

Plasma membrane, Nuclear, Mitochondrial

Comment

Ovarian function

Follicle atresia

Comment

Progestin and adipoQ Receptor 7, Progesterone Membrane Receptor Component 1 (PGRMC1) and PGRMC2 and Their Role in Regulating Progesterone's Ability to Suppress Human Granulosa/Luteal Cells from Entering into the Cell Cycle. Sueldo C et al. (2015) The present studies were designed to determine the role of Progesterone Receptor Membrane Component 1 (PGRMC1), PGRMC2, Progestin and AdipoQ Receptor 7 (PAQR7) and Progesterone Receptor (PGR) in mediating the anti-mitotic action of progesterone (P4) in human granulosa/luteal cells. For these studies granulosa/luteal cells of ten women undergoing controlled ovarian hyperstimulation were isolated, maintained in culture, and depleted of PGRMC1, PGRMC2, PAQR7 or PGR by siRNA treatment. The rate of entry into the cell cycle was assessed using the FUCCI cell cycle sensor to determine the percentage of cells in the G1/S stage of the cell cycle. PGRMC1, PGRMC2, PAQR7 or PGR mRNA levels were assessed by real-time PCR and their interactions monitored by in situ proximity ligation assays (PLAs). These studies revealed that PGRMC1, PGRMC2, PAQR7 and PGR were expressed by granulosa/luteal cells from all patients with PGRMC1 mRNA being most abundant followed by PAQR7, PGRMC2 and PGR. However, their mRNA levels showed considerable patient variation. P4's ability to suppress entry into the cell cycle was dependent on PGRMC1, PGRMC2 and PAQR7 but not PGR. Moreover, PLAs indicated that PGRMC1, PGRMC2 and PAQR7 formed a complex within the cytoplasm. Based on these studies, it is proposed that these three P4 mediators form a complex within the cytoplasm that is required for P4's action. Moreover, P4's ability to regulate human follicle development may be dependent in part on the expression levels of each of these P4 mediators.//////////////////

Expression regulated by

Comment

Ovarian localization

Oocyte, Cumulus, Granulosa, Theca, Surface epithelium

Comment

Expression of Progesterone Receptor Membrane Component-2 Within the Immature Rat Ovary and Its Role in Regulating Mitosis and Apoptosis of Spontaneously Immortalized Granulosa Cells. Griffin D 2014 et al. Progesterone receptor membrane component 2 (Pgrmc2) mRNA was detected in the immature rat ovary. By 48 h after eCG, Pgrmc2 mRNA levels decreased by 40% and were maintained at 48 h post hCG. Immunohistochemical studies detected PGRMC2 in oocytes and ovarian surface epithelial, interstitial, thecal, granulosa and luteal cells. PGRMC2 was also present in spontaneously immortalized granulosa cells (SIGCs), localizing to the cytoplasm of interphase cells and apparently to the mitotic spindle of cells in metaphase. Interestingly, PGRMC2 levels appeared to decrease during the G1 stage of the cell cycle. Moreover, over expression of PGRMC2 suppressed entry into the cell cycle, possibly by binding the p58 form of cyclin dependent kinase 11b. Conversely, Pgrmc2 siRNA treatment increased the percentage of cells in G1 and M stage but did not increase the number of cells, which was likely due to an increase in apoptosis. Depleting PGRMC2 did not inhibit cellular (3)H-progesterone binding, but attenuated the ability of progesterone (P4) to suppress mitosis and apoptosis. Taken together these studies suggest that PGRMC2 affects granulosa cell mitosis by acting at two specific stages of the cell cycle. First, PGRMC2 regulates the progression from the G0 into the G1 stage of the cell cycle. Second, PGRMC2 appears to localize to the mitotic spindle, where it likely promotes the final stages of mitosis. Finally, siRNA knockdown studies indicate that PGRMC2 is required for P4 to slow the rate of granulosa cell mitosis and apoptosis. These findings support a role for PGRMC2 in ovarian follicle development. ///////////////////////// The human cumulus-oocyte complex gene-expression profile. Assou S et al. BACKGROUND: The understanding of the mechanisms regulating human oocyte maturation is still rudimentary. We have identified transcripts differentially expressed between immature and mature oocytes and cumulus cells.

Follicle stages

Comment

Phenotypes

Mutations

4 mutations

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos. McCoy RC et al. (2015) Aneuploidy, the inheritance of an atypical chromosome complement, is common in early human development and is the primary cause of pregnancy loss. By screening day-3 embryos during in vitro fertilization cycles, we identified an association between aneuploidy of putative mitotic origin and linked genetic variants on chromosome 4 of maternal genomes. This associated region contains a candidate gene, Polo-like kinase 4 (PLK4), that plays a well-characterized role in centriole duplication and has the ability to alter mitotic fidelity upon minor dysregulation. Mothers with the high-risk genotypes contributed fewer embryos for testing at day 5, suggesting that their embryos are less likely to survive to blastocyst formation. The associated region coincides with a signature of a selective sweep in ancient humans, suggesting that the causal variant was either the target of selection or hitchhiked to substantial frequency.PGRMC2 is another candidate gene. //////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Conditional Ablation of Progesterone Receptor Membrane Component 2 Causes Female Premature Reproductive Senescence. Clark NC et al. (2016) The non-classical progesterone receptors, progesterone receptor membrane component (PGRMC) 1 and PGRMC2 have been implicated in regulating cell survival of endometrial and ovarian cells in vitro and are abundantly expressed in these cell types. The objective of this study was to determine if Pgrmc1 and Pgrmc2 are essential for normal female reproduction. To accomplish this objective, Pgrmc1 and/or Pgrmc2 floxed mice (Pgrmc2(fl/fl) and Pgrmc1/2(fl/fl)) were crossed with Pgr-cre mice which resulted in the conditional ablation of Pgrmc1 and/or Pgrmc2 from female reproductive tissues (i.e., Pgrmc2(d/d) and Pgrmc1/2(d/d) mice). A breeding trial revealed that conditional ablation of Pgrmc2 initially led to subfertility with Pgrmc2(d/d) female mice producing 47% fewer pups/litter than Pgrmc2(fl/fl) mice (p=0.001). Pgrmc2(d/d) mice subsequently underwent premature reproductive senescence by parities 2-5, producing 37.8% fewer litters overall during the trial compared to Pgrmc2(fl/fl) mice (p=0.020). Similar results were observed with Pgrmc1/2(d/d) mice. Based on ovarian morphology and serum P4 the subfertility/infertility was not due to faulty ovulation or luteal insufficiency. Rather an analysis of mid-gestation implantation sites revealed that post-implantation embryonic death was the major cause of the subfertility/infertility. As with our previous report of Pgrmc1(d/d) mice, Pgrmc2(d/d) and Pgrmc1/2(d/d) mice developed endometrial cysts consistent with accelerated aging of this tissue. Given the timing of post-implantation embryonic demise, uterine decidualization may be disrupted in mice deficient in PGRMC2 or PGRMC1/2. Overall, this study revealed that Pgrmc1 and/or Pgrmc2 are required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan.//////////////////

Species: other
Mutation name:
type: null mutation
fertility: subfertile
Comment: Subfertility and reduced progestin synthesis in Pgrmc2 knockout zebrafish. Wu XJ et al. (2019) Progestin receptor membrane component (Pgrmc1 & 2) is a heme-binding protein. Studies on Pgrmc1 have suggested possible roles in heme binding, activation of steroid-synthesizing P450s, along with binding and transferring of membrane proteins. However, the studies of Pgrmc1's paralog, Pgrmc2 are still lacking. In order to determine the physiologic function(s) of Pgrmc2, we generated a zebrafish mutant line (pgrmc2^-/-). We found a reduction in both spawning frequency and the number of embryos produced in female pgrmc2^-/-. This subfertility is caused by reduced oocyte maturation (germinal vesicle breakdown, GVBD) in pgrmc2^-/- in vivo. Nonetheless, oocytes from pgrmc2^-/- had similar sensitivity to 17α,20β-dihydroxy-4-pregnen-3-one (DHP, a maturation induced progestin in zebrafish) compared with wildtype (wt) in vitro. Therefore, we hypothesized that oocyte maturation tardiness found in vivo, could be due to lack of progestin in pgrmc2^-/-. Interestingly, we found significant reduced expression of hormones, receptors, and steroid synthesizing enzymes including lhcgr, egfra, ar, and esr2, cyp11a1 and hsd3b1. In addition, DHP levels in pgrmc2^-/- ovaries showed a significant decrease compared to those in wt. In summary, we have provided a plausible molecular mechanism for the physiological functions of Pgrmc2 in the regulation of female fertility, likely via regulation of receptors and steroids in the ovary, which in turn regulates oocyte maturation in zebrafish.//////////////////

Species: None
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: Subfertility and reduced progestin synthesis in Pgrmc2 knockout zebrafish. Wu XJ et al. (2020) Progestin receptor membrane component (Pgrmc1 & 2) is a heme-binding protein. Studies on Pgrmc1 have suggested possible roles in heme binding, activation of steroid-synthesizing P450s, along with binding and transferring of membrane proteins. However, the studies of Pgrmc1's paralog, Pgrmc2 are still lacking. In order to determine the physiologic function(s) of Pgrmc2, we generated a zebrafish mutant line (pgrmc2^-/-). We found a reduction in both spawning frequency and the number of embryos produced in female pgrmc2^-/-. This subfertility is caused by reduced oocyte maturation (germinal vesicle breakdown, GVBD) in pgrmc2^-/- in vivo. Nonetheless, oocytes from pgrmc2^-/- had similar sensitivity to 17α,20β-dihydroxy-4-pregnen-3-one (DHP, a maturation induced progestin in zebrafish) compared with wildtype (wt) in vitro. Therefore, we hypothesized that oocyte maturation tardiness found in vivo, could be due to lack of progestin in pgrmc2^-/-. Interestingly, we found significant reduced expression of hormones, receptors, and steroid synthesizing enzymes including lhcgr, egfra, ar, and esr2, cyp11a1 and hsd3b1. In addition, DHP levels in pgrmc2^-/- ovaries showed a significant decrease compared to those in wt. In summary, we have provided a plausible molecular mechanism for the physiological functions of Pgrmc2 in the regulation of female fertility, likely via regulation of receptors and steroids in the ovary, which in turn regulates oocyte maturation in zebrafish.//////////////////

Genomic Region

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Phenotypes and GWAS

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Links

OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
OMIM \ Animal Model
KEGG Pathways

Recent Publications

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June 20, 2006, 11:26 a.m.

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Aug. 7, 2020, 3:04 p.m.

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