Pregnancy-specific 1-glycoprotein Research Articles

Trophoblast organoids as a model for maternal–fetal interactions during human placentation

The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for both mother and child, our knowledge of the human placenta is limited due to lack of functional experimental models1. Upon implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, the proliferative villous cytotrophoblast cells (VCT) differentiate into two main sub-populations: syncytiotrophoblast (SCT), the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast (EVT) that anchor the placenta to the maternal decidua and transform the maternal spiral arteries2. Here, we describe the generation of long-term, genetically-stable organoid cultures of trophoblast cells that can differentiate to SCT and EVT. We used HLA-typing to confirm the organoids are fetally-derived, and verified their identity against four trophoblast-specific criteria3. The cultures organise into villous-like structures, and we detected secretion of placental-specific peptides and hormones, including hCG, GDF15, PSGs and PAPPA, by mass spectrometry. The organoids also differentiate to HLA-G+ EVT that vigorously invade in 3D. Analysis of the methylome reveals the organoids closely resemble normal first-trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.

The Platelet Releasate is Altered in Human Pregnancy.

Healthy pregnancy is characterized by an increase in platelet activation and a decrease in the number of circulating platelets with gestation. Despite this recognized importance, proteomic studies investigating platelets in healthy pregnancy have not been performed. As platelet cargo can be altered in different conditions, it is hypothesized that platelets may store a relevant and bespoke collection of molecules during pregnancy. Comparative label-free quantitative proteomic profiling of platelet releasates (PRs) is performed from 18 healthy pregnant and 13 non-pregnant women using an MS/MS approach. Of the 723 proteins identified, 69 PR proteins are found to be differentially released from platelets in pregnancy, including proteins only expressed during pregnancy such as pregnancy-specific glycoproteins and human placental lactogen. Moreover, the population of exosomal vesicles present in the PR is also modified in pregnancy. Receiver operating characteristic analysis shows the predictive ability of 11 PR proteins to distinctly classify pregnant and nonpregnant women with an area under the curve of 0.876, a sensitivity of 88.9%, and a specificity of 84.6%. Taken together this demonstrates that platelets and their released cargo are 'educated' in physiologic stressful conditions such as pregnancy and may represent a promising platform to study pregnancy complications.

Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease

Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor β1 (TGF-β), a cytokine essential for the differentiation of tolerance-inducing CD4+FoxP3+ regulatory T cells (Tregs). Consistent with this observation, treatment of naïve murine T cells with PSG1 resulted in a significant increase in FoxP3+ cells that was blocked by a TGF-β receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-β in vivo. As the role of CD4+FoxP3+ cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissue-infiltrating inflammatory CD3+ T cells and had increased expression of FoxP3 in T cells compared with vehicle-treated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus-leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency.

Kr\xfcppel-Like Factor 10 participates in cervical cancer immunoediting through transcriptional regulation of Pregnancy-Specific Beta-1 Glycoproteins

Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. Using in silico DNA copy number analysis, we have demonstrated that ~20% of CC samples exhibit gain of 8q22.3 and 19q13.31; the regions of the genome that encodes the KLF10 and PSG genes, respectively. Gene expression studies demonstrated that there were no alterations in KLF10 mRNA expression, whilst the PSG2 and −5 genes were up-regulated by 1.76 and 3.97-fold respectively in CC compared to normal tissue controls. siRNA and ChIP experiments in SiHa cells have demonstrated that KLF10 participates in immune response through regulation of IL6, IL25 and PSG2 and PSG5 genes. Using cervical tissues from KLF10−/− mice, we have identified down-regulation of PSG17, −21 and −23 and IL11. These results suggest that KLF10 may regulate immune system response genes in cervical cancer among other functions. KLF10 and PSG copy number variations and alterations in mRNA expression levels could represent novel molecular markers in CC.

Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma

Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN ( ⩾ 149.97 ng/mL), MMP7 ( ⩾ 2.28 ng/mL), and PSG9 ( ⩾ 45.59 ng/mL) were prognostic indicators of reduced OS (P < 0.001, P < 0.001, and P = 0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P = 0.008) and DFS (P = 0.038). Plasma OPN + MMP7 + PSG9 elevation in combination was a prognostic factor for OS (P < 0.001). OPN was demonstrated to be a risk factorassociated OS in stage I patients with HCC and patients with low α-fetoprotein levels ( < 20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.

Recent expansion and adaptive evolution of the carcinoembryonic antigen family in bats of the Yangochiroptera subgroup

BackgroundExpansions of gene families are predictive for ongoing genetic adaptation to environmental cues. We describe such an expansion of the carcinoembryonic antigen (CEA) gene family in certain bat families. Members of the CEA family in humans and mice are exploited as cellular receptors by a number of pathogens, possibly due to their function in immunity and reproduction. The CEA family is composed of CEA-related cell adhesion molecules (CEACAMs) and secreted pregnancy-specific glycoproteins (PSGs). PSGs are almost exclusively expressed by trophoblast cells at the maternal-fetal interface. The reason why PSGs exist only in a minority of mammals is still unknown.ResultsAnalysis of the CEA gene family in bats revealed that in certain bat families, belonging to the subgroup Yangochiroptera but not the Yinpterochiroptera subgroup an expansion of the CEA gene family took place, resulting in approximately one hundred CEA family genes in some species of the Vespertilionidae. The majority of these genes encode secreted PSG-like proteins (further referred to as PSG). Remarkably, we found strong evidence that the ligand-binding domain (IgV-like domain) of PSG is under diversifying positive selection indicating that bat PSGs may interact with structurally highly variable ligands. Such ligands might represent bacterial or viral pathogen adhesins. We have identified two distinct clusters of PSGs in three Myotis species. The two PSG cluster differ in the amino acids under positive selection. One cluster was only expanded in members of the Vespertilionidae while the other was found to be expanded in addition in members of the Miniopteridae and Mormoopidae. Thus one round of PSG expansion may have occurred in an ancestry of all three families and a second only in Vespertilionidae. Although maternal ligands of PSGs may exist selective challenges by two distinct pathogens seem to be likely responsible for the expansion of PSGs in Vespertilionidae.ConclusionsThe rapid expansion of PSGs in certain bat species together with selection for diversification suggest that bat PSGs could be part of a pathogen defense system by serving as decoy receptors and/or regulators of feto-maternal interactions.

Pregnancy specific glycoproteins are disrupted in idiopathic preterm birth and impact cytotrophoblast differentiation

Pregnancy specific glycoproteins are disrupted in idiopathic preterm birth and impact cytotrophoblast differentiation

Role of the pregnancy-specific glycoprotein in regulation of the cytokine and chemokine profiles of intact mononuclear cells.

The effect of human pregnancy-specific glycoprotein (PSG) on the cytokine and chemokine production in vitro by intact mononuclear cells was studied by the method of flow fluorimetry. PSG inhibited production of the proinflammatory cytokines IL-6, IL-8, IL-17, IFN-γ, and TNF-α and chemokines CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1; at the same time, PSG stimulated IL-12(p70) production. Simultaneously with increasing the VEGF level, PSG inhibited production of IL-9, IL-13, G-CSF, and GM-CSF. The PSG effect discovered can be interpreted as a contribution into the immune tolerance formation during pregnancy.

Food Intake Affects Sperm-Egg Fusion Through the GIP/PSG17 Axis in Mice.

In addition to overeating, starvation also reduces fecundity in mammals. However, little is known about the molecular mechanisms linking food intake to fertility, especially in males. Gastric inhibitory polypeptide (GIP), which is released from intestinal K-cells after meal ingestion, stimulates insulin secretion from pancreatic β-cells through the action of incretin and has several extrapancreatic effects. Here, we identified GIP receptor (Gipr) expression in mouse spermatids. Microarray analysis revealed that pregnancy-specific glycoprotein 17 (Psg17), a potential CD9-binding partner, was significantly decreased in GIP receptor-knockout (Gipr-/-) testes. Glycosylphosphatidylinositol-anchored PSG17 was expressed on the surface of acrosome-reacted sperm, and Gipr-/- sperm led to a lower fertilization rate in vitro, compared with that of Gipr+/+ sperm, both in the absence and presence of the zona pellucida. Plasma GIP concentrations and Psg17 messenger RNA (mRNA) were immediately increased in the testis after a single meal, whereas ingestion of a chronic high-fat diet markedly decreased Gipr and Psg17 mRNA. These results suggest that reduced GIP signaling, by decreased GIP levels or the downregulation of Gipr, is associated with the reduction of fecundity due to starvation or overeating. Thus, proper regulation of GIP signaling in the testis could be a potential unique therapeutic target for male infertility in obese and diabetic individuals.

PSG9 promotes angiogenesis by stimulating VEGFA production and is associated with poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant solid tumor characterized by rich vascularization. Pregnancy-specific glycoprotein 9 (PSG9) is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy. We previously identified PSG9 as an HCC-related protein. However, the expression of PSG9 and its regulation during HCC carcinogenesis remain poorly explored. In the present study, we first found that the levels of PSG9 protein were significantly increased in the plasma of HCC patients. PSG9 overexpression also increased the proliferation ability of an HCC cell line. High expression of PSG9 was associated with angiogenesis by accelerating VEGFA expression. In addition, Cox's proportional hazards model analysis revealed that the plasma level of PSG9 was an independent prognostic factor for overall survival. We propose that PSG9 is a novel indicator of prognosis in patients with HCC and could serve as a novel therapeutic target for HCC. Furthermore, our results indicate that PSG9 protein may facilitate the development of HCC by fostering angiogenesis via promoting VEGFA production in cancer cells.

Psg22 null mouse embryos develop normally under normoxic and hypoxic conditions of pregnancy&amp;nbsp; &amp;nbsp; &amp;nbsp;

Pregnancy-specific glycoproteins are secreted immunoglobulin superfamily members encoded by multigene families in eutherian mammals with haemochorial placentation. They are expressed predominantly in placental trophoblast and exhibits immunomodulatory, anti-platelet and pro-angiogenic functions. An inversion of Psg22 in the mouse locus is associated with relatively high Psg22 expression in the first half of the pregnancy. Bioinformatic analysis of seventeen mouse strains indicated that the Psg22 inversion arose at least 1.7 MYA. We used CRISPR-Cas9 mutagenesis to generate Psg22 null mutants, two of which were analysed in detail (Psg22Δ10 and Psg22Δ16). Both mutants contain frame-shifting deletions in exon 2, resulting in premature stop codons, and Psg22 mRNA was virtually undetectable. Both mutants are fertile and there was no distortion of Mendelian ratios in heterozygous crosses. Housing of pregnant females in a hypoxic (11% O2) environment for five (E5 - E10) or ten (E5 - E15) days did not induce differential growth or survival of Psg22 wildtype and null mutant genotypes. Our results indicate that Psg22 is dispensable for embryonic development and reproduction under laboratory conditions. As PSGs are secreted into maternal blood, future work will focus on whether Psg22 deficiency alters maternal physiology.

Functional Consequences of Mannose and Asialoglycoprotein Receptor Ablation

The mannose receptor (ManR, Mrc1) and asialoglycoprotein receptor (ASGR, Asgr1 and Asgr2) are highly abundant endocytic receptors expressed by sinusoidal endothelial cells and parenchymal cells in the liver, respectively. We genetically manipulated either receptor individually or in combination, revealing phenotypic changes in female and male mice associated with changes in circulating levels of many glycoproteins. Both receptors rise and fall in response to progesterone during pregnancy. Thirty percent of Asgr2(-/-) and 65% of Mrc1(-/-)Asgr2(-/-) mice are unable to initiate parturition at the end of pregnancy, whereas Mrc1(-/-) mice initiate normally. Twenty five percent of Mrc1(-/-)Asgr2(-/-) male mice develop priapism when mating due to thrombosis of the penile vein, but neither Mrc1(-/-) nor Asgr2(-/-) mice do so. The half-life for luteinizing hormone (LH) clearance increases in Mrc1(-/-) and Mrc1(-/-)Asgr2(-/-) mice but not in Asgr2(-/-) mice; however, LH and testosterone are elevated in all three knockouts. The ManR clears LH thus regulating testosterone production, whereas the ASGR appears to mediate clearance of an unidentified glycoprotein that increases LH levels. More than 40 circulating glycoproteins are elevated >3.0-fold in pregnant Mrc1(-/-)Asgr2(-/-) mice. Pregnancy-specific glycoprotein 23, undetectable in WT mice (<50 ng/ml plasma), reaches levels of 1-10 mg/ml in the plasma of Mrc1(-/-)Asgr2(-/-) and Asgr2(-/-) mice, indicating it is cleared by the ASGR. Elevation of multiple coagulation factors in Mrc1(-/-)Asgr2(-/-) mice may account for priapism seen in males. These male and female phenotypic changes underscore the key roles of the ManR and ASGR in controlling circulating levels of numerous glycoproteins critical for regulating reproductive hormones and blood coagulation.

Roles for the pregnancy specific glycoproteins in trophoblast differentiation

Roles for the pregnancy specific glycoproteins in trophoblast differentiation

Pregnancy-specific glycoprotein 9 (PSG9), a driver for colorectal cancer, enhances angiogenesis via activation of SMAD4.

PSG9 is a member of the pregnancy-specific glycoprotein (PSG) family and has been shown to contribute to the progression of colorectal cancer (CRC) and cancer-related angiogenesis. Here, we aim to investigate abnormal PSG9 levels in patients with CRC and to emphasize the role of PSG9 in driving tumorigenesis. Serum from 140 patients with CRC and 125 healthy controls as well as 74 paired tumors and adjacent normal tissue were used to determine PSG9 levels. We discovered that PSG9 was significantly increased in serum (P<0.001) and in tumor tissues (P<0.001) from patients with CRC. Interestingly, the increased PSG9 levels correlated with poor survival (P=0.009) and microvessel density (MVD) (P=0.034). The overexpression of PSG9 strongly promoted the proliferation and migration of HCT-116 and HT-29 cells. However, PSG9 depletion inhibited the proliferation of SW-480 cells. Using a human umbilical vein endothelial cell tube-forming assay, we found that PSG9 promoted angiogenesis. The overexpression of PSG9 also increased the growth of tumor xenografts in nude mice. Co-immunoprecipitation experiments revealed that PSG9 was bound to SMAD4. The PSG9/SMAD4 complex recruited cytoplasmic SMAD2/3 to form a complex, which enhanced SMAD4 nuclear retention. The PSG9 and SMAD4 complex activated the expression of multiple angiogenesis-related genes (included IGFBP-3, PDGF-AA, GM-CSF, and VEGFA). Together, our findings illustrate the innovative mechanism by which PSG9 drives the progression of CRC and tumor angiogenesis. This occurs via nuclear translocation of PSG9/SMAD4, which activates angiogenic cytokines. Therefore, our study may provide evidence for novel treatment strategies by targeting PSG9 in antiangiogenic cancer therapy.

PSG9 Stimulates Increase in FoxP3+ Regulatory T-Cells through the TGF-β1 Pathway.

The pregnancy-specific glycoproteins (PSGs) are a family of proteins secreted by the syncytiotrophoblast of the placenta and are the most abundant trophoblastic proteins in maternal blood during the third trimester. The human PSG family consists of 10 protein-coding genes, some of which have a possible role in maintaining maternal immune tolerance to the fetus. PSG9 was reported as a potential predictive biomarker of pre-eclampsia, a serious complication of pregnancy that has been related to immunological dysfunction at the fetal-maternal interface. Therefore, we hypothesized that PSG9 may have an immunoregulatory role during pregnancy. We found that PSG9 binds to LAP and activates the latent form of TGF-β1. In addition, PSG9 induces the secretion of TGF-β1 from macrophages but not from CD4+ T-cells. TGF-β1 is required for the ex vivo differentiation of regulatory T-cells and, consistent with the ability of PSG9 to activate this cytokine, we observed that PSG9 induces the differentiation of FoxP3+ regulatory T-cells from naïve murine and human T-cells. Cytokines that are associated with inflammatory responses were also reduced in the supernatants of T-cells treated with PSG9, suggesting that PSG9, through its activation of TGFβ-1, could be a potent inducer of immune tolerance.

Effect of pregnancy-specific β1-glycoprotein on indoleamine-2,3-dioxygenase activity in human monocytes.

The role of heterogenic human pregnancy-specific glycoprotein (PSG), obtained by the authors' technology, in the regulation of the indoleamine-2,3-dioxygenase (IDO) activity in female blood monocytes has been studied in vitro. PSG stimulated IDO activity under the conditions of induction of the monocytes by interferon-γ. Upon the induction of cell proliferation by lipopolysaccharides, the stimulating effect was obtained only with 10 μg/mL of PSG. Enhanced IDO activity is probably a factor of peripheral immunological tolerance and antimicrobial protection against intracellular infections in the gestation period.

Graft Versus Host Disease (GvHD) Is Attenuated By Administration of Pregnancy Specific Glycoproteins through Induction of Immune Tolerance

Hematopoietic stem cell transplantation is curative for many disorders; however, it can be associated with significant morbidity and mortality, often as a result of graft versus host disease (GvHD). GvHD is an immune mediated reaction in which donor T-cells recognize the host antigens as foreign, causing donor T-cells to proliferate and attack host tissues. Establishment of a tolerogenic immune environment while preserving immune response to infectious agents and malignancy is required for successful bone marrow transplantationand GvHD presents a significant obstacle to this.Pregnancy specific glycoproteins (PSGs) are synthesized by the placenta at the onset of pregnancy and are believed to play a role in maintaining a tolerogenic immune environment to prevent rejection of the fetus by the maternal immune system. Two specific PSG proteins, PSG1 and PSG9, are of particular note as they have both been shown to be involved in pathways devoted to induction of immune tolerance. Both PSG1 and PSG9 are involved in activation of transforming growth factor-β (TGFβ), a cytokine essential to suppression of inflammatory T-cells and important for differentiation of tolerance inducing CD4+ CD25+ FoxP3+ regulatory T-cells (Tregs), a cell population shown to be important in the prevention of GvHD. We thus hypothesized that PSG1 and PSG9 (PSG1/9) could be used to treat or prevent GvHD by inducing immune tolerance through TGFβ.Using surface plasmon resonance (SPR) analysis, we have shown that PSG1/9 bind directly to the latency associated peptide (LAP), a protein that confers latency to mature TGFβ, effectively blocking binding of TGFβ to its receptors. Further, bioassays and ELISA data show an increase in the levels of bioactive TGFβ after treatment with PSG1/9, indicating that these proteins have a role in TGFβ activation through their interaction with LAP. In vitro data using naïve mouse T-cells showed that upon treatment with PSG1, there was a significant increase of CD4+ CD25+ cells expressing FoxP3 (18%±1.5; n=3) compared to only 2% in untreated controls (2%±0.4; n=6) (p<0.0001). Similarly, PSG9 treatment also increased FoxP3 expression (11%±2.8; n=3) over controls (p<0.0001). The increase in FoxP3 expression was also observed upon treatment of primary naïve human T-cells with both PSG1 and PSG9 (PSG1, p=0.0073; PSG9, p=0.0028). When a TGFβ receptor inhibitor was added to cell culture, the increase in FoxP3 expression was effectively blocked, further supporting the hypothesis that PSG1/9 induce expression of FoxP3+ Tregs through regulation of TGFβ. As IL-2 is important for the stability and differentiation of Tregsin vivo and its transcription is suppressed by TGFβ, we performed bioassays on CD4+ naïve T-cells with no added IL-2. We observed that in the absence of added IL-2, treatment with PSG1/9 resulted in an inhibition of IL-2 secretion by activated CD4+ T-cells, and there was no increase in the number and percentage of FoxP3 expressing cells.SBE-luc mice, which express luciferase in response to activation of the TGFβ-SMAD pathway, exhibited significantly increased luciferase expression in the abdomen when injected intraperitoneally with PSG1. This supports the idea that PSG1 induces expression of FoxP3 through the TGFβ receptor pathway in vivo. Finally, using a murine model of GvHD, we observed that mice receiving PSG1 had reduced numbers of infiltrating inflammatory CD3+ T-cells in the colon and showed a marked improvement physically and histologically over untreated controls. In addition, PSG1 treated mice had significantly higher expression of FoxP3 in CD4+ CD25+ splenic cells (30%±9.6; n=4) when compared to untreated GvHD controls (8.6%±3.2; n=3) (p=0.0287).Currently, we are studying the cytokine profiles of mice treated with PSG to determine the efficacy of PSG1/9 in reducing the release of pro-inflammatory cytokines during GvHD. Overall, our data suggests that PSG1/9 induce immune tolerance in GvHD and may be a future treatment option for these patients. DisclosuresNo relevant conflicts of interest to declare.

Use of biochemical tests of placental function for improving pregnancy outcome.

Use of biochemical tests of placental function for improving pregnancy outcome.

Recombinant N-Domain of Pregnancy-Specific Glycoprotein from E. coli Cells: Analysis of the Spectrum of Polyclonal Antibodies.

We studied antibody spectrum in antisera to IgG-like recombinant N-domain of pregnancyspecific glycoprotein-1 (rPSG-N) from E. coli cells. In three experimental series, the fraction of IgG antibodies from anti-rPSG-N sera was immobilized on 3 immunoadsorbents: by polymerization with glutaraldehyde, on glutaraldehyde activated biogel P-300, and on commercial CNBr-activated 4B sepharose. Retroplacental serum was incubated with immobilized antibodies to rPSG1-N, protein was eluted and tested in the precipitation test in standard test systems with PSG1, IgG, and human serum albumin. Three proteins were eluted from all 3 immunoadsorbents: PSG1, IgG, and human serum albumin, which demonstrated the spectrum of antibodies to 3 proteins present also in natural serum PSG1 complex. The proportions of PSG1 and IgG obtained in these experiments were similar to those in natural serum PSG1 complex, while the level of human serum albumin was significantly higher in natural PSG1 complex. Thus, we failed to obtain PSG1 monoprotein free from IgG and human serum albumin. Antigenic mosaicism of the polypeptide chain of IgG-like rPSG1-N relative to the antigenic polyvalence of the complex of three proteins present in bioactive preparation of natural serum PSG1 was discussed.

A significant risk locus on 19q13 for bipolar disorder identified using a combined genome-wide linkage and copy number variation analysis

BackgroundThe genetic background to bipolar disorder (BPD) has been attributed to different genetic and genomic risk factors. In the present study we hypothesized that inherited copy number variations (CNVs) contribute to susceptibility of BPD. We screened 637 BP-pedigrees from the NIMH Genetic Initiative and gave priority to 46 pedigrees. In this subsample we performed parametric and non-parametric genome-wide linkage analyses using ~21,000 SNP-markers. We developed an algorithm to test for linkage restricted to regions with CNVs that are shared within and across families.ResultsFor the combined CNV and linkage analysis, one region on 19q13 survived correction for multiple comparisons and replicates a previous BPD risk locus. The shared CNV map to the pregnancy-specific glycoprotein (PSG) gene, a gene-family not previously implicated in BPD etiology. Two SNPs in the shared CNV are likely transcription factor binding sites and are linked to expression of an F-box binding gene, a key regulator of neuronal pathways suggested to be involved in BPD etiology.ConclusionsOur CNV-weighted linkage approach identifies a risk locus for BPD on 19q13 and forms a useful tool to future studies to unravel part of the genetic vulnerability to BPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13040-015-0076-y) contains supplementary material, which is available to authorized users.