Alternative titles; symbols
HGNC Approved Gene Symbol: CGB3
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,022,869-49,024,333 (from NCBI)
Human chorionic gonadotropin (CG) is a glycoprotein hormone produced by trophoblastic cells of the placenta beginning 10 to 12 days after conception. Maintenance of the fetus in the first trimester of pregnancy requires the production of CG, which binds to the corpus luteum of the ovary which is stimulated to produce progesterone which in turn maintains the secretory endometrium. The glycoprotein hormone family to which CG belongs includes the pituitary hormones luteinizing hormone (LH; 152780), follicle-stimulating hormone (FSH; 136530), and thyroid-stimulating hormone (TSH; 188540). Each of these hormones consists of a noncovalent dimer of alpha and beta subunits. The alpha subunit is the same for all 4 hormones (see CGA; 118850), and the beta subunits define the endocrine function of the dimer (Talmadge et al., 1983).
By restriction digest analysis, Talmadge et al. (1983) determined that the 7 CGB genes are extremely similar but not identical. Otani et al. (1988) found that CGB3 and CBG8 (608827) were expressed at 2-fold lower levels than CGB5 (608825) following transfection into a mouse adrenocortical cell line.
Bo and Boime (1992) determined that most of the sequence variation among the CGB genes occurs in the nontranslated region of exon 1. They further found that CGB3 was expressed at about the same levels as CGB8 in first trimester placenta and in a choriocarcinoma cell line, and both were expressed at a lower level than CGB5.
Jameson and Lindell (1988) determined that each of the CGB genes contains 3 exons. Otani et al. (1988) determined that the promoter regions contain no CAAT or TATAA boxes.
By use of restriction probes in human-rodent hybrids, Naylor et al. (1983) assigned the CG alpha subunit to chromosome 6 and the beta subunit to chromosome 19. Special attention was paid to the exclusion of chromosomes 10 and 18 as sites of these genes. CGA mapped to the 6q12-6q21 region. The alpha and beta genes are on mouse chromosomes 4 and 7, respectively. Mouse 7 carries 2 other homologs of human 19: Pep-7 and Gpi, homologous to PEPD (613230) and GPI (172400), respectively.
Boorstein et al. (1982) concluded that the beta subunit of CG is encoded by at least 8 genes arranged in tandem and inverted pairs. They stated that 'until sequence analysis is complete, we cannot exclude the possibility that the eight genes include some pseudogenes or the related gene, beta-LH.' The beta subunits of luteinizing hormone (LHB) and CG show about 82% amino acid homology. The homology with beta-FSH and beta-TSH is much lower.
Talmadge et al. (1983) mapped the CGB3 gene to a gene cluster that contains 7 CGB genes and LHB (152780). This gene cluster is located on chromosome 19q13.32. Jameson and Lindell (1988) determined that the CGB gene cluster spans 68 kb.
Policastro et al. (1983, 1986) found 6 nonallelic copies of the CGB gene and a single-copy LHB gene. All were contained in a single 58-kb EcoRI fragment. The hCG beta-subunit is unique in the family of beta-containing glycoprotein hormones in that it contains an extension of 29 amino acids at its COOH end.
In somatic cell hybrids, Julier et al. (1984) used a cDNA probe for the beta unit of CG (CGB) and one for the beta unit of pituitary LH (LHB; 152780) to assign these loci to chromosome 19. Strict concordance between permissivity of hybrid cells to enteroviruses (determined by specific cell receptors coded by human chromosome 19) and the presence of LHB and CGB sequences confirmed the assignment.
Graham et al. (1987) isolated a cosmid clone containing the entire CGB cluster. The restriction map of this clone was determined by an indirect-end-label FIGE (field inversion gel electrophoresis) method. Analysis of this cosmid clone showed that human genomic DNA contains 6 CGB genes.
One of the major structural differences between the LH-beta and CG-beta subunits is the C-terminal region. Beyond residue 114, LH-beta has a hydrophobic heptapeptide stretch, while CG-beta contains a 31-residue hydrophilic C-terminal peptide (CTP) that is O-glycosylated. The CG-beta subunit is secreted quantitatively as a monomer and assembles efficiently whereas secretion and assembly of LH-beta is inefficient. Muyan et al. (1996) tested the function of the heptapeptide and CTP domains by fusing them to their counterparts at residues 114 of CG-beta or LH-beta subunits. The secretion and assembly of these chimeras were examined in transfected Chinese hamster ovary cells. Removal of the heptapeptide enhanced the amount of LH-beta subunit secreted 4-fold compared with intact LH-beta. Fusion of this heptapeptide to CG-beta-114, i.e., CG-beta lacking the CTP, decreased the amount of secreted subunit 2-fold compared with type human CG-beta. These data support the hypothesis that the C-terminal regions of LH-beta and CG-beta subunits play a role in the intracellular behavior of the corresponding heterodimers.
Kaposi sarcoma (148000) occurs more often in men than in women. Lunardi-Iskander et al. (1995) described an immortalized Kaposi sarcoma cell line from an AIDS patient and showed that these cells produce malignant metastatic tumors in nude mice but are killed in vitro and in vivo (apparently by apoptosis) by the beta-chain of human chorionic gonadotropin. Chorionic gonadotropin also killed cells of another neoplastic cell line established from a non-HIV-associated Kaposi sarcoma, as well as the hyperplastic Kaposi sarcoma cells from clinical specimens grown in short-term culture, but did not kill normal endothelial cells. The results had implications for the hormonal treatment of this tumor.
Zygmunt et al. (2002) proposed that human CG promotes angiogenesis. Physiologic concentrations of human CG significantly increased in vitro capillary formation and migration of endothelial cells in a Boyden chamber assay in a dose-dependent manner, whereas it had no effect on cell proliferation. In vivo, CG induced neovascularization in the chicken chorioallantoic membrane assay comparable to the activity of vascular endothelial growth factor (VEGF; 192240). The authors concluded that their data indicated a novel function for human CG in uterine adaptation to early pregnancy as well as in tumor development and underlined the importance of CG as a theretofore unrecognized angiogenic factor.
Ferguson-Smith (2003) traced the development of noninvasive approaches to prenatal screening and diagnosis and commented on the use of circulating fetal nucleic acid in maternal plasma. Ng et al. (2003) provided direct evidence that the placenta is an important source of fetal nucleic acid release into maternal plasma by demonstrating that mRNA transcripts from 2 placenta-expressed genes, those coding for the beta subunit of chorionic gonadotropin and placental lactogen (PL; 150200), are readily detectable in maternal plasma. The surprising stability of such placental mRNA species in maternal plasma and their rapid clearance after delivery demonstrated that circulating mRNA molecules are practical markers for clinical use.
Associations Pending Confirmation
Amato et al. (2002) reported a patient with a 9-year history of secondary infertility due to an anti-CG autoantibody. Although she had regular menstrual cycles, had conceived spontaneously, and had good hormonal and follicular responses to gonadotropic stimulation regimens during the in vitro fertilization workup, she presented with apparent recurrent pregnancy loss associated with prolonged raised CG levels. She was found to have specific, low-affinity, but high-capacity anti-CG antibody. Crossreaction with recombinant FSH (136530), recombinant LH, CG-alpha, and CG-beta was low. In addition, heat-inactivated serum and the affinity-purified IgG were shown to inhibit the action of CG in an in vitro bioassay. The authors concluded that the persisting titer of the antibody was responsible for the patient's infertility.
Warburton et al. (1990) used expression of the CGB gene as well as the presence of the INSR (147670) and APOC2 (608083) genes to test for the retention of a single chromosome 19 in rodent-human hybrids created by the new method they devised. Human lymphoblastoid lines were infected with the retroviral vector SP-1, which contains the bacterial his-D gene, allowing mammalian cells to grow in the presence of histidinol. They then used microcell fusion of the infected lymphoblastoid cells with CHO cells to produce hybrids containing single human chromosomes retained by histidinol selection. The retroviral vector integrates into human chromosomes singly and with precisely defined ends, facilitating the analysis of the integration site. The histidinol dehydrogenase gene from Salmonella typhimurium codes for the enzyme that converts histidinol to histidine. Mammalian cells lacking this gene are killed by histidinol through competition with histidine for the histidyl-tRNA synthetase.
Amato, F., Warnes, G. M., Kirby, C. A., Norman, R. J. Infertility caused by hCG autoantibody. J. Clin. Endocr. Metab. 87: 993-997, 2002. [PubMed: 11889150] [Full Text: https://doi.org/10.1210/jcem.87.3.8334]
Bo, M., Boime, I. Identification of the transcriptionally active genes of the chorionic gonadotropin beta gene cluster in vivo. J. Biol. Chem. 267: 3179-3184, 1992. [PubMed: 1371113]
Boorstein, W. R., Vamvakopoulos, N. C., Fiddes, J. C. Human chorionic gonadotropin beta-subunit is encoded by at least eight genes arranged in tandem and inverted pairs. Nature 300: 419-422, 1982. [PubMed: 6183595] [Full Text: https://doi.org/10.1038/300419a0]
Ferguson-Smith, M. A. Placental mRNA in maternal plasma: prospects for fetal screening. (Commentary) Proc. Nat. Acad. Sci. 100: 4360-4362, 2003. [PubMed: 12682290] [Full Text: https://doi.org/10.1073/pnas.0830966100]
Fiddes, J. C., Goodman, H. M. The cDNA for the beta-subunit of human chorionic gonadotropin suggests evolution of a gene by readthrough into the 3-prime-untranslated region. Nature 286: 684-687, 1980. [PubMed: 6774259] [Full Text: https://doi.org/10.1038/286684a0]
Graham, M. Y., Otani, T., Boime, I., Olson, M. V., Carle, G. F., Chaplin, D. D. Cosmid mapping of the human chorionic gonadotropin beta subunit genes by field-inversion gel electrophoresis. Nucleic Acids Res. 15: 4437-4448, 1987. [PubMed: 3035494] [Full Text: https://doi.org/10.1093/nar/15.11.4437]
Jameson, J. L., Lindell, C. M. Isolation and characterization of the human chorionic gonadotropin beta subunit (CG-beta) gene cluster: regulation of a transcriptionally active CG-beta gene by cyclic AMP. Molec. Cell. Biol. 8: 5100-5107, 1988. [PubMed: 2468994] [Full Text: https://doi.org/10.1128/mcb.8.12.5100-5107.1988]
Julier, C., Weil, D., Couillin, P., Cote, J. C., Boue, A., Thririon, J. P., Kaplan, J. C., Junien, C. Confirmation of the assignment of the genes coding for human chorionic gonadotropin beta subunit to chromosome 19. (Abstract) Cytogenet. Cell Genet. 37: 501-502, 1984.
Julier, C., Weil, D., Couillin, P., Cote, J. C., Van Cong, N., Foubert, C., Boue, A., Thirion, J. P., Kaplan, J. C., Junien, C. The beta chorionic gonadotropin-beta luteinizing gene cluster maps to human chromosome 19. Hum. Genet. 67: 174-177, 1984. [PubMed: 6204923] [Full Text: https://doi.org/10.1007/BF00272995]
Lunardi-Iskander, Y., Bryant, J. L., Zeman, R. A., Lam, V. H., Samaniego, F., Besnier, J. M., Hermans, P., Thierry, A. R., Gill, P., Gallo, R. C. Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone. Nature 375: 64-68, 1995. Note: Erratum: Nature 376: 447 only, 1995. [PubMed: 7723844] [Full Text: https://doi.org/10.1038/375064a0]
Muyan, M., Furuhashi, M., Sugahara, T., Boime, I. The carboxy-terminal region of the beta-subunits of luteinizing hormone and chorionic gonadotropin differentially influence secretion and assembly of the heterodimers. Molec. Endocr. 10: 1678-1687, 1996. [PubMed: 8961276] [Full Text: https://doi.org/10.1210/mend.10.12.8961276]
Naylor, S. L., Chin, W. W., Goodman, H. M., Lalley, P. A., Grzeschik, K.-H., Sakaguchi, A. Y. Chromosome assignment of the genes encoding the alpha and beta subunits of the glycoprotein hormones in man and mouse. Somat. Cell Genet. 9: 757-770, 1983. [PubMed: 6581542] [Full Text: https://doi.org/10.1007/BF01539478]
Ng, E. K. O., Tsui, N. B. Y., Lau, T. K., Leung, T. N., Chiu, R. W. K., Panesar, N. S., Lit, L. C. W., Chan, K.-W., Lo, Y. M. D. mRNA of placental origin is readily detectable in maternal plasma. Proc. Nat. Acad. Sci. 100: 4748-4753, 2003. [PubMed: 12644709] [Full Text: https://doi.org/10.1073/pnas.0637450100]
Otani, T., Otani, F., Krych, M., Chaplin, D. D., Boime, I. Identification of a promoter region in the CG-beta gene cluster. J. Biol. Chem. 263: 7322-7329, 1988. Note: Erratum: J. Biol. Chem. 263: 19256-19257, 1988. [PubMed: 2452822]
Policastro, P. F., Daniels-McQueen, S., Carle, G., Boime, I. A map of the hCG-beta-LH-beta gene cluster. J. Biol. Chem. 261: 5907-5916, 1986. [PubMed: 2422163]
Policastro, P., Ovitt, C. E., Hoshina, M., Fukuoka, H., Boothby, M. R., Biome, I. The beta-subunit of human chorionic gonadotropin is encoded by multiple genes. J. Biol. Chem. 258: 11492-11499, 1983. [PubMed: 6194155]
Talmadge, K., Boorstein, W. R., Fiddes, J. C. The human genome contains seven genes for the beta-subunit of chorionic gonadotropin but only one gene for the beta-subunit of luteinizing hormone. DNA 2: 281-289, 1983. [PubMed: 6319099] [Full Text: https://doi.org/10.1089/dna.1983.2.281]
Talmadge, K., Vamvakopoulos, N. C., Fiddes, J. C. Evolution of the genes for the beta subunits of human chorionic gonadotropin and luteinizing hormone. Nature 307: 37-40, 1984. [PubMed: 6690982] [Full Text: https://doi.org/10.1038/307037a0]
Warburton, D., Gersen, S., Yu, M.-T., Jackson, C., Handelin, B., Housman, D. Monochromosomal rodent-human hybrids from microcell fusion of human lymphoblastoid cells containing an inserted dominant selectable marker. Genomics 6: 358-366, 1990. [PubMed: 2307476] [Full Text: https://doi.org/10.1016/0888-7543(90)90577-h]
Zygmunt, M., Herr, F., Keller-Schoenwetter, S., Kunzi-Rapp, K., Munstedt, K., Rao, C. V., Lang, U., Preissner, K. T. Characterization of human chorionic gonadotropin as a novel angiogenic factor. J. Clin. Endocr. Metab. 87: 5290-5296, 2002. [PubMed: 12414904] [Full Text: https://doi.org/10.1210/jc.2002-020642]