Alternative titles; symbols
HGNC Approved Gene Symbol: FCGR1A
Cytogenetic location: 1q21.2 Genomic coordinates (GRCh38): 1:149,782,694-149,800,609 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.2 | [IgG receptor I, phagocytic, familial deficiency of] | 3 |
Fc-gamma receptors (FCGRs), such as FCGR1A, are integral membrane glycoproteins that exhibit complex activation or inhibitory effects on cell functions after aggregation by complexed immunoglobulin G (IgG). FCGR1A is a 72-kD activating FCGR found exclusively on antigen-presenting cells (APCs) of macrophage and dendritic cell (DC) lineages and has a high affinity for monomeric IgG1 (summary by Rodrigo et al., 2006).
Pearse et al. (1991) stated that the FCGR1 gene encodes a high-affinity Fc-gamma receptor that plays a pivotal role in the immune response. Also known as CD64, it is a 72-kD glycoprotein that is constitutively expressed on human monocytes and macrophages.
Using immunoprecipitation and immunoblot analyses with human and mouse cells, Beekman et al. (2008) showed that FCGR1 predominantly resided in detergent-resistant membrane domains, also known as lipid rafts, along with FCR gamma chain (FCER1G; 147139). Confocal microscopy demonstrated copatching with a microdomain-enriched glycolipid, GM1. Residence of CD64 in lipid rafts did not require prior triggering of the receptor.
Using in situ hybridization, Wang et al. (2019) showed that Fcgr1 was expressed in mouse joint-innervating dorsal root ganglion (DRG) neurons.
By genomic cloning, Pearse et al. (1991) determined the structure of the gene encoding human FCGR1. They focused on the structure of its promoter and characterized the DNA sequences responsible for its induction by gamma-interferon (IFNG; 147570). They found a 39-nucleotide sequence, called by them the IFN-gamma response region (GRR), that was both necessary and sufficient for gamma-interferon inducibility.
Osman et al. (1992) demonstrated that the Fcg1 locus in the mouse is on chromosome 3, near the end of the region that shows homology to human chromosome 1. Analysis of human x rodent somatic cell hybrid cell lines indicated that the human FCGR1 locus is on human chromosome 1 and is therefore probably linked to the other FCGR genes. Oakey et al. (1992) also mapped the FCGR1 gene to mouse chromosome 3. It is likely that FCGR1 is on the short arm of human chromosome 1 close to CD2 (186990), which is located at 1p13. The related genes FCGR2A (146790) and FCGR3 (146740) are located on human chromosome 1q23 and mouse chromosome 1. However, Takai et al. (1994) demonstrated by FISH that the FCGR1 gene is located on human chromosome 1q21.2-q21.3.
By FISH analysis of human cells and Southern analysis of cell lines containing 1p and 1q, Maresco et al. (1996) demonstrated that the 3 FCGR1 genes, FCGR1A, FCGR1B (601502), and FCGR1C (601503), flank the centromere of chromosome 1 at bands 1p12 and 1q21. FCGR1B was found at 1p12, whereas both FCGR1A and FCGR1C were localized to 1q21. This placed the FCGR1 gene family within a large pericentric linkage group that is conserved between humans and mice. Maresco et al. (1996) hypothesized that the 3 FCGR1 genes were separated by a pericentric inversion, known to have occurred on human chromosome 1, which relocated FCGR1A and FCGR1C to the long arm and left FCGR1B positioned on the short arm.
Indik et al. (1994) transfected a monkey fibroblast line lacking endogenous FCGR with human FCGR1 to examine the role of FCGR-mediated phagocytosis. They showed that FCGR1, unlike either FCGR2A (146790) or FCGR3A (146740) paired with its gamma subunit (FCER1G), FCGR1 did not induce phagocytosis of IgG-sensitized red blood cells. However, when expressed in mouse macrophages, FCGR1 stimulated phagocytosis. Mutant FCGR1 lacking the cytoplasmic domain showed no loss of phagocytic capacity. Phagocytosis could be inhibited by chemical blockers of tyrosine phosphorylation. Activation of FCGR1 in human monocytes suggested interaction with other receptors. Transfection of both FCGR1 and FCGR2A into primate fibroblasts failed to induce phagocytosis, but transfection of FCGR1, with or without the cytoplasmic domain, with the gamma subunit of FCGR3A, but not the beta subunit of FCER1 (MSFA2; 147138), resulted in binding and phagocytic function. Indik et al. (1994) concluded that the cytoplasmic domain of FCGR1 is not required for all cellular responses and that cell surface receptors may transmit signals by mechanisms independent of the cytoplasmic domain.
Using flow cytometry, Fanger et al. (1996) demonstrated that expression of CD83 (604534) and HLA-DRA (142860) was upregulated in human blood DCs, but not in monocytes, after 2 days of culture. CD64 was constitutively expressed in DCs, but at a lower level than in monocytes, and did not decrease during culture. Incubation with IFNG upregulated CD64 expression in both cell types. Phagocytosis mediated by both CD32 (FCGR2A) and CD64 occurred in DCs, but at a lower level than in monocytes. Fanger et al. (1996) proposed that DCs may play a role in uptake of foreign particles before trafficking to T cell-reactive sites.
Fanger et al. (1997) reported that stimulation with either IFNG or IL10 (124092) increased CD64 expression in human DCs and monocytes, whereas IL4 (147780) decreased CD64 expression in monocytes. Monocytes, but not DCs, generated robust FCR-dependent superoxide anion release and antibody-dependent cytotoxicity activity. DCs were more efficient than monocytes in inducing T-cell activation when antigen was targeted specifically to CD64.
By expressing human CD64 mutants in a murine macrophage line, Edberg et al. (2002) demonstrated that serine phosphorylation of the cytoplasmic domain was important for receptor-induced activation and phagocytosis. However, mutation of serines to alanine did not recapitulate the effects of cytoplasmic domain truncation on cytokine production. Edberg et al. (2002) concluded that the cytoplasmic domain of FCGR1A regulates different functional capacities of the FCGR1A receptor complex.
CD64 and CD32 are abundant on the surface of cells that are permissive to infection with dengue virus (see 614371). A gamma chain bearing an immunoreceptor tyrosine-based activation motif (ITAM) associates with CD64, whereas the ITAM is a constitutive component of CD32. By expressing human receptors with and without the ITAM in monkey kidney cells, Rodrigo et al. (2006) determined that CD32 mediated greater infectivity of dengue-2 virus immune complexes than CD64, and that the gamma chain was critical for CD64-mediated phagocytosis and infectivity. Mutation in the ITAM complex had an impact on phagocytosis mediated by both receptors, but not on CD32-mediated infectivity. Rodrigo et al. (2006) concluded that CD64 and CD32 have fundamental differences in respect to immune-enhancing capabilities as well as different mechanisms of dengue virus immune complex internalization.
Wang et al. (2019) found that IgG immune complex (IgG-IC) directly activated joint sensory afferents and induced acute joint nociceptive behaviors in mice without obvious inflammation. These pronociceptive effects of IgG-IC were mediated by Fcgr1 expressed in primary sensory neurons. Similarly, an antigen-induced arthritis (AIA) mouse model showed upregulation of Fcgr1 expression and function in joint sensory neurons. Fcgr1 deletion in AIA mice attenuated arthritis pain without obvious effects on joint inflammation. Likewise, pharmacologic blockade of peripheral Fcgr1 reversed arthritis pain without attenuation of inflammation in the AIA model. In addition, AIA-induced hyperactivity of joint sensory afferents was reduced in Fcgr1 -/- mice.
In 4 individuals in the same family, van de Winkel et al. (1995) demonstrated lack of phagocyte expression of CD64. As a result, their monocytes were unable to support mouse IgG2a anti-CD3-induced T cell mitogenesis, i.e., they were nonresponders. Southern blotting showed that the CD64 gene was present in nonresponders without major structural changes. Nucleotide sequencing showed identical promoter regions of the gene in all individuals. At the message level, a distinct difference was noted between monocytes from control (responder) donors and from nonresponders. Both a 1.7- and 1.6-kb message was found in responders, whereas in nonresponders only the 1.6-kb species was detectable. Reverse transcriptase-PCR analyses showed that the CD64 transcript (encoding a receptor with 3 extracellular Ig-like domains) was present at a level approximately 15- to 20-fold lower than in nonresponder monocytes. They could demonstrate a single nucleotide difference (C-to-T) within the extracellular domain, exon 1-encoding region of the FCGR1 gene in nonresponders, resulting in the change of codon 92 from arginine to a stop. This change probably affected mRNA stability and thereby led to undetectable expression of CD64 in phagocytes. Despite this defect these individuals were apparently healthy, suggesting that FCGR1 is dispensable for phagocyte functioning. The 4 deficient individuals were sisters. The mother, 2 sisters, and 1 brother of the nonresponder subjects responded normally and were all healthy. The father had died at age 45 of cancer.
Beekman, J. M., van der Linden, J. A., van de Winkel, J. G. J., Leusen, J. H. W. Fc-gamma-RI (CD64) resides constitutively in lipid rafts. Immun. Lett. 116: 149-155, 2008. [PubMed: 18207250] [Full Text: https://doi.org/10.1016/j.imlet.2007.12.003]
Edberg, J. C., Qin, H., Gibson, A. W., Yee, A. M. F., Redecha, P. B., Indik, Z. K., Schreiber, A. D., Kimberly, R. P. The CY domain of the Fc-gamma-RIa alpha-chain (CD64) alters gamma-chain tyrosine-based signaling and phagocytosis. J. Biol. Chem. 277: 41287-41293, 2002. [PubMed: 12200451] [Full Text: https://doi.org/10.1074/jbc.M207835200]
Fanger, N. A., Voigtlaender, D., Liu, C., Swink, S., Wardwell, K., Fisher, J., Graziano, R. F., Pfefferkorn, L. C., Guyre, P. M. Characterization of expression, cytokine regulation, and effector function of the high affinity IgG receptor Fc-gamma-RI (CD64) expressed on human blood dendritic cells. J. Immun. 158: 3090-3098, 1997. [PubMed: 9120261]
Fanger, N. A., Wardwell, K., Shen, L., Tedder, T. F., Guyre, P. M. Type I (CD64) and type II (CD32) Fc-gamma receptor-mediated phagocytosis by human blood dendritic cells. J. Immun. 157: 541-548, 1996. [PubMed: 8752900]
Indik, Z. K., Hunter, S., Huang, M. M., Pan, X. Q., Chien, P., Kelly, C., Levinson, A. I., Kimberly, R. P., Schreiber, A. D. The high affinity Fc-gamma receptor (CD64) induces phagocytosis in the absence of its cytoplasmic domain: the gamma-subunit of Fc-gamma-RIIIA imparts phagocytic function to Fc-gamma-RI. Exp. Hemat. 22: 599-606, 1994. [PubMed: 7516890]
Maresco, D. L., Chang, E., Theil, K. S., Francke, U., Anderson, C. L. The three genes of the human FCGR1 gene family encoding Fc-gamma-RI flank the centromere of chromosome 1 at 1p12 and 1q21. Cytogenet. Cell Genet. 73: 157-163, 1996. [PubMed: 8697799] [Full Text: https://doi.org/10.1159/000134330]
Oakey, R. J., Howard, T. A., Hogarth, P. M., Tani, K., Seldin, M. F. Chromosomal mapping of the high affinity Fc-gamma receptor gene. Immunogenetics 35: 279-282, 1992. [PubMed: 1347284] [Full Text: https://doi.org/10.1007/BF00166834]
Osman, N., Kozak, C. A., McKenzie, I. F. C., Hogarth, P. M. Structure and mapping of the gene encoding mouse high affinity Fc-gamma-RI and chromosomal location of the human Fc-gamma-RI gene. J. Immun. 148: 1570-1575, 1992. [PubMed: 1531670]
Pearse, R. N., Feinman, R., Ravetch, J. V. Characterization of the promoter of the human gene encoding the high-affinity IgG receptor: transcriptional induction by gamma-interferon is mediated through common DNA response elements. Proc. Nat. Acad. Sci. 88: 11305-11309, 1991. [PubMed: 1837149] [Full Text: https://doi.org/10.1073/pnas.88.24.11305]
Rodrigo, W. W. S. I., Jin, X., Blackley, S. D., Rose, R. C., Schlesinger, J. J. Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fc-gamma-RIA (CD64) or Fc-gamma-RIIA (CD32). J. Virol. 80: 10128-10138, 2006. [PubMed: 17005690] [Full Text: https://doi.org/10.1128/JVI.00792-06]
Takai, S., Kasama, M., Yamada, K., Kai, N., Hirayama, N., Namiki, H., Taniyama, T. Human high-affinity Fc-gamma-RI (CD64) gene mapped to chromosome 1q21.2-q21.3 by fluorescence in situ hybridization. Hum. Genet. 93: 13-15, 1994. [PubMed: 8270248] [Full Text: https://doi.org/10.1007/BF00218905]
van de Winkel, J. G. J., de Wit, T. P. M., Ernst, L. K., Capel, P. J. A., Ceuppens, J. L. Molecular basis for a familial defect in phagocyte expression of IgG receptor I (CD64). J. Immun. 154: 2896-2903, 1995. [PubMed: 7533186]
Wang, L., Jiang, X., Zheng, Q., Jeon, S.-M., Chen, T., Liu, Y., Kulaga, H., Reed, R., Dong, X., Caterina, M. J., Qu, L. Neuronal Fc-gamma-RI mediates acute and chronic joint pain. J. Clin. Invest. 129: 3754-3769, 2019. [PubMed: 31211699] [Full Text: https://doi.org/10.1172/JCI128010]