Alternative titles; symbols
HGNC Approved Gene Symbol: FCGR2A
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,505,457-161,524,048 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | {Lupus nephritis, susceptibility to} | 152700 | Autosomal dominant | 3 |
| {Malaria, severe, susceptibility to} | 611162 | 3 | ||
| {Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis} | 219700 | Autosomal recessive | 3 |
Receptors for the Fc portion of IgG such as FCGR2A play an essential role in the protection of the organism against foreign antigens by removing antigen-antibody complexes from the circulation (Hibbs et al., 1988). Receptors are present on monocytes, macrophages, neutrophils, natural killer (NK) cells, and T and B lymphocytes, and they participate in diverse functions such as phagocytosis of immune complexes and modulation of antibody production by B cells.
Hibbs et al. (1988) isolated cDNA clones for the FcGR gene by cross-species hybridization by probing cDNA libraries with a low-affinity FcGR beta-1 cDNA clone from mouse, as well as a pool of oligonucleotides constructed from the nucleotide sequence of this FcGR. Analysis of the amino acid sequence predicted from cDNA clones indicated that the human FcGR protein is synthesized with a 34-amino acid leader and that the mature protein is composed of 281 amino acids. The extracellular region of this FcGR was divided into 2 domains, which were very similar to each other and to the corresponding regions of both mouse alpha and beta FcGRs and showed a clear relationship to immunoglobulin variable regions.
Grundy et al. (1988) mapped the immunoglobulin Fc receptor II and Fc receptor III genes (see FCGR3A; 146740) to chromosome 1 by means of spot-blot analysis of sorted chromosomes. By hybridizing each probe to human DNA digested with 8 different 'rare-cutting' restriction enzymes and separated by pulsed field gel electrophoresis, Grundy et al. (1988) showed that the 2 genes mapped to the same fragment, the smallest of which was 250 kb long. Peltz et al. (1989) showed physical linkage of the 2 genes within a maximum distance of 200 kb. The conclusion on the basis of Southern and in situ data of Grundy et al. (1989) that there are three 8- to 10-kb Fc-gamma-RII loci per haploid genome was confirmed by Qiu et al. (1990), who named the genes A, A-prime, and B to reflect their homology and presumed evolution. Lebo et al. (1991) noted that occasionally these 3 genes, which lie within a 200-kb region, could be resolved in individual metaphase chromatids by multicolor fluorescence in situ hybridization.
By in situ hybridization, Sammartino et al. (1988) assigned the IGFR2 gene to 1q23-q24. In the course of constructing a physical map of human 1q21-q23, Oakey et al. (1992) placed FCGR2A in that region, close to MPP (159440) and APOA2 (107670). The homologous gene in the mouse, Ly-17, maps to mouse chromosome 1 (Hibbs et al., 1985). See review by Unkeless (1989).
Crystal Structure
Lu et al. (2008) described the structural mechanism for pentraxin's binding to Fc-gamma-R and its functional activation of Fc-gamma-R-mediated phagocytosis and cytokine secretion. The complex structure between human serum amyloid P component (SAP; 104770) and Fc-gamma-RIIa shows a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from 2 SAP subunits. The 1:1 stoichiometry between SAP and Fc-gamma-RIIa implies the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies showed that pentraxins are diverse in their binding specificity for Fc-gamma-R isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG causes competition for Fc-gamma-R binding and the inhibition of immune complex-mediated phagocytosis by soluble pentraxins. Lu et al. (2008) concluded that their results established antibody-like functions for pentraxins in the Fc-gamma-R pathway, suggested an evolutionary overlap between the innate and adaptive immune systems, and had therapeutic implications for autoimmune diseases.
CD64 (FCGR1A; 146760) 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.
By determining the nature and rate of copy number variation (CNV) mutation and investigating the global variation of disease-associated variation at the FCGR locus, Machado et al. (2012) determined that CNV of the FCGR3 genes is mediated by recurrent nonallelic homologous recombination between the 2 segmental duplications that carry FCGR3A and FCGR3B (610665). They showed that pathogen richness, particularly helminth pathogens, is likely to have influenced the patterns of variation in FCGRs in humans. Machado et al. (2012) proposed that alterations to IgG binding in the context of helminth infection have driven positive selection in FCGR among different mammalian species, linking evolutionary pressure of helminth infection with autoimmune disease via adaptation at the genetic level. This model supports the 'hygiene hypothesis,' which states that in the absence of chronic helminth infection in modern populations, previously selected alleles respond to immune system challenges differently and therefore may alter susceptibility to autoimmune disease.
Stein et al. (2000) found that C-reactive protein (CRP; 123260) showed decreased binding to cells from FCGR2A H131 homozygotes (which bind IgG2 with high affinity). However, interferon-gamma (147570) enhanced FCGR1A (146760) expression by H131 monocytes and increased CRP binding. FCGR2A heterozygotes showed intermediate binding. CRP initiated increases in Ca(2+) in polymorphonuclear leukocytes from R131, but not from H131, homozygotes. These experiments provided direct genetic evidence for FCGR2A as a functional, high-affinity CRP receptor on leukocytes, while emphasizing the reciprocal relationship between IgG and CRP binding avidities. The counterbalance may affect the contribution of FCGR2A alleles to host defense and autoimmunity.
Susceptibility to Lupus Nephritis
Allelic variants of the Fc-gamma receptor confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Salmon et al. (1996) noted that the FCGR2A gene has 2 codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The 2 alleles differ by the amino acid, arginine or histidine, at position 131. H131 is the only Fc-gamma receptor that recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Since immune complex clearance is essential in systemic lupus erythematosus (SLE; 152700), Salmon et al. (1996) hypothesized that the FCGR2A genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a 2-stage cross-sectional study, they compared the distribution of FCGR2A alleles in 43 African Americans with SLE to that in 39 African American non-SLE controls. A deficiency of H131 homozygotes were found in a preliminary study of SLE patients; 9% of patients were homozygous for the H131 variant, as compared with 36% of controls. This was confirmed in a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of FCGR2A alleles was more striking in lupus nephritis, with a highly significant decrease in H131 as the likelihood for lupus nephritis increased. The results were considered by the authors as consistent with a protective effect of the H131 allele against lupus nephritis.
In a collection of 31 African American families with multiple cases of SLE, Moser et al. (1998) found linkage between the R131H polymorphism of the FCGR2A gene and the disease.
Susceptibility to Chronic Infection by Pseudomonas Aeruginosa in Cystic Fibrosis
In 69 Italian patients with cystic fibrosis (CF; 219700) due to homozygosity for the delF508 mutation in the CFTR gene (602421.0001), De Rose et al. (2005) found that those who also carried the R131 allele of FCGR2A had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients.
Susceptibility to Inflammatory Bowel Disease
In a 2-stage genomewide association and replication study involving a total of 1,384 Japanese patients with ulcerative colitis (UC; see IBD1, 266600) and 3,057 controls, Asano et al. (2009) found significant association (heterogeneity-corrected p = 1.56 x 10(-12); odds ratio, 0.63) between UC and a nonsynonymous SNP (H131R; rs1801274) in the FCGR2A gene. The authors noted that the H131 variant was the susceptibility allele for UC, a reversal of previous associations observed between R131 and other autoimmune diseases.
Susceptibility to Severe Malaria
By studying 2,504 Ghanaian children with severe malaria (611162) and 2,027 healthy matched controls, Schuldt et al. (2010) found that homozygosity for 131R was positively associated with severe malaria (odds ratio = 1.20; p = 0.007; p corrected for multiple testing = 0.021), and, after stratification for phenotypes, with severe anemia (odds ratio = 1.33; p = 0.001; p corrected = 0.009), but not with cerebral malaria or other malaria complications or with parasitemia levels. Schuldt et al. (2010) concluded that the CRP-binding variant of FCGR2A is associated with malarial anemia, suggesting a role for CRP defense mechanisms in pathogenesis of this condition.
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Salmon, J. E., Millard, S., Schachter, L. A., Arnett, F. C., Ginzler, E. M., Gourley, M. F., Ramsey-Goldman, R., Peterson, M. G. E., Kimberly, R. P. Fc-gamma-RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J. Clin. Invest. 97: 1348-1354, 1996. [PubMed: 8636449] [Full Text: https://doi.org/10.1172/JCI118552]
Sammartino, L., Webber, L. M., Hogarth, P. M., McKenzie, I. F. C., Garson, O. M. Assignment of the gene coding for human FcRII (CD32) to bands q23q24 on chromosome 1. Immunogenetics 28: 380-381, 1988. [PubMed: 2971615] [Full Text: https://doi.org/10.1007/BF00364238]
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