* 146740

Fc FRAGMENT OF IgG RECEPTOR IIIa; FCGR3A


Alternative titles; symbols

Fc FRAGMENT OF IgG, LOW AFFINITY IIIa, RECEPTOR FOR
IMMUNOGLOBULIN G Fc RECEPTOR III-2
FCRIII-2
CD16A


HGNC Approved Gene Symbol: FCGR3A

Cytogenetic location: 1q23.3     Genomic coordinates (GRCh38): 1:161,541,759-161,550,737 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q23.3 Immunodeficiency 20 615707 AR 3

TEXT

Description

The Fc receptor with low affinity for IgG (FCGR3, or CD16) is encoded by 2 nearly identical genes, FCGR3A and FCGR3B (610665), resulting in tissue-specific expression of alternative membrane-anchored isoforms. FCGR3A encodes a transmembrane protein expressed on activated monocytes/macrophages, natural killer (NK) cells, and a subset of T cells. In contrast, FCGR3B encodes a glycosylphosphatidylinositol (GPI)-anchored protein that is expressed constitutively by neutrophils and after gamma-interferon (IFNG; 147570) stimulation by eosinophils (summary by Gessner et al., 1995).


Cloning and Expression

By Western blot and flow cytometric analyses, Ravetch and Perussia (1989) demonstrated differential expression of FCGR3 on polymorphonuclear neutrophils (PMNs) and NK cells. The glycoprotein on NK cells (FCGR3A) had a molecular mass 6 to 10 kD larger than that on neutrophils (FCGR3B) and was resistant to phosphatidylinositol-specific phospholipase C. Transcripts derived from FCGR3A and FCGR3B in NK cells and PMNs, respectively, have multiple single nucleotide differences, including 1 that converts a termination codon to a codon encoding arg, thereby extending the cytoplasmic domain by 21 amino acids and introducing a transmembrane anchor for FCGR3A in NK cells. The deduced FCGR3A protein contains 254 amino acids, whereas the deduced FCGR3B protein contains 233 amino acids. Ravetch and Perussia (1989) concluded that cell type-specific expression of 2 genes encoding alternative FCGR3 proteins has a significant effect on the biologic functions of the molecules.


Gene Structure

Gessner et al. (1995) isolated and sequenced genomic clones of FCGR3A and FCGR3B, located their transcription initiation sites, identified the different organizations of their 5-prime regions, and demonstrated 4 distinct classes of FCGR3A transcripts compared with a single class of FCGR3B transcripts. The gene promoters displayed different tissue-specific transcriptional activities reflecting expression of FCGR3A in NK cells and FCGR3B in neutrophils.


Mapping

Le Coniat et al. (1990) mapped the FCGR3A gene to chromosome 1q23 by in situ hybridization.


Gene Function

Anderson et al. (1990) concluded that CD16 is included in the zeta natural killer cell receptor complex (CD3Z; 186780).

Some gamma-delta T cells (see TCRG, 186970 and TCRD, 186810) express CD16. Using flow cytometric analysis, Bodman-Smith et al. (2000) examined the relative proportions of CD16+ gamma-delta T cells in the blood and synovial fluid of rheumatoid arthritis (RA; 180300) patients and the blood of control subjects. There was a significant reduction in CD16+ gamma-delta T cells in synovial fluid compared with the circulation. Mitogenic stimulation of circulating gamma-delta T cells resulted in an increased expression of the HLA-DR activation marker and a concomitant time-dependent decrease in the expression of CD16. Bodman-Smith et al. (2000) concluded that CD16 expression is lost in the synovial compartment as a result of activation.

Wang et al. (2017) noted that dengue virus infection (see 614371) can be exacerbated to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) when it occurs in the presence of reactive, nonneutralizing IgG (RNNIg) through the mechanism of antibody-dependent enhancement (ADE). However, this progression to severe disease occurs in less than 15% of RNNIg-positive patients. Wang et al. (2017) found that patients with DHF/DSS produced IgG with enhanced affinity to FCGR3A due to the presence of afucosylated (i.e., lacking fucose sugar units) glycans of the IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Wang et al. (2017) proposed that therapeutics and vaccines that restrict afucosylated IgG1 RNNIg production during infection may prevent ADE of dengue virus disease.


Molecular Genetics

By cloning and sequencing FCGR3A cDNA from NK cells and macrophages of a heterozygous donor, de Haas et al. (1996) identified a 230T-G SNP that resulted in a leu48-to-arg (L48R) substitution in the first extracellular Ig-like domain and caused a higher electrophoretic mobility of deglycosylated FCGR3A. PCR and restriction analysis identified a 230T-A SNP, resulting in a leu48-to-his (L48H; see 146740.0002) substitution, in another donor. Genotype analysis revealed a gene frequency of 86% for 230T (L48), 6% for 230G (R48), and 8% for 230A (H48) in 93 FCGR3B-positive individuals. In contrast, the frequency of the 230G allele was significantly higher in 12 FCGR3B-deficient donors. The H48 and R48 variants exhibited a higher binding capacity for IgG1, IgG3, and IgG4 than did the common L48 variant. De Haas et al. (1996) concluded that SNPs at position 230 of FCGR3A influence IgG binding, as well as reactivity of CD16 monoclonal antibodies. Grier et al. (2012) noted that Leu48 is the same as Leu66 in the FCGR3A protein.

Koene et al. (1997) used PCR-based restriction analysis to genotype 87 donors for a 559T-G SNP in FCGR3A that results in a phe158-to-val (F158V) substitution. They found gene frequencies of 57% and 43% for F158 and V158, respectively. F158 was linked to L48, and V158 was linked to R48 or H48. Through functional analysis, Koene et al. (1997) determined that the previously identified differences in IgG binding among the 3 FCGR3A variants at position 48 are a consequence of the linked polymorphism at position 158.

Immunodeficiency 20

In a 5-year-old girl with a primary immunodeficiency-20 (IMD20; 615707), Jawahar et al. (1996) identified a homozygous c.230T-A transversion in the FCGR3A gene, resulting in a leu66-to-his (L66H; 146740.0002) substitution in the first extracellular Ig-like domain of the FCGR3A protein. The patient presented in infancy with recurrent otitis media and sinusitis, as well as recurrent herpes viral infections. Circulating NK cells were decreased, and those in circulation expressed a mutant CD16 protein, as evidenced by antibody testing. Examination of NK cell function showed markedly decreased spontaneous cytotoxicity, but preserved antibody-dependent cellular cytotoxicity (ADCC). The number and function of other circulating immune cells was normal, indicating an isolated NK defect. The unaffected mother was heterozygous for the mutation; DNA from the father was unavailable.

De Vries et al. (1996) identified homozygosity for the 230T-A mutation in the FCGR3A gene in a 3-year-old boy with recurrent viral respiratory tract infections since birth. The child also had severe clinical problems with BCG vaccination and after Epstein-Barr virus and varicella-zoster virus infections.

Grier et al. (2012) identified homozygosity for the L66H mutation in the FCGR3A gene in a boy with recurrent lymph node EBV-driven Castleman disease and papillomavirus of the hands and feet. Both patient NK cells and control NK cells were recognized by an anti-CD16 monoclonal antibody against the 3G8 epitope, indicating that the CD16 molecule was expressed. However, only control NK cells were recognized by a different anti-CD16 antibody that recognized the specific B73.1 epitope, suggesting a defect in CD16. Grier et al. (2012) found that IMD20 patient NK cells exhibited deficient spontaneous cell cytotoxicity, but retained ADCC, suggesting that CD16 has a costimulatory role in NK cell cytotoxicity that is independent of IgG Fc binding/ADCC. Flow cytometric analysis of patient NK cells showed a significant decrease of CD2 (186990) expression on mature NK cells compared to controls. Similar flow cytometric results were observed in cells from the patient reported by Jawahar et al. (1996). Mechanistic studies in a human NK cell lines with and without CD16 expression showed that CD16 expression correlated with CD2 surface levels and enabled cytotoxic killing of a melanoma cell line. CD16 and CD2 associated at the immunologic synapse, which elicited CD16 signaling after CD2 engagement. The findings indicated that CD16 serves a role in NK-mediated spontaneous cytotoxicity through an interaction with CD2 via the non-Fc-binding distal domain of CD16.

Other Disease Associations

Among 1,115 patients with rheumatoid arthritis (RA; 180300) and 654 controls, Robinson et al. (2012) found no significant association between FCGR3A copy number and disease.

Although nearly all adults have been exposed to herpes simplex virus (HSV)-1, the clinical course of infection varies remarkably. By analyzing the contribution of gene families on chromosomes 1, 6, 12, and 19 to susceptibility to HSV-1 infection in 302 individuals, Moraru et al. (2012) identified no specific susceptibility locus. However, they found that the risk of suffering clinical HSV-1 infection was modified by MHC class I allotypes, HLA-C1 (142840) interaction with KIR2DL2 (604937), and the phe/val polymorphism at codon 158 of CD16A.


Evolution

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. 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.


Animal Model

Pinheiro da Silva et al. (2007) found that Fcrg (FCER1G; 147139) -/- mice showed reduced mortality in an acute peritonitis model caused by cecal ligation and puncture (CLP) compared with wildtype mice. The reduced mortality in Fcrg -/- mice was associated with lower serum and peritoneal Tnf (191160) and significantly increased capacity of neutrophils and macrophages to phagocytose E. coli. Fcgr3 -/- mice also had reduced sepsis after CLP. Fcgr3 bound E. coli, inducing Fcrg phosphorylation, recruitment of tyrosine phosphatase Shp1 (PTPN6; 176883), and dephosphorylation of phosphatidylinositol 3-kinase (PI3K; see 171834). Decreased Pi3k activity inhibited E. coli phagocytosis and increased Tnf production through Tlr4 (603030). Confocal microscopy demonstrated negative regulation of Marco (604870) by Fcrg. Interaction of E. coli with Fcgr3 induced recruitment of Shp1 to Marco and inhibited E. coli phagocytosis. Pinheiro da Silva et al. (2007) concluded that binding of E. coli to FCGR3 triggers an inhibitory FCRG pathway that impairs MARCO-mediated bacterial clearance and activates TNF secretion.


ALLELIC VARIANTS ( 2 Selected Examples):

.0001 MOVED TO 610665.0001


.0002 IMMUNODEFICIENCY 20

FCGR3A, LEU66HIS
  
RCV000015953...

In a 5-year old girl with primary immunodeficiency (IMD20; 615707), Jawahar et al. (1996) identified a homozygous c.230T-A transversion in the FCGR3A gene, resulting in a leu66-to-his (L66H) substitution in the first extracellular Ig-like domain of the FCGR3A protein. The patient presented in infancy with recurrent otitis media and sinusitis, as well as recurrent herpes viral infections. Circulating NK cells were decreased, and those in circulation expressed a mutant CD16 protein, as evidenced by antibody testing. Examination of NK cell function showed markedly decreased spontaneous cytotoxicity, but preserved antibody-dependent cellular cytotoxicity (ADCC). The number and function of other circulating immune cells were normal, indicating an isolated NK defect. The unaffected mother was heterozygous for the mutation; DNA from the father was unavailable. (De Haas et al. (1996) had identified the c.230T-A transversion in the FCGR3A gene in a heterozygous donor. They stated that the protein change was leu48 to his (LEU48HIS); Grier et al. (2012) noted that the LEU48HIS change is the same as the LEU66HIS change.)

De Vries et al. (1996) identified homozygosity for the 230T-A mutation in the FCGR3A gene in a 3-year-old boy with recurrent viral respiratory tract infections since birth. The patient's NK cells had an unusual CD16 phenotype. The child had also had severe problems with BCG vaccination and with Epstein-Barr virus and varicella-zoster virus infections. The clinical pattern was considered compatible with an in vivo dysfunction of NK cells.

Grier et al. (2012) identified homozygosity for the L66H mutation in the FCGR3A gene in a boy with recurrent lymph node EBV-driven Castleman disease and papillomavirus of the hands and feet. Both patient NK cells and control NK cells were recognized by an anti-CD16 monoclonal antibody against the 3G8 epitope, indicating that the CD16 molecule was expressed. However, only control NK cells were recognized by a different anti-CD16 antibody that recognized the specific B73.1 epitope, suggesting a defect in CD16. The patient's NK cells exhibited deficient spontaneous cell cytotoxicity, but retained ADCC.


REFERENCES

  1. Anderson, P., Caligiuri, M., O'Brien, C., Manley, T., Ritz, J., Schlossman, S. F. Fc-gamma receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells. Proc. Nat. Acad. Sci. 87: 2274-2278, 1990. [PubMed: 2138330, related citations] [Full Text]

  2. Bodman-Smith, M. D., Anand, A., Durand, V., Youinou, P. Y., Lydyard, P. M. Decreased expression of Fc-gamma-RIII (CD16) by gamma/delta T cells in patients with rheumatoid arthritis. Immunology 99: 498-503, 2000. [PubMed: 10792496, images, related citations] [Full Text]

  3. de Haas, M., Koene, H. R., Kleijer, M., de Vries, E., Simsek, S., van Tol, M. J. D., Roos, D., von dem Borne, A. E. G. K. A triallelic Fc-gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc-gamma-RIIIa. J. Immun. 156: 2948-2955, 1996. [PubMed: 8609432, related citations]

  4. de Vries, E., Koene, H. R., Vossen, J. M., Gratama, J.-W., von dem Borne, A. E. G. K., Waaijer, J. L. M., Haraldsson, A., de Haas, M., van Tol, M. J. D. Identification of an unusual Fc-gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood 88: 3022-3027, 1996. [PubMed: 8874200, related citations]

  5. Gessner, J. E., Grussenmeyer, T., Kolanus, W., Schmidt, R. E. The human low affinity immunoglobulin G Fc receptor III-A and III-B genes: molecular characterization of the promoter regions. J. Biol. Chem. 270: 1350-1361, 1995. [PubMed: 7836402, related citations] [Full Text]

  6. Grier, J. T., Forbes, L. R., Monaco-Shawver, L., Oshinsky, J., Atkinson, T. P., Moody, C., Pandey, R., Campbell, K. S., Orange, J. S. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J. Clin. Invest. 122: 3769-3780, 2012. [PubMed: 23006327, images, related citations] [Full Text]

  7. Jawahar, S., Moody, C., Chan, M., Finberg, R., Geha, R., Chatila, T. Natural Killer (NK) cell deficiency associated with an epitope-deficient Fc receptor IIIA (CD16-II). Clin. Exp. Immun. 103: 408-413, 1996. [PubMed: 8608639, related citations] [Full Text]

  8. Koene, H. R., Kleijer, M., Algra, A., Roos, D., von dem Borne, A. E. G. K., de Haas, M. Fc-gamma-RIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc-gamma-RIIIa, independently of the Fc-gamma-RIIIa-48L/R/H phenotype. Blood 90: 1109-1114, 1997. [PubMed: 9242542, related citations]

  9. Le Coniat, M., Kinet, J.-P., Berger, R. The human genes for the alpha and gamma subunits of the mast cell receptor for immunoglobulin E are located on human chromosome band 1q23. Immunogenetics 32: 183-186, 1990. [PubMed: 2146219, related citations] [Full Text]

  10. Machado, L. R., Hardwick, R. J., Bowdrey, J., Bogle, H., Knowles, T. J., Sironi, M., Hollox, E. J. Evolutionary history of copy-number-variable locus for the low-affinity Fc-gamma receptor: mutation rate, autoimmune disease, and the legacy of helminth infection. Am. J. Hum. Genet. 90: 973-985, 2012. [PubMed: 22608500, images, related citations] [Full Text]

  11. Moraru, M., Cisneros, E., Gomez-Lozano, N., de Pablo, R., Portero, F., Canizares, M., Vaquero, M., Roustan, G., Millan, I., Lopez-Botet, M., Vilches, C. Host genetic factors in susceptibility to herpes simplex type 1 virus infection: contribution of polymorphic genes at the interface of innate and adaptive immunity. J Immun. 188: 4412-4420, 2012. [PubMed: 22490439, related citations] [Full Text]

  12. Pinheiro da Silva, F., Aloulou, M., Skurnik, D., Benhamou, M., Andremont, A., Velasco, I. T., Chiamolera, M., Verbeek, J. S., Launay, P., Monteiro, R. C. CD16 promotes Escherichia coli sepsis through an FcR-gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nature Med. 13: 1368-1374, 2007. [PubMed: 17934470, related citations] [Full Text]

  13. Ravetch, J. V., Perussia, B. Alternative membrane forms of Fc-gamma-RIII(CD16) on human natural killer cells and neutrophils: cell type-specific expression of two genes that differ in single nucleotide substitutions. J. Exp. Med. 170: 481-497, 1989. [PubMed: 2526846, related citations] [Full Text]

  14. Robinson, J. I., Carr, I. M., Cooper, D. L., Rashid, L. H., Martin, S. G., Emery, P., Isaacs, J. D., Barton, A., BRAGGSS, Wilson, A. G., Barrett, J. H., Morgan, A. W. Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis. Hum. Mutat. 33: 741-749, 2012. [PubMed: 22290871, related citations] [Full Text]

  15. Wang, T. T., Sewatanon, J., Memoli, M. J., Wrammert, J., Bournazos, S., Bhaumik, S. K., Pinsky, B. A., Chokephaibulkit, K., Onlamoon, N., Pattanapanyasat, K., Taubenberger, J. K., Ahmed, R., Ravetch, J. V. IgG antibodies to dengue enhanced for Fc-gamma-RIIIA binding to determine disease severity. Science 355: 395-398, 2017. [PubMed: 28126818, related citations] [Full Text]


Paul J. Converse - updated : 08/17/2017
Cassandra L. Kniffin - updated : 3/24/2014
Paul J. Converse - updated : 5/6/2013
Matthew B. Gross - updated : 9/4/2012
Paul J. Converse - updated : 8/9/2012
Matthew B. Gross - updated : 8/2/2012
Paul J. Converse - updated : 7/26/2012
Cassandra L. Kniffin - updated : 4/16/2012
Paul J. Converse - updated : 9/5/2008
Paul J. Converse - updated : 1/7/2008
Ada Hamosh - updated : 7/31/2000
Paul J. Converse - updated : 6/15/2000
Creation Date:
Victor A. McKusick : 10/4/1988
mgross : 09/30/2020
mgross : 08/17/2017
carol : 08/15/2016
carol : 03/25/2014
ckniffin : 3/24/2014
mgross : 5/6/2013
mgross : 9/4/2012
terry : 8/9/2012
mgross : 8/3/2012
mgross : 8/2/2012
mgross : 8/2/2012
mgross : 7/30/2012
terry : 7/26/2012
alopez : 4/23/2012
terry : 4/17/2012
ckniffin : 4/16/2012
mgross : 9/15/2008
mgross : 9/15/2008
terry : 9/5/2008
mgross : 2/4/2008
terry : 1/7/2008
alopez : 7/31/2000
carol : 6/15/2000
alopez : 6/23/1998
alopez : 7/29/1997
terry : 7/7/1997
mark : 6/14/1997
jamie : 1/8/1997
terry : 12/18/1996
terry : 12/9/1996
mark : 11/14/1996
terry : 7/10/1995
carol : 7/9/1995
mark : 6/16/1995
carol : 12/14/1993
carol : 12/6/1993
carol : 8/27/1992

* 146740

Fc FRAGMENT OF IgG RECEPTOR IIIa; FCGR3A


Alternative titles; symbols

Fc FRAGMENT OF IgG, LOW AFFINITY IIIa, RECEPTOR FOR
IMMUNOGLOBULIN G Fc RECEPTOR III-2
FCRIII-2
CD16A


HGNC Approved Gene Symbol: FCGR3A

Cytogenetic location: 1q23.3     Genomic coordinates (GRCh38): 1:161,541,759-161,550,737 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q23.3 Immunodeficiency 20 615707 Autosomal recessive 3

TEXT

Description

The Fc receptor with low affinity for IgG (FCGR3, or CD16) is encoded by 2 nearly identical genes, FCGR3A and FCGR3B (610665), resulting in tissue-specific expression of alternative membrane-anchored isoforms. FCGR3A encodes a transmembrane protein expressed on activated monocytes/macrophages, natural killer (NK) cells, and a subset of T cells. In contrast, FCGR3B encodes a glycosylphosphatidylinositol (GPI)-anchored protein that is expressed constitutively by neutrophils and after gamma-interferon (IFNG; 147570) stimulation by eosinophils (summary by Gessner et al., 1995).


Cloning and Expression

By Western blot and flow cytometric analyses, Ravetch and Perussia (1989) demonstrated differential expression of FCGR3 on polymorphonuclear neutrophils (PMNs) and NK cells. The glycoprotein on NK cells (FCGR3A) had a molecular mass 6 to 10 kD larger than that on neutrophils (FCGR3B) and was resistant to phosphatidylinositol-specific phospholipase C. Transcripts derived from FCGR3A and FCGR3B in NK cells and PMNs, respectively, have multiple single nucleotide differences, including 1 that converts a termination codon to a codon encoding arg, thereby extending the cytoplasmic domain by 21 amino acids and introducing a transmembrane anchor for FCGR3A in NK cells. The deduced FCGR3A protein contains 254 amino acids, whereas the deduced FCGR3B protein contains 233 amino acids. Ravetch and Perussia (1989) concluded that cell type-specific expression of 2 genes encoding alternative FCGR3 proteins has a significant effect on the biologic functions of the molecules.


Gene Structure

Gessner et al. (1995) isolated and sequenced genomic clones of FCGR3A and FCGR3B, located their transcription initiation sites, identified the different organizations of their 5-prime regions, and demonstrated 4 distinct classes of FCGR3A transcripts compared with a single class of FCGR3B transcripts. The gene promoters displayed different tissue-specific transcriptional activities reflecting expression of FCGR3A in NK cells and FCGR3B in neutrophils.


Mapping

Le Coniat et al. (1990) mapped the FCGR3A gene to chromosome 1q23 by in situ hybridization.


Gene Function

Anderson et al. (1990) concluded that CD16 is included in the zeta natural killer cell receptor complex (CD3Z; 186780).

Some gamma-delta T cells (see TCRG, 186970 and TCRD, 186810) express CD16. Using flow cytometric analysis, Bodman-Smith et al. (2000) examined the relative proportions of CD16+ gamma-delta T cells in the blood and synovial fluid of rheumatoid arthritis (RA; 180300) patients and the blood of control subjects. There was a significant reduction in CD16+ gamma-delta T cells in synovial fluid compared with the circulation. Mitogenic stimulation of circulating gamma-delta T cells resulted in an increased expression of the HLA-DR activation marker and a concomitant time-dependent decrease in the expression of CD16. Bodman-Smith et al. (2000) concluded that CD16 expression is lost in the synovial compartment as a result of activation.

Wang et al. (2017) noted that dengue virus infection (see 614371) can be exacerbated to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) when it occurs in the presence of reactive, nonneutralizing IgG (RNNIg) through the mechanism of antibody-dependent enhancement (ADE). However, this progression to severe disease occurs in less than 15% of RNNIg-positive patients. Wang et al. (2017) found that patients with DHF/DSS produced IgG with enhanced affinity to FCGR3A due to the presence of afucosylated (i.e., lacking fucose sugar units) glycans of the IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Wang et al. (2017) proposed that therapeutics and vaccines that restrict afucosylated IgG1 RNNIg production during infection may prevent ADE of dengue virus disease.


Molecular Genetics

By cloning and sequencing FCGR3A cDNA from NK cells and macrophages of a heterozygous donor, de Haas et al. (1996) identified a 230T-G SNP that resulted in a leu48-to-arg (L48R) substitution in the first extracellular Ig-like domain and caused a higher electrophoretic mobility of deglycosylated FCGR3A. PCR and restriction analysis identified a 230T-A SNP, resulting in a leu48-to-his (L48H; see 146740.0002) substitution, in another donor. Genotype analysis revealed a gene frequency of 86% for 230T (L48), 6% for 230G (R48), and 8% for 230A (H48) in 93 FCGR3B-positive individuals. In contrast, the frequency of the 230G allele was significantly higher in 12 FCGR3B-deficient donors. The H48 and R48 variants exhibited a higher binding capacity for IgG1, IgG3, and IgG4 than did the common L48 variant. De Haas et al. (1996) concluded that SNPs at position 230 of FCGR3A influence IgG binding, as well as reactivity of CD16 monoclonal antibodies. Grier et al. (2012) noted that Leu48 is the same as Leu66 in the FCGR3A protein.

Koene et al. (1997) used PCR-based restriction analysis to genotype 87 donors for a 559T-G SNP in FCGR3A that results in a phe158-to-val (F158V) substitution. They found gene frequencies of 57% and 43% for F158 and V158, respectively. F158 was linked to L48, and V158 was linked to R48 or H48. Through functional analysis, Koene et al. (1997) determined that the previously identified differences in IgG binding among the 3 FCGR3A variants at position 48 are a consequence of the linked polymorphism at position 158.

Immunodeficiency 20

In a 5-year-old girl with a primary immunodeficiency-20 (IMD20; 615707), Jawahar et al. (1996) identified a homozygous c.230T-A transversion in the FCGR3A gene, resulting in a leu66-to-his (L66H; 146740.0002) substitution in the first extracellular Ig-like domain of the FCGR3A protein. The patient presented in infancy with recurrent otitis media and sinusitis, as well as recurrent herpes viral infections. Circulating NK cells were decreased, and those in circulation expressed a mutant CD16 protein, as evidenced by antibody testing. Examination of NK cell function showed markedly decreased spontaneous cytotoxicity, but preserved antibody-dependent cellular cytotoxicity (ADCC). The number and function of other circulating immune cells was normal, indicating an isolated NK defect. The unaffected mother was heterozygous for the mutation; DNA from the father was unavailable.

De Vries et al. (1996) identified homozygosity for the 230T-A mutation in the FCGR3A gene in a 3-year-old boy with recurrent viral respiratory tract infections since birth. The child also had severe clinical problems with BCG vaccination and after Epstein-Barr virus and varicella-zoster virus infections.

Grier et al. (2012) identified homozygosity for the L66H mutation in the FCGR3A gene in a boy with recurrent lymph node EBV-driven Castleman disease and papillomavirus of the hands and feet. Both patient NK cells and control NK cells were recognized by an anti-CD16 monoclonal antibody against the 3G8 epitope, indicating that the CD16 molecule was expressed. However, only control NK cells were recognized by a different anti-CD16 antibody that recognized the specific B73.1 epitope, suggesting a defect in CD16. Grier et al. (2012) found that IMD20 patient NK cells exhibited deficient spontaneous cell cytotoxicity, but retained ADCC, suggesting that CD16 has a costimulatory role in NK cell cytotoxicity that is independent of IgG Fc binding/ADCC. Flow cytometric analysis of patient NK cells showed a significant decrease of CD2 (186990) expression on mature NK cells compared to controls. Similar flow cytometric results were observed in cells from the patient reported by Jawahar et al. (1996). Mechanistic studies in a human NK cell lines with and without CD16 expression showed that CD16 expression correlated with CD2 surface levels and enabled cytotoxic killing of a melanoma cell line. CD16 and CD2 associated at the immunologic synapse, which elicited CD16 signaling after CD2 engagement. The findings indicated that CD16 serves a role in NK-mediated spontaneous cytotoxicity through an interaction with CD2 via the non-Fc-binding distal domain of CD16.

Other Disease Associations

Among 1,115 patients with rheumatoid arthritis (RA; 180300) and 654 controls, Robinson et al. (2012) found no significant association between FCGR3A copy number and disease.

Although nearly all adults have been exposed to herpes simplex virus (HSV)-1, the clinical course of infection varies remarkably. By analyzing the contribution of gene families on chromosomes 1, 6, 12, and 19 to susceptibility to HSV-1 infection in 302 individuals, Moraru et al. (2012) identified no specific susceptibility locus. However, they found that the risk of suffering clinical HSV-1 infection was modified by MHC class I allotypes, HLA-C1 (142840) interaction with KIR2DL2 (604937), and the phe/val polymorphism at codon 158 of CD16A.


Evolution

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. 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.


Animal Model

Pinheiro da Silva et al. (2007) found that Fcrg (FCER1G; 147139) -/- mice showed reduced mortality in an acute peritonitis model caused by cecal ligation and puncture (CLP) compared with wildtype mice. The reduced mortality in Fcrg -/- mice was associated with lower serum and peritoneal Tnf (191160) and significantly increased capacity of neutrophils and macrophages to phagocytose E. coli. Fcgr3 -/- mice also had reduced sepsis after CLP. Fcgr3 bound E. coli, inducing Fcrg phosphorylation, recruitment of tyrosine phosphatase Shp1 (PTPN6; 176883), and dephosphorylation of phosphatidylinositol 3-kinase (PI3K; see 171834). Decreased Pi3k activity inhibited E. coli phagocytosis and increased Tnf production through Tlr4 (603030). Confocal microscopy demonstrated negative regulation of Marco (604870) by Fcrg. Interaction of E. coli with Fcgr3 induced recruitment of Shp1 to Marco and inhibited E. coli phagocytosis. Pinheiro da Silva et al. (2007) concluded that binding of E. coli to FCGR3 triggers an inhibitory FCRG pathway that impairs MARCO-mediated bacterial clearance and activates TNF secretion.


ALLELIC VARIANTS 2 Selected Examples):

.0001   MOVED TO 610665.0001


.0002   IMMUNODEFICIENCY 20

FCGR3A, LEU66HIS
SNP: rs10127939, gnomAD: rs10127939, ClinVar: RCV000015953, RCV000454581

In a 5-year old girl with primary immunodeficiency (IMD20; 615707), Jawahar et al. (1996) identified a homozygous c.230T-A transversion in the FCGR3A gene, resulting in a leu66-to-his (L66H) substitution in the first extracellular Ig-like domain of the FCGR3A protein. The patient presented in infancy with recurrent otitis media and sinusitis, as well as recurrent herpes viral infections. Circulating NK cells were decreased, and those in circulation expressed a mutant CD16 protein, as evidenced by antibody testing. Examination of NK cell function showed markedly decreased spontaneous cytotoxicity, but preserved antibody-dependent cellular cytotoxicity (ADCC). The number and function of other circulating immune cells were normal, indicating an isolated NK defect. The unaffected mother was heterozygous for the mutation; DNA from the father was unavailable. (De Haas et al. (1996) had identified the c.230T-A transversion in the FCGR3A gene in a heterozygous donor. They stated that the protein change was leu48 to his (LEU48HIS); Grier et al. (2012) noted that the LEU48HIS change is the same as the LEU66HIS change.)

De Vries et al. (1996) identified homozygosity for the 230T-A mutation in the FCGR3A gene in a 3-year-old boy with recurrent viral respiratory tract infections since birth. The patient's NK cells had an unusual CD16 phenotype. The child had also had severe problems with BCG vaccination and with Epstein-Barr virus and varicella-zoster virus infections. The clinical pattern was considered compatible with an in vivo dysfunction of NK cells.

Grier et al. (2012) identified homozygosity for the L66H mutation in the FCGR3A gene in a boy with recurrent lymph node EBV-driven Castleman disease and papillomavirus of the hands and feet. Both patient NK cells and control NK cells were recognized by an anti-CD16 monoclonal antibody against the 3G8 epitope, indicating that the CD16 molecule was expressed. However, only control NK cells were recognized by a different anti-CD16 antibody that recognized the specific B73.1 epitope, suggesting a defect in CD16. The patient's NK cells exhibited deficient spontaneous cell cytotoxicity, but retained ADCC.


REFERENCES

  1. Anderson, P., Caligiuri, M., O'Brien, C., Manley, T., Ritz, J., Schlossman, S. F. Fc-gamma receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells. Proc. Nat. Acad. Sci. 87: 2274-2278, 1990. [PubMed: 2138330] [Full Text: https://doi.org/10.1073/pnas.87.6.2274]

  2. Bodman-Smith, M. D., Anand, A., Durand, V., Youinou, P. Y., Lydyard, P. M. Decreased expression of Fc-gamma-RIII (CD16) by gamma/delta T cells in patients with rheumatoid arthritis. Immunology 99: 498-503, 2000. [PubMed: 10792496] [Full Text: https://doi.org/10.1046/j.1365-2567.2000.00017.x]

  3. de Haas, M., Koene, H. R., Kleijer, M., de Vries, E., Simsek, S., van Tol, M. J. D., Roos, D., von dem Borne, A. E. G. K. A triallelic Fc-gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc-gamma-RIIIa. J. Immun. 156: 2948-2955, 1996. [PubMed: 8609432]

  4. de Vries, E., Koene, H. R., Vossen, J. M., Gratama, J.-W., von dem Borne, A. E. G. K., Waaijer, J. L. M., Haraldsson, A., de Haas, M., van Tol, M. J. D. Identification of an unusual Fc-gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood 88: 3022-3027, 1996. [PubMed: 8874200]

  5. Gessner, J. E., Grussenmeyer, T., Kolanus, W., Schmidt, R. E. The human low affinity immunoglobulin G Fc receptor III-A and III-B genes: molecular characterization of the promoter regions. J. Biol. Chem. 270: 1350-1361, 1995. [PubMed: 7836402] [Full Text: https://doi.org/10.1074/jbc.270.3.1350]

  6. Grier, J. T., Forbes, L. R., Monaco-Shawver, L., Oshinsky, J., Atkinson, T. P., Moody, C., Pandey, R., Campbell, K. S., Orange, J. S. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J. Clin. Invest. 122: 3769-3780, 2012. [PubMed: 23006327] [Full Text: https://doi.org/10.1172/JCI64837]

  7. Jawahar, S., Moody, C., Chan, M., Finberg, R., Geha, R., Chatila, T. Natural Killer (NK) cell deficiency associated with an epitope-deficient Fc receptor IIIA (CD16-II). Clin. Exp. Immun. 103: 408-413, 1996. [PubMed: 8608639] [Full Text: https://doi.org/10.1111/j.1365-2249.1996.tb08295.x]

  8. Koene, H. R., Kleijer, M., Algra, A., Roos, D., von dem Borne, A. E. G. K., de Haas, M. Fc-gamma-RIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc-gamma-RIIIa, independently of the Fc-gamma-RIIIa-48L/R/H phenotype. Blood 90: 1109-1114, 1997. [PubMed: 9242542]

  9. Le Coniat, M., Kinet, J.-P., Berger, R. The human genes for the alpha and gamma subunits of the mast cell receptor for immunoglobulin E are located on human chromosome band 1q23. Immunogenetics 32: 183-186, 1990. [PubMed: 2146219] [Full Text: https://doi.org/10.1007/BF02114971]

  10. Machado, L. R., Hardwick, R. J., Bowdrey, J., Bogle, H., Knowles, T. J., Sironi, M., Hollox, E. J. Evolutionary history of copy-number-variable locus for the low-affinity Fc-gamma receptor: mutation rate, autoimmune disease, and the legacy of helminth infection. Am. J. Hum. Genet. 90: 973-985, 2012. [PubMed: 22608500] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.018]

  11. Moraru, M., Cisneros, E., Gomez-Lozano, N., de Pablo, R., Portero, F., Canizares, M., Vaquero, M., Roustan, G., Millan, I., Lopez-Botet, M., Vilches, C. Host genetic factors in susceptibility to herpes simplex type 1 virus infection: contribution of polymorphic genes at the interface of innate and adaptive immunity. J Immun. 188: 4412-4420, 2012. [PubMed: 22490439] [Full Text: https://doi.org/10.4049/jimmunol.1103434]

  12. Pinheiro da Silva, F., Aloulou, M., Skurnik, D., Benhamou, M., Andremont, A., Velasco, I. T., Chiamolera, M., Verbeek, J. S., Launay, P., Monteiro, R. C. CD16 promotes Escherichia coli sepsis through an FcR-gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nature Med. 13: 1368-1374, 2007. [PubMed: 17934470] [Full Text: https://doi.org/10.1038/nm1665]

  13. Ravetch, J. V., Perussia, B. Alternative membrane forms of Fc-gamma-RIII(CD16) on human natural killer cells and neutrophils: cell type-specific expression of two genes that differ in single nucleotide substitutions. J. Exp. Med. 170: 481-497, 1989. [PubMed: 2526846] [Full Text: https://doi.org/10.1084/jem.170.2.481]

  14. Robinson, J. I., Carr, I. M., Cooper, D. L., Rashid, L. H., Martin, S. G., Emery, P., Isaacs, J. D., Barton, A., BRAGGSS, Wilson, A. G., Barrett, J. H., Morgan, A. W. Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis. Hum. Mutat. 33: 741-749, 2012. [PubMed: 22290871] [Full Text: https://doi.org/10.1002/humu.22031]

  15. Wang, T. T., Sewatanon, J., Memoli, M. J., Wrammert, J., Bournazos, S., Bhaumik, S. K., Pinsky, B. A., Chokephaibulkit, K., Onlamoon, N., Pattanapanyasat, K., Taubenberger, J. K., Ahmed, R., Ravetch, J. V. IgG antibodies to dengue enhanced for Fc-gamma-RIIIA binding to determine disease severity. Science 355: 395-398, 2017. [PubMed: 28126818] [Full Text: https://doi.org/10.1126/science.aai8128]


Contributors:
Paul J. Converse - updated : 08/17/2017
Cassandra L. Kniffin - updated : 3/24/2014
Paul J. Converse - updated : 5/6/2013
Matthew B. Gross - updated : 9/4/2012
Paul J. Converse - updated : 8/9/2012
Matthew B. Gross - updated : 8/2/2012
Paul J. Converse - updated : 7/26/2012
Cassandra L. Kniffin - updated : 4/16/2012
Paul J. Converse - updated : 9/5/2008
Paul J. Converse - updated : 1/7/2008
Ada Hamosh - updated : 7/31/2000
Paul J. Converse - updated : 6/15/2000

Creation Date:
Victor A. McKusick : 10/4/1988

Edit History:
mgross : 09/30/2020
mgross : 08/17/2017
carol : 08/15/2016
carol : 03/25/2014
ckniffin : 3/24/2014
mgross : 5/6/2013
mgross : 9/4/2012
terry : 8/9/2012
mgross : 8/3/2012
mgross : 8/2/2012
mgross : 8/2/2012
mgross : 7/30/2012
terry : 7/26/2012
alopez : 4/23/2012
terry : 4/17/2012
ckniffin : 4/16/2012
mgross : 9/15/2008
mgross : 9/15/2008
terry : 9/5/2008
mgross : 2/4/2008
terry : 1/7/2008
alopez : 7/31/2000
carol : 6/15/2000
alopez : 6/23/1998
alopez : 7/29/1997
terry : 7/7/1997
mark : 6/14/1997
jamie : 1/8/1997
terry : 12/18/1996
terry : 12/9/1996
mark : 11/14/1996
terry : 7/10/1995
carol : 7/9/1995
mark : 6/16/1995
carol : 12/14/1993
carol : 12/6/1993
carol : 8/27/1992