RBCC Red Blood Cell Collection

FCGR3A (CD16A, FCG3, FCGR3, IGFR3) [Confidence: low (only semi-automatic identification from reviews)]
Low affinity immunoglobulin gamma Fc region receptor III-A (CD16a antigen; Fc-gamma RIII-alpha; Fc-gamma RIII; Fc-gamma RIIIa; FcRIII; FcRIIIa; FcR-10; IgG Fc receptor III-2; CD16a; Flags: Precursor)

UniProt P08637
ID FCG3A_HUMAN Reviewed; 254 AA.
AC P08637; A2N6W9; Q53FJ0; Q53FL6; Q5EBR4; Q65ZM6; Q6PIJ0;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-AUG-1990, sequence version 2.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Low affinity immunoglobulin gamma Fc region receptor III-A;
DE AltName: Full=CD16a antigen;
DE AltName: Full=Fc-gamma RIII-alpha;
DE Short=Fc-gamma RIII;
DE Short=Fc-gamma RIIIa;
DE Short=FcRIII;
DE Short=FcRIIIa;
DE AltName: Full=FcR-10;
DE AltName: Full=IgG Fc receptor III-2;
DE AltName: CD_antigen=CD16a;
DE Flags: Precursor;
GN Name=FCGR3A; Synonyms=CD16A, FCG3, FCGR3, IGFR3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2526846; DOI=10.1084/jem.170.2.481;
RA Ravetch J.V., Perussia B.;
RT "Alternative membrane forms of Fc gamma RIII(CD16) on human natural
RT killer cells and neutrophils. Cell type-specific expression of two
RT genes that differ in single nucleotide substitutions.";
RL J. Exp. Med. 170:481-497(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Blood;
RX PubMed=16951347;
RA Rogers K.A., Scinicariello F., Attanasio R.;
RT "IgG Fc receptor III homologues in nonhuman primate species: genetic
RT characterization and ligand interactions.";
RL J. Immunol. 177:3848-3856(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-176.
RC TISSUE=Synovium;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-176.
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-39.
RC TISSUE=Placenta;
RX PubMed=7836402; DOI=10.1074/jbc.270.3.1350;
RA Gessner J.E., Grussenmeyer T., Kolanus W., Schmidt R.E.;
RT "The human low affinity immunoglobulin G Fc receptor III-A and III-B
RT genes. Molecular characterization of the promoter regions.";
RL J. Biol. Chem. 270:1350-1361(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 22-254, AND VARIANT VAL-176.
RX PubMed=7700021; DOI=10.1038/ki.1994.462;
RA Morcos M., Hansch G.M., Schonermark M., Ellwanger S., Harle M.,
RA Heckl-Ostreicher B.;
RT "Human glomerular mesangial cells express CD16 and may be stimulated
RT via this receptor.";
RL Kidney Int. 46:1627-1634(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 31-254.
RC TISSUE=Lung;
RX PubMed=2525780; DOI=10.1073/pnas.86.13.5079;
RA Scallon B.J., Scigliano E., Freedman V.H., Miedel M.C., Pan Y.C.,
RA Unkeless J.C., Kochan J.P.;
RT "A human immunoglobulin G receptor exists in both polypeptide-anchored
RT and phosphatidylinositol-glycan-anchored forms.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:5079-5083(1989).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 21-193 IN COMPLEX WITH IGHG1,
RP FUNCTION, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-63 AND ASN-180.
RX PubMed=22023369; DOI=10.1111/j.1365-2443.2011.01552.x;
RA Mizushima T., Yagi H., Takemoto E., Shibata-Koyama M., Isoda Y.,
RA Iida S., Masuda K., Satoh M., Kato K.;
RT "Structural basis for improved efficacy of therapeutic antibodies on
RT defucosylation of their Fc glycans.";
RL Genes Cells 16:1071-1080(2011).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 19-208 IN COMPLEX WITH IGHG1,
RP FUNCTION, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-63 AND ASN-180.
RX PubMed=21768335; DOI=10.1073/pnas.1108455108;
RA Ferrara C., Grau S., Jager C., Sondermann P., Brunker P.,
RA Waldhauer I., Hennig M., Ruf A., Rufer A.C., Stihle M., Umana P.,
RA Benz J.;
RT "Unique carbohydrate-carbohydrate interactions are required for high
RT affinity binding between FcgammaRIII and antibodies lacking core
RT fucose.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:12669-12674(2011).
RN [11]
RP VARIANTS ARG-66 AND HIS-66.
RX PubMed=8609432;
RA de Haas M., Koene H.R., Kleijer M., de Vries E., Simsek S.,
RA van Tol M.J.D., Roos D., von dem Borne A.E.G.K.;
RT "A triallelic Fc gamma receptor type IIIA polymorphism influences the
RT binding of human IgG by NK cell Fc gamma RIIIa.";
RL J. Immunol. 156:2948-2955(1996).
RN [12]
RP VARIANT VAL-176.
RX PubMed=9242542;
RA Koene H.R., Kleijer M., Algra J., Roos D., von dem Borne A.E.G.K.,
RA de Haas M.;
RT "Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by
RT natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-
RT 48L/R/H phenotype.";
RL Blood 90:1109-1114(1997).
RN [13]
RP VARIANT VAL-176.
RX PubMed=9276722; DOI=10.1172/JCI119616;
RA Wu J., Edberg J.C., Redecha P.B., Bansal V., Guyre P.M., Coleman K.,
RA Salmon J.E., Kimberly R.P.;
RT "A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function
RT and predisposes to autoimmune disease.";
RL J. Clin. Invest. 100:1059-1070(1997).
CC -!- FUNCTION: Receptor for the Fc region of IgG. Binds complexed or
CC aggregated IgG and also monomeric IgG. Mediates antibody-dependent
CC cellular cytotoxicity (ADCC) and other antibody-dependent
CC responses, such as phagocytosis.
CC -!- SUBUNIT: Exists as a heterooligomeric receptor complex with Fc
CC epsilon receptor I gamma subunit and / or the CD3 zeta subunit.
CC Interacts with INPP5D/SHIP1 (By similarity).
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein (Potential). Secreted. Note=Exists also as a soluble
CC receptor.
CC -!- TISSUE SPECIFICITY: Expressed on natural killer cells,
CC macrophages, subpopulation of T-cells, immature thymocytes and
CC placental trophoblasts.
CC -!- PTM: Glycosylated. Contains high mannose- and complex-type
CC oligosaccharides. Glycosylation at Asn-180 is mandatory for high
CC affinity binding to the Fc and for discrimination between
CC fucosylated and afucosylated IgG glycoforms.
CC -!- PTM: The soluble form is produced by a proteolytic cleavage.
CC -!- MISCELLANEOUS: Encoded by one of two nearly indentical genes:
CC FCGR3A (Shown here) and FCGR3B which are expressed in a tissue-
CC specific manner. The Phe-203 in III-A determines the transmembrane
CC domains whereas the 'Ser-203' in III-B determines the GPI-
CC anchoring.
CC -!- SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD96988.1; Type=Erroneous initiation;
CC Sequence=BAD97015.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=FCGR3Abase; Note=FCGR3A mutation db;
CC URL="http://bioinf.uta.fi/FCGR3Abase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FCGR3A";
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DR EMBL; X52645; CAA36870.1; -; mRNA.
DR EMBL; AK223268; BAD96988.1; ALT_INIT; mRNA.
DR EMBL; AK223295; BAD97015.1; ALT_INIT; mRNA.
DR EMBL; AL590385; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017865; AAH17865.1; -; mRNA.
DR EMBL; BC033678; AAH33678.1; -; mRNA.
DR EMBL; Z46222; CAA86295.1; -; Genomic_DNA.
DR EMBL; S76824; AAB33925.2; -; mRNA.
DR EMBL; M24853; AAA53506.1; -; mRNA.
DR PIR; JL0107; JL0107.
DR RefSeq; NP_000560.5; NM_000569.6.
DR RefSeq; NP_001121064.1; NM_001127592.1.
DR RefSeq; NP_001121065.1; NM_001127593.1.
DR RefSeq; NP_001121067.1; NM_001127595.1.
DR RefSeq; NP_001121068.1; NM_001127596.1.
DR UniGene; Hs.372679; -.
DR PDB; 3AY4; X-ray; 2.20 A; C=21-193.
DR PDB; 3SGJ; X-ray; 2.20 A; C=19-208.
DR PDB; 3SGK; X-ray; 2.40 A; C=19-208.
DR PDBsum; 3AY4; -.
DR PDBsum; 3SGJ; -.
DR PDBsum; 3SGK; -.
DR ProteinModelPortal; P08637; -.
DR SMR; P08637; 24-231.
DR IntAct; P08637; 2.
DR STRING; 9606.ENSP00000356946; -.
DR DrugBank; DB00054; Abciximab.
DR DrugBank; DB00051; Adalimumab.
DR DrugBank; DB00092; Alefacept.
DR DrugBank; DB00087; Alemtuzumab.
DR DrugBank; DB00074; Basiliximab.
DR DrugBank; DB00112; Bevacizumab.
DR DrugBank; DB00002; Cetuximab.
DR DrugBank; DB00111; Daclizumab.
DR DrugBank; DB00095; Efalizumab.
DR DrugBank; DB00005; Etanercept.
DR DrugBank; DB00056; Gemtuzumab ozogamicin.
DR DrugBank; DB00078; Ibritumomab.
DR DrugBank; DB00028; Immune globulin.
DR DrugBank; DB00075; Muromonab.
DR DrugBank; DB00108; Natalizumab.
DR DrugBank; DB00110; Palivizumab.
DR DrugBank; DB00073; Rituximab.
DR DrugBank; DB00081; Tositumomab.
DR DrugBank; DB00072; Trastuzumab.
DR MEROPS; I43.001; -.
DR PhosphoSite; P08637; -.
DR DMDM; 119876; -.
DR PaxDb; P08637; -.
DR PRIDE; P08637; -.
DR DNASU; 2214; -.
DR Ensembl; ENST00000367967; ENSP00000356944; ENSG00000203747.
DR Ensembl; ENST00000436743; ENSP00000416607; ENSG00000203747.
DR Ensembl; ENST00000540048; ENSP00000444971; ENSG00000203747.
DR GeneID; 2214; -.
DR KEGG; hsa:2214; -.
DR UCSC; uc001gar.3; human.
DR CTD; 2214; -.
DR GeneCards; GC01M161511; -.
DR HGNC; HGNC:3619; FCGR3A.
DR HPA; CAB032435; -.
DR MIM; 146740; gene.
DR neXtProt; NX_P08637; -.
DR PharmGKB; PA28065; -.
DR eggNOG; NOG47725; -.
DR HOVERGEN; HBG051602; -.
DR InParanoid; P08637; -.
DR KO; K06463; -.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; FCGR3A; human.
DR EvolutionaryTrace; P08637; -.
DR GeneWiki; FCGR3A; -.
DR GenomeRNAi; 2214; -.
DR NextBio; 8979; -.
DR PRO; PR:P08637; -.
DR ArrayExpress; P08637; -.
DR Bgee; P08637; -.
DR CleanEx; HS_FCGR3A; -.
DR Genevestigator; P08637; -.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR SMART; SM00409; IG; 2.
DR PROSITE; PS50835; IG_LIKE; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Complete proteome; Disulfide bond;
KW Glycoprotein; IgG-binding protein; Immunoglobulin domain; Membrane;
KW Polymorphism; Receptor; Reference proteome; Repeat; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1 16 Potential.
FT CHAIN 17 254 Low affinity immunoglobulin gamma Fc
FT region receptor III-A.
FT /FTId=PRO_0000015150.
FT TOPO_DOM 17 208 Extracellular (Potential).
FT TRANSMEM 209 229 Helical; (Potential).
FT TOPO_DOM 230 254 Cytoplasmic (Potential).
FT DOMAIN 24 105 Ig-like C2-type 1.
FT DOMAIN 107 189 Ig-like C2-type 2.
FT CARBOHYD 56 56 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 63 63 N-linked (GlcNAc...).
FT CARBOHYD 92 92 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 180 180 N-linked (GlcNAc...).
FT CARBOHYD 187 187 N-linked (GlcNAc...) (Potential).
FT DISULFID 47 89
FT DISULFID 128 172
FT VARIANT 66 66 L -> H (in dbSNP:rs10127939).
FT /FTId=VAR_008800.
FT VARIANT 66 66 L -> R (in dbSNP:rs10127939).
FT /FTId=VAR_008799.
FT VARIANT 147 147 G -> D (in dbSNP:rs443082).
FT /FTId=VAR_058398.
FT VARIANT 158 158 Y -> H (in dbSNP:rs396716).
FT /FTId=VAR_058399.
FT VARIANT 176 176 F -> V (shows a higher binding capacity
FT of IgG1, IgG3 and IgG4; dbSNP:rs396991).
FT /FTId=VAR_003960.
FT VARIANT 203 203 F -> S (in dbSNP:rs1042206).
FT /FTId=VAR_058400.
FT CONFLICT 106 106 I -> V (in Ref. 3; BAD96988/BAD97015).
FT CONFLICT 195 195 A -> S (in Ref. 5; AAH33678).
FT STRAND 28 33
FT STRAND 35 38
FT STRAND 43 47
FT STRAND 51 54
FT STRAND 60 65
FT STRAND 71 78
FT HELIX 81 83
FT STRAND 85 89
FT STRAND 100 105
FT STRAND 107 112
FT STRAND 116 119
FT STRAND 124 130
FT HELIX 131 133
FT STRAND 137 143
FT STRAND 146 153
FT STRAND 157 161
FT HELIX 164 166
FT STRAND 168 176
FT STRAND 179 182
FT STRAND 186 191
SQ SEQUENCE 254 AA; 29089 MW; D38D178D32C67337 CRC64;
MWQLLLPTAL LLLVSAGMRT EDLPKAVVFL EPQWYRVLEK DSVTLKCQGA YSPEDNSTQW
FHNESLISSQ ASSYFIDAAT VDDSGEYRCQ TNLSTLSDPV QLEVHIGWLL LQAPRWVFKE
EDPIHLRCHS WKNTALHKVT YLQNGKGRKY FHHNSDFYIP KATLKDSGSY FCRGLFGSKN
VSSETVNITI TQGLAVSTIS SFFPPGYQVS FCLVMVLLFA VDTGLYFSVK TNIRSSTRDW
KDHKFKWRKD PQDK
//

MIM 146740
*RECORD*
*FIELD* NO
146740
*FIELD* TI
*146740 Fc FRAGMENT OF IgG, LOW AFFINITY IIIa, RECEPTOR FOR; FCGR3A
;;IMMUNOGLOBULIN G Fc RECEPTOR III-2;;
read moreFCRIII-2;;
CD16A
*FIELD* TX

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

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.

MOLECULAR GENETICS

On the natural killer (NK) cells of a 3-year-old boy who suffered from
recurrent viral respiratory tract infections since birth, de Vries et
al. (1996) found an unusual CD16 phenotype. The child also had severe
clinical problems with BCG vaccination and after Epstein-Barr virus and
varicella-zoster virus infections. His peripheral blood lymphocytes
contained a normal percentage and absolute number of CD3(-)CD7(+) cells,
which were positively stained with CD16 monoclonal antibodies. FCGR3
expression on granulocytes appeared to be normal. Sequence analysis of
the FCGR3A gene, encoding CD16 on NK cells and macrophages, showed a
T-to-A nucleotide substitution at position 230 on both alleles,
predicting a leucine to histidine amino acid change at position 48
(146740.0002).

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)
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.

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.

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.

*FIELD* AV
.0001
MOVED TO 610665.0001
.0002
VIRAL INFECTIONS, RECURRENT, SUSCEPTIBILITY TO
FCGR3A, LEU48HIS

In a 3-year-old boy who had suffered from recurrent viral respiratory
tract infections since birth, de Vries et al. (1996) found an unusual
CD16 phenotype on the natural killer (NK) cells. Sequence analysis of
the IGFR3 gene showed a T-to-A nucleotide substitution at position 230
on both alleles, predicting a leucine-to-histidine amino acid change at
position 48 in the first extracellular Ig-like domain of the FCGR3A
protein. 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. Only 1 patient with absolute NK cell deficiency had been
previously described. Biron et al. (1989) reported the case of an
adolescent with recurrent life-threatening herpesvirus infections, who
completely lacked CD16 and/or CD56 positive cells in vivo and
NK-activity in vitro. In a note added in proof, de Vries et al. (1996)
called attention to the case of homozygosity for a IGFR3 mutation
reported by Jawahar et al. (1996).

*FIELD* RF
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.

2. Biron, C. A.; Byron, K. S.; Sullivan, J. L.: Severe herpesvirus
infections in an adolescent without natural killer cells. New Eng.
J. Med. 320: 1731-1735, 1989.

3. 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.

4. 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.

5. 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.

6. 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.

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.

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.

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.

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.

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.

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.

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.

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.

*FIELD* CN
Paul J. Converse - updated: 05/06/2013
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

*FIELD* CD
Victor A. McKusick: 10/4/1988

*FIELD* ED
mgross: 05/06/2013
mgross: 9/4/2012
terry: 8/9/2012
mgross: 8/3/2012
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
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