A naturally occurring mutation in Fc gamma RIIA: a Q to K127 change confers unique IgG binding properties to the R131 allelic form of the receptor.
Fc gamma RIIa is widely expressed on hematopoietic cells. There are two known allelic polymorphic forms of Fc gamma RIIa, Fc gamma RIIa-R131 and Fc gamma RIIa-H131, which differ in the amino acid at position 131 in the second lg-like domain. In contrast to Fc gamma RIIa-R131, Fc gamma RIIa-H131 binds hlgG2 but not mIgG1, and this differential binding has clinical implications for host defense, autoimmune disease, immunohematologic disease, and response to therapeutic monoclonal antibodies. We identified a novel Fc gamma RIIA genotype in a healthy individual homozygous for Fc gamma RIIA R/R131 in whom a C to A substitution at codon 127 changes glutamine (Q) to lysine (K) in one of the two Fc gamma RIIA genes. This individual's homozygosity for Fc gamma RIIA-R/R131 leads to the prediction that the receptors on her cells would not bind hIgG2. Monocyte and neutrophil phagocytosis of hIgG2-opsonized erythrocytes was significantly higher (P < .05) for cells from this K/Q127, R/R131 individual than for Q/Q127, R/R131 donors. Platelet aggregation stimulated by an mIgG1 anti-CD9 antibody in this individual was significantly different (P < .05) from Q/Q127, H/R131 and Q/Q127, H/H131 donors and similar to Q/Q127, R/R131. Our data show that the K127/R131 receptors have a unique phenotype, binding both hIgG2 and mIgG1. Further functionally significant mutations in human Fc gamma receptors and possible novel mechanisms for inherited differences in disease susceptibility should be sought with unbiased screening methods.
Norris
C F
CF
Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA.
Pricop
L
L
Millard
S S
SS
Taylor
S M
SM
Surrey
S
S
Schwartz
E
E
Salmon
J E
JE
McKenzie
S E
SE
D000483:Alleles; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology*; D009154:Mutation; D009504:Neutrophils / Q000276:immunology*; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D017452:Receptors, IgG