A NATURALLY-OCCURRING MUTATION IN FC-GAMMA-RIIA - A Q TO K-127 CHANGECONFERS UNIQUE IGG BINDING-PROPERTIES TO THE R-131 ALLELIC FORM OF THE RECEPTOR

Fc gamma RIIa is widely expressed on hematopoietic cells. There are tw o known allelic polymorphic forms of Fc gamma RIIa, Fc gamma RIIa-R-13 1 and Fc gamma RIIa-H-131, which differ in the amino acid at position 131 in the second Ig-like domain. In contrast to Fc gamma RIIa-R-131, Fc gamma RIIa-H-131 binds hIgG(2) but not mIgG(1), and this differenti al binding has clinical implications for host defense, autoimmune dise ase, 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/R-131 in whom a C to A subs titution at codon 127 changes glutamine (Q) to lysine (K) in one of th e two Fc gamma RIIA genes. This individual's homozygosity for Fc gamma RIIA-R/R-131 leads to the prediction that the receptors on her cells would not bind hIgG(2). Monocyte and neutrophil phagocytosis of hIgG(2 )-opsonized erythrocytes was significantly higher (P < .05) for cells from this K/Q(127), R/R-131 individual than for Q/Q(127), R/R-131 dono rs. Platelet aggregation stimulated by an mIgG(1) anti-CD9 antibody in this individual was significantly different (P < .05) from Q/Q(127), H/R-131 and Q/Q(127), H/H-131 donors and similar to Q/Q(127), R/R-131. Our data show that the K-127/R-131 receptors have a unique phenotype binding both hIgG(2) and mIgG(1). Further functionally significant mut ations in human Fc gamma receptors and possible novel mechanisms for i nherited differences in disease susceptibility should be sought with u nbiased screening methods. (C) 1998 by The American Society of Hematol ogy.