A single amino acid distinguishes the high-responder from the low-responder form of Fc receptor II on human monocytes.
The low-affinity Fc receptor on human peripheral blood monocytes (Fc gamma RIIA) is polymorphic with respect to its ability to bind murine IgG1. The two allelic forms of the receptor, high responder (HR) and low responder (LR), yield characteristic patterns after isoelectric focusing and react differently with the anti-Fc gamma RII monoclonal antibody (mAb), 41H16. We recently cloned cDNA encoding the extracellular domains of Fc gamma RIIA on monocytes from one HR and two LR donors, and found that they differed at only a single base. The cDNA isolated from the HR donor had a G at position 519 and would be expected to encode an aginine at residue 133 in the mature protein, while the cDNA isolated from both LR donors had an A at position 519 and would be expected to encode a histidine at the same residue. To determine whether this single amino acid substitution actually accounts for the functional polymorphism involving Fc gamma RIIA, we transfected COS cells with full-length HR and LR Fc gamma RIIA cDNA, and examined them for their ability to react with anti-Fc gamma RIIA mAb and to bind red blood cells (RBC) coated with either murine IgG2b or murine IgG1. Whereas COS cells transfected with either the HR cDNA or the LR cDNA reacted with the anti-Fc gamma RII mAb, IV.3, and bound murine IgG2b-coated RBC, only COS cells transfected with the HR cDNA formed rosettes with murine IgG1-coated RBC and reacted strongly with mAb 41H16. A total of nine LR donors were identified, and all were homozygous for the A substitution at position 519. We conclude that at an A at position 519 in the cDNA encoding Fc gamma RIIA is the primary molecular basis for the LR form of the receptor, and that the amino acid at residue 133 determines whether Fc gamma RIIA efficiently binds murine IgG1.
Clark
M R
MR
Rosalind Russell Arthritis Research Laboratory, Department of Medicine, University of California, San Francisco.
Stuart
S G
SG
Kimberly
R P
RP
Ory
P A
PA
Goldstein
I M
IM
D000328:Adult; D000943:Antigens, Differentiation / Q000032:analysis* / Q000235:genetics; D001483:Base Sequence; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011961:Receptors, Fc / Q000032:analysis* / Q000235:genetics; D017452:Receptors, IgG; D013329:Structure-Activity Relationship; D014162:Transfection
D000943:Antigens, Differentiation; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG