A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa

A donor-dependent difference in electrophoretic mobility of deglycosylated released Fc gamma RIIIa derived from NK cells and macrophages was observed, We investigated whether this was based on a polymorphism of the Fc gamma RIIIA gene, Cloning and sequencing of Fc gamma RIIIa-encoding cDNA derived from an apparently heterozygous donor showed one single nucleotide substitution at position 230 (T-->G), which was responsible for a leucine (L)-->arginine (R) substitution at position 48 in the first extracellular Ig-like domain (EC1) of Fc gamma RIIIa and caused a higher electrophoretic mobility of Fc gamma RIIIa, An allele-specific primer annealing PCR assay was developed to amplify specifically an Fc gamma RIIIA gene-derived fragment, which was digested with AciI (recognizing G(230)) or MnlI (recognizing T-230). MnlI restriction analysis revealed the presence of a third Fc gamma RIIIa allele with a T-230-->A substitution, which predicts a change of 48-leucine into 48-histidine (H), A gene frequency of 86% for the T-230 (48-L) allele, 6% for G(230) (48-R), and 8% for A(230) (48-H) was found, A significantly different genotype distribution was found among 12 unrelated Caucasian Fc gamma RIIIB gene-deficient donors, Fc gamma RIIIa-48R and Fc gamma RIIIa-48H showed a higher binding capacity of human (h)IgG1, hIG3, and hIgG4 compared with Fc gamma RIIIa-48L. Finally, the CD16 mAbs 1D3 and MEM154 bound more strongly and Leu11c (B73.1) bound less to the newly identified Fc gamma RIIIa isoforms.