ARG89CYS SUBSTITUTION RESULTS INS VERY-LOW MEMBRANE EXPRESSION OF THEDUFFY ANTIGEN RECEPTOR FOR CHEMOKINES IN FY(X) INDIVIDUALS/

The Duffy (FY) blood group antigens are carried by the DARC glycoprote in, a widely expressed chemokine receptor. The molecular basis of the Fy(a)/Fy(b) and Fy(a-b-) polymorphisms has been clarified, hut little is known about the Fy(x) antigen and the FYX allele associated with w eak expression of Fy(b), Fy3, Fy5, and Fy6 antigens. We analyzed here the structure and expression of the FY gene in 4 Fy(a-b(weak)) individ uals. As compared with Fy(a-b+) controls, the Fy(a-b(weak)) red blood cell membranes contained residual amount of DARC polypeptide and these cells were poorly bound by anti-fy antibodies and chemokines. The FY gene from Fy(a-b+) and Fy(a-b(weak)) individuals differed by one subst itution, C286T. The resulting Arg89Cys amino acid change reduced the b inding of anti-fy antibodies and chemokines to DARC transfectants. We concluded that the Fyb(weak) donors carried the FYX allele at the FY locus and that the Fy(x) antigen corresponds to highly reduced express ion of a grossly normal Fy(b) polypeptide caused by the Arg89Cys subst itution. Because FY is a single copy gene, this defect should also aff ect DARC expression in nonerythroid cells. Because the Fy(x) phenotype is not associated with apparent clinical consequences, we discussed t hese findings in the light of the putative roles of DARC in various ti ssues. Finally, we developed a Fy(x) DNA typing assay that should be u seful for genetic studies and clinical transfusion medicine. (C) 1998 by The American Society of Hematology.