Arg89Cys substitution results ins very low membrane expression of the Duffy antigen/receptor for chemokines in Fyx individuals

The Duffy (FY) blood group antigens are carried by the DARC glycoprotein, 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 FY*X allele associated with weak 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)) individuals. 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 substitution, C286T. The resulting Arg89Cys amino acid change reduced the binding of anti-fy antibodies and chemokines to DARC transfectants. We concluded that the Fyb(weak) donors carried the FY*X allele at the FY locus and that the Fy(x) antigen corresponds to highly reduced expression of a grossly normal Fy(b) polypeptide caused by the Arg89Cys substitution. Because FY is a single copy gene, this defect should also affect DARC expression in nonerythroid cells. Because the Fy(x) phenotype is not associated with apparent clinical consequences, we discussed these findings in the light of the putative roles of DARC in various tissues. Finally, we developed a Fy(x) DNA typing assay that should be useful for genetic studies and clinical transfusion medicine. (C) 1998 by The American Society of Hematology.