Mutations in the erythrocyte chemokine receptor (Duffy) gene: the molecular basis of the Fy^a/Fy^b antigens and identification of a deletion in the Duffy gene of an apparently healthy individual with the Fy(a – b–) phenotype

Abstract

The erythrocyte chemokine receptor, a receptor for Plasmodium vivax, carries the antigens of the Duffy blood group system. Sequence analysis of reticulocyte RNA from individuals of known Duffy phenotype showed that the Fya antigen differs from the Fyb antigen as a result of a single nucleotide difference (A131 or G) encoding amino acid Gly44 (Fya) or Asp (Fyb) in the N-terminal extracellular domain of the glycoprotein. Evidence is presented for two different genetic backgrounds giving rise to the Fy(a-b-) phenotype. The most likely genetic mechanism in most individuals of the Fy(a-b-) phenotype is down-regulation of Duffy glycoprotein mRNA. However, the Duffy gene from a very rare Caucasian individual (AZ) with the Fy(a-b-) phenotype has a 14 base-pair deletion (nucleotides 287-301) resulting in a frameshift which introduces a stop codon and produces a putative truncated 118 amino acid protein. The occurrence of this mutation in an apparently healthy individual raises questions about the functional importance of the Duffy glycoprotein not only in normal erythrocytes but also in all human cells and tissues.

The Duffy Antigen/Receptor for Chemokines Exists in an Oligomeric Form in Living Cells and Functionally Antagonizes CCR5 Signaling through Hetero-Oligomerization

“…That individuals in areas prone to Plasmodium vivax malaria have developed erythroid-specific promoter mutations that abolish expression of DARC on red blood cells, yet retain expression of DARC in other tissues argues for an important physiological role for DARC (Tournamille et al, 1995;Zimmerman et al, 1999). However, this evidence needs to be married with data from both DARC knockout mice and individuals who fail to express DARC as a result of rare coding region mutations, yet have an apparently normal phenotype (Mallinson et al, 1995;Luo et al, 2000).…”

Semi-nested, multiplex polymerase chain reaction for detection of human malaria parasites and evidence of Plasmodium vivax infection in Equatorial Guinea.

“…This possible association could, for example, be detected by carrying out a study of the Fy genotype and its mutations. 25 …”

Close Association of the First and Fourth Extracellular Domains of the Duffy Antigen/Receptor for Chemokines by a Disulfide Bond Is Required for Ligand Binding

“…1B shows that, in a dose-dependent fashion, IL-8 could displace the three bound anti-Fy mAbs and that a plateau corresponding to 30% and 40% displacement was reached when 200 nM IL-8 was added after incubation with anti-Fy6 and anti-Fy a or anti-Fy3, respectively. polymorphism, associated with a G42D substitution (9, 13, 26, 29) has no effect on the chemokine receptor properties of DARC (20,29). In the converse experiment, red cells were preincubated with various amounts of unlabeled IL-8 before anti-Fy mAbs were added.…”