Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy–negative individuals

Abstract

The mRNA for the Duffy blood group antigen, the erythrocyte receptor for the Plasmodium vivax malaria parasite, has recently been cloned and shown to encode a widely expressed chemokine receptor. Here, we show that the Duffy antigen/chemokine receptor gene (DARC) is composed of a single exon and that most Duffy-negative blacks carry a silent FY*B allele with a single T to C substitution at nucleotide -46. This mutation impairs the promoter activity in erythroid cells by disrupting a binding site for the GATA1 erythroid transcription factor. With the recent characterization of the FY*A and FY*B alleles, these findings provide the molecular basis of the Duffy blood group system and an explanation for the erythroid-specific repression of the DARC gene in Duffy-negative individuals.

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

“…Approximately 70% of African Americans lack erythrocyte expression of DARC. The Duffy-negative blood phenotype comes from a single T to C promoter mutation (Tournamille et al, 1995;Castilho et al, 2004;Chaudhuri et al, 2004). African American men have a 60% greater incidence of prostate cancer and a twofold higher mortality rate than the Caucasian men.…”

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

“…1 One of the clearest manifestations of such genetic control is malaria, where the parasite seems to have influenced the gene pool of the human host in areas of endemic disease, including retention of otherwise deleterious, disease-causing alleles at erythroid-specific genes (reviewed in Fortin et al 2 ). These include polymorphisms in the Duffy gene at the GATA-1-binding site of the chemokine receptor (DARC, also known as Fy) expressed on erythrocytes, 3 sickle cell anemia, 4 a and b thalassemia, 5,6 glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency, 7,8 and alterations in proteins associated with red cell integrity, such as deletions in the erythrocytic band 3 protein 9 or in the erythrocytic structural protein glycophorin C. 10 Furthermore, Class I and II HLA haplotypes 11 and genetically controlled variations in the level of the proinflammatory cytokine TNFa 12 have been shown to affect the severity and outcome of malaria. Finally, genetic linkage studies by whole genome scanning have shown that several chromosomal regions additionally affect innate susceptibility, extent of host response, and type of disease, 2 although the individual genes involved have yet to be identified.…”

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…In 1976, he discovered that an autosomal recessive deficiency of the Duffy antigen and receptor for chemokines (DARC) in erythrocytes prevented the infection of these cells with Plasmodium vivax in vitro and the infection of individuals in vivo (1). An elegant set of follow-up studies demonstrated that this resistance could be attributed to a single nucleotide mutation in the DARC promoter, preventing the binding of the transcription factor GATA-binding protein 1 (GATA1), which is required for DARC expression in the erythrocyte lineage (4). Affected individuals express DARC normally in other cells.…”