C O N T E N T S
FY Gene locus - FY
In 1950, the Duffy blood group was named for the multiply transfused hemophiliac whose serum contained the first example of anti-Fya. In 1951, the antibody to the antithetical antigen?, Fyb, was discovered in the serum of a woman who had been pregnant three times. Using these antibodies three common phenotypes were defined: Fy(a+b+), Fy(a+b-), and Fy(a-b+). Differences in the racial distribution of the Duffy antigens were discovered four years later when it was reported that the majority of Blacks had the erythrocyte phenotype Fy(a-b-). This phenotype is exceedingly rare in Whites. The frequency of the Fy(a-b-) phenotype is 68 percent in American Blacks and 88-100 percent in African Blacks.
The Duffy system of blood groups is genetically simple, being controlled by four allelic genes at one locus, of which only three are sufficiently common to be of anthropological and medical significance. Since the letter D is used for the principal gene of the Rh system the last two letters of the name Duffy are used in the gene symbols, Fya, Fyb , and Fy4. The Fy4 gene is very rare outside Africa and very common within that continent. Not only is it therefore an important anthropological marker, but, it provides one of the few cases where we think we know, in terms of natural selection, why one population differs from another in their blood-group frequencies.(1)
The Duffy genes, located on chromosome? one at position 1922-23, have recently been cloned and sequenced. The difference between Fya and Fyb is a change in the amino acid at position 43 from aspartic acid (Fya) to glycine (Fyb). Studies have shown that blacks whose erythrocytes express Fyb antigen also have the antigen on the cells of their kidney, heart, muscle, brain and placenta. The Duffy gene codes for a protein known as a chemokine receptor, which is important in the inflammatory process. Accordingly, the Fy protein is also known as DARC (Duffy Antigen Receptor for Chenokines).
The molecular basis for the Fy(c-b-) phenotype is the result of a point mutation in the erythroid specific promoter. The absence of Duffy antigens on erythrocytes results in their resistance to invasion by two malaria parasites, Plasmodium vivax and Plasmodium knowlesi. This racial variation in distribution of the Duffy system antigens provides one of the few known examples of selective advantage conferred by a blood group phenotype.
Sanger discovered that a high percentage of African Negroes are of the phenotype Fy (a- b-), which is apparently a third gene termed Fyx which does not react with anti-Fya or anti -Fyb. In 1975 Miller was able to show that this type is probably specifically resistant to Vivax malaria, to which Africans have long been known to be resistant.
Duffy has been found to act as a multispecific receptor for chemokines? of both the C-C and C-X-C families, including: MGSA, regulated upon activation normal T expressed and secreted (RANTES; CCL5), monocyte [Chemotaxis? chemotatic] protein-1 (MCP-1; CCL2) and the angiogenic CXC chemokines [Interleukin-8 (IL-8)? interleukin-8] (IL-8, CXCL8), growth related gene alpha (GRO-α, CXCL1), neutrophil activating peptide-2 (NAP-2, CXCL7) and ENA-78 (CXCL5). Consequently the Fy protein is also known as DARC (Duffy Antigen Receptor for Chenokines).
While Duffy is expressed on erythrocytes the Duffy antigen? is found on some epithelial cells (kidney collecting ducts), Purkinje cells of the cerebellum, endothelial cells of thyroid capillaries, the post-capillary venules of some organs and the large lung alveoli.
On erythrocytes the Duffy antigen acts as a receptor for invasion by the human malarial parasites Plasmodium vivax and Plasmodium knowlesi; Duffy negative individuals whose erythrocytes do not express the receptor are resistant to infection. This antigen may also play a role in erythrocyte invasion in the rodent malarial parasite Plasmodium yoelii.
gp-Fy plays a role in inflammation and in malaria infection. It is a member of the super-family of [Chemokines? chemokine] receptors and the receptor for the human malarial parasite Plasmodium vivax and the simian malarial parasite Plasmodium knowlesi. The parasite-specific binding site, the binding site for chemokines and the major antigenic domains are located in overlapping regions at the exocellular N-terminal terminus.
In DARC-transfected cells, DARC is internalized following ligand binding and this led to the hypothesis that expression of DARC on the surface of erythocytes, endothelial, neuronal cells and epithelial cells may act as a sponge and provide a mechanism by which inflammatory chemokines may be removed from circulation as well as their concentration modified in the local environment. This hypothesis has also been questioned after knock out mice were created. These animals appeared healthy and had normal responses to infection.
Homozygous Duffy-deleted mice (Dfy-/-) are indistinguishable from their [wild type? wild-type] in size, health, embryonic development and neurological behavior.The only difference noted is a diminution of neutrophil trafficking in the mutant mice (to be published). The human equivalents of the Dfy-/- mice are also healthy; they are individuals whose phenotype is Fy(a-b-) and who lack gp-Fy on erythrocytes; its level of expression on non-erythroid cells is not known. This phenotype or the absence of the protein on the erythrocyte surface, appears to be protective against malaria Plasmodium vivax parasite.
About the alleles
The [Antigen? antigenic] determinants reside in an acidic glycoprotein (gp-Fy), which spans the membrane seven times and has an exocellular N-Terminal domain and an endocellular C-terminal domain.
The system is defined by three common alleles: FYA and FYB encode two antithetical antigens, Fya and Fyb; FYBES (ES stands for erythroid silent) is the major allele in African American and Blacks and occurs rarely in other populations; a mutation? in the promoter region abolishes expression of gp-Fy in erythroid but not in non-erythroid cells. This phenotype, or the absence of the protein on the erythrocyte surface appears to be protective against malaria vivax.
So far, the molecular basis has been documented for only a few types of rare alleles, FYBWK (WK stands for "weak") and FYAO or FYBO. FYBWK is characterized by a Fy (a-,b+wk) phenotype exhibiting a weak reaction with anti-Fyb. The ability of the Fy (a-,b+wk) erythrocytes to bind to all anti-Fy antibodies, as well as chemokines, albeit weakly, indicates that the overall structure of the Fy protein is not grossly altered but rather that its amount is markedly reduced. FYAO and FYBO are very rare alleles whose products do not appear at the surface of the erythocytes and thus result in Duffy (Fy) null phenotypes. A few cases of apparently healthy, non Black, Duffy-negative individuals (other than those having the FYBES alleles) have been documented and the molecular bases established for the absence of the reactive antigens. The allelic frequency of FYBWK for Caucasians or Blacks is ~ 0.02.
In the list of alleles the cDNA and translation changes are numbered from the codon for the initiator Met; note the following problem in the number assignements of amino acids: two kinds of Duffy mRNA have been described; a less abundant splicoform that encodes a protein of 338 residues was discovered first and used for cloning (acc. no UO1839, seq. MASSGYVLQAELS...) and the more abundant form, that encodes a protein of 336 residues (not in GenBank, ref. Iwamoto et al., seq. MGNCLHRAELS...). FYB, sequence acc. no. U01839 is taken as reference. Genomic sequence acc. no. X85785 can be used to visualize the sites of mutations in the list of alleles. (Coding sequence starts at nt. 979.)
The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth
FASEB J. 2006 Jan;20(1):59-64. Shen H, Schuster R, Stringer KF, Waltz SE, Lentsch AB.
Contribution of Duffy antigen to chemokine function
Cytokine Growth Factor Rev. 2005 Dec;16(6):687-94. Epub 2005 Jul 27.
A structural model of a seven-transmembrane helix receptor: the Duffy antigen/receptor for chemokine (DARC)
Biochim Biophys Acta. 2005 Aug 5;1724(3):288-306.
de Brevern AG, Wong H, Tournamille C, Colin Y, Le Van Kim C, Etchebest C.
The human Duffy antigen binds selected inflammatory but not homeostatic chemokines
Biochem Biophys Res Commun. 2004 Aug 20;321(2):306-12. Gardner L, Patterson AM, Ashton BA, Stone MA, Middleton J.
1. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983.
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