|Blood Group Antigen Gene Mutation Database|
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Duffy Blood Group System
Gene locus - DARC
The antigenic determinants reside in an acidic glycoprotein (gp-DARC or gp-FY), which spans the membrane seven times and has an exocellular N-Terminal domain and an endocellular C-terminal domain.
The Duffy transcription unit encompasses 1572 nucleotides, including exon 1 of 55 nucleotides, a single intron of 479 nucleotides and exon 2 of 1038 nucleotides. Exon 1 encodes seven residues in frame with the 329 residues in exon 2. A most notable feature of the glycoprotein is that it is a receptor for the malaria parasite Plasmodium vivax and Pasmodium knowlesi and plays a role in angiogenesis
The orthologous mouse Duffy gene, named Dfy, also is a single copy gene, located in the same region of chromosome 1, as the human gene. The mouse Duffy-like protein shows 60% homology with the human protein. However, mouse erythrocytes are serologically Duffy-negative and mouse erythrocyte membrane proteins do not cross-react with two Duffy-specific rabbit polyclonal antibodies (Luo et al.).
Function of proteins
gp-Fy plays a role in inflammation and in malaria infection. It is a member of the super-family of chemokine receptors and plays its role as a silent angiogenesis chemokine. Also, it is a 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.
gp-Fy is expressed in erythroid and non-erythroid cells including the endothelial cells of capillary and postcapillary venules, the epithelial cells of kidney collecting ducts, in lung alveoli and in the Purkinje cells of the cerebellum.
None apparent; however a recent report suggests that lack of DARC protein on the surface of the red cell is associated with increased susceptibility to HIV-Aids (He W et al. Cell Host and Microbe, 2008 4 52-62). In contrast, overexpression of DARC is associated with a better prognosis in the course of carcinogenesis. Homozygous Duffy-deleted mice (Dfy-/-) are indistinguishable from their 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.
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 Americans and Blacks and occurs rarely in other populations;it is the predominant allele across sub-Saharan Africa (Howes et al Nat.Commun.2001 2 266); 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 Plasmodium 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; however there is a problem with numbering of variant nucleotides and amino acids because two kinds of Duffy mRNA have been described; a less abundant spliceform that encodes a protein of 338 residues was discoverd first and used for cloning (acc. no UO1839, seq. MASSGYVLQAELS...designated variant 1 or isoform a)) and the more abundant form, that encodes a protein of 336 residues (ref. Iwamoto et al., seq. MGNCLHRAELS...designated variant 2)).More recently two sequences have become available in GenBank,acc. no. NM_001122951.2 for variant 1 and acc.nos.NM_002036.3 and NG_011626 for variant2..The NG_011626 seq. is now designated the NCBI reference seq.for DARC. Either variant1 or variant2 sequences are used by investigators as reference sequences in defining DNA variations (noted under "Details" of respective entries). This has become confusing when compiling the DNA changes in the database.For example the change of FYA to FYB may appear at nt. 125 in some publications or at nt 131 in others. Here, we use as reference the FYB sequence of variant1, acc. no. U01839, and take the liberty of changing the authors' numbering designation to conform to the reference sequence . Genomic sequence acc. no. X85785 is also used as a reference to document the sites of mutations in the 5' region. ( see for example, "Details" under allele FYB ES) Another confusing aspect is the identification, in ref.sequences, of "ATG" that mark the beginning of coding regions. Thus in X85785 it resides at nt506, the GATA motif "TTATCT" residing -64 nt downstream of the A of this "ATG". In the sequence NG_011626 of variant 2, the beginning of the coding sequence resides at nt 5241with GATA motif at nt -64.)
When searching for a particular allele, use "name" if DNA alteration is known or, if you wish to search by phenotype or the designation used by author, use "alias" (see "Details").
Other database IDs and links
NG_011626 for variant2(MGNCLHRALS)
NM_002036.3 for variant2
X85785 for genomic (for 5' region)
A. Osca Pogo and Asok Chaudhuri, Department of Cell Biology, Linsdsley F. Kimball Research Institute, The New York Blood Center, 310 East 67th St., New York, N.Y.10021; Tel. 212-570-3023; Fax. 212-570-3195; email: email@example.com
Contributors for specific alleles are listed with the alleles.
Updated 2015-08-22 03:15:06.223