Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 115685001;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.2 | [Blood group, Duffy system] | 110700 | Autosomal dominant; Autosomal recessive | 3 | ACKR1 | 613665 |
A number sign (#) is used with this entry because the Duffy blood group system (Fy) is based on variation in the ACKR1 gene (613665) on chromosome 1q23.
Complete resistance to infection by the malarial parasite Plasmodium vivax (see 611162) is associated with the Duffy phenotype Fy(a-b-), which results from a polymorphism in the ACKR1 promoter (613665.0002).
The Duffy blood group system, which consists of 4 alleles, 5 phenotypes, and 5 antigens, is important in clinical medicine because of transfusion incompatibilities and hemolytic disease of the newborn. Duffy antigens are located on ACKR1 (613665), or DARC, an acidic glycoprotein found on erythrocytes and other cells throughout the body. The 2 principal antigens, Fy(a) and Fy(b), are produced by the FYA and FYB codominant alleles (see 613665.0001). Four phenotypes are defined by the corresponding antibodies, anti-Fy(a) and anti-Fy(b): Fy(a+b-), Fy(a-b+), Fy(a+b+), and Fy(a-b-). Fy(a-b-), or Duffy null, is the major phenotype in African and American blacks and is characterized by the presence of Fy(b) on nonerythroid cells, but an absence of Fy(b) on erythrocytes. The Fy(a-b-) phenotype is associated with complete resistance to infection by the malarial parasite Plasmodium vivax (see 611162). Individuals with the Fy(a-b-) phenotype have the FYB-erythroid silent (FYB-ES) allele with a mutation in the DARC promoter (613665.0002). A fifth phenotype, Fy(bwk), or Fy(x), is characterized by weak Fy(b) expression on erythrocytes due to a reduced amount of protein. Individuals with the Fy(bwk) phenotype have the FYB-weak (FYB-WK) allele, also called the FYX allele, with a missense mutation in DARC (613665.0003). Other Duffy antigens include Fy3, Fy4, Fy5, and Fy6 (reviews by Pogo and Chaudhuri (2000), Langhi and Bordin (2006), and Meny (2010)).
An association between sickle cell trait (603903) and Duffy-null blood group was demonstrated in Saudi Arabs (Gelpi and King, 1976). Neither linkage nor association of the usual type was the basis, but rather a protection against malaria provided by both traits.
Nichols et al. (1987) reported a new Duffy specificity, Fy6, defined by a murine monoclonal antibody. Fy6 is related to susceptibility to invasion of red cells by P. vivax.
Maternal allo-immunization to antigens of the Duffy blood group system can result in hemolytic disease of the newborn (HDN). Hessner et al. (1999) evaluated the use of allele-specific PCR for prenatal genotyping of the Duffy antigen system to identify pregnancies at risk for HDN. Oligonucleotide primers were designed for FYA, FYB, and null-FY alleles. The authors found a perfect match between results of serotyping and detection by molecular methods. They suggested that this assay is particularly useful for rapid genotyping of fetal amniotic cells to identify pregnancies at risk for HDN due to maternal-fetal incompatibilities within the Duffy blood group system.
The Duffy system enjoys the distinction of being the first blood group whose genetic locus was assigned to a specific autosome, i.e., chromosome 1 (Donahue et al., 1968). Duffy and the locus for a form of hereditary cataract (116200) are closely linked. From extensive family studies, Robson et al. (1973) arrived at a tentative map of chromosome 1.
Palmer et al. (1977) studied a parent with transposition of segment 1q31-1q32 from the long arm to the short arm of chromosome 1 and a child in whom crossing-over had resulted in duplication of this segment. The Duffy type in the father and a normal son with the same transposition was Fy(ab), while in the mother it was Fy(b). In the proband with the duplication it was Fy(b), suggesting that the Duffy locus is situated at 1q2.
The demonstration of close linkage to alpha-spectrin (SPTA1; 182860) suggests the location of Fy in the q21 band (Raeymaekers et al., 1988). McAlpine et al. (1989) concluded that Fy lies distal to SPTA1.
By fluorescence in situ hybridization, Chaganti (1993) mapped the Fy gene, DARC, to chromosome 1q22-q23.
FYA/FYB Polymorphism
Tournamille et al. (1995) found that a single amino acid difference (G42D; 613665.0001) in DARC accounts for the difference between the FYA and FYB alleles at the Duffy blood group locus. Mallinson et al. (1995) also reported the basis for the FYA/FYB polymorphism.
For further information on the FYA/FYB polymorphism, see MOLECULAR GENETICS in 613665.
Fy(a-b-) Phenotype
The Fy(a-b-) phenotype is rare among white and Asian populations, whereas it is the predominant phenotype among populations of black people, especially those originating in West Africa. Tournamille et al. (1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype is a point mutation, -67T-C (613665.0002), in a consensus binding site for GATA1 (305371), a transcription factor active in erythroid cells. The Fy(a-b-) phenotype provides complete protection from Plasmodium vivax infection (see 611162).
Mallinson et al. (1995) presented evidence for 2 different genetic backgrounds giving rise to the Fy(a-b-) phenotype. The Duffy gene from a very rare Caucasian individual (AZ) with the Fy(a-b-) phenotype had a 14-bp deletion (613665.0004) that resulted in a frameshift that introduced a stop codon and produced a putative truncated DARC protein. The only known examples of the Fy(a-b-) phenotype in Caucasians were AZ and Czech gypsies.
For further information on the molecular genetics underlying the Fy(a-b-) phenotype, see MOLECULAR GENETICS in 613665.
Fy(bwk) Phenotype
Tournamille et al. (1998) and Olsson et al. (1998) described a Duffy allele, FYB-WK, or FYX, in approximately 3.5% of the population that, because of an arg89-to-cys (R89C; 613665.0003) substitution in the first cytoplasmic domain of DARC, results in reduced levels of protein, lower antigen expression, and reduced ability to bind chemokines. The phenotype is called Fy(bwk), Fy(x), or either Fy(a-b+(weak)) or Fy(a+b+(weak))
For further information on the molecular genetics underlying the Fy(bwk) phenotype, see MOLECULAR GENETICS in 613665.
On the basis of families studied in Rochester, N.Y., Weitkamp (1972) could demonstrate no linkage of Duffy and the HBB locus (141900), as had been suggested by Nance et al. (1970). An earlier suspicion of localization to chromosome 16 (Crawford et al., 1967) was apparently in error.
From study of a family with a pericentric inversion of chromosome 1, Lee et al. (1974) suggested that the most probable location of the Fy locus is close to the centromere on the short arm (favored) or near the distal end of the centric heterochromatin on the long arm. Assuming that each arm of chromosome 1 is 140 male cM in length, Cook et al. (1974) concluded that, measured from the centromere, map positions are as follows: PGD (172200) 1p124--Rh (see 111700) 1p109--PGM1 (171900) 1p079--Fy 1p010--PEPC (170000) 1q030.
In the course of paternity testing, Herbich et al. (1985) found an apparent maternal exclusion by the PGM1 enzyme system--mother's PGM1 type, 1; child's PGM1 type, 2; and by the Duffy blood group system--mother, Fy(a-b+); child, Fy(a+b-). The father was not available for testing. The karyotype of the child showed a 'new fragile site' at 1p31. The authors concluded that the PGM1 and Duffy loci are located in the 1p31 band, which they stated to be 'a position supposed to carry the PGM1 and the Duffy loci.' The last statement is incorrect and the assignment to 1p31 is inconsistent with previous well-established assignments of PGM1 and Fy to 1p22.1 and 1q12-q21, respectively.
Chaganti, R. S. K. Personal Communication. New York, N. Y. 10/22/1993.
Cook, P. J. L., Page, B. M., Johnston, A. W., Stanford, W. K., Gavin, J. Four further families informative for 1q and the Duffy blood group. Cytogenet. Cell Genet. 22: 378-380, 1978. [PubMed: 752508] [Full Text: https://doi.org/10.1159/000130976]
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Crawford, M. N., Punnett, H. H., Carpenter, G. G. Deletion of the long arm of chromosome 16 and an unexpected Duffy blood group phenotype reveal a possible autosomal linkage. Nature 215: 1075-1076, 1967. [PubMed: 6053430] [Full Text: https://doi.org/10.1038/2151075a0]
Donahue, R. P., Bias, W. B., Renwick, J. H., McKusick, V. A. Probable assignment of the Duffy blood group locus to chromosome 1 in man. Proc. Nat. Acad. Sci. 61: 949-955, 1968. [PubMed: 5246559] [Full Text: https://doi.org/10.1073/pnas.61.3.949]
Gelpi, A. P., King, M. C. Association of Duffy blood groups with the sickle cell trait. Hum. Genet. 32: 65-68, 1976. [PubMed: 1262023] [Full Text: https://doi.org/10.1007/BF00569977]
Herbich, J., Szilvassy, J., Schnedl, W. Gene localisation of the PGM-1 enzyme system and the Duffy blood groups on chromosome no. 1 by means of a new fragile site at 1p31. Hum. Genet. 70: 178-180, 1985. [PubMed: 3159642] [Full Text: https://doi.org/10.1007/BF00273078]
Hessner, M. J., Pircon, R. A., Johnson, S. T., Luhm, R. A. Prenatal genotyping of the Duffy blood group system by allele-specific polymerase chain reaction. Prenatal Diag. 19: 41-45, 1999. [PubMed: 10073905] [Full Text: https://doi.org/10.1002/(sici)1097-0223(199901)19:1<41::aid-pd463>3.0.co;2-a]
Howard, P. N., Stoddard, G. R., Goddard, M. W., Seely, J. R. Giemsa banding of chromosome 1qh+ and linkage analysis. J. Med. Genet. 12: 44-48, 1975. [PubMed: 47395] [Full Text: https://doi.org/10.1136/jmg.12.1.44]
Langhi, D. M., Jr., Bordin, J. O. Duffy blood group and malaria. Hematology 11: 389-398, 2006. [PubMed: 17607593] [Full Text: https://doi.org/10.1080/10245330500469841]
Lee, C. S. N., Ying, K. L., Bowen, P. Position of the Duffy locus on chromosome 1 in relation to breakpoints for structural rearrangements. Am. J. Hum. Genet. 26: 93-102, 1974. [PubMed: 4204536]
Mallinson, G., Soo, K. S., Schall, T. J., Pisacka, M., Anstee, D. J. 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. Brit. J. Haemat. 90: 823-829, 1995. [PubMed: 7669660] [Full Text: https://doi.org/10.1111/j.1365-2141.1995.tb05202.x]
McAlpine, P. J., Coopland, G., Guy, C., James, S., Komarnicki, L., MacDonald, M., Stranc, L., Lewis, M., Philipps, S., Coghlan, G., Kaita, H., Cox, D. W., Guinto, E. R., MacGillivray, R. Mapping the genes for erythrocytic alpha-spectrin 1 (SPTA1) and coagulation factor V (F5). (Abstract) Cytogenet. Cell Genet. 51: 1042, 1989.
Meny, G. M. The Duffy blood group system: a review. Immunohematology 26: 51-56, 2010. [PubMed: 20932074]
Miller, L. H., Mason, S. J., Dvorak, J. A. Erythrocyte receptors of Plasmodium knowlesi malaria: Duffy blood group determinants. Science 189: 561-562, 1975. [PubMed: 1145213] [Full Text: https://doi.org/10.1126/science.1145213]
Nance, W. E., Conneally, M., Kang, K. W., Reed, T. E., Schroder, J., Rose, S. Genetic linkage analysis of human hemoglobin variants. Am. J. Hum. Genet. 22: 453-459, 1970. [PubMed: 5432289]
Nichols, M. E., Rubinstein, P., Barnwell, J., Rodriguez de Cordoba, S., Rosenfield, R. E. A new human Duffy blood group specificity defined by a murine monoclonal antibody: immunogenetics and association with susceptibility to Plasmodium vivax. J. Exp. Med. 166: 776-785, 1987. [PubMed: 2442291] [Full Text: https://doi.org/10.1084/jem.166.3.776]
Olsson, M. L., Smythe, J. S., Hansson, C., Poole, J., Mallinson, G., Jones, J., Avent, N. D., Daniels, G. The Fy(x) phenotype is associated with a missense mutation in the Fy(b) allele predicting Arg89Cys in the Duffy glycoprotein. Brit. J. Haemat. 103: 1184-1191, 1998. [PubMed: 9886340] [Full Text: https://doi.org/10.1046/j.1365-2141.1998.01083.x]
Palmer, C. G., Christian, J. C., Merritt, A. D. Partial trisomy 1 due to a 'shift' and probable location of the Duffy (Fy) locus. Am. J. Hum. Genet. 29: 371-377, 1977. [PubMed: 879169]
Pasvol, G., Wilson, R. J. M. The interaction of malaria parasites with red blood cells. Brit. Med. Bull. 38: 133-140, 1982. [PubMed: 7052193] [Full Text: https://doi.org/10.1093/oxfordjournals.bmb.a071749]
Pogo, A. O., Chaudhuri, A. The Duffy protein: a malarial and chemokine receptor. Semin. Hemat. 37: 122-129, 2000. [PubMed: 10791881] [Full Text: https://doi.org/10.1016/s0037-1963(00)90037-4]
Raeymaekers, P., Van Broeckhoven, C., Backhovens, H., Wehnert, A., Muylle, L., De Jonghe, P., Gheuens, J., Vandenberghe, A. The Duffy blood group is linked to the alpha-spectrin locus in a large pedigree with autosomal dominant inheritance of Charcot-Marie-Tooth disease type 1. Hum. Genet. 78: 76-78, 1988. [PubMed: 2892777] [Full Text: https://doi.org/10.1007/BF00291239]
Ritter, H. Zur formalen Genetik des Duffy-systems. Untersuchung von 247 Familien. Humangenetik 4: 59-61, 1967. [PubMed: 6081913] [Full Text: https://doi.org/10.1007/BF00279180]
Robson, E. B., Cook, P. J. L., Corney, G., Hopkinson, D. A., Noades, J., Cleghorn, T. E. Linkage data on Rh, PGM, PGD, peptidase C and Fy from family studies. Ann. Hum. Genet. 36: 393-399, 1973. [PubMed: 4201296] [Full Text: https://doi.org/10.1111/j.1469-1809.1973.tb00603.x]
Tournamille, C., Colin, Y., Cartron, J. P., Le Van Kim, C. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nature Genet. 10: 224-228, 1995. [PubMed: 7663520] [Full Text: https://doi.org/10.1038/ng0695-224]
Tournamille, C., Le Van Kim, C., Gane, P., Cartron, J.-P., Colin, Y. Molecular basis and PCR-DNA typing of the Fya/fyb blood group polymorphism. Hum. Genet. 95: 407-410, 1995. [PubMed: 7705836] [Full Text: https://doi.org/10.1007/BF00208965]
Tournamille, C., Le Van Kim, C., Gane, P., Le Pennec, P. Y., Roubinet, F., Babinet, J., Cartron, J. P., Colin, Y. Arg89Cys substitution results in very low membrane expression of the Duffy antigen/receptor for chemokines in Fy(x) individuals. Blood 92: 2147-2156, 1998. Note: Erratum: Blood 95: 2753 only, 2000. [PubMed: 9731074]
Weitkamp, L. R. Personal Communication. Rochester, N. Y. 1972.