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The molecular genetics of blood group polymorphism

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Abstract

Over 300 blood group specificities on red cells have been identified, many of which are polymorphic. The molecular mechanisms responsible for these polymorphisms are diverse, though many simply represent single nucleotide polymorphisms (SNPs). Other mechanisms include the following: gene deletion; single nucleotide deletion and sequence duplication, which introduce reading-frame shifts; nonsense mutation; intergenic recombination between closely linked genes, giving rise to hybrid genes and hybrid proteins; and a SNP in the promoter region of a blood group gene. Examples of these various genetic mechanisms are taken from the ABO, Rh, Kell, and Duffy blood group systems. Null phenotypes, in which no antigens of a blood group system are expressed, are not generally polymorphic, but provide good examples of the effect of inactivating mutations on blood group expression. As natural human ‘knock-outs’, null phenotypes provide useful clues to the functions of blood group antigens. Knowledge of the molecular backgrounds of blood group polymorphisms provides a means to predict blood group phenotypes from genomic DNA. This has two main applications in transfusion medicine: determination of foetal blood groups to assess whether the foetus is at risk from haemolytic disease and ascertainment of blood group phenotypes in multiply transfused, transfusion-dependent patients, where serological tests are precluded by the presence of donor red cells. Other applications are being developed for the future.

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References

  • Anstee DJ (2009) Red cell genotyping and the future of pretransfusion testing. Blood 114:248–256

    Article  CAS  PubMed  Google Scholar 

  • Avent ND (2008) Large-scale blood group genotyping—clinical implications. Br J Haematol 144:3–13

    Article  PubMed  Google Scholar 

  • Avent ND, Butcher SK, Liu W, Mawby WJ, Mallinson G, Parsons SF, Anstee DJ, Tanner MJ (1992) Localization of the C termini of the Rh (Rhesus) polypeptides to the cytoplasmic face of the human erythrocyte membrane. J Biol Chem 267:15134–15139

    CAS  PubMed  Google Scholar 

  • Avent ND, Martinez A, Flegel WA, Olsson ML, Scott ML, Nogués N, Písăcka M, Daniels G, van der Schoot E, Muñiz-Diaz E, Madgett TE, Storry JR, Beiboer SH, Maaskant-van Wijk PA, von Zabern I, Jiménez E, Tejedor D, López M, Camacho E, Cheroutre G, Hacker A, Jinoch P, Svobodova I, de Haas M (2007) The BloodGen project: towards mass-scale comprehensive genotyping of blood donors in the European Union and beyond. Transfusion 47(1S):40S–46S

    Article  CAS  PubMed  Google Scholar 

  • Bandyopadhyay S, Zhan R, Chaudhuri A, Watabe M, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Pauza ME, Hayashi S, Wang Y, Mohinta S, Mashimo T, Iiizumi M, Furuta E, Watabe K (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12:933–938

    Article  CAS  PubMed  Google Scholar 

  • Bruce LJ, Beckmann R, Ribeiro ML, Peters LL, Chasis JA, Delaunay J, Mohandas N, Anstee DJ, Tanner MJ (2003) A band 3-based macrocomplex of integral and peripheral proteins in the RBC membrane. Blood 101:4180–4188

    Article  CAS  PubMed  Google Scholar 

  • Burton NM, Anstee DJ (2008) Nature, function and significance of Rh proteins in red cells. Curr Opin Hematol 15:625–630

    Article  CAS  PubMed  Google Scholar 

  • Chan KCA, Ding C, Gerovassili A, Yeung SW, Chiu RW, Leung TN, Lau TK, Chim SS, Chung GT, Nicolaides KH, Lo YM (2006) Hypermethylated RASSF1A in maternal plasma: a universal fetal DNA marker that improves the reliability of noninvasive prenatal diagnosis. Clin Chem 52:2211–2218

    Article  CAS  PubMed  Google Scholar 

  • Cherif-Zahar B, Raynal V, Gane P, Mattei MG, Bailly P, Gibbs B, Colin Y, Cartron JP (1996) Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Nat Genet 12:168–173

    Article  CAS  PubMed  Google Scholar 

  • Chérif-Zahar B, Matassi G, Raynal V, Gane P, Mempel W, Perez C, Cartron JP (1998) Molecular defects of the RHCE gene in the Rh-deficient individuals of the amorph type. Blood 92:639–646

    PubMed  Google Scholar 

  • Chester MA, Olsson ML (2001) The ABO blood group gene: a locus of considerable genetic diversity. Transfus Med Rev 15:177–200

    Article  CAS  PubMed  Google Scholar 

  • Clapéron A, Rose C, Gane P, Collec E, Bertrand O, Ouimet T (2005) The Kell protein of the common K2 phenotype is a catalytically active metalloprotease, whereas the rare Kell K1 antigen is inactive. J Biol Chem 280:21272–21283

    Article  PubMed  Google Scholar 

  • Cockburn IA, Mackinnon MJ, O’Donnell A, Allen SJ, Moulds JM, Baisor M, Bockarie M, Reeder JC, Rowe JA (2004) A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci USA 101:272–277

    Article  CAS  PubMed  Google Scholar 

  • Conroy MJ, Bullough PA, Merrick M, Avent ND (2005) Modelling the human rhesus proteins: implications for structure and function. Br J Haematol 131:543–551

    Article  CAS  PubMed  Google Scholar 

  • Cserti CM, Dzik WH (2007) The ABO blood group system and Plasmodium falciparum malaria. Blood 110:2250–2258

    Article  CAS  PubMed  Google Scholar 

  • Danek A (ed) (2005) Neuroacanthocytosis syndromes. Springer, Berlin

    Google Scholar 

  • Daniels G (2002) Human blood groups, 2nd edn. Blackwell Science, Oxford

    Google Scholar 

  • Daniels G (2007) Functions of red cell surface proteins. Vox Sang 93:331–340

    Article  CAS  PubMed  Google Scholar 

  • Daniels GL, Faas BHW, Green CA, Smart E, Maaskant-van Wijk PA, Avent ND, Zondervan HA, von dem Borne AE, van der Schoot CE (1998) The Rh VS and V blood group polymorphisms in Africans: a serological and molecular analysis. Transfusion 38:951–958

    Article  CAS  PubMed  Google Scholar 

  • Daniels GL, Fletcher A, Garratty G et al (2004) Blood group terminology 2004. From the ISBT committee on terminology for red cell surface antigens. Vox Sang 87:304–316

    Article  CAS  PubMed  Google Scholar 

  • Daniels G, Castilho L, Flegel WA et al (2009a) International society of blood transfusion committee on terminology for red cell surface antigens: Macao report. Vox Sang 96:153–156

    Article  CAS  PubMed  Google Scholar 

  • Daniels G, Finning K, Martin P, Massey E (2009b) Non-invasive prenatal diagnosis of fetal blood group phenotypes: current practice and future prospects. Prenat Diagn 29:101–107

    Article  CAS  PubMed  Google Scholar 

  • Endeward V, Cartron J-P, Ripoche P, Gros G (2008) RhAG protein of the Rhesus complex is a CO2 channel in the human red cell membrane. FASEB J 22:64–73

    Article  CAS  PubMed  Google Scholar 

  • Faas BHW, Beckers EAM, Wildoer P, Ligthart PC, Overbeeke MA, Zondervan HA, von dem Borne AE, van der Schoot CE (1997) Molecular background of VS and weak C expression in blacks. Transfusion 37:38–44

    Article  CAS  PubMed  Google Scholar 

  • Finning K, Martin P, Summers J, Daniels G (2007) Fetal genotyping for the K (Kell) and Rh C, c, and E blood groups on cell-free fetal DNA from maternal plasma. Transfusion 47:2126–2133

    Article  CAS  PubMed  Google Scholar 

  • Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G (2008) Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. Br Med J 336:816–818

    Article  Google Scholar 

  • Hadley TJ, Peiper SC (1997) From malaria to chemokine receptor: the emerging physiologic role of the Duffy blood group antigen. Blood 89:3077–3091

    CAS  PubMed  Google Scholar 

  • Hashmi G, Shariff T, Zhang Y, Cristobal J, Chau C, Seul M, Vissavajjhala P, Baldwin C, Hue-Roye K, Charles-Pierre D, Lomas-Francis C, Reid ME (2007) Determination of 24 minor red cell antigens for more then 2000 blood donors by high-throughput DNA analysis. Transfusion 47:736–747

    Article  CAS  PubMed  Google Scholar 

  • Hellberg Å, Chester MA, Olsson ML (2005) Two previously proposed P1/P2-differentiating and nine novel polymorphisms at the A4GALT (Pk) locus do not correlated with the presence of the P1 blood group antigen. BMC Genet 6:49

    Article  PubMed  Google Scholar 

  • Hillyer C, Shaz BH, Winkler AM, Reid M (2008) Integrating molecular technologies for red blood cell typing and compatibility testing into blood centers and transfusion services. Transfus Med Rev 22:117–132

    Article  PubMed  Google Scholar 

  • Huang C-H, Chen Y, Reid ME, Seidl C (1998) Rhnull disease: the amorph type results from a novel double mutation in RhCe gene on D-negative background. Blood 92:664–671

    CAS  PubMed  Google Scholar 

  • Karamatic Crew V, Mallinson G, Green C, Poole J, Uchikawa M, Tani Y, Geisen C, Oldenburg J, Daniels G (2007) Different inactivating mutations in the LU genes of three individuals with the Lutheran-null phenotype. Transfusion 47:492–498

    Article  PubMed  Google Scholar 

  • Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB (1995) Sequence and expression of a candidate for the human Secretor blood group α(1, 2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem 270:4640–4649

    Article  CAS  PubMed  Google Scholar 

  • King CL, Michon P, Shakri AR, Marcotty A, Stanisic D, Zimmerman PA, Cole-Tobian JL, Mueller I, Chitnis CE (2008) Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection. Proc Natl Acad Sci USA 105:8363–8368

    Article  CAS  PubMed  Google Scholar 

  • Lee S (1997) Molecular basis of Kell blood group phenotypes. Vox Sang 73:1–11 (Erratum in: Vox Sang 1998;74:58)

  • Lee S, Lin M, Mele A, Cao Y, Farmar J, Russo D, Redman C (1999) Proteolytic processing of big endothelin-3 by the Kell blood group protein. Blood 94:1440–1450

    CAS  PubMed  Google Scholar 

  • Lee HJ, Barry CH, Borisova SN, Seto NO, Zheng RB, Blancher A, Evans SV, Palcic MM (2005) Structural basis for the inactivity of human blood group O2 glycosyltransferase. J Biol Chem 280:525–529

    CAS  PubMed  Google Scholar 

  • Lentsch AB (2002) The Duffy antigen/receptor for chemokines (DARC) and prostate cancer. A role as clear as black and white? FASEB J 16:1093–1095

    Article  CAS  PubMed  Google Scholar 

  • Lo YMD, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CWG (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350:485–487

    Article  CAS  PubMed  Google Scholar 

  • Lögdberg L, Reid ME, Lamont RE, Zelinski T (2005) Human blood group genes 2004: chromosomal locations and cloning strategies. Transfus Med Rev 19:45–57

    Article  PubMed  Google Scholar 

  • Loscertales M-P, Owens S, O’Donnell J, Bunn J, Bosch-Capblanch X, Brabin BJ (2007) ABO blood group phenotypes and Plasmodium falciparum malaria: unlocking a pivotal mechanism. Adv Parasitol 65:1–50

    Article  PubMed  Google Scholar 

  • Mayer DCG, Jiang L, Achur RN, Kakizaki I, Gowda DC, Miller LH (2006) The glycophorin C N-linked glycan is a critical component of the ligand for the Plasmodium falciparum erythrocyte receptor BAEBL. Proc Nat Acad Sci USA 103:2358–2362

    Article  CAS  PubMed  Google Scholar 

  • Mayer DCG, Cofie J, Jiang L, Hartl DL, Tracey E, Kabat J, Mendoza LH, Miler LH (2009) Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1. Proc Natl Acad Sci USA 106:5348–5352

    Article  CAS  PubMed  Google Scholar 

  • Mohandas N, Gallagher PG (2008) Red cell membrane: past, present, and future. Blood 112:3939–3948

    Article  CAS  PubMed  Google Scholar 

  • Mohandas N, Narla A (2005) Blood group antigens in health and disease. Curr Opin Hematol 12:135–140

    Article  CAS  PubMed  Google Scholar 

  • Mouro I, Colin Y, Chérif-Zahar B, Cartron J-P, Le Van Kim C (1993) Molecular genetic basis of the human Rhesus blood group system. Nat Genet 5:62–65

    Article  CAS  PubMed  Google Scholar 

  • Oriol R (1995) ABO, Hh, Lewis, and secretion, serology, genetics, and tissue distribution. In: Cartron J-P, Rouger P (eds) Blood cell biochemistry, vol 6. Plenum Press, New York, pp 36–73

    Google Scholar 

  • Page-Christiaens GCML, Bossers B, van der Schoot CE, de Haas M (2006) Use of bi-allelic insertion/deletion polymorphisms as a positive control in maternal blood. First clinical experience. Acad Sci 1075:123–129

    Article  CAS  Google Scholar 

  • Pasvol G, Wainscoat JS, Weatherall DJ (1982) Erythrocytes deficient in glycophorin resist invasion by the malarial parasite Plasmodium falciparum. Nature 297:64–66

    Article  CAS  PubMed  Google Scholar 

  • Perreault J, Lavoie J, Painchaud P, Côté R, Delage G, Dubuc S, Lemieux R, St-Louis M (2009) Set-up and routine use of a database of 10,555 genotyped blood donors to facilitate the screening of compatible blood components for alloimmunised patients. Vox Sang 97:61–68

    Article  CAS  PubMed  Google Scholar 

  • Pham B-N, Peyrard T, Juszczak G, Dubeaux I, Gien D, Blancher A, Cartron J-P, Rouger P, Le Pennec P-Y (2009) Heterogeneous molecular background of the weak C, VS+, hrB−, HrB− phenotype in black persons. Transfusion 49:495–504

    Article  CAS  PubMed  Google Scholar 

  • Poole J, Warke N, Hustinx H, Taleghani BM, Martin P, Finning K, Karamatic Crew V, Green C, Bromilow I, Daniels G (2006) A KEL gene encoding serine at position 193 of the Kell glycoprotein results in expression of KEL1 antigen. Transfusion 46:1879–1885

    Article  CAS  PubMed  Google Scholar 

  • Poole J, Tilley L, Warke N, Spring FA, Overbeeke MAM, van der Mark-Zoet JACM, Ahrens N, Armstrong D, Williams M, Daniels G (2007) Two missense mutations in the CD44 gene encode two new antigens of the Indian blood group system. Transfusion 47:1306–1311

    Article  CAS  PubMed  Google Scholar 

  • Pruenster M, Rot A (2006) Throwing light on DARC. Biochem Soc Trans 34:1005–1008

    Article  CAS  PubMed  Google Scholar 

  • Reid ME, Mohandas N (2004) Red blood cell blood group antigens: structure and function. Semin Hematol 41:93–117

    Article  CAS  PubMed  Google Scholar 

  • Ridgwell K, Eyers SAC, Mawby WJ, Anstee DJ, Tanner MJA (1994) Studies on the glycoprotein associated with Rh (Rhesus) blood group antigen expression in the human red blood cell membrane. J Biol Chem 269:6410–6416

    CAS  PubMed  Google Scholar 

  • Rowe JA, Moulds JM, Newbold CI, Miller LH (1997) P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 388:292–295

    Article  CAS  PubMed  Google Scholar 

  • Seltsam A, Blasczyk R (2005) Missense mutations outside the catalytic domain of the ABO glycosyltransferase can cause weak blood group A and B phenotypes. Transfusion 45:1663–1669

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Schuster R, Stringer KF, Walthz SE, Lentsch AB (2006) The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. FASEB J 20:59–64

    Article  CAS  PubMed  Google Scholar 

  • Sim BKL, Chitnis CE, Wasniowska K, Hadley TJ, Miller LH (1994) Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264:1941–1944

    Article  CAS  PubMed  Google Scholar 

  • Singleton BK, Green CA, Avent ND, Martin PG, Smart E, Daka A, Narter-Olaga EG, Hawthorne LM, Daniels G (2000) The presence of an RHD pseudogene containing a 37 base pair duplication and a nonsense mutation in most Africans with the Rh D-negative blood group phenotype. Blood 95:12–18

    CAS  PubMed  Google Scholar 

  • Singleton BK, Burton NM, Green C, Brady RL, Anstee DJ (2008) Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype. Blood 112:2081–2088

    Article  CAS  PubMed  Google Scholar 

  • Spring FA, Dalchau R, Daniels GL, Spring FA, Dalchau R (1988) The Ina and Inb blood group antigens are located on a glycoprotein of 80,000 MW (the CDw44 glycoprotein) whose expression is influenced by the In(Lu) gene. Immunology 64:37–43

    CAS  PubMed  Google Scholar 

  • Telen MJ (2005) Erythrocyte adhesion receptors: blood group antigens and related molecules. Transfus Med Rev 19:32–44

    Article  PubMed  Google Scholar 

  • Tilley L, Green C, Daniels G (2006) Sequence variation in the 5′ untranslated region of the human A4GALT gene is associated with, but does not define, the P1 blood group polymorphism. Vox Sang 90:198–203

    Article  CAS  PubMed  Google Scholar 

  • Tilley L, Green C, Poole J, Gaskell A, Ridgwell K, Burton NM, Uchikawa M, Akkøk CA, Garvik LJ, Daniels G (2009) A new blood group system, RHAG: three antigens resulting from amino acid substitutions in the Rh-associated glycoprotein. Vox Sang (in press)

  • Tournamille C, Colin Y, Cartron JP, Le Van Kim C (1995) Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat Genet 10:224–228

    Article  CAS  PubMed  Google Scholar 

  • Uneke CJ (2007) Plasmodium falciparum malaria and ABO blood group: is there any relationship? Parasitol Res 100:759–765

    Article  CAS  PubMed  Google Scholar 

  • van der Schoot CE, Ait Soussan A, Koelewijn J, Bonsel G, Paget-Christiaens LG, de Haas M (2006) Non-invasive antenatal RHD typing. Transfus Clin Biol 13:53–57

    Article  PubMed  Google Scholar 

  • Wagner FF, Flegel WA (2000) RHD gene deletion occurred in the Rhesus box. Blood 95:3662–3668

    CAS  PubMed  Google Scholar 

  • Yamamoto F, Clausen H, White T, Marken J, Hakomori S (1990) Molecular genetic basis of the histo-blood group ABO system. Nature 345:229–233

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto F, McNeill PD, Hakomori S (1992) Human histo-blood group A2 transferase coded by A2 allele, one of the A subtypes, is characterized by a single base deletion in the coding sequence, which results in an additional domain at the carboxyl terminal. Biochem Biophys Res Commun 187:366–374

    Article  CAS  PubMed  Google Scholar 

  • Yazer MH (2005) What a difference 2 nucleotides make: a short review of ABO genetics. Transfus Med Rev 19:200–209

    Article  PubMed  Google Scholar 

  • Yazer MH, Hosseini-Maaf B, Olsson ML (2008) Blood grouping discrepancies between ABO genotype and phenotype caused by O alleles. Curr Opin Hematol 15:618–624

    Article  PubMed  Google Scholar 

  • Zimmerman PA, Woolley I, Masinde GL, Miller SM, McNamara DT, Hazlett F, Mgone CS, Alpers MP, Genton B, Boatin BA, Kazura JW (1999) Emergence of FY*A null in a Plasmodium vivax-endemic region of Papua New Guinea. Proc Natl Acad Sci USA 96:13973–13977

    Article  CAS  PubMed  Google Scholar 

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  1. Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, North Bristol Park, Filton, Bristol, BS34 7QH, UK

    Geoff Daniels

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Daniels, G. The molecular genetics of blood group polymorphism. Hum Genet 126, 729–742 (2009). https://doi.org/10.1007/s00439-009-0738-2

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