Histo-Blood Group A Variants, O Variants, and Their Alleles

Reference work entry


The allelic basis of the blood group ABO system was established in 1990 when the genes for human blood group A and B synthesizing glycosyltransferases were cloned (Yamamoto et al. 1990) and it was shown that there were only four amino acid differences between the blood group A and B synthesizing glycosyltransferases GTA and GTB (Arg/Gly176, Gly/Ser235, Leu/Met266 and Gly/Ala268). The O gene had a single-nucleotide deletion which resulted in a truncated inactive enzyme. Since the ABO system is based on red blood cell agglutination, it has been possible to identify many other alleles from routine blood typing carried out worldwide in blood banking centers (Storry and Olsson 2009; Yamamoto et al. 2012). Thus subgroups of A and B can be identified by weak and/or anomalous agglutination patterns in forward and reverse blood typing. DNA sequencing is carried out on any samples suspected of having alleles other than the original three. Currently (May 2013) 306 ABO alleles are tabulated in the blood group antigen mutation database (BGMUT) that is part of the dbRBC resource of the National Center for Biotechnology (Patnaik et al. 2012). However, new alleles are continually being identified. ABO is therefore considered to be one of the most genetically complex blood group systems.


Blood Group Critical Amino Acid Inactive Enzyme Human Blood Group Allelic Basis 


  1. Alfaro JA, Zheng RB, Persson M, Letts JA, Polakowski R, Bai Y, Borisova SN, Seto NOL, Lowary TL, Palcic MM, Evans SV (2008) ABO(H) blood group A and B glycosyltransferases recognize substrate via specific conformational changes. J Biol Chem 283:10097–100108PubMedCrossRefGoogle Scholar
  2. Bremer EG, Levery SB, Sonnino S, Ghidoni R, Canevari S, Kannagi R, Hakomori S (1984) Characterization of a glycosphingolipid antigen defined by the monoclonal antibody MBrJ expressed in normal and neoplastic epithelial cells of human mammary gland. J Biol Chem 259:14773–l4777PubMedGoogle Scholar
  3. Brew K, Tumbale P, Acharya KR (2010) Family 6 glycosyltransferases in vertebrates and bacteria: inactivation and horizontal transfer may enhance mutualism between vertebrates and bacteria. J Biol Chem 285:37121–37127PubMedCrossRefGoogle Scholar
  4. Cai X, Jin S, Liu X, Fan L, Lu Q, Wang J, Shen W, Gong S, Qiu L, Xiang D (2013) Molecular genetic analysis of ABO blood group variations reveals 29 novel ABO subgroup alleles. Transfusion (in press). doi:10.1111/trf.12168Google Scholar
  5. Chen DP, Tseng CP, Wang WT, Sun CF (2005) Identification of a novel A2 allele derived from the A transferase gene through a nucleotide substitution G539C. Vox Sang 88:196–199PubMedCrossRefGoogle Scholar
  6. Chen YJ, Chen PS, Liu HM, Lyou JY, Hu HY, Lin JS, Tseng CH (2006) Novel polymorphisms in exons 6 and 7 of A/B alleles detected by polymerase chain reaction-single strand conformation polymorphism. Vox Sang 90:119–127PubMedCrossRefGoogle Scholar
  7. Clausen H, Watanabe K, Kannagi R, Levery SB, Nudelman ED, Arao-Tomono Y, Hakomori S (1984) Blood group A glycolipid (AX) with globo-series structure which is specific for blood group A1 erythrocytes: one of the chemical bases for A1 and A2 distinction. Biochem Biophys Res Commun 124:523–529PubMedCrossRefGoogle Scholar
  8. Clausen H, Levery SB, Nudelman ED, Tsuchiya S, Hakomori S (1985) Repetitive A epitope (type 3 chain A) defined by blood group A1-specific monoclonal antibody TH-l: chemical basis of qualitative A1 and A2 distinction. Proc Natl Acad Sci USA 82:1199–1203PubMedCrossRefGoogle Scholar
  9. Clausen H, Holmes E, Hakomori S (1986) Novel blood group H glycolipid antigens exclusively expressed in blood group A and AB erythrocytes (type 3 chain H). II. Differential conversion of different H substrates by A1 and A2 enzymes, and type 3 chain H expression in relation to secretor status. J Biol Chem 261:1388–1392PubMedGoogle Scholar
  10. Clausen H, Levery SB, Kannagi R, Hakomori S (l986) Novel blood group H glycolipid antigens exclusively expressed in blood group A and AB erythrocytes (type 3 chain H). l. Isolation and chemical characterization. J Biol Chem 261:1380–1387Google Scholar
  11. Estalote AC, Palatnik M, Chester MA, Olsson ML, Sant’Anna Gomes BM (2004) A novel B subgroup: serological and genetic studies. Transfus Med 14:173–180PubMedCrossRefGoogle Scholar
  12. Goldstein J, Lenny L, Davies D, Voak D (1989) Further evidence for the presence of A antigen on group B erythrocytes through the use of specific exoglycosidases. Vox Sang 57:142–146PubMedCrossRefGoogle Scholar
  13. Greenwell P, Yates AD, Watkins WM (1986) UDP-N-acetyl-d-galactosamine as a donor substrate for the glycosyltransferase encoded by the B gene at the human blood group ABO locus. Carbohydr Res 149:149–170PubMedCrossRefGoogle Scholar
  14. Grunnet N, Steffenson R, Bennett EP, Clausen H (1994) Evaluation of histo-blood group ABO genotyping in a Danish population: frequency of a novel O allele defined as O 2. Vox Sang 67:210–215PubMedCrossRefGoogle Scholar
  15. Hosseini-Maaf B, Irshaid NM, Hellberg A, Wagner T, Levene C, Hustinix H, Steffensen R, Chester MA, Olsson ML (2005) New and unusual O alleles at the ABO locus are implicated in unexpected blood group phenotypes. Transfusion 45:70–81PubMedCrossRefGoogle Scholar
  16. Hosseini-Maaf B, Letts JA, Persson M, Smart E, LePennec PY, Hustinx H, Zhao Z, Palcic MM, Evans SV, Chester MA, Olsson ML (2007a) Structural basis for red cell phenotypic changes in newly identified, naturally occurring subgroup mutants of the human blood group B glycosyltransferase. Transfusion 47:864–875PubMedCrossRefGoogle Scholar
  17. Hosseini-Maaf B, Hellberg A, Chester MA, Olsson ML (2007b) An extensive polymerase chain reaction-allele-specific polymorphism strategy for clinical ABO blood group genotyping that avoids potential errors caused by null, subgroup, and hybrid alleles. Transfusion 47:2110–2125PubMedCrossRefGoogle Scholar
  18. Hult AK, Olsson ML (2010) Many genetically defined ABO subgroups exhibit characteristic flow cytometric patterns. Transfusion 50:308–323PubMedCrossRefGoogle Scholar
  19. Hult AK, Yazer MH, Jorgensen R, Hellberg A, Hustinx H, Peyrard T, Palcic MM, Olsson ML (2010) Weak A phenotypes associated with novel ABO alleles carrying the A2-related 1061C deletion and various missense substitutions. Transfusion 50:1471–1486PubMedCrossRefGoogle Scholar
  20. Kisailus EC, Kabat EA (1978) Immunochemical studies on blood groups. LXVI. Competitive binding assays of A1 and A2 blood group substances with insolubilized anti-A serum and insolubilized A agglutinin from Dolichos biflorus. J Exp Med 147:830–843PubMedCrossRefGoogle Scholar
  21. Kitano T, Blancher A, Saitou N (2012) The functional A allele was resurrected via recombination in the human ABO blood group gene. Mol Biol Evol 29:1791–1796PubMedCrossRefGoogle Scholar
  22. Lee HJ, Barry CH, Borisova SN, Seto NOL, Zheng RB, Blancher A, Evans SV, Palcic MM (2005) Structural basis for the inactivity of human blood group O2 glycosyltransferase. J Biol Chem 280:525–529PubMedGoogle Scholar
  23. Marcus SL, Polakowski R, Seto NOL, Leinala E, Borisova S, Blancher A, Roubinet F, Evans SV, Palcic MM (2003) A single point mutation reverses the donor specificity of hman blood group B-synthesizing galactosyltransferase. J Biol Chem 278:12403–12405PubMedCrossRefGoogle Scholar
  24. Moreno C, Lundblad A, Kabat EA (1971) Immunochemical studies on blood groups. LI. A comparative study of the reaction of A1 and A2 blood group glycoproteins with human anti-A. J Exp Med 134:439–457PubMedCentralPubMedCrossRefGoogle Scholar
  25. Ogasawara K, Bannai M, Saitou N, Yabe R, Nakata K, Takenaka M, Fujisawa K, Uchikawa M, Ishikawa Y, Juji T (1996a) Extensive polymorphism of ABO blood group gene: three major lineages of the alleles for the common ABO phenotypes. Hum Genet 97:777–783PubMedCrossRefGoogle Scholar
  26. Ogasawara K, Yabe R, Uchikawa M, Saitou N, Bannai M, Nakata K, Takenada M, Fujisawa K, Ishikawa Y, Juji T, Tokunaga K (1996b) Molecular genetic analysis of variant phenotypes of the ABO blood group system. Blood 88:2732–2737PubMedGoogle Scholar
  27. Olsson ML, Thuresson B, Chester MA (1995) An AEL allele-specific nucleotide insertion at the blood group ABO locus and its detection using a sequence-specific polymerase chain reaction. Biochem Biophys Res Commun 216:642–647PubMedCrossRefGoogle Scholar
  28. Olsson ML, Chester MA (1996) Evidence for a new type of O allele at the ABO locus, due to a combination of the A2 nucleotide deletion and the Ael nucleotide insertion. Vox Sang 71:113–117PubMedCrossRefGoogle Scholar
  29. Olsson ML, Santos SE, Guerreiro JF, Zago MA, Chester MA (1998) Heterogeneity of the O allele at the blood group ABO locus in Amerindians. Vox Sang 74:46–50PubMedCrossRefGoogle Scholar
  30. Olsson ML, Irshaid NM, Hosseini-Maaf B, Hellberg A, Moulds MK, Sareneva H, Chester MA (2001) Genomic analysis of clinical samples with serologic ABO blood grouping discrepancies: identification of 15 novel A and B subgroup alleles. Blood 98:1585–1593PubMedCrossRefGoogle Scholar
  31. Olson ML, Chester MA (2001) Polymorphism and recombination events at the ABO locus: a major challenge for genomic ABO blood grouping strategies. Transfu Med 11:295–313CrossRefGoogle Scholar
  32. Patenude SI, Seto NOL, Borisova SN, Szpacenko A, Marcus SL, Palcic MM, Evans S (2002) The structural basis for specificity in human ABO(H) blood group biosynthesis. Nature Struct Biol 9:685–690CrossRefGoogle Scholar
  33. Patnaik SK, Blumenfeld OO (2011) Patterns of human genetic variation inferred from comparative analysis of allelic mutations in blood group antigen genes. Hum Mutat 32:263–271PubMedCrossRefGoogle Scholar
  34. Patnaik SK, Helmberg W, Blumenfeld OO (2012) BGMUT: NCBI dbRBC database of allelic variations of genes encoding antigens of blood group systems. Nucleic Acids Res 40:D1023–D1029PubMedCentralPubMedCrossRefGoogle Scholar
  35. Persson M, Letts JA, Hosseini-Maaf H, Borisova SN, Palcic MM, Evans SV, Olsson ML (2007) Structural effects of naturally occurring human blood group B galactosyltransferase mutations adjacent to the DXD motif. J Biol Chem 282:9564–9570PubMedCrossRefGoogle Scholar
  36. Race RR, Sanger R (1975) Blood groups in man. Blackwell Scientific, OxfordGoogle Scholar
  37. Roubinet F, Javier D, Blancer A (2002) A novel cis AB allele derived from a B allele through a single point mutation. Transfusion 42:239–246PubMedCrossRefGoogle Scholar
  38. Schachter H, Michaels MA, Tilley CA, Crookston MC, Crookston JH (1973) Qualitative differences in the N-acetyl-d-galactosaminyltransferases produced by human Al and A2 genes. Proc Natl Acad Sci USA 70:220–224PubMedCrossRefGoogle Scholar
  39. Segurel L, Thompson EE, Flurte T, Lovstad J, Venkat A, Margulis SW, Moyse J, Ross S, Gamble K, Sella G, Ober C, Przeworski M (2012) The ABO blood group is a trans-species polymorphism in primates. Proc Natl Acad Sci USA 109:18493–18498PubMedCrossRefGoogle Scholar
  40. Seltsam A, Hallensleben M, Kollmann A, Blasczyk R (2003) The nature of diversity and diversification at the ABO locus. Blood 102:3035–3042PubMedCrossRefGoogle Scholar
  41. Seto NOL, Palcic MM, Compston CA, Li H, Bundle DR, Narang SA (1997) Sequential interchange of four amino acids from blood group B to blood group A glycosyltransferase boosts catalytic activity and progressively modifies substrate recognition in human recombinant enzymes. J Biol Chem 272:14133–14138PubMedCrossRefGoogle Scholar
  42. Storry JR, Olsson ML (2009) The ABO blood group system revisited: a review and update. Immunohematology 25:48–59PubMedGoogle Scholar
  43. Svensson L, Rydberg L, Hellberg A, Gilliver LG, Olsson ML, Henry SM (2005) Novel glycolipid variations revealed by monoclonal antibody immunochemical analysis of weak ABO subgroups of A. Vox Sang 89:27–38PubMedCrossRefGoogle Scholar
  44. Svensson L, Rydberg L, de Mattos LC, Henry SM (2009) Blood group A1 and A2 revisited: an immunochemical analysis. Vox Sang 96:56–61PubMedCrossRefGoogle Scholar
  45. Topping MD, Watkins WM (1975) Isoelectric points of the human blood group A1, A2 and B gene-associated glycosyltransferases in ovarian cyst fluids and serum. Biochem Biophys Res Commun 64:89–96PubMedCrossRefGoogle Scholar
  46. Turcot-Dubois AL, Le Moullac-Vaidye B, Despiau S, Roubinet F, Bovia N, Le Pendu J, Blancher A (2010) Long-term evolution of the CAZY glycosyltransferase 6 (ABO) gene family from fishes to mammals- a birth-and-death evolution model. Glycobiology 17:516–528CrossRefGoogle Scholar
  47. von Dungern E, Hirszfeld L (1911) Über gruppenspezifische Strukturen des Blutes: III Mitteilung. Z Immunitatsforsch Exp Ther 8:526–538Google Scholar
  48. Yamaguchi H, Okubo Y, Hazama F (1965) An A2B3 phenotype blood showing a typical mode of inheritance. Proc Jpn Acad Sci 41:316–320Google Scholar
  49. Yamaguchi H, Okubo Y, Tanaka M (1970) A rare blood B x analogous to A x in a Japanese family. Proc Jpn Acad Sci 46:446–449Google Scholar
  50. Yamamoto F, Clausen H, White T, Marken J, Hakomori S (1990) Molecular and genetic basis of the histo-blood group ABO system. Nature 345:229–233PubMedCrossRefGoogle Scholar
  51. Yamamoto F, McNeill PD, Hakomori S (1992) Human histo-blood group A2 transferase coded by A 2 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 187:366–374PubMedCrossRefGoogle Scholar
  52. Yamamoto F, McNeill PD, Kominato Y, Yamamoto M, Hakomori S, Ishimoto S, Nishida S, Shima M, Fujimura Y (1993a) Molecular genetic analysis of the ABO blood group system. 2. cis-AB alleles. Vox Sang 64:120–123PubMedCrossRefGoogle Scholar
  53. Yamamoto F, McNeill PD, Yamamoto M, Hakomori S, Bromilow IM, Duguid JKM (1993b) Molecular genetic analysis of the ABO blood group system. 4. Another type of O allele. Vox Sang 64:175–178PubMedCrossRefGoogle Scholar
  54. Yamamoto F, McNeill PD, Yamamoto M, Hakomori S, Harris T (1993c) Molecular genetic analysis of the ABO blood group system. 3. A x and B(A) alleles. Vox Sang 64:171–174PubMedCrossRefGoogle Scholar
  55. Yamamoto F, McNeill PD, Yamamoto M, Hakomori S, Harris T, Judd WJ, Davenport RD (l993d) Molecular genetic analysis of the ABO blood group system. 1. Weak sub-groups: A 3 and B3alleles. Vox Sang 64:116–119CrossRefGoogle Scholar
  56. Yamamoto F, Cid E, Yamamoto M, Blancher A (2012) ABO research in the modern era of genomics. Transfus Med Rev 26:103–118PubMedCrossRefGoogle Scholar
  57. Yazer MH, Denomme GA, Rose NL, Palcic MM (2005) Amino-acid substitution in the disordered loop of blood group B-glycosyltransferase enzyme causes weak B phenotype. Transfusion 45:1178–1182PubMedCrossRefGoogle Scholar
  58. Yazer MH, Olsson ML, Palcic MM (2006) The cis-AB blood group phenotype: fundamental lessons in glycobiology. Transfus Med Rev 20:207–217PubMedCrossRefGoogle Scholar
  59. Yazer MH, Olsson ML (2008) The O2 allele:questioning the phenotypic definition of an ABO allele. Immunohematology 24:138–47.PubMedGoogle Scholar
  60. Yip SP (2000) Single-tube multiplex PCR-SSCP analysis distinguishes 7 common ABO alleles and readily identifies new alleles. Blood 95:487–492Google Scholar
  61. Yip SP, Choi PS, Lee SY, Leung KH, El-Kawahri MM, Luqmani YA (2006) ABO blood group in Kuwaitis: detailed allele frequency distribution and identification of novel alleles. Transfusion 46:773–779PubMedCrossRefGoogle Scholar
  62. Yu Q, Deng ZH, Wu GG, Liang YL, Su YQ (2006) Novel A group allele with a 556>G substitution previously found in a B subgroup allele. Transfus Med 16:75–76PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Division of Biomembrane Research, Pacific Northwest Research Institute Departments of Microbiology and PathobiologyUniversity of WashingtonSeattleUSA
  2. 2.Carlsberg LaboratoryCopenhagen VDenmark

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