Glycophorins A (GYPA; this protein) and B (GYPB) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups. In addition to the M or N and S or s antigens, that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include all the variants of the Miltenberger complex and several isoforms of Sta; also, Dantu, Sat, He, Mg, and deletion variants Ena, S-s-U- and Mk. Most of the variants are the result of gene recombinations between GYPA and GYPB.
GypA, GypB and GypE are members of the same family and are located on the long arm of chromosome 4 (chromosome 4q31). The family evolved via two separate gene duplication events. The initial duplication gave rise to two genes one of subsequently evolved into GypA and the other which give rise via a second duplication event to GypB and GypE. These events appear to have occurred within a relatively short time span. The second duplication appears to have occurred via an unequal crossing over event.
The GypA gene itself consists of 7 exons and has 97% sequence homology with GypB and GypE from the 5' untranslated transcription region (UTR) to the coding sequence encoding the first 45 amino acids. The exon at this point encodes the transmembrane domain. Within the intron downstream of this pint is an Alu repeat. The cross over event which created the genes ancestral to GypA and GypB/E occurred within this region.
There are about one million copies of this protein per erythrocyte. [Reference needed]
The MNS blood group was the second set of antigens discovered. M and N were identified in 1927 by Landsteiner and Levine. S and s in were described later in 1947.
The frequencies of these antigens are
- M: 78% Caucasian; 74% Negroid
- N: 72% Caucasian; 75% Negroid
- S: 55% Caucasian; 31% Negroid
- s: 89% Caucasian; 93% Negroid
The M and N antigens differ at two amino acid residues: the M allele has serine at position 1 (C at nucleotide 2) and glycine at position 5 (G at nucleotide 14) while the N allele has leucine at position 1 (T at nucleotide 2) and glutamate at position 5 (A at nucleotide 14). Both glycophorin A and B bind the Vicia graminea anti-N lectin.
There are about 40 known variants in the MNS blood group system. These have arisen largely as a result of mutations within the 4 kb region coding for the extracellular domain. These include the antigens Mg, Dantu, Henshaw (He), Miltenberger, Nya, Osa, Orriss (Or), Raddon (FR) and Stones (Sta). Chimpanzees also have an MN blood antigen system. In chimpanzees M reacts strong but N only weakly.
In individuals who lack both glycophorin A and B the phenotype has been designated Mk.
The Dantu antigen was described in 1984. The Dantu antigen has an apparent molecular weight of 29 kiloDaltons (kDa) and 99 amino acids. The first 39 amino acids of the Dantu antigen are derived from glycophorin B and residues 40-99 are derived from glycophorin A. Dantu is associated with very weak s antigen, a protease-resistant N antigen and either very weak or no U antigen. There are at least three variants: MD, NE and Ph. The Dantu phenotype occurs with a frequency of Dantu phenotype is ~0.005 in American Blacks and < 0.001 in Germans.
The Henshaw (He) antigen is due to a mutation of the N terminal region. There are three differences in the first three amino acid residues: the usual form has Tryptophan1-Serine-Threonine-Serine-Glycine5 while Henshaw has Leucine1-Serine-Threonine-Threonine-Glutamate5. This antigen is rare in Caucasians but occurs at a frequency of 2.1% in US and UK of African origin. It occurs at the rate of 7.0% in blacks in Natal and 2.7% in West Africans. At least 3 variants of this antigen have been identified.
The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mia, Vw, Mur, Hil and Hut) now has 11 recognised phenotypes numbered I to XI (The antigen 'Mur' is named after to the patient the original serum was isolated from - a Mrs Murrel.) The name originally given to this complex refers to the reaction erythrocytes gave to the standard Miltenberger antisera used to test them. The subclasses were based on additional reactions with other standard antisera.
Mi-I (Mia), Mi-II(Vw), Mi-VII and Mi-VIII are carried on glycophorin A. Mi-I is due to a mutation at amino acid 28 (threonine to methionine: C→T at nucleotide 83) resulting in a loss of the glycosylation at the asparagine26 residue. Mi-II is due to a mutation at amino acid 28 (threonine to lysine:C->A at nucleotide 83). Similar to the case of Mi-I this mutation results in a loss of the glycosylation at the asparagine26 residue. This alteration in glycoslation is detectable by the presence of a new 32kDa glycoprotein stainable with PAS. Mi-VII is due to a double mutation in glycophorin A converting an arginine residue into a threonine residue and a tyrosine residue into a serine at the positions 49 and 52 respectively. The threonine-49 residue is glycosylated. This appears to be the origin of one of the Mi-VII specific antigens (Anek) which is known to lie between residues 40-61 of glycophorin A and comprises sialic acid residue(s) attached to O-glycosidically linked oligosaccharide(s). This also explains the loss of a high frequency antigen ((EnaKT)) found in normal glycophorin A which is located within the residues 46-56. Mi-VIII is due to a mutation at amino acid residue 49 (arginine->threonine). M-VIII shares the Anek determinant with MiVII. Mi-III, Mi-VI and Mi-X are due to rearrangements of glycophorin A and B in the order GlyA (alpha)-GlyB (delta)-GlyA (alpha). Mil-IX in contrast is a reverse alpha-delta-alpha hybrid gene. Mi-V, MiV(J.L.) and Sta are due to unequal but homologous crossing-over between alpha and delta glycophorin genes. The MiV and MiV(J.L.) genes are arranged in the same 5' alpha-delta 3' frame whereas Sta gene is in a reciprocal 5'delta-alpha 3' configuration.
Peptide constructs representative of Mia mutations MUT and MUR have been attached onto red blood cells (known as kodecytes) and are able to detect antibodies against these Miltenberger antigens
Although uncommon in Caucasians (0.0098%) and Japanese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwanese aboriginal tribes (up to 90%). In contrast its frequency is 2-3% in Han Taiwanese (Minnan). The Mi-III phenotype occurs in 6.28% of Hong Kong Chinese.
Stones (Sta) has been shown to be the product of a hybrid gene of which the 5'-half is derived from the glycophorin B whereas the 3'-half is derived from the glycophorin A. Several isoforms are known. This antigen is now considered to be part of the Miltenberger complex.
A related antigen is Sat. This gene has six exons of which exon I to exon IV are identical to the N allele of glycophorin A whereas its 3' portion, including exon V and exon VI, are derived from the glycophorin B gene. The mature protein SAT protein contains 104 amino acid residues.
Orriss (Or) appears to be a mutant of glyphorin A but its precise nature has not yet been determined.
The Mg antigen is carried on glycophorin A and lacks three O-glycolated side chains.
Anti-M although occurring naturally has rarely been implicated in transfusion reactions. Anti-N is not considered to cause transfusion reactions. Severe reactions have been reported with anti-Miltenberger. Anti Mi-I (Vw) and Mi-III has been recognised as a cause of haemolytic disease of the newborn. Raddon has been associated with severe transfusion reactions.
Relevance for infection
The Wright b antigen (Wrb) is located on glycophorin A and acts as a receptor for the malaria parasite Plasmodium falciparum. Cells lacking glycophorins A (Ena) are resistant to invasion by this parasite.
The erythrocyte binding antigen 175 of P. falciparum recognises the terminal Neu5Ac(alpha 2-3)Gal-sequences of glycophorin A.
- "Entrez Gene: GYPA glycophorin A (MNS blood group)".
- Blumenfeld OO, Adamany AM, Puglia KV, Socha WW (April 1983). "The chimpanzee M blood-group antigen is a variant of the human M-N glycoproteins". Biochem. Genet. 21 (3–4): 333–48. doi:10.1007/BF00499143. PMID 6860297.
- Tokunaga E, Sasakawa S, Tamaka K, Kawamata H, Giles CM, Ikin EW, Poole J, Anstee DJ, Mawby W, Tanner MJ (December 1979). "Two apparently healthy Japanese individuals of type MkMk have erythrocytes which lack both the blood group MN and Ss-active sialoglycoproteins". J. Immunogenet. 6 (6): 383–90. doi:10.1111/j.1744-313X.1979.tb00693.x. PMID 521666.
- Contreras M, Green C, Humphreys J, Tippett P, Daniels G, Teesdale P, Armitage S, Lubenko A (1984). "Serology and genetics of an MNSs-associated antigen Dantu". Vox Sang. 46 (6): 377–86. doi:10.1111/j.1423-0410.1984.tb00102.x. PMID 6431691.
- Dahr W, Pilkington PM, Reinke H, Blanchard D, Beyreuther K (May 1989). "A novel variety of the Dantu gene complex (DantuMD) detected in a Caucasian". Blut. 58 (5): 247–53. doi:10.1007/BF00320913. PMID 2470445.
- Unger P, Procter JL, Moulds JJ, Moulds M, Blanchard D, Guizzo ML, McCall LA, Cartron JP, Dahr W (July 1987). "The Dantu erythrocyte phenotype of the NE variety. II. Serology, immunochemistry, genetics, and frequency". Blut. 55 (1): 33–43. doi:10.1007/BF00319639. PMID 3607294.
- Reid ME, Lomas-Francis C, Daniels GL, Chen V, Shen J, Ho YC, Hare V, Batts R, Yacob M, Smart E (1995). "Expression of the erythrocyte antigen Henshaw (He; MNS6): serological and immunochemical studies". Vox Sang. 68 (3): 183–6. doi:10.1111/j.1423-0410.1995.tb03924.x. PMID 7625076.
- Chalmers JN, Ikin EW, Mourant AE (July 1953). "A study of two unusual blood-group antigens in West Africans". Br Med J. 2 (4829): 175–7. doi:10.1136/bmj.2.4829.175. PMC 2028931. PMID 13059432.
- Cleghorn TE (1966). "A memorandum on the Miltenberger blood groups". Vox Sang. 11 (2): 219–22. doi:10.1111/j.1423-0410.1966.tb04226.x. PMID 5955790.
- Huang CH, Spruell P, Moulds JJ, Blumenfeld OO (July 1992). "Molecular basis for the human erythrocyte glycophorin specifying the Miltenberger class I (MiI) phenotype". Blood. 80 (1): 257–63. PMID 1611092.
- Dahr W, Newman RA, Contreras M, Kordowicz M, Teesdale P, Beyreuther K, Krüger J (January 1984). "Structures of Miltenberger class I and II specific major human erythrocyte membrane sialoglycoproteins". Eur. J. Biochem. 138 (2): 259–65. doi:10.1111/j.1432-1033.1984.tb07910.x. PMID 6697986.
- Blanchard D, Asseraf A, Prigent MJ, Cartron JP (August 1983). "Miltenberger Class I and II erythrocytes carry a variant of glycophorin A". Biochem. J. 213 (2): 399–404. PMC 1152141. PMID 6615443.
- Dahr W, Beyreuther K, Moulds JJ (July 1987). "Structural analysis of the major human erythrocyte membrane sialoglycoprotein from Miltenberger class VII cells". Eur. J. Biochem. 166 (1): 27–30. doi:10.1111/j.1432-1033.1987.tb13478.x. PMID 2439339.
- Dahr W, Vengelen-Tyler V, Dybkjaer E, Beyreuther K (August 1989). "Structural analysis of glycophorin A from Miltenberger class VIII erythrocytes". Biol. Chem. Hoppe-Seyler. 370 (8): 855–9. doi:10.1515/bchm3.1989.370.2.855. PMID 2590469.
- Dybkjaer E, Poole J, Giles CM (1981). "A new Miltenberger class detected by a second example of Anek type serum". Vox Sang. 41 (5–6): 302–5. doi:10.1111/j.1423-0410.1981.tb01053.x. PMID 6172902.
- Huang CH, Blumenfeld OO (April 1991). "Molecular genetics of human erythrocyte MiIII and MiVI glycophorins. Use of a pseudoexon in construction of two delta-alpha-delta hybrid genes resulting in antigenic diversification". J. Biol. Chem. 266 (11): 7248–55. PMID 2016325.
- Huang CH, Skov F, Daniels G, Tippett P, Blumenfeld OO (November 1992). "Molecular analysis of human glycophorin MiIX gene shows a silent segment transfer and untemplated mutation resulting from gene conversion via sequence repeats". Blood. 80 (9): 2379–87. PMID 1421409.
- Huang CH, Blumenfeld OO (April 1991). "Identification of recombination events resulting in three hybrid genes encoding human MiV, MiV(J.L.), and Sta glycophorins". Blood. 77 (8): 1813–20. PMID 2015404.
- Chandanyingyong D, Pejrachandra S (1975). "Studies on the Miltenberger complex frequency in Thailand and family studies". Vox Sang. 28 (2): 152–5. doi:10.1111/j.1423-0410.1975.tb02753.x. PMID 1114793.
- Heathcote D, Flower R, Henry S (2008). "Development of novel alloantibody screening cells – the first example of the addition of peptide antigens to human red cells using KODE technology. ISBT Regional Congress, Macao SAR China, 2008". (P-303)". Vox Sanguinis. 95 (Suppl 1): 174.
- Heathcote D, Carroll T, Wang JJ, Flower R, Rodionov I, Tuzikov A, Bovin N & Henry S. Novel antibody screening cells, MUT+Mur kodecytes, created by attaching peptides onto erythrocytes. Transfusion 2010;50:635-641
- Flower R, Lin P-H, Heathcote D, Chan M, Teo D, Selkirk A, Shepherd R, Henry S. Insertion of KODE peptide constructs into red cell membranes: Creating artificial variant MNS blood group antigens. ISBT Regional Congress, Macao SAR China, 2008. (P-396) Vox Sanguinis 2008; 95:Suppl 1, 203-204
- Mak KH, Banks JA, Lubenko A, Chua KM, Torres de Jardine AL, Yan KF (March 1994). "A survey of the incidence of Miltenberger antibodies among Hong Kong Chinese blood donors". Transfusion. 34 (3): 238–41. doi:10.1046/j.1537-2995.1994.34394196622.x. PMID 8146897.
- Skov F, Green C, Daniels G, Khalid G, Tippett P (1991). "Miltenberger class IX of the MNS blood group system". Vox Sang. 61 (2): 130–6. doi:10.1111/j.1423-0410.1991.tb00258.x. PMID 1722368.
- Bacon JM, Macdonald EB, Young SG, Connell T (1987). "Evidence that the low frequency antigen Orriss is part of the MN blood group system". Vox Sang. 52 (4): 330–4. doi:10.1111/j.1423-0410.1987.tb04902.x. PMID 2442891.
- Green C, Daniels G, Skov F, Tippett P (1994). "Mg+ MNS blood group phenotype: further observations". Vox Sang. 66 (3): 237–41. doi:10.1111/j.1423-0410.1994.tb00316.x. PMID 8036795.
- Daniels GL, Bruce LJ, Mawby WJ, Green CA, Petty A, Okubo Y, Kornstad L, Tanner MJ (May 2000). "The low-frequency MNS blood group antigens Ny(a) (MNS18) and Os(a) (MNS38) are associated with GPA amino acid substitutions". Transfusion. 40 (5): 555–9. doi:10.1046/j.1537-2995.2000.40050555.x. PMID 10827258.
- Rearden A, Frandson S, Carry JB (1987). "Severe hemolytic disease of the newborn due to anti-Vw and detection of glycophorin A antigens on the Miltenberger I sialoglycoprotein by Western blotting". Vox Sang. 52 (4): 318–21. doi:10.1111/j.1423-0410.1987.tb04900.x. PMID 2442890.
- Baldwin ML, Barrasso C, Gavin J (1981). "The first example of a Raddon-like antibody as a cause of a transfusion reaction". Transfusion. 21 (1): 86–9. doi:10.1046/j.1537-2995.1981.21181127491.x. PMID 7466911.
- Ridgwell K, Tanner MJ, Anstee DJ (January 1983). "The Wrb antigen, a receptor for Plasmodium falciparum malaria, is located on a helical region of the major membrane sialoglycoprotein of human red blood cells". Biochem. J. 209 (1): 273–6. PMC 1154085. PMID 6342608.
- Facer CA (November 1983). "Merozoites of P. falciparum require glycophorin for invasion into red cells". Bull Soc Pathol Exot Filiales. 76 (5): 463–9. PMID 6370471.
- Orlandi PA, Klotz FW, Haynes JD (February 1992). "A malaria invasion receptor, the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum recognizes the terminal Neu5Ac(alpha 2-3)Gal- sequences of glycophorin A". J. Cell Biol. 116 (4): 901–9. doi:10.1083/jcb.116.4.901. PMC 2289329. PMID 1310320.
- Sánchez G, Aragonès L, Costafreda MI, Ribes E, Bosch A, Pintó RM (September 2004). "Capsid region involved in hepatitis A virus binding to glycophorin A of the erythrocyte membrane". J. Virol. 78 (18): 9807–13. doi:10.1128/JVI.78.18.9807-9813.2004. PMC 514964. PMID 15331714.
- Thacker TC, Johnson FB (September 1998). "Binding of bovine parvovirus to erythrocyte membrane sialylglycoproteins". J. Gen. Virol. 79. ( Pt 9): 2163–9. PMID 9747725.
- Wybenga LE, Epand RF, Nir S, Chu JW, Sharom FJ, Flanagan TD, Epand RM (July 1996). "Glycophorin as a receptor for Sendai virus". Biochemistry. 35 (29): 9513–8. doi:10.1021/bi9606152. PMID 8755731.
- Ohyama K, Endo T, Ohkuma S, Yamakawa T (May 1993). "Isolation and influenza virus receptor activity of glycophorins B, C and D from human erythrocyte membranes". Biochim. Biophys. Acta. 1148 (1): 133–8. doi:10.1016/0005-2736(93)90170-5. PMID 8499461.
- Svensson L (September 1992). "Group C rotavirus requires sialic acid for erythrocyte and cell receptor binding". J. Virol. 66 (9): 5582–5. PMC 289118. PMID 1380096.
- Tavakkol A, Burness AT (November 1990). "Evidence for a direct role for sialic acid in the attachment of encephalomyocarditis virus to human erythrocytes". Biochemistry. 29 (47): 10684–90. doi:10.1021/bi00499a016. PMID 2176879.
- Paul RW, Lee PW (July 1987). "Glycophorin is the reovirus receptor on human erythrocytes". Virology. 159 (1): 94–101. doi:10.1016/0042-6822(87)90351-5. PMID 3604060.
- Blumenfeld OO, Huang CH (1996). "Molecular genetics of the glycophorin gene family, the antigens for MNSs blood groups: multiple gene rearrangements and modulation of splice site usage result in extensive diversification". Hum. Mutat. 6 (3): 199–209. doi:10.1002/humu.1380060302. PMID 8535438.
- Blumenfeld OO, Huang CH (1997). "Molecular genetics of glycophorin MNS variants". Transfusion clinique et biologique : journal de la Société française de transfusion sanguine. 4 (4): 357–65. doi:10.1016/s1246-7820(97)80041-9. PMID 9269716.
- Johnson ST, McFarland JG, Kelly KJ, et al. (2002). "Transfusion support with RBCs from an Mk homozygote in a case of autoimmune hemolytic anemia following diphtheria-pertussis-tetanus vaccination". Transfusion. 42 (5): 567–71. doi:10.1046/j.1537-2995.2002.00093.x. PMID 12084164.
- Tomita M, Marchesi VT (1976). "Amino-acid sequence and oligosaccharide attachment sites of human erythrocyte glycophorin". Proc. Natl. Acad. Sci. U.S.A. 72 (8): 2964–8. doi:10.1073/pnas.72.8.2964. PMC 432899. PMID 1059087.
- Lemmon MA, Flanagan JM, Hunt JF, et al. (1992). "Glycophorin A dimerization is driven by specific interactions between transmembrane alpha-helices". J. Biol. Chem. 267 (11): 7683–9. PMID 1560003.
- Huang CH, Spruell P, Moulds JJ, Blumenfeld OO (1992). "Molecular basis for the human erythrocyte glycophorin specifying the Miltenberger class I (MiI) phenotype". Blood. 80 (1): 257–63. PMID 1611092.
- Huang CH, Kikuchi M, McCreary J, Blumenfeld OO (1992). "Gene conversion confined to a direct repeat of the acceptor splice site generates allelic diversity at human glycophorin (GYP) locus". J. Biol. Chem. 267 (5): 3336–42. PMID 1737789.
- Barton P, Collins A, Hoogenraad N (1991). "A variant of glycophorin A resulting from the deletion of exon 4". Biochim. Biophys. Acta. 1090 (2): 265–6. doi:10.1016/0167-4781(91)90115-3. PMID 1932122.
- Huang CH, Blumenfeld OO (1991). "Identification of recombination events resulting in three hybrid genes encoding human MiV, MiV(J.L.), and Sta glycophorins". Blood. 77 (8): 1813–20. PMID 2015404.
- Huang CH, Blumenfeld OO (1991). "Molecular genetics of human erythrocyte MiIII and MiVI glycophorins. Use of a pseudoexon in construction of two delta-alpha-delta hybrid genes resulting in antigenic diversification". J. Biol. Chem. 266 (11): 7248–55. PMID 2016325.
- Hamid J, Burness AT (1990). "The mechanism of production of multiple mRNAs for human glycophorin A." Nucleic Acids Res. 18 (19): 5829–36. doi:10.1093/nar/18.19.5829. PMC 332322. PMID 2216775.
- Dill K, Hu SH, Berman E, et al. (1990). "One- and two-dimensional NMR studies of the N-terminal portion of glycophorin A at 11.7 Tesla". J. Protein Chem. 9 (2): 129–36. doi:10.1007/BF01025303. PMID 2386609.
- Kudo S, Fukuda M (1989). "Structural organization of glycophorin A and B genes: glycophorin B gene evolved by homologous recombination at Alu repeat sequences". Proc. Natl. Acad. Sci. U.S.A. 86 (12): 4619–23. doi:10.1073/pnas.86.12.4619. PMC 287322. PMID 2734312.
- Matsui Y, Natori S, Obinata M (1989). "Isolation of the cDNA clone for mouse glycophorin, erythroid-specific membrane protein". Gene. 77 (2): 325–32. doi:10.1016/0378-1119(89)90080-2. PMID 2753361.
- Vignal A, Rahuel C, el Maliki B, et al. (1989). "Molecular analysis of glycophorin A and B gene structure and expression in homozygous Miltenberger class V (Mi. V) human erythrocytes". Eur. J. Biochem. 184 (2): 337–44. doi:10.1111/j.1432-1033.1989.tb15024.x. PMID 2792104.
- Tate CG, Tanner MJ (1988). "Isolation of cDNA clones for human erythrocyte membrane sialoglycoproteins alpha and delta". Biochem. J. 254 (3): 743–50. PMC 1135146. PMID 3196288.
- Huang CH, Puglia KV, Bigbee WL, et al. (1989). "A family study of multiple mutations of alpha and delta glycophorins (glycophorins A and B)". Hum. Genet. 81 (1): 26–30. doi:10.1007/BF00283724. PMID 3198123.
- Rahuel C, London J, d'Auriol L, et al. (1988). "Characterization of cDNA clones for human glycophorin A. Use for gene localization and for analysis of normal of glycophorin-A-deficient (Finnish type) genomic DNA". Eur. J. Biochem. 172 (1): 147–53. doi:10.1111/j.1432-1033.1988.tb13866.x. PMID 3345758.
- Siebert PD, Fukuda M (1986). "Isolation and characterization of human glycophorin A cDNA clones by a synthetic oligonucleotide approach: nucleotide sequence and mRNA structure". Proc. Natl. Acad. Sci. U.S.A. 83 (6): 1665–9. doi:10.1073/pnas.83.6.1665. PMC 323144. PMID 3456608.
- Siebert PD, Fukuda M (1987). "Molecular cloning of a human glycophorin B cDNA: nucleotide sequence and genomic relationship to glycophorin A." Proc. Natl. Acad. Sci. U.S.A. 84 (19): 6735–9. doi:10.1073/pnas.84.19.6735. PMC 299158. PMID 3477806.
- GYPA+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Cartoon of glycophorin A - http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/Glycoproteins.html