Glycophorin A

Glycophorin A (MNS blood group), also known as GYPA, is a protein which in humans is encoded by the GYPA gene.[3] GYPA has also recently been designated CD235a (cluster of differentiation 235a).

GYPA
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesGYPA, CD235a, GPA, GPErik, GPSAT, HGpMiV, HGpMiXI, HGpSta(C), MN, MNS, PAS-2, glycophorin A (MNS blood group)
External IDsOMIM: 617922 HomoloGene: 48076 GeneCards: GYPA
Orthologs
SpeciesHumanMouse
Entrez

2993

n/a

Ensembl

ENSG00000170180

n/a

UniProt

P02724

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RefSeq (mRNA)

NM_001308187
NM_001308190
NM_002099

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RefSeq (protein)

NP_001295116
NP_001295119
NP_002090

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Location (UCSC)Chr 4: 144.11 – 144.14 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Function

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.[3]

Genomics

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.

GypA can be found in all primates. GypB can be found only in gorillas and some of the higher primates suggesting that the duplication events occurred only recently.

Molecular biology

There are about one million copies of this protein per erythrocyte.[4]

Blood groups

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% Caucasoid; 74% Negroid
  • N: 72% Caucasoid; 75% Negroid
  • S: 55% Caucasoid; 31% Negroid
  • s: 89% Caucasoid; 93% Negroid

Molecular medicine

Transfusion medicine

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.[5] In chimpanzees M reacts strong but N only weakly.

Null mutants

In individuals who lack both glycophorin A and B the phenotype has been designated Mk.[6]

Dantu antigen

The Dantu antigen was described in 1984.[7] 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.[8] The Dantu phenotype occurs with a frequency of Dantu phenotype is ~0.005 in American Blacks and < 0.001 in Germans.[9]

Henshaw antigen

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[10] and 2.7% in West Africans.[11] At least 3 variants of this antigen have been identified.

Miltenberger subsystem

The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mia, Vw, Mur, Hil and Hut)[12] 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.[13][14] Mi-II is due to a mutation at amino acid 28 (threonine to lysine:C->A at nucleotide 83).[14] 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.[15] 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.[16] 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).[17] M-VIII shares the Anek determinant with MiVII.[18] 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).[19] Mil-IX in contrast is a reverse alpha-delta-alpha hybrid gene.[20] Mi-V, MiV(J.L.) and Sta are due to unequal but homologous crossing-over between alpha and delta glycophorin genes.[21] 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.

The incidence of Mi-I in Thailand is 9.7%.[22]

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[23][24][25]

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.[26]

Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark.[27]

Stone's antigen

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.

Sat antigen

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 antigen

Orriss (Or) appears to be a mutant of glycophorin A but its precise nature has not yet been determined.[28]

Mg antigen

The Mg antigen is carried on glycophorin A and lacks three O-glycolated side chains.[29]

Os antigen

Osa (MNS38) is due to a mutation at nucleotide 273 (C->T) lying within exon 3 resulting in the replacement of a proline residue with a serine.[30]

Ny antigen

Nya (MNS18) is due to a mutation at nucleotide 194 (T->A) which results in the substitution of an aspartate residue with a glutamate.[30]

Reactions

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.[31] Raddon has been associated with severe transfusion reactions.[32]

Relevance for infection

The Wright b antigen (Wrb) is located on glycophorin A and acts as a receptor for the malaria parasite Plasmodium falciparum.[33] Cells lacking glycophorins A (Ena) are resistant to invasion by this parasite.[34] The erythrocyte binding antigen 175 of P. falciparum recognises the terminal Neu5Ac(alpha 2-3)Gal-sequences of glycophorin A.[35]

Several viruses bind to glycophorin A including hepatitis A virus (via its capsid),[36] bovine parvovirus,[37] Sendai virus,[38] influenza A and B,[39] group C rotavirus,[40] encephalomyocarditis virus[41] and reoviruses.[42]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000170180 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Entrez Gene: GYPA glycophorin A (MNS blood group)".
  4. Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 12, The MNS blood group. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2274/
  5. 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. S2CID 23990336.
  6. 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". European Journal of Immunogenetics. 6 (6): 383–90. doi:10.1111/j.1744-313X.1979.tb00693.x. PMID 521666. S2CID 21109436.
  7. 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. S2CID 10869726.
  8. 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. S2CID 21559983.
  9. 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. S2CID 10130228.
  10. 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. S2CID 2642482.
  11. 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.
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  13. 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. doi:10.1182/blood.V80.1.257.257. PMID 1611092.
  14. 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.
  15. 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. doi:10.1042/bj2130399. PMC 1152141. PMID 6615443.
  16. 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.
  17. 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.
  18. 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. S2CID 27162982.
  19. 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. doi:10.1016/S0021-9258(20)89637-9. PMID 2016325.
  20. 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. doi:10.1182/blood.V80.9.2379.2379. PMID 1421409.
  21. 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. doi:10.1182/blood.V77.8.1813.1813. PMID 2015404.
  22. 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. S2CID 7483916.
  23. 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.
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  25. 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
  26. 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. S2CID 38287351.
  27. 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. S2CID 24337520.
  28. 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. S2CID 36810910.
  29. 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. S2CID 83905143.
  30. 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. S2CID 6891686.
  31. 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. S2CID 33092281.
  32. 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. S2CID 39840648.
  33. 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. doi:10.1042/bj2090273. PMC 1154085. PMID 6342608.
  34. 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.
  35. 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.
  36. 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.
  37. Thacker TC, Johnson FB (September 1998). "Binding of bovine parvovirus to erythrocyte membrane sialylglycoproteins". J. Gen. Virol. 79. 79 ( Pt 9) (9): 2163–9. doi:10.1099/0022-1317-79-9-2163. PMID 9747725.
  38. 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.
  39. 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.
  40. Svensson L (September 1992). "Group C rotavirus requires sialic acid for erythrocyte and cell receptor binding". J. Virol. 66 (9): 5582–5. doi:10.1128/JVI.66.9.5582-5585.1992. PMC 289118. PMID 1380096.
  41. 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.
  42. 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.

Further reading

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