Glycophorin B (MNS blood group) (gene designation GYPB) also known as sialoglycoprotein delta and SS-active sialoglycoprotein is a protein which in humans is encoded by the GYPB gene. GYPB has also recently been designated CD235b (cluster of differentiation 235b).
Glycophorin A (GYPA) and B (GYPB; this protein) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups respectively. 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 the Miltenberger (Mi) complex and several isoforms of Stones (Sta); also Dantu, Sat, Henshaw (He or MNS6), Mg and deletion variants Ena, S-s-U- and Mk. Most of these are the result of gene recombinations between GYPA and GYPB.
The gene has 97% sequence homology with the glycophorin A gene from the 5' UTR approximately 1 kilobase upstream from the exon encoding the transmembrane regions to the portion of the coding sequence encoding the first 45 amino acids. There is a signal sequence of 19 amino acid residues. The leader peptide differs by one amino acid and the next 26 amino acids are identical. Amino acids 27-55 of glycophorin A are absent from glycophorin B. This section includes an N-glycosylation site. Only O-glycosylation sites are found on glycoprotein B and these are linked via serine or threonine. Residues 80-100 of glycophorin A and 51-71 of glycophorin B are very similar. The intervening residues in contrast differ significantly. The antigenic determinant for the blood group Ss is located at residue 29 where S has a methionine and s a threonine. This is due to a mutation at nucleotide 143 (C->T). The S antigen is also known as MSN3 and the s antigen as MNS4.
It seems likely that this gene evolved by gene duplication and subsequent mutation of glycophorin A. The transition site from homologous to nonhomologous sequences can be localized within Alu repeat sequences.
There are ~80000 copies of glycophorin B per erythrocyte. Both glycophorin A and B are expressed on the renal endothelium and epithelium.
The first 40 amino acids of the mature protein are extracellular. The next 22 form a transmembrane segment and the remainder are intra cellular.
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)
Glycophorin B carries the blood group antigens N, Ss and U. Both glycophorin A and B bind the Vicia graminea anti-N lectin. S and s antigens are not affected by treatment with trypsin or sialidase but are destroyed or much depressed by treatment with papain, pronase or alpha-chymotrypsin.
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 Mv, Dantu, Henshaw (He), Orriss (Or), Miltenberger, Raddon (FR) and Stones (Sta). Chimpanzees also have an MN blood antigen system. In chimpanzees M reacts strong but N only weakly.
Individuals who lack GypB have the phenotype S-s-U-. This may occur at frequencies of 20% in some African pygmies.
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 glycosylation 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.
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.
Both anti-S and anti-s have been implicated in transfusion reactions and haemolytic disease of the newborn. 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-U and 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.
Glycophorin B acts as a receptor for erythrocyte binding Ligand (EBl-1) of Plasmodium falciparum involved in malaria. Both the Dantu and the S-s-U- cells phenotypes have been shown to be protective against P. falciparum infection while the Henshaw phenotype is not protective.
Influenza A and B bind to glycophorin B.
- "Entrez Gene: GYPB glycophorin B (MNS blood group)".
- Siebert PD, Fukuda M (October 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Dolan SA, Proctor JL, Alling DW, Okubo Y, Wellems TE, Miller LH (March 1994). "Glycophorin B as an EBA-175 independent Plasmodium falciparum receptor of human erythrocytes". Mol. Biochem. Parasitol. 64 (1): 55–63. doi:10.1016/0166-6851(94)90134-1. PMID 8078523.
- Field SP, Hempelmann E, Mendelow BV, Fleming AF (February 1994). "Glycophorin variants and Plasmodium falciparum: protective effect of the Dantu phenotype in vitro". Hum. Genet. 93 (2): 148–50. doi:10.1007/BF00210600. PMID 8112738.
- Facer CA (1983). "Erythrocyte sialoglycoproteins and Plasmodium falciparum invasion". Trans. R. Soc. Trop. Med. Hyg. 77 (4): 524–30. doi:10.1016/0035-9203(83)90130-X. PMID 6356506.
- 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.
- 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.
- Rearden A, Phan H, Dubnicoff T, et al. (1990). "Identification of the crossing-over point of a hybrid gene encoding human glycophorin variant Sta. Similarity to the crossing-over point in haptoglobin-related genes". J. Biol. Chem. 265 (16): 9259–63. PMID 1971625.
- 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.
- Kudo S, Fukuda M (1990). "Identification of a novel human glycophorin, glycophorin E, by isolation of genomic clones and complementary DNA clones utilizing polymerase chain reaction". J. Biol. Chem. 265 (2): 1102–10. PMID 2295603.
- 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.
- 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.
- 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.
- Blanchard D, Dahr W, Hummel M, et al. (1987). "Glycophorins B and C from human erythrocyte membranes. Purification and sequence analysis". J. Biol. Chem. 262 (12): 5808–11. PMID 3571235.
- Dahr W, Beyreuther K, Moulds J, Unger P (1987). "Hybrid glycophorins from human erythrocyte membranes. I. Isolation and complete structural analysis of the hybrid sialoglycoprotein from Dantu-positive red cells of the N.E. variety". Eur. J. Biochem. 166 (1): 31–6. doi:10.1111/j.1432-1033.1987.tb13479.x. PMID 3595615.
- Onda M, Fukuda M (1995). "Detailed physical mapping of the genes encoding glycophorins A, B and E, as revealed by P1 plasmids containing human genomic DNA". Gene. 159 (2): 225–30. doi:10.1016/0378-1119(95)00075-H. PMID 7622054.
- Kudo S, Onda M, Fukuda M (1995). "Characterization of glycophorin A transcripts: control by the common erythroid-specific promoter and alternative usage of different polyadenylation signals". J. Biochem. 116 (1): 183–92. PMID 7798177.
- Rahuel C, Elouet JF, Cartron JP (1995). "Post-transcriptional regulation of the cell surface expression of glycophorins A, B, and E.". J. Biol. Chem. 269 (52): 32752–8. PMID 7806496.
- Huang CH, Reid ME, Blumenfeld OO (1994). "Remodeling of the transmembrane segment in human glycophorin by aberrant RNA splicing". J. Biol. Chem. 269 (14): 10804–12. PMID 8144668.
- Huang CH, Lomas C, Daniels G, Blumenfeld OO (1994). "Glycophorin He(Sta) of the human red blood cell membrane is encoded by a complex hybrid gene resulting from two recombinational events". Blood. 83 (11): 3369–76. PMID 8193374.
- Huang CH, Reid ME, Blumenfeld OO (1993). "Exon skipping caused by DNA recombination that introduces a defective donor splice site into the human glycophorin A gene". J. Biol. Chem. 268 (7): 4945–52. PMID 8444872.
- Cherif-Zahar B, Raynal V, Gane P, et al. (1996). "Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency". Nat. Genet. 12 (2): 168–73. doi:10.1038/ng0296-168. PMID 8563755.