GYPA
Encyclopedia
Glycophorin A, also known as GYPA, is a protein
which in humans is encoded by the GYPA gene
. GYPA has also recently been designated CD235a (cluster of differentiation
235a).
) 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.
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 gorilla
s and some of the higher primates suggesting that the duplication events occurred only recently.
The frequencies of these antigens are
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, Henwshaw (He), Miltenberger, Nya, Osa, Orriss (Or), Raddon (FR) and Stones (Sta). Chimpanzee
s also have an MN blood antigen system. In chimpanzees M reacts strong but N only weakly.
1-Serine-Threonine-Serine-Glycine
5 while Henshaw has Leucine
1-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.
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 asparagine
26 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 deteminant 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.
The incidence of Mi-I in Thailand
is 9.7%.
Peptide constructs representative of Mia mutations MUT and MUR have been attached onto red blood cells (known as kodecyte
s) and are able to detect antibodies against these Miltenberger antigens
Although uncommon in Caucasians (0.0098%) and Japan
ese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwan
ese 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.
Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark
.
residue with a serine
.
. 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.
Several viruses bind to glycophorin A including virus (via its capsid), bovine , , and , group C , and es.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the GYPA gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. GYPA has also recently been designated CD235a (cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
235a).
Function
Glycophorins A (GYPA; this protein) and B (GYPBGYPB
Glycophorin B also known as sialoglycoprotein delta and SS-active sialoglycoprotein is a protein which in humans is encoded by the GYPB gene...
) 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.
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
Alû
Alû is one of the Utukku, vengeful spirits in the lore of the ancient Assyrians.Stephen Herbert Langdon cites a translation of a cuneiform script by Major-General Sir H. C. Rawlinson. From v Pl. 50, A, line 42: "Whom in his bed the wicked Alû covered,/Whom the wicked ghost by night overwhelmed"...
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 gorilla
Gorilla
Gorillas are the largest extant species of primates. They are ground-dwelling, predominantly herbivorous apes that inhabit the forests of central Africa. Gorillas are divided into two species and either four or five subspecies...
s and some of the higher primates suggesting that the duplication events occurred only recently.
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% CaucasianWhite peopleWhite people is a term which usually refers to human beings characterized, at least in part, by the light pigmentation of their skin...
; 74% Negroid - N: 72% Caucasian; 75% Negroid
- S: 55% Caucasian; 31% Negroid
- s: 89% Caucasian; 93% Negroid
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, Henwshaw (He), Miltenberger, Nya, Osa, Orriss (Or), Raddon (FR) and Stones (Sta). Chimpanzee
Chimpanzee
Chimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s also have an MN blood antigen system. 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.Dantu antigen
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.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 TryptophanTryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
1-Serine-Threonine-Serine-Glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
5 while Henshaw has Leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
1-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
Natal, South Africa
Natal is a region in South Africa. It stretches between the Indian Ocean in the south and east, the Drakensberg in the west, and the Lebombo Mountains in the north. The main cities are Pietermaritzburg and Durban...
and 2.7% in West Africans. 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) 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
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
:C->A at nucleotide 83). Similar to the case of Mi-I this mutation results in a loss of the glycosylation at the asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
26 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
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
residue into a threonine residue and a tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
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
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
->threonine). M-VIII shares the Anek deteminant 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.
The incidence of Mi-I in Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
is 9.7%.
Peptide constructs representative of Mia mutations MUT and MUR have been attached onto red blood cells (known as kodecyte
Kodecyte
A kodecyte is a living cell that has been surface modified with KODE Technologyto gain a new or novel biological, chemical or technological function...
s) and are able to detect antibodies against these Miltenberger antigens
Although uncommon in Caucasians (0.0098%) and Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
ese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwan
Taiwan
Taiwan , also known, especially in the past, as Formosa , is the largest island of the same-named island group of East Asia in the western Pacific Ocean and located off the southeastern coast of mainland China. The island forms over 99% of the current territory of the Republic of China following...
ese 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.
Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
.
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 glyphorin A but its precise nature has not yet been determined.Mg antigen
The Mg antigen is carried on glycophorin A and lacks three O-glycolated side chains.Os antigen
Osa (MNS38) is due to a mutation at nucleotide 273 (C->T) lying within exon 3 resulting in the replacement of a prolineProline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
residue with a serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
.
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.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 hameolytic disease of the newborn. Raddon has been associated with severe transfusion reactions.Other areas
The Wright b antigen (Wrb) is located on glycophorin A and acts as a receptor for the malaria parasite Plasmodium falciparumPlasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
. 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.
Several viruses bind to glycophorin A including virus (via its capsid), bovine , , and , group C , and es.
Further reading
External links
- Cartoon of glycophorin A - http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/Glycoproteins.html