Glycophorin A (
MNS blood group), also known as GYPA, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
which in humans is encoded by the ''GYPA''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
GYPA has also recently been designated CD235a (
cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophe ...
235a).
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.
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
Primates is an order of mammals, which is further divided into the strepsirrhines, which include lemurs, galagos, and lorisids; and the haplorhines, which include tarsiers and simians ( monkeys and apes). Primates arose 74–63 ...
. GypB can be found only in
gorilla
Gorillas are primarily herbivorous, terrestrial great apes that inhabit the tropical forests of equatorial Africa. The genus ''Gorilla'' is divided into two species: the eastern gorilla and the western gorilla, and either four or five su ...
s 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.
[Dean L. Blood Groups and Red Cell Antigens nternet 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/
]
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
The Caucasian race (also Caucasoid, Europid, or Europoid) is an obsolete racial classification of humans based on a now-disproven theory of biological race. The ''Caucasian race'' was historically regarded as a biological taxon which, dependin ...
; 74%
African descent
Black is a racial classification of people, usually a political and skin color-based category for specific populations with a mid- to dark brown complexion. Not all people considered "black" have dark skin and often additional phenotypical ...
* N: 72% Caucasoid; 75% African descent
* S: 55% Caucasoid; 31% African descent
* s: 89% Caucasoid; 93% African descent
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, Ny
a, Os
a, Orriss (Or), Raddon (FR) and Stones (St
a).
Chimpanzee
The chimpanzee (; ''Pan troglodytes''), also simply known as the chimp, is a species of Hominidae, great ape native to the forests and savannahs of tropical Africa. It has four confirmed subspecies and a fifth proposed one. When its close rel ...
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 M
k.
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
Tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
1-Serine-Threonine-Serine-
Glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
5 while Henshaw has
Leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...
1-Serine-Threonine-Threonine-
Glutamate
Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
5. 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.
Miltenberger subsystem
The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mi
a, V
w, 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 (Mi
a), Mi-II(V
w), 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 asparagine
26 residue.
Mi-II is due to a mutation at amino acid 28 (threonine to
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
: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 (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
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 is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
residue into a threonine residue and a
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
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 is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
->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 St
a 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 St
a gene is in a reciprocal 5'delta-alpha 3' configuration.
The incidence of Mi-I in
Thailand
Thailand, officially the Kingdom of Thailand and historically known as Siam (the official name until 1939), is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. With a population of almost 66 million, it spa ...
is 9.7%.
Peptide constructs representative of Mi
a mutations MUT and MUR have been attached onto red blood cells (known as
kodecytes) and are able to detect antibodies against these Miltenberger antigens
[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]
Although uncommon in Caucasians (0.0098%) and
Japan
Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
ese (0.006%), the frequency of Mi-III is exceptionally high in several
Taiwan
Taiwan, officially the Republic of China (ROC), is a country in East Asia. The main geography of Taiwan, island of Taiwan, also known as ''Formosa'', lies between the East China Sea, East and South China Seas in the northwestern Pacific Ocea ...
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 is a Nordic countries, Nordic country in Northern Europe. It is the metropole and most populous constituent of the Kingdom of Denmark,, . also known as the Danish Realm, a constitutionally unitary state that includes the Autonomous a ...
.
Stone's antigen
Stones (St
a) 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.
Mg antigen
The Mg antigen is carried on glycophorin A and lacks three O-glycolated side chains.
Os antigen
Os
a (MNS38) is due to a mutation at nucleotide 273 (C->T) lying within exon 3 resulting in the replacement of a
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
residue with a
serine
Serine
(symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
.
Ny antigen
Ny
a (MNS18) is due to a mutation at nucleotide 194 (T->A) which results in the substitution of an
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...
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 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
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''.
Cells lacking glycophorins A (En
a) 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
hepatitis A
Hepatitis A is an infectious liver disease caused by Hepatitis A virus (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them, is ...
virus (via its capsid),
bovine
parvovirus,
Sendai virus
''Murine respirovirus'', formerly ''Sendai virus'' (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an Viral envelope, enveloped, 150-200 nm–diameter, negative sense, single ...
,
influenza A
''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...
and
B,
group C
rotavirus
Rotaviruses are the most common cause of diarrhea, diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity (medical), Immunity develops with ...
,
encephalomyocarditis virus and
reoviruses.
See also
*
Glycophorin
References
Further reading
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External links
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*Cartoon of glycophorin A - https://web.archive.org/web/20161008211618/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/Glycoproteins.html
{{Clusters of differentiation
Clusters of differentiation