Glycophorin C (GYPC; CD236/CD236R; glycoprotein beta; glycoconnectin; PAS-2) plays a functionally important role in maintaining erythrocyte shape and regulating membrane material properties, possibly through its interaction with protein 4.1. Moreover, it has previously been shown that membranes deficient in protein 4.1 exhibit decreased content of glycophorin C. It is also an

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane proteins can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs comp ...

of the

erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...

and acts as the

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

for the ''

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 ...

'' protein PfEBP-2 (erythrocyte binding protein 2; baebl; EBA-140).

History

The antigen was discovered in 1960 when three women who lacked the antigen made anti-Gea in response to pregnancy. The antigen is named after one of the patients – a Mrs Gerbich. The following year a new but related antigen was discovered in a Mrs Yus for whom an antigen in this system is also named. In 1972 a numerical system for the antigens in this blood group was introduced.

Genomics

Despite the similar names glycophorin C and D are unrelated to the other three glycophorins which encoded on chromosome 4 at location 4q28-q31. These latter proteins are closely related. Glycophorin A and glycophorin B carry the blood group MN and Ss

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

s respectively. There are ~225,000 molecules of GPC and GPD per erythrocyte. Originally it was thought that glycophorin C and D were the result of a gene duplication event but it was only later realised that they were encoded by the same gene. Glycophorin D (GPD) is generated from the glycophorin C

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

by leaky translation at an in frame AUG at

codon Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...

30: glycophorin D = glycophorin C residues 30 to 128. This leaky translation appears to be a uniquely human trait. Glycophorin C (GPC) is a single

polypeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...

chain of 128

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

and is encoded by a

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 ...

on the long arm of

chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost ei ...

(2q14-q21). The gene was first cloned in 1989 by High ''et al.'' The GPC gene is organized in four

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s distributed over 13.5 kilobase pairs of

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. Exon 1 encodes residues 1-16, exon 2 residues 17-35, exon 3 residues 36-63 and exon 4 residues 64-128. Exons 2 and 3 are highly homologous, with less than 5% nucleotide divergence. These exons also differ by a 9 amino acid insert at the 3' end of exon 3. The direct repeated segments containing these exons is 3.4 kilobase pairs long and may be derived from a recent duplication of a single ancestral domain. Exons 1, 2 and most of exon 3 encode the N-terminal extracellular domain while the remainder of exon 3 and exon 4 encode transmembrane and cytoplasmic domains. Two

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s are known and the gene is expressed in a wide variety of tissues including

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

thymus The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...

stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

, adult

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and erythrocyte. In the non erythroid cell lines, expression is lower than in the erythrocyte and the protein is differentially

glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

. In the erythrocyte glycophorin C makes up ~4% of the membrane sialoglycoproteins. The average number of O linked chains is 12 per molecule. The

is expressed early in the development of the erythrocyte, specifically in the erythroid burst-forming unit and erythroid colony-forming unit. The mRNA from human erythroblasts is ~1.4 kilobases long and the transcription start site in erythroid cells has been mapped to 1050 base pairs 5' of the start codon. It is expressed early in development and before the Kell antigens, Rhesus-associated glycoprotein, glycophorin A,

band 3 Band 3 anion transport protein, also known as anion exchanger 1 (AE1) or band 3 or solute carrier family 4 member 1 (SLC4A1), is a protein that is encoded by the gene in humans. Band 3 anion transport protein is a phylogenetically-preserved ...

, the Rhesus antigen and glycophorin B. In melanocytic cells Glycophorin C gene expression may be regulated by MITF. GPC appears to be synthesized in excess in the erythrocyte and that the membrane content is regulated by band 4.1 (protein 4.1). Additional data on the regulation of glycophorin C i
here
In a study of this gene among the

Hominoidea Apes (collectively Hominoidea ) are a Family (biology), superfamily of Old World simians native to sub-Saharan Africa and Southeast Asia (though they were more widespread in Africa, most of Asia, and Europe in prehistory, and counting humans ...

two finding unique to humans emerged: (1) an excess of non-synonymous divergence among species that appears to be caused solely by accelerated evolution and (2) the ability of the single GYPC gene to encode both the GPC and GPD proteins. The cause for this is not known but it was suggested that these findings might be the result of infection by ''Plasmodium falciparum''.

Molecular biology

After separation of red cell membranes by SDS-polyacrylamide gel electrophoresis and staining with periodic acid-Schiff staining (PAS) four glycophorins have been identified. These have been named glycophorin A, B, C and D in order of the quantity present in the membrane – glycophorin A being the most and glycophorin D the least common. A fifth ( glycophorin E) has been identified within the human genome but cannot easily be detected on routine gel staining. In total the glycophorins constitute ~2% of the total erythrocyte membrane protein mass. Confusingly these proteins are also known under different nomenclatures but they are probably best known as the glycophorins. Glycophorin C was first isolated in 1978. Glycophorin C and D are minor sialoglycoproteins contributing to 4% and 1% to the PAS-positive material and are present at about 2.0 and 0.5 x 10⁵ copies/cell respectively. In polyacrylimide gels glycophorin C's apparent weight is 32 kilodaltons (32 kDa). Its structure is similar to that of other glycophorins: a highly glycoslated extracellular domain (residues 1-58), a transmembrane domain (residues 59-81) and an intracellular domain (residues 82-128). About 90% of the glycophorin C present in the erythrocyte is bound to the cytoskeleton and the remaining 10% moves freely within the membrane. Glycophorin D's apparent molecular weight is 23kDa. On average this protein has 6 O linked oligosaccharides per molecule. Within the erythrocyte it interacts with band 4.1 (an 80-kDa protein) and p55 (a palmitoylated peripheral membrane phosphoprotein and a member of the membrane-associated guanylate kinase family) to form a

ternary complex A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, such as a ...

that is critical for the shape and stability of erythrocytes. The major attachment sites between the erythrocyte

spectrin Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma mem ...

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

and the lipid bilayer are glycophorin C and

. The interaction with band 4.1 and p55 is mediated by the N terminal 30 kD domain of band 4.1 binding to a 16 amino acid segment (residues 82-98: residues 61-77 of glycophorin D) within the cytoplasmic domain of glycophorin C and to a positively charged 39 amino acid motif in p55. The majority of protein 4.1 is bound to glycophorin C. The magnitude of the strength of the interaction between glycophorin C and band 4.1 has been estimated to be 6.9 microNewtons per meter, a figure typical of protein–protein interactions. Glycophorin C normally shows oscillatory movement in the erythrocyte membrane. This is reduced in Southeast Asian ovalocytosis a disease of erythrocytes due to a mutation in band 3.

Transfusion medicine

These glycophorins are associated with eleven antigens of interest to transfusion medicine: the Gerbich (Ge2, Ge3, Ge4), the Yussef (Yus), the Webb (Wb or Ge5), the Duch (Dh(a) or Ge8), the Leach, the Lewis II (Ls(a) or Ge6), the Ahonen (An(a) or Ge7) and GEPL (Ge10*), GEAT (Ge11*) and GETI (Ge12*). Six are of high prevalence (Ge2, Ge3, Ge4, Ge10*, Ge11*, Ge12*) and five of low prevalence (Wb, Ls(a), An(a), Dh(a) and Ge9).

Gerbich antigen

Glycophorin C and D encode the Gerbich (Ge)

s. There are four

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

s, Ge-1 to Ge-4. Three types of Ge antigen negativity are known: Ge-1,-2,-3 (Leach phenotype), Ge-2,-3 and Ge-2,+3. A 3.4 kilobase pair deletion within the gene, which probably arose because of unequal crossing over between the two repeated domains, is responsible for the formation of the Ge-2,-3

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

. The breakpoints of the deletion are located within

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

s 2 and 3 and results in the deletion of

3. This mutant gene is transcribed as a

with a continuous

open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...

extending over 300

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

s and is translated into the sialoglycoprotein found on Ge-2,-3 red cells. A second 3.4 kilobase pair deletion within the glycophorin C gene eliminates only exon 2 by a similar mechanism and generates the mutant

encoding for the abnormal glycoprotein found on Ge-2,+3 erythrocytes. The Ge2 epitope is antigenic only on glycophorin D and is a cryptic antigen in glycophorin C. It is located within exon 2 and is sensitive to

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...

and

papain Papain, also known as papaya proteinase I, is a cysteine protease () enzyme present in papaya (''Carica papaya'') and mountain papaya (''Vasconcellea cundinamarcensis''). It is the namesake member of the papain-like protease family. It has wi ...

but resistant to chymotrypsin and pronase. The Ge3 epitope is encoded by exon 3. It is sensitive to

but resistant to chymotrypsin,

and pronase. It is thought to lie in the between amino acids 42-50 in glycophorin C (residues 21-49 in glycophorin D). Ge4 is located within the first 21 amino acids of glycophorin C. It is sensitive to trypsin, papain, pronase and

neuraminidase Exo-α-sialidase (, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycosidic linkag ...

Leach antigen

The relatively rare Leach phenotype is due either to a deletion in exons 3 and 4 or to a

frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet natur ...

causing a premature stop codon in the glycophorin C gene, and persons with this phenotype are less susceptible (~60% of the control rate) to invasion by ''

''. Such individuals have a subtype of a condition called

hereditary elliptocytosis Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the person's red blood cells are elliptical rather than the typical biconcave disc shape. Such morphologically distinctiv ...

. The abnormally shaped cells are known as elliptocytes or cameloid cells. The basis for this phenotype was first reported by Telen ''et al.'' The phenotype is Ge:-2,-3,-4.

Yussef antigen

The Yussef (Yus)

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

is due to a 57 base pair deletion corresponding to exon 2. The antigen is known as GPC Yus. Glycophorin C mutations are rare in most of the Western world, but are more common in some places where malaria is endemic. In

Melanesia Melanesia (, ) is a subregion of Oceania in the southwestern Pacific Ocean. It extends from New Guinea in the west to the Fiji Islands in the east, and includes the Arafura Sea. The region includes the four independent countries of Fiji, Vanu ...

a greater percentage of the population is Gerbich negative (46.5%) than in any other part of the world. The incidence of Gerbich-negative phenotype caused by an exon 3 deletion in the Wosera (

East Sepik Province East Sepik is a province in Papua New Guinea. Its capital is Wewak. East Sepik has an estimated population of 450,530 people (2011 census) and is 43,426 km square in size. Its density is 10.4 people per square kilometer. History Cherubim D ...

) and Liksul (

Madang Province Madang is a Provinces of Papua New Guinea, province of Papua New Guinea. The province is on the northern coast of mainland Papua New Guinea and has many of the country's highest peaks, active volcanoes and its biggest mix of languages. The capi ...

) populations of

Papua New Guinea Papua New Guinea, officially the Independent State of Papua New Guinea, is an island country in Oceania that comprises the eastern half of the island of New Guinea and offshore islands in Melanesia, a region of the southwestern Pacific Ocean n ...

is 0.463 and 0.176 respectively.

Webb antigen

The rare Webb (Wb) antigen (~1/1000 donors), originally described in 1963 in

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

, is the result of an alteration in

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

of glycophorin C: an A to G transition at nucleotide 23 results in an

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 ...

residue instead of the normal

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 − ...

residue with the resultant loss of glycosylation. The antigen is known as GPC Wb.

Duch antigen

The rare Duch (Dh) antigen was discovered in

Aarhus Aarhus (, , ; officially spelled Århus from 1948 until 1 January 2011) is the second-largest city in Denmark and the seat of Aarhus municipality, Aarhus Municipality. It is located on the eastern shore of Jutland in the Kattegat sea and app ...

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 ...

(1968) and is also found on glycophorin C. It is due to a C to T transition at

40 resulting in the replacement of

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 ...

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...

. This antigen is sensitive to trypsin but resistant to chymotrypsin and Endo F.

Lewis antigen

The Lewis II (Ls(a); Ge-6) antigen has insert of 84 nucleotides into the ancestral GPC gene: the insert corresponds to the entire sequence of exon 3. Two subtypes of this antigen are known: beta Ls(a) which carries the Ge3 epitope and gamma Ls(a) which carries both the Ge2 and Ge3 epitopes. This antigen is also known as the Rs(a) antigen.

Ahonen antigen

The Ahonen (Ana) antigen was first reported in 1972. The antigen is found on glycophorin D. This antigen was discovered in a Finnish man on May 5, 1968, during post operative blood cross matching for an aortic aneurism repair. In Finland the incidence of this antigen was found to be 6/10,000 donors. In Sweden the incidence was 2/3266 donors. The molecular basis for the origin of this antigen lies within exon 2 where a G->T substitution in codon 67 (base position 199) converts an

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...

to a

residue. While this epitope exists within glycophorin C there it is a cryptantigen. It is only antigenic in glycophorin D because of the truncated N terminus.

Others

A duplicated exon 2 has erythrocytes also been reported in Japanese blood donors (~2/10,000). This mutation has not been associated with a new antigen.

Antibodies

Antibodies to the Gerbich antigens have been associated with transfusion reactions and mild hemolytic disease of the newborn. In other studies naturally occurring anti-Ge antibodies have been found and appear to be of no clinical significance. Immunological tolerance towards Ge antigen has been suggested.

Other areas

High expression of glycophorin C has been associated with a poor prognosis for acute lymphoblastic leukaemia in Chinese populations. Glycophorin C is the receptor for the protein erythrocyte binding antigen 140 (EBA140) of ''

''. This interaction mediates a principal invasion pathway into the erythrocytes. The partial resistance of erythrocytes lacking this protein to invasion by ''P. falciparum'' was first noted in 1982. The lack of Gerbich antigens in the population of Papua New Guinea was noted in 1989. Influenza A and B bind to glycophorin C.

References

External links

Erythrocyte membrane cartoon
* {{transfusion medicine Clusters of differentiation Glycoproteins Transmembrane receptors Blood antigen systems Transfusion medicine