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.
[3] Glycophorin C (GPC) is a single polypeptide chain of 128 amino acids and is encoded by a gene on the long arm of chromosome 2 (2q14-q21).
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.
Two isoforms are known and the gene is expressed in a wide variety of tissues including kidney, thymus, stomach, breast, adult liver and erythrocyte.
[6] GPC appears to be synthesized in excess in the erythrocyte and that the membrane content is regulated by band 4.1 (protein 4.1).
In a study of this gene among the Hominoidea 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 major attachment sites between the erythrocyte spectrin-actin cytoskeleton and the lipid bilayer are glycophorin C and band 3.
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.
This is reduced in Southeast Asian ovalocytosis a disease of erythrocytes due to a mutation in band 3.
[9] 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*).
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.
This mutant gene is transcribed as a messenger RNA with a continuous open reading frame extending over 300 nucleotides and is translated into the sialoglycoprotein found on Ge-2,-3 red cells.
Ge4 is located within the first 21 amino acids of glycophorin C. It is sensitive to trypsin, papain, pronase and neuraminidase.
The relatively rare Leach phenotype is due either to a deletion in exons 3 and 4 or to a frameshift mutation 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 Plasmodium falciparum.
Glycophorin C mutations are rare in most of the Western world, but are more common in some places where malaria is endemic.
The rare Duch (Dh) antigen was discovered in Aarhus, Denmark (1968) and is also found on glycophorin C. It is due to a C to T transition at nucleotide 40 resulting in the replacement of leucine by phenylalanine.
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 to a serine residue.
[19] Antibodies to the Gerbich antigens have been associated with transfusion reactions and mild hemolytic disease of the newborn.
High expression of glycophorin C has been associated with a poor prognosis for acute lymphoblastic leukaemia in Chinese populations.