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Other entities represented in this entry:
HGNC Approved Gene Symbol: GYPC
Cytogenetic location: 2q14.3 Genomic coordinates (GRCh38): 2:126,656,158-126,696,667 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.3 | [Blood group, Gerbich] | 616089 | 3 | |
| {Malaria, resistance to} | 611162 | 3 |
The GYPC gene encodes glycophorin C (GPC) and glycophorin D (GPD) through the use of alternative translational start sites. GPC and GPD interact with protein 4.1R (EPB41; 130500) and contribute stability to the red blood cell membrane (review by Walker and Reid, 2010).
Colin et al. (1986) isolated cDNA clones for red cell glycophorin C and deduced its complete amino acid sequence. It is a single polypeptide chain of 128 amino acids sharing little homology with the major red cell membrane glycophorins A (GYPA; 617922) and B (GYPB; 617923), which carry the blood group MN (111300) and Ss (111740) antigens, respectively, and are closely related proteins.
Le Van Kim et al. (1987) presented evidence that GPC and GPD are encoded by the same gene. El-Maliki et al. (1989) concluded from sequence data that glycophorin D is an abridged version of glycophorin C. Glycophorin C is a single polypeptide chain of 128 amino acid residues. GYPD is smaller than GYPC (24 kD vs 32 kD). Amino acid sequence showed identity of GYPD with residues of 30 to 126 of GYPC. The mechanism generating GYPC and GYPD from the same gene may involve translation of the same mRNA to in-phase AUGs by leaky translation (Cartron et al., 1990). Available sequencing information on GYPD was consistent with this model. From studies of the molecular basis of the rare blood group An(a) antigen, Daniels et al. (1993) obtained further evidence that glycophorin D is a product of the GYPC gene.
In their review, Walker and Reid (2010) stated that the GYPC gene contains 4 exons and spans 13.5 kb. Exons 2 and 3 are homologous, with less than 5% nucleotide divergence.
Mattei et al. (1986) used a cDNA clone for GYPC in studies by in situ hybridization to assign the GYPC gene to chromosome 2q14-q21.
Gross (2014) mapped the GYPC gene to chromosome 2q14.3 based on an alignment of the GYPC sequence (GenBank AY838876) with the genomic sequence (GRCh38).
By differentiating mouse embryonic stem cells lacking Gypc toward erythropoiesis, followed by in vitro infection assays, Yiangou et al. (2016) found that the mouse malaria parasite, Plasmodium berghei, like the human malaria parasite, P. falciparum (see 611162), used Gypc to invade mouse erythrocytes. Deletion of band 3 (SLC4A1; 109270), which is also used by P. falciparum, had no effect on P. berghei invasion.
Glycophorin C carries determinants of the Gerbich blood group (616089); Ge antigens are also present on glycophorin D. Using a cDNA prepared from the mRNA of glycophorin C, Le Van Kim et al. (1987) found that the Ge-negative condition in donors with nonelliptocytic red cells was associated with a 3-kb deletion in the glycophorin C gene. Their findings also suggested that the same gene codes for glycophorin D.
Winardi et al. (1993) characterized the deficiency of glycophorins C and D in erythrocytes of the Leach phenotype of the Gerbich blood group system. They found that the deficiency was the consequence of deletion or marked alteration of exons 3 and 4 of the GYPC gene. The mutant gene encoded an mRNA stable enough to be detected in circulating reticulocytes. The protein encoded by this mRNA would not be expected to be expressed in the cell membrane because it would lack the transmembrane and cytoplasmic domains.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
By comparing 5 ape species and humans from 6 different global populations for polymorphism patterns at GYPC, Wilder et al. (2009) found an excess of nonsynonymous divergence solely attributable to accelerated evolution of GYPC in the human lineage. The ability of GYPC to encode both GPC and GPD is unique to humans and is caused by evolution of the GPC start codon. The authors postulated a hitchhiking event to explain the evolution, with relatively recent positive natural selection due to binding and invasion of P. falciparum parasites to human erythrocytes via GPC. Wilder et al. (2009) proposed that GYPC is a model of protein innovation through cooption of the UTR sequence following formation of a new start codon. In humans, the presumably beneficial ancestral protein GPD continues to be produced through leaky translation.
In the Yussef (Yus) phenotype of the Gerbich blood group system (616089), Chang et al. (1991) demonstrated a 57-bp deletion corresponding precisely with exon 2 of the GYPC gene.
In the Gerbich phenotype of the Gerbich blood group system (616089), Chang et al. (1991) identified deletion of the 84-bp exon 3 of the GYPC gene.
Deletion of exon 3 in the GYPC gene has been found in Melanesians; this alteration changes the serologic phenotype of the Ge blood group system, resulting in Ge negativity (Booth and McLoughlin, 1972; Serjeantson et al., 1994). The GYPC ex3del allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria (611162) is hyperendemic (Patel et al., 2001). The Plasmodium falciparum erythrocyte-binding antigen-140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Maier et al. (2003) showed that the receptor for EBA140 is glycophorin C and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.
Using archival blood samples from children less than 6 years old in a malaria-endemic district of Papua New Guinea, Tavul et al. (2008) performed a case-control study to investigate the role of the GYPC exon 3 deletion in protection against severe malarial anemia (SMA). They confirmed the high frequency of the exon 3 deletion in this population, but they found no association between the polymorphism and protection from SMA.
The rare Webb antigen of the Gerbich blood group system (616089) was first described by Simmons and Albrey (1963) in Australia. Bloomfield et al. (1986) found 8 examples of Wb-positive antigen, 2 in the same family, among 10,117 random blood donors in South Wales. Family studies confirmed autosomal dominant inheritance. The Webb antigen segregated independently of several other blood group systems; furthermore, it was not X-linked or Y-linked. Whereas the cDNA generated from mRNA in the Yus (110750.0001) and Gerbich (110750.0002) phenotypes is shorter than normal, that from the Webb phenotype is of normal size. Chang et al. (1991) demonstrated an A-to-G transition at nucleotide 23 of the coding sequence, resulting in substitution of asparagine by serine. This modification accounted for the altered glycosylation of glycophorin seen with the Webb phenotype. Telen et al. (1991) likewise found a point mutation resulting in substitution of serine for asparagine at amino acid position 8.
Duch, Dh(a), an exceedingly rare red cell antigen of the Gerbich blood group (616089), is recognized by an antibody found in Aarhus, Denmark, in 1968 (Jorgensen et al., 1982). The antigen was found in 5 persons in 3 generations and segregated independently of several other blood groups.
Spring (1991) detected the Duch antigen on a variant of glycophorin C that had the same apparent molecular mass as normal GPC. The location of Dh(a) on GPC was tentatively assigned to the sequence between residues 1 and 47. Since the Dh(a) antigen was not detected on GPD but was present on GPC, it was presumed to reside within residues 1-21 at the N-terminal domain of GPC. By sequencing PCR-amplified DNA, King et al. (1992) demonstrated a C-to-T transition at nucleotide 40 responsible for a substitution of leucine by phenylalanine at amino acid residue 14.
Bloomfield, L., Rowe, G. P., Green, C. The Webb (Wb) antigen in South Wales donors. Hum. Hered. 36: 352-356, 1986. [PubMed: 3539763] [Full Text: https://doi.org/10.1159/000153659]
Booth, P. B., McLoughlin, K. The Gerbich blood group system, especially in Melanesians. Vox Sang. 22: 73-84, 1972. [PubMed: 5011657] [Full Text: https://doi.org/10.1111/j.1423-0410.1972.tb03968.x]
Cartron, J.-P., Colin, Y., Kudo, S., Fukuda, M. Molecular genetics of human erythrocyte sialoglycoproteins A, B, C, and D. In: Harris, J. R. (ed.): Erythroid Cells. Blood Cell Biochemistry. Vol. 1. New York: Plenum Press (pub.) 1990. Pp. 299-335.
Chang, S., Reid, M. E., Conboy, J., Kan, Y. W., Mohandas, N. Molecular characterization of erythrocyte glycophorin C variants. Blood 77: 644-648, 1991. [PubMed: 1991173]
Colin, Y., Rahuel, C., London, J., Romeo, P. H., d'Auriol, L., Galibert, F., Cartron, J.-P. Isolation of cDNA clones and complete amino acid sequence of human erythrocyte glycophorin C. J. Biol. Chem. 261: 229-233, 1986. [PubMed: 2416746]
Daniels, G., King, M.-J., Avent, N. D., Khalid, G., Reid, M., Mallinson, G., Symthe, J., Cedergren, B. A point mutation in the GYPC gene results in the expression of the blood group An(a) antigen on glycophorin D but not on glycophorin C: further evidence that glycophorin D is a product of the GYPC gene. Blood 82: 3198-3203, 1993. [PubMed: 8219208]
El-Maliki, B., Blanchard, D., Dahr, W., Beyreuther, K., Cartron, J.-P. Structural homology between glycophorins C and D of human erythrocytes. Europ. J. Biochem. 183: 639-643, 1989. [PubMed: 2776757] [Full Text: https://doi.org/10.1111/j.1432-1033.1989.tb21093.x]
Gross, M. B. Personal Communication. Baltimore, Md. 11/13/2014.
Jorgensen, J., Drachmann, O., Gavin, J. Duch, Dh(a), a low frequency red cell antigen. Hum. Hered. 32: 73-75, 1982. [PubMed: 7095818] [Full Text: https://doi.org/10.1159/000153263]
King, M. J., Avent, N. D., Mallinson, G., Reid, M. E. Point mutation in the glycophorin C gene results in the expression of the blood group antigen Dh(a). Vox Sang. 63: 56-58, 1992. [PubMed: 1413665] [Full Text: https://doi.org/10.1111/j.1423-0410.1992.tb01220.x]
Le Van Kim, C., Colin, Y., Blanchard, D., Dahr, W., London, J., Cartron, J.-P. Gerbich blood group deficiency of the Ge:-1,-2,-3 and Ge:-1,-2,3 types: immunochemical study and genomic analysis with cDNA probes. Europ. J. Biochem. 165: 571-579, 1987. [PubMed: 3595602] [Full Text: https://doi.org/10.1111/j.1432-1033.1987.tb11478.x]
Maier, A. G., Duraisingh, M. T., Reeder, J. C., Patel, S. S., Kazura, J. W., Zimmerman, P. A., Cowman, A. F. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nature Med. 9: 87-92, 2003. [PubMed: 12469115] [Full Text: https://doi.org/10.1038/nm807]
Mattei, M. G., Colin, Y., Le Van Kim, C., Mattei, J. F., Cartron, J. P. Localization of the gene for human erythrocyte glycophorin C to chromosome 2, q14-q21. Hum. Genet. 74: 420-422, 1986. [PubMed: 3793105] [Full Text: https://doi.org/10.1007/BF00280497]
Patel, S. S., Mehlotra, R. K., Kastens, W., Mgone, C. S., Kazura, J. W., Zimmerman, P. A. The association of the glycophorin C exon 3 deletion with ovalocytosis and malaria susceptibility in the Wosera, Papua New Guinea. Blood 98: 3489-3491, 2001. [PubMed: 11719395] [Full Text: https://doi.org/10.1182/blood.v98.12.3489]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Serjeantson, S. W., White, B. S., Bhatia, K., Trent, R. J. A 3.5 kb deletion in the glycophorin C gene accounts for the Gerbich-negative blood group in Melanesians. Immun. Cell Biol. 72: 23-27, 1994. [PubMed: 8157284] [Full Text: https://doi.org/10.1038/icb.1994.4]
Simmons, R. T., Albrey, J. A. A 'new' blood group antigen Webb (Wb) of low frequency found in two Australian families. Med. J. Aust. 1: 8-10, 1963. [PubMed: 13977437] [Full Text: https://doi.org/10.5694/j.1326-5377.1963.tb26536.x]
Spring, F. A. Immunochemical characterisation of the low-incidence antigen, Dh(a). Vox Sang. 61: 65-68, 1991. [PubMed: 1719701] [Full Text: https://doi.org/10.1111/j.1423-0410.1991.tb00930.x]
Tavul, L., Mueller, I., Rare, L., Lin, E., Zimmerman, P. A., Reeder, J., Siba, P., Michon, P. Glycophorin C delta-exon3 is not associated with protection against severe anaemia in Papua New Guinea. PNG Med. J. 51: 149-154, 2008.
Telen, M. J., Le Van Kim, C., Guizzo, M. L., Cartron, J.-P., Colin, Y. Erythrocyte Webb-type glycophorin C variant lacks N-glycosylation due to an asparagine to serine substitution. Am. J. Hemat. 37: 51-52, 1991. [PubMed: 1902622] [Full Text: https://doi.org/10.1002/ajh.2830370112]
Walker, P. S., Reid, M. E. The Gerbich blood group system: a review. Immunohematology 26: 60-65, 2010. [PubMed: 20932076]
Wilder, J. A., Hewett, E. K., Gansner, M. E. Molecular evolution of GYPC: evidence for recent structural innovation and positive selection in humans. Molec. Biol. Evol. 26: 2679-2687, 2009. [PubMed: 19679754] [Full Text: https://doi.org/10.1093/molbev/msp183]
Winardi, R., Reid, M., Conboy, J., Mohandas, N. Molecular analysis of glycophorin C deficiency in human erythrocytes. Blood 81: 2799-2803, 1993. [PubMed: 7683929]
Yiangou, L., Montandon, R., Modrzynska, K., Rosen, B., Bushell, W., Hale, C., Billker, O., Rayner, J. C., Pance, A. A stem cell strategy identifies glycophorin C as a major erythrocyte receptor for the rodent malaria parasite Plasmodium berghei. PLoS One 11: e0158238, 2016. Note: Electronic Article. [PubMed: 27362409] [Full Text: https://doi.org/10.1371/journal.pone.0158238]