Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q31.21 | [Blood group, Ss] | 111740 | 3 | GYPB | 617923 |
A number sign (#) is used with this entry because antigens of the Ss blood group result from variation in the gene encoding glycophorin B (GYPB; 617923) on chromosome 4q31.
Ss blood group antigens reside on the red-cell glycoprotein GYPB. The S and s antigens result from a polymorphism at amino acid 29 of GYPB, where S has met29 and s has thr29. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. GYPB, glycophorin A (GYPA; 617922), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. Antigens of the MN blood group (111300) reside on GYPA. The M and N antigens differ at amino acids 1 and 5 of GYPA, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. The N terminus of GYPB is essentially identical to that of GYPA except that it always expresses the N antigen, denoted 'N' or N-prime. Recombination and gene conversion between GYPA, GYPB, and GYPE lead to hybrid glycophorin molecules and generation of low-incidence antigens. Thus, the MN and Ss blood groups are together referred to as the MNSs blood group system (see 111300). Recombination results in 3 glycophorin-null phenotypes: En(a-) cells lack GYPA due to recombination between GYPA and GYPB; GYPB-negative (S-s-U-) cells lack GYPB due to recombination in GYPB; and M(k) cells (M-N-S-s-U-) lack both GYPA and GYPB due to recombination between GYPA and GYPE. Individuals with glycophorin-null phenotypes have decreased sialic acid content and increased resistance to malarial infection (see 611162). GYPA and GYPB are not essential for red-cell development or survival, and GYPA- and GYPB-null phenotypes are not associated with anemia or altered red-cell function (review by Cooling, 2015).
Blumenfeld and Adamany (1978) found that the MM blood group polypeptide differs from the NN polypeptide in 2 amino acids, these being serine and glycine in MM and leucine and glutamic acid in NN. The MN individual shows all 4 amino acids. The 2 major sialoglycoproteins of the human red cell membrane, alpha and delta (glycophorins A and B, respectively), carry the MNSs antigenic specificities. They have identical amino acid sequences for the first 26 residues from the N terminus. Alpha expresses M or N blood group activity; delta carries only blood group N activity. Furthermore, the asparagine at position 26 of the alpha carries an oligosaccharide chain that is absent from the same position of delta. The 2 sialoglycoproteins differ in their remaining amino acid sequence, and delta expresses Ss activity.
Ss and MN are closely linked but separate gene loci on chromosome 4q28-q31. Several instances of recombination between Ss and MN loci have been observed (see review by Race and Sanger, 1975). Close linkage of the genes for the 2 sialoglycoproteins that carry the MN and Ss specificities, respectively, was also indicated by the identification of hybrid molecules that appear to have arisen by a Lepore-type mechanism (Mawby et al., 1981). The erythrocyte glycophorins, which lie partly within the cell membrane and partly exposed to the exterior, contain 203 amino acids. The amino-terminal half is exposed and is the one that bears the oligosaccharide complexes that determine blood-group antigen specificities and serve as receptors for viruses and plant agglutinins. As indicated in 111300, the Ss blood group antigens are located on glycophorin B. The structural difference between SS and ss specificities is a methionine-to-threonine polymorphism at position 29. Ferrari and Pavia (1986) synthesized 2 peptides, each 8 amino acids long, carrying the Ss specificities: SS, asn-gly-glu-met-gly-gln-leu-val; ss, asn-gly-glu-thr-gly-gln-leu-val. Glycophorin C (GYPC; 110750) is the site of the Gerbich blood group antigen specificity (616089).
Huang et al. (1987) presented evidence derived from protein and genomic DNA analyses that erythrocytes of 2 unrelated persons homozygous for the S-s-U- blood group phenotype lack delta-glycophorin as a result of a delta-glycophorin gene deletion. Dantu and Stones are 2 variant antigens carried by hybrid glycoproteins that appear to be products of delta and alpha glycophorin fusion genes. In Stones, symbolized St(a), the junction is from amino acid residue 26 or 28 of delta to residue 59 or 61 of alpha, whereas in Dantu, residue 38 or 39 of delta is joined to residue 71 or 72 of alpha.
Huang and Blumenfeld (1988) delineated the structure of the alpha and delta glycophorins at the genomic level in the DNA from a 3-generation black family in which both the presence of Dantu and Mi-III (another rare MNs antigen) and the absence of delta-glycophorin were seen.
Red cells with the rare En(a-) variant are resistant to falciparum malaria (see 611162) (Pasvol et al., 1982). Such cells lack glycophorin A (Siebert and Fukuda, 1986). The rare U(-) variant of the Ss system, which lacks the other major sialoglycoprotein, glycophorin B, is relatively resistant to invasion. Wr(b)-negative cells are also resistant to invasion by P. falciparum despite the fact that they have normal amounts of glycophorins A and B on their surface. All of these observations, as well as experiments using antibodies to glycophorins and certain sugars, particularly N-acetylglucosamine, have led to a tentative model of the role of glycophorin in the red cell invasion of P. falciparum (Pasvol and Wilson, 1982).
By analyzing genome sequence data from human populations, Leffler et al. (2017) identified a diverse array of large copy-number variants affecting GYPA and GYPB. They found that a complex structural rearrangement involving loss of GYPB and gain of 2 GYPB-GYPA hybrid genes encoding the Dantu antigen of the MNSs blood group system explained the association of a nearby region with protection from severe malaria. The protective haplotype had 5 GYP genes, including 2 copies of GYPE, 2 copies of the Dantu hybrid genes, and 1 copy of GYPA, compared with the reference haplotype of 3 genes (GYPE, GYPB, and GYPA). The protective haplotype reduced the risk of severe malaria by 40% in regions of Kenya, but it had not yet been found in west Africa.
Glycophorin A (GYPA; 111300) and B, which determine the MN and Ss blood types, respectively, are 2 major receptors that are expressed on erythrocyte surfaces and interact with Plasmodium falciparum ligands. Ko et al. (2011) analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. Ko et al. (2011) identified a haplotype causing 3 amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in 5 populations with high exposure to malaria. Ko et al. (2011) observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. By contrast, Ko et al. (2011) observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion was correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection.
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Cooling, L. Blood groups in infection and host susceptibility. Clin. Microbiol. Rev. 28: 801-870, 2015. [PubMed: 26085552] [Full Text: https://doi.org/10.1128/CMR.00109-14]
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Huang, C.-H., Blumenfeld, O. O. Characterization of a genomic hybrid specifying the human erythrocyte antigen Dantu: Dantu gene is duplicated and linked to a delta glycophorin gene deletion. Proc. Nat. Acad. Sci. 85: 9640-9644, 1988. [PubMed: 2462250] [Full Text: https://doi.org/10.1073/pnas.85.24.9640]
Huang, C.-H., Johe, K., Moulds, J. J., Siebert, P. D., Fukuda, M., Blumenfeld, O. O. Delta-glycophorin (glycophorin B) gene deletion in two individuals homozygous for the S--s--U-- blood group phenotype. Blood 70: 1830-1835, 1987. [PubMed: 2823938]
Ko, W.-Y., Kaercher, K. A., Giombini, E., Marcatili, P., Froment, A., Ibrahim, M., Lema, G., Nyambo, T. B., Omar, S. A., Wambebe, C., Ranciaro, A., Hirbo, J. B., Tishkoff, S. A. Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations. Am. J. Hum. Genet. 88: 741-754, 2011. [PubMed: 21664997] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.005]
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Pasvol, G., Wainscoat, J. S., Weatherall, D. J. Erythrocytes deficient in glycophorin resist invasion by the malarial parasite Plasmodium falciparum. Nature 297: 64-66, 1982. [PubMed: 7040988] [Full Text: https://doi.org/10.1038/297064a0]
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Siebert, P. D., Fukuda, M. Isolation and characterization of human glycophorin A cDNA clones by a synthetic oligonucleotide approach: nucleotide sequence and mRNA structure. Proc. Nat. Acad. Sci. 83: 1665-1669, 1986. [PubMed: 3456608] [Full Text: https://doi.org/10.1073/pnas.83.6.1665]