Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 115682003;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q31.21 | [Blood group, MNSs system] | 111300 | 3 | GYPA | 617922 |
A number sign (#) is used with this entry because antigens of the MN blood group result from variation in the gene encoding glycophorin A (GYPA; 617922) on chromosome 4q31.
MN antigens reside on GYPA, one of the most abundant red-cell glycoproteins. The M and N antigens are 2 autosomal codominant antigens encoded by the first 5 amino acids of GYPA and include 3 O-linked glycans as part of the epitope. M and N differ at amino acids 1 and 5, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. M is the ancestral GYPA allele and is common in all human populations and Old World apes. GYPA, glycophorin B (GYPB; 617923), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. 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. Antigens of the Ss blood group (111740) reside on GYPB, and 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 or MNS blood group system. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. 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).
By in situ hybridization using a cDNA probe, Mattei et al. (1987) mapped the GYPA gene to chromosome 4q28-q31.
By in situ hybridization and RFLP studies in a case of balanced de novo translocation between chromosomes 2 and 4, Divelbiss et al. (1989) concluded that the fibrinogen gene cluster (134830) lies proximal to the GYPA/GYPB loci and that all of these loci lie in the 4q28 band.
In a malformed female infant with de novo interstitial deletion of 4q, Wakui et al. (1991) found that the MN locus was intact. On the basis of this finding and previous mapping data (see HISTORY), they concluded that the MN locus is in the 4q28.2-q31.1 segment.
Onda and Fukuda (1995) reported that the GYPA, GYPB, and GYPE gene cluster spans about 330 kb of chromosome 4q31.
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.
Using antibodies directed against different structural regions of the major sialoglycoprotein alpha, Mawby et al. (1981) confirmed that 2 variant forms (Miltenberger class V and Ph) represented hybrid sialoglycoprotein molecules that arose from anomalous crossover events between the genes coding for alpha and delta. The genes appear to be closely linked, in the order alpha-delta (5-prime to 3-prime).
Red cells with the rare En(a-) variant are resistant to falciparum malaria (Pasvol et al., 1982). Such cells lack glycophorin A, the major red cell sialoglycoprotein (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).
Langlois et al. (1986) studied the frequency of red cells with loss of expression at the glycophorin A locus (GPA). Glycophorin A is present in about 500,000 copies per red cell. The 2 allelic forms of GPA, blood group M and blood group N, are identical except for 2 amino acid substitutions at positions 1 and 5 from the amino terminus (Prohaska et al., 1981). Using monoclonal antibodies, Langlois et al. (1986) identified expression loss mutants. They found a frequency of about 1 in 100,000 cells in normals and a significant increase in the variant cells in cancer patients after exposure to mutagenic chemotherapy drugs.
Langlois et al. (1987) demonstrated a linear relationship between frequency of mutations at the glycophorin A locus and radiation exposure in atomic bomb survivors.
Rahuel et al. (1988) showed, by Southern blot analysis of genomic DNA from normal En(a+) and rare En(a-) persons, that the glycophorin A gene has a complex organization and is largely deleted in persons of the En(a-) phenotype (Finnish type), who lack glycophorin A on their red cells. Rahuel et al. (1988) concluded that the Finnish variant is homozygous for a complete deletion of the glycophorin A gene without any detectable abnormality of the genes encoding glycophorins B or C. In the genome of the UK variant of En(a-), Rahuel et al. (1988) identified several abnormalities of the glycophorin A and B genes, leading them to conclude that both are largely deleted, being replaced by a gene fusion product composed of the N-terminal portion of a blood group M-type glycophorin A and of the C-terminal portion of glycophorin B.
Okubo et al. (1988) described 2 Japanese sisters with consanguineous parents who were apparently homozygous for M(k). Total absence of sialoglycoproteins A (alpha) and B (delta) from red cell membranes was demonstrated in 1 of the sisters. This is the third reported family; one of the other families was also Japanese. All affected individuals had been healthy except for the proposita in the present study who had Hodgkin disease.
Huang et al. (1988) studied a family in which 3 different glycophorin mutations were present in 2 individuals of a 16-member family. The variant Dantu glycophorin showed properties consistent with a delta-alpha (GPB/GPA) hybrid glycophorin. This gene was linked to a gene coding for the M-specific alpha glycophorin. Another variant glycophorin, Mi-III glycophorin, was transmitted as an autosomal dominant trait and was associated with N blood group activity. The inheritance pattern indicated that it could be a variant of delta glycophorin (glycophorin B). In the persons with both Dantu and Mi-III glycophorins, a delta glycophorin deficiency was observed, suggesting that a deletion or alteration of the delta gene may exist on the same chromosome as the Dantu gene. Huang et al. (1989) showed that the St(a) (Stone) antigen is likewise determined by a fusion hybrid of the glycophorin A and B genes.
As noted earlier, the glycophorin variant Miltenberger class V-like molecule (MiV) is a hybrid: Kudo et al. (1990) showed that the 5-prime half of the gene is derived from the GPA gene, whereas the 3-prime half is derived from the GPB gene. This structure is reciprocal to the glycophorin variant St(a), which has a GPB-GPA hybrid structure. Huang et al. (1992) identified the molecular nature of the change responsible for the Miltenberger class I (MiI) phenotype in a white family in which the first homozygote was observed.
The St(a) antigen has been shown to be associated with several isoforms of glycophorin. The St(a) alleles are genetically associated with splicing mutations in the GPA gene or with hybrid formation between GPA and GPB genes. Huang et al. (2000) reported the first and rare gene conversion event in which GPE recombined with GPA, giving rise to a novel GPA-E-A hybrid gene encoding the St(a) antigen.
Blumenfeld and Huang (1995) reviewed the molecular genetics of 25 variants of the glycophorin gene family, whose common denominator is that they arise from unequal gene combinations or gene conversions coupled to splice site mutations. Most rearrangements occur within a 2-kb region mainly within GPA and GPB and only rarely within the third member, GPE. They observed that the key feature is the shuffling of sequences within 2 specific exons (1 of which is silent), which are homologous in the 2 parent genes. This results in expression of a mosaic of sequences within the region, leading to polymorphism.
MNSs Blood Group System and Malaria
Red cells with the rare En(a-) variant are resistant to falciparum malaria (see 611162) (Pasvol et al., 1982). Such cells lack glycophorin A, the major red cell sialoglycoprotein (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).
GYPA and GYPB, 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) observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, they identified fixed adaptive changes at exons 3 to 4 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. Ko et al. (2011) also 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.
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.
Kariuki et al. (2020) demonstrated the effect of Dantu on the ability of the merozoite form of the malaria parasite P. falciparum to invade red blood cells. Kariuki et al. (2020) found that Dantu is associated with extensive changes to the repertoire of proteins found on the red blood cell surface, but, unexpectedly, inhibition of invasion does not correlate with specific red blood cell (RBC)-parasite receptor-ligand interactions. By following invasion using video microscopy, Kariuki et al. (2020) found a strong link between RBC tension and merozoite invasion, and identified a tension threshold above which invasion rarely occurs, even in non-Dantu RBCs. Dantu RBCs have higher average tension than non-Dantu RBCs, meaning that a greater proportion resist invasion. Kariuki et al. (2020) concluded that their findings provided both an explanation for the protective effect of Dantu, and fresh insight into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs found both within and between individuals.
GYPA Variant Assay
Grant and Bigbee (1994) discussed the use of the GPA assay to evaluate the creation of somatic mutations by cancer chemotherapy.
Rothman et al. (1995) used the GPA assay to evaluate the effects of occupational exposure to benzene. The GPA assay measures the frequency of variant erythrocytes that have lost expression of the blood type M in blood samples from heterozygous (MN) individuals. Variant cells are detected by treating sphered, fixed erythrocytes with fluorescent-labeled monoclonal antibodies specific for the M and N forms and, by flow cytometry, counting variant cells that bind the anti-N antibody but not the anti-M antibody. The variant cells possess the phenotype N-zero (single-copy expression of N and no expression of M) or NN (double-copy expression of N and no expression of M). These phenotypic variants arise from different mutational mechanisms in precursor cells: N-zero cells are thought to arise from point mutations, deletions, or gene inactivation, whereas NN cells presumably arise from mitotic recombination, chromosome loss and reduplication, or gene conversion. Rothman et al. (1995) used this GPA assay to evaluate DNA damage produced by benzene in 24 heavily exposed workers in Shanghai, China and 23 matched controls. A significant increase in the MN GPA variant cell frequency was found in benzene-exposed workers, but no significant difference existed between the 2 groups for N-zero cells. Furthermore, lifetime cumulative occupational exposure to benzene was associated with the NN frequency, but not with the N-zero frequency, suggesting that NN mutations occur in longer-lived bone marrow stem cells.
On the basis of studies in the family of a child with a translocation chromosome, German et al. (1968) suggested that the MN locus is either in the middle of chromosome 2 or near the distal end of the long arm of chromosome 4. Using 'banding techniques,' German and Chaganti (1973) restudied the translocation they reported in 1968 and concluded that MN can be tentatively assigned to the area of band q14 in the proximal portion of the long arm of chromosome 2. Weitkamp et al. (1972) presented data suggesting that the MN locus and the beta hemoglobin locus (141900) are linked. (This has, of course, been disproved.) Barbosa et al. (1975) excluded a recombination fraction of less than 0.30 for MN and Hb beta. The results supported a lower recombination fraction for males. Linkage with the Alzheimer locus (104300) and with colonic polyposis (175100) had been suspected. Recombination data suggested that the MN and acid phosphatase (ACP1; 171500) loci are far apart (Weitkamp et al., 1975). Cook et al. (1978) excluded MNSs from chromosome 9 by exclusion mapping that incorporated data both from families with chromosome markers and from linkage studies with firmly assigned markers. MNSs was subsequently assigned to chromosome 4. In a further study of the propositus of the 2q;4q translocation family, German et al. (1979) showed by banding that the breaks had occurred at 2q14 and 4q29 and that a minute segment had been lost at the site of break. Whether the loss was from chromosome 2 or 4 was not certain because both have several short bands at these sites and only one band was missing in the proband. The proband lacked blood type 's,' which he should have received from his 'ss' father, had signs of a modified red cell membrane, and had developmental abnormalities. Since the abnormalities of phenotype appeared at the same time as the chromosomal abnormality, German et al. (1979) suggested that deletion was the basis of all the changes. Since Weitkamp (1978) reported observations indicating strongly that MNSs is not near 2q14, German et al. (1979) concluded that it must be in a band near 4q29. Cook et al. (1980) favored 4q28 over 4q31. For males, Bias and Meyers (1979) found a maximal lod score of 3.99 at theta 0.18 for linkage of Stoltzfus (111800) and MNS. Acid phosphatase and Kidd both gave lods of 0.32 with Stoltzfus at a male-theta of 0.20. Linkage of Gc and MNSs at recombination frequencies of less than 25% in males and 30% in females was excluded by Weitkamp (1978). For MN versus Gc, Falk et al. (1979) found a male lod score of 3.75 at a recombination fraction of 0.30. In females the maximal lod score was 0.34 at a recombination fraction of 0.42. From analysis of MNSs blood groups in families with chromosome 4 rearrangements, both deletion analysis and family linkage study, Cook et al. (1981) concluded that the MNSs locus lies in the region 4q28-q31. Gedde-Dahl and Olaisen (1981) suggested that the sequence may be MN--Ss--Gc.
One of the longest genetic intervals measured in man in the pre-RFLP era was that between GC and MN with a lod score, in males, of 3.79 at a recombination fraction of 0.32 (Falk, 1984). In a linkage analysis of 146 informative families for MN and Ss, Spence et al. (1984) found 7 recombinant children out of 467, including 1 confirmed recombinant (retested and HLA-compatible) and 6 not verified. The 95% confidence interval of the estimate of recombination was 0.0033-0.1167.
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