MNS was the second blood group system to be discovered (1927). In a deliberate attempt to discover more blood group antigens, Landsteiner and Levine immunized rabbits with human red blood cells. The discovery and elucidation of inheritance was one of the most brilliant achievements in this field of biology; out of forty-one sera four were found to have a distinctive agglutinin that reacted independently of the then known ABO Blood Group types. By selective immunization and absorption, the serological specificities and inheritance of M and N were described. It was twenty years before the third antigen of the group, S, was identified; followed shortly by the discovery of the product of its antithetical allele, s. Because of this system's usefulness in testing inheritance within pedigrees, several newly discovered blood group antigens were found to be associated with this system; some being high incidence antigens (i.e. U, Ena) or, more frequently, low incidence antigens (i.e. Mg, He, Mta, etc). To date there have been over 43 antigens associated with this blood group system.
The MNS antigens are located on either glycophorin A, glycophorin B, hybrid or mutant structures of both of these sialoglycoproteins which are encoded by two highly homologous and closely linked genes on the long arm of chromosome 4. This system was the first non-water soluble blood group system to be biochemically investigated. Many of the low incidence antigens associated with hybrid structures could only have been assigned to this system through biochemical and DNA investigation.
The MNS antigens are found predominately on the red cells with some found on the renal endothelium and epithelium. Antibodies against M are fairly common, being the most frequently found antibody in non-transfused children, however antibodies against N are exceedingly rare (undoubtedly because N can be encoded by some forms of glycophorin A when the N gene is present and the most common form of glycophorin B). Even though anti–M antibodies are found in multiply-transfused individuals and multiparous females, it rarely if ever is associated with hemolysis of red cells. Antibodies against S, s and the majority of the remaining high and low incidence MNS antigens have been associated with hemolytic transfusion reactions and hemolytic disease of the newborn.
As with most blood group systems, this system has its "null" individuals. Those that lack both glycophorin A and B are referred to as MkMk (there are no detectable MNS antigens on these individuals' red cells). Those that lack glycophorin A but have a normal glycophorin B are En(a-) individuals and those that have glycophorin A but lack glycophorin B are S-s-U- individuals.
Interestingly, Landsteiner and Levine’s discovery prompted them to test apes with antisera prepared by immunizing rabbits with human M blood. These studies led them, conversely, to immunized rabbits with rhesus monkey blood in order to prepare anti-M reagents. Refer to the Rh blood group system and LW blood group system for their discovery.
The genetics of the system seem to imply that the N antigen is actually a precursor substance and the N gene is an amorph which leaves the N antigen unchanged while the M gene of the heterozygote converts part of the N antigen into M, and in the homozygote converts nearly all of the precursor to M. The MN antigens seem to have a direct interaction with membrane bound sialic acids, as M and N specificities seem to be linked to the presence of sialic acid variations.
It has been suggested that the antigenic variations may result from specific sialyl transferase activities, which transfer sialic acids to disaccharides bearing specific T and Tn specificities that characterize specific cryptic antigens. A.E. Mourant considered this blood group of interest only to the geneticist, due to a lack of disease association, however several diverse associations have surfaced including: an association of ankylosing spondylitis with homozygous MM () and an association between heterozygous MN and homozygous NN with environmental induced hyperlipidemia (Martin).
Cruz et. al. studied the tendency of Easter Islanders to become "hypertensive" upon moving to the mainland and concluded that homozygous NN was significantly more liable to develop hypertension. There was a significantly different distribution of MNS phenotypes in comparisons of essential and atherosclerotic renovascular hypertensives with normotensive controls. Essential hypertensives had a lower frequency of the S gene and a higher frequency of s in whites (X2 = 12.21, p less than 0.005). Atherosclerotic renovascular hypertensives differed from the normotensive population in the frequencies of both MN (X 2 = 4.34, p less than 0.05) and Ss (X2 = 4.21, p less than 0.05). ()
These are interesting disease associations, yet probably result more from co-dependent alleles than from a direct membrane bound antigen interaction.
The expansion of the MN system
When the MN system was first discovered it appeared rather uninteresting. It was of virtually no medical importance, and the frequencies of the M and N genes were closely similar, each near 5o per cent, in most populations available for testing. Only the American Indians, with much more M than N, relieved this uniformity. The discovery of the S and s antigens in 1947 and 1951 came at a fortunate time, for a model of closely linked genes in the Rh system had been very thoroughly studied, and so it was soon realized that here again closely linked loci were involved, two in number, one determining the alleles M and N and the other S and s. Thus in the MN system we now have the possibility of four haplotypes MS, Ms, NS, and Ns and, as we shall see, this expansion of the system greatly enhances its anthropological value.
A considerable number of other antigens are now known to be determined by genes closely linked to MN and Ss but only one of these, the Henshaw or He antigen, has any great anthropological value, for it appears to be totally limited to populations of African ancestry. The hypothetical allele of the He gene, which we may call he, has not yet been shown to give rise to an antigen.()
Antigens are glycophorins A and B (GPA and GPB), products of two tightly linked homologous genes GYPA and GYPB of the glycophorin gene family, each present in two different allelic forms. GPA bears the epitopes for the M,N blood groups and GPB, for S,s blood groups. The M and N allelic forms are about equally distributed in world populations. GPA and GPB are type I integral membrane proteins. GPA is the major sialoglycoproteins of the erythrocyte membrane present in about one million copies per cell; it contains ~ 50% carbohydrate,clustered in its extracellular domain in form of sialylated tri- and tetrasaccharide O- glycans and a single complex biantennary N-glycan.The level of GPB at the membrane surface is one tenth less; GPB has the same disposition and pattern of glycosylation but it lacks the N- linked unit. GPE, another member of the gene family, does not appear to be expressed under normal physiological conditions; however, it participates in gene rearrangments resulting in variant alleles.
The three glycophorin genes show a high degree of sequence homology and probably arose by gene duplication. Each gene is ~30 kb and they reside in a ~350 kb gene cluster (5'-GYPA-GYPB-GYPE-3') on 4q28-q31. Their high degree of sequence homology and organization along the chromosome may be responsible for the relatively frequent occurrence of unequal homologous recombinations and gene conversions among the three genes. A number of the resulting glycophorin products show variant blood group phenotypes, whose molecular studies, in turn, led to the documentation of those gene rearrangements.
Function of proteins
The function of GPA and GPB is not yet clear. However the absence of GPA and/or GPB from erythrocytes, as documented in certain variant erythrocytes in homozygous states (Mk, En(a), S-s-) does not result in significant physiological abnormalities. Possibly, as membrane abundantly glycosylated glycoproteins they provide a glycan coat to the erythrocyte; they serve as receptors for complement, cytokines, bacteria, viruses, P. falciparum; they may participate in regulation of the integrity of the membrane by association with cytoskeleton proteins. A role in Band 3 function is suggested by the absence of GPA in erythrocyte membranes from mice in which band 3 gene (SLC4A1) was inactivated (Hassouns H. et al., Blood, 91:2146, 1998).
Erythroid tissues exclusively.
About the alleles
The MNS system is nearly unique (except for the Rh system) in that gene rearrangements are a prevailing mechanism for the observed DNA variation resulting in variant alleles. Names of alleles are based on serological phenotypes and on the nature of gene rearrangement, whenever it occurs. Incidence in world populations of most rare alleles is less than 1%, except GPSta (Japan: 6%), GPMiIII (over 90% in certain regions of Taiwan), GPHenshaw or deletion of GPB (high in certain Black populations). A recent study details, by genotyping, the incidence of variant alleles encoding the Miltenberger and Sta phenotypes among the Taiwanese (Shihset al.).
In the list of alleles, the genomic or cDNA changes are numbered according to recommendations of den Dunnen and Antonarakis (Human Mutation 2000, 15:7-12) so that "A" of the first codon is no. 1. Note that codon 20 is the first codon expressed in the mature protein. GenBank sequences L31860 for GYPA and J02982 for GYPB are used as reference sequences.
Atopic and nonatopic asthma in children
J Asthma. 2005 Feb ;42:25-8 N Bottini, F Ronchetti, Fulvia Gloria-Bottini, L Stefanini, Egidio Bottini, N Lucarini
- In 155 asthmatic children we have studied the relationship between prick test positivity and a set of genetic factors previously found to be associated with bronchial asthma. Among these factors, MN system (p = 0.009) and age at onset of symptoms (p = 0.05) are the most important variables separating prick test negative from prick test positive children. MN and age at onset influence independently prick test positivity pointing to an additive effect of the two variables. M phenotype appears correlated positively with an increased susceptibility to nonallergic asthma in all age groups, whereas N phenotype appears correlated positively with age at onset but in allergic asthma only. The MN system codifies for glycophorin A, a sialoglycoprotein that represents a major ligand for several bacteria and viruses that recognize the N-acetylneuraminic acid present in this protein. The present data suggest that genetic variability in this system might influence bacterial and viral competition and mucosal damage influencing susceptibility to asthmatic reactions in absence of IgE hyperproduction.
Blood pressure and blood group markers. Association with the MN locus
Blood pressure and blood group markers. Association with the MN locus
J Hypertens. 1984 Aug;2(4):337-41.
Gleiberman L, Gershowitz H, Harburg E, Schork MA.
- The relationship of blood pressure levels to 12 blood, salivary and serum protein polymorphisms is reported for a sample of 4000+ adult Caucasians from Tecumseh, Michigan. Males with the MN phenotype had significantly higher unadjusted systolic and diastolic blood pressures than those who were homozygous MM or NN. When blood pressure was adjusted for age and weight, males who were Duffy (a-) had higher diastolic pressures than those who were Duffy (a+), and females who were Kidd (b-) had higher diastolic pressures than females who were Kidd (b+). A review of studies reporting on MN- blood pressure associations indicates that six of the eight presented significant findings. These findings, and others from the literature, present evidence that the MN locus (and possibly the Jk locus) actively participates in controlling the response to environmental/dietary stimuli affecting differences in blood pressure. We suggest that the MN blood group be investigated further, particularly vis-a-vis physiological parameters known to be related to blood pressure.
MN and Jk systems influence environmental variability in serum lipid levels
MN and Jk systems influence environmental variability in serum lipid levels
Clin Genet. 1983 Jul;24(1):1-14. Martin NG, Rowell DM, Whitfield JB.
- Significant heterogeneity in the distribution of within pair variances of serum total cholesterol, HDL cholesterol, non HDL cholesterol and triglyceride levels has been found in one or both of two samples of MZ twins. We have found some support for the observation of Magnus et al. (1981) that M- pairs have greater environmental variability in cholesterol levels than M+ pairs and weaker evidence that Jka+ pairs are more variable than Jka- pairs. However, these effects appear to be more striking on triglyceride levels. The low power of the variance ratio test is advanced as a possible reason for the inconsistencies in these findings.
A search for association between gene markers and serum cholesterol, triglyceride, urate and blood pressure
A search for association between gene markers and serum cholesterol, triglyceride, urate and blood pressure.
Ann Hum Biol. 1981 Jan-Feb;8(1):39-48. Buckton K, Lai LY, Gibson JB.
- This study was carried out to search for possible association between some polymorphic systems including ABO, MNSs, Rh, Duffy, Kell, Kidd, haptoglobin (Hp) and red cell acid phosphatase (PHs), and the variables serum cholesterol, triglyceride, urate, haemoglobin and blood pressure, in two separate samples of the Australian white population. Allele frequencies of each of the gene marker systems were comparable to those obtained by other workers for Australian whites. There were significant departures from Hardy-Weinberg proportions for red cell acid phosphatase and MNSs systems in one of the samples, and a possible cause for this is discussed. No associations were found between levels of cholesterol, triglyceride, urate and haemoglobin and most of the gene markers in either of the samples. However, a relationship was demonstrated between systolic blood pressure and two polymorphic systems, MNSs and Hp in both populations, and between diastolic blood pressure and red cell acid phosphatase in one of the samples.
Other database IDs and links
Gene nomenclature database ID
Genbank nucleic acids
NCBI homologenes for homologs and orthologs
NCBI dbSNP for single nucleotide polymorphisms
HGMD ID - at the Human Gene Mutation Database
OMIM ID - at Online Mendelian Inheritance in Man
- This article is licensed under the GNU Free Documentation License. Sections excerpted from Blood Group Antigen Gene Mutation Database. See: Blumenfeld OO, Patnaik SK. Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Human Mutation. 2004 Jan; 23(1):8-16. PubMed ID: 14695527