B l o o d G r o u p R e v i e w An update on the MNS blood group system

L. Castilho

This update of the MNS blood group system (Reid ME. MNS produces Mur, Hil, MUT, and MINY, but the resulting GP(B- blood group system: a review. Immunohematology 2009;25:95– A-B) hybrid has p.Ser51, which distinguishes this from 101) reports three new antigens of the MNS system numbered other known GP(B-A-B) hybrids that have p.Tyr51.6,7 MNS49, MNS47, MNS48, and MNS49; new (GP) variants associated with silent and weak expression of MNS antigens; also named JENU, is a high-prevalence antigen on GPB and the results of new studies on associations of MNS antigens encoded by GYPB, defined as an within the amino acid with band 3, Rh , and malaria. The addition of these sequence between positions 38 and 49 (38SYISSQTNGETG49) three antigens brings the total number of antigens in the MNS system (International Society of Blood Transfusion system 2) to that is absent from the GP.Mur hybrid as it is disrupted by the 49. Immunohematology 2019;35:61–62. insertion of hybrid exon 3.1,8 New alleles and hybrid associated with MNS antigen Key Words: MNS blood group system, GYPA, GYPB, GYPE, expressions have also been identified, and the complete list of glycophorin MNS antigens and alleles is available at http://www.isbtweb. org/working-parties/red-cell-immunogenetics-and-blood- Update on the MNS Blood Group System group-terminology. The molecular bases and predicted amino acid changes of glycophorin variants and antigens are also The MNS blood group system is highly complex, with 49 available at http://www.erythrogene.com. antigens currently recognized by the International Society of Another addition to the MNS system was the identification Blood Transfusion.1 All antigens are carried by glycophorin of new GP variants associated with silent and weak expression A (GPA), glycophorin B (GPB), or multiple glycophorin (GP) of MNS antigens. It has been shown that in addition to the variants resulting from unequal crossover or conversion three major genetic backgrounds known to drive the S–s– events between GYPA and GYPB genes.2 GYPE, the other phenotype in black individuals (GYPB deletion, GYPB*P2, glycophorin gene family member, does not encode detectable and GYPB*NY alleles), gene conversion events between antigens on the (RBC) surface but has been GYPB and GYPE can also abolish the expression of S and s.9 shown to be involved in gene rearrangements encoding Partial or complete skipping of exon 5 in GYPB was associated hybrid proteins.3 The homology of the three genes of the GYP with weakened expression or silencing of s, respectively.10,11 locus facilitates the occurrence of cross-over events between Finally, three causal GYPB deletions underlying the S–s–U– them, generating new alleles and variants. Since publication phenotype were recently characterized.12 of the original review,4 three new antigens have been added A novel variant called En(IND) insertional GYPA variant to the MNS system (Table 1). MNS47, also named SARA, was the first new genetic basis for the En(a–) phenotype is a low-prevalence antigen on GPA encoded by a single in 30 years, and it has been found to be associated with nucleotide change c.240G>T in exon 3 of GYPA, which changes the single nucleotide insertion G at position c.314-315 in p.Arg80Ser.5,6 MNS48, also named KIPP, is a low-prevalence exon 5 of GYPA, causing absence of GPA.13 Studies on the antigen encoded by the same GYP(B-A-B) hybrid that associations of MNS antigens with band 3 and Rh proteins

Table 1. New antigens of the MNS blood group system

Antigen Number Name Prevalence Molecular basis Protein change Reference MNS47 SARA Low GYPA c . 240G>T p.Arg80Ser 5, 6 MNS48 KIPP Low GYP(B-A-B) hybrid p.Ser51 6, 7 MNS49 JENU High GYPB, defined as an epitope within Interrupted by the amino acids encoded by the 1, 8 38SYISSQTNGETG49 GYPA exon 3 insertion in the GP.Mur hybrid protein encoded by GYP*501

IMMUNOHEMATOLOGY, Volume 35, Number 2, 2019 61 L. Castilho

demonstrated that the variant GP.Mur may play a pivotal role 8. Lopes GH, Wilson B, Liew Y-W, et al. An alloantibody in a in supporting Wrb antigen expression on Mi.III RBCs and homozygous GYP*Mur individual defines JENU (MNS49), a new high-frequency antigen on glycophorin B. Transfusion affects differential erythroid expression of Rh/RhAG before 2017;57:716–7. 14,15 16 protein translation. Recently, Leffler et al. demonstrated 9. Willemetz A, Nataf J, Honier V, Peyrard T, Arnaud L. Gene that the loss of GYPB and gain of two GYPB-A hybrid genes, conversion events between GYPB and GYPE abolish expression which encodes the Dantu antigen, reduces the risk of severe of the S and s blood group antigens. Vox Sang 2015;108:410–6. 10. Yazer MH, Gabert K, Bolen N, Sood C, Ocha G. A new variant at malaria caused by by 40 percent. position IVS5+5 of GYPB*s associated with an s– phenotype. Considering the complexity of the MNS system and the Transfusion 2015;55(Suppl):147A(SP233). new technologies that are emerging, new alleles, variants, and 11. Slayten JK, Halverson GR, Yassai MB, Bedel B, Denomme GA. var antigens are still expected to be identified. Suspected U blood donor homozygous for a novel s (MNS4) allele. Transfusion 2015;55(Suppl):147A(SP234). 12. Gassner C, Denomme G, Portmann C, et al. Two prevalent References GYPB deletions are causative of MNS blood group U negativity in Black Africans. Vox Sang 2018;113(Suppl 1):250(P-546). 1. Storry JR, Clausen FB, Castilho L, et al. International 13. Lindholm PF, Drouillard JS, Hartman K, et al. En(IND), a Society of Blood Transfusion Working Party on Red Cell single nucleotide-insertion GYPA variant causing absence of Immunogenetics and Blood Group Terminology: Report of . Transfusion 2018;58(Suppl):175A(IGT34). the Dubai, Copenhagen and Toronto meetings. Vox Sang 2019;114:95–102. 14. Hsu K, Lin Y-C, Lee T-Y, Lin M. Miltenberger blood group antigen subtype III (Mi.III) supports Wrb expression. Vox Sang 2. Daniels G. Human blood groups. 3rd ed. Oxford, UK: Wiley- 2011;100:389–94. Blackwell, 2013. 15. Hsu K, Kuo M-S, Yao C-C, et al. The MNS glycophorin variant 3. Reid ME, Lomas-Francis C, Olsson ML. The blood group GP.Mur affects differential erythroid expression of Rh/RhAG antigen factsbook. 3rd ed. New York: Elsevier, 2012. transcripts. Vox Sang 2017;112:671–7. 4. Reid ME. MNS blood group system: a review. 16. Leffler EM, Band G, Busby GBJ, et al. Resistance to malaria Immunohematology 2009;25:95–101. through structural variation of red blood cell invasion receptors. 5. McBean RS, Hyland CA, Hendry JL, Shabani-Rad M-T, Flower Science. 16 June 2017. doi: 10.1126/science.aam6393. RL. SARA: a “new” low-frequency MNS antigen (MNS47) provides further evidence of the extreme diversity of the MNS blood group system. Transfusion 2015;55:1451–6. Lilian Castilho, PhD, Professor and Researcher, Hemocentro 6. Storry JR, Castilho L, Chen Q, et al. International Society of Campinas, University of Campinas, Rua Carlos Chagas, 480, Caixa Blood Transfusion Working Party on Red Cell Immunogenetics Postal 6198, CEP 13081-970 Barão Geraldo, Campinas, SP, Brazil, and Terminology: Report of the Seoul and London meetings. [email protected]. Vox Sang 2016;11:118–22. 7. Lopes GH, Wei L, Ji Y, Condon JA, Luo G, Hyland CA, Flower RL. GYP*Kip, a novel GYP(B-A-B) hybrid allele, encoding the MNS48 (KIPP) antigen. Transfusion 2016;56:539–41.

For information concerning the National Reference Immunohematology is on the Web! Laboratory for Blood Group Serology, including the American Rare Donor Program, contact Sandra Nance, by phone at www.redcrossblood.org/hospitals/immunohematology (215) 451-4362, by fax at (215) 451-2538, or by e-mail at [email protected]. For more information, send an e-mail to [email protected].

62 IMMUNOHEMATOLOGY, Volume 35, Number 2, 2019