Abstract
The Working Party has met twice since the last report: in Seoul, South Korea 2014, and in London, UK 2015, both in association with the International Society of Blood Transfusion (ISBT) Congress. As in previous meetings, matters pertaining to blood group antigen nomenclature were discussed. Eleven new blood group antigens were added to seven blood group systems. This brings the current total of blood group antigens recognized by the ISBT to 346, of which 308 are clustered within 36 blood groups systems. The remaining 38 antigens are currently unassigned to a known blood group system.
Keywords: blood groups, genetics, terminology
The Working Party has met twice since the last report: in Seoul, South Korea 2014, and in London, UK 2015, both in association with the International Society of Blood Transfusion (ISBT) Congress. As in previous meetings, matters pertaining to blood group antigen nomenclature were discussed.
A total of seven blood group antigens were added to four of the current blood group systems (Table 1). Three new blood group systems were created, one de novo (CD59), and two others Vel (VEL) and Augustine (AUG), elevating the previously homeless high-incidence antigens Vel and Ata, respectively. This brings the current total of recognized blood group antigens to 346, of which 308 are clustered within 36 blood group systems. Thus, there remain 38 serologically defined antigens that have not been assigned to a blood group system as yet. Six of those are in the high prevalence series (901), 17 in the low prevalence series (700) and a further 15 reside in one of six collections (the 200 series).
Table 1.
New antigens added to blood group systems
| Blood group system | Antigen number | Alt. name | Prevalence | Molecular basis | Protein change |
|---|---|---|---|---|---|
| MNS | MNS47 | SARA | Low | GYPA c.240G>T | p.Arg80Ser |
| MNS | MNS48 | KIPP | Low | GYP(B-A-B) hybrid | p.Ser51a GPB(1-26)-GPwB(27-54)-GPA(55-57)-Bs(58-103) |
| LU | LU23 | LUIT | High | LU c.469G>A, 1289C>T | p.Gly157Arg, p.Thr430Ile |
| LU | LU24 | LUGA | High | LU c.212G>A | p.Arg71His |
| DO | DO9 | DOLC | High | ART4 c.566C>T | p.Thr189Met |
| DO | DO10 | DODE | High | ART4 c.405C>A | p.Asp135Glu |
| GLOB | GLOB2 | PX2 | Highb | B3GALNT1 | c |
| Vel | VEL1 | Vel | High | SMIM1 c.64_80delGTCAGCCTAGGGGCTGT | p.Ser22Glnfs*270 |
| CD59 | CD59.1 | – | High | CD59 c.146delA | p.Asp49Valfs*31 |
| AUG | AUG1 | – | High | ENT1 c.589 + 1G>C | p.Ser197fs |
| AUG | AUG2 | Ata | High | ENT1 c.1171G>A | p.Glu391Lys |
Distinguishes this protein from other known GP(B-A-B) hybrids.
Although PX2 is a product of β1,3GalNAc-T1 and therefore present on RBCs of common phenotype, it is absent from RBCs of and phenotypes whilst highly expressed on RBCs of the p phenotype.
Thus, all mutations causing the of and phenotypes also cause lack of PX2.
New blood group antigens
System 2: MNS
Two antigens have been added to the MNS system. Exome sequence analysis of samples from SARA+ and SARA− family members [1] identified a single nucleotide change c.240G>T in exon 3 of GYPA, which changes p.Arg80Ser. Sequence analysis of unrelated SARA+ samples confirmed the causative polymorphism [2]. The provisionally assigned number MNS47 was ratified by the working party and the low-prevalence series number 700052 has been made obsolete.
Molecular characterization of the GP.Kip and GP.Yak hybrid glycophorins showed that they were one and the same and are encoded by the same GYP(B-A-B) hybrid that produces Mur, Hil, MUT, MINY, as well as the antigen KIPP [3, 4]. KIPP is recognized by the anti-Hop+Nob sera, Anek and Raddon, but not by antisera specific for the Hop or Nob antigens; as well as by the original anti-Kipp serum [5]. The resulting GP(B-A-B) hybrid retains p.Ser51, which distinguishes this hybrid protein from other known GP(B-A-B) hybrids, which have p.Tyr51. The provisionally assigned number MNS48 was ratified by the working party.
System 5: Lutheran
A new high-prevalence antigen, LUIT was assigned to the Lutheran blood group system based on the serology (LU23) and the identification of two changes in LU: sequencing showed two novel homozygous mutations, one in exon 4, c.469G>A (p.Gly157Arg), and one in exon 10, c.1289C>T (p.Thr430Ile). [6]. There was insufficient evidence to determine which of the amino acids are responsible for the absence of the antigen, and thus, the allele number remains provisional: LU*02.−23. The proband’s RBCs typed Lu: −1,2,3,4,5,6w,8,13, although the weakening of LU6 expression is not understood.
A second new high-prevalence antigen named LUGA (LU24) was assigned to Lutheran based on the serology and the identification of a single missense change c.212G>A (p.Arg71His) in exon 3 of LU [7]. The proband’s plasma failed to react with Lu: −12 and Lu: −17 RBCs, as well as Lu(a−b−) RBCs and her own cells. However, anti-Lu12 could be excluded since the RBCs of the proband were reactive with anti-Lu12, and anti-Lu17 could be excluded based on the sequencing results which predicted homozygosity for Lu17. The serology may also be explained in part by the location of the novel amino acid change, which is predicted to lie in the first extracellular immunoglobulin domain of the Lu glycoprotein that also expresses Lu12, LURC, Lua/Lub, Lu21, Lu5 and Lu17. In addition, homozygosity for two silent changes were observed in exon 6 (c.711C>T and c.714C>T).
System 14: Dombrock
Two new high-prevalence antigens were assigned to the Dombrock blood group system, based both on serology and molecular analysis. The first, named DOLC, was based on the serology (DO9) and the identification of the c.566C>T (p.Thr189Met) change in exon 2 of DO. The proposita’s RBCs typed Do(a+b−), Hy+, Jo(a+), DOYA+, DOLG+ and her plasma was non-reactive with Gy(a−) RBCs and only weakly reactive with Hy− RBCs [8]. Similarly, an antibody with serological characteristics consistent with Dombrock antibodies, in that it was nonreactive with trypsin-treated RBCs and weakly reactive only with DTT-treated RBCs, was shown to be directed at a new high-prevalence antigen, subsequently named DODE. Molecular analysis identified a c.405C>A (p.Asp135Glu) change in exon 2 of DO [9]. The antigen was assigned as DO10.
System 28: GLOB
PX2, a carbohydrate antigen belonging to the GLOB collection (209) and determined by a terminal β3-N-acetyl-galactosamine added to paragloboside, was shown to be the product of B3GALNT1, also known as the P antigen synthase [10]. PX2 was therefore reclassified as a member of the GLOB blood group system (028). The P antigen was previously assigned the name GLOB1 (028001), and thus, PX2 was named GLOB2 (028002). This leaves LKE as the sole remaining antigen in the GLOB (209) collection, and the former PX2 number, 209004, was made obsolete.
New blood group systems
System 34: VEL
A founder mutation in the previously undescribed small integral protein 1 (SMIM1) gene, c.64_80delGTCAGCCTAGGGGCTGT, was identified as the primary molecular basis underlying the Vel− phenotype [11–13]. The presence or absence of Vel antigen was directly correlated to the presence or absence of SMIM1, a single-pass integral membrane protein. The considerable variation in antigen strength was shown not only to correlate with zygosity for the wild-type SMIM1 but could also be affected by two rare missense mutations, c.152T>A and c.152T>G (encoding p.Met51Lys and p.Met51Arg, respectively). Furthermore, a single nucleotide polymorphism in intron 2 (rs1175550) situated in a GATA-1 binding site also considerably influenced Vel antigen expression [12, 14, 15].
Based on the molecular and biochemical evidence, Vel was assigned blood group system status (034); system name: Vel; symbol: VEL, antigen: VEL1 (034001). There was no molecular evidence that ABTI was dependent on SMIM1 for expression, despite historical serological evidence of a phenotypic association [16]. As a consequence, collection 200212 was made obsolete and ABTI was returned to the 901 series and reassigned its old number (901015).
As yet, the function of SMIM1 remains unknown; however, elegant work by Arnaud and colleagues has suggested the protein to be a type 2 integral membrane protein [17].
System 35: CD59
Based on the publication of a case report in which a young patient with a CD59 deficiency produced an alloantibody specific for CD59, blood group status was unanimously assigned [18–20]. Both the blood group system and symbol are CD59 (035), and the antigen defined by the antibody maker in this case report has been named CD59.1.
System 36: AUG
The erythrocyte protein, equilibrative nucleoside transporter 1 (ENT1), was identified as the carrier of the Ata antigen. Daniels and colleagues showed that the At(a−) phenotype in individuals of African origin is defined by an amino acid polymorphism on the ENT1 protein (c.1171G>A; p.Glu391Lys) and that the At(a−) members of a family affected by bone malformation lacked the protein due to an inactivating mutation in the ENT1 gene: c.589+1G>C [21]. Based on the evidence, and following a discussion on names, the blood group system Augustine (symbol AUG) was created (036). The antigen defined by the antibody produced by the null phenotype was named AUG1, and the antigen defined by the amino acid Glu391 (Ata) was named AUG2.
Gene terminology
The Working Party ontinues to update the allele nomenclature tables and these can be found on the ISBT website. (http://www.isbtweb.org/working-parties/red-cell-immunogenetics-and-blood-group-terminology/) We anticipate an expansion of these tables, and a more detailed monograph on guidelines and usage is planned.
Table 2.
New blood group systems
| Blood group system | Symbol | Number | Reference sequence | Number of antigens | References |
|---|---|---|---|---|---|
| Vel | VEL | 034 | NM_001163724 | 1 | Storry, Jöud et al.[11], Cvejic et al.[12], Ballif et al. [13] |
| CD59 | CD59 | 035 | NM_000611.5 | 1 | Anliker et al. [19], Hochsmann et al. [20] |
| Augustine | AUG | 036 | NM_001078175.2 | 2 | Daniels et al.[21] |
Acknowledgments
Since the last report [22], Dr Philippe Rouger and Dr Lung-Chi Yu resigned from the Working Party. We sincerely thank them for their helpful contributions during the years. We also note with sadness the passing of our dear colleague Professor George Garratty, who was an active member of the Working Party to the end. As members of the Working Party, all authors have contributed equally to the discussion and conclusions drawn in this paper. CAH is funded by the Australian Red Cross Blood Service and acknowledges the Australian Governments that fund the Blood Service for provision of blood, blood products and services to the Australian Community.
Appendix 1. Members of the Working Party for Red Cell Immunogenetics and Blood Group Terminology 2014–2016
Dr Jill R Storry (Chair): Dept. of Clinical Immunology and Transfusion Medicine, Office for Medical Services, Lund, Sweden. jill.storry@med.lu.se
Prof Dr Lilian Castilho: University of Campinas/Hemocentro, Campinas, Brazil. castilho@unicamp.br
Dr Qing Chen: Jiangsu Province Blood Center, Nanjing, Jiangsu, China. qngchen@gmail.com
Dr Geoff L Daniels: International Blood Group Reference Laboratory, NHS Blood and Transplant, Bristol, UK. geoff.daniels.bris@outlook.com
Prof Dr Masja de Haas: Sanquin Blood Supply Foundation, Amsterdam, The Netherlands. m.dehaas@sanquin.nl
Dr Greg Denomme: Blood Center of Wisconsin, Milwaukee, WI, USA. greg.denomme@bcw.edu
Prof Dr Bill (W)A Flegel: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA. flegelwa@cc.nih.gov
Dr Christoph Gassner: Blutspende Zurich, Zurich, Switzerland. c.gassner@zhbsd.ch
Dr Catherine Hyland: Australian Red Cross Blood Services, Brisbane, Australia. chyland@arcbs.redcross.org.au
Dr Margaret Keller: American Red Cross Blood Services, Philadelphia, PA, USA. Margaret.Keller@redcross.org
Ms Christine Lomas Francis: New York Blood Center, New York, NY, USA. cfrancis@nybloodcenter.org
Dr Joann M Moulds: GRIFOLS ImmunoHematology Center, 201 Carlson Circle, San Marcos, TX, USA. joann.moulds@grifols.com
Dr Nuria Nogues: Banc de Sang i Teixits, Barcelona, Spain. nnogues@bst.cat
Prof Dr Martin L Olsson: Department of Laboratory Medicine, Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden. Martin_L.Olsson@med.lu.se
Dr. Thierry Peyrard, Institut National de la Transfusion Sanguine, Département Centre National de Référence pour les Groupes Sanguins, Paris, France. tpeyrard@ints.fr
Prof Dr C Ellen van der Schoot: Sanquin Research at CLB, Amsterdam, The Netherlands. e.vanderschoot@sanquin.nl
Dr Yoshihiko Tani: Japanese Red Cross Kinki Block Blood Center, Ibaraki-shi Osaka, Japan. y-tani@kk.bbc.jrc.or.jp
Ms Nicole Thornton: International Blood Group Reference Laboratory, NHS Blood and Transplant, Bristol, UK. nicole. thornton@nhsbt.nhs.uk
Dr Franz Wagner, Red Cross Blood Service NSTOB, Springe, Germany. fwagner@bsd-nstob.de
Dr Silvano Wendel: Blood Bank, Hospital Sirio-Libanes, São Paulo, Brazil. snwendel@terra.com.br
Dr Connie M Westhoff: New York Blood Center, New York, NY, USA. cwesthoff@nybloodcenter.org
Dr Vered Yahalom: NBGRL Magen David Adom, Ramat Gan, Israel. veredy@mda.org.il.
Footnotes
Conflict of interests
The authors declare no conflict of interest.
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