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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-07-2064.
RED CELLS
From the Department of Transfusion Medicine, University
of Ulm, DRK (German Red Cross)-Blood Donation Service
Baden-Württemberg-Hessen, Institute Ulm, Germany;
and International Blood Group Reference Laboratory, Bristol,
United Kingdom.
The Scianna blood group encompasses the high-frequency
antigens Sc1 and Sc3 and the low-frequency antigen Sc2. Another
low-frequency antigen Rd (Radin) was suggested to belong to the Scianna
blood group. The molecular basis of the Scianna blood group was
unknown. The erythrocyte membrane-associated protein (ERMAP) shared the genomic location, protein product size, and localization to the red
blood cell (RBC) membrane surface with Scianna. The
ERMAP gene was sequenced in probands with known
Scianna and Radin phenotypes. In a Sc:-1,-2 proband, only an
ERMAP allele with a 2-bp deletion in exon 3 causing a
frameshift could be detected. A Sc:-1,2 proband was homozygous for the
ERMAP(Gly57Arg) allele. An Rd+
proband was heterozygous for the ERMAP(Pro60Ala) allele.
Polymerase chain reaction with sequence-specific priming (PCR-SSP)
systems was developed to detect the Sc2 and Rd alleles of the
ERMAP gene. The 2 alleles occurred with about 1% and less
than 1% frequency in the population, which was compatible with the
frequency of the Sc2 and Rd antigens known in whites. Two
Sc2+ and one Rd+ samples that were found by
genotyping were confirmed by serology. The antigens of the Scianna
blood group include Rd and are expressed by the human ERMAP protein.
Sc2 is caused by an ERMAP(Gly57Arg) allele and Rd by
an ERMAP(Pro60Ala) allele. Scianna is the last of
the previously characterized protein-based blood group systems whose
molecular basis was discerned. Hence, the phenotype prediction by
genotyping became possible for all human blood group systems encoded by proteins.
(Blood. 2003;101:752-757) The molecular characterization of polymorphism
underlying blood group antigens has made enormous advances during the
past 15 years.1 Currently, 26 blood group systems are
recognized.2 The antigens of 22 blood group systems are
determined by epitopes on proteins. They may function as transport or
adhesion proteins, ectoenzymes, or cytokine receptors present on the
red blood cell (RBC) surface.1 Most recently, the
DOK1 gene determining the Dombrock blood group system (ISBT
014) had been characterized,3 leaving Scianna (ISBT 013)
the last protein-based blood group system whose molecular basis
remained obscure.
The Scianna blood group system comprises 2 antithetical antigens, the
high-frequency antigen Sc1 (ISBT 013.001, formerly Sm) and the
low-frequency antigen Sc2 (ISBT 013.002, formerly Bua).
Lewis et al4 recognized the relationship of the
antigens and coined the name Scianna.5 The antigen Sc3
(ISBT 013.003) is expressed on all RBCs except those of the very rare
Sc:-1,-2 phenotype, 3 clusters of which were observed in circumscribed populations.5
The Scianna antigens were shown to reside on a Scianna glycoprotein of
about 60 to 68 kD.6 Scianna antigens were inherited linked
to the RH antigens but were shown to be distinct.7 The latest data indicated a genomic position of 1p34 to 1p36.8 A second low-frequency antigen, Radin (Rd; 700.015) shared this position9,10 and was found on a protein of similar
size.11 Both anti-Sc212 and
anti-Rd13 are clinically relevant, having caused hemolytic
disease of the newborn. The molecular basis and function of the Scianna
blood group system and its glycoprotein remained unknown.
We demonstrated that the Scianna antigens are expressed by the red cell
adhesion protein erythrocyte membrane-associated protein (ERMAP). The
polymorphism underlying the Sc2 and Rd antigens was determined.
Polymerase chain reaction with sequence-specific priming (PCR-SSP)
methods that allow the genotypic prediction of these antigens was developed.
Rare Scianna phenotypes
Nucleotide sequencing
PCR-SSP PCR-SSP methods were devised to detect the C>T polymorphism at nucleotide 54 (counted relative to the A of the start codon in the cDNA), the C>T polymorphism at position 76, the G>A polymorphism at position 169 causing the Sc1/Sc2 polymorphism, and the G at position 178 in Rd (Table 3). The reactions were triggered to work under similar PCR conditions as a PCR-SSP system previously developed for RHD typing.14,15 Thermocycling conditions consisted of an initial denaturation of 2 minutes at 94°C, followed by 10 cycles of 10-second denaturation at 94°C and 1-minute annealing/extension at 65°C and finally of 25 cycles of 30-second denaturation at 94°C, 1 minute annealing at 61°C, and 30-second extension at 72°C.15 Amplifications were carried out with Taq (Qiagen, Hilden, Germany) in a final volume of 10 µL. HGH control primers were used at a concentration of 0.75 µM to amplify the 434-bp control PCR fragment derived from the human growth hormone gene.
PCR-RFLP The PCR product also used for exon 3 sequencing (Table 2) was digested for 3 hours at 37°C with PvuII and SmaI (Pharmacia, Freiburg, Germany). In this assay (restriction fragment length polymorphism [RFLP]), PvuII was added in addition to SmaI to ensure that the resulting fragments were in a size range that allowed easy distinction of fragments that were or were not cut by SmaI.Population screen for ERMAP alleles The prevalence of the 54C>T and 76C>T polymorphism was determined in 111 blood samples from blood donors in Baden-Württemberg (South-Western Germany) by PCR-SSP. Maximum likelihood estimates of allele frequencies were calculated by using the counting method.16 The presence of ERMAP alleles representative of Sc2 and Rd was checked by PCR-SSP in 305 samples.Modeling The extent of the signal peptide was determined by using Signal P V2.0 (http://www.cbs.dtu.dk/services/SignalP-2.0/) web server.17,18 A 3-dimensional model of the immunoglobulin domain of ERMAP was modeled at the 3D-JIGSAW server (http://www.bmm.icnet.uk/~3djigsaw/)19,20 by using the heavy chain of the Fab fragment of the murine monoclonal antibody 3A221 as template. Stereoscopic views were rendered by using Deep View Swiss-PdbViewer (http://www.expasy.ch/spdbv/).
The nucleic acid and amino acid sequence data were deposited in EMBL/GenBank/DDBJ under accession nos. AJ505027 to AJ505034 (Sc:-1,-2,-3 allele), AJ505035 to AJ505042 (Sc2 allele), and AJ505043 to AJ505050 (Rd allele). The chromosomal position of the ERMAP gene and the molecular weight of the encoded ERMAP protein matched the data closely that were previously established for the Scianna glycoprotein.22,23 These observations prompted us to explore whether ERMAP alleles were underlying the Scianna antigens. A Sc:-1-2 proband is probably homozygous for a nonfunctional ERMAP allele We determined the nucleotide sequence of the 11 ERMAP exons in a proband that lacked the Sc1, Sc2, and Sc3 antigens (EMBL/GenBank/DDBJ accession nos. AJ505027 to AJ505034). In exon 3, the ERMAP allele harbored a 2-bp deletion that was possibly caused by a slippage error of the DNA polymerase in the GAGAGA repetitive sequence. This frameshift caused a truncated protein of 113 amino acids (Figure 1). Additional nucleotide substitutions 54C>T and 76C>T were detected in exon 2, the latter of which caused a His Thr amino acid substitution at codon 26 (not shown). No evidence for a second ERMAP allele was
observed, suggesting homozygosity for the ERMAP(54C>T,
76C>T, 307del2) allele. As an unlikely alternative, the
ERMAP(54C>T, 76C>T, 307del2) could be in trans to a second nonfunctional allele that possessed gross structural changes, preventing amplification of exons 2 and 3 by PCR.
Sc2 antigen is due to an ERMAP(Gly57Arg) allele Sc:2 samples carry an ERMAP(Gly57Arg) allele.
The ERMAP gene of a Sc:-1,2 proband was sequenced to
determine the molecular basis of the Sc2 antigen and to corroborate
that Scianna and ERMAP are identical (EMBL/GenBank/DDBJ
accession nos. AJ505035 to AJ505042). A substitution of guanosine (G)
by adenosine (A) was detected at the predicted cDNA position 169 (relative to the A of the start codon) that indicated the homozygous presence of an ERMAP allele with a Gly
ERMAP(Gly57Arg) is rare in the population. DNA from 305 blood donors was checked for the presence of an ERMAP(Gly57Arg) allele by PCR-SSP. Five samples carried this allele in heterozygous form, as a wild-type allele could be detected by PCR-SSP, too. A haplotype frequency of 0.008 was deduced for ERMAP(Gly57Arg). ERMAP(Gly57Arg)-positive samples are Sc:2. Red cells of 2 ERMAP(Gly57Arg) heterozygous donors detected by PCR-SSP were tested for the Sc1 and Sc2 antigens by serology. Both donors were found to be Sc:1,2. Rd antigen is due to an ERMAP(Pro60Ala) allele An Rd+ sample carries an ERMAP(Pro60Ala)
allele.
The ERMAP gene of an Rd+ proband was sequenced
to assess if Rd belongs to the Scianna blood group system
(EMBL/GenBank/DDBJ accession nos. AJ505043 to AJ505050). A C>G
heterozygosity was detected at the predicted cDNA position 178 that
indicated the heterozygous presence of an ERMAP allele with
a Pro
ERMAP(Pro60Ala) is very rare in the population. Among the 305 blood donors previously tested for ERMAP(Gly57Arg), no donor was positive for the ERMAP(Pro60Ala) allele. However, among a different set of 20 random donors, an ERMAP(Pro60Ala)-positive sample was inadvertently found. The second ERMAP(Pro60Ala)-positive sample is Rd+. Red cells of the ERMAP(Pro60Ala)-positive donor detected by PCR-SSP were tested for the Sc1, Sc2, and Rd antigens by serology and were found to be Sc:1,-2; Rd+. Population frequencies of the ERMAP(His26Tyr) allele and the silent 54C>T polymorphism The 54C>T and 76C>T polymorphisms initially observed in the rare Sc:-1,-2 phenotype were also encountered in control samples. Therefore, 111 blood donors were systematically checked for the presence of an ERMAP(His26Tyr) allele or a 54C>T polymorphism (Table 4). Maximum likelihood estimates of the allele frequencies were derived. ERMAP(His26Tyr) occurred with a frequency of 0.33. Most of these alleles (allele frequency 0.28) were predicted to carry a 54C>T substitution, too, whereas an ERMAP(His26Try) with the wild-type C at position 54 occurred less frequently (allele frequency 0.05). In contrast, the ERMAP alleles encoding a His at position 26 carried a C at position 54 (allele frequency 0.67) and represented the wild-type allele.22,23
Modeling of the ERMAP immunoglobulin domain On the basis of the known similarity of ERMAP to immunoglobulin, we modeled the tertiary structure of the amino acids 46 to 131 representing part of the extracellular domain of ERMAP. The Pro substituted in the Rd allele was exposed on the protein's surface. The amino acid causing the Sc1/Sc2 polymorphism was located in a pocket of the protein's surface, thereby rendering it less accessible to antibodies. However, the amino acids involved in the Sc2 polymorphism were predicted to alter the 3-dimensional structure of this extracellular domain considerably, which may explain the immunogenicity of the ERMAP polymorphism (Figure 4).
The antigens of the Scianna blood group system are carried by the ERMAP protein. We formally proved that the low-frequency Rd antigen belongs to the Scianna blood group system, because it is expressed by a variant ERMAP protein. A third amino acid polymorphism His26Tyr was frequently observed but located in the signal peptide. The human ERMAP gene was a good candidate gene for the Scianna blood group locus: Its genomic position23 was almost in the midst of the position 1p34 to 1p36 reported for the Scianna locus.8 ERMAP was expressed on RBCs22,23 and shared homology to chicken blood group antigens.23 The molecular weight of 60 to 68 kD determined for the glycosylated Scianna protein11 was compatible with 446 amino acids predicted for the mature ERMAP protein. The identity of the ERMAP gene with the gene underlying the Scianna blood group system was based on 2 independent lines of evidence: (1) The expression of the Sc antigens was lacking in a proband who carried no functional ERMAP allele. (2) The expression of the Sc1 and Sc2 antigens correlated with the presence of a wild-type ERMAP allele and the otherwise rare ERMAP(Gly57Arg) allele, respectively. Each observation alone could have been explained by a linkage to a neighboring gene; their coincidence, however, must be considered convincing evidence of the identity of ERMAP and Scianna. Alternative explanations for the accrued data are unlikely: The assumption that Scianna antigens depend on the interaction of several membrane proteins, like Wrb that is defined by an interaction of the anion exchanger AE1 and glycophorin A,24,25 could hardly be reconciled with the earlier demonstration11 that Scianna antigens reside on one glycoprotein as defined by immunoblotting. The most parsimonious explanation for the observed coincidence of mutations in the ERMAP immunoglobulin domain with antigens of the Scianna glycoproteins is the identity of ERMAP and Scianna. However, a formal proof would have to rely on the expression of ERMAP recombinant proteins carrying the proposed Sc/Rd mutations in eukaryotic cells followed by cell surface analysis with antibodies specific for Sc and Rd antigens. Such studies could also address the question of whether the ERMAP protein is expressed in a complex with other membrane proteins, like the Rh proteins, the in vitro expression of which is regulated by the RhAG protein.26 The low-frequency Rd antigen was often suspected to belong to the Scianna blood group,11 but a final verification was lacking. We showed Rd to be associated with the distinct rare ERMAP(Pro60Ala) allele, rendering Rd part of the Scianna blood group system. Sc:-1,-2 RBCs have been reported to lack several distinguishable high-incidence antigens.27 It will be straightforward to check for the association of high- and low-frequency antigens with ERMAP alleles, possibly extending the number of antigens known to belong to this blood group system. ERMAP is the fourth blood group protein belonging to the immunoglobulin superfamily, along with LU (ISBT 005),28 LW (ISBT 016),29 and OK (ISBT 024).30 As expected, the amino acids involved in the Sc1/Sc2 and Rd blood group polymorphisms occurred in an extracellular protein segment. The Gly at position 57 representative of the Sc1 antigen was rather inaccessible at the protein's surface, as shown by modeling of the immunoglobulin domain of ERMAP. However, the amino acid substitution in Sc2 was predicted to cause considerable displacement of the neighboring amino acids, which may explain its immunogenicity. A third amino acid polymorphism His26Tyr was frequent in our population. Because the 29 aminoterminal amino acids of ERMAP probably represented its signal peptide, this polymorphism was not expected to be part of the mature ERMAP protein. Accordingly, a correlation with a blood group antigen was neither expected nor established. Although the His26Tyr polymorphism was also observed in the ERMAP allele of the Sc:-1,-2,-3 proband, there was no indication that it prevented Sc1 expression: The His26Tyr substitution and the frameshift destroying the functional peptide sequence occurred in the same PCR product encompassing ERMAP exons 2 and 3, excluding the possibility that these 2 aberrations from the normal nucleotide sequence related to 2 different nonfunctional alleles. Furthermore, the frequent occurrence of a nonfunctional His26Tyr allele in the donor population would be incompatible with the known extreme rarity of Sc:-1,-2,-3 individuals. Scianna was the last previously defined blood group system encoded by a protein whose molecular basis was resolved. Hence, the identification of the gene underlying Scianna rendered genotyping possible for all protein-encoded blood groups. The ERMAP protein is believed to represent an adhesion protein and possesses a C1q recognition sequence.22,23 It is characterized by the presence of an extracellular immunoglobulin domain and an intracellular B30.2 domain. The immunoglobulin domain is most similar to myelin/oligodendrocyte glycoprotein (MOG), a component of the myelin sheath on the surface of oligodendrocytes and Schwann cells and is a common autoantigen in patients with multiple sclerosis.23 B30.2 domains occur in combination with quite dissimilar N-terminal structures, like immunoglobulin domains, RING finger domains, and leucine zippers,31 and are found in transmembrane, intracellular, and secreted proteins.31 Because the familial Mediterranean fever (MIM 249100) and Opitz G/BBB syndrome (MIM 300000) are associated with mutations in the B30.2 domains of pyrin and of MID1, respectively, they are assumed to be functionally important.31 The concatenation of immunoglobulin and B30.2 domains, as observed in ERMAP, resembles most closely butyrophilin, a major protein of the milk droplet. Additional functional motifs detected in ERMAP include several phosphorylation consensus sequences for tyrosine kinase, casein kinase, and protein kinase C, a motif resembling a consensus site for SH3 domain binding, a dileucine motif that can mediate internalization of membrane receptors, and a possible leucine zipper.22 Although the function of ERMAP has not been fully established, it is known to be expressed throughout erythropoesis.22 Because the probands of the known kindreds with Sc:-1,-2 phenotype appear to be healthy,5 its function may likely be compensated by other proteins. Even the lack of functional important proteins as the water transporter in Co(a-b-) individuals32 may become symptomatic only in very special circumstances.33 It may be worthwhile to check if the polymorphisms observed in ERMAP influence its binding characteristics and function.
We thank John J. Moulds (Ortho Diagnostics, Raritan, NJ) and Joann M. Moulds (Hahnemann University, Philadelphia, PA) for rare RBC and serum samples from SCARF, and Cornelie B. Lonicer (Munich, Germany) for providing an anti-Sc2 serum. We acknowledge the expert technical assistance of Marianne Lotsch, Hedwig Bohnacker, Anita Hacker, and Nicole Stampfl in Ulm and Jackie Banks in Bristol.
Submitted July 10, 2002; accepted August 8, 2002.
Prepublished online as Blood First Edition Paper, August 22, 2002; DOI 10.1182/blood-2002-07-2064.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Willy A. Flegel, Abteilung Transfusionsmedizin, Universitätsklinikum Ulm, and DRK-Blutspendedienst Baden-Württemberg-Hessen, Institut Ulm, Helmholtzstrasse 10, D-89081 Ulm, Germany; e-mail: waf{at}ucsd.edu.
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Gubin AN, Njoroge JM, Wojda U, et al.
Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family.
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© 2003 by The American Society of Hematology.
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  D. Hodge, E. Coghill, J. Keys, T. Maguire, B. Hartmann, A. McDowall, M. Weiss, S. Grimmond, and A. Perkins A global role for EKLF in definitive and primitive erythropoiesis Blood, April 15, 2006; 107(8): 3359 - 3370. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
