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- Hellberg, Åsa, et al.
(author)
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A novel RHCE*02 allele, containing the single-nucleotide change c.460A>G, encodes weakened expression of C and e antigens
- 2016
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In: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 56:9, s. 2391-2392
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Journal article (peer-reviewed)abstract
- We report a novel RHCE*02 allele in a Swedish blood donor that is characterized by the change c.460A>G (Arg154Gly). The blood donor's red blood cells showed variable reactivity with different monoclonal anti-C and anti-e and antigen strength was markedly weakened. We believe that these changes represent both a quantitative and qualitative alteration of the antigens encoded by this allele.
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| 5. |
- Ricci Hagman, Jennifer, et al.
(author)
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An update on the GLOB blood group system (and former GLOB collection)
- 2018
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In: Immunohematology. - 0894-203X. ; 34:4, s. 161-163
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Journal article (peer-reviewed)abstract
- CONCLUSIONS: The main change that has occurred in the GLOB blood group system since the GLOB review published in this journal in 2013 is the addition of an antigen. The high-prevalence PX2 antigen, originally recognized as the x2 glycosphingolipid, is expressed on red blood cells of most individuals and is elevated in the rare PP1Pk-negative p blood group phenotype. P synthase, encoded by B3GALNT1, was found to elongate paragloboside to PX2 by adding the terminal β3GalNAc moiety. Hence, PX2 was moved from the GLOB collection to the GLOB system. The presence of naturally-occurring anti-PX2 was noted in P1k and P2k individuals exhibiting nonfunctional P synthase. Although the clinical significance of this specificity remains unclear, a recommendation to avoid transfusing Pk patients with p phenotype blood has been made. Currently, 13 mutations at the highly conserved B3GALNT1 locus have been found to abolish P synthase function and are recognized as null alleles by the International Society of Blood Transfusion. A new allele with a missense mutation but resulting in normal expression of P has been assigned GLOB*02. Finally, the GLOB collection was made obsolete after the move of LKE antigen to the 901 series.
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| 7. |
- Stenfelt, Linn, et al.
(author)
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Missense mutations in the C-terminal portion of the B4GALNT2-encoded glycosyltransferase underlying the Sd(a−) phenotype
- 2019
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In: Biochemistry and Biophysics Reports. - : Elsevier BV. - 2405-5808. ; 19
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Journal article (peer-reviewed)abstract
- Sda is a high-frequency carbohydrate histo-blood group antigen, GalNAcβ1-4(NeuAcα2-3)Galβ, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a−) phenotype observed in 4% of individuals who may produce anti-Sda. A candidate gene (B4GALNT2), encoding a Sda-synthesizing β-1,4-N-acetylgalactosaminyltransferase (β4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sda deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize B4GALNT2 variants in nine Sd(a−) individuals. Homozygosity for rs7224888:T > C dominated the cohort (n = 6) and causes p.Cys466Arg, which targets a highly conserved residue located in the enzymatically active domain and is judged deleterious to β4GalNAc-T2. Its allele frequency was 0.10–0.12 in different cohorts. A Sd(a−) compound heterozygote combined rs7224888:T > C with a splice-site mutation, rs72835417:G > A, predicted to alter splicing and occurred at a frequency of 0.11–0.12. Another compound heterozygote had two rare nonsynonymous variants, rs148441237:A > G (p.Gln436Arg) and rs61743617:C > T (p.Arg523Trp), in trans. One sample displayed no differences compared to Sd(a+). When investigating linkage disequilibrium between B4GALNT2 variants, we noted a 32-kb block spanning intron 9 to the intergenic region downstream of B4GALNT2. This block includes RP11-708H21.4, a long non-coding RNA recently reported to promote tumorigenesis and poor prognosis in colon cancer. The expression patterns of B4GALNT2 and RP11-708H21.4 correlated extremely well in >1000 cancer cell lines. In summary, we identified a connection between variants of the cancer-associated B4GALNT2 gene and Sda, thereby establishing a new blood group system and opening up for the possibility to predict Sd(a+) and Sd(a‒) phenotypes by genotyping. © 2019 The Authors
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| 8. |
- Stenfelt, Linn, et al.
(author)
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The P1 histo-blood group antigen is present on human red blood cell glycoproteins
- 2019
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In: Transfusion. - : Wiley. - 0041-1132. ; 59:3, s. 1108-1117
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Journal article (peer-reviewed)abstract
- BACKGROUND: The P1 antigen was first described in 1927 and belongs to the P1PK histo-blood group system, together with Pk and NOR. The A4GALT-encoded 4-α-galactosyltransferase synthesizes these antigens and has been considered to extend glycolipids exclusively. However, contradicting studies have been published regarding the presence of P1 on human glycoproteins. In other species, P1 occurs on glycoproteins. Furthermore, human ABH antigens occur on both glycolipids and glycoproteins and are biochemically related to P1. Thus, we hypothesized that P1 is present on RBC glycoproteins in humans. STUDY DESIGN AND METHODS: RBCs of known P1/P2 status (phenotype and rs8138197 genotype) were used. The RBC surface glycans were modified with α-galactosidases, papain, and/or peptide-N-glycosidase F. RBC membrane proteins were analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis/immunoblot. A new P1/P2-allelic discrimination assay based on rs5751348 was validated. RESULTS: P1 occurs on various glycoproteins, seen as smearlike patterns in anti-P1-stained immunoblots with RBC membranes of P1 but not P2 or p phenotype. There was a significant difference between the staining of P1-homozygous and P1-heterozygous RBCs (P1P1 > P1P2), as well as intragenotypic variation. Immunoblotting banding patterns show major carriers at approximately 50 and 100 kDa. P1 staining was lost after treatment of RBCs with α-galactosidase of broad Galα-1,3/4/6-specificity. Peptide-N-glycosidase F treatment reduced the P1 signal, while papain or α-1,3-specific galactosidase did not. P1/P2 status was confirmed by a new rs5751348 assay. CONCLUSION: Our data indicate that the P1 antigen can reside on human RBC glycoproteins. Glycosidase studies suggest that at least part of the epitopes occur on N-glycans.
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| 9. |
- Westman, Julia, et al.
(author)
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Identification of the Molecular and Genetic Basis of PX2, a Glycosphingolipid Blood Group Antigen Lacking on Globoside-deficient Erythrocytes
- 2015
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 290:30, s. 18505-18518
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Journal article (peer-reviewed)abstract
- The x(2) glycosphingolipid is expressed on erythrocytes from individuals of all common blood group phenotypes and elevated on cells of the rare P/P1/P-k-negative p blood group phenotype. Globoside or P antigen is synthesized by UDP-N-acetylgalactosamine: globotriaosyl-ceramide 3-beta-N-acetylgalactosaminyl-transferase encoded by B3GALNT1. It is the most abundant non-acid glycosphingolipid on erythrocytes and displays the same terminal disaccharide, GalNAc beta 3Gal, as x(2). We encountered a patient with mutations in B3GALNT1 causing the rare P-deficient P-1(k) phenotype and whose pretransfusion plasma was unexpectedly incompatible with p erythrocytes. The same phenomenon was also noted in seven other unrelated P-deficient individuals. Thin-layer chromatography, mass spectrometry, and flow cytometry were used to show that the naturally occurring antibodies made by p individuals recognize x(2) and sialylated forms of x(2), whereas x(2) is lacking on P-deficient erythrocytes. Overexpression of B3GALNT1 resulted in synthesis of both P and x(2). Knockdown experiments with siRNA against B3GALNT1 diminished x(2) levels. We conclude that x(2) fulfills blood group criteria and is synthesized by UDP-N-acetylgalactosamine: globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase. Based on this linkage, we proposed that x(2) joins P in the GLOB blood group system (ISBT 028) and is renamed PX2 (GLOB2). Thus, in the absence of a functional P synthase, neither P nor PX2 are formed. As a consequence, naturally occurring anti-P and anti-PX2 can be made. Until the clinical significance of anti-PX2 is known, we also recommend that rare P-1(k) or P-2(k) erythrocyte units are preferentially selected for transfusion to P-k patients because p erythrocytes may pose a risk for hemolytic transfusion reactions due to their elevated PX2 levels.
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| 10. |
- Westman, Julia S., et al.
(author)
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Allele-selective RUNX1 binding regulates P1 blood group status by transcriptional control of A4GALT
- 2018
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 131:14, s. 1611-1616
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Journal article (peer-reviewed)abstract
- P1 and Pk are glycosphingolipid antigens synthesized by the A4GALT-encoded α1,4-galactosyltransferase, using paragloboside and lactosylceramide as acceptor substrates, respectively. In addition to the compatibility aspects of these histo-blood group molecules, both constitute receptors for multiple microbes and toxins. Presence or absence of P1 antigen on erythrocytes determines the common P1 (P1+Pk+) and P2 (P1-Pk+weak) phenotypes. A4GALT transcript levels are higher in P1 individuals and SNPs in non-coding regions of A4GALT, particularly rs5751348, correlate with P1/P2 status. Despite these recent findings, the molecular mechanism underlying these phenotypes remains elusive. The In(Lu) phenotype is caused by KLF1 haploinsufficiency and shows decreased P1 levels on erythrocytes. We therefore hypothesized KLF1 to regulate A4GALT expression. Intriguingly, P1 -specific sequences including rs5751348 revealed potential binding sites for several hematopoietic transcription factors, including KLF1. However, KLF1 binding did not explain P1-specific EMSA shifts and siRNA silencing of KLF1 did not affect A4GALT transcript levels. Instead, protein pull-down experiments using P1 but not P2 oligonucleotide probes identified RUNX1 by mass spectrometry. Furthermore, RUNX1 binds P1 alleles selectively and knockdown of RUNX1 significantly decreased A4GALT transcription. These data indicate that RUNX1 regulates A4GALT and thereby the expression of clinically important glycosphingolipids implicated in blood-group incompatibility and host-pathogen interactions.
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