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| 2. |
- Hult, Annika K, et al.
(författare)
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A new missense variant in exon 7 of the ABO gene, c.662G>A, in a family with B w phenotype.
- 2022
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Ingår i: Transfusion. - : Wiley. - 1537-2995 .- 0041-1132. ; 62:10, s. 55-58
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Tidskriftsartikel (refereegranskat)abstract
- 1 BACKGROUNDWeak expression of ABO antigens is encountered in the clinical laboratory occasionally, and subgroups of A are more commonly observed in Europeans than subgroups of B. To date, weakly expressing B variant phenotypes have been associated with 38 different alleles according to ISBT (https://www.isbtweb.org/resource/001aboalleles.html). This number is an underrepresentation since there have been several reports of aberrant B expression due to variant alleles since the last update of the ISBT allele table. The current study was initiated by an unusual blood group typing result in a 55-year-old male patient of Czech origin and previously reported as an abstract.12 BRIEF METHODSBlood grouping was performed according to standard blood banking practice, initially using an automatic analyzer (Galileo, Immucor) followed by confirmation with manual gel (BioRad; DG-Gel) and tube agglutination techniques. Initial genotyping analysis was done using a PCR-SSP kit (Innotrain), microarray (BloodChip Reference, Progenika) and subsequently verified by expanded PCR-ASP and PCR-RFLP as described previously.2, 3 ABO exons 1–7 and splice sites were amplified and analyzed, together with the product(s) of PCR-ASP for exons 6–7, by Sanger sequencing.4 A single nucleotide variation (SNV) was detected, and the localization of the affected amino acid is visualized in a 3D-model of ABO glycosyltransferase by Cn3D (v.4.3.1, www.ncbi.nih.gov) and a detailed view obtained by AlphaFold.5, 6 Flow cytometry testing with monoclonal ABO reagents was performed as described previously.73 RESULTSThe proband's red blood cells (RBCs) initially typed as group O but the plasma typing gave negative or weak reactions with test RBCs of group B, depending on the method used, Table 1. An ABO*B.01/O.01.01 genotype was revealed, normally consistent with group B. Screening for selected A and B subgroup allele markers was negative.2 After informed consent, samples from family members were drawn and further investigation was performed.In samples from the proband, his sister and niece, sequence analysis revealed heterozygosity for a SNV in ABO exon 7, c.662G>A (no rs number available) in an otherwise normal ABO*B.01 allele. Significantly weakened B antigen expression was observed in all three individuals. An overview of serological testing and genetic results is shown in Table 1.SNV c.662G>A encodes an amino acid change, p.Gly221Asp. The glycine residue is completely evolutionarily conserved among the members of the GT6 family of glycosyltransferases8 and centrally located in the enzyme, seven amino acids away from the DVD motif (pp. 211–213) that coordinates the Mn2+ ion and the UDP part of the UDP-galactose donor substrate (Figure 1A). However, it is not directly interfering with the catalytic site. Instead, the change of the small neutral glycine to the bulkier and charged aspartic acid is predicted to abolish selected hydrogen bonds and is therefore hypothesized to destabilize the protein conformation (Figure 1B).5, 6
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| 3. |
- Hult, Annika K., et al.
(författare)
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GBGT1 is allelically diverse but dispensable in humans and naturally occurring anti-FORS1 shows an ABO-restricted pattern
- 2018
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Ingår i: Transfusion. - : Wiley. - 0041-1132. ; 58:8, s. 2036-2045
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The FORS histo-blood group system was described in 2013 and much remains to be investigated regarding its genetic and immunohematologic characteristics, as well as its clinical importance. While presence of the c.887G>A-mutated GBGT1 gene, which results in FORS1 glycosphingolipid expression on human red blood cells (RBCs), is rare in the populations tested so far, naturally occurring anti-FORS1 in plasma appears common. STUDY DESIGN AND METHODS: The Erythrogene database was utilized to probe genetic variation in GBGT1 among 2504 individuals in the 1000 Genomes Project. We screened 1108 Swedish blood donors for three principally important single-nucleotide polymorphisms (c.363C>A, c.886C>T, and c.887G>A) and selected samples were analyzed further. Screening for naturally occurring anti-FORS1 in plasma from 100 donors was performed using antigen-positive RBCs. RESULTS: We identified 68 GBGT1 alleles, of which three were previously listed blood group alleles. Eight potential null alleles were observed, based on three different nonsense mutations. Four healthy donors were found homozygous for c.363C>A, which truncates the GBGT1-encoded Fs synthase prematurely. This is the first description of human knock-outs for GBGT1. The c.886C>T mutation that alters the same codon (p.Arg296Trp) changed by c.887G>A (p.Arg296Gln) was overexpressed to investigate if it induces the FORS1+ phenotype. However, c.886C>T did not result in synthesis of FORS1. We detected anti-FORS1 in 10% of all donors tested but none in the A1 or A1B groups. CONCLUSION: We have extended the knowledge of GBGT1 variants, allele frequencies, and the characteristics of naturally occurring antibodies in our newest carbohydrate blood group system, FORS. The finding of c.363C>A-homozygous donors indicates that GBGT1 is dispensable.
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| 4. |
- Hult, Annika K., et al.
(författare)
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May the FORS be with you : a system sequel
- 2020
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Ingår i: Immunohematology. - 0894-203X. ; 36:1, s. 14-18
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Forskningsöversikt (refereegranskat)abstract
- This article is an update of the review of the FORS system published in Immunohematology in 2017 (Hult AK, Olsson ML. The FORS awakens: review of a blood group system reborn. Immunohematology 2017;33:64-72). This update incorporates the most recently presented knowledge on this still enigmatic system and its genetic, enzymatic, and immunological aspects. Further insight into the genetic variation and allele frequencies of the GBGT1 locus has been reported, and screening studies regarding the prevalence of naturally occurring anti-FORS1 in human plasma have been performed and presented. More basic knowledge on the specificity of the gene product, the Forssman synthase, has been obtained in several detailed studies, and its relation to the homologous ABO gene has been investigated. Taken together, we summarize recently added information about the carbohydrate-based FORS blood group system (International Society of Blood Transfusion number 031).
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| 5. |
- Jakobsen, Marianne A., et al.
(författare)
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A novel ABO allele with a 21-bp duplication identified in two unrelated European individuals with weak A expression
- 2020
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Ingår i: Transfusion Medicine. - : Wiley. - 0958-7578 .- 1365-3148. ; 30:6, s. 508-512
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To carry out genetic and serological analyses of a Swiss blood donor and a Danish patient carrying an aberrant ABO phenotype with weak A expression. Background: ABO is the most clinically important blood group system but also one of the most complex. The system antigens are determined by carbohydrate structures generated by A and B glycosyltransferases encoded by the ABO gene. Genetic variants of ABO may encode a glycosyltransferase with reduced activity, leading to weak expression of A antigen. Methods: Samples from two individuals were examined using genetic testing and extended immunohaematological evaluation, including standard serological methods, flow cytometry and analysis of plasma glycosyltransferase activity. Results: Both individuals were serologically determined to be AweakB. Genetic testing revealed that both were heterozygous for a novel ABO*A1.01-like allele with an in-frame duplication of 21 nucleotides in exon 7 (c.543_563dup), leading to the insertion of seven amino acids (QDVSMRR). Flow cytometric testing of native red blood cells (RBCs) showed very weak A antigen expression. This was in accordance with the enzyme activity test. Conclusion: In summary, we describe a novel A allele with a duplication of 21 nucleotides in exon 7 that significantly decreases the enzyme activity and leads to very weak expression of A antigen. (200 words).
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| 6. |
- Joseph, Abigail, et al.
(författare)
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ABO Genotyping finds more A2 to B kidney transplant opportunities than lectin-based subtyping
- 2023
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135. ; 23:4, s. 512-519
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Tidskriftsartikel (refereegranskat)abstract
- ABO compatibility is important for kidney transplantation, with longer waitlist times for blood group B kidney transplant candidates. However, kidneys from non-A1 (eg, A2) subtype donors, which express less A antigen, can be safely transplanted into group B recipients. ABO subtyping is routinely performed using anti-A1 lectin, but DNA-based genotyping is also possible. Here, we compare lectin and genotyping testing. Lectin and genotype subtyping was performed on 554 group A deceased donor samples at 2 transplant laboratories. The findings were supported by 2 additional data sets of 210 group A living kidney donors and 124 samples with unclear lectin testing sent to a reference laboratory. In deceased donors, genotyping found 65% more A2 donors than lectin testing, most with weak lectin reactivity, a finding supported in living donors and samples sent for reference testing. DNA sequencing and flow cytometry showed that the discordances were because of several factors, including transfusion, small variability in A antigen levels, and rare ABO∗A2.06 and ABO∗A2.16 sequences. Although lectin testing is the current standard for transplantation subtyping, genotyping is accurate and could increase A2 kidney transplant opportunities for group B candidates, a difference that should reduce group B wait times and improve transplant equity.
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| 9. |
- Popova, Inna S., et al.
(författare)
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Synthesis of blood group Forssman pentasaccharide GalNAcα1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ–R
- 2019
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Ingår i: Mendeleev Communications. - : Elsevier BV. - 0959-9436. ; 29:5, s. 578-580
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Tidskriftsartikel (refereegranskat)abstract
- Synthesis of the glycan part of Forssman glycolipid GalNAcα1-3GalNAcβ1-3Galα1-4Galβ1-4Glc–Cer in the form of 2-aminoethyl glycoside has been carried out. The glycoside has been converted into a lipophilic derivative capable of controlled inserting into erythrocytes. The obtained surface-modified cells, termed kodecytes, revealed a high level of the blood group system FORS serological activity.
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| 10. |
- Seo, Ean Jeong, et al.
(författare)
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Network pharmacology of triptolide in cancer cells : implications for transcription factor binding
- 2021
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Ingår i: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 39:6, s. 1523-1537
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Tidskriftsartikel (refereegranskat)abstract
- Background Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (p = 0.65 × 10–2) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. Conclusion Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.
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