scholarly journals Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jesse Eernstman ◽  
Barbera Veldhuisen ◽  
Peter Ligthart ◽  
Marieke von Lindern ◽  
C. Ellen van der Schoot ◽  
...  
Keyword(s):  
Blood Group ◽  
High Frequency ◽  
Target Gene ◽  
Fetal Hemoglobin ◽  
Antigen Expression ◽  
Donor Group ◽  
Wild Type ◽  
Blood Group Typing ◽  
Novel Variants ◽  
Indian Blood

AbstractBeta-hemoglobinopathies become prominent after birth due to a switch from γ-globin to the mutated β-globin. Haploinsufficiency for the erythroid specific indispensable transcription factor Krueppel-like factor 1 (KLF1) is associated with high persistence of fetal hemoglobin (HPFH). The In(Lu) phenotype, characterized by low to undetectable Lutheran blood group expression is caused by mutations within KLF1 gene. Here we screened a blood donor cohort of 55 Lutheran weak or negative donors for KLF1 variants and evaluated their effect on KLF1 target gene expression. To discriminate between weak and negative Lutheran expression, a flow cytometry (FCM) assay was developed to detect Lu antigen expression. The Lu(a−b−) (negative) donor group, showing a significant decreased CD44 (Indian blood group) expression, also showed increased HbF and HbA2 levels, with one individual expressing HbF as high as 5%. KLF1 exons and promoter sequencing revealed variants in 80% of the Lutheran negative donors. Thirteen different variants plus one high frequency SNP (c.304 T > C) were identified of which 6 were novel. In primary erythroblasts, knockdown of endogenous KLF1 resulted in decreased CD44, Lu and increased HbF expression, while KLF1 over-expressing cells were comparable to wild type (WT). In line with the pleiotropic effects of KLF1 during erythropoiesis, distinct KLF1 mutants expressed in erythroblasts display different abilities to rescue CD44 and Lu expression and/or to affect fetal (HbF) or adult (HbA) hemoglobin expression. With this study we identified novel KLF1 variants to be include into blood group typing analysis. In addition, we provide further insights into the regulation of genes by KLF1.

scholarly journals Novel variants in Krueppel Like Factor 1 that cause Persistence of Fetal Hemoglobin in In(Lu) individuals

2021 ◽  
Author(s):  
Jesse Eernstman ◽  
Barbera Veldhuisen ◽  
Peter Ligthart ◽  
Marieke von Lindern ◽  
Ellen van der Schoot ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Transcription Factor ◽  
Blood Group ◽  
High Frequency ◽  
Fetal Hemoglobin ◽  
Donor Group ◽  
Wild Type ◽  
Novel Variants ◽  
Klf1 Gene ◽  
Indian Blood

Abstract Beta-hemoglobinopathies become prominent after birth due to a switch from γ-globin to the mutated β-globin. Haploinsufficiency for the erythroid specific indispensable transcription factor Krueppel-like factor 1 (KLF1) is associated with high persistence of fetal hemoglobin (HPFH). The In(Lu) phenotype, characterized by low to undetectable Lutheran blood group expression is caused by mutations within KLF1 gene. These KLF1 variants often lead to KLF1 haploinsufficiency. We screened a donor cohort of 55 Lutheran weak or negative donors for KLF1 variants. To discriminate between weak and negative Lutheran expression, a flow cytometry (FCM) assay was developed to detect Lu polymorphisms. The Lu(a-b-) (negative) donor group, showing a significant decreased CD44 (Indian blood group) expression, also showed increased HbF and HbA2 levels, with outliers expressing >5% HbF. KLF1 exons and promoter sequencing revealed variants in 80% of the Lutheran negative donors. Thirteen different variants plus one high frequency SNP (c.304T>C) were identified of which 6 were novel. In primary erythroblasts, knockdown of endogenous KLF1 resulted in decreased CD44, Lu and increased HbF expression, while KLF1 over-expressing cells were comparable to wild type (WT). In line with the pleiotropic effects of KLF1 during erythropoiesis, distinct KLF1 mutants expressed in erythroblasts display different abilities to rescue CD44 and Lu expression and/or to affect fetal (HbF) or adult (HbA) hemoglobin expression.

Normal Synaptonemal Complex and Abnormal Recombination Nodules in Two Alleles of the Drosophila Meiotic Mutant mei-W68

Genetics ◽  
2003 ◽  
Vol 163 (4) ◽  
pp. 1337-1356 ◽  
Author(s):  
Adelaide T C Carpenter
Keyword(s):  
Electron Microscopy ◽  
Synaptonemal Complex ◽  
High Frequency ◽  
Serial Section ◽  
The Other ◽  
Wild Type ◽  
Recombination Nodules ◽  
Section Electron ◽  
Serial Section Electron Microscopy ◽  
Section Electron Microscopy

Abstract The meiotic phenotypes of two mutant alleles of the mei-W68 gene, 1 and L1, were studied by genetics and by serial-section electron microscopy. Despite no or reduced exchange, both mutant alleles have normal synaptonemal complex. However, neither has any early recombination nodules; instead, both exhibit high numbers of very long (up to 2 μm) structures here named “noodles.” These are hypothesized to be formed by the unchecked extension of identical but much shorter structures ephemerally seen in wild type, which may be precursors of early recombination nodules. Although the mei-W68L1 allele is identical to the mei-W681 allele in both the absence of early recombination nodules and a high frequency of noodles (i.e., it is amorphic for the noodle phene), it is hypomorphic in its effects on exchange and late recombination nodules. The differential effects of this allele on early and late recombination nodules are consistent with the hypothesis that Drosophila females have two separate recombination pathways—one for simple gene conversion, the other for exchange.

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

Biomimetic ABO Blood-Group Typing

2006 ◽  
Vol 45 (16) ◽  
pp. 2626-2629 ◽  
Author(s):  
Oliver Hayden ◽  
Karl-J. Mann ◽  
Stefan Krassnig ◽  
Franz L. Dickert
Keyword(s):  
Blood Group ◽  
Abo Blood Group ◽  
Blood Group Typing

scholarly journals Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals

2021 ◽  
Vol 11 (2) ◽  
pp. 94
Author(s):  
Masaki Kumondai ◽  
Akio Ito ◽  
Evelyn Marie Gutiérrez Rico ◽  
Eiji Hishinuma ◽  
Akiko Ueda ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Three Dimensional ◽  
Warfarin Dose ◽  
Catalytic Efficiency ◽  
Therapeutic Window ◽  
Wild Type ◽  
Drug Metabolizing Enzyme ◽  
Novel Variants ◽  
Metabolizing Enzyme ◽  
Almost All

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.

scholarly journals ABO and P1 Blood Group Antigen Expression andstxGenotype and Outcome of ChildhoodEscherichia coliO157:H7 Infections

2002 ◽  
Vol 185 (2) ◽  
pp. 214-219 ◽  
Author(s):  
Srdjan Jelacic ◽  
Cheryl L. Wobbe ◽  
Daniel R. Boster ◽  
Marcia A. Ciol ◽  
Sandra L. Watkins ◽  
...  
Keyword(s):  
Blood Group ◽  
Antigen Expression ◽  
Blood Group Antigen

ABO histo-blood group antigen expression on the graft endothelium long term after ABO-compatible, non-identical heart transplantation.

2006 ◽  
Vol 13 (2) ◽  
pp. 166-170 ◽  
Author(s):  
Simon C. Koestner ◽  
Andreas Kappeler ◽  
Thomas Schaffner ◽  
Thierry P. Carrel ◽  
Paul J. Mohacsi
Keyword(s):  
Heart Transplantation ◽  
Blood Group ◽  
Antigen Expression ◽  
Blood Group Antigen

Modulation of ABH histo-blood group antigen expression in normal and myasthenic human thymus

Apmis ◽  
2006 ◽  
Vol 114 (10) ◽  
pp. 669-674
Author(s):  
VICTORIA S. SARAFIAN ◽  
TSVETANA T. MARINOVA
Keyword(s):  
Blood Group ◽  
Antigen Expression ◽  
Blood Group Antigen ◽  
Human Thymus

scholarly journals Increase of Fetal Hemoglobin and Loss of Blood Group Antigen B in a Patient with Leukemia

1969 ◽  
Vol 99 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Hiroshige Kurokawa ◽  
Syusaku Katsura ◽  
Mitsugi Kamada ◽  
Wataru Matsuo ◽  
Kazuo Tokiwa ◽  
...  
Keyword(s):  
Blood Group ◽  
Fetal Hemoglobin ◽  
Blood Group Antigen ◽  
Antigen B

scholarly journals Cellular retinol-binding protein type III is a PPARγ target gene and plays a role in lipid metabolism

2008 ◽  
Vol 295 (6) ◽  
pp. E1358-E1368 ◽  
Author(s):  
Cynthia F. Zizola ◽  
Gary J. Schwartz ◽  
Silke Vogel
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Free Fatty Acid ◽  
Target Gene ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Wild Type ◽  
Type Iii ◽  
Cellular Retinol Binding Protein

Cellular retinol-binding protein (CRBP) type III (CRBP-III) belongs to the family of intracellular lipid-binding proteins, which includes the adipocyte-binding protein aP2. In the cytosol, CRBP-III binds retinol, the precursor of retinyl ester and the active metabolite retinoic acid. The goal of the present work is to understand the regulation of CRBP-III expression and its role in lipid metabolism. Using EMSAs, luciferase reporter assays, and chromatin immunoprecipitation assays, we found that CRBP-III is a direct target of peroxisome proliferator-activated receptor-γ (PPARγ). Moreover, CRBP-III expression was induced in adipose tissue of mice after treatment with the PPARγ agonist rosiglitazone. To examine a potential role of CRBP-III in regulating lipid metabolism in vivo, CRBP-III-deficient (C-III-KO) mice were maintained on a high-fat diet (HFD). Hepatic steatosis was decreased in HFD-fed C-III-KO compared with HFD-fed wild-type mice. These differences were partly explained by decreased serum free fatty acid levels and decreased free fatty acid efflux from adipose tissue of C-III-KO mice. In addition, the lack of CRBP-III was associated with reduced food intake, increased respiratory energy ratio, and altered body composition, with decreased adiposity and increased lean body mass. Furthermore, expression of genes involved in mitochondrial fatty acid oxidation in brown adipose tissue was increased in C-III-KO mice, and C-III-KO mice were more cold tolerant than wild-type mice fed an HFD. In summary, we demonstrate that CRBP-III is a PPARγ target gene and plays a role in lipid and whole body energy metabolism.

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