bims-conane 2024-11-17 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2024–11–17
twelve papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.
Prevalence and screening of hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in Yemeni blood donors.
Whole Blood Transcriptome Analysis in Congenital Anemia Patients.
Activation of γ-globin expression by a common variant disrupting IKAROS-binding motif in β-thalassemia.
A glutamine metabolic switch supports erythropoiesis.
Mitapivat for Acquired Pyruvate Kinase Deficiency.
Identification and functional analysis of novel SPTB and ANK1 mutations in hereditary spherocytosis patients.
Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1).
Effects of Thalidomide on Endothelial Activation and Stress Index in Children with β-Thalassemia Major.
New Insights into the Fanconi Anemia Pathogenesis: A Crosstalk Between Inflammation and Oxidative Stress.
Contribution of p53-dependent and -independent mechanisms to upregulation of p21 in Fanconi anemia.
Increased exercise tolerance in humanized G6PD deficient mice.

Int J Mol Sci. 2024 Oct 23. pii: 11408. [Epub ahead of print]25(21):

Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.

International Hemoglobinopathy Research Network (INHERENT)

  Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 to identify eligible GWAS studies following PRISMA guidelines. Four independent reviewers screened, extracted, and synthesized data using narrative and descriptive methods. Study quality was assessed using a modified version of the Q-Genie tool. Pathway enrichment analysis was conducted on gene lists derived from the selected GWAS studies. Out of 113 initially screened studies, 62 underwent full-text review, and 16 met the inclusion criteria for quality assessment and data synthesis. A total of 939 significant SNP-trait associations (p-value < 1 × 10-5) were identified, mapping to 133 genes (23 with overlapping variant positions) and 103 intergenic sequences. Most SNP-trait associations converged around BCL11A (chr.2), HBS1L-MYB, (chr.6), olfactory receptor and beta globin (HBB) gene clusters (chr.11), with less frequent loci including FHIT (chr.3), ALDH8A1, BACH2, RPS6KA2, SGK1 (chr.6), JAZF1 (chr.7), MMP26 (chr.11), COCH (chr.14), ABCC1 (chr.16), CTC1, PFAS (chr.17), GCDH, KLF1, NFIX, and ZBTB7A (chr.19). Pathway analysis highlighted Gene Ontology (GO) terms and pathways related to olfaction, hemoglobin and haptoglobin binding, and oxygen carrier activity. This systematic review confirms established genetic modifiers of HbF level, while highlighting less frequently associated loci as promising areas for further research. Expanding research across ethnic populations is essential for advancing personalized therapies and enhancing outcomes for individuals with sickle cell disease or β-thalassemia.

Keywords:  F cells; GWAS; SNP; beta thalassemia; fetal hemoglobin (HbF); genetic modifier; sickle cell disease (SCD); systematic review

DOI:  https://doi.org/10.3390/ijms252111408
Hematology. 2024 Dec;29(1): 2424504

Prevalence and screening of hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in Yemeni blood donors.

Mohammed A W Almorish, Ahmed M E Elkhalifa, Elsharif A Bazie, Elsadig Mohamed Ahmed, Isameldin Mohamed Abdalla Hamad, Omer M Aburaida, Rabei M Elbadry, Yasir S Kaloda, Tarig Babikir Algak Khalid.

  OBJECTIVES: This study aimed to determine the prevalence of total blood cell abnormalities, hemoglobinopathies and G6PD deficiency and evaluate the efficacy of red blood cell (RBC) indices, mentzer index (MI) and naked-eye single tube red cell osmotic fragility (NESTROF) test as screening tools for diagnosis of β thalassemia trait among Yemeni blood donors.METHODS: A cross-sectional study was conducted with 106 volunteer blood donors who met the national standard criterion of blood donation. Various tests were performed, including complete blood count (CBC), serum ferritin, sickling test, G6PD assay, NESTROF test and high-performance liquid chromatography (HPLC).
RESULTS: The prevalence of hematological abnormalities among blood donors reached 68.9%, with functional RBC abnormalities at 51.9%, leukopenia at 10.4%, thrombocytosis at 1.9%, and thrombocytopenia at 4.7%. Additionally, hemoglobinopathies were found in 21.7% of donors, with β-thalassemia trait at 3.8%, sickle cell trait at 1.9%, and suspected α-thalassemia trait at 16%, while G6PD deficiency and iron deficiency were present in 12.3% and 17.9% of donors, respectively. The NESTROF test, MCV and MCH demonstrated a sensitivity rate of 100%. MI and MCH exhibited the highest specificity followed by NESTROF test in the screening of β-thalassemia trait.
CONCLUSIONS: The prevalence of hemoglobinopathies and G6PD deficiency appear to be common among Yemeni blood donors. These results emphasize the necessity of comprehensive blood donation screening programs to safeguard the blood supply and promote early detection and management of hemoglobinopathies and G6PD deficiency in Yemen.

Keywords:  G6PD deficiency; HPLC; Hemoglobinopathies; MI; NESTROF test; α-thalassemia trait; β-thalassemia trait

DOI:  https://doi.org/10.1080/16078454.2024.2424504
Int J Mol Sci. 2024 Oct 31. pii: 11706. [Epub ahead of print]25(21):

Whole Blood Transcriptome Analysis in Congenital Anemia Patients.

Maria Sanchez-Villalobos, Eulalia Campos Baños, Elena Martínez-Balsalobre, Veronica Navarro-Ramirez, María Asunción Beltrán Videla, Miriam Pinilla, Encarna Guillén-Navarro, Eduardo Salido-Fierrez, Ana Belén Pérez-Oliva.

  Congenital anemias include a broad range of disorders marked by inherent abnormalities in red blood cells. These abnormalities include enzymatic, membrane, and congenital defects in erythropoiesis, as well as hemoglobinopathies such as sickle cell disease and thalassemia. These conditions range in presentation from asymptomatic cases to those requiring frequent blood transfusions, exhibiting phenotypic heterogeneity and different degrees of severity. Despite understanding their different etiologies, all of them have a common pathophysiological origin with congenital defects of erythropoiesis. We can find different types, from congenital sideroblastic anemia (CSA), which is a bone marrow failure anemia, to hemoglobinopathies as sickle cell disease and thalassemia, with a higher prevalence and clinical impact. Recent efforts have focused on understanding erythropoiesis dysfunction in these anemias but, so far, deep gene sequencing analysis comparing all of them has not been performed. Our study used Quant 3' mRNA-Sequencing to compare transcriptomic profiles of four sickle cell disease patients, ten thalassemia patients, and one rare case of SLC25A38 CSA. Our results showed clear differentiated gene map expressions in all of them with respect to healthy controls. Our study reveals that genes related to metabolic processes, membrane genes, and erythropoiesis are upregulated with respect to healthy controls in all pathologies studied except in the SLC25A38 CSA patient, who shows a unique gene expression pattern compared to the rest of the congenital anemias studied. Our analysis is the first that compares gene expression patterns across different congenital anemias to provide a broad spectrum of genes that could have clinical relevance in these pathologies.

Keywords:  blood disorders; congenital sideroblastic anemia (CSA); sickle cell disease (SCD); transcriptomic analysis; β-thalassemia

DOI:  https://doi.org/10.3390/ijms252111706
J Genet Genomics. 2024 Nov 07. pii: S1673-8527(24)00289-3. [Epub ahead of print]

Activation of γ-globin expression by a common variant disrupting IKAROS-binding motif in β-thalassemia.

Hualei Luo, Jueheng Wang, Lang Qin, Xinhua Zhang, Hailiang Liu, Chao Niu, Mengyang Song, Congwen Shao, Peng Xu, Miao Yu, Haokun Zhang, Yuhua Ye, Xiangmin Xu.

  Programmed silencing of γ-globin genes in adult erythropoiesis is mediated by several chromatin remodeling complexes, which determine the stage-specific genome architecture in this region. Identification of cis- or trans-acting mutations contributing to the diverse extent of Hb F might illustrate the underlying mechanism of γ-β globin switching. Here, we recruit a cohort of 1142 β-thalassemia patients and dissect the natural variants in the whole β-globin gene cluster through a targeted next-generation sequencing panel. A previously unreported SNP rs7948668, predicted to disrupt the binding motif of IKAROS as a key component of chromatin remodeling complexes, is identified to be significantly associated with higher levels of Hb F and age at onset. Gene-editing on this SNP leads to elevation of Hb F in both HUDEP-2 and primary CD34+ cells while the extent of elevation is amplified in the context of β-thalassemia mutations, indicating epistasis effects of the SNP in the regulation of Hb F. Finally, we perform ChIP-qPCR and 4C assays to prove that this variant disrupts the binding motif of IKAROS, leading to enhanced competitiveness of HBG promoters to locus control regions. This study highlights the significance of common regulatory SNPs and provides potential targets for treating of β-hemoglobinopathy.

Keywords:  Fetal hemoglobin; IKAROS; Locus control region; Single nucleotide polymorphism; β-thalassemia

DOI:  https://doi.org/10.1016/j.jgg.2024.10.015
Science. 2024 Nov 15. 386(6723): eadh9215

A glutamine metabolic switch supports erythropoiesis.

Junhua Lyu, Zhimin Gu, Yuannyu Zhang, Hieu S Vu, Christophe Lechauve, Feng Cai, Hui Cao, Julia Keith, Valentina Brancaleoni, Francesca Granata, Irene Motta, Maria Domenica Cappellini, Lily Jun-Shen Huang, Ralph J DeBerardinis, Mitchell J Weiss, Min Ni, Jian Xu.

Metabolic requirements vary during development, and our understanding of how metabolic activity influences cell specialization is incomplete. Here, we describe a switch from glutamine catabolism to synthesis required for erythroid cell maturation. Glutamine synthetase (GS), one of the oldest functioning genes in evolution, is activated during erythroid maturation to detoxify ammonium generated from heme biosynthesis, which is up-regulated to support hemoglobin production. Loss of GS in mouse erythroid precursors caused ammonium accumulation and oxidative stress, impairing erythroid maturation and recovery from anemia. In β-thalassemia, GS activity is inhibited by protein oxidation, leading to glutamate and ammonium accumulation, whereas enhancing GS activity alleviates the metabolic and pathological defects. Our findings identify an evolutionarily conserved metabolic adaptation that could potentially be leveraged to treat common red blood cell disorders.

DOI: https://doi.org/10.1126/science.adh9215
Pediatr Blood Cancer. 2024 Nov 13. e31440

Mitapivat for Acquired Pyruvate Kinase Deficiency.

Hanny Al-Samkari.

  Pyruvate kinase (PK) activation is emerging as a promising treatment modality for numerous congenital hemolytic anemias of diverse pathophysiology, and one agent, mitapivat, is already licensed to treat patients with congenital PK deficiency. However, PK deficiency may also be acquired in the setting of clonal myeloid disorders and other pathologies, where it may result in severe hemolytic anemia and remains without known therapies. This case report describes the novel application of mitapivat therapy in a patient with acquired PK deficiency causing red cell transfusion dependence, liberating the patient from transfusions and resulting in marked improvement in symptoms and quality of life.

Keywords:  acquired pyruvate kinase deficiency; hemolytic anemia; mitapivat; pyruvate kinase; transfusion‐dependent

DOI:  https://doi.org/10.1002/pbc.31440
Sci Rep. 2024 11 09. 14(1): 27362

Identification and functional analysis of novel SPTB and ANK1 mutations in hereditary spherocytosis patients.

Charuwan Panarach, Chaiwat Netsawang, Issarang Nuchprayoon, Kamonlak Leecharoenkiat.

  Hereditary spherocytosis (HS) is the most prevalent form of congenital hemolytic anemia, being caused by genetic mutations in genes encoding red blood cell cytoskeletal proteins. Mutations in the ANK1 and SPTB genes are the most common causes of HS.; however, pathogenicity analyses of these mutations remain limited. This study identified three novel heterozygous mutations in 3 HS patients: c.1994 C > A in ANK1, c.5692 C > T, and c.3823delG in SPTB by whole-exome sequencing (WES) and validated by Sanger sequencing. To investigate the functional consequences of these mutations, we studied their pathogenicity using in vitro culture erythroblast derived from CD34 + stem cells. All three mutations lead to the generation of a premature stop codon. Real-time PCR assay revealed that the two SPTB mutations resulted in reduced SPTB mRNA expression, suggesting a potential role for the nonsense-mediated mRNA degradation pathway. For the ANK1 mutation, gene expression was not reduced but was predicted to produce a truncated version of the ANK1 protein. Flow cytometry analysis of red blood cell-derived microparticles (MPs) revealed that HS patients had higher MP levels compared to normal subjects. This study contributes to the current understanding of the molecular mechanisms underlying mutations in the ANK1 and SPTB genes in HS.

Keywords:  ANK1; DNA sequencing; Hereditary spherocytosis; Mutation; NGS; SPTB

DOI:  https://doi.org/10.1038/s41598-024-78622-w
Blood Cells Mol Dis. 2024 Nov 02. pii: S1079-9796(24)00076-7. [Epub ahead of print]110 102898

Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1).

Alexandre Raynor, Katell Peoc'h, Camille Boi, Hana Manceau, Serge Pissard, Karim Diallo, Caroline Kannengiesser, Pierre Rohrlich.

  Congenital microcytic anemias are rare diseases associated with decreased hemoglobin synthesis and red blood cells of low corpuscular volume. DMT1/NRAMP2 is a highly conserved divalent cation transporter encoded by the SLC11A2 gene, expressed at the membrane of various cells. It ensures ferrous iron absorption from the apical membrane of enterocytes, iron recovery from urine by renal tubules, and acidified endosome uptake after transferrin internalization. Pathogenic DMT1 variants have been described in 10 individuals to date, associated with recessive hypochromic anemia and iron overload. Herein, we report a new variant of SLC11A2 (c.469A>G, p.Ile157Val) compound with known p.Arg416Cys associated with a frankly microcytic anemia and increased transferrin saturation. The clinical picture observed in the patient was exceptionally mild, extending the field of the DMT1 phenotypes to borderline anemias.

Keywords:  Anemia; DMT1; Iron; Microcytosis; NRAMP2

DOI:  https://doi.org/10.1016/j.bcmd.2024.102898
Mediterr J Hematol Infect Dis. 2024 ;16(1): e2024076

Effects of Thalidomide on Endothelial Activation and Stress Index in Children with β-Thalassemia Major.

Jie Chen, Wenqiang Kong, Jian Xiao, Xiaodong Liu, Kun Yang.



Keywords:  Children; Endothelial Activation; Stress Index; Thalidomide; β-thalassemia major

DOI:  https://doi.org/10.4084/MJHID.2024.076
Int J Mol Sci. 2024 Oct 29. pii: 11619. [Epub ahead of print]25(21):

New Insights into the Fanconi Anemia Pathogenesis: A Crosstalk Between Inflammation and Oxidative Stress.

Anna Repczynska, Barbara Ciastek, Olga Haus.

  Fanconi anemia (FA) represents a rare hereditary disease; it develops due to germline pathogenic variants in any of the 22 currently discovered FANC genes, which interact with the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway to maintain genome integrity. FA is characterized by a triad of clinical traits, including congenital anomalies, bone marrow failure (BMF) and multiple cancer susceptibility. Due to the complex genetic background and a broad spectrum of FA clinical symptoms, the diagnostic process is complex and requires the use of classical cytogenetic, molecular cytogenetics and strictly molecular methods. Recent findings indicate the interplay of inflammation, oxidative stress, disrupted mitochondrial metabolism, and impaired intracellular signaling in the FA pathogenesis. Additionally, a shift in the balance towards overproduction of proinflammatory cytokines and prooxidant components in FA is associated with advanced myelosuppression and ultimately BMF. Although the mechanism of BMF is very complex and needs further clarification, it appears that mutual interaction between proinflammatory cytokines and redox imbalance causes pancytopenia. In this review, we summarize the available literature regarding the clinical phenotype, genetic background, and diagnostic procedures of FA. We also highlight the current understanding of disrupted autophagy process, proinflammatory state, impaired signaling pathways and oxidative genotoxic stress in FA pathogenesis.

Keywords:  Fanconi anemia; autophagy; bone marrow failure; cancers; inflammatory process; oxidative stress

DOI:  https://doi.org/10.3390/ijms252111619
PLoS Genet. 2024 Nov 07. 20(11): e1011474

Contribution of p53-dependent and -independent mechanisms to upregulation of p21 in Fanconi anemia.

Xavier Renaudin, Baraah Al Ahmad Nachar, Benedetta Mancini, Anna Gueiderikh, Noémie Louis-Joseph, Frédérique Maczkowiak-Chartois, Filippo Rosselli.

Abnormal expression of the cell cycle inhibitor and p53 target CDKN1A/p21 has been associated with paradoxical outcomes, such as hyperproliferation in p53-deficient cancer cells or hypoproliferation that affects hematopoietic stem cell behavior, leading to bone marrow failure (BMF). Notably, p21 is known to be overexpressed in Fanconi anemia (FA), which is a rare syndrome that predisposes patients to BMF and cancer. However, why p21 is overexpressed in FA and how it contributes to the FA phenotype(s) are still poorly understood. Here, we revealed that while the upregulation of p21 is largely dependent on p53, it also depends on the transcription factor microphthalmia (MITF) as well as on its interaction with the nucleolar protein NPM1. Upregulation of p21 expression in FA cells leads to p21 accumulation in the chromatin fraction, p21 immunoprecipitation with PCNA, S-phase lengthening and genetic instability. p21 depletion in FA cells rescues the S-phase abnormalities and reduces their genetic instability. In addition, we observed that reactive oxygen species (ROS) accumulation, another key feature of FA cells, is required to trigger an increase in PCNA/chromatin-associated p21 and to impact replication progression. Therefore, we propose a mechanism by which p21 and ROS cooperate to induce replication abnormalities that fuel genetic instability.

DOI: https://doi.org/10.1371/journal.pgen.1011474
Blood Adv. 2024 Nov 08. pii: bloodadvances.2024013968. [Epub ahead of print]

Increased exercise tolerance in humanized G6PD deficient mice.

Francesca I Cendali, Christina Lisk, Monika Dzieciatkowska, Ian S LaCroix, Julie A Reisz, Julie Harral, Daniel Stephenson, Ariel M Hay, Eric Wartchow, Anza Darehshouri, Karolina Dziewulska, Paul W Buehler, Philip J Norris, Xutao Deng, Michael P Busch, Eric J Earley, Grier P Page, Kirk C Hansen, James C Zimring, David Irwin, Travis Nemkov, Angelo D'Alessandro.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects 500 million people globally, impacting red blood cell (RBC) antioxidant pathways and increasing susceptibility to hemolysis under oxidative stress. Despite the systemic generation of reactive oxygen species during exercise, the effects of exercise on individuals with G6PD deficiency remain poorly understood This study utilized humanized mouse models expressing the G6PD Mediterranean variant (S188F, with 10% enzymatic activity) to investigate exercise performance and molecular outcomes. Surprisingly, despite decreased enzyme activity, G6PD-deficient mice have faster critical speed (CS) compared to mice expressing human canonical G6PD. Post-exercise, deficient mice did not exhibit differences in RBC morphology or hemolysis, but had improved cardiac function, including cardiac output, stroke volume, sarcomere length and mitochondrial content. Proteomics analyses of cardiac and skeletal muscles (gastrocnemius, soleus) from G6PD deficient compared to sufficient mice revealed improvements in mitochondrial function and increased protein turnover via ubiquitination, especially for mitochondrial and structural myofibrillar proteins. Mass spectrometry-based metabolomics revealed alterations in energy metabolism and fatty acid oxidation. These findings challenge the traditional assumptions regarding hemolytic risk during exercise in G6PD deficiency, suggesting a potential metabolic advantage in exercise performance for individuals carrying non-canonical G6PD variants.

DOI: https://doi.org/10.1182/bloodadvances.2024013968