bims-conane Biomed News
on Congenital anemias
Issue of 2024–10–13
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Genetic modifications of EGLN1 reactivate HbF production in β0-thalassemia/HbE.
  2. TR4 and BCL11A Repress γ-globin Transcription via Independent Mechanisms.
  3. Characterization of a novel 8.2 kb deletion causing beta-thalassemia.
  4. Delivery Aspects for Implementing siRNA Therapeutics for Blood Diseases.
  5. Genetic medicine gestating for α-thalassemia.
  6. Leveraging Multi-Omics Approaches and Advanced Technologies to Unravel the Molecular Complexities, Modifiers, and Precision Medicine Strategies for Hemoglobin H Disease.
  7. Alpha Thalassemia Screening in Multiethnic Population in Northern Europe Using Hb Bart's Immunochromatographic Test.
  8. The unlikely combination: Anderson-Fabry disease and congenital dyserythropoietic anemia type II in a pediatric patient.
  1. Heliyon. 2024 Sep 30. 10(18): e38020
    Genetic modifications of EGLN1 reactivate HbF production in β0-thalassemia/HbE.
    Varit Jan-Ngam, Siriraj Boontha, Alisa Tubsuwan, Somsakul Pop Wongpalee, Kanda Fanhchaksai, Adisak Tantiworawit, Pimlak Charoenkwan, Pinyaphat Khamphikham.
      Reactivation of fetal hemoglobin (HbF, α2γ2) potentially alleviates clinical presentation in β-thalassemia. Prolyl hydroxylase domain enzymes (PHDs) play roles in the canonical oxygen-sensing pathway and maintain the stability of cellular hypoxia-inducible factor α (HIF-α) in response to low oxygen levels or hypoxia. Pharmacological inhibition of PHDs has been shown to increase HbF production in erythroid progenitors derived from healthy donors. Here, we demonstrated the relationship between PHD2, the main PHD isoform, and clinical phenotypes in β0-thalassemia/HbE disease. Although the targeted sequencing annotated several common variants within EGLN1, the gene encoding PHD2, none of these variants were located in the functional domains of PHD2 and were irrelevant to the clinical phenotypes. CRISPR-mediated EGLN1 modifications at the functional regions; however, led to significantly reduce PHD2 expression and increase HbF expression levels in severe β-thalassemia erythroblasts. Moreover, these beneficial phenotypes were independent to the two well-known HbF regulators including BCL11A and GATA1. Our findings introduce an additional mechanism for HbF regulation in β-thalassemia and propose that targeting the canonical oxygen-sensing pathway, particularly PHD2 functional domains, might offer a promising therapeutic strategy to β-thalassemia diseases.
    Keywords:  EGLN1; Fetal hemoglobin; Oxygen-sensing pathway; PHD2; β-thalassemia
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38020
  2. Blood. 2024 Oct 11. pii: blood.2024024599. [Epub ahead of print]
    TR4 and BCL11A Repress γ-globin Transcription via Independent Mechanisms.
    Yu Wang, Greggory Myers, Lei Yu, Kaiwen Deng, Ginette Balbin-Cuesta, Sharon A Singh, Yuanfang Guan, Rami Khoriaty, James Douglas Engel.
      Nuclear receptor TR4 was previously shown to bind to the -117 position of the -globin gene promoters in vitro, which overlaps the more recently described BCL11A binding site. The role of TR4 in human -globin gene repression has not been extensively characterized in vivo, while any relationship between TR4 and BCL11A regulation through the -globin promoters is unclear at present. We show here that TR4 and BCL11A competitively bind in vitro to distinct, overlapping sequences, including positions overlapping -117 of the -globin promoter. We found that TR4 represses -globin transcription and HbF accumulation in vivo in a BCL11A-independent manner. Finally, examination of the chromatin occupancy of TR4 within the -globin locus, when compared to BCL11A, shows that both bind avidly to the locus control region and other sites, but that only BCL11A binds to the -globin promoters at statistically significant frequency. These data resolve an important discrepancy in the literature, and thus clarify possible approaches to the treatment of sickle cell disease and -thalassaemia.
    DOI:  https://doi.org/10.1182/blood.2024024599
  3. Clin Biochem. 2024 Oct 05. pii: S0009-9120(24)00126-7. [Epub ahead of print] 110832
    Characterization of a novel 8.2 kb deletion causing beta-thalassemia.
    Ge Wang, Haoyang Huang, Li Chen, Qizhi Xiao, Wei Zhang, Qianqian Zhang.
       BACKGROUND: Thalassemia is a prevalent monogenic blood disorder, clinically classified into alpha- and beta-thalassemia, characterized by the imbalance of the alpha- and beta-globin chains that constitute adult hemoglobin. Copy number variations (CNVs) and single nucleotide variants in globin genes are the primary genetic defects causing thalassemia.
    CASE REPORT: During a prenatal examination, a pregnant woman was suspected to be a carrier of thalassemia, exhibiting microcytic hypochromic anemia and abnormal hemoglobin constituents. Gap-polymerase chain reaction (Gap-PCR) and reverse dot blot (PCR-RDB) techniques did not detect any common thalassemia mutations. We conducted hematological examination and further genetic analyses on the proband's family with three generations. Multiplex ligation-dependent probe amplification (MLPA) was employed to identify CNVs, targeted next-generation sequencing was used to screen for potential pathogenic variants, which were subsequently validated by Sanger sequencing. The hematological parameters of the proband, her father and her son all indicated they were beta-thalassemia carriers. MLPA results revealed a large deletion in beta-globin cluster. Further investigation confirmed the presence of a novel 8.2 kb deletion (NC_000011.10:g.5224208_5232469del) in the proband, her father, and her son, specifically covering the entire HBB gene while not impacting other globin genes.
    CONCLUSION: We found a novel 8.2 kb deletion leading to beta-thalassemia in a Chinese family in which three generations had been affected. This novel deletion may broaden the spectrum of known mutations in thalassemia and provide a reference for clinically suspected cases.
    Keywords:  Beta-globin gene cluster; Deletion; Next-generation sequencing; Thalassemia
    DOI:  https://doi.org/10.1016/j.clinbiochem.2024.110832
  4. Biochemistry. 2024 Oct 10.
    Delivery Aspects for Implementing siRNA Therapeutics for Blood Diseases.
    Saba Abbasi Dezfouli, Marcel E Michailides, Hasan Uludag.
      Hematological disorders result in significant health consequences, and traditional therapies frequently entail adverse reactions without addressing the root cause. A potential solution for hematological disorders characterized by gain-of-function mutations lies in the emergence of small interfering RNA (siRNA) molecules as a therapeutic option. siRNAs are a class of RNA molecules composed of double-stranded RNAs that can degrade specific mRNAs, thereby inhibiting the synthesis of underlying disease proteins. Therapeutic interventions utilizing siRNA can be tailored to selectively target genes implicated in diverse hematological disorders, including sickle cell anemia, β-thalassemia, and malignancies such as lymphoma, myeloma, and leukemia. The development of efficient siRNA silencers necessitates meticulous contemplation of variables such as the RNA backbone, stability, and specificity. Transportation of siRNA to specific cells poses a significant hurdle, prompting investigations of diverse delivery approaches, including chemically modified forms of siRNA and nanoparticle formulations with various biocompatible carriers. This review delves into the crucial role of siRNA technology in targeting and treating hematological malignancies and disorders. It sheds light on the latest research, development, and clinical trials, detailing how various pharmaceutical approaches leverage siRNA against blood disorders, mainly concentrating on cancers. It outlines the preferred molecular targets and physiological barriers to delivery while emphasizing the growing potential of various therapeutic delivery methods. The need for further research is articulated in the context of overcoming the shortcomings of siRNA in order to enrich discussions around siRNA's role in managing blood disorders and aiding the scientific community in advancing more targeted and effective treatments.
    Keywords:  Hematological malignancies; RNAi; delivery systems; leukemia; siRNA
    DOI:  https://doi.org/10.1021/acs.biochem.4c00327
  5. Blood. 2024 Oct 10. 144(15): 1554-1556
    Genetic medicine gestating for α-thalassemia.
    Daniel E Bauer.
      
    DOI:  https://doi.org/10.1182/blood.2024025938
  6. Eur J Haematol. 2024 Oct 09.
    Leveraging Multi-Omics Approaches and Advanced Technologies to Unravel the Molecular Complexities, Modifiers, and Precision Medicine Strategies for Hemoglobin H Disease.
    Akshata Pahelkar, Deep Sharma, Payaam Vohra, Sayli Sawant.
      Hemoglobin H (HbH) disease, a form of alpha-thalassemia, poses significant clinical challenges due to its complex molecular underpinnings. It is characterized by reduced synthesis of the alpha-globin chain. The integration of multi-omics and precision medicine holds immense potential to comprehensively understand and capture interactions at the molecular and genetic levels. This review integrates current multi-omics approaches and advanced technologies in HbH research. Furthermore, it delves into detailed pathophysiology and possible therapeutics in the upcoming future. We explore the role of genomics, transcriptomics, proteomics, and metabolomics studies, alongside bioinformatics tools and gene-editing technologies like CRISPR/Cas9, to identify genetic modifiers, decipher molecular pathways, and discover therapeutic targets. Recent advancements are unveiling novel genetic and epigenetic modifiers impacting HbH disease severity, paving the way for personalized precision medicine interventions. The significance of multi-omics research in unraveling the complexities of rare diseases like HbH is underscored, highlighting its potential to revolutionize clinical practice through precision medicine approaches. This paradigm shift can pave the way for a deeper understanding of HbH complexities and improved disease management.
    Keywords:  gene‐editing; genomics; hemoglobin H disease; molecular modifiers; multi‐omics; precision medicine
    DOI:  https://doi.org/10.1111/ejh.14319
  7. Int J Lab Hematol. 2024 Oct 09.
    Alpha Thalassemia Screening in Multiethnic Population in Northern Europe Using Hb Bart's Immunochromatographic Test.
    Nik Fatma Fairuz Nik Mohd Hasan, Sandra J G Arkesteijn, Jeanet Ter Huurne, Maaike Verschuren, Sharda Bhagwandien-Bisoen, Rianne Schaap, Linda Vijfhuizen, Hakima El Idrissi, Tamara T Koopmann, Cornelis L Harteveld.
      
    Keywords:  Hemoglobin Bart's; alpha thalassemia; immunochromatographic test
    DOI:  https://doi.org/10.1111/ijlh.14381
  8. Clin Case Rep. 2024 Oct;12(10): e9354
    The unlikely combination: Anderson-Fabry disease and congenital dyserythropoietic anemia type II in a pediatric patient.
    Yasmine Elsherif, Ismail A Ibrahim, Omar Elsherif, Hana J Abukhadijah.
       Key Clinical Message: Anderson-Fabry disease, a rare X-linked lysosomal disorder, and congenital dyserythropoietic anemia (CDA) Type II, an autosomal recessive condition, both have distinct inheritance patterns. Their co-occurrence is extremely rare, never been reported before. Therefore, screening is crucial for early management, and families should seek genetic counseling for children showing unusual presentations.
    Abstract: Anderson-Fabry disease (AFD) is a rare condition, characterized by a lysosomal storage disorder affecting lipid storage. It manifests in two forms: classic (early-onset) and nonclassic (late-onset). Conversely, congenital dyserythropoietic anemia (CDA) is a rare blood disorder caused by ineffective erythropoiesis, which results in the production of abnormal erythroblasts during the maturation of red blood cells, with CDA type II being the most frequent type. Both disorders have well-understood pathophysiologies, yet they are genetically distinct. AFD is inherited in an X-linked manner, whereas CDA type II follows an autosomal recessive pattern of inheritance. Although both AFD and CDA type II have been reported separately in the literature. The co-existence for both AFD and CDA type II has not been reported. We describe a 10-year-old boy, with both which is believed to be the first documented case.
    Keywords:  Anderson‐Fabry disease; CDA type II; congenital dyserythropoietic anemia; co‐occurrence; genetic distinction; lysosomal disorder
    DOI:  https://doi.org/10.1002/ccr3.9354
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