bims-conane Biomed News
on Congenital anemias
Issue of 2025–12–07
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Downregulation of ZBTB7A/LRF increases fetal hemoglobin expression in β0-thalassemia/hemoglobin E erythroid cells.
  2. Case Report: Identification and functional characterization of a novel heterozygous splice-donor (c.647+1G>A) site mutation in the SPTB gene that causes hereditary spherocytosis with hemolytic anemia.
  3. When a Trait Becomes a Disease: A Rare Hematologic Overlap of Sickle Cell Trait and Hereditary Spherocytosis.
  4. Thalassemia and hypercoagulability.
  5. From treatment to biology and back: managing iron overload in transfused hemoglobinopathies.
  6. Molecular surprises in evaluations of red cell disorders.
  7. Follow-Up of 3-Year Luspatercept Treatment in a Transfused ß-Thalassemia Patient. Bone Marrow: An Undervalued Iron Store.
  8. Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy.
  9. Assessment of Adherence to Iron Chelation Therapy Among Thalassemia Patients in Palestine.
  10. Single-cell transcriptomics reveals heterocellular g-globin gene expression in Agdb-thalassemia.
  11. Large-scale proteomic and phosphoproteomic analysis of erythroid enucleation and maturation.
  1. Sci Rep. 2025 Dec 05.
    Downregulation of ZBTB7A/LRF increases fetal hemoglobin expression in β0-thalassemia/hemoglobin E erythroid cells.
    Sukanya Chumchuen, Tanapat Pornsukjantra, Pawarit Innachai, Pinyaphat Khamphikham, Chokdee Wongborisuth, Usanarat Anurathapan, Duantida Songdej, Orapan Sripichai, Amornrat Tangprasittipap, Suradej Hongeng.
      Zinc finger and BTB domain-containing 7A (ZBTB7A) is a transcription factor repressor of fetal hemoglobin (HbF; α2γ2) in erythroid cells. Reactivating γ-globin expression represents a promising therapeutic strategy for β-hemoglobinopathies, including β-thalassemia. While ZBTB7A knockdown is known to elevate HbF levels in HUDEP-2 erythroid cell line and human hematopoietic stem/progenitor cell (HSPC)-derived erythroblasts, its effects in patient-derived cells remain less defined. This study investigates the effects of ZBTB7A downregulation in erythroid cells derived from both β0 thalassemia/hemoglobin E (β0-thal/HbE) patients and healthy donors. ZBTB7A knockdown upregulated embryonic and fetal globin genes (ε-, ζ-, γ-globin), and robust HbF induction while suppressing adult globin gene expression (α-, β-, δ-globin) in both groups. Notably, partial ZBTB7A inhibition was sufficient to achieve HbF reactivation. ZBTB7A depletion delayed erythroid maturation in healthy cells, but not in β⁰-thal/HbE cells, revealing a context-dependent effect on differentiation. These findings support ZBTB7A as a compelling target for β-thalassemia therapy, where partial inhibition could potentially offer therapeutic benefit while minimizing adverse effects on erythroid differentiation.
    Keywords:  Fetal hemoglobin (HbF); ZBTB7A/LRF; β-thalassemia/hemoglobin E
    DOI:  https://doi.org/10.1038/s41598-025-30762-3
  2. Front Genet. 2025 ;16 1626155
    Case Report: Identification and functional characterization of a novel heterozygous splice-donor (c.647+1G>A) site mutation in the SPTB gene that causes hereditary spherocytosis with hemolytic anemia.
    Ke Cao, Xiaojuan Luo, Lianlian Liu, Xiaoning Mao, Ruping Liu, Yunsheng Chen, Santasree Banerjee.
       Objective: Hereditary spherocytosis (HS) is an inherited disorder characterized by spherical erythrocytes and abnormalities of several erythrocyte membrane proteins with extreme genotypic and phenotypic heterogeneity. HS patients were clinically diagnosed by the presence of spherical erythrocytes on the peripheral blood smear, hemolytic anemia, jaundice, and splenomegaly, with or without cholelithiasis or gallstones. To date, mutations of five genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB) have been reported to be associated with different subtypes of HS. Germline mutations of the SPTB gene cause autosomal dominant HS (Spherocytosis 2, SPH2), the rarest subtype of HS.
    Methods: In this study, we investigated a 10-year-old Chinese girl clinically diagnosed with HS and neonatal hemolytic anemia. The proband's mother was also identified with HS and hemolytic anemia, but the proband's father was phenotypically normal. We performed a standard G-banding karyotype to identify structural abnormalities of chromosomes in this proband. Then, we performed whole-exome sequencing and Sanger sequencing to identify the disease-causing variants in this proband. Finally, we functionally characterized the identified novel variant by performing reverse transcription polymerase chain reaction, cDNA sequencing, quantitative real-time polymerase chain reaction (PCR), and Western blot.
    Results: Whole exome sequencing identified a heterozygous novel splice-donor-site (c.647 + 1G>A) mutation in the SPTB gene in the proband. Sanger sequencing confirmed that the proband inherited this mutation from her mother, while her father was devoid of it. Reverse transcription polymerase chain reaction and cDNA sequencing showed that this novel splice-donor-site (c.647 + 1G>A) mutation causes abolition of the wild-type splice donor site, which leads to the aberrant splicing of SPTB mRNA, followed by the formation of an alternative transcript with complete loss of exon 5. The relative expression of mutated SPTB mRNA was significantly reduced in the proband and her mother compared with her father, showing normal expression of wild-type SPTB mRNA.
    Conclusion: Our present study highlighted the significance of whole-exome sequencing as the most promising path to genetic molecular diagnosis for patients with HS.
    Keywords:  SPTB gene; hemolytic anemia; hereditary spherocytosis; novel mutation; splice-donor site mutation
    DOI:  https://doi.org/10.3389/fgene.2025.1626155
  3. Am J Hematol. 2025 Dec 04.
    When a Trait Becomes a Disease: A Rare Hematologic Overlap of Sickle Cell Trait and Hereditary Spherocytosis.
    Omar Ammari, Mina Shah, Yasmin Elgammal, Ammar Husami, Theodosia A Kalfa, Jahnavi Gollamudi.
      
    Keywords:  avascular necrosis; hereditary spherocytosis; retinopathy; sickle cell trait
    DOI:  https://doi.org/10.1002/ajh.70154
  4. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 285-290
    Thalassemia and hypercoagulability.
    Maria Domenica Cappellini, Ali T Taher, Irene Motta.
      Although the management of β-thalassemia has improved significantly, patients still suffer from many complications, including thrombotic events. A hypercoagulable state has been demonstrated in these conditions, particularly in non-transfusion-dependent β-thalassemia, because of disease-specific contributors that play a role in the pathogenesis, including reactive oxygen species, pathological erythroid cells, circulating microparticles, free heme, and endothelial activation. Splenectomy further contributes to the complexity of thrombotic risk in such patients, together with emerging complications related to increased survival, such as atrial fibrillation. Moreover, in recent years the role of new drugs in further modifying the thrombotic risk of these patients has been demonstrated, as in the case of luspatercept. However, its role still needs to be elucidated. The currently available prevention and clinical management of thrombosis in thalassemia patients mainly relies on the international guidelines for the general population, although, given the peculiar pathophysiology and the disease-related risk factors, robust data and evidence are necessary to develop dedicated guidelines.
    DOI:  https://doi.org/10.1182/hematology.2025000716
  5. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 103-110
    From treatment to biology and back: managing iron overload in transfused hemoglobinopathies.
    Thomas D Coates.
      Before effective iron chelation became available, patients with transfusion-dependent thalassemia often died from iron-induced cardiomyopathy and endocrine failure in their second decade of life. This experience shaped long-standing expectations of poor outcomes and continues to fuel provider and patient anxiety in all conditions associated with iron overload. While severe iron overload and toxicity still cause considerable morbidity and mortality globally, advances in the understanding of iron metabolism, noninvasive organ-specific iron monitoring, and chelation therapy have significantly reduced their impact. Clinical insights from hemoglobinopathies have reinforced iron biology findings from animal models and highlighted shared mechanisms of iron toxicity across disorders, guiding broader management approaches that address the prevention of iron toxicity independently of the removal of organ iron burden. The resulting significant improvement in survival now presents new challenges tied to prolonged exposure to both anemia and iron overload, which must be addressed in long-term treatment planning.
    DOI:  https://doi.org/10.1182/hematology.2025000693
  6. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 370-376
    Molecular surprises in evaluations of red cell disorders.
    Yasmin Elgammal, Wenying Zhang, Theodosia A Kalfa.
      Red cell disorders may present with overlapping clinical presentation and laboratory findings; in addition, complete phenotypic characterization of the patients' red cells is more challenging in the most severe cases, which are typically transfusion-dependent. The increasing availability of next-generation sequencing over the past 2 decades, initially with focused gene panels for certain disease groups, optimized to include the known coding and noncoding pathogenic variants for those diseases, has improved the accuracy and timeliness of diagnosis. The ongoing expansion to whole-exome and genome sequencing has been revealing unexpected, rare, overlooked, or previously unknown genetic disorders and expands our knowledge on the pathophysiology of known and novel human diseases. The vast information gained by genetic sequencing should still be checked against the phenotype to confirm agreement. A positive result does not always guarantee that the cause of the patient's symptoms has been identified; phenotype-genotype correlation is critical. In our era of targeted treatments and progress in gene therapy, utilization of genetic workup to improve the timing and precision of diagnosis is crucial to ensure that patients receive effective management, improving their outcome.
    DOI:  https://doi.org/10.1182/hematology.2025000726
  7. EJHaem. 2025 Dec;6(6): e70193
    Follow-Up of 3-Year Luspatercept Treatment in a Transfused ß-Thalassemia Patient. Bone Marrow: An Undervalued Iron Store.
    Matthias Bleeke, Claudia Niekrens, Soumya Datta, Regine Grosse, Filomena Longo, Isabel Molwitz, Roland Fischer.
       Introduction: Treatment with luspatercept may improve transfusion requirements in transfusion-dependent thalassemia (TDT), but the improved erythroid maturation in the bone marrow influences body iron distribution.
    Case Report: We report on sequential organ iron measurements in a TDT patient under luspatercept treatment. Despite a decline in transfusion requirement and ferritin, we observed a redistribution of body iron stores from spleen and bone marrow to the liver, increasing liver iron concentration (LIC).
    Conclusion: Luspatercept treatment affects the informative value of ferritin and LIC in the assessment of total body iron stores, which should be considered in the management of iron chelation therapy.
    DOI:  https://doi.org/10.1002/jha2.70193
  8. bioRxiv. 2025 Nov 22. pii: 2025.11.21.689741. [Epub ahead of print]
    Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy.
    Matthew S Karafin, Aaron V Issaian, Shaun Bevers, Julie A Reisz, Ariel Hay, Gregory R Keele, Monika Dzieciatkowska, Francesca I Cendali, Zachary B Haiman, Alicia M Key, Travis Nemkov, Daniel Stephenson, Erin Marsh, Amy L Moore, Mitasha S Palha, Eric A Legenzov, Derek R Lamb, Xutao Deng, Mars Stone, Kirk C Hansen, Steve Kleinman, Philip J Norris, Michael P Busch, Francesca Vallese, Bernhard O Palsson, Steven L Spitalnik, Joseph P Y Kao, Nareg H Roubinian, John Janetzko, Grier P Page, Elan Z Eisenmesser, James C Zimring, Paul W Buehler, Angelo D'Alessandro.
      Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy, affects 6% of the global population, yet its impact on blood storage and transfusion efficacy remains undefined. We integrated genome-metabolome-proteome analyses of 13,091 blood donors (362 G6PD SNPs), validated in a recalled cohort (n=643), linked donor-recipient databases, humanized mouse models (canonical, African A- [V68M+N126D], Mediterranean [S188F]), and a prospective sickle cell disease study. Common G6PD variants reduced protein abundance, reprogrammed redox metabolism, and increased storage hemolysis. In mice, G6PD-deficient RBCs showed lower post-transfusion recovery, higher oxidative stress, and impaired renal oxygenation. Clinically, recipients of G6PD-deficient units exhibited smaller hemoglobin increments and reduced RBC L¹Cr-survival (-8% at 24 h; -12% at 4 weeks). Structural studies revealed kinetic fragility for A- and thermodynamic fragility for Med-, linking genotype to protein instability and transfusion outcome. These findings identify donor G6PD genotype as a determinant of transfusion efficacy, supporting genotype-aware inventory-management strategies.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2025.11.21.689741
  9. Anemia. 2025 ;2025 6649477
    Assessment of Adherence to Iron Chelation Therapy Among Thalassemia Patients in Palestine.
    Hamzeh Al Zabadi, Zein Ieran, Ibrahim Taha.
       Background: Beta-thalassemia major (β-TM) is a severe hereditary blood disorder, common in Palestine due to high consanguinity rates. Lifelong iron chelation therapy (ICT) is vital for managing iron overload from regular transfusions, but adherence remains a major challenge.
    Objective: This study investigates factors influencing ICT adherence among β-TM patients in Palestine, focusing on sociodemographic, clinical, psychological, and healthcare-related aspects.
    Methods: A cross-sectional study was conducted at the National Thalassemia Center, Nablus, from July 2024 to the end of October 2024, including 120 β-TM patients aged 3-33. Data were collected through structured interviews using a validated questionnaire covering demographics, disease knowledge, adherence, and satisfaction with healthcare. Adherence was based on missed doses and ferritin levels, analyzed using SPSS V21.0.
    Results: 62.5% of patients were adherent, with ferritin levels ≤ 2500, while nonadherent patients had levels ≥ 2501 (p < 0.001). Although 98.7% of adherent and 100% of nonadherent patients had good disease knowledge, it did not predict adherence. Barriers included psychological distress (21.7%), medication side effects (16.7%), and inconsistent medication supply. Satisfaction with healthcare staff (p < 0.001) and socioeconomic status, particularly income (p = 0.014), significantly affected adherence.
    Conclusion: Adherence is influenced more by psychological, economic, and healthcare service factors than knowledge. A multidisciplinary approach-providing psychological support, stable medication access, and stronger patient-provider relationships-is essential to improve adherence and outcomes for β-TM patients in Palestine.
    DOI:  https://doi.org/10.1155/anem/6649477
  10. Blood Adv. 2025 Dec 06. pii: bloodadvances.2025016755. [Epub ahead of print]
    Single-cell transcriptomics reveals heterocellular g-globin gene expression in Agdb-thalassemia.
    Phillip A Doerfler, Yichao Li, Yu Yao, Ruopeng Feng, Thiyagaraj Mayuranathan, Jingjing Zhang, Emilia Kooienga, David Cullins, Rohith Jesudas, Dillon C Williams, Jane S Hankins, Yong Cheng, David K Wood, Mitchell J Weiss.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025016755
  11. Blood Sci. 2025 Dec;7(4): e00263
    Large-scale proteomic and phosphoproteomic analysis of erythroid enucleation and maturation.
    Yuanliang Peng, Liming Zhu, Min Duan, Jing Liu.
      
    DOI:  https://doi.org/10.1097/BS9.0000000000000263
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