bims-conane Biomed News
on Congenital anemias
Issue of 2025–11–23
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. The Masked Thalassemia: A Rare Case of a Patient with Normal HbA2 Levels, β-Thalassemia Pathogenic Variant (CD39 C>T), and a Novel δ-Globin Gene Deletion.
  2. Multi-centric origins and gene flow shape the diversity of β-thalassemia mutations in Southern East Asia.
  3. KLF1 (Krüppel-like factor 1) variants in the pathogenesis of hematological diseases
  4. X-Linked Sideroblastic Anemia Induced by a Novel ALAS2 Nonsense Mutation: A Case Report and Literature Review.
  5. Cellular and molecular targets in β-Thalassemia: advances in iron Regulation, Erythropoiesis, and Gene-Based therapies.
  6. Establishing a Reference Interval for Flow Cytometric Analysis of Red Blood Cell Osmotic Fragility in a Healthy Korean Population.
  7. Metabolic Rigidity as a Mechanical Barrier to Malaria: Flickering Loss in PKLR-Deficient Erythrocytes.
  8. Red Blood Cell Exchange for Naphthalene-Induced Methemoglobinemia in a Child With Glucose-6-Phosphate Dehydrogenase Deficiency: A Case Report.
  9. First Reported Case of Glucose-6-Phosphate Isomerase Deficiency in a Saudi Child With Hemolytic Anemia.
  10. DNA Methylation Episignature as a Novel Diagnostic Tool for Diamond-Blackfan Anemia Syndrome.
  11. Mouse Gata1 3'UTR modulates Gata1 levels to affect erythropoiesis.
  12. KLF1 (Krüppel-like factor 1) as a key regulator of erythroid gene expression
  13. Irradiation-Free Reduced Intensity Conditioning Stem Cell Transplantation for Young Patients With Diamond-Blackfan Anemia Syndrome Is Well-Tolerated and Effective.
  1. Appl Clin Genet. 2025 ;18 233-241
    The Masked Thalassemia: A Rare Case of a Patient with Normal HbA2 Levels, β-Thalassemia Pathogenic Variant (CD39 C>T), and a Novel δ-Globin Gene Deletion.
    Massimiliano Chetta, Annamaria Salamandra, Marina Tarsitano, Marcella D'Antonio, Elvira Sannino, Serena Torre, Carmina Fatigati, Silvia Costantini, Paola D'Ambrosio, Manuela Priolo, Paolo Ricchi.
      Thalassemia is a group of inherited blood disorders caused by defects in hemoglobin production, the protein that transports oxygen in red blood cells. These diseases are characterized by either diminished or missing production of one of the globin chains, which are often the alpha or beta chains that comprise hemoglobin. Diagnosis is based on a combination of laboratory tests, including hemoglobin electrophoresis, globin chain chromatography, and genetic analysis. However, diagnosis can become challenging when typical hematological features of thalassemia are not matched by expected biochemical findings. One such situation occurs when HbA2 levels appear normal despite a suspected β-thalassemia trait. This can happen when a β-globin gene variant is present alongside a δ-globin gene pathogenic variant, producing an atypical profile that may mask the true diagnosis. In this case report, we describe a patient carrying a heterozygous β-globin pathogenic variant (HBB c.118C>T; p.Gln40Ter, also known as codon 39) coexisting with a large novel 1.6 kb deletion in the delta-globin gene (HBD) that removes the first two exons. We discuss the diagnostic challenges and clinical implications associated with this rare genetic combination, emphasizing the critical role of comprehensive molecular testing in accurately identifying complex thalassemia cases. This report contributes to the literature by documenting a novel δ-globin deletion in combination with a β-thalassemia variant, providing valuable insights for clinicians and geneticists in the interpretation and management of atypical thalassemia profiles.
    Keywords:  masked thalassemia; molecular diagnosis; next-generation sequencing; normal HbA2; novel δ-globin deletion; β-thalassemia
    DOI:  https://doi.org/10.2147/TACG.S544633
  2. Nat Commun. 2025 Nov 20. 16(1): 10220
    Multi-centric origins and gene flow shape the diversity of β-thalassemia mutations in Southern East Asia.
    Qianqian Zhang, Jialong Li, Haoyang Huang, Xuan Shang, Yuhua Ye, Wei Zhang, Peng Lin, Yi Gong, Boon-Peng Hoh, Qingming Luo, Tizhen Yan, Xinghua Pan, Mark Stoneking, Shuhua Xu, Xiangmin Xu, Lian Deng.
      Over 400 β-thalassemia mutations show population-differentiated spectra, yet their origins and evolution remain unclear. Focusing on targeted sequencing of 20,222 individuals and 510 β-thalassemia patients in southern China, we identified three major haplotype groups (HG) at the β-globin locus and observed highest haplotype diversity for CD41/42, -50, and HbE among 13 prevalent mutations in 993 carriers. Allele dating suggest these mutations emerged during agricultural expansions in the past 7420 years, represented by CD41/42 arising in mainland China. However, the -50 mutation likely originated on Hainan Island within 3900 years, subsequently spreading to the mainland and experiencing lineage-specific selection. HbE exhibits substantial haplotype heterogeneity in Yunnan, with network analyses indicating bidirectional disseminations between southern China and South/Southeast Asia. We further suggest an ameliorating effect of HG2, associated with elevated hemoglobin and fetal hemoglobin levels. These findings highlight multi-centric origins of β-thalassemia mutations and underscore the evolutionary context shaping their clinical impact.
    DOI:  https://doi.org/10.1038/s41467-025-65019-0
  3. Postepy Biochem. 2025 06 30. 71(2): 153-161
    KLF1 (Krüppel-like factor 1) variants in the pathogenesis of hematological diseases
    Klaudia Kulczynska-Figurny, Mirosława Siatecka.
      KLF1 (Krüppel-like factor 1) is an erythroid transcription factor involved in various stages of red blood cell formation. KLF1 plays key functions at the megakaryocyte-erythrocyte progenitor stage, where it is involved in the development of the erythrocyte lineage. It participates in the global expression of erythrocyte genes, playing a direct role in globin switching. KLF1 also participates in the final maturation of erythrocytes, controlling exit from the cell cycle and the enucleation process. KLF1 has a domain structure: N-terminal transactivation domain and C-terminal DNA-binding domain. Many variants (mutations) have been described in the KLF1 gene, which lead to the development of a whole spectrum of phenotypes: from clinically insignificant morphological changes, through mild changes, to severe pathological conditions. Two mutations are dominant. One occurs in mice and causes neonatal anemia with congenital spherocytosis (Nan), the other in humans and leads to congenital dyserythropoietic anemia type IV (CDA).
    DOI:  https://doi.org/10.18388/pb.2021_614
  4. Ann Clin Lab Sci. 2025 Sep;55(5): 827-830
    X-Linked Sideroblastic Anemia Induced by a Novel ALAS2 Nonsense Mutation: A Case Report and Literature Review.
    Hang Yin, Qing Shen, Chun-Li Xu, Dong-Ping Huang, Yu Chen.
       OBJECTIVE: To clarify the clinical manifestations of X-linked sideroblastic anemia (XLSA) and the mutational profiles of the aminolevulinate synthase 2 (ALAS2) gene, thereby optimizing treatment and prognosis.
    CASE REPORT: The proband, a 16-year-old male student, presented with microcytic hypochromic anemia, with hemoglobin (Hb) 55 g/L, red cell distribution width (RDW) 22.5%, mean corpuscular hemoglobin concentration (MCHC) 314 g/L, mean corpuscular hemoglobin (MCH) 23.9 pg, and mean corpuscular volume (MCV) 76.1 fL. Next-generation sequencing followed by Sanger sequencing of his family identified a de novo heterozygous nonsense mutation in ALAS2 (c.224C>A); this identification led to the final diagnosis of XLSA with a novel ALAS2 mutation.
    DISCUSSION: Incorporating genetic analyses into diagnostic algorithms can improve the precision of XLSA diagnosis and support personalized treatment strategies for patients and families.
    CONCLUSIONS: Our findings expand the mutational spectrum of ALAS2 and highlight that integrating next-generation sequencing (NGS) with Sanger validation into diagnostic workflows can significantly improve the diagnostic accuracy of XLSA.
    Keywords:  ALAS2; X-linked sideroblastic anemia; congenital sideroblastic anemia; nonsense mutation
  5. Funct Integr Genomics. 2025 Nov 18. 25(1): 246
    Cellular and molecular targets in β-Thalassemia: advances in iron Regulation, Erythropoiesis, and Gene-Based therapies.
    Xueting Shan, Qianlian Li, Meijuan Wang, Yifan Niu, Zhongxin Sun, Xiang Ma, Tao Wang, Xiangmin Tong, Jufang Zhang, Dong Niu.
      β-Thalassemia is a prevalent autosomal recessive genetic disorder caused by mutations in the β-globin gene, leading to impaired hemoglobin production and chronic anemia. While traditional treatments such as regular blood transfusions, iron chelation, and supportive care have significantly improved patient survival, these methods remain palliative. The availability of curative options is limited, with allogeneic hematopoietic stem cell transplantation (HSCT) presenting risks due to donor constraints and procedure-related complications. Recent advances in the molecular understanding of β-thalassemia have opened the door to novel therapeutic strategies. Gene therapy approaches, including lentiviral vector-mediated β-globin gene addition and CRISPR/Cas9-mediated genome editing targeting the BCL11A enhancer, have shown promising results in clinical trials and have gained regulatory approval in several regions. Pharmacological interventions, such as luspatercept, which enhances erythroid maturation, and other fetal hemoglobin inducers, offer valuable alternatives for patients who are ineligible for gene-based therapies. This review explores the current landscape of β-thalassemia, including its epidemiology, pathophysiology, and clinical manifestations, while highlighting recent advances in treatment options. We critically evaluate the clinical data emerging from gene therapies and other innovative treatments, address the ongoing challenges, and outline future directions for enhancing patient outcomes through personalized and accessible care strategies.
    Keywords:  CRISPR/Cas9; Gene therapy; Hemoglobinopathy; Luspatercept; Β-Thalassemia
    DOI:  https://doi.org/10.1007/s10142-025-01756-1
  6. Ann Clin Lab Sci. 2025 Sep;55(5): 797-801
    Establishing a Reference Interval for Flow Cytometric Analysis of Red Blood Cell Osmotic Fragility in a Healthy Korean Population.
    HyeSeong Ryu, Miyoung Kim, Daehyun Chu, Young-Uk Cho, Sang-Hyun Hwang, Seongsoo Jang, Chan-Jeoung Park.
       OBJECTIVE: The flow cytometric osmotic fragility test (OFT) screens for hereditary spherocytosis (HS) and other red blood cell (RBC) membrane disorders. It has been suggested that the proportion of residual RBCs at the midpoint region of the time/forward scatter plot would be just as informative for HS diagnosis as that at the terminal region. We established reference intervals for both regions in healthy Korean adults using one of the most recently available flow cytometry systems.
    METHODS: This cross-sectional study included 249 adults (129 men and 120 women) with normal complete blood cell counts. The proportions of residual RBCs after exposure to hypotonic solution were measured at defined intervals using the BD FACSLyric system. Sex-specific differences were determined.
    RESULTS: The reference intervals for the midpoint region for men and women were 16.49-19.61% (median: 18.24%) and 16.27-19.22% (18.18%), respectively, while those for the endpoint region were 7.00-15.21% (11.20%) and 5.58-15.16% (10.87%), respectively. The differences between the sexes and age groups were not statistically significant at either time point.
    CONCLUSION: We established reference intervals for the flow cytometric OFT at the midpoint and endpoint time/forward scatter plot regions in a Korean population for the first time.
    Keywords:  Hereditary spherocytosis; Korea; flow cytometry; osmotic fragility; reference interval
  7. FASEB J. 2025 Nov 30. 39(22): e71234
    Metabolic Rigidity as a Mechanical Barrier to Malaria: Flickering Loss in PKLR-Deficient Erythrocytes.
    Natalia Hernando-Ospina, Macarena Calero, Guillermo Solís, Isabel G Azcárate, Diego Herráez-Aguilar, Niccolò Caselli, Lara H Moleiro, Jose-Carlos Segovia, José M Bautista, Francisco Monroy.
      Pyruvate kinase (PK) deficiency is a rare hereditary enzymopathy caused by mutations in the PKLR gene, leading to reduced glycolytic ATP production in red blood cells (RBCs) and contributing to chronic hemolytic anemia. Here, we use high-speed flickering spectroscopy and non-invasive microrheology to assess how ATP depletion reshapes the nanomechanical properties of RBC membranes. Compared to healthy controls, PKLR-mutant erythrocytes exhibit marked reductions in ATP-dependent flickering amplitude and membrane fluidity, consistent with impaired metabolic elasticity. Strikingly, when infected with Plasmodium yoelii, these metabolically rigidified cells retain mechanical properties that appear to hinder parasite-induced membrane remodeling. By mapping single-cell viscoelastic landscapes across healthy, mutated, infected, and coinfected mouse RBC populations, we uncover a potential biomechanical barrier against malaria imposed by glycolytic insufficiency. These findings highlight a mechanobiological axis of host resistance and position label-free flickering analysis as a powerful tool for diagnosing RBC enzymopathies and probing infection susceptibility at the single-cell level.
    DOI:  https://doi.org/10.1096/fj.202502505R
  8. J Clin Apher. 2025 Dec;40(6): e70070
    Red Blood Cell Exchange for Naphthalene-Induced Methemoglobinemia in a Child With Glucose-6-Phosphate Dehydrogenase Deficiency: A Case Report.
    Hanan Hassan El-Sheity, Nagwan Yossery Saleh, Shady Mohamed Elkholy, Amira Zaki Badawy.
      Naphthalene toxicity is a rare but serious cause of methemoglobinemia and hemolysis, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, in whom methylene blue is contraindicated. We present a case of a 6-year-old girl with a family history of G6PD deficiency who developed cyanosis, jaundice, dark urine, and an oxygen saturation of 50% after ingesting a mothball. Laboratory findings confirmed hemolytic anemia with suspected methemoglobinemia. Methylene blue was avoided, and initial treatment with high-flow oxygen, ascorbic acid, and N-acetylcysteine failed to improve her condition. Red blood cell exchange (RCE) was performed, leading to rapid normalization of oxygen saturation and resolution of hemolysis. G6PD deficiency was later confirmed by enzyme assay. We concluded that in G6PD-deficient children with naphthalene-induced methemoglobinemia, RCE provides an effective alternative to methylene blue, resulting in rapid recovery.
    Keywords:  G6PD deficiency; hemolytic anemia; methemoglobinemia; naphthalene; red blood cell exchange
    DOI:  https://doi.org/10.1002/jca.70070
  9. Cureus. 2025 Oct;17(10): e94817
    First Reported Case of Glucose-6-Phosphate Isomerase Deficiency in a Saudi Child With Hemolytic Anemia.
    Wejdan Alotaibi, Shady Wafa, Lina Elzubair, Ayman Abualama, Badriah G Alasmari.
      Glucose-6-Phosphate Isomerase (GPI) deficiency constitutes a rare autosomal recessive enzymopathy that causes hereditary nonspherocytic hemolytic anemia (HNSHA). The condition is linked to homozygous or compound heterozygous mutations in the GPI gene located on chromosome 19q13. This enzyme deficiency disrupts glycolysis, leading to hemolysis of red blood cells. This report documents the first Saudi patient officially diagnosed with GPI deficiency. The diagnosis was conclusively established using whole-exome sequencing (WES), which identified a homozygous pathogenic variant in the GPI gene.
    Keywords:  chronic hemolytic anemia; enzymopathy; first saudi patient; glucose-6-phosphate isomerase (gpi); whole-genome sequencing
    DOI:  https://doi.org/10.7759/cureus.94817
  10. Am J Hematol. 2025 Nov 17.
    DNA Methylation Episignature as a Novel Diagnostic Tool for Diamond-Blackfan Anemia Syndrome.
    Paola Quarello, Karim Karimi, Slavica Trajkova, Emanuela Garelli, Mehdi Samadieh, Emanuela Iovino, Tommaso Pippucci, Giovanni Papagni, Sandra Dalfonso, Lucia Corrado, Serena Rizzo, Adriana Carando, Jennifer Kerkhof, Jessica Rzasa, Haley McConkey, Michael Levy, Marco Zecca, Francesca Fioredda, Angelica Barone, Simone Cesaro, Maria Gabelli, Francesca Torchio, Giulia Zucchetti, Maria Elena Cantarini, Paola Corti, Ugo Ramenghi, Franco Locatelli, Franca Fagioli, Bekim Sadikovic, Alfredo Brusco.
      Diamond-Blackfan Anemia Syndrome (DBAS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by impaired erythropoiesis and significant genetic heterogeneity. Diagnosis can be challenging due to clinical variability and the lack of sensitive and specific biomarkers. We investigated the evidence for a DNA methylation (DNAm) episignature in a cohort of 80 DBAS patients with causative variants in various ribosomal protein genes: DBA1 (RPS19, n = 30), DBA4 (RPS17, n = 6), DBA5 (RPL35A, n = 8), DBA6 (RPL5, n = 15), DBA7 (RPL11, n = 13), DBA10 (RPS26, n = 8). We identified a distinct and highly accurate episignature biomarker for DBAS, clearly differentiating it from both Fanconi anemia and a broad spectrum of other episignature-positive disorders. Furthermore, we developed a specific DNAm classifier for the clinically similar DBA6 and DBA7 subtypes. Applying the DBAS episignature analysis to six molecularly uncharacterized cases, three exhibited the DBAS pattern. Subsequent genome sequencing identified causative genetic variants in two (RPL5: c.325-380A>G:p.?; RPL26: c.-6 + 3_-6 + 25del:p.?), validating the test robustness. Methylation profiles from two revertant cases (RPS19:P47L and RPS17 full gene deletion) exhibited the DBAS episignature, suggesting it to be a stable epigenetic mark associated with the underlying genetic mutation, likely established early in development. In conclusion, we propose DNAm profiling as a robust diagnostic tool for DBAS, providing a biomarker applicable to all patients with clinical suspicion of the disease and critically aiding in the resolution of variants of uncertain significance and molecularly uncharacterized cases.
    Keywords:  DBAS; episignature; methylation
    DOI:  https://doi.org/10.1002/ajh.70141
  11. Exp Hematol. 2025 Nov 19. pii: S0301-472X(25)00616-2. [Epub ahead of print] 105327
    Mouse Gata1 3'UTR modulates Gata1 levels to affect erythropoiesis.
    Ling Ling, Jiawen Huang, Zhichen Dai, Lan Yang, Fan Yang, Fangyu Gong, Xinhui Qiu, Mengying Lv, Fangfang Wang, Jingyan Liang, Sheng He, Duonan Yu.
      The 3' untranslated region (3'UTR) of mRNA is crucial for post-transcriptional gene regulation, primarily through miRNAs. However, the overall role of the Gata1 3'UTR in mammals remains unclear. In this study, we knocked out the Gata1 3'UTR and observed a defect in erythropoiesis in mutant mice, evidenced by macrocytic anemia at baseline. The deletion of the Gata1 3'UTR also caused deficiencies in erythropoiesis within fetal livers. Mechanistically, removing the Gata1 3'UTR destabilizes Gata1 mRNA, leading to decreased levels of GATA1 protein. This reduced stability results from the dissociation of AU-rich elements in the 3'UTR from a trans-acting factor called ELAVL1. Specifically, we conducted an RNA pulldown assay followed by mass spectrometry to identify proteins that bind to the Gata1 3'UTR. Gene Ontology analysis revealed that ELAVL1 is a binding partner across nearly all categories related to mRNA stabilization. Western blotting, RNA immunoprecipitation, and mutagenesis assays confirmed the direct interaction between the Gata1 3'UTR and ELAVL1. Modulating ELAVL1 activity or protein levels with the small molecule inhibitor Dihydro-tanshinone-I, or through ectopic expression in erythroid cells, validated ELAVL1 as a stabilizing factor for Gata1 mRNA. Our results highlight the important role of the Gata1 mRNA 3'UTR in erythroid development. Teaser Abstract: The role of the Gata1 3'UTR in mammals remains unclear. In this study, we generated Gata1 3'UTR knockout mice and observed a defect in erythropoiesis, evidenced by macrocytic anemia at baseline. Mechanistically, removing the Gata1 3'UTR destabilizes Gata1 mRNA and causes reduced expression of GATA1 protein. This low mRNA stability results from the dissociation of AU-rich elements in the 3'UTR from trans-acting factor ELAVL1, rather than from loss of miRNA binding or loss of poly A sequences. Our results highlight the crucial role of the Gata1 3'UTR in erythroid development.
    Keywords:  3’UTR; ELAVL1; Gata1; erythropoiesis; miRNA
    DOI:  https://doi.org/10.1016/j.exphem.2025.105327
  12. Postepy Biochem. 2025 06 30. 71(2): 145-152
    KLF1 (Krüppel-like factor 1) as a key regulator of erythroid gene expression
    Klaudia Kulczynska-Figurny, Miroslawa Siatecka.
      KLF1 (Krüppel-like factor 1) is an essential transcription factor involved in almost all stages of erythropoiesis. KLF1 promotes the transition of myeloid progenitor cells towards the erythroid lineage, while inhibiting the megakaryopoietic pathway. Its expression is tissue-specific and limited to hematopoietic organs. It begins in the yolk sac, then in the liver and in bone marrow. KLF1 plays a role as a global regulator of erythrocyte development. It regulates many processes, including globin synthesis, heme, iron acquisition, red blood cell membrane antigens expression. KLF1 is composed of two domains: an N-terminal transactivation domain and a C-terminal DNA-binding domain. KLF1 is the first known transcription factor from the Kruppel-like Factor family, which currently includes 17 members. Their characteristic feature is C2H2 zinc finger motifs interacting with DNA. In addition to erythropoiesis, KLF factors play a key role in regulating gene expression of various biological processes, including cell proliferation, differentiation, and apoptosis.
    DOI:  https://doi.org/10.18388/pb.2021_613
  13. Pediatr Blood Cancer. 2025 Nov 19. e70007
    Irradiation-Free Reduced Intensity Conditioning Stem Cell Transplantation for Young Patients With Diamond-Blackfan Anemia Syndrome Is Well-Tolerated and Effective.
    Helena Yu, Eric J Anderson, Deborah E Schiff, Nicholas J Gloude.
      Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with Diamond-Blackfan anemia (DBA) syndrome. Myeloablative regimens have generally been standard practice, but reduced intensity conditioning (RIC) regimens are increasingly used to minimize toxicities. We retrospectively analyzed patients with transfusion-dependent DBA who underwent RIC HSCT with distal alemtuzumab, fludarabine, melphalan, and thiotepa at our institution. Median neutrophil engraftment was Day +15. Maximum acute graft-versus-host disease (GVHD) was grade II and chronic GVHD was NIH chronic moderate. All patients remain transfusion-free with excellent donor chimerism at a median follow-up of 52 months. HSCT with irradiation-free RIC was well-tolerated and effective for DBA.
    Keywords:  Diamond‐Blackfan anemia syndrome; hematopoietic stem cell transplant; reduced intensity conditioning
    DOI:  https://doi.org/10.1002/pbc.70007
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