bims-conane 2025-06-01 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–06–01
twelve papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Upregulation of miR-17-3p is associated with HbF in patients with β-thalassemia and induces γ-globin expression by targeting BCL11A.
Thalidomide confers therapeutic benefit in beta thalassemia patients by enhancing hemoglobin and hematopoietic gene expression: A non-randomized clinical trial.
Unveiling the molecular landscape of δ-thalassemia and δ-globin variants in southern China: novel mutations, gene spectrum, and implications for thalassemia diagnosis.
Oxidative stress markers and tissue iron overload after 12-months vitamin E supplementation for children with transfusion-dependent β-thalassemia on different iron chelators: A randomized placebo-controlled trial.
Dysregulation of Ceruloplasmin, α2-Macroglobulin, and Alpha-2-HS-Glycoprotein in Transfusion-Dependent Thalassemia.
Red blood cell exchange in Hemoglobin Evans: A novel therapeutic avenue for a rare hemoglobinopathy.
Hb Lepore Rochester-MN, a novel βδβ double crossover hemoglobin variant.
Hemoglobin Disorders Associated with Neurological Impairment: First Report of ATR-X Syndrome and Recessive Congenital Methemoglobinemia Type II in Tunisia.
A Coordinated Translational Control Mediated by eEF2 Phosphorylation Safeguards Erythroid Differentiation.
Thalassemia traits may modulate protective mir-155 levels in dengue infection.
Antenatal presentations of congenital sideroblastic anaemia as severe fetal anaemia.
Survival and thalassaemia-related complications in HbE/beta-thalassaemia and alpha-thalassaemia: A 10-year longitudinal study in Thailand.

Orphanet J Rare Dis. 2025 May 30. 20(1): 260

Upregulation of miR-17-3p is associated with HbF in patients with β-thalassemia and induces γ-globin expression by targeting BCL11A.

Siwen Zhang, Meihuan Chen, Wantong Zhao, Junhao Zheng, Yanhong Zhang, Aixiang Lv, Jingmin Li, Hua Cao, Liangpu Xu, Hailong Huang.

   BACKGROUND: Large number of microRNAs (miRNAs) have been found to be dysregulated in β-thalassemia, but their roles in β-thalassemia are poorly reported. This study aims to investigate the clinical significance of miR-17-3p in β-thalassemia, and to elucidate its regulatory effect on erythropoiesis and γ-globin expression.
METHODS: We collected peripheral blood samples from 17 patients with β-thalassemia (including intermedia and major subtypes) and 17 healthy controls, and the expression levels of miR-17-3p, BCL11 transcription factor A (BCL11A) and γ-globin were detected by qRT-PCR, and their correlations were analyzed. The regulation of miR-17-3p on BCL11A was evaluated in K562 cells by bioinformatics, luciferase reporter gene assay, fluorescence in situ hybridization and Western blotting. Furthermore, the effects on miR-17-3p overexpression and knockdown on erythropoiesis including cell proliferation, cell cycle, cell apoptosis, and erythroid differentiation of K562 cells were assessed by CCK-8, flow cytometry and benzidine blue staining.
RESULTS: The expression of miR-17-3p was upregulated in patients with β-thalassemia, and was positively correlated with fetal hemoglobin (HbF) levels. BCL11A expression was reduced in β-thalassemia patients, and was negatively correlated with miR-17-3p and γ-globin expression. BCL11A was identified as a target gene of miR-17-3p, and was negatively regulated by miR-17-3p. Furthermore, miR-17-3p mediated the upregulation of γ-globin expression in K562 cells through BCL11A. In addition, neither overexpression nor knockdown of miR-17-3p appeared to affect cell proliferation, cell cycle, cell apoptosis or erythroid differentiation of K562 cells in vitro.
CONCLUSION: The upregulated miR-17-3p is associated with HbF in patients with β-thalassemia. Although miR-17-3p does not affect erythropoiesis, it promotes γ-globin expression by targeting BCL11A, suggesting that miR-17-3p may be a promising miRNA for the treatment of β-thalassemia.

Keywords:  BCL11A; Erythropoiesis; HbF; miR-17-3p; β-thalassemia

DOI:  https://doi.org/10.1186/s13023-025-03806-0
Blood Cells Mol Dis. 2025 May 23. pii: S1079-9796(25)00028-2. [Epub ahead of print]113-114 102936

Thalidomide confers therapeutic benefit in beta thalassemia patients by enhancing hemoglobin and hematopoietic gene expression: A non-randomized clinical trial.

Inayat Ur Rahman, Muhammad Tariq Masood Khan, Zahid Ali, Shafiq Ahmad, Muhammad Shahid, Shafaq Zafar, Faheela Faizi Aamir, Imran Khan, Muhammad Ali, Musharraf Jelani, Khalid Khan, Nafees Ahmad, Yasar Yousafzai, Afsar Ali Mian, Sami Siraj.

   BACGROUND: Transfusion-dependent β-thalassemia (TDT) requires regular transfusions, often causing iron overload and organ damage. Thalidomide, a fetal hemoglobin (HbF) inducer, may reduce transfusion needs, but scientific data are limited.
METHODS: This two-arm, non-randomized clinical trial followed a total of 164 TDT patients over 30 months: 72 received thalidomide and 92 underwent standard transfusions. Complete blood count was assessed at baseline and 6, 12, 18, 24, and 30 months. SNP genotyping and β-globin mutation analysis were performed using sanger sequencing. GATA-1 and KLF gene expression were assessed at baseline and after 30 months via qRT-PCR RESULTS: Hemoglobin level in the thalidomide group significantly increased from 6.12 ± 0.65 g/dL to 8.36 ± 2.04 g/dL (p < 0.001). Among thalidomide-treated patients, 34.7 % were excellent responders (ER), 25 % good responders (GR), 13.9 % partial responders (PR), and 26.4 % non-responders (NR). ERs showed the highest GATA-1 [3.09 (IQR 2.0-3.38)] and KLF [3.24 (IQR 3.01-5.42)] expression levels (p < 0.001). Better response was observed in patients with AFT >12 months and those carrying the minor allele C at HBS1L-MYB rs9399137 (p < 0.05) CONCLUSION: Thalidomide effectively increases hemoglobin levels and reduces transfusion needs in TDT patients, particularly through upregulation of GATA-1 and KLF. AFT and SNP genotype at HBS1L-MYB rs9399137 may help predict response TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT06146478.

Keywords:  BCL11A; GATA; HBS1L-MYB; Thalidomide; Transfusion-dependent β-thalassemia

DOI:  https://doi.org/10.1016/j.bcmd.2025.102936
Front Genet. 2025 ;16 1584310

Unveiling the molecular landscape of δ-thalassemia and δ-globin variants in southern China: novel mutations, gene spectrum, and implications for thalassemia diagnosis.

Youqiong Li, Lihua Ye, Liang Liang, Lihong Zheng, Yongjun Xiao, Zhongchan Lao, Jinping Bai, Xi He, Qixun Fang, Ting Qin.

   Objectives: δ-thalassemia and δ-globin variants are rare hemoglobinopathies. However, co-inheritance of β-thalassemia and δ-globin gene mutations may affect the diagnosis of β-thalassemia carriers when based on the elevated Hb A2. This study aimed to identify and characterize δ-thalassemia and δ-globin variants in Southern China.
Methods: Ninety samples with suspected δ-globin gene mutations from 15,642 participants were selected for further molecular analysis based on their Hb A2 level (≦1.8%) and hematological parameters. Additionally, 37 samples with suspected δ-globin gene mutations were sent from other hospital to our laboratory for identification. GAP-PCR and PCR-reverse dot blot (PCR-RDB) were used to detect common α- and β-thalassemia in the Chinese population, and Sanger sequencing was used to identify δ-globin gene mutations.
Results: Among 15,642 samples examined, samples with δ-globin gene mutations were identified in 127 (0.81%) cases with as many as 28 different genotypes, including 81 (0.52%) cases of δ-thalassemia and 46 (0.29%) cases of δ-globin variants. The most prevalent δ-thalassemia and δ-globin variants of this study were HBD:c.-127T>C (75.3%, 61/81) and Hb A2-Melbourne (54.3%, 25/46). Most of the samples were heterozygous (87.4%, 111/127), and only two cases of homozygous were detected. There were three double heterozygotes and 11 cases of combined α/β-globin mutations. Notably, we also identified eight cases of novel mutations in the δ-globin gene. In both heterozygous and homozygous cases, δ-globin mutations maintained hematological parameters within normal ranges, while their co-occurrence with α- or β-thalassemia manifested as a thalassemia phenotype characterized by significantly reduced MCV and MCH values.
Conclusion: The study reveals that δ-globin gene mutations are prevalence in the South China and necessitates integration of δ-globin screening into existing thalassemia prevention protocols.

Keywords:  HBD gene; Hb A2; thalassemia; δ-globin variants; δ-thalassemia

DOI:  https://doi.org/10.3389/fgene.2025.1584310
Clin Nutr. 2025 May 14. pii: S0261-5614(25)00131-1. [Epub ahead of print]50 154-163

Oxidative stress markers and tissue iron overload after 12-months vitamin E supplementation for children with transfusion-dependent β-thalassemia on different iron chelators: A randomized placebo-controlled trial.

Mohamed A ElLaboudy, Maha M Saber, Amira A Adly, Eman A Ismail, Fatma A Ibrahim, Omar M Elalfy.

   BACKGROUND: Vitamin E is an anti-oxidant depleted in thalassemia as a result of iron overload.
AIM: We investigated the efficacy and safety of vitamin E as an adjuvant therapy to iron chelators in transfusion-dependent thalassemia patients in relation to tissue iron overload and examine its potential corrective value to oxidative stress markers including peroxiredoxin-2 (PRDX2).
METHODS: This randomized prospective study included 180 pediatric patients with transfusion-dependent β-thalassemia who were equally divided into three groups to either receive desferrioxamine (DFO), deferiprone (DFP) or deferasirox (DFX). Patients in each group were further randomized to receive vitamin E supplementation (400 mg daily) or matching placebo. Patients were followed-up for 12 months with assessment of oxidative stress markers (malondialdehyde [MDA], reduced glutathione, superoxide dismutase, glutathione peroxidase and PRDX2), serum ferritin (SF), liver iron content (LIC) and cardiac T2∗ by magnetic resonance imaging. The primary endpoint was the change between groups from baseline to 12 months as regards LIC.
RESULTS: After vitamin E therapy, transfusion index, SF and LIC were significantly decreased while hemoglobin and cardiac T2∗ were elevated compared with baseline levels or placebo group. MDA levels were decreased while the studied antioxidants were improved after vitamin E supplementation compared with baseline levels or placebo. DFX-treated patients had the highest hemoglobin level with the lowest SF, LIC and MDA levels compared with DFO or DFP subgroups.
CONCLUSIONS: Vitamin E is a safe adjuvant anti-oxidant therapy that potentiates the efficacy of DFX in reducing iron burden in transfusion-dependent β-thalassemia patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT06509581.

Keywords:  Oxidative stress; Peroxiredoxin-2; Tissue iron overload; Transfusion-dependent thalassemia; Vitamin E

DOI:  https://doi.org/10.1016/j.clnu.2025.05.003
Adv Hematol. 2025 ;2025 2179600

Dysregulation of Ceruloplasmin, α2-Macroglobulin, and Alpha-2-HS-Glycoprotein in Transfusion-Dependent Thalassemia.

Afshan Sumera, Ammu K Radhakrishnan, Soon Keng Cheong, Abdul Aziz Baba.

  Transfusion-dependent thalassemia (TDT) is a severe inherited anemia characterized by impaired synthesis of hemoglobin chains. Disease progression and TDT severity are potentially linked to oxidative stress and protein damage. This study aimed to explore the expression patterns of ceruloplasmin (CP), α2-macroglobulin (A2M), and alpha-2-HS-glycoprotein (AHSG) in TDT serum through quantitative proteomic profiling. The results were validated using enzyme-linked immunosorbent assays (ELISA). The study participants were divided into three groups based on the duration of blood transfusion. Age and gender-matched normal individuals served as controls. The results revealed the downregulation of these proteins. The reduced levels of these proteins may contribute to tissue damage in TDT patients, primarily due to increased oxidative stress. For example, decreased CP levels can disrupt iron and copper metabolism, leading to heightened oxidative stress and rendering red blood cell membranes more susceptible to rupture due to active oxygen radicals. In summary, CP, A2M, and AHSG association with iron metabolism, inflammation, and oxidative stress underscores their potential relevance in understanding TDT's pathogenesis and progression. These findings may pave the way for improved diagnostic and therapeutic strategies for TDT patients.

Keywords:  alpha-2-HS-glycoprotein (AHSG); ceruloplasmin (CP); transfusion-dependent thalassemia (TDT); α2-macroglobulin (A2M)

DOI:  https://doi.org/10.1155/ah/2179600
Transfus Clin Biol. 2025 May 22. pii: S1246-7820(25)00091-6. [Epub ahead of print]

Red blood cell exchange in Hemoglobin Evans: A novel therapeutic avenue for a rare hemoglobinopathy.

Radheshyam Meher.

DOI: https://doi.org/10.1016/j.tracli.2025.05.005
Blood Cells Mol Dis. 2025 May 23. pii: S1079-9796(25)00029-4. [Epub ahead of print]113-114 102937

Hb Lepore Rochester-MN, a novel βδβ double crossover hemoglobin variant.

Aruna Rangan, Kenneth C Swanson, Michelle Savedra, Xi Zhang, James D Hoyer, Jennifer L Herrick.

   INTRODUCTION: The β-globin gene cluster harbors highly homologous globin genes. Crossover events involving the δ (HBD) and β (HBB) genes result in Lepore (δβ) and anti-Lepore (βδ) hemoglobins (Hbs). Recently, double crossover (βδβ) variants have been reported. Herein, we report βδβ variants identified in our laboratory including the novel Hb Lepore Rochester-MN (LRM).
METHODS: Blood samples were obtained with Institutional Review Board approval. Protein characterization included cation exchange high performance liquid chromatography (HPLC), capillary electrophoresis (CE) and mass spectrometry (MS). Molecular analysis included HBB Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA).
RESULTS: Two distinct βδβ crossover variants were identified: Novel Hb LRM (2 infants, 1 adult) and Hb Wanjiang. Hb LRM separated on protein studies (HPLC, CE and MS) and showed identical protein characteristics as Hb Lepore-Hollandia, however, it was expressed at a higher percentage. Sanger sequencing characterized the variant as NM_000518.4(HBB):c.28_68delins41 (p.Ser10_Glu23delins14TAVNALWGKVNVDA). Hb Wanjiang protein did not separate from Hb A using routine methods (HPLC, CE and IEF) but was identifiable by MS and DNA sequencing as NM_000518.4(HBB):c.255_264delinsTTTTTCTCAG (p.A87_T88delinsSQ).
CONCLUSIONS: The copy neutral incorporation of δ segments into β gene does not worsen the clinical phenotype. Some substitutions may even have a protective effect when coinherited with Hb S. These uncommon double crossover βδβ variants can pose a diagnostic challenge for laboratories as they can be mistaken for other similar variants on protein evaluation. Also, they may require specialized analysis such as MS, Sanger sequencing or NGS. Interpretation can be challenging if comparison to δ-gene is not considered.

Keywords:  Anti-Lepore; Hb Lepore Rochester-MN; Hb Wanjiang; Lepore; βδβ double crossover

DOI:  https://doi.org/10.1016/j.bcmd.2025.102937
Int J Mol Sci. 2025 May 16. pii: 4803. [Epub ahead of print]26(10):

Hemoglobin Disorders Associated with Neurological Impairment: First Report of ATR-X Syndrome and Recessive Congenital Methemoglobinemia Type II in Tunisia.

Houyem Ouragini, Emna Bouatrous, Manel Kasdallah, Sonia Nouira, Hamza Dallali, Samia Rekaya, Dorra Chaouachi, Monia Ouederni, Samia Menif.

  Hemoglobin disorders are among the most common inherited diseases worldwide. Their clinical manifestations range from anemia to more severe forms associated with neurological impairments. These complications can result as secondary consequences of the disease's clinical manifestations or be directly linked to genetic mutations. In this study, we present two families with neurological impairments who were referred to us for complementary hematological and biochemical analyses. Complete blood count, methemoglobin level, and methemoglobin reductase activity were assessed. Molecular analyses were performed using whole-exome sequencing, and the segregation of the identified mutations was confirmed with direct sequencing. Their pathogenicity and conservation were evaluated using various bioinformatics tools. Clinical and hematological findings suggested X-linked alpha-thalassemia/impaired intellectual development syndrome in the first family and recessive congenital methemoglobinemia type II in the second. This was confirmed by the identification of pathogenic mutations ATRX: p.Arg2131Gln and CYB5R3: p.Ala179Thr, respectively. Although these variants have been previously reported worldwide, they were identified for the first time in our population. Our results contribute to the understanding of the pathogenesis of these rare disorders and provide a basis for diagnosis, treatment, and genetic counseling. The mechanisms by which these mutations contribute to neurological symptoms are discussed.

Keywords:  ATR-X syndrome; WES; diagnosis; mutation; neurological disease; recessive congenital methemoglobinemia type II

DOI:  https://doi.org/10.3390/ijms26104803
Int J Mol Sci. 2025 May 16. pii: 4801. [Epub ahead of print]26(10):

A Coordinated Translational Control Mediated by eEF2 Phosphorylation Safeguards Erythroid Differentiation.

Yao Ma, Haozhuo Song, Siming Liu, Wenjing Yu, Guanying Feng, Cuiping Yang, Zhiduo Liu.

  Translational control is crucial for maintaining cellular homeostasis, yet the distinct features and regulatory requirements governing protein synthesis during erythropoiesis remain unclear. Here, we reveal that erythroid cells exhibit an extraordinarily high demand for protein synthesis, which is required for their differentiation but also implies the need for tight regulation to prevent excessive erythropoiesis. Notably, we identify significant phosphorylation of eukaryotic elongation factor 2 (eEF2) at threonine 56 during erythroid differentiation, which reduces protein synthesis and acts as a molecular brake to limit unchecked erythropoiesis. This is evidenced by elevated red blood cell counts in peripheral blood and increased incidence of blood hyperviscosity and thrombosis in eEF2_T56M mice, which are deficient in eEF2 phosphorylation. Mechanistic studies demonstrate that eEF2 phosphorylation selectively regulates the translation of a subset of proteins, including NFE2, which partially mediates the effects of eEF2 modification. Collectively, our findings highlight a previously unappreciated role for translational control in achieving efficient and balanced erythropoiesis, with eEF2 phosphorylation serving as a critical protective mechanism against hyperactive erythropoiesis and offering a potential therapeutic target for hematologic disorders such as polycythemia vera.

Keywords:  eEF2; elongation; erythroid differentiation; erythropoiesis; protein synthesis

DOI:  https://doi.org/10.3390/ijms26104801
Med Microbiol Immunol. 2025 May 29. 214(1): 27

Thalassemia traits may modulate protective mir-155 levels in dengue infection.

Konstantinos I Papadopoulos, Alexandra Papadopoulou, Tar-Choon Aw.



Keywords:  Dengue; Malaria; Mir-155; SARS-CoV-2; Thalassemia

DOI:  https://doi.org/10.1007/s00430-025-00839-x
BMJ Case Rep. 2025 May 26. pii: e257172. [Epub ahead of print]18(5):

Antenatal presentations of congenital sideroblastic anaemia as severe fetal anaemia.

Kelly Ng, Michelle Rougerie, Daniel Lorber Rolnik.

  Severe fetal anaemia of unknown aetiology can present a diagnostic challenge. Rare causes of fetal anaemia include congenital sideroblastic anaemia (CSA), a rare group of disorders that typically manifest during infancy and early childhood. This case report describes three pregnancies complicated by CSA presenting antenatally in the same woman. The index case was a twin pregnancy in which both neonates were born severely anaemic with one surviving twin. The subsequent cases of severe fetal anaemia were detected during pregnancy and successfully managed with intrauterine blood transfusions (IUTs). The three surviving children required several neonatal transfusions and were later diagnosed with CSA. To our knowledge, this is the first case report describing CSA presenting in the antenatal period with surviving patients and thereby highlights the importance of considering fetal anaemia early in pregnancy and the potential for early intervention with IUTs to improve survival outcomes in this group of patients.

Keywords:  Congenital disorders; Haematology (incl blood transfusion); Materno-fetal medicine; Pregnancy

DOI:  https://doi.org/10.1136/bcr-2023-257172
Br J Haematol. 2025 May 26.

Survival and thalassaemia-related complications in HbE/beta-thalassaemia and alpha-thalassaemia: A 10-year longitudinal study in Thailand.

Nattiya Teawtrakul, Arunee Jetsrisuparb, Saranya Pongudom, Kanchana Chansung, Chittima Sirijerachai, Supan Fucharoen.

  Despite advancements in thalassaemia care, survival rates and complications vary significantly by genotype. This study assesses survival outcomes and associated complications in patients with thalassaemia in north-eastern Thailand. A longitudinal cohort study from October 2012 to September 2023 involved patients aged ≥10 years (median: 31 years, range: 20-74) attending Srinagarind and Udonthani Hospitals. Cox regression analyses identified predictors of survival and complications. Of 380 enrolled patients, 340 completed follow-up. Over 10 years, 39 patients (11.4%) died, primarily from cardiovascular complications (61.5%), at a median age of 45 years (range: 22-72). Patients were grouped as HbE/β-thalassaemia, HbH/HbHCS with HbE mutation and HbH/HbHCS. Survival at 60 years was lower in HbE/β-thalassaemia (55.9%) and HbH/HbHCS with HbE mutation (58.3%) compared to HbH/HbHCS (79.6%, p = 0.08). Significant predictors of mortality included cardiovascular complications (HR 2.4; 95% CI, 1.01-5.5; p = 0.04), recurrent bacterial infections (HR 7.6; 95% CI, 3.1-18.8; p < 0.001) and elevated ferritin (>2500 ng/mL; HR 2.0; 95% CI, 1.01-3.9; p = 0.04). Cardiovascular complications, recurrent bacterial infections and high ferritin levels significantly influence survival in thalassaemia patients. Deletional alpha-thalassaemia patients had superior survival, while HbE/β-thalassaemia and non-deletional alpha-thalassaemia or co-inherited HbE mutation had poorer outcomes, underscoring the need for genotype-specific management strategies.

Keywords:  cardiovascular complications; survival outcomes; thalassaemia genotypes

DOI:  https://doi.org/10.1111/bjh.20179