bims-conane Biomed News
on Congenital anemias
Issue of 2024–10–27
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Association study of common KLF1 variants with Hb F and Hb A2 levels in β-thalassaemia carriers of Portuguese ancestry.
  2. Upregulation of miR‑6747‑3p affects red blood cell lineage development and induces fetal hemoglobin expression by targeting BCL11A in β‑thalassemia.
  3. Gene Therapy: A Revolutionary Step in Treating Thalassemia.
  4. Exploring alterations of gut/blood microbes in addressing iron overload-induced gut dysbiosis and cognitive impairment in thalassemia patients.
  5. Molecular epidemiological characteristics, variant spectrum and genotype-phenotype correlation of glucose-6-phosphate dehydrogenase deficiency in China: A population-based multicenter study using newborn screening.
  6. G>A transition at 376 position of the glucose-6-phosphate dehydrogenase (G6PD) gene plays a key role in causing G6PD deficiency in the Siddi population of Karnataka.
  7. [Research progress on erythroblastic islands in erythroid development and related diseases].
  8. Digenic Inheritance of Hereditary Spherocytosis Type III and X-linked Agammaglobulinemia: Coexistence of Two Distinct Recessive Disorders in a Male Child.
  9. Organ-Specific Iron Overload in Non-Transfusion-Dependent Thalassemia Patients: Insights from Quantitative MRI Evaluation.
  1. J Genet. 2024 ;pii: 32. [Epub ahead of print]103
    Association study of common KLF1 variants with Hb F and Hb A2 levels in β-thalassaemia carriers of Portuguese ancestry.
    Licínio Manco, Celeste Bento, Luís Relvas, Tabita Maia, Letícia Ribeiro.
      Kruppel-like factor 1 (KLF1) is an essential erythroid-specific transcription factor. Several reports have shown that KLF1 gene mutations are associated with increased levels of Hb F and Hb A2. However, scarce population studies have analysed common KLF1 variations. This study examines the potential association with Hb F and Hb A2 levels in β-thalassemia (β-thal) carriers of Portugueseancestry of the four common KLF1 gene variants: -251C>G (rs3817621) and -148G>A (rs79334031), in the promoter region; and c.115A>C (p.Met39Leu) (rs112631212) and c.304T>C (p.Ser102Pro) (rs2072597), in exon 2. Ninety-two Portuguese β-thal carriers (43 males and 49 females) aged 2 to 77 years old (mean 32.55 years) were engaged in the study. Hb F levels range from 0.2 to 12.5% and Hb A2 was above the normal level, ranging from 3.6 to 6%. The Hb A2 and Hb F levels were determined by high-performance liquid chromatography. Single-nucleotide polymorphisms were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Minor allele frequencies for SNPs rs3817621 (G), rs79334031 (A), rs112631212 (C) and rs2072597 (C) were 0.196, 0.016, 0.011 and 0.169, respectively. Basic simple linear regression in the total population showed no significant associations with the levels of Hb F (P>0.05). For the low-frequency variant -148A, a statistically significant association was found with increased levels of Hb A2 (β = 0.855; P = 0.017). In conclusion, an association signal with Hb A2 levels was observed for the variant -148A>G (rs79334031). The complex pattern of SNP interactions related to their influence on the KLF1 transcriptional activity mayexplain the absence of association with Hb F levels.
  2. Mol Med Rep. 2025 Jan;pii: 7. [Epub ahead of print]31(1):
    Upregulation of miR‑6747‑3p affects red blood cell lineage development and induces fetal hemoglobin expression by targeting BCL11A in β‑thalassemia.
    Aixiang Lv, Meihuan Chen, Siwen Zhang, Wantong Zhao, Jingmin Li, Siyang Lin, Yanping Zheng, Na Lin, Liangpu Xu, Hailong Huang.
      In β‑thalassemia, excessive α‑globin chain impedes the normal development of red blood cells resulting in anemia. Numerous miRNAs, including miR‑6747‑3p, are aberrantly expressed in β‑thalassemia major (β‑TM), but there are no reports on the mechanism of miR‑6747‑3p in regulating red blood cell lineage development and fetal hemoglobin (HbF) expression. In the present study, RT‑qPCR was utilized to confirm miR‑6747‑3p expression in patients with β‑TM and the healthy controls. Electrotransfection was employed to introduce the miR‑6747‑3p mimic and inhibitor in both HUDEP‑2 and K562 cells, and red blood cell lineage development was evaluated by CCK‑8 assay, flow cytometry, Wright‑Giemsa staining and Benzidine blue staining. B‑cell lymphoma/leukemia 11A (BCL11A) was selected as a candidate target gene of miR‑6747‑3p for further validation through FISH assay, dual luciferase assay and Western blotting. The results indicated that miR‑6747‑3p expression was notably higher in patients with β‑TM compared with healthy controls and was positively related to HbF levels. Functionally, miR‑6747‑3p overexpression resulted in the hindrance of cell proliferation, promotion of cell apoptosis, facilitation of cellular erythroid differentiation and γ‑globin expression in HUDEP‑2 and K562 cells. Mechanistically, miR‑6747‑3p could specifically bind to the 546‑552 loci of BCL11A 3'‑UTR and induce γ‑globin expression. These data indicate that upregulation of miR‑6747‑3p affects red blood cell lineage development and induces HbF expression by targeting BCL11A in β‑thalassemia, highlighting miR‑6747‑3p as a potential molecular target for β‑thalassemia therapy.
    Keywords:  B‑cell lymphoma/leukemia 11A; fetal hemoglobin; miR‑6747‑3p; red blood cell lineage development; β‑thalassemia
    DOI:  https://doi.org/10.3892/mmr.2024.13372
  3. Hematol Rep. 2024 Oct 21. 16(4): 656-668
    Gene Therapy: A Revolutionary Step in Treating Thalassemia.
    Jhancy Malay, Rasha Aziz Attia Salama, Ghania Shehzad Alam Qureshi, Ali Raafat Ali Ahmed Ammar, Gayatri Janardhan, Maryam Safdar, Hesham Amin Hamdy Elshamy.
      Beta thalassemia is an inherited blood disorder that results in inefficient erythropoiesis due to genetic mutation that leads to the reduction or absence of the hemoglobin beta-globulin protein. Approximately 8.5% of UAE residents suffer from β-thalassemia, a significant health and financial problem. The treatment options available for β-Thalassemia major are limited and associated with a wide range of complications. β-thalassemia gene therapy is emerging as a potential novel treatment option that eliminates the complications caused by the current long-term treatment modalities and the associated economic burden. This paper reviews the scientific literature related to emerging gene therapy for β-Thalassemia by analyzing all the articles published from January 2010 to December 2023 in the English language on Databases like PubMed, Scopus, ProQuest, and CINAHL. The use of gene therapy has demonstrated promising outcomes for a permanent cure of β-Thalassemia. To conclude, gene therapy is an innovative solution. It demonstrates a promising future, but does come with its own setbacks and is something that must be tackled in order to revolutionize it in the medical world. FDA-approved ZYNTEGLO is a potentially one-time curative treatment for β-Thalassemia. Although cutting-edge, its use is limited because of the high cost-a price of USD 2.8 million per patient.
    Keywords:  Cooley’s anemia; Mediterranean Anemia; beta thalassemia major; gene addition; gene editing; gene modification; transfusion-dependent beta thalassemia
    DOI:  https://doi.org/10.3390/hematolrep16040064
  4. Sci Rep. 2024 10 23. 14(1): 24951
    Exploring alterations of gut/blood microbes in addressing iron overload-induced gut dysbiosis and cognitive impairment in thalassemia patients.
    Kanokphong Suparan, Kornkanok Trirattanapa, Pokpong Piriyakhuntorn, Sirawit Sriwichaiin, Chanisa Thonusin, Wichwara Nawara, Sasiwan Kerdpoo, Nipon Chattipakorn, Adisak Tantiworawit, Siriporn C Chattipakorn.
      Iron overload causes cognitive impairment in thalassemia patients. The gut-brain axis plays an important role in cognitive function. However, the association between gut/blood microbiome, cognition, and iron burden in thalassemia patients has not been thoroughly investigated. We aimed to determine those associations in thalassemia patients with different blood-transfusion regimens. Sixty participants: healthy controls, transfusion-dependent thalassemia (TDT) patients, and non-transfusion-dependent (NTDT) patients, were recruited to evaluate iron overload, cognition, and gut/blood microbiome. TDT patients exhibited greater iron overload than NTDT patients. Most thalassemia patients developed gut dysbiosis, and approximately 25% of the patients developed minor cognitive impairment. Increased Fusobacteriota and Verrucomicrobiota with decreased Fibrobacterota were observed in both TDT and NTDT groups. TDT patients showed more abundant beneficial bacteria: Verrucomicrobia. Iron overload was correlated with cognitive impairment. Increased Butyricimonas and decreased Paraclostridium were associated with higher cognitive function. No trace of blood microbiota was observed. Differences in blood bacterial profiles of thalassemia patients and controls were insignificant. These findings suggest iron overload plays a role in the imbalance of gut microbiota and impaired cognitive function in thalassemia patients. Harnessing probiotic potential from those microbes could prevent the gut-brain disturbance in thalassemia patients.
    Keywords:  Blood bacteria; Cognitive decline; Gut dysbiosis; Iron overload; Thalassemia
    DOI:  https://doi.org/10.1038/s41598-024-76684-4
  5. PLoS One. 2024 ;19(10): e0310517
    Molecular epidemiological characteristics, variant spectrum and genotype-phenotype correlation of glucose-6-phosphate dehydrogenase deficiency in China: A population-based multicenter study using newborn screening.
    Minyi Tan, Xiulian Liu, Yinhong Zhang, Yifan Yin, Ting Chen, Yulin Li, Lulu Feng, Bo Zhu, Chunjing Xu, Chengfang Tang, Meng Sun, Liyun Jia, Weiwei Jin, Chunna Fan, Hui Huang, Xiaohua Wang, Jizhen Feng, Hui Zou, Lianshu Han, Jingkun Miao, Baosheng Zhu, Cidan Huang, Yonglan Huang.
       BACKGROUND AND AIMS: Newborn screening (NBS) for glucose-6-phosphate dehydrogenase (G6PD) deficiency by biochemical tests is being used worldwide, however, the outcomes arising from combined genetic and biochemical tests have not been evaluated. This research aimed to evaluate the outcomes of application of combined genetic and biochemical NBS for G6PD deficiency and to investigate the molecular epidemiological characteristics, variant spectrum, and genotype-phenotype correlation of G6PD deficiency in China.
    METHODS: A population-based cohort of 29,601 newborns were prospectively recruited from eight NBS centers in China between February 21 and December 30, 2021. Biochemical and genetic NBS was conducted simultaneously.
    RESULTS: The overall prevalence of G6PD deficiency was 1.12% (1.86% for male, and 0.33% for female; 1.94% for South China and 0.08% for North China). Genetic NBS identified 10 male patients undetected by biochemical NBS. The overall positive predictive values (PPVs) of biochemical and genetic NBS were 79.95% and 47.57%, respectively. A total of 15 variants were identified, with the six most common variants being c.1388G > A, c.1376G > T, c.95A > G, c.871G > A, c.1024C > T and c.392G > T (94.2%). The activity of G6PD was correlated with the type and WHO classification of variants.
    CONCLUSION: This study highlighted that combined screening could enhance the efficiency of current NBS for diagnosing G6PD deficiency. The prevalence, variant spectrum and allele frequency of G6PD deficiency vary across different regions. Our data provide valuable references for clinical practice and optimization of future screening strategies for G6PD deficiency.
    DOI:  https://doi.org/10.1371/journal.pone.0310517
  6. Natl Med J India. 2024 Jul-Aug;37(4):pii: 10.25259/NMJI_304_2023. [Epub ahead of print]37(4): 233
    G>A transition at 376 position of the glucose-6-phosphate dehydrogenase (G6PD) gene plays a key role in causing G6PD deficiency in the Siddi population of Karnataka.
    Smita Hegde, Rajat Hegde, Madhuri D Biradar, Suyamindra S Kulkarni, Pramod B Gai.
      
    DOI:  https://doi.org/10.25259/NMJI_304_2023
  7. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Oct;40(10): 936-941
    [Research progress on erythroblastic islands in erythroid development and related diseases].
    Linru Zou, Jian Bai, Tiaoxia Wei, Lei Feng, Hongyan Qin.
      Erythroblastic islands (EBIs) are specialized structures that are formed by a central macrophage surrounded by maturating erythroblasts. The central macrophage mediates EBI formation and plays a crucial role in the proliferation, differentiation, enucleation, and maturation of erythroblasts. In stress erythropoiesis, the expression levels of several adhesion molecules mediating EBI formation become abnormal, leading to various erythroid diseases. These findings have indicated that targeting central macrophages may become a new therapeutic approach for treating erythroid diseases. This review summarizes the structure and function of EBIs, macrophage-erythroblast interactions in EBIs, and potential therapeutic direction of EBI central macrophages for erythroid diseases, providing new insights for the clinical treatment of erythroid diseases.
  8. Cureus. 2024 Sep;16(9): e69887
    Digenic Inheritance of Hereditary Spherocytosis Type III and X-linked Agammaglobulinemia: Coexistence of Two Distinct Recessive Disorders in a Male Child.
    Khaled A Almutairy, Badriah G Alasmari, Syed Rayees.
      Hereditary spherocytosis (HS) is a common inherited hemolytic disease caused by mutations in genes encoding proteins crucial to the red blood cell (RBC) membrane, leading to a change in RBC shape from biconcave to spherical. There are five distinct types of hereditary spherocytosis, with types III and V being autosomal recessive and types I, II, and IV autosomal dominant. X-linked agammaglobulinemia (XLA) is a common inborn error of immunity that impairs B cell maturation and differentiation. We report a case of a two-year-old Saudi boy with persistent anemia, recurrent chest infections, and a subgaleal abscess. A whole exome sequencing study revealed digenic inheritance of hereditary spherocytosis type III and XLA. Despite a variant of uncertain significance in the Bruton's tyrosine kinase (BTK) gene, the patient's clinical and biochemical profile strongly indicated XLA. This case highlights how digenic inheritance can manifest as a complex phenotype, illustrating the challenges in diagnosing and managing patients with multigenic diseases.
    Keywords:  hereditary spherocytosis; immunology; pediatric hematology; recessive; x linked agammaglobinemia
    DOI:  https://doi.org/10.7759/cureus.69887
  9. Eur J Radiol. 2024 Oct 10. pii: S0720-048X(24)00466-2. [Epub ahead of print]181 111750
    Organ-Specific Iron Overload in Non-Transfusion-Dependent Thalassemia Patients: Insights from Quantitative MRI Evaluation.
    Xiaojing Ning, Siyu Tan, Fei Peng, Chaotian Luo, Cheng Tang, Fangyan Xiao, Peng Peng.
       OBJECTIVE: To elucidate the iron load in different organs of non-transfusion-dependent thalassemia (NTDT) patients using magnetic resonance imaging (MRI) T2* scan.
    METHODS: Thirty-four NTDT patients, including 28 NTDT iron chelation without and 6 NTDT with iron chelation, together with 15 normal controls, underwent MRI examination between December 2022 and July 2024 were enrolled in the study. Measured T2* of the pituitary gland, kidney cortex, heart, liver, pancreas, spleen. Liver and spleen volumes were evaluated.
    RESULTS: Of the 28 patients in NTDT without iron chelation group, 19 patients with iron overload in the liver, 9 patients with iron overload in the kidneys, and 4 patients with iron overload in the spleen. Most patients with abnormal kidney and spleen iron (76.9 %) had liver iron overload. Compared with the control group, NTDT without iron chelation patients had lower T2* in the liver, kidney, and spleen (p < 0.05). And heart T2* was correlated with kidney T2* (r = 0.480, p = 0.010) and pancreas (r = 0.411, p = 0.037). Liver T2* was correlated with spleen T2* (r = 0.479, p = 0.011). Pancreas T2* was correlated with pituitary T2* (r = -0.433, p = 0.031).
    CONCLUSIONS: NTDT patients exhibit significant organ-specific iron overload, particularly in the liver, kidneys, and spleen. The correlations between iron levels in different organs suggest interconnected mechanisms of iron accumulation. These findings highlight the importance of regular MRI screening to monitor and manage iron overload in NTDT patients.
    Keywords:  Iron overload; Kidney; MRI; Non-transfusion-dependent thalassemia; Pituitary; Volume
    DOI:  https://doi.org/10.1016/j.ejrad.2024.111750
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