bims-conane Biomed News
on Congenital anemias
Issue of 2026–02–08
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Many faces of non‑deletional α‑thalassaemia variants in neonate and early childhood.
  2. Impact of iron chelation therapy on thyroid function in beta-thalassemia major patients from Pakistan.
  3. Nemo-like kinase modulates glucocorticoid-induced erythroid progenitor differentiation by regulating stability of the glucocorticoid receptor.
  4. Genetic Analysis of 23 SNVs of Nine Genes Involved in RBC Membranopathies with the Hematological Parameters of Mexican Patients.
  5. Multi-omics analysis of red blood cells reveals thalassemia severity beyond globin gene mutations.
  6. Switching and Sniffing around the β-globin cluster.
  7. Hereditary Anemias as a Monogenic Etiology for Nonimmune Hydrops Fetalis.
  1. Ann Hematol. 2026 Feb 04. 105(3): 80
    Many faces of non‑deletional α‑thalassaemia variants in neonate and early childhood.
    Patcharee Komvilaisak, Napat Laoaroon, Pongsatorn Paopongsawan, Junya Jirapradittha, Pakaphan Kiatchoosakun, Kunanya Suwannaying, Ratana Komwilaisak, Worrawalan Lerttham.
      Non-deletional α-thalassemia variants, particularly hemoglobin Constant Spring (Hb CS) and hemoglobin Pakse, are prevalent in northeastern Thailand and neighboring regions. Homozygous Hb CS and compound heterozygous Hb CS/Hb Pakse can present with a wide clinical spectrum. In this study, 49 patients with these α-globin variants-with or without co-inheritance of beta-thalassemia-were evaluated. Genotypes included homozygous Hb CS (n = 27), homozygous Hb CS with Hb E (n = 8), compound heterozygous Hb CS/Hb Pakse (n = 10), compound heterozygous Hb CS/Hb Pakse with Hb E (n = 3), and homozygous Hb Pakse (n = 1). Fetal anemia with hydrops fetalis occurred in 25 patients; 21 underwent intrauterine transfusions (IUTs), resulting in favorable postnatal outcomes in most cases. Two patients with homozygous Hb CS died from complications of severe anemia and prematurity. Early neonatal jaundice occurred in 27 patients, most requiring phototherapy. Direct hyperbilirubinemia was observed in 10 patients; most recovered with supportive care and transfusion, though one died from progressive cholestasis. Twenty four patients required 1-2 postnatal transfusions, with only two requiring later transfusion. Four patients with childhood anemia were initially misdiagnosed with iron deficiency anemia before confirmation of α-thalassemia variants. After the first few months of life, patients typically exhibit mild hypochromic microcytic anemia, elevated red cell distribution width, and reticulocytosis, with basophilic stippling more prominent in Hb CS. During follow-up (3-160 months, median 66), no patients developed hepatosplenomegaly, iron overload, or gallstones. These α-thalassemia variants may cause severe fetal anemia requiring IUT but generally evolve into transfusion-independent mild anemia. Early detection and targeted intervention can improve outcomes in high-prevalence regions.
    Keywords:  Alpha thalassemia; Fetal anemia; Hemoglobin constant spring
    DOI:  https://doi.org/10.1007/s00277-026-06856-x
  2. Sci Rep. 2026 Feb 06.
    Impact of iron chelation therapy on thyroid function in beta-thalassemia major patients from Pakistan.
    Arsalan Waqas Ahmad Shah, Sulaiman Shams, Muhammad Jaseem Khan, Noor Ullah, Muhammad Jawad Ullah, Fawad Inayat.
      Transfusion-Dependent Thalassemia (TDT) causes severe anemia requiring chronic transfusions, leading to iron overload and endocrine complications, including hypothyroidism. Iron chelation therapy (ICT) mitigates iron toxicity, but its effects on thyroid function remain understudied in resource-limited settings like Pakistan. This cross-sectional study compared 100 TDT patients receiving ICT (deferasirox, deferoxamine, or deferiprone) for ≥ 6 months with 100 Control group who have not taken ICT. Thyroid function tests (free T3, free T4, TSH), serum ferritin, and hepatic/renal biomarkers were analyzed. Statistical analyses included t-tests, ANOVA, Pearson correlation, and multivariate regression (SPSS v25). ICT-treated patients had significantly lower TSH (3.10 ± 0.62 vs. 9.95 ± 3.19 μIU/mL, p < 0.001) and higher free T3/T4 levels than controls (p < 0.001). Deferasirox users exhibited the lowest TSH (2.43 ± 0.06 μIU/mL) among chelators (p < 0.001). Ferritin strongly correlated with TSH (r = 0.94, p < 0.001) and independently predicted TSH levels (coefficient = 0.0010, p = 0.048). ICT also preserved hepatic (ALT: 50.55 ± 41.87 vs. 291.36 ± 161.99 U/L, p < 0.001) and renal function (creatinine: 0.97 ± 0.22 vs. 1.65 ± 0.34 mg/dL, p < 0.001). ICT, particularly deferasirox, protects against thyroid dysfunction in TDT, with ferritin as a key predictor. These findings support personalized chelation strategies and routine endocrine monitoring in thalassemia management.
    Keywords:  Endocrine system diseases; Ferritins; Hypothyroidism; Iron chelating agents; Transfusion-dependent thalassemia
    DOI:  https://doi.org/10.1038/s41598-026-36200-2
  3. FEBS J. 2026 Feb 02.
    Nemo-like kinase modulates glucocorticoid-induced erythroid progenitor differentiation by regulating stability of the glucocorticoid receptor.
    Swati Srivastava, Sangita Chowdhury, Vishal Upadhyay, Arunim Shah, Arppita Sethi, Shivkant Mishra, Shailendra Prasad Verma, Arun Kumar Trivedi.
      Glucocorticoid receptor (GR) is a critical regulator of erythroid progenitor proliferation, while Nemo-like kinase (NLK) is reported to be hyperactivated in Diamond-Blackfan anemia (DBA), suggesting a possible cross talk. Here, we demonstrate that NLK directly interacts with multiple domains of GR and promotes its ubiquitin-mediated proteasomal degradation. Co-immunoprecipitation assays confirmed endogenous NLK-GR interaction in K562 cells, enhanced by proteasomal inhibition. NLK overexpression downregulated levels of GR in a kinase-dependent manner across HEK293T, K562, and MEL cells, an effect reversed by MG132 or a ubiquitination-defective mutant. NLK directly phosphorylated GR at Ser226, as shown by in vitro kinase assays and site-specific immunoblotting. Conversely, NLK depletion reduced basal GR phosphorylation while increasing total GR. We identified OTS167 as a direct NLK inhibitor through cellular thermal shift and kinase assays. OTS167 suppressed NLK autophosphorylation and decreased Ser226 phosphorylation of GR, stabilizing GR protein. Functionally, among all the inhibitors tested, OTS167 maximally inhibited proliferation of K562 and MEL cells by 40-90%. OTS167 also induced erythroid differentiation in K562 and MEL by increasing CD71/TER119 expression and benzidine-positive cells by 60-80%, while NLK overexpression inhibited hemin-induced benzidine staining by 25%. In primary human CD34+ cells, NLK and GR exhibited inverse temporal expression during erythropoiesis. OTS167 or dexamethasone expanded CD71+ and CFU-E populations and enhanced proliferation (Ki67+) across BFU-E, CFU-E, and proerythroblast stages. Conversely, dexamethasone upregulated NLK, suppressing GR and suggesting a feedback loop. Thus, NLK-mediated GR downregulation constrains erythropoiesis, and its inhibition by OTS167 promotes erythroid expansion, revealing a targetable pathway in erythroid disorders.
    Keywords:  BFU‐Es; GR; NLK; anemia; erythroid differentiation
    DOI:  https://doi.org/10.1111/febs.70422
  4. Genet Test Mol Biomarkers. 2026 Feb 03. 19450265261417994
    Genetic Analysis of 23 SNVs of Nine Genes Involved in RBC Membranopathies with the Hematological Parameters of Mexican Patients.
    Laura Lucía Espinoza-Mata, Isis Mariela Herrera-Tirado, Francisco Javier Borrayo-López, Bertha Ibarra-Cortés, Francisco Javier Perea-Díaz.
      Red blood cell (RBC) membranopathies, caused by genetic alterations in membrane and cytoskeletal proteins, lead to significant variability in clinical presentation. This study analyzes 23 single nucleotide variants across nine genes (ADD1, ADD2, ANK1, EPB41, PIEZO1, SLC4A1, SPTA1, SPTB, and TAF3) in 225 Mexican patients with suspected RBC membranopathies and their effects on hematological parameters. Key variants, such as ADD2:c.1797C>T, SPTA1:c.5992G>C, SPTA1:c.6046C>A and SPTA1:c.6531-12C>T, were significantly associated with decreased RBC count, hemoglobin levels, packed cell volume, mean corpuscular hemoglobin and/or mean corpuscular hemoglobin concentration. Additionally, the following six combinations showed significant associations with two or three hematological parameters: SPTA1:c.5992G>C + SPTA1:c.6046C>A, SPTA1:c.5992G>C + ADD1:c.1378G>T, ADD1:c.1378G>T + ADD2:c.1797C>T, ADD1:c.1378G>T + PIEZO1:c.6793A>G, ADD2:c.1797C>T + PIEZO1:c.6793A>G, and TAF3:c.410-2550A>G + SPTA1:c.6531-12C>T. These findings underscore the importance of selected population genetic studies to increase our understanding of genotype-hematological phenotype relationships in RBC membranopathies.
    Keywords:  Mexican population; RBC membranopathies; SPTA1 haplotypes; SPTA1 variants
    DOI:  https://doi.org/10.1177/19450265261417994
  5. Blood Adv. 2026 Jan 30. pii: bloodadvances.2025016677. [Epub ahead of print]
    Multi-omics analysis of red blood cells reveals thalassemia severity beyond globin gene mutations.
    Nibedita Mitra, Upasana Bhattacharyya, Prosanto Kumar Chowdhury, Arijit Pal, Arvind Korwar, Samsidhhi Bhattacharjee, Anupam Basu.
      Hemoglobinopathies are the most common monogenic genetic disorders, primarily managed through blood transfusions or bone marrow transplantation. Clinical severity other than mutational effect not well investigated and still unknown. This study aims to identify dysregulated molecular pathways in red blood cells contributing to thalassemia severity. From a cohort of 285 hemoglobinopathy patients, 10 age-matched individuals with identical compound heterozygous mutations (IVS 1-5 G>C and CD 26 G>A) were screened. Five had severe thalassemia requiring regular transfusions, while five had a non-severe form requiring fewer transfusions. RNA sequencing and proteome analysis were conducted on isolated RBCs, through Novaseq and Orbitrap MS platform respectively. Bioconductor-R and different bioinformatics tools were utilized subsequently. Integrated transcriptome-proteome analysis revealed a global loss of mRNA-protein concordance. CDK11A and MCTS1 lost positive correlation, whereas RLP38 and H3C1 showed compensatory overtranslation, linked to transcription factors regulating erythropoiesis. In TDT, WNK3, HNRNPUL1, COPS7A, and HTATSF1 displayed discordant expression, indicating post-transcriptional aberrations. PTR analysis showed reduced cytoskeletal (ankyrin, spectrin) expression, elevated chaperone activity, ferroptosis markers (FTH1, FTL, HMOX1), and suppressed autophagy. Collectively, these multilayered alterations-splicing dysfunction, post-transcriptional deregulation, ferroptosis, autophagy suppression, oxidative stress, and cytoskeletal fragility-underlie the greater disease severity observed in TDT compared with NTDT.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016677
  6. Blood. 2026 Feb 05. 147(6): 609-610
    Switching and Sniffing around the β-globin cluster.
    Douglas Higgs, Kinam Gupta.
      
    DOI:  https://doi.org/10.1182/blood.2025032184
  7. Clin Ther. 2026 Feb 03. pii: S0149-2918(26)00005-6. [Epub ahead of print]
    Hereditary Anemias as a Monogenic Etiology for Nonimmune Hydrops Fetalis.
    Mona M Makhamreh, Stephanie M Rice, Kavya Shivashankar, Casey J Brewer, Rodney A McLaren, Seth I Berger, Huda B Al-Kouatly.
       PURPOSE: Hereditary anemias are a cause of nonimmune hydrops fetalis (NIHF). Our objective was to review the spectrum of hereditary anemia genes in NIHF diagnosed by exome sequencing (ES).
    METHODS: We performed a systematic review of ES studies in NIHF from January 1, 2000 to August 1, 2024 with emphasis on genes causing fetal anemia as a primary phenotype.
    FINDINGS: Forty-one ES studies with 207 genetically diagnosed NIHF cases met our inclusion criteria; 6 cases within 6 studies involved NIHF and hereditary anemia. Among the six cases, five had definitive diagnosis or likely diagnosis supported by pathogenic or likely pathogenic variants, while one case harbored only variants of uncertain significance and was classified as a possible diagnosis. The six different hereditary anemia genes included SEC23B, SPTA1, KLF1, RPL11, UNC13D, and RFWD3.
    IMPLICATIONS: Overall, ES confirmed the etiology of hereditary anemia in 2.4% (5/207) of genetically diagnosed NIHF cases. Hereditary anemias, therefore, represent a distinct and clinically relevant subset of ES-diagnosed NIHF cases. ES should be considered first line in fetuses with NIHF, as common non-genetic causes such as fetomaternal hemorrhage, infectious etiologies, and alloimmunization are excluded. It is also indicated when fetal anemia is suspected, particularly in the setting of elevated MCA Dopplers with a negative evaluation for common hemoglobinopathies and nongenetic etiologies.
    DOI:  https://doi.org/10.1016/j.clinthera.2026.01.002
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