bims-conane 2026-02-01 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2026–02–01
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Hereditary Spherocytosis: Linking Ion Transport Defects to Osmotic Gradient Ektacytometry Profiles-A Review.
Anemia-associated mutations disrupt the CDIN1-Codanin1 complex in inherited congenital dyserythropoietic anemia I (CDA-I) disease.
Association of CYP2C19 gene single nucleotide polymorphisms (rs12248560 and rs4244285) with response to thalidomide in transfusion dependent β-thalassemia patients- a 12-months follow-up study.
GATA1 N-terminus coordinates metabolic reprogramming in erythropoiesis.
DNA methylation matters: methylation of the γ-globin (HBG) gene promoters is required for postnatal silencing of HbF.
Using Patient Feedback to Improve Treatment Outcomes for Patients with Congenital Dyserythropoietic Anaemia Type I Receiving Interferon Therapy.
Functional Abnormalities of the Endocrine System in Beta-Thalassemia Major Patients: Insights From a Hospital-Based Observational Study.
TMPRSS6 Non-Coding Variants in the Expression of Iron Refractory Iron Deficiency Anemia in Monoallelic Subjects.

Int J Mol Sci. 2026 Jan 10. pii: 721. [Epub ahead of print]27(2):

Hereditary Spherocytosis: Linking Ion Transport Defects to Osmotic Gradient Ektacytometry Profiles-A Review.

Joan Lluís Vives-Corrons, Elena Krishnevskaya.

  Hereditary spherocytosis (HS) is the most common inherited red blood cell (RBC) membrane disorder and has traditionally been attributed to defects in cytoskeletal proteins such as spectrin, ankyrin, band 3, and protein 4.2. Growing evidence, however, shows that disturbances in ion transport also contribute to HS pathophysiology. This review summarizes current understanding of HS by integrating membrane structural defects with abnormalities in ion homeostasis and highlights the diagnostic value of osmotic gradient ektacytometry (OGE). Beyond membrane instability, HS erythrocytes exhibit increased cation permeability with abnormal Na+ influx and K+ loss, leading to cellular dehydration, elevated mean corpuscular hemoglobin concentration (MCHC), and reduced deformability. Dysregulation of mechanosensitive and Ca2+-activated K+ channels (PIEZO1, KCNN4) may modulate disease expression. OGE-now the reference functional test for RBC deformability-identifies reproducible phenotypes reflecting hydration status, including dehydrated (HS1) and partially hydrated (HS2) HS profiles. When combined with next-generation sequencing (NGS), OGE improves differentiation between HS and overlapping membranopathies such as hereditary xerocytosis or stomatocytosis. In conclusion, HS is a multifactorial disorder resulting from the interplay between cytoskeletal fragility, oxidative stress, and dysregulated ion transport. Integrated diagnostic strategies that combine hematologic indices, OGE, and targeted NGS enhance diagnostic accuracy, support genotype-phenotype interpretation, and guide individualized clinical management. Future efforts should focus on ion-channel modulation and wider adoption of functional assays in precision hematology.

Keywords:  PIEZO1; erythrocyte membrane disorders; gardos channel; hereditary spherocytosis; ion transport dysregulation; osmotic gradient ektacytometry; red blood cell deformability

DOI:  https://doi.org/10.3390/ijms27020721
FEBS J. 2026 Jan 29.

Anemia-associated mutations disrupt the CDIN1-Codanin1 complex in inherited congenital dyserythropoietic anemia I (CDA-I) disease.

Martin Stojaspal, Tomas Brom, Ivona Nečasová, Tomáš Janovič, Pavel Veverka, Naina Verma, Lukáš Uhrík, Lenka Hernychova, Ctirad Hofr.

  Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease marked by ineffective erythropoiesis, a characteristic spongy heterochromatin structure in erythroblasts, and mutations in the genes CDAN1 and CDIN1, which encode the proteins Codanin1 and CDIN1. Codanin1 regulates histone shuttling via the chaperone ASF1, yet the role of CDIN1 in CDA-I pathology remains unclear. Notably, CDIN1 is known to interact directly with the C-terminus of Codanin1. Although mutations in both genes are critical to the disease phenotype, their molecular-level effects have not been fully elucidated. Here, we present a comprehensive structural and functional analysis of the CDIN1-Codanin1 C-terminus complex. Using complementary biophysical techniques, we show that CDIN1 and Codanin1 C-terminus form a high-affinity heterodimeric complex with equimolar stoichiometry. We further delineate the essential interacting regions of CDIN1 and Codanin1. We demonstrate that CDA-I-associated mutations in either protein disrupt the CDIN1-Codanin1 interaction, suggesting a potential molecular mechanism underlying the disease.

Keywords:  C15orf41; CDIN1; Codanin1; chromatin; congenital dyserythropoietic anemia; protein–protein interaction; quantitative biochemistry

DOI:  https://doi.org/10.1111/febs.70421
Pharmacogenomics. 2026 Jan 28. 1-8

Association of CYP2C19 gene single nucleotide polymorphisms (rs12248560 and rs4244285) with response to thalidomide in transfusion dependent β-thalassemia patients- a 12-months follow-up study.

Inayat Ur Rahman, Muhammad Shahid, Muhammad Tariq Humayun Khan, Naseer Ahmed, Shafiq Ahmad, Amir Muhammad, Sher Afghan Khan, Abdus Saboor, Muhammad Tariq Masood Khan, Sami Siraj.

   AIM: This study aimed to evaluate the efficacy of thalidomide in transfusion-dependent β-thalassemia (TDT) patients and explore its association with CYP2C19 polymorphisms (rs12248560 and rs4244285).
METHODS: Hemoglobin levels of 190 TDT patients were assessed at baseline and after 3, 6, and 12 months of thalidomide treatment. Patients were categorized into response groups based on Hb improvement. Genotyping of rs12248560 and rs4244285 was performed using Sanger sequencing.
RESULTS: The Hb levels of study patients increased from baseline (6.6 ± 1.12 g/dL) to 12 months (8.0 ± 2.03 g/dL) of thalidomide treatment (p < 0.001). Thirty-five (36.8%) patients were excellent responders, 24 (25.3%) good, 12 (12.6%) partial, and 24 (25.3%) non-responders. The genotype patterns were as follows: 88 (46.3%) were CC, 84 (44.2%) were CT, and 18 (9.5%) were TT for rs12248560, while 74 (38.9%) were GG, 46 (45.3%) were GA, and 30 (15.8%) were AA for rs4244285. Response to thalidomide was significantly better in patients having minor allele T at rs12248560(p < 0.05).
CONCLUSION: The findings suggest thalidomide as an effective option for TDT and highlight the potential role of CYP2C19 genetic variation in modulating treatment response.

Keywords:  CYP2C19; rs12248560; rs4244285; thalidomide; transfusion-dependent β-thalassemia

DOI:  https://doi.org/10.1080/14622416.2026.2622318
Blood. 2026 Jan 26. pii: blood.2025030464. [Epub ahead of print]

GATA1 N-terminus coordinates metabolic reprogramming in erythropoiesis.

Te Ling, Lavanya Bezavada, Rashid Mehmood, Kevin Zhang, Anitria Cotton, Jeremy Chase Crawford, Hongjian Jin, Surbhi Sona, Lei Li, Yan Ju, Lei Han, Nana Liu, Tam Tran, Hieu Vu, Yan Jin, Jinbin Zhai, Shondra M Pruett-Miller, Senthil Velan Bhoopalan, Jian Xu, Min Ni, John D Crispino.

Mutations in GATA1 that cause skipping of exon 2, which encodes the N-terminus, are associated with the myeloid leukemia of Down syndrome and Diamond-Blackfan anemia (DBA). To elucidate the molecular function of this N-terminal region, we employed single-cell RNA sequencing (scRNA-seq) on fetal liver cells from Gata1 mutant embryos that express only the short isoform of GATA1 (GATA1s) lacking the N-terminus of full-length GATA1 (GATA1FL). scRNA-seq revealed defects in erythropoiesis and aberrant upregulation of glycolytic genes, including PKM, which encodes pyruvate kinase to catalyze the final and irreversible step of glycolysis. Using precision nuclear run-on sequencing (PRO-seq) and cleavage under targets and release using nuclease (CUT&RUN) following acute GATA1 deletion in erythroid cells, we identified PKM as a direct target of GATA1. Substitution of GATA1FL with GATA1s induced histone lactylation at the PKM promoter, increased PKM expression and activity, and enhanced glycolytic flux in erythroid progenitors, without affecting mitochondrial respiration. Importantly, PKM expression is also significantly elevated in DBA patients with RPS19 mutations, which is associated with reduced levels of GATA1, further supporting a link between GATA1s-driven defective erythropoiesis and dysregulated glycolysis. Together, these findings reveal that GATA1 controls not only heme metabolism, but also glycolytic reprogramming.

DOI: https://doi.org/10.1182/blood.2025030464
Blood. 2026 Jan 26. pii: blood.2025031153. [Epub ahead of print]

DNA methylation matters: methylation of the γ-globin (HBG) gene promoters is required for postnatal silencing of HbF.

Gordon D Ginder, Shengzhe Shang, David C Williams.

Expression of a sufficient level of fetal hemoglobin (HbF), which is normally silenced after birth, can ameliorate the pathophysiologic basis of both sickle cell disease (SCD) and b-thalassemia postnatally. DNA methylation has been posited for many years to mediate silencing of HbF expression, but its role has been somewhat controversial. Recent publications provide definitive evidence for the critical role of HBG gene promoter methylation in silencing as well as providing insight into the mechanisms involved. The data support a model in which methylation of CpG sites in the HBG promoters is required, along with repressive transcription factors, to recruit the MBD2-NuRD chromatin remodeling complex which enforces silencing. These findings have implications for the treatment of b-globin disorders.

DOI: https://doi.org/10.1182/blood.2025031153
J Clin Med. 2026 Jan 22. pii: 901. [Epub ahead of print]15(2):

Using Patient Feedback to Improve Treatment Outcomes for Patients with Congenital Dyserythropoietic Anaemia Type I Receiving Interferon Therapy.

Karl Frey, Sanja Brolih, Caroline Scott, Nicholas Fordham, Sam Burrows, Nyree Cole, Karen Deem, Christopher Jenkins, Melanie Proven, Christian Babbs, Noemi Bernadette Alice Roy.

  Congenital dyserythropoietic anaemia type-I (CDA-I) is a rare autosomal recessive disease characterised by ineffective erythropoiesis, haemolysis and non-haematological developmental abnormalities. Its treatment is multifactorial, including the management of anaemia, iron overload and prevention of osteoporosis. The only treatment specific to CDA-I is subcutaneous interferon alpha (IFNα) 2A. This study presents the first summary of all published cases of CDA-I patients (n = 33) treated with IFNα and categorises their outcome. We also present new unpublished cases (n = 7). Overall, we find that IFNα administration causes a statistically significant mean increase in haemoglobin of 30.7 g/L (p < 0.001). However, we note that previous studies do not assess the impact of IFNα therapy on providing symptomatic benefit to patients with CDA-I, or the weight of side effects on their quality of life. We collaborate directly with patients through the organisation Congenital Anaemia Network to establish patient preferences regarding IFNα treatment. We propose a classification framework for the use of IFNα in CDA-I that includes patient-reported outcome measures in addition to grading response according to changes in Hb levels. We believe that the use of this framework will aid standardisation in measuring response to therapy, improve clinical practice and assist in future research.

Keywords:  Congenital Anaemia Network; PROMS; congenital dyserythropoietic anaemia I; interferon; patient response

DOI:  https://doi.org/10.3390/jcm15020901
Cureus. 2025 Dec;17(12): e100190

Functional Abnormalities of the Endocrine System in Beta-Thalassemia Major Patients: Insights From a Hospital-Based Observational Study.

Upendra Prasad Sahu, Yuthika Kumari, Neha Rani, Omar Hasan, Naghma Mobin, Shrasta Soumya, Praveen Kumar Singh, Neetu Kumari, Niraj Kumar.

  Background Beta-thalassemia major (BTM) predisposes children to several endocrine complications, primarily driven by iron overload and repeated transfusions. This study aimed to determine the prevalence, patterns, and risk factors of endocrine dysfunction among multi-transfused pediatric patients with BTM. Methods A hospital-based cross-sectional study was conducted at Rajendra Institute of Medical Sciences (RIMS), Ranchi, including 100 pediatric patients aged two to 14 years diagnosed with BTM. Clinical profiles, transfusion history, anthropometric parameters, and laboratory investigations, including HbA1c, thyroid profile, serum ferritin, ALP, calcium, phosphate, parathyroid hormone, and cortisol, were analyzed. Statistical tests were performed using IBM SPSS Statistics version 26, with p ≤ 0.05 considered significant. Results Endocrine disorders were highly prevalent: diabetes mellitus (14.6%), growth hormone deficiency (11.2%), hypothyroidism (9.8%), and hypoparathyroidism (6.3%). Mean HbA1c was 6.8 ± 1.2%, with significantly higher levels in patients with diabetes (p = 0.002), hypothyroidism (p = 0.035), and growth hormone deficiency (p = 0.018). Logistic regression showed that iron overload (p = 0.022), frequent transfusions (p = 0.059), and older age (>10 years) (p = 0.041) were major predictors of endocrine dysfunction, while chelation therapy did not show a strong protective effect (p = 0.072). Conclusion Multi-transfused BTM patients are at substantial risk of developing endocrine abnormalities due to cumulative iron overload and chronic transfusion exposure. Regular endocrine screening, optimized iron chelation, and individualized transfusion protocols are essential to prevent long-term metabolic and hormonal complications. Strengthening multidisciplinary care is crucial for improving growth, development, and overall outcomes in this vulnerable population.

Keywords:  beta-thalassemia major; blood transfusion; chelation therapy; diabetes mellitus; endocrine dysfunction; growth hormone deficiency; hypoparathyroidism; hypothyroidism; iron overload; pediatric hematology

DOI:  https://doi.org/10.7759/cureus.100190
Genes (Basel). 2026 Jan 08. pii: 74. [Epub ahead of print]17(1):

TMPRSS6 Non-Coding Variants in the Expression of Iron Refractory Iron Deficiency Anemia in Monoallelic Subjects.

Vera Hoving, Albertine E Donker, Roel J P Smeets, Bert P W J van den Heuvel, Saskia E M Schols, Dorine W Swinkels.

   BACKGROUND: Iron-refractory iron deficiency anemia (IRIDA) is a rare hereditary disorder caused by pathogenic variants in TMPRSS6, characterized by microcytic anemia, low circulating iron levels, and inappropriately high hepcidin levels. Although IRIDA is typically an autosomal recessive disorder, some individuals with a monoallelic pathogenic exonic TMPRSS6 variant exhibit the phenotype, suggesting additional contributing factors. The mechanisms underlying monoallelic IRIDA remain unclear, complicating diagnosis. This study aimed to investigate the potential role of non-coding TMPRSS6 variants and polygenic inheritance in monoallelic IRIDA.
METHODS: We performed full-gene sequencing of TMPRSS6 in a cohort of 27 subjects, including 6 families (7 symptomatic monoallelic, 7 asymptomatic monoallelic, and 4 wild-type subjects) and 9 isolated symptomatic monoallelic subjects. Whole-exome sequencing of other iron-regulating genes was conducted to evaluate polygenic inheritance. Non-coding variants were assessed for inheritance patterns using family segregation analysis, when available, and for pathogenic potential using in silico prediction tools.
RESULTS: Sequencing identified 219 non-coding variants, of which 31 (14 trans-inherited and 17 with unknown inheritance) were exclusive to symptomatic subjects. Two trans-inherited variants (rs80140288 (c.229+945C>T) and rs146953827 (c.230-938_230-937del)) were predicted to affect splicing, while two additional variants (rs78987624 (c.-7001G>A) and rs117575523 (c.*503C>G)) were located in regulatory regions (with unknown inheritance). Whole-exome sequencing did not support polygenic involving other iron-regulating genes.
CONCLUSIONS: This study highlights four candidate non-coding variants that may contribute to IRIDA expression in monoallelic subjects, offering new insights into its genetic basis. Functional validation is required to confirm their role in disease pathogenesis, refine genotype-phenotype correlations, and improve diagnostic accuracy in monoallelic IRIDA.

Keywords:  IRIDA; TMPRSS6; monoallelic; non-coding variants

DOI:  https://doi.org/10.3390/genes17010074