bims-conane 2025-12-28 papers

Malays J Pathol. 2025 Dec;47(3): 457-465

Genetic mutations of Transfusion Dependent Thalassaemia (TDT) in paediatric patients.

N N Mohd Nor, H N Kamal, M Abdul Razak, Z Muda, N H Musa, M Mohamad, E Esa.

INTRODUCTION: Thalassaemia comprises inherited disorders characterised by impaired synthesis of globin chains, leading to varying phenotypes from mild to severe anaemia, transfusion-dependent. The Malaysian Thalassaemia Registry reports that 57.69% of patients are classified as Transfusion-Dependant Thalassaemia (TDT). Despite diagnostic advancements, local data linking genetic mutations with clinical and laboratory features of TDT remain limited. This study aims to address this gap by evaluating paediatric TDT patients at Hospital Tuanku Azizah (HTA), Kuala Lumpur, Malaysia.
MATERIALS AND METHODS: A single-centre, cross-sectional study involving TDT patients at HTA from January to December 2022.
RESULTS: The cohort included 95 patients (52.6% male, 47.4% female), predominantly Malay (88.4%). Twenty-seven distinct genetic mutations were identified across alpha and beta globin genes, the most common being βE. All patients had at least two mutations, with the most prevalent combination being HbE beta thalassaemia (45.3%), followed by beta thalassaemia major (32.6%), HbH disease (15.8%), and co-inheritance of alpha and beta thalassaemia (6.3%). Beta thalassaemia major shows the most severe phenotype: mean age at diagnosis is 12 months, mean haemoglobin at diagnosis of 5.2 g/dL, and mean age of regular transfusion is 16 months. Mean serum ferritin is highest in co-inheritance of alpha and beta thalassaemia (2616µg/L). The One-Way ANOVA test confirms the statistically significant differences in the median age of diagnosis (p=0.006), median age of starting regular transfusion (p=0.001), and median haemoglobin level at diagnosis (p=0.002) among different DNA combinations.
CONCLUSION: This study demonstrates that genetic mutations significantly influence the phenotypes of TDT patients and are essential in guiding management and prognosis.

Front Immunol. 2025 ;16 1699306

Monocyte-red blood cell crosstalk supports clearance and heme metabolism in sickle cell anemia.

Marina Dorigatti Borges, Matheus Ajeje de Souza, Izabela Felice Paes, Daniela Pinheiro Leonardo, Dulcinéia Martins Albuquerque, Carolina Lanaro, Sara Teresinha Ollala Saad, Renata Sesti-Costa, Fernando Ferreira Costa.

Background: Monocytes can interact with erythroid cells and contribute to macrophage pools under anemic stress, thereby supporting the erythropoietic niche. In sickle cell anemia (SCA), extensive hemolysis and ineffective erythropoiesis may expose circulating monocytes to abnormal red blood cells (RBCs), potentially altering their phenotype and function to accommodate the higher erythropoietic response and iron demand.
Methods and results: We characterized circulating monocytes from SCA patients at steady state using flow cytometry and in vitro phagocytosis assays. Intracellular RBC material was detected in all circulating monocyte subsets from SCA patients, indicating active erythrophagocytosis. Mechanistically, SCA monocytes displayed upregulated VCAM-1 and reduced SIRP-α expression, favoring RBC binding and internalization even when CD47 expression on RBCs was preserved. Following RBC engulfment, monocytes upregulated heme oxygenase-1 (HO-1) and ferroportin (FPN), consistent with enhanced heme degradation and iron export, and expressed higher levels of CD206, suggesting a regulatory phenotype. In vitro assays confirmed that both sickle RBCs and SCA monocytes synergistically promoted erythrophagocytosis.
Conclusion: Circulating monocytes from SCA patients undergo phenotypic and functional reprogramming upon interaction with sickled RBCs, acquiring features reminiscent of erythroblastic island macrophages. These findings highlight a previously underappreciated role for monocytes in RBC clearance, heme metabolism, and iron recycling in SCA, with potential implications for inflammation and disease progression.

Keywords: erythroblastic island; hemolytic anemia; iron metabolism; macrophages; sickle cell disease

DOI: https://doi.org/10.3389/fimmu.2025.1699306

Cells. 2025 Dec 11. pii: 1971. [Epub ahead of print]14(24):

The Non-Coding RNome Landscape in Erythropoiesis: Pathophysiological Implications.

Emma Brisot, Laurent Metzinger, Valérie Metzinger-Le Meuth.

Erythropoiesis is a multistage process critical for red blood cell production and systemic oxygen transport. It is tightly regulated, and recent advances have highlighted the pivotal regulatory roles of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in governing both physiological and pathological erythropoiesis. These ncRNAs have roles in the fine-tuning of the classical transcriptional and post-transcriptional control. This review explores the complex landscape of the non-coding RNome in erythroid differentiation, maturation, and function. We summarize how specific miRNAs influence erythroid lineage commitment, hemoglobin switching, iron metabolism, and cellular morphology, as well as their modulation by environmental and pathological cues. We also discuss emerging evidence on lncRNAs regulating chromatin remodeling, alternative splicing, apoptosis, enucleation, and erythroid-specific gene expression. These insights suggest that ncRNAs are instrumental orchestrators of erythropoiesis and accordingly, potential biomarkers and therapeutic targets in anemia and related hematologic disorders.

Keywords: biomarker; erythropoiesis; gene regulation; long non-coding RNA; microRNA; red blood cell

DOI: https://doi.org/10.3390/cells14241971

Hemasphere. 2025 Dec;9(12): e70264

MMS22L is a novel key actor of normal and pathological erythropoiesis.

The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the CDAN1 gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the MMS22L gene. Combined mms22l and cdan1 haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of MMS22L leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.

DOI: https://doi.org/10.1002/hem3.70264

Int J Gen Med. 2025 ;18 7547-7557

Analysis of Hematological Parameters in Relation to Genotypes in 497 Patients with Hemoglobin H Disease.

Liubing Lan, Zhiyuan Zheng, Heming Wu.

Background: Hemoglobin H (Hb H) disease is a common type of α-thalassemia, characterized by anemia caused by abnormal hemoglobin synthesis, and its hematological phenotype show significant heterogeneity. The purpose is to explore the relationship between genotypes and hematological parameters in Hb H disease, in order to provide scientific basis for the prevention and treatment of Hb H disease.
Methods: A total of 497 Hb H disease patients at Meizhou People's Hospital from December 2016 to December 2023, were retrospectively analyzed. Genotype testing was performed to determine the types of α-thalassemia and β-thalassemia. The hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and hemoglobin electrophoresis results of the patients were collected to evaluate their hematological manifestations. The relationship between genotypes and hematological manifestations was analyzed.
Results: There were 449 (90.3%) cases with deletional Hb H disease and 48 (9.7%) with non-deletional Hb H disease. The detection rate of Hb H was higher in patients with non-deletional Hb H disease than in those with deletional Hb H disease (73.8% vs 66.8%). The proportion of severe anemia in patients with Hb H disease combined with β-thalassemia was lower than that of patients with isolated Hb H disease (11.1% vs 26.9%). Non-deletional Hb H disease exhibited more severe anemia compared to those with deletional Hb H disease (low Hb, p=0.002), accompanied by significantly higher MCV (p<0.001) and MCH (p=0.001). The degree of microcytosis and hypochromia in Hb H disease patients without β-thalassemia is less severe than that in patients with β-thalassemia.
Conclusion: Non-deletional Hb H disease exhibited higher detection rate of Hb H and proportion of severe anemia, and patients with --SEA/αCSα have the highest proportion of severe anemia. There are differences in the genotypes distribution of Hb H disease among different populations.

Keywords: genotype; hematological parameters; hemoglobin H disease; thalassemia

DOI: https://doi.org/10.2147/IJGM.S567328