bims-conane 2024-08-04 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2024‒08‒04
fifteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease.
Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.
Exploring the genetic mechanisms: SELP gene's contribution to alleviating vaso-occlusive crisis in sickle cell disease.
Telomere Dynamics in Sickle Cell Anemia: Unraveling Molecular Aging and Disease Progression.
Automated red blood cell exchange with a post-procedure haematocrit targeted at 34% in the chronic management of sickle cell disease.
Does hemoglobin affect measures of mitochondrial respiration in red blood cells? Comment to "Increased retention of functional mitochondria in mature sickle red blood cells is associated with increased sickling tendency, hemolysis and oxidative stress".
EPCR shedding light on sickle nephropathy.
CRISPR technology in human diseases.
Designing a single-arm phase 2 clinical trial of mitapivat for adult patients with erythrocyte membranopathies (SATISFY): a framework for interventional trials in rare anaemias - pilot study protocol.
The Ugandan sickle Pan-African research consortium registry: design, development, and lessons.
Atrial Arrhythmia in Sickle Cell Anemia Adults: A missing link towards understanding and preventing strokes.
Hemoglobin Oviedo (c.115A > G; p.T39A): A Cause of Low Oxygen Saturation.
Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life.
METTL16 participates in haemoglobin H disease through m6A modification.
Advances in Hemoglobinopathies and Thalassemia Evaluation.

Sci Adv. 2024 Aug 02. 10(31): eadn8750

PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease.

Yanan Sun, Hajar Benmhammed, Salam Al Abdullatif, Alawi Habara, Eric Fu, Jordan Brady, Christopher Williams, Adrian Ilinski, Anusha Sharma, Kiana Mahdaviani, Yuriy O Alekseyev, Joshua D Campbell, Martin H Steinberg, Shuaiying Cui.

Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. Additional pharmacologic agents to induce sufficient fetal hemoglobin to diminish clinical severity is an unmet medical need. We recently found that up-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecule, SR-18292, increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells, β-globin yeast artificial chromosome mice, and sickle cell disease mice. In SR-18292-treated sickle mice, sickled red blood cells are significantly reduced, and disease complications are alleviated. SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.

DOI: https://doi.org/10.1126/sciadv.adn8750
Mol Ther. 2024 Jul 30. pii: S1525-0016(24)00477-5. [Epub ahead of print]

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Varun Katta, Kiera O'Keefe, Yichao Li, Thiyagaraj Mayurathan, Cicera R Lazzarotto, Rachael K Wood, Rachel M Levine, Alicia Powers, Kalin Mayberry, Garret Manquen, Yu Yao, Jingjing Zhang, Yoonjeong Jang, Nikitha Nimmagadda, Erin A Dempsey, GaHyun Lee, Naoya Uchida, Yong Cheng, Frank Fazio, Tim Lockey, Mike Meagher, Akshay Sharma, John F Tisdale, Sheng Zhou, Jonathan S Yen, Mitchell J Weiss, Shengdar Q Tsai.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ HSPCs from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies towards clinical trials for treating SCD and other blood disorders.

DOI: https://doi.org/10.1016/j.ymthe.2024.07.022
Gene. 2024 Jul 28. pii: S0378-1119(24)00686-3. [Epub ahead of print]928 148805

Exploring the genetic mechanisms: SELP gene's contribution to alleviating vaso-occlusive crisis in sickle cell disease.

Parul Gupta, Vaishali Choudhari, Ravindra Kumar.

  Sickle cell disease is a catastrophic inflammatory disorder characterized by microvascular vaso-occlusion, leading to high morbidity and increased mortality. P-selectin, a cell adhesion molecule, plays a crucial role in the pathogenesis and severity of sickle cell disease. Its expression and binding with its ligand PSGL-1 is involved in various mechanisms that contribute to inflammation and immune response, resulting in complications in sickle cell disease. Preclinical data have verified the efficacy of P-Selectin inhibition in mitigating vaso-occlusive events and severity of disease. Currently clinical trials are ongoing to evaluate the safety and efficiency of P-Selectin-targeted therapies and concede the challenges and limitations associated with their use. Despite of its proven role in reducing severity in sickle cell disease, future research should focus on identifying other novel targets within the adhesion cascade and explore combination therapies. Conducting trials and addressing concerns about accessibility are crucial steps towards fully harnessing the potential of P selectin inhibitors as a groundbreaking treatment option. This review focuses on understanding the role of p selectin and its interactions with molecules involved in inflammation providing insights about the molecular etiology, pathophysiology, and potential therapeutic targets in sickle cell disease.

Keywords:  Cell adhesion molecules; Crizanlizumab; Endothelium; Sickle cell disease; Vaso-occlusive crisis; p-Selectin

DOI:  https://doi.org/10.1016/j.gene.2024.148805
J Blood Med. 2024 ;15 313-323

Telomere Dynamics in Sickle Cell Anemia: Unraveling Molecular Aging and Disease Progression.

Emmanuel Ifeanyi Obeagu, Getrude Uzoma Obeagu.

  Sickle Cell Anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While extensive research has unraveled many aspects of the genetic and molecular basis of SCA, the role of telomere dynamics in disease progression remains a relatively unexplored frontier. This review seeks to provide a comprehensive examination of telomere biology within the context of SCA, aiming to elucidate its potential impact on molecular aging and the progression of the disease. The impact of oxidative stress on telomere dynamics in SCA is explored, with a particular focus on how increased reactive oxygen species (ROS) may contribute to accelerated telomere shortening and genomic instability. Furthermore, the potential relationship between telomere dysfunction and cellular senescence in SCA is investigated, shedding light on how telomere dynamics may contribute to the premature aging of cells in this population. The review concludes by summarizing key findings and proposing potential therapeutic strategies targeting telomere dynamics to mitigate disease progression in SCA. It also identifies gaps in current understanding and suggests avenues for future research, emphasizing the importance of further investigating telomere biology to advance our understanding of molecular aging and disease progression in Sickle Cell Anemia. This comprehensive exploration of telomere dynamics in SCA offers insights into potential mechanisms of molecular aging and disease progression, paving the way for targeted therapeutic interventions and improved disease management.

Keywords:  hemoglobinopathy; molecular aging; oxidative stress; sickle cell anemia; telomere; telomere shortening

DOI:  https://doi.org/10.2147/JBM.S462758
Br J Haematol. 2024 Jul 30.

Automated red blood cell exchange with a post-procedure haematocrit targeted at 34% in the chronic management of sickle cell disease.

Jules M Ross, Stéphanie Forté, Nicolas Mercure-Corriveau, Anne-Sophie Lemay, Benjamin Rioux-Massé, Brian J Potter, Denis Soulières.

  Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron-related outcomes in 101 patients on chronic RCE with a post-procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSβ0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre-procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post-procedure Ht targeted at 34% is not iron-neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements.

Keywords:  blood transfusion; erythropoiesis; iron deficiency; iron overload; sickle cell disease

DOI:  https://doi.org/10.1111/bjh.19674
Haematologica. 2024 Aug 01.

Does hemoglobin affect measures of mitochondrial respiration in red blood cells? Comment to "Increased retention of functional mitochondria in mature sickle red blood cells is associated with increased sickling tendency, hemolysis and oxidative stress".

Wayne T Willis, Alexander C Berry, Bruce L Gladden.

DOI: https://doi.org/10.3324/haematol.2024.286135
Blood. 2024 Aug 01. 144(5): 472-474

EPCR shedding light on sickle nephropathy.

Erica M Sparkenbaugh.

DOI: https://doi.org/10.1182/blood.2024025479
MedComm (2020). 2024 Aug;5(8): e672

CRISPR technology in human diseases.

Qiang Feng, Qirong Li, Hengzong Zhou, Zhan Wang, Chao Lin, Ziping Jiang, Tianjia Liu, Dongxu Wang.

  Gene editing is a growing gene engineering technique that allows accurate editing of a broad spectrum of gene-regulated diseases to achieve curative treatment and also has the potential to be used as an adjunct to the conventional treatment of diseases. Gene editing technology, mainly based on clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein systems, which is capable of generating genetic modifications in somatic cells, provides a promising new strategy for gene therapy for a wide range of human diseases. Currently, gene editing technology shows great application prospects in a variety of human diseases, not only in therapeutic potential but also in the construction of animal models of human diseases. This paper describes the application of gene editing technology in hematological diseases, solid tumors, immune disorders, ophthalmological diseases, and metabolic diseases; focuses on the therapeutic strategies of gene editing technology in sickle cell disease; provides an overview of the role of gene editing technology in the construction of animal models of human diseases; and discusses the limitations of gene editing technology in the treatment of diseases, which is intended to provide an important reference for the applications of gene editing technology in the human disease.

Keywords:  CRISPR–Cas9; clinical research; gene editing technology; gene therapy; human diseases; sickle cell disease

DOI:  https://doi.org/10.1002/mco2.672
BMJ Open. 2024 Jul 30. 14(7): e083691

Designing a single-arm phase 2 clinical trial of mitapivat for adult patients with erythrocyte membranopathies (SATISFY): a framework for interventional trials in rare anaemias - pilot study protocol.

Andreas Glenthøj, Eduard J van Beers, Richard van Wijk, Minke A E Rab, Evelyn Groot, Niels Vejlstrup, Nina Toft, Selma Kofoed Bendtsen, Jesper Petersen, Jens Helby, Fatiha Chermat, Pierre Fenaux, Kevin H M Kuo.

  INTRODUCTION: Membranopathies encompass haemolytic disorders arising from genetic variants in erythrocyte membrane proteins, including hereditary spherocytosis and stomatocytosis. Congenital dyserythropoietic anaemia type II (CDA II) is associated with the SEC23B gene and can exhibit phenotypic similarities to membranopathies. Current treatment options for these conditions, apart from splenectomy, are primarily supportive. Mitapivat, a novel pyruvate kinase (PK) activator, has demonstrated efficacy in increasing haemoglobin levels and reducing haemolysis in patients with PK deficiency, thalassemia, sickle cell disease and a mouse model of hereditary spherocytosis.METHODS AND ANALYSES: Safety and efficacy of mitapivat sulfate in adult patients with erythrocyte membranopathies (SATISFY) is a prospective, multicentre, single-arm phase two trial involving approximately 25 adult patients (≥18 years) diagnosed with a membranopathy or CDA II. During the 8-week dose escalation period, subjects will receive an initial dose of 50 mg mitapivat two times per day and may increase to 100 mg two times per day at week 4 based on the safety and changes in haemoglobin levels. Patients tolerating mitapivat well may be eligible to continue in two consecutive 24-week fixed dose periods.The primary objective of this study is to evaluate the safety of mitapivat, assessed through the occurrence of treatment-emergent adverse events. Secondary objectives include assessing the effects of mitapivat on haemoglobin levels, haemolysis, erythropoiesis, patient-reported outcome measures and spleen size.SATISFY aims to assess the safety and efficacy of mitapivat in adult patients with red blood cell membranopathies and CDA II, with the aim of establishing proof-of-concept in patients living with these rare conditions.
ETHICS AND DISSEMINATION: NCT05935202/CTIS:2023-503271-24-01. Findings will be published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, NCT05935202. CTIS:2023-503271-24-01. Registered 07-July-2023. Protocol number: 2.1. https://clinicaltrials.gov/study/NCT05935202.

Keywords:  Anaemia; Clinical trials; HAEMATOLOGY; Quality of Life

DOI:  https://doi.org/10.1136/bmjopen-2023-083691
BMC Med Inform Decis Mak. 2024 Jul 29. 24(1): 212

The Ugandan sickle Pan-African research consortium registry: design, development, and lessons.

Mike Nsubuga, Henry Mutegeki, Daudi Jjingo, Deogratias Munube, Ruth Namazzi, Robert Opoka, Philip Kasirye, Grace Ndeezi, Heather Hume, Ezekiel Mupere, Grace Kebirungi, Isaac Birungi, Jack Morrice, Mario Jonas, Victoria Nembaware, Ambroise Wonkam, Julie Makani, Sarah Kiguli.

  BACKGROUND: Sub-Saharan Africa bears the highest burden of sickle cell disease (SCD) globally with Nigeria, Democratic Republic of Congo, Tanzania, Uganda being the most affected countries. Uganda reports approximately 20,000 SCD births annually, constituting 6.67% of reported global SCD births. Despite this, there is a paucity of comprehensive data on SCD from the African continent. SCD registries offer a promising avenue for conducting prospective studies, elucidating disease severity patterns, and evaluating the intricate interplay of social, environmental, and genetic factors. This paper describes the establishment of the Sickle Pan Africa Research Consortium (SPARCo) Uganda registry, encompassing its design, development, data collection, and key insights learned, aligning with collaborative efforts in Nigeria, Tanzania, and Ghana SPARCo registries.METHODS: The registry was created using pre-existing case report forms harmonized from the SPARCo data dictionary and ontology to fit Uganda clinical needs. The case report forms were developed with SCD data elements of interest including demographics, consent, baseline, clinical, laboratory and others. That data was then parsed into a customized REDCap database, configured to suit the optimized ontologies and support retrieval aggregations and analyses. Patients were enrolled from one national referral and three regional referral hospitals in Uganda.
RESULTS: A nationwide electronic patient-consented registry for SCD was established from four regional hospitals. A total of 5,655 patients were enrolled from Mulago National Referral Hospital (58%), Jinja Regional Referral (14.4%), Mbale Regional Referral (16.9%), and Lira Regional Referral (10.7%) hospitals between June 2022 and October 2023.
CONCLUSION: Uganda has been able to develop a SCD registry consistent with data from Tanzania, Nigeria and Ghana. Our findings demonstrate that it's feasible to develop longitudinal SCD registries in sub-Saharan Africa. These registries will be crucial for facilitating a range of studies, including the analysis of SCD clinical phenotypes and patient outcomes, newborn screening, and evaluation of hydroxyurea use, among others. This initiative underscores the potential for developing comprehensive disease registries in resource-limited settings, fostering collaborative, data-driven research efforts aimed at addressing the multifaceted challenges of SCD in Africa.

Keywords:  Disease registry; SPARCo; Sickle cell disease

DOI:  https://doi.org/10.1186/s12911-024-02618-9
Blood Adv. 2024 Jul 05. pii: bloodadvances.2024013208. [Epub ahead of print]

Atrial Arrhythmia in Sickle Cell Anemia Adults: A missing link towards understanding and preventing strokes.

Thomas d'Humières, Zineb Sadraoui, Laurent Savale, Laurent Boyer, Henri Guillet, Lara Alassaad, Gonzalo De Luna, Sihem Iles, Paul Balfanz, Anoosha Habibi, Suella Martino, Ziana Amorouayeche, Thuy Linh Dang, Anne-Laure Pham Hung d'Alexandry d'Orengiani, Dominique Rideau, Laura Train, Theo Simon, Christine Ibrahim, Laurent A Messonnier, Etienne Audureau, Haytham Derbel, David Calvet, Nicolas Lellouche, Geneviève Derumeaux, Pablo Bartolucci.

Although sickle cell disease (SCD) patients carry both significant left atrial (LA) remodeling and increased risk of stroke, the prevalence of atrial arrhythmia (AA) has never been prospectively evaluated. This study aims to investigate the prevalence and predictors of atrial arrhythmia in homozygous SCD (SCA). From 2019 to 2022, 130 patients with SCA were referred to the physiology department to specifically analyze cardiac function and prospectively included in the DREPACOEUR registry. They underwent a 24-hour electrocardiogram monitoring (24h-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary endpoint was the occurrence of AA, defined by the presence of excessive supraventricular ectopic activity (ESVEA) on ECG-Holter (i.e., >720 premature atrial contractions [PACs] or any run ≥ 20 PACs), recent history of paroxysmal atrial fibrillation (AF), or persistent AF. The mean patient age was 45±12 years and 48% of male. Overall, AA was found in 34 (26%) patients. Age (52±9 vs. 42±12 years, P=0.002), LA dilation (LAVi, 71±24 vs. 52±14 ml/m², P<0.001) and history of stroke without underlying cerebral vasculopathy or other defined cause (26% vs. 5%, P=0.009, OR=6.6 [1.4; 30.3]) were independently associated with AA. Age and LAVi correlated with PAC load per 24 hours on ECG-Holter (R=0.56 and 0.33, P<0.001 respectively) and an age over 47 years or a LAVi >55mL/m² could predict AA with a PPV of 33% and a NPV of 92%. AAs are frequent in SCA patients and increase with age and LA remodeling, leading to a major additional risk factor for ischemic stroke. This study provides arguments and means to early screen for AA potentially preventing cerebral complications.

DOI: https://doi.org/10.1182/bloodadvances.2024013208
Hemoglobin. 2024 Aug 02. 1-4

Hemoglobin Oviedo (c.115A > G; p.T39A): A Cause of Low Oxygen Saturation.

Luis Vega López, Alberto Medina, Helena Gil-Peña, Ariana Fonseca Mourelle, Jose Ramón Gutiérrez Martínez.

  We report a new low-affinity hemoglobinopathy (Hemoglobin Oviedo) in a family with isolated low oxygen saturation (89-92%) caused by a previously undescribed variant (NM_000518.5: c.115A > G;p.Thr39Ala) in the hemoglobin subunit β encoding gene (HBB gene) located on chromosome 11.

Keywords:  Hemoglobin; Oviedo; low; oxygen; saturation

DOI:  https://doi.org/10.1080/03630269.2024.2382775
Hemoglobin. 2024 Aug 02. 1-8

Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life.

Sukrita Bhattacharjee, Shouriyo Ghosh, Jyoti Shaw, Sunistha Bhattacharjee, Maitreyee Bhattacharyya.

  Transfusion-dependent thalassemia (TDT) is a major public health concern in India, requiring regular transfusions for survival. There is also significant morbidity caused by iron overload and transfusion related infections. Novel therapies targeting fetal hemoglobin induction are the need of the hour in resource-poor institutions for patients where transplant is not feasible for various reasons. This single arm, non-randomised prospective trial evaluated the efficacy and safety of a combination of low dose thalidomide and hydroxyurea in TDT along with the impact on quality of life (QoL). It included 41 TDT patients, who failed a reasonable trial of hydroxyurea. Complete response (CR) was defined as transfusion independence and partial response (PR) denoted at least a 50% reduction in transfusion requirement. The rest were defined as non-responders (NR). The mean age of the cohort was 20.78 years (range 12-45 years). There were 13 males and 28 females. Nineteen (46.3%), 7 (17.1%), and 15 (36.6%) patients achieved CR, PR, and no response respectively. The overall response rate (CR + PR) was 63.4%. There was a significant increase in hemoglobin levels with decrement in transfusion burden and ferritin levels. There were no significant adverse reactions. No significant predictors of response were found including amongst genetic modifiers. It improved the health related QoL amongst responders. The combination of thalidomide and hydroxyurea appear safe and effective in the reduction in transfusion requirement of TDT patients. The judicious use of these drugs can improve the quality of life and pave the way for patients not eligible for a stem cell transplant.

Keywords:  Thalassemia; hydroxyurea; thalidomide; transfusion dependent; transplant ineligible

DOI:  https://doi.org/10.1080/03630269.2024.2386076
PLoS One. 2024 ;19(8): e0306043

METTL16 participates in haemoglobin H disease through m6A modification.

Yuping Liao, Feng Zhang, Fang Yang, Shijin Huang, Sha Su, Xuemei Tan, Linlin Zhong, Lingjie Deng, Lihong Pang.

BACKGROUND: Haemoglobin H (HbH) disease is caused by a disorder of α-globin synthesis, and it results in a wide range of clinical symptoms. M6A methylation modification may be one of the mechanisms of heterogeneity. Therefore, this article explored the role of methyltransferase like 16 (METTL16) in HbH disease.METHOD: The results of epigenetic transcriptome microarray were analysed and verified through bioinformatic methods and qRT-PCR, respectively. The overexpression or knock down of METTL16 in K562 cells was examined to determine its role in reactive oxygen species (ROS), cell cycle processes or iron overload. YTH domain family protein 3 (YTHDF3) was knocked down in K562 cells and K562 cells overexpressing METTL16 via siRNA to investigate its function. In addition, haemoglobin expression was detected through benzidine staining. qRT-PCR, WB, methylated RNA Immunoprecipitation (MeRIP) and (RNA Immunoprecipitation) RIP experiments were conducted to explore the mechanism of intermolecular interaction.
RESULTS: METTL16, YTHDF3 and solute carrier family 5 member 3 (SLC5A3) mRNA and the methylation level of SLC5A3 mRNA were downregulated in HbH patients. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA expression was negatively correlated with HGB content among patients with HbH-CS disease. Overexpression of METTL16 increased ROS and intracellular iron contents in K562 cells, changed the K562 cell cycle, reduced hemin-induced haemoglobin synthesis, increased the expressions of SLC5A3 and HBG and increased SLC5A3 mRNA methylation levels. Knockdown of METTL16 reduced ROS and intracellular iron contents in K562 cells. Hemin treatment of K562 cells for more than 14 days reduced the protein expressions of METTL16 and SLC5A3 and SLC5A3 mRNA methylation levels. Knockdown of YTHDF3 rescued the intracellular iron content changes induced by the overexpression of METTL16. The RIP experiment revealed that SLC5A3 mRNA can be enriched by METTL16 antibody.
CONCLUSION: METTL16 may affect the expression of SLC5A3 by changing its m6A modification level and regulating ROS synthesis, intracellular iron and cycle of red blood cells. Moreover, METTL16 possibly affects the expression of haemoglobin through IGF2BP3, which regulates the clinical phenotype of HbH disease.

DOI: https://doi.org/10.1371/journal.pone.0306043
Clin Lab Med. 2024 Sep;pii: S0272-2712(24)00017-9. [Epub ahead of print]44(3): 441-453

Advances in Hemoglobinopathies and Thalassemia Evaluation.

Archana M Agarwal, Anton V Rets.

  Hemoglobin (Hb) disorders are among the most prevalent inherited diseases. Despite a limited number of involved genes, these conditions represent a broad clinical and prognostic spectrum. The menu of laboratory tests is extensive. From widely available modalities, for example, complete blood count to rather sophisticated molecular technologies, the investigation of Hb disorders recapitulates an increasing complexity of laboratory workup in other medical fields. This review highlights a current state of biochemical and molecular investigation of Hb disorders and offers a glimpse on technologies that are yet to be fully embraced in clinical practice.

Keywords:  Capillary electrophoresis; Hemoglobinopathy; High-performance liquid chromatography; Next-generation sequencing; Sequencing; Thalassemia

DOI:  https://doi.org/10.1016/j.cll.2024.04.006