Comprehensive <i>in silico</i> and functional studies for classification of <i>EPAS1/HIF2A</i> genetic variants identified in patients with erythrocytosis

Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of paraganglioma, pheochromocytoma and somatostatinoma. In the present study, we describe a unique European collection of 41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. In addition we identified two infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. The aim of this study was to determine the causal role of these genetic variants, to establish pathogenicity, and to identify potential candidates eligible for the new hypoxia-inducible factor-2 α (HIF-2α) inhibitor treatment. Pathogenicity was predicted with in silico tools and the impact of 13 HIF-2b variants has been studied by using canonical and real-time reporter luciferase assays. These functional assays consisted of a novel edited vector containing an expanded region of the erythropoietin promoter combined with distal regulatory elements which substantially enhanced the HIF-2α-dependent induction. Altogether, our studies allowed the classification of 11 mutations as pathogenic in 17 patients and 23 relatives. We described four new mutations (D525G, L526F, G527K, A530S) close to the key proline P531, which broadens the spectrum of mutations involved in erythrocytosis. Notably, we identified patients with only erythrocytosis associated with germline mutations A530S and Y532C previously identified at somatic state in tumors, thereby raising the complexity of the genotype/phenotype correlations. Altogether, this study allows accurate clinical follow-up of patients and opens the possibility of benefiting from HIF-2α inhibitor treatment, so far the only targeted treatment in hypoxia-related erythrocytosis disease

Les substituts de globules rouges (passé, présent, futur)

La transfusion de concentrés globulaires rouges est considérée comme un acte thérapeutique à risque par l'ensemble de la communauté médicale. Néanmoins, elle demeure nécessaire dans un grand nombre de situations chirurgicales ou d'urgence. Pour pallier aux risques infectieux et immunologiques, les chercheurs tentent depuis de nombreuses années de proposer des substituts de globules rouges. Parmi ceux-ci, les solutions d'hémoglobine et les émulsions perfluorées ont fait l'objet de nombreuses études scientifiques et cliniques. L'historique de ces produits, leurs développements récents, leurs qualités et leurs défauts sont étudiés. Ce travail propose ensuite la mise en oeuvre d'une nouvelle génération de molécules fluorées, modèlisées pour être plus efficaces qu'une émulsion standard et pour être totalement hydrosolubles. Le cahier des charges et la chimie de ces produits sont présentésPARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Interprétation des hyperferritinémies à l'heure du diagnostic de l'hémochromatose génétique

Depuis dix ans l'identification de la mutation C282Y a bouleversé la stratégie diagnostique de l'hémochromatose. De nombreux progrès, réalisés tant sur les plans moléculaire qu'épidémiologique, ont permis d'identifier une nouvelle entité, l'hépatosidérose dysmétabolique. Nous montrerons, en nous appuyant sur une revue de la littérature, l'importance jouée par le syndrome métabolique au niveau du spectre des surcharges en fer. Nous tenterons de donner une stratégie diagnostique quant à l'identification des surcharges en fer à partir de cette anomalie biologique potentiellement fréquente en médecine générale qu'est l'hyperferritinémie. Nous essaierons également de dégager les enjeux thérapeutiques soulevés autour de ce thème. Nous étudierons le spectre des surcharges en fer au sein d'une cohorte de patients traités par saignées ; nous identifierons les circonstances de découverte qui mènent au diagnostic des surcharges en fer, en tentant de confronter l'état des connaissances et des recommandations à l'état des pratiquesSince ten years, the discovery of the homozygote C282Y mutation in the HFE gene, allowed to improve knowledges about iron metabolism, epidemiology of haemochromatosis and simplified the diagnosis of this disease. In the same time, Insulin-Resistance related hepatic iron overload (IRHIO) was described. Hyperferritinemia and iron overload related to the metabolic syndrome might be quite frequent in the general adult population, in everydays physicians' practising. We will describe the aetiological spectrum of iron overloads in a cohort of phlebotomized patients, regarding phenotype and genotype data. We will try to underline the importance of the dysmetabolic pathway in such a cohort. We will examine then, the circumstances that leed to the dagnosis of iron overload, and will confront physicians' practises to the official recommandationsPARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Modeling the public health impact of voxelotor in the management of sickle cell disease in France.

Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia, vaso-occlusive crises, and end-organ damage associated with early mortality. Despite standard of care, patients with SCD still experience complications and early mortality, highlighting remaining unmet treatment needs. Voxelotor is a first-in-class HbS polymerization inhibitor approved by the US Food and Drug Administration as a treatment for SCD and by the European Medicines Agency for hemolytic anemia due to SCD. In clinical studies, voxelotor has been shown to increase hemoglobin (Hb) and decrease hemolytic markers in patients with SCD. The objective of this study was to estimate the impact of voxelotor on the burden of SCD in France using a modeling approach, accounting for its anticipated adoption and diffusion over the next 5 years. We designed a sequential multi-cohort model to project and compare the cumulative incidence of SCD complications over a 20-year time horizon in a world with and without voxelotor. A distribution of patients was simulated across various levels of Hb response based on the phase 3 HOPE trial results, and relative risk reduction was adjusted using published meta-analysis results that projected risk reduction due to a 1 g/dL increase in Hb. In 6100 modeled patients with SCD treated with voxelotor, the model projected the number of deaths to decrease by 39.4%, with an increase of 1.8% in life-years gained. The model also projected life expectancy to increase by 15.8%, and incident cases of stroke, pulmonary hypertension, and chronic kidney disease to decrease by 19.8%, 24.5%, and 25.1%, respectively. The model suggests that improving Hb using a treatment such as voxelotor may have a positive public health impact by reducing the burden of SCD for patients and the healthcare system

Neonatal cyanosis with Hb St Mandé, a low O 2 affinity hemoglobin variant affecting β‐globin

International audienc

HB belliard [α56(e5)LYS→ASN] a new fast-moving α chain variant found in a subject of Spanish origin

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Place de la greffe de moelle dans le traitement de la drepanocytose

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Manipulating hemoglobin oxygenation using silica nanoparticles: a novel prospect for artificial oxygen carriers

International audienceSilica nanoparticles act as an effector for human native and sickle cell hemoglobin while preserving their tetrameric structure.Manipulating hemoglobin oxygenation using nanoparticles opens the way for the rational design of hemoglobin-based oxygen carriers.Recently, nanoparticles have attracted much attention as new scaffolds for hemoglobin-based oxygen carriers (HBOCs). Indeed, the development of bionanotechnology paves the way for the rational design of blood substitutes, providing that the interaction between the nanoparticles and hemoglobin at a molecular scale and its effect on the oxygenation properties of hemoglobin are finely controlled. Here, we show that human hemoglobin has a high affinity for silica nanoparticles, leading to the adsorption of hemoglobin tetramers on the surface. The adsorption process results in a remarkable retaining of the oxygenation properties of human adult hemoglobin and sickle cell hemoglobin, associated with an increase of the oxygen affinity. The cooperative oxygen binding exhibited by adsorbed hemoglobin and the comparison with the oxygenation properties of diaspirin cross-linked hemoglobin confirmed the preservation of the tetrameric structure of hemoglobin loaded on silica nanoparticles. Our results show that silica nanoparticles can act as an effector for human native and mutant hemoglobin. Manipulating hemoglobin oxygenation using nanoparticles opens the way to the design of novel HBOCs