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

Autor: Karaghiannis V; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Maric D; Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System, University of Fribourg, CH-1700 Fribourg, Switzerland; National Center of Competence in Research 'Kidney.CH'., Garrec C; Service de Génétique Médicale, CHU de Nantes, Nantes., Maaziz N; Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon., Buffet A; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France; Département de Médecine Génomique des Tumeurs et des Cancers, AP-HP, Hôpital européen Georges Pompidou, F-75015 Paris., Schmitt L; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Antunes V; Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System, University of Fribourg, CH-1700 Fribourg, Switzerland; National Center of Competence in Research 'Kidney.CH'., Airaud F; Service de Génétique Médicale, CHU de Nantes, Nantes., Aral B; Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon., Le Roy A; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Corbineau S; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Mansour-Hendili L; Département de Biochimie-Biologie Moléculaire, Pharmacologie, Génétique Médicale, APHP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Université Paris-Est Créteil, IMRB Equipe Pirenne, Laboratoire d'excellence LABEX GRex, Créteil., Lesieur V; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Rimbert A; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Laporte F; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Delamare M; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes., Rab M; Central Diagnostic Laboratory - Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht., Bézieau S; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Service de Génétique Médicale, CHU de Nantes, Nantes., Cassinat B; Université Paris Cité, APHP, Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire, Paris., Galacteros F; Université Paris-Est Créteil, IMRB Equipe Pirenne, Laboratoire d'excellence LABEX GRex, Créteil, France; Red Cell Disease Referral Center-UMGGR, AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil., Gimenez-Roqueplo AP; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France; Département de Médecine Génomique des Tumeurs et des Cancers, AP-HP, Hôpital européen Georges Pompidou, F-75015 Paris., Burnichon N; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France; Département de Médecine Génomique des Tumeurs et des Cancers, AP-HP, Hôpital européen Georges Pompidou, F-75015 Paris., Cario H; Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm., Van Wijk R; Central Diagnostic Laboratory - Research, University Medical Center Utrecht, Utrecht University, Utrecht., Bento C; Hematology Department, Centro Hospitalar e Universitário de Coimbra; CIAS, University of Coimbra., Girodon F; Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon, France; Inserm U1231, Université de Bourgogne, Dijon, France; Laboratoire d'Excellence GR-Ex., Hoogewijs D; Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System, University of Fribourg, CH-1700 Fribourg, Switzerland; National Center of Competence in Research 'Kidney.CH'., Gardie B; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Laboratoire d'Excellence GR-Ex.
Jazyk: angličtina
Zdroj: Haematologica [Haematologica] 2023 Jun 01; Vol. 108 (6), pp. 1652-1666. Date of Electronic Publication: 2023 Jun 01.
DOI: 10.3324/haematol.2022.281698
Abstrakt: 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.
Databáze: MEDLINE
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