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https://hdl.handle.net/10316/111884
Título: | Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis | Autor: | Delamare, Marine Le Roy, Amandine Pacault, Mathilde Schmitt, Loïc Garrec, Céline Maaziz, Nada Myllykoski, Matti Rimbert, Antoine Karaghiannis, Valéna Aral, Bernard Catherwood, Mark Airaud, Fabrice Mansour-Hendili, Lamisse Hoogewijs, David Peroni, Edoardo Idriss, Salam Lesieur, Valentine Caillaud, Amandine Si-Tayeb, Karim Chariau, Caroline Gaignerie, Anne Rab, Minke Haferlach, Torsten Meggendorfer, Manja Bézieau, Stéphane Benetti, Andrea Casadevall, Nicole Hirsch, Pierre Rose, Christian Wemeau, Mathieu Galacteros, Frédéric Cassinat, Bruno Bellosillo, Beatriz Bento, Celeste van Wijk, Richard Petrides, Petro E Randi, Maria Luigia McMullin, Mary Frances Koivunen, Peppi Girodon, François Gardie, Betty |
Data: | 1-Nov-2023 | Editora: | Ferrata Storti Foundation | Projeto: | This study was supported by grants from the Région des Pays de la Loire (project “EryCan”); the ANR (PRTS 2015 “GenRED” and AAPG 2020 “SplicHypoxia”); the labex GR-Ex, reference ANR-11-LABX-0051; Fonds Européen de Développement Régional (FEDER) Bourgogne Franche Comté; the VHL Alliance USA, the VHL France; the Génavie association and the Fondation Maladies Rares (FMR). | Título da revista, periódico, livro ou evento: | Haematologica | Volume: | 108 | Número: | 11 | Resumo: | Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases. | URI: | https://hdl.handle.net/10316/111884 | ISSN: | 1592-8721 0390-6078 |
DOI: | 10.3324/haematol.2023.282913 | Direitos: | openAccess |
Aparece nas coleções: | FMUC Medicina - Artigos em Revistas Internacionais |
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Characterization-of-genetic-variants-in-the-EGLN1PHD2-gene-identified-in-a-European-collection-of-patients-with-erythrocytosisHaematologica.pdf | 2.21 MB | Adobe PDF | Ver/Abrir |
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