학술논문
Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis.
Document Type
Academic Journal
Author
Delamare M; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Le Roy A; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Pacault M; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Service de Génétique Médicale, CHU de Nantes, Nantes.; Schmitt L; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Garrec C; Service de Génétique Médicale, CHU de Nantes, Nantes.; Maaziz N; Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon.; Myllykoski M; Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland. 90014 Oulu.; Rimbert A; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Karaghiannis V; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Aral B; Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon.; Catherwood M; Belfast Health and Social Care Trust, Belfast N.Ireland.; Airaud F; Service de Génétique Médicale, CHU de Nantes, Nantes.; Mansour-Hendili L; Département de Biochimie-Biologie Moléculaire, Pharmacologie, Génétique Médicale AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Université Paris-Est Créteil, IMRB Equipe Pirenne, Laboratoire d'excellence LABEX GRex, Créteil.; 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'.; Peroni E; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, 35128 Padova, Italy; Medical Genetics Unit, Mater Domini University Hospital, 88100 Catanzaro.; Idriss S; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Lesieur V; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Caillaud A; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Si-Tayeb K; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes.; Chariau C; Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, FR-44000, Nantes.; Gaignerie A; Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, FR-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.; Haferlach T; Munich Leukemia Laboratory, Munich.; Meggendorfer M; Munich Leukemia Laboratory, Munich.; Bézieau S; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Service de Génétique Médicale, CHU de Nantes, Nantes.; Benetti A; Department of Medicine-DIMED, University of Padua, Via Giustiniani 2, 35128, Padua.; Casadevall N; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, 75012, Paris.; Hirsch P; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, 75012, Paris.; Rose C; Service d'onco-hématologie, Saint-Vincent de Paul Hospital, Boulevard de Belfort, Université Catholique de Lille, Univ. Nord de France, F-59000 Lille.; Wemeau M; Hematology Department, Claude Huriez Hospital, Lille Hospital, 59000 Lille.; Galacteros F; Département de Biochimie-Biologie Moléculaire, Pharmacologie, Génétique Médicale AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Red Cell Disease Referral Center-UMGGR, AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil.; Cassinat B; Université Paris Cité, APHP, Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire, Paris.; Bellosillo B; Pathology Department, Hospital del Mar-IMIM, Barcelona.; Bento C; Hematology Department, Centro Hospitalar e Universitário de Coimbra; CIAS, University of Coimbra.; Van Wijk R; Central Diagnostic Laboratory - Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht.; Petrides PE; Hematology Oncology Center and Ludwig-Maximilians-University Munich Medical School, Munich.; Randi ML; Department of Medicine-DIMED, University of Padua, Via Giustiniani 2, 35128, Padua.; McMullin MF; Belfast Health and Social Care Trust, Belfast N.Ireland; Queen's University, Belfast, N. Ireland.; Koivunen P; Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland. 90014 Oulu.; 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.; Gardie B; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Laboratoire d'Excellence GR-Ex.
Source
Publisher: Ferrata Storti Foundation Country of Publication: Italy NLM ID: 0417435 Publication Model: Electronic Cited Medium: Internet ISSN: 1592-8721 (Electronic) Linking ISSN: 03906078 NLM ISO Abbreviation: Haematologica Subsets: MEDLINE
Subject
Language
English
Abstract
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.