Inherited erythrocytosis

Betty Gardie

The adaptation of cells to a decrease in oxygen concentration (hypoxia) is a major biological pathway whose regulatory mechanisms are complex and still poorly understood. Notably, germline mutations in the genes encoding the major regulators of the hypoxia pathway predispose patients to the development of a broad spectrum of diseases, and in particular the overproduction of red blood cells (polycythemia also called erythrocytosis) that can be complicated by pulmonary arterial hypertension and thrombotic events, and/or the development of multiple tumors (hemangioblastoma, pheochromocytoma, renal cancer). The aim of this project is to identify the subtle molecular mechanisms at the origin of different phenotypes associated with mutations in the hypoxia pathway genes.

Since 2015, we have recruited 450 cases with hereditary erythrocytosis thanks to Pr Girodon (CHU Dijon) and through the department of medical genetics of Nantes led by Stéphane Bézieau. Next generation sequencing was performed to screen for the presence of mutations in 28 genes.
We have identified variants in 25% of patients and set up functional studies for seven genes of the hypoxia pathway signaling (VHL, PHD1, PHD2, HIF1A, HIF2A, EPO, LNK).

We have demonstrated complex splicing of genes of the hypoxia pathway with the identification of new splicing isoforms dysregulated in pathologies.
Notably, we discovered a new exon in the VHL (von Hippel-Lindau) gene (termed E1') located deep in intron 1, which is mutated in patients with erythrocytosis or VHL disease. A comprehensive study was performed on mutations in E1’ and we showed that the mutations induce a dysregulation of VHL splicing with excessive retention of E1’. This splicing dysregulation differentially impacts splicing in correlation with phenotype severity and is associated with a downregulation of VHL protein expression.

In parallel, we set up a cellular model of hereditary erythrocytosis by starting a collection of human induced pluripotent stem cells (hiPSC) from patients. We differentiated the hiPS in erythropoietin-producing cells (responsible for erythrocytosis) of the liver type that produces EPO during fetal life (in collaboration Team IV), and for the first time in neural crest cells, the cell type responsible for EPO production in adults.


Comprehensive in silico and functional studies for classification of EPAS1/HIF2A genetic variants identified in patients with erythrocytosis. Karaghiannis V*, Maric D*, Garrec C, Maaziz N, Buffet A, Schmitt L2,Antunes V, Fabrice Airaud F, Aral B , Le Roy A, Corbineau S, Mansour-Hendili L, Lesieur V, Rimbert A, Laporte F, Delamare M, Rab M, Bézieau S Cassinat B, Galacteros F, Gimenez-Roqueplo AP, Burnichon N, Cario H, van Wijk R, Bento C, Girodon F#, Hoogewijs D#, Gardie B#.*, #: equal contribution to the work. Haematologica, 2023 in press.

Increased incidence of germline PIEZO1 mutations in individuals with idiopathic erythrocytosis. Filser M, Giansily-Blaizot M, Grenier M, Monedero Alonso D, Bouyer G, Laurent Pérès, Egée S, Aral B, Airaud F, Da Costa L, Picard V, Cougoul P, Palach M, Béziau S, Garrec C, Patricia Aguilar-Martinez P, Gardie B*, Girodon F*. Letter. Blood. 2020 Nov 12.  
* equally contribution to this work.

Low incidence of EPOR mutations in idiopathic erythrocytosis. Filser M, Aral B, Airaud F, Chauveau A, Bruce A,  Polfrit Y, Thiebaut Y, Gauthier M, Le Maréchal C, Lippert E, Béziau S, Garrec C, Gardie B, Girodon F. Haematologica. 2020 Mar 12.

High HFE mutation incidence in idiopathic erythrocytosis. Burlet B, Bourgeois V, Buriller C, Aral B, Airaud F, Garrec C, Bézieau S, Gardie B, Girodon F. Br. J. Haematol. 185: 794–795, 2019.

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease. Lenglet M, Robriquet F, Schwarz K, Camps C, Couturier A, Hoogewijs D, Buffet A, Knight SJL, Gad S, Couvé S, Chesnel F, Pacault M, Lindenbaum P, Job S, Dumont S, Besnard T, Cornec M, Dreau H, Pentony M, Kvikstad E, Deveaux S, Burnichon N, Ferlicot S, Vilaine M, Mazzella J-M, Airaud F, Garrec C, Heidet L, Irtan S, Mantadakis E, Bouchireb K, Debatin K-M, Redon R, Bezieau S, Bressac-de Paillerets B, Teh BT, Girodon F, Randi M-L, Putti MC, Bours V, Van Wijk R, Göthert JR, Kattamis A, Janin N, Bento C, Taylor JC, Arlot-Bonnemains Y, Richard S, Gimenez-Roqueplo A-P, Cario H, Gardie B. Blood 132: 469–483, 2018.
Gene panel sequencing in idiopathic erythrocytosis. Girodon F, Airaud F, Garrec C, Bézieau S, Gardie B. Haematologica 102: e30, 2017.


This project has been financed by :

  • Agence Nationale de la Recherche
  • Ecole Pratique des Hautes Etudes
  • Fondation Genavie
  • Fondation Maladies Rares
  • Horizon Europe
  • Kiwanis
  • Région des Pays de la Loire
  • VHL Alliance
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Mis à jour le 26 June 2023 - Stéphanie CHATEL.