Inherited erythrocytosis

Betty Gardie

Investigator : Betty Gardie
Post-doc : Salam Idriss
Support staff : Esther Juguet
 

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 1200 cases with hereditary erythrocytosis thanks to Pr Girodon (CHU Dijon). Next generation sequencing was performed to screen for the presence of mutations in 28 genes (CHU Dijon and CHU Nantes).

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).

Thanks to our involvement in two European networks dedicated to erythrocytosis (MPN&MPNr-EuroNet) and hypoxia (Hypoxianet), we have carried out a collaborative effort that led to major advances in the field. This work enabled the publication of the two largest international cohorts of patients with erythrocytosis, for which my team conducted functional analyses of over one hundred genetic variants in the hypoxia pathway (Delamare et al., Haematologica 2023) (Karaghiannis et al., Haematologica 2023). Notably, we discovered a new exon in the VHL (von Hippel-Lindau) gene located deep in intron 1 (termed E1'), which is mutated in patients with erythrocytosis and VHL disease (Lenglet et al., Blood 2018).  More recently, we identified a novel cause of erythrocytosis linked to a previously unknown mechanism of EPO regulation (Martin et al., NEJM 2025).
 

Learn more about our projects :

Identification of Hepatic-like EPO as a Cause of Polycythemia.  Martin L#, Maric D#, Idriss S#, Delamare M#, Le Roy A, Maaziz N, Caillaud A, Si-Tayeb K, Robriquet F, Lenglet M, Erceau L, Bellanné-Chantelot C, Plo I, Aral B, Garrec C, Airaud F, Gianfermi C, Antunes V, Keppner A, Vincent S M, Desfontaine A, Modé N, Laporte F, Gaignerie A, Chariau C, Leray I, Rogue C, David L, Redon R, Bézieau S, Mansour-Hendili L, Galactéros F, Maillet T, Pasquet M, Cougoul P, Nloga A-M, Gardin C, Guitton C, Dubruille V, Giacobbi-Milet V, Leblanc T, Kaya Z, Semama D, James C, Carillo S, Ochmann M, Waage A, Mortier E, Maillasson M, Quéméner A, Cario H, Skoda R C, Zermati Y*, Hoogewijs D*, Marchand A*, Girodon F*, Gardie B*. *, #: equal contribution to the work. The New England Journal of Medicine. 2025 May 1;392(17):1684-1697

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.

Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis. Delamare M, Le Roy A, Pacault M, Schmitt L, Garrec C, Maaziz N, Myllykoski M, Rimbert A, Karaghiannis V, Aral B, Catherwood M, Airaud F, Mansour-Hendili L, Hoogewijs D, Peroni E, Idriss S, Lesieur V, Caillaud A, Si-Tayeb K, Chariau C, Gaignerie A, Rab M, Haferlach T, Meggendorfer M, Bézieau S, Benetti A, Casadevall N, Hirsch P, Rose C, Wemeau M, Galacteros F, Cassinat B, Bellosillo B, Bento C, van Wijk R, Petrides P, Randi ML, McMullin MF, Koivunen P, ECYT-3 consortium, Girodon F and Gardie B. Haematologica. 2023 Jun 15.

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.

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
 

Funding

  • Agence Nationale de la Recherche
  • Congressionally Directed Medical Research Programs (CDMRP), USA Agency
  • LABEX GR-Ex
  • VHL Alliance USA
  • VHL France
  • Ecole Pratique des Hautes Etudes
  • Fondation Maladies Rares
  • Horizon Europe


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Updated on 26 August 2025.