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 270 cases with hereditary erythrocytosis through the department of medical genetics led by Stéphane Bézieau. Next generation sequencing was performed to screen for the presence of mutations in 28 genes.
We identified 66 variants (25% patients) in 12 genes and set up functional studies of seven genes of the hypoxia pathway signaling (VHL, PHD1, PHD2, HIF1A, HIF2A, EPO, LNK).

We have demonstrated complex splicing of some genes of this pathway with the identification of new splicing isoforms which expression is deregulated in pathologies.
Notably, we identified a new exon in the VHL (von Hippel Lindau) gene (which we termed E1') located deep in intron 1, which was 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 with K. Si-Tayeb, team IV), and for the first time in neural crest cells, the cell type responsible for EPO production in adults.


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 :

  • Région des Pays de la Loire,
  • Agence Nationale de la Recherche
  • Laboratory of Excellence GR-Ex (#ANR-11-LABX-0051)
  • Fondation Maladies Rares
  • VHL France
  • VHL Alliance
  • Kiwanis
  • Fondation Genavie