Betty Gardie

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 on 250 patients 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).

Notably, we identified a complex regulation of VHL splicing. We first demonstrated that synonymous mutations may induce exon skipping. More importantly, we identified a new VHL cryptic-exon (which we termed E1'), deep in intron 1, which was mutated in patients with erythrocytosis or VHL disease. A comprehensive study was performed on mutations in E1’ (microsatellite analysis, segregation studies, phylogenetic analysis, expression measurement of mRNA and proteins, functional studies of the potential VHL1’ protein, minigene experiments and RNA sequencing of biological samples from the patients). We showed that the mutations induce a dysregulation of VHL splicing with excessive retention of E1’. In both cases (exon skipping or retention), 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 hiPS 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 (paper in preparation).


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.

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.
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 Recherche (Programme de Recherche Translationnelle en Sante 2015 GenRED)
  • Laboratory of Excellence GR-Ex (#ANR-11-LABX-0051)
  • Fondation Maladies Rares
  • VHL France
  • Kiwanis
  • Fondation Genavie