Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia
Charline Ladroue, David Hoogewijs, Sophie Gad, Romain Carcenac, Federica Storti, Michel Barrois, Anne-Paule Gimenez-Roqueplo, Michel Leporrier, Nicole Casadevall, Olivier Hermine, Jean-Jacques Kiladjian, André Baruchel, Fadi Fakhoury, Brigitte Bressac-de Paillerets, Jean Feunteun, Nathalie Mazure, Jacques Pouysségur, Roland H. Wenger, Stéphane Richard, Betty Gardie

Author Affiliations

  1. Charline Ladroue1,*,
  2. David Hoogewijs2,*,
  3. Sophie Gad1,
  4. Romain Carcenac1,
  5. Federica Storti2,
  6. Michel Barrois3,
  7. Anne-Paule Gimenez-Roqueplo4,
  8. Michel Leporrier5,
  9. Nicole Casadevall6,
  10. Olivier Hermine7,
  11. Jean-Jacques Kiladjian8,
  12. André Baruchel9,
  13. Fadi Fakhoury10,
  14. Brigitte Bressac-de Paillerets3,11,
  15. Jean Feunteun12,
  16. Nathalie Mazure13,
  17. Jacques Pouysségur13,
  18. Roland H. Wenger2,
  19. Stéphane Richard1,14 and
  20. Betty Gardie1
  1. 1Génétique Oncologique EPHE, INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif et Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
  2. 2Institute of Physiology and Zürich Center for Integrative Human Physiology ZIHP, University of Zürich, Zürich, Switzerland
  3. 3Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France
  4. 4Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France; INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France
  5. 5CHU de Caen, Service d’Hématologie Clinique, France
  6. 6Hôpital Saint Antoine, Assistance Publique–Hôpitaux de Paris and Pierre et Marie Curie University, Institut Gustave Roussy, Inserm, UMR790, Villejuif, France
  7. 7Service d’Hématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  8. 8Centre d’Investigations Cliniques, Hôpital Saint-Louis, AP-HP, Paris, France
  9. 9Service d’Hématologie, Hôpital St. Louis, Paris, France
  10. 10Service de Néphrologie, Hôpital Necker, Paris, France
  11. 11Unité INSERM U946, Variabilité Génétique et Maladies Humaines, Fondation Jean Dausset/CEPH Unité, Paris, France
  12. 12Institut de Cancérologie Gustave Roussy, CNRS-UMR8200, Villejuif, France
  13. 13Institut de Biologie du Développement et Cancer, Université de Nice - Sophia Antipolis, CNRS UMR-6543, France
  14. 14Centre Expert National Cancers Rares INCa “PREDIR” and Réseau National INCa, AP-HP, Service d’Urologie, CHU, Le Kremlin-Bicêtre and Service de Néphrologie, Hôpital Necker, Paris, France
  1. Correspondence: Betty Gardie, Laboratoire de Génétique Oncologique EPHE, INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif, France. E-mail: betty.gardie{at}inserm.fr
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Background Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma.

Design and Methods Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively.

Results This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category.

Conclusions As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.

  • Received March 28, 2011.
  • Revision received July 6, 2011.
  • Accepted September 5, 2011.
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