title: Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia.
abstract: 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.
  
  
  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.
authors.affiliation: Villejuif et Faculté de Médecine Paris-Sud, Génétique Oncologique EPHE, INSERM U753, Institut de Cancérologie Gustave Roussy, Le Kremlin-Bicêtre, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Ladroue
authors.forename: David
authors.initials: D
authors.lastname: Hoogewijs
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
authors.forename: Romain
authors.initials: R
authors.lastname: Carcenac
authors.forename: Federica
authors.initials: F
authors.lastname: Storti
authors.forename: Michel
authors.initials: M
authors.lastname: Barrois
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Michel
authors.initials: M
authors.lastname: Leporrier
authors.forename: Nicole
authors.initials: N
authors.lastname: Casadevall
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Kiladjian
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: Fadi
authors.initials: F
authors.lastname: Fakhoury
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mazure
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Betty
authors.initials: B
authors.lastname: Gardie
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism*; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050505:Mutant Proteins; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases