title: The role of PHD2 mutations in the pathogenesis of erythrocytosis.
abstract: The transcription of the erythropoietin (EPO) gene is tightly regulated by the hypoxia response pathway to maintain oxygen homeostasis. Elevations in serum EPO level may be reflected in an augmentation in the red cell mass, thereby causing erythrocytosis. Studies on erythrocytosis have provided insights into the function of the oxygen-sensing pathway and the critical proteins involved in the regulation ofEPOtranscription. The α subunits of the hypoxia-inducible transcription factor are hydroxylated by three prolyl hydroxylase domain (PHD) enzymes, which belong to the iron and 2-oxoglutarate-dependent oxygenase superfamily. Sequence analysis of the genes encoding the PHDs in patients with erythrocytosis has revealed heterozygous germline mutations only occurring in Egl nine homolog 1 (EGLN1, also known asPHD2), the gene that encodes PHD2. To date, 24 differentEGLN1mutations comprising missense, frameshift, and nonsense mutations have been described. The phenotypes associated with the patients carrying these mutations are fairly homogeneous and typically limited to erythrocytosis with normal to elevated EPO. However, exceptions exist; for example, there is one case with development of concurrent paraganglioma (PHD2-H374R). Analysis of the erythrocytosis-associated PHD2 missense mutations has shown heterogeneous results. Structural studies reveal that mutations can affect different domains of PHD2. Some are close to the hypoxia-inducible transcription factor α/2-oxoglutarate or the iron binding sites for PHD2. In silico studies demonstrate that the mutations do not always affect fully conserved residues. In vitro and in cellulo studies showed varying effects of the mutations, ranging from mild effects to severe loss of function. The exact mechanism of a potential tumor-suppressor role for PHD2 still needs to be elucidated. A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels) and demonstrates that haploinsufficiency and partial deregulation of PHD2 is sufficient to cause erythrocytosis.
authors: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes, Villejuif; Unité Mixte de Recherche, Institut national de la santé et de la recherche médicale U892, Centre national de la recherche scientifique 6299, Centre de Recherche en Cancérologie Nantes/Angers, Université de Nantes, Nantes, France.
authors: Betty
authors: B
authors: Gardie
authors: Department of Haematology, Belfast City Hospital, Belfast, UK.
authors: Melanie J
authors: MJ
authors: Percy
authors: Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors: David
authors: D
authors: Hoogewijs
authors: Department of Chemistry and Oxford Centre for Integrative Systems Biology, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
authors: Rasheduzzaman
authors: R
authors: Chowdhury
authors: Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors: Celeste
authors: C
authors: Bento
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Patrick R
authors: PR
authors: Arsenault
authors: Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes, Villejuif; Institut national de la santé et de la recherche médicale U753, Institut de cancérologie Gustave Roussy (IGR), Villejuif, France; Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
authors: Stéphane
authors: S
authors: Richard
authors: Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors: Helena
authors: H
authors: Almeida
authors: Heart of England NHS Trust, Birmingham, UK.
authors: Joanne
authors: J
authors: Ewing
authors: Center for Human Genetics, Pathology Institute, UniLab-Lg, Molecular Haemato-Oncology Unit, CHU of Liege, Liege, Belgium.
authors: Frédéric
authors: F
authors: Lambert
authors: Department of Haematology, Queen's University, Belfast, UK.
authors: Mary Frances
authors: MF
authors: McMullin
authors: Department of Chemistry and Oxford Centre for Integrative Systems Biology, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
authors: Christopher J
authors: CJ
authors: Schofield
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Frank S
authors: FS
authors: Lee
keywords: EGLN1; HIF; PHD2; erythrocytosis; erythropoietin; hypoxia