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The role of PHD2 mutations in the pathogenesis of erythrocytosis

Authors Gardie B, Percy MJ, Hoogewijs D, Chowdhury R, Bento C, Arsenault P, Richard S, Almeida H, Ewing J, Lambert F, McMullin MF, Schofield CJ, Lee FS

Received 1 February 2014

Accepted for publication 20 March 2014

Published 1 July 2014 Volume 2014:2 Pages 71—90

DOI https://doi.org/10.2147/HP.S54455

Checked for plagiarism Yes

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Peer reviewer comments 2


Video abstract presented by Betty Gardie et al.

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Betty Gardie,1,2 Melanie J Percy,3 David Hoogewijs,4 Rasheduzzaman Chowdhury,5 Celeste Bento,6 Patrick R Arsenault,7 Stéphane Richard,1,8,9 Helena Almeida,6 Joanne Ewing,10 Frédéric Lambert,11 Mary Frances McMullin,12 Christopher J Schofield,5 Frank S Lee7

1Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes, Villejuif, 2Unité 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; 3Department of Haematology, Belfast City Hospital, Belfast, UK; 4Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; 5Department of Chemistry and Oxford Centre for Integrative Systems Biology, Chemistry Research Laboratory, University of Oxford, Oxford, UK; 6Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; 7Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 8Institut national de la santé et de la recherche médicale U753, Institut de cancérologie Gustave Roussy (IGR), Villejuif, France; 9Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France; 10Heart of England NHS Trust, Birmingham, UK; 11Center for Human Genetics, Pathology Institute, UniLab-Lg, Molecular Haemato-Oncology Unit, CHU of Liege, Liege, Belgium; 12Department of Haematology, Queen's University, Belfast, UK

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 of EPO transcription. 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 as PHD2), the gene that encodes PHD2. To date, 24 different EGLN1 mutations 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.

Keywords: PHD2, EGLN1, HIF, hypoxia, erythropoietin, erythrocytosis

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