A Family with Erythrocytosis Establishes a Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis

The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigation...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 103; no. 3; pp. 654 - 659
Main Authors Percy, Melanie J., Zhao, Quan, Flores, Adrian, Harrison, Claire, Lappin, Terence R. J., Maxwell, Patrick H., McMullin, Mary Frances, Lee, Frank S.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 17.01.2006
National Acad Sciences
SeriesFrom the Cover
Subjects
Adult
Amino Acid Substitution
Biological Sciences
Cell Line
Enzymes
Epics
Erythrocytes
Female
Gene expression regulation
Genetic mutation
Genetics
HEK293 cells
Hematocrit
Homeostasis - physiology
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases
Immediate-Early Proteins - genetics
Immediate-Early Proteins - physiology
Isoenzymes - physiology
Kidneys
Male
Middle Aged
Oxygen
Oxygen - blood
Point Mutation
Polycythemia
Polycythemia - blood
Polycythemia - enzymology
Polycythemia - genetics
Procollagen-Proline Dioxygenase - genetics
Procollagen-Proline Dioxygenase - physiology
Protein Binding - genetics
Protein Structure, Tertiary
Reporter genes
Tumors
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Summary:The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigations of erythropoietin regulation identified the transcription factor hypoxia-inducible factor (HIF). HIF is now recognized as being a key regulator of genes that function in a comprehensive range of processes besides erythropoiesis, including energy metabolism and angiogenesis. HIF itself is regulated through the α-subunit, which is hydroxylated in the presence of oxygen by a family of three prolyl hydroxylase domain proteins (PHDs)/HIF prolyl hydroxylases/egg-laying-defective nine enzymes. Hydroxylation allows capture by the von Hippel-Lindau tumor suppressor gene product, ubiquitination, and destruction by the proteasome. Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a previously unrecognized cause of this condition. Our findings indicate that PHD2 is critical for normal regulation of HIF in humans.
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Abbreviations: Epo, erythropoietin; GSH, glutathione; Hct, hematocrit; mU, milliunits; HIF, hypoxia-inducible factor; PHD, prolyl hydroxylase domain protein; VHL, von Hippel–Lindau tumor suppressor protein; HRE, hypoxia response element.
M.F.M. and F.S.L. contributed equally to this work.
To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 605 Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail: franklee@mail.med.upenn.edu.
This paper was submitted directly (Track II) to the PNAS office.
Edited by Steven L. McKnight, University of Texas Southwestern Medical Center, Dallas, TX, and approved November 28, 2005
Conflict of interest statement: P.H.M. is a director and consultant of and holds equity in ReOx Ltd., which aims to develop therapeutic inhibitors of the HIF hydroxylase enzymes.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0508423103