A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis

M.J. Percy, P.H. Maxwell, F.S. Lee, Q. Zhao, A. Flores, C. Harrison, Terence Lappin, Mary McMullin

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275 Citations (Scopus)


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 -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.
Original languageEnglish
Pages (from-to)654-659
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume103 (3)
Issue number3
Publication statusPublished - 17 Jan 2006

ASJC Scopus subject areas

  • General
  • Genetics


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