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A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis
Open accessAbstract
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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“Conversely, several PHD2 missense mutations have been identified that resulted in diminished hydroxylase activity. 157, 158”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [157]
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“Patients, who were heterozygous for these mutations were characterized by increased rbc values in the presence of inappropriately normal serum EPO levels. 157–162”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [157]
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Metadata
- Authors
- Percy, M. J., Zhao, Q., Flores, A., Harrison, C., Lappin, T. R. J., Maxwell, P. H., McMullin, M. F., & Lee, F. S.
- Affiliations
- Queen's University Belfast (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-01-09
- Volume
- 103
- Issue
- 3
- Pages
- 654-659
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1334658
- OpenAlex
- W2059951197
- Cited by
- 330
- References
- 49
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 14 · 2020: 11 · 2019: 9 · 2018: 12 · 2017: 12 · 2016: 20 · 2015: 13 · 2014: 16 · 2013: 22 · 2012: 21
- FWCI
- 19.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- National Cancer Institute (R01CA090261)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
- Keywords
- PHD2, familial erythrocytosis, hypoxia-inducible factor, oxygen homeostasis, erythropoietin regulation, von Hippel-Lindau tumor suppressor, erythropoiesis
- MeSH terms
- Adult, Cell Line, Female, Homeostasis, Humans, Isoenzymes, Male, Middle Aged, Oxygen, Polycythemia, Procollagen-Proline Dioxygenase, Protein Binding, Point Mutation, Protein Structure, Tertiary, Immediate-Early Proteins, Amino Acid Substitution, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases
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