Erythrocytosis associated with a novel missense mutation in the HIF2A gene
Open accessAbstract
The ERYTHROPOIETIN (EPO) gene is regulated by the transcription factor Hypoxia Inducible Factor-alpha (HIF-alpha). In this pathway, Prolyl Hydroxylase Domain protein 2 (PHD2) hydroxylates two prolyl residues in HIF-alpha, which in turn promotes HIF-alpha degradation by the von Hippel Lindau (VHL) protein. Evidence that HIF-2alpha is the important isoform for EPO regulation in humans comes from the recent observation that mutations in the HIF2A gene are associated with cases of erythrocytosis. We report here a new erythrocytosis-associated mutation, p.Asp539Glu, in the HIF2A gene. Similar to all reported cases, the affected residue is in close vicinity and C-terminal to the primary hydroxylation site in HIF-2alpha, Pro531. This mutation, however, is notable in producing a rather subtle amino acid substitution. Nonetheless, we find that this mutation compromises binding of HIF-2alpha to both PHD2 and VHL, and we propose that this mutation is the cause of erythrocytosis in this individual.
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Most gain-of-function mutations in HIF-2α are in direct proximity to proline residue 531.
“Most gain-of-function mutations in HIF-2α are in direct proximity to proline residue 531, which is one of the two main hydroxylation sites (the other major hydroxylation site is proline 405). 147–154”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [152]
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References 18 · Cited by 38
Research works printed but not linked: 5
- Semenza GL. Life with oxygen. Science. 2007;318(5847):62-4.
- Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, et al. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylaccep- tor proline. Biol Chem. 2009;284(14): 9050- 8.
- Huang J, Zhao Q, Mooney SM, Lee FS. Sequence determinants in hypoxia- inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem. 2002;277(42): 39792-800.
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- Authors
- van Wijk, R., Sutherland, S., Van Wesel, A. C. W., Huizinga, E. G., Percy, M. J., Bierings, M., & Lee, F. S.
- Affiliations
- University of Pennsylvania (US)
- Utrecht University (NL)
- Belfast City Hospital (GB)
- Corresponding author
- Lee, F. S.
- Venue
- Haematologica
- Published
- 2009-12-08
- Volume
- 95
- Issue
- 5
- Pages
- 829-832
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC2864390
- OpenAlex
- W4213073076
- Cited by
- 38
- References
- 18
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 3 · 2016: 4 · 2014: 2 · 2013: 6 · 2012: 2
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- University of Pennsylvania
- National Institutes of Health
- 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 › Hemoglobinopathies and Related Disorders
- Keywords
- erythrocytosis, HIF-2α, missense mutations, PHD2, von Hippel-Lindau protein, prolyl hydroxylation, erythropoietin regulation, protein-protein binding
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adolescent, Female, Humans, Polycythemia, Mutation, Missense, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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