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A Gain-of-Function Mutation in the HIF2A Gene in Familial Erythrocytosis
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Hypoxia-inducible factor (HIF) alpha, which has three isoforms, is central to the continuous balancing of the supply and demand of oxygen throughout the body. HIF-alpha is a transcription factor that modulates a wide range of processes, including erythropoiesis, angiogenesis, and cellular metabolism. We describe a family with erythrocytosis and a mutation in the HIF2A gene, which encodes the HIF-2alpha protein. Our functional studies indicate that this mutation leads to stabilization of the HIF-2alpha protein and suggest that wild-type HIF-2alpha regulates erythropoietin production in adults.
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“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 [147]
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“They may result from hyperaf fi ne hemoglobin variants, abnormalities in the hypoxia pathway (such as a gain-of-function mutation in the HIF-2 α gene [130] or Chuvash erythrocytosis, caused by mutations in the VHL gene leading to constitutive activation of the HIF pathway [131, 132]), exceptional…”
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“[22,27,28] The erythropoietin is accompanied by the growth factor 166-amino-acid glycoprotein, and its molecular weight is about 39000d Da.”
Génétique des phéochromocytomes et paragangliomes
Buffet, A., & Gimenez-Roqueplo, A. (2018) · EMC - Endocrinologie - Nutrition · doi:10.1016/s1155-1941(18)83576-4
I. Physiological Function and Regulated Production of Erythrocytes
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Policitemia vera: a propósito de um caso clínico
Macedo, J., Costa, E., Barbot, J., & Neto, C. (2015) · doi:10.25753/birthgrowthmj.v24.i2.8565
EPAS1 (Endothelial PAS Domain Protein 1)
Mohlin, S., Hamidian, A., Bexell, D., Påhlman, S., & Wigerup, C. (2014) · Atlas of Genetics and Cytogenetics in Oncology and Haematology · doi:10.4267/2042/54007
A translational link between Fe and Epo
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家族性赤血球増加症における低酸素誘導因子(HIF)およびHIF制御分子異常
則夫, 小. (2009) · 臨床血液 · doi:10.11406/rinketsu.50.1589
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Pheochromocytomas and Paragangliomas: Genetics and Pathophysiology
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The Pathogenesis, Diagnosis, and Treatment of Polycythaemia Vera
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“The HIF-2a gene is responsible for familial erythrocytosis in humans [94] and for comparatively high hemoglobin concentrations in polycystic kidney disease (pericystic hypoxia leading to HIF-2 induction) [95].”
Background
Metadata
- Authors
- Percy, M. J., Furlow, P. W., Lucas, G. S., Li, X., Lappin, T. R. J., McMullin, M. F., & Lee, F. S.
- Affiliations
- Belfast City Hospital (GB)
- University of Pennsylvania (US)
- Manchester Royal Infirmary (GB)
- Queen's University (CA)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-01-10
- Volume
- 358
- Issue
- 2
- Pages
- 162-168
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2295209
- OpenAlex
- W2086913408
- Cited by
- 314
- References
- 0
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 14 · 2022: 8 · 2021: 16 · 2020: 24 · 2019: 23 · 2018: 16 · 2017: 14 · 2016: 14 · 2015: 13 · 2014: 22 · 2013: 25 · 2012: 19
- FWCI
- 19.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- University of Pennsylvania
- U.S. Public Health Service (R01 C090261)
- 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
- HIF-2α, familial erythrocytosis, gain-of-function mutations, hypoxia-inducible factor alpha, protein stabilization, erythropoietin regulation, erythropoiesis, hereditary erythrocytosis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adult, DNA Mutational Analysis, Erythropoiesis, Erythropoietin, Female, Genotype, Hematocrit, Hemoglobins, Humans, Male, Pedigree, Polycythemia, Polymerase Chain Reaction, Point Mutation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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