A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis
Open accessAbstract
HIF2A transcription factor plays a central role in the regulation of the hypoxia responding pathway in mammalian cells, by modulating erythropoiesis and angiogenesis. Molecular alterations of oxygen sensing pathway constituents are implicated in hereditary erythrocytosis. Here we show that 2 members of a family with idiopathic erythrocytosis exhibited a new heterozygous G to A mutation at base 1605 of the exon 12 of hypoxia-inducible factor-2A (HIF2A) gene. This mutation determines the replacement of methionine by isoleucine at the position 535, very close to the position 531, where the hydroxyl acceptor prolyne is located. In addition, we found that mRNA expression of erythropoietin receptor, vascular endothelial growth factor, transferrin receptor, adrenomedullin and N-myc downstream regulated gene 1, up-regulated by HIF2A or hypoxia, were significantly higher in patients carrying the mutation than in normal controls. These results suggest that the HIF2A(M535I) gene mutation could induce hereditary erythrocytosis at a young age.
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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 [150]
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- Authors
- Martini, M., Teofili, L., Cenci, T., Giona, F., Torti, L., Rea, M., Foa, R., Leone, G., & Larocca, L. M.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Sapienza University of Rome (IT)
- Venue
- Haematologica
- Published
- 2008-01-01
- Volume
- 93
- Issue
- 7
- Pages
- 1068-1071
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- OpenAlex
- W2108582916
- Cited by
- 73
- References
- 21
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 1 · 2016: 9 · 2015: 3 · 2014: 8 · 2013: 8 · 2012: 4
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- HIF-2α, familial erythrocytosis, idiopathic erythrocytosis, hypoxia response, erythropoiesis, erythropoietin receptor, vascular endothelial growth factor, transferrin receptor, adrenomedullin, NDRG1, prolyl hydroxylation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adolescent, Adult, Hypoxia, Female, Gene Expression Regulation, Heterozygote, Humans, Male, Mutation, Oxygen, Polycythemia, Receptors, Transferrin, Vascular Endothelial Growth Factor A, Basic Helix-Loop-Helix Proteins, Adrenomedullin
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