Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia
Open accessAbstract
BACKGROUND: Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. DESIGN AND METHODS: Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. RESULTS: This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. CONCLUSIONS: As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.
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Patients heterozygous for PHD2 mutations are characterized by increased red blood cell values with inappropriately normal serum EPO levels.
“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 [158]
Several PHD2 missense mutations result in diminished hydroxylase activity.
“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 [158]
The PHD2 mutation H374R is associated with paraganglioma development.
“Furthermore, H374R was associated with paraganglioma development”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [158]
PHD2 may function as a tumor suppressor.
“indicating that PHD2 may functions as a tumor suppressor.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [158]
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- Authors
- Ladroue, C., Hoogewijs, D., Gad, S., Carcenac, R., Storti, F., Barrois, M., Gimenez-Roqueplo, A.-P., Leporrier, M., Casadevall, N., Hermine, O., Kiladjian, J.-J., Baruchel, A., Fakhoury, F., Bressac-de Paillerets, B., Feunteun, J., Mazure, N., Pouyssegur, J., Wenger, R. H., Richard, S., & Gardie, B.
- Affiliations
- Inserm (FR)
- University of Zurich (CH)
- Institut Gustave Roussy (FR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Hôpital Necker-Enfants Malades (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Haematologica
- Published
- 2011-09-20
- Volume
- 97
- Issue
- 1
- Pages
- 9-14
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC3248925
- OpenAlex
- W2064967620
- Cited by
- 55
- References
- 47
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 7 · 2018: 5 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 8 · 2012: 3
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- other-oa
- Locations
- Haematologica (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Institut National Du Cancer
- Commercializations Promotion Agency for R and D Outcomes
- Swiss National Centre of Competence in Research Kidney Control of Homeostasis
- National Cancer Institute
- 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
- prolyl hydroxylase domain 2, hypoxia-inducible factor alpha, polycythemia, von Hippel-Lindau disease, Chuvash polycythemia, germline mutations, paraganglioma, cancer susceptibility, hypoxia signaling
- MeSH terms
- Adolescent, Adult, Base Sequence, Cells, Cultured, Female, Humans, Hydrolysis, Male, Middle Aged, Polycythemia, Procollagen-Proline Dioxygenase, Germ-Line Mutation, Mutant Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Young Adult, HEK293 Cells, Hypoxia-Inducible Factor-Proline Dioxygenases
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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