Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors
Abstract
Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C>T) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1α (HIF-1α), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL 598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P < .0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1α and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL 598C>T homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.
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Self-citation
- Authors
- Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Butman, J. A., Jedlickova, K., Prchal, J. T., & Polyakova, L. A.
- Affiliations
- National Institutes of Health (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2004-05-15
- Volume
- 103
- Issue
- 10
- Pages
- 3924-3932
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1979891446
- Cited by
- 273
- References
- 43
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 18 · 2021: 13 · 2020: 10 · 2019: 10 · 2018: 9 · 2017: 9 · 2016: 15 · 2015: 13 · 2014: 6 · 2013: 14 · 2012: 15
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Digital Howard (Howard University) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL5007-09, UH1-HL03679-05, UH1HL003679, R01HL066333, R01HL66333-01)
- National Center for Research Resources (M01RR010284, M01-RR10284)
- 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
- Chuvash polycythemia, von Hippel-Lindau gene, hypoxia sensing, HIF-1α, erythropoietin, thrombosis, vertebral hemangioma, varicose veins, vascular endothelial growth factor, hypoxia adaptation, von Hippel-Lindau disease
- MeSH terms
- Adaptation, Physiological, Adolescent, Adult, Hypoxia, Child, Cross-Sectional Studies, Female, Homozygote, Humans, Male, Mutation, Neoplasms, Polycythemia, Retrospective Studies, Russia, Syndrome, Thrombosis, Transcription Factors, Vascular Diseases, Survival Rate, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor A, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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