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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3924-3932. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-07-2535. This Article Full Text (PDF) All Versions of this Article: 2003-07-2535v1 103/10/3924    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gordeuk, V. R Articles by Polyakova, L. A Search for Related Content PubMed PubMed Citation Articles by Gordeuk, V. R Articles by Polyakova, L. A Social Bookmarking                   What's this? Submitted July 28, 2003 Accepted January 5, 2004 Congenital disorder of oxygen-sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors Victor R Gordeuk*, Adelina I Sergueeva, Galina Y Miasnikova, Daniel Okhotin, Yaroslav Voloshin, Peter L Choyke, John A Butman, Katerina Jedlickova, Josef T Prchal, and Lydia A Polyakova Center for Sickle Cell Disease and Medicine, Howard University, Washington, DC, USA Pediatrics, Cheboksary Children's Hospital, Cheboksary, Chuvashia, Russian Federation Medicine, Chuvash Republic Clinical Hospital No. 1, Cheboksary, Chuvashia, Russian Federation Russian Research Services, San Diego, CA, USA Diagnostic Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA Medicine, Baylor University, Houston, TX, USA * Corresponding author; email: vgordeuk{at}howad.edu. 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. While endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1 (HIF-1), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures and elevated serum vascular endothelial growth factor (VEGF) concentrations (P<0.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL were not found, suggesting that overexpression of HIF-1 and VEGF is not sufficient for tumorigenesis. While hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL598C>T homozygotes than 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. M. Cohen, R. D. Storer, K. A. Criswell, N. G. Doerrer, V. L. Dellarco, D. G. Pegg, Z. W. Wojcinski, D. E. Malarkey, A. C. Jacobs, J. E. Klaunig, et al. Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance Toxicol. Sci., September 1, 2009; 111(1): 4 - 18. 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