Journal
BLOOD CELLS MOLECULES AND DISEASES
Volume 28, Issue 1, Pages 57-62Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/bcmd.2002.0488
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Funding
- NHLBI NIH HHS [R01HL5007-08, R01HL66333-01, UH1 HL03679-03] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [UH1HL003679, R01HL066333] Funding Source: NIH RePORTER
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Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash fan-dlies which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1alpha resulting in accumulation of HIF-1alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis. (C) 2002 Elsevier Science (USA).
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