Regular Article
Endemic Polycythemia in Russia: Mutation in the VHL Gene,☆☆

https://doi.org/10.1006/bcmd.2002.0488Get rights and content

Abstract

ABSTRACT

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 families 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-1α 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-1α), 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-1α resulting in accumulation of HIF-1α, 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.

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This work was supported by Grants R01HL66333-01, R01HL5007-08 NHLBI, and UH1 HL03679-03 from the National Heart, Lung, and Blood Institute, National Institutes of Health (Bethesda, MD).

☆☆

Communicated by E. Beutler, M.D., 01/28/02

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Correspondence and reprint requests to: J. Prchal, Baylor College of Medicine, One Baylor Plaza, Suite 802E, Houston, TX 77030. Fax: 713-798-6132. E-mail: [email protected].

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Both authors contributed equally and should be considered first authors.

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