Endemic polycythemia in Russia: mutation in the VHL gene.
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-1 alpha 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-1 alpha), 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-1 alpha resulting in accumulation of HIF-1 alpha, 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.
Ang
Sonny O
SO
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Chen
Hua
H
Gordeuk
Victor R
VR
Sergueeva
Adelina I
AI
Polyakova
Lydia A
LA
Miasnikova
Galina Y
GY
Kralovics
Robert
R
Stockton
David W
DW
Prchal
Josef T
JT
D002893:Chromosomes, Human, Pair 3; D004252:DNA Mutational Analysis; D019353:Endemic Diseases; D004921:Erythropoietin / Q000097:blood; D005192:Family Health; D008040:Genetic Linkage; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D017354:Point Mutation; D011086:Polycythemia / Q000453:epidemiology / Q000235:genetics*; D012426:Russia / Q000453:epidemiology; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D004921:Erythropoietin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human