Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.

Abstract	Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel-Lindau syndrome, VHL, maps to this region, and homozygosity with respect to a C-->T missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein VHL modulates the ubiquitination and subsequent destruction of hypoxia-inducible factor 1, subunit alpha (HIF1alpha). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1alpha, reducing the rate of degradation of HIF1alpha and resulting in increased expression of downstream target genes including EPO (encoding erythropoietin), SLC2A1 (also known as GLUT1, encoding solute carrier family 2 (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular endothelial growth factor).
Authors	Sonny O Ang, Hua Chen, Kiichi Hirota, Victor R Gordeuk, Jaroslav Jelinek, Yongli Guan, Enli Liu, Adelina I Sergueeva, Galina Y Miasnikova, David Mole, Patrick H Maxwell, David W Stockton, Gregg L Semenza, Josef T Prchal
Journal	Nature genetics (Nat Genet) Vol. 32 Issue 4 Pg. 614-21 (Dec 2002) ISSN: 1061-4036 [Print] United States
PMID	12415268 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	DNA-Binding Proteins HIF1A protein, human Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Receptors, Transferrin Transcription Factors Transferrin Tumor Suppressor Proteins Ubiquitins Erythropoietin Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein Ligases VHL protein, human Oxygen
Topics	Adolescent Adult Alleles Amino Acid Substitution Cells, Cultured Chromosomes, Human, Pair 3 DNA-Binding Proteins (chemistry, metabolism) Erythropoietin (blood, genetics) Female Gene Expression Regulation Gene Frequency Germ-Line Mutation Haplotypes Homeostasis Homozygote Humans Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Ligases (genetics, metabolism) Male Mutation, Missense Nuclear Proteins (chemistry, metabolism) Oxygen (metabolism) Pedigree Polycythemia (etiology, genetics, metabolism) Protein Binding Receptors, Transferrin (blood, genetics) Russia Transcription Factors (genetics, metabolism) Transferrin (analysis, genetics) Tumor Cells, Cultured Tumor Suppressor Proteins Ubiquitin-Protein Ligases Ubiquitins (metabolism) Von Hippel-Lindau Tumor Suppressor Protein von Hippel-Lindau Disease (genetics)

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