title: 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.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sonny O
authors.initials: SO
authors.lastname: Ang
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guan
authors.forename: Enli
authors.initials: E
authors.lastname: Liu
authors.forename: Adelina I
authors.initials: AI
authors.lastname: Sergueeva
authors.forename: Galina Y
authors.initials: GY
authors.lastname: Miasnikova
authors.forename: David
authors.initials: D
authors.lastname: Mole
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: David W
authors.initials: DW
authors.lastname: Stockton
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006239:Haplotypes; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010375:Pedigree; D011086:Polycythemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000097:blood / Q000235:genetics; D012426:Russia; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000032:analysis / Q000235:genetics; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011990:Receptors, Transferrin; D014157:Transcription Factors; D014168:Transferrin; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; D004921:Erythropoietin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human; D010100:Oxygen