Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.
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).
Ang
Sonny O
SO
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Chen
Hua
H
Hirota
Kiichi
K
Gordeuk
Victor R
VR
Jelinek
Jaroslav
J
Guan
Yongli
Y
Liu
Enli
E
Sergueeva
Adelina I
AI
Miasnikova
Galina Y
GY
Mole
David
D
Maxwell
Patrick H
PH
Stockton
David W
DW
Semenza
Gregg L
GL
Prchal
Josef T
JT
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
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