Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

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

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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 α (HIFα). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1α, reducing the rate of degradation of HIF1α 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).

Original languageEnglish (US)
Pages (from-to)614-621
Number of pages8
JournalNature genetics
Volume32
Issue number4
DOIs
StatePublished - Dec 1 2002

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ASJC Scopus subject areas

  • Genetics

Cite this

Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., Maxwell, P. H., Stockton, D. W., Semenza, G. L., & Prchal, J. T. (2002). Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature genetics, 32(4), 614-621. https://doi.org/10.1038/ng1019