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

Research output: Contribution to journalArticle

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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Polycythemia
Homeostasis
Oxygen
von Hippel-Lindau Disease
Hypoxia-Inducible Factor 1
Transferrin Receptors
Facilitative Glucose Transport Proteins
Ubiquitination
Missense Mutation
Transferrin
Erythropoietin
Rivers
Tryptophan
Vascular Endothelial Growth Factor A
Genes
Arginine
Chromosomes
Amino Acids
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., ... Prchal, J. T. (2002). Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genetics, 32(4), 614-621. https://doi.org/10.1038/ng1019

Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. / Ang, Sonny O.; Chen, Hua; Hirota, Kiichi; Gordeuk, Victor R.; Jelinek, Jaroslav; Guan, Yongli; Liu, Enli; Sergueeva, Adelina I.; Miasnikova, Galina Y.; Mole, David; Maxwell, Patrick H.; Stockton, David W.; Semenza, Gregg L; Prchal, Josef T.

In: Nature Genetics, Vol. 32, No. 4, 01.12.2002, p. 614-621.

Research output: Contribution to journalArticle

Ang, SO, Chen, H, Hirota, K, Gordeuk, VR, Jelinek, J, Guan, Y, Liu, E, Sergueeva, AI, Miasnikova, GY, Mole, D, Maxwell, PH, Stockton, DW, Semenza, GL & Prchal, JT 2002, 'Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia', Nature Genetics, vol. 32, no. 4, pp. 614-621. https://doi.org/10.1038/ng1019
Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genetics. 2002 Dec 1;32(4):614-621. https://doi.org/10.1038/ng1019
Ang, Sonny O. ; Chen, Hua ; Hirota, Kiichi ; Gordeuk, Victor R. ; Jelinek, Jaroslav ; Guan, Yongli ; Liu, Enli ; Sergueeva, Adelina I. ; Miasnikova, Galina Y. ; Mole, David ; Maxwell, Patrick H. ; Stockton, David W. ; Semenza, Gregg L ; Prchal, Josef T. / Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. In: Nature Genetics. 2002 ; Vol. 32, No. 4. pp. 614-621.
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