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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 α (HIF1α). 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).

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Figure 1: Positional cloning.
Figure 2: Response of erythroid progenitors from individuals affected with Chuvash polycythemia to erythropoietin.
Figure 3: Effect of Arg200Trp substitution on VHL function.
Figure 4: Analysis of HIF1-dependent reporter gene expression.
Figure 5: Expression of endogenous HIF1 target genes.

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Acknowledgements

This work was supported by grants from the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health. The authors would like to thank W. Kaelin for providing 786-O cells.

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Correspondence to Josef T. Prchal.

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Ang, S., Chen, H., Hirota, K. et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32, 614–621 (2002). https://doi.org/10.1038/ng1019

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