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

doi:10.1038/ng1019

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

400 Scopus citations

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 language	English (US)
Pages (from-to)	614-621
Number of pages	8
Journal	Nature genetics
Volume	32
Issue number	4
DOIs	https://doi.org/10.1038/ng1019
State	Published - Dec 1 2002

ASJC Scopus subject areas

Genetics

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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 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).",

author = "Ang, {Sonny O.} and Hua Chen and Kiichi Hirota and Gordeuk, {Victor R.} and Jaroslav Jelinek and Yongli Guan and Enli Liu and Sergueeva, {Adelina I.} and Miasnikova, {Galina Y.} and David Mole and Maxwell, {Patrick H.} and Stockton, {David W.} and Semenza, {Gregg L.} and Prchal, {Josef T.}",

note = "Funding Information: 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.",

year = "2002",

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doi = "10.1038/ng1019",

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T1 - Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

AU - Ang, Sonny O.

AU - Chen, Hua

AU - Hirota, Kiichi

AU - Gordeuk, Victor R.

AU - Jelinek, Jaroslav

AU - Guan, Yongli

AU - Liu, Enli

AU - Sergueeva, Adelina I.

AU - Miasnikova, Galina Y.

AU - Mole, David

AU - Maxwell, Patrick H.

AU - Stockton, David W.

AU - Semenza, Gregg L.

AU - Prchal, Josef T.

N1 - Funding Information: 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.

PY - 2002/12/1

Y1 - 2002/12/1

N2 - 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).

AB - 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).

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Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

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