Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
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DOI：
10.1038/ng1019
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发表时间：
2002-12-01
期刊：
影响因子：
30.8
通讯作者：
Prchal, JT
中科院分区：
文献类型：
--
作者：
Ang, SO;Chen, H;Prchal, JT
楚瓦什红细胞增多症是一种常染色体隐性遗传病，是伏尔加河中游地区的地方病。我们之前将与楚瓦什红细胞增多症相关的基因座定位到染色体 3p25。与 von Hippel-Lindau 综合征 (VHL) 相关的基因映射到该区域，并且在所有楚瓦什红细胞增多症患者中均发现了 VHL 中 C-->T 错义突变的纯合性，该突变导致氨基酸残基 200 (Arg200Trp) 处精氨酸变为色氨酸。蛋白质 VHL 调节缺氧诱导因子 1、α 亚基 (HIF1α) 的泛素化和随后的破坏。我们的数据表明，Arg200Trp 取代损害了 VHL 与 HIF1α 的相互作用，降低了 HIF1α 的降解率，并导致下游靶基因的表达增加，包括 EPO（编码促红细胞生成素）、SLC2A1（也称为 GLUT1，编码溶质载体家族 2（易化葡萄糖转运蛋白），成员 1）、TF （编码转铁蛋白）、TFRC（编码转铁蛋白受体（p90、CD71））和 VEGF（编码血管内皮生长因子）。
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).