Tibetan PHD2, an allele with loss-of-function properties
Tibetan PHD2, an allele with loss-of-function properties
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DOI：
10.1073/pnas.1920546117
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发表时间：
2020-06-02
影响因子：
11.1
通讯作者：
Lee, Frank S.
中科院分区：
文献类型：
--
作者：
Song, Daisheng;Navalsky, Bradleigh E.;Lee, Frank S.
全基因组研究一致发现，在缺氧诱导因子途径的两个基因PHD2和HIF2A中，自然选择的遗传特征令人信服。前者的产物引起后者产物的降解。在这里，我们报道了Asp-4或Cys-127位点或附近的额外PHD2突变会损害体外与p23的相互作用。这种现象在p23突变的小鼠中被表型复制，该突变消除了PHD2:p23的相互作用。
Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, PHD2 and HIF2A. The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan PHD2 are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan PHD2 is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan Phd2 allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in p23 that abrogates the PHD2:p23 interaction. Hif2a haploinsufficiency, but not the Tibetan Phd2 allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan Phd2 allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.