Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.
Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.
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DOI：
10.1096/fj.10-177378
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Robbins PA
中科院分区：
文献类型：
--
作者：
Formenti F;Beer PA;Croft QP;Dorrington KL;Gale DP;Lappin TR;Lucas GS;Maher ER;Maxwell PH;McMullin MF;O'Connor DF;Percy MJ;Pugh CW;Ratcliffe PJ;Smith TG;Talbot NP;Robbins PA
低氧诱导因子(HIF：亚型HIF-1α、HIF-2α、HIF-3α)介导对低氧的多种反应。它们的调节主要是由氧依赖的降解启动的，这种降解是由特定的脯氨酸残基的羟基化然后与von Hippel-Lindau(VHL)蛋白结合而开始的。丘瓦什红细胞增多症是一种HIF升高的疾病。它是由亚型VHL等位基因的胚系纯合引起的，具有血液学、心肺和代谢异常的表型。这项研究探索了另外两种低氧诱导因子途径疾病的表型：经典的VHL病和低氧诱导因子-2α功能获得突变。经典型VHL病均未检出心肺异常。低氧诱导因子-2α功能获得突变与肺高压、心输出量增加、心率增加和肺通气量增加相关。HIF-2α功能增益反应与丘瓦什红细胞增多症研究数据的比较表明，丘瓦什表型的其他方面减少或缺失。在经典的VHL疾病中，患者是VHL突变的种系杂合子，目前的结果表明，VHL的单个野生型等位基因足以维持正常的心肺功能。HIF-2α功能增益表型可能比Chuvash表型更有限，这是因为在前一种情况下HIF-1α没有升高，或者是因为在丘瓦什红细胞增多症中VHL的其他不依赖于HIF的功能受到干扰。M.J.，Pugh，C.W.，Ratcliffe，P.J.，Smith，T.G.，Talbot，N.P.，Robbins，P.A.在两种低氧诱导因子途径的人类疾病中的心肺功能：von Hippel-Lindau病和HIF-2α功能获得突变。
The hypoxia-inducible factors (HIFs; isoforms HIF-1α, HIF-2α, HIF-3α) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2α gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2α gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2α gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2α gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1α is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia.—Formenti, F., Beer, P. A., Croft, Q. P. P., Dorrington, K. L., Gale, D. P., Lappin, T. R. J., Lucas, G. S., Maher, E. R., Maxwell, P. H., McMullin, M. F., O'Connor, D. F., Percy, M. J., Pugh, C. W., Ratcliffe, P. J., Smith, T. G., Talbot, N. P., Robbins, P. A. Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2α gain-of-function mutation.
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作者：
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DOI：
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发表时间：
2000-03-15
影响因子：
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通讯作者：
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