Talbot Nick P, Smith Thomas G, Balanos George M, Dorrington Keith L, Maxwell Patrick H, Robbins Peter A
Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
School of Sport, Exercise and Rehabilitation Science, University of Birmingham, Birmingham, United Kingdom.
Physiol Rep. 2017 Apr;5(7). doi: 10.14814/phy2.13224.
Oxygen-dependent regulation of the erythropoietin gene is mediated by the hypoxia-inducible factor (HIF) family of transcription factors. When oxygen is plentiful, HIF undergoes hydroxylation by a family of oxygen-dependent prolyl hydroxylase domain (PHD) proteins, promoting its association with the von Hippel-Lindau (VHL) ubiquitin E3 ligase and subsequent proteosomal degradation. When oxygen is scarce, the PHD enzymes are inactivated, leading to HIF accumulation and upregulation not only of erythropoietin expression, but also the expression of hundreds of other genes, including those coordinating cardiovascular and ventilatory adaptation to hypoxia. Nevertheless, despite the identification of over 50 mutations in the PHD-HIF-VHL pathway in patients with previously unexplained congenital erythrocytosis, there are very few reports of associated cardiopulmonary abnormalities. We now report exaggerated pulmonary vascular and ventilatory responses to acute hypoxia in a 35-year-old man with erythrocytosis secondary to heterozygous mutation in , the most abundant of the PHD isoforms. We compare this phenotype with that reported in patients with the archetypal disorder of cellular oxygen sensing, Chuvash polycythemia, and discuss the possible clinical implications of our findings, particularly in the light of the emerging role for small molecule PHD inhibitors in clinical practice.
促红细胞生成素基因的氧依赖性调节由转录因子缺氧诱导因子（HIF）家族介导。当氧气充足时，HIF会被一族氧依赖性脯氨酰羟化酶结构域（PHD）蛋白进行羟基化，促进其与冯希佩尔-林道（VHL）泛素E3连接酶结合，随后被蛋白酶体降解。当氧气稀缺时，PHD酶失活，导致HIF积累，不仅促红细胞生成素表达上调，数百个其他基因的表达也上调，包括那些协调心血管和通气对缺氧适应的基因。然而，尽管在先前不明原因的先天性红细胞增多症患者中已鉴定出PHD-HIF-VHL途径中的50多个突变，但相关心肺异常的报道却很少。我们现在报告一名35岁男性因最丰富的PHD亚型杂合突变继发红细胞增多症，其对急性缺氧的肺血管和通气反应过度。我们将这种表型与细胞氧感应原型疾病楚瓦什红细胞增多症患者的表型进行比较，并讨论我们研究结果可能的临床意义，特别是鉴于小分子PHD抑制剂在临床实践中日益重要的作用。
