种系 VHL 缺陷对生长、代谢和线粒体的影响。
Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria.
机构信息
From the Departments of Woman, Child, and General and Specialized Surgery (S.P., D.R., M. Caiazza, S.S., I.T., M. Casale), Precision Medicine (D.B., E.S., A.B., F.D.R.), and Advanced Medical and Surgical Sciences (A.A.S.), University of Campania Luigi Vanvitelli, Naples, and the Departments of Pharmacology and Biomolecular Science, University of Milan, Milan (P.C., A.M.R.) - both in Italy; the Departments of Physiology, Development, and Neuroscience (K.A.O., A.J.M.) and Biochemistry (J.A.W., J.L.G.), University of Cambridge, Cambridge, the Centre for Ultrastructural Imaging (L.A., R.A.F.) and the Centre for Human and Applied Physiological Sciences, Faculty of Life Sciences and Medicine (F.F.), King's College London, London, and the Department of Physiology, Anatomy, and Genetics (P.A.R., F.F.) and Nuffield Division of Anaesthetics (F.F.), University of Oxford, Oxford - all in the United Kingdom; and the Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia (C.F.-A.).
出版信息
N Engl J Med. 2020 Feb 27;382(9):835-844. doi: 10.1056/NEJMoa1907362.
Mutations in , which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).
编码 von Hippel-Lindau 肿瘤抑制因子 (VHL) 的 基因突变与多种疾病有关。我们描述了一名患者，其患有明显的红细胞增多症和明显的线粒体改变，这与由于纯合性新型同义突变 (c.222C→A，p.V74V) 导致的严重种系 VHL 缺乏有关。该疾病的特点是全身性早期发病，与 Chuvash 红细胞增多症 (c.598C→T) 不同，它与生长速度明显降低、持续低血糖和有限的运动能力有关。我们报告了基因表达的变化，这些变化重新编程了碳水化合物和脂质代谢，损害了肌肉线粒体呼吸功能，并使氧消耗与 ATP 产生脱耦联。此外，我们还发现了不寻常的线粒体间连接管。我们的发现增加了关于 VHL-缺氧诱导因子 (HIF) 轴对人类表型重要性的意外信息。（由意大利癌症研究协会和其他机构资助）。
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