• Silverio Perrotta, Domenico Roberti, Debora Bencivenga, Paola Corsetto, Katie A O'Brien, Martina Caiazza, Emanuela Stampone, Leanne Allison, Roland A Fleck, Saverio Scianguetta, Immacolata Tartaglione, Peter A Robbins, Maddalena Casale, James A West, Clara Franzini-Armstrong, Julian L Griffin, Angela M Rizzo, Antonio A Sinisi, Andrew J Murray, Adriana Borriello, Federico Formenti, and Fulvio Della Ragione.
• 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.).
• N. Engl. J. Med. 2020 Feb 27; 382 (9): 835-844.

AbstractMutations in VHL, 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.).Copyright © 2020 Massachusetts Medical Society.

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