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Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria

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Silverio Perrotta, Domenico Roberti, Debora Bencivenga, Paola Corsetto, Katie O'Brien, Martina Caiazza, Emanuela Stampone, Leanne Allison, Roland Fleck, Saverio Scianguetta, Imma Tartaglione, Peter A. Robbins, Maddalena Casale, James A. West, Clara Franzini-Armstrong, Julian L Friffin, Angela M Rizzo, Antonio Sinisi, Andrew J Murray, Adriana Borriello & 2 more Federico Formenti, Fulvio Della Ragione

Original languageEnglish
Pages (from-to)835-844
Number of pages10
JournalNew England Journal of Medicine
Issue number9
Early online date27 Feb 2020
Accepted/In press6 Nov 2019
E-pub ahead of print27 Feb 2020
Published27 Feb 2020


King's Authors


Mutations 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.).

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