Research output: Contribution to journal › Article › peer-review
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
Original language | English |
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Pages (from-to) | 835-844 |
Number of pages | 10 |
Journal | New England Journal of Medicine |
Volume | 382 |
Issue number | 9 |
Early online date | 27 Feb 2020 |
DOIs | |
Accepted/In press | 6 Nov 2019 |
E-pub ahead of print | 27 Feb 2020 |
Published | 27 Feb 2020 |
Additional links |
Effects of Germline VHL_PERROTTA_Publishedonline27February2020_GREEN VoR
Effects_of_Germline_VHL_PERROTTA_Publishedonline27February2020_GREEN_VoR.pdf, 381 KB, application/pdf
Uploaded date:04 Mar 2020
Version:Final published version
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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