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

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; Federico Formenti; Fulvio Della Ragione

doi:10.1056/NEJMoa1907362

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

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 BorrielloFederico Formenti, Fulvio Della Ragione

University of Oxford

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Abstract

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.).

Original language	English
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	https://doi.org/10.1056/NEJMoa1907362
Publication status	Published - 27 Feb 2020

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10.1056/NEJMoa1907362

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Perrotta, S., Roberti, D., Bencivenga, D., Corsetto, P., O'Brien, K., Caiazza, M., Stampone, E., Allison, L., Fleck, R., Scianguetta, S., Tartaglione, I., Robbins, P. A., Casale, M., West, J. A., Franzini-Armstrong, C., Friffin, J. L., Rizzo, A. M., Sinisi, A., Murray, A. J., ... Della Ragione, F. (2020). Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria. New England Journal of Medicine, 382(9), 835-844. https://doi.org/10.1056/NEJMoa1907362

@article{4a382b94dca94b83ae717f6cf2bb5634,

title = "Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria",

abstract = "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.).",

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

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day = "27",

doi = "10.1056/NEJMoa1907362",

language = "English",

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Perrotta, S, Roberti, D, Bencivenga, D, Corsetto, P, O'Brien, K, Caiazza, M, Stampone, E, Allison, L, Fleck, R, Scianguetta, S, Tartaglione, I, Robbins, PA, Casale, M, West, JA, Franzini-Armstrong, C, Friffin, JL, Rizzo, AM, Sinisi, A, Murray, AJ, Borriello, A, Formenti, F & Della Ragione, F 2020, 'Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria', New England Journal of Medicine, vol. 382, no. 9, pp. 835-844. https://doi.org/10.1056/NEJMoa1907362

TY - JOUR

T1 - Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria

AU - Perrotta, Silverio

AU - Roberti, Domenico

AU - Bencivenga, Debora

AU - Corsetto, Paola

AU - O'Brien, Katie

AU - Caiazza, Martina

AU - Stampone, Emanuela

AU - Allison, Leanne

AU - Fleck, Roland

AU - Scianguetta, Saverio

AU - Tartaglione, Imma

AU - Robbins, Peter A.

AU - Casale, Maddalena

AU - West, James A.

AU - Franzini-Armstrong, Clara

AU - Friffin, Julian L

AU - Rizzo, Angela M

AU - Sinisi, Antonio

AU - Murray, Andrew J

AU - Borriello, Adriana

AU - Formenti, Federico

AU - Della Ragione, Fulvio

PY - 2020/2/27

Y1 - 2020/2/27

N2 - 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.).

AB - 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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U2 - 10.1056/NEJMoa1907362

DO - 10.1056/NEJMoa1907362

M3 - Article

SN - 1533-4406

VL - 382

SP - 835

EP - 844

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 9

ER -

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

Abstract

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