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Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: insights into the enzyme's activity, stability, and allosteric modulation

Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examine...

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Main Authors: Korchak, Emilie J. (Author) , Sharafi, Mona (Author) , Jaen Maisonet, Isabella (Author) , Salazar-Chaparro, Andres (Author) , Semenova, Irina V. (Author) , Khan, Hamza (Author) , O’Neil, Alison L. (Author) , Caro, Pilar (Author) , Schaaf, Christian P. (Author) , Buhrlage, Sara J. (Author) , Bezsonova, Irina (Author)
Format: Article (Journal)
Language:English
Published: September 22, 2025
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2025, Volume: 122, Issue: 39, Pages: 1-10
ISSN:1091-6490
DOI:10.1073/pnas.2510252122
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1073/pnas.2510252122
Verlag, kostenfrei, Volltext: https://www.pnas.org/doi/10.1073/pnas.2510252122
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Author Notes:Emilie J. Korchak, Mona Sharafi, Isabella Jaen Maisonet, Andres Salazar-Chaparro, Irina V. Semenova, Hamza Khan, Alison L. O'Neil, Pilar Caro, Christian P. Schaaf, Sara J. Buhrlage, and Irina Bezsonova
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Summary:Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme’s activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.
Item Description:Gesehen am 12.02.2026
Physical Description:Online Resource
ISSN:1091-6490
DOI:10.1073/pnas.2510252122

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