biostudies-literatureKorchak EJHelen Gurley Brown Foundation and Jean Strouse Sharf and Lisa Sharf Green Cancer Research FundHHS | NIH | National Institute of General Medical SciencesNINDS NIH HHSHHS | NIHHHS | NIH (NIH)HHS | NIH | National Institute of General Medical Sciences (NIGMS)NIGMS NIH HHSFoundation for USP7-Related Diseasee2510252122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12501124biostudies-literatureUnknown122(39)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 inProceedings of the National Academy of Sciences of the United States of AmericaFunctional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation.PMC12501124R35GM128864N/AR35 GM128864R21 NS135343R35GM156397R35 GM156397R21NS135343Khan HJaen Maisonet IKorchak EJSchaaf CPBezsonova ISalazar-Chaparro ACaro PSemenova IVO'Neil ALBuhrlage SJSharafi MfalseFunctional 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 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 in2025-01-01T00:00:00Z2025 Sep2026-07-15T14:33:31.147Z2026-07-06T03:08:36.755ZS-EPMC125011244098268610.1073/pnas.2510252122