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We report on a pediatric patient with a de novo heterozygous missense mutation R24W in USP5 who exhibits pain insensitivity. We created a CRISPR knock-in mouse harboring this mutation and performed detailed behavioral analyses in acute and chronic pain models. Heterozygous R24W mice of both sexes are resistant to acute pain and to thermal hypersensitivity in chronic inflammatory and neuropathic pain models. In contrast, only male R24W mice confer resistance to development of mechanical hypersensitivity. R24W mice lack upregulation of Cav3.2 and USP5 that is normally observed with CFA-induced inflammation. Moreover, mutant USP5 exhibits a dramatic reduction in enzymatic activity but stronger interactions with Cav3.2. Hence, R24W mutant USP5 is a critical regulator of chronic and acute pain states in humans by acting as a dominant-negative regulator of Cav3.2. Our data validate USP5 as a potential therapeutic target for chronic pain in humans.<\/jats:p>","DOI":"10.1084\/jem.20241877","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T02:20:47Z","timestamp":1745374847000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0620-2984","authenticated-orcid":true,"given":"Flavia T.T.","family":"Antunes","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03yjb2x39","id-type":"ROR","asserted-by":"publisher"}],"name":"Hotchkiss Brain Institute and Alberta Children\u2019s Hospital Research Institute, Cumming School of Medicine, University of Calgary 1 Department of Clinical Neurosciences, , 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