ArticleThe Journal of experimental medicine2025
A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain.
Article in The Journal of experimental medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- A framework to infer de novo exonic variants when parental genotypes are missing enhances association studies of autism.Bioinformatics (Oxford, England) · 2026Article
- Pharmacological inhibition of NaV1.8 by suzetrigine reveals potent analgesic potential without tolerance development in mice.Molecular brain · 2025Article
- Degradation of voltage-gated calcium channels: mechanisms and applications in neurological and cardiovascular diseases.Cell communication and signaling : CCS · 2025Review
- CRISPR helps to show why a boy felt no pain.Nature · 2025Article
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12 authors.
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Abstract
Cav3.2 T-type calcium channels and their dysregulation by the deubiquitinase USP5 contribute to development of inflammatory and neuropathic pain. 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.
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