A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain
Bibliographic record
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".