Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis
Bibliographic record
Abstract
Mutations in the human NPHP5 gene cause retinal and renal disease, but the precise mechanism by which NPHP5 functions is not understood. We report that NPHP5 is a centriolar protein whose depletion inhibits an early step of ciliogenesis, a phenotype reminiscent of Cep290 loss and contrary to IFT88 loss. Functional dissection of NPHP5 interactions with Cep290 and CaM reveals a requirement of the former for ciliogenesis, while the latter prevents NPHP5 self-aggregation. Disease-causing mutations lead to truncated products unable to bind Cep290 and localize to centrosomes, thereby compromising cilia formation. In contrast, a modifier mutation cripples CaM binding but has no overt effect on ciliogenesis. Drugs that antagonize negative regulators of the ciliogenic pathway can rescue ciliogenesis in cells depleted of NPHP5, with response profiles similar to those of Cep290- but not IFT88-depleted cells. Our results uncover the underlying molecular basis of disease and provide novel insights into mitigating NPHP5 deficiency.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".