Functional studies of human variants in <i>C. elegans</i> link iron metabolism to DPD deficiency and 5-FU sensitivity
Bibliographic record
Abstract
Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD, is a key enzyme in pyrimidine catabolism, and its deficiency leads to severe toxicity in patients treated with 5-fluorouracil (5-FU). While pathogenic DPYD variants account for many cases of DPD deficiency, they do not fully explain all instances of 5-FU sensitivity, suggesting additional genetic factors are involved. Recent studies have implicated variants in CIAO1, a gene encoding a subunit of the cytosolic iron-sulfur (Fe-S) cluster assembly targeting complex, in reducing DPD stability and function. In this study, we established a C. elegans model to assess DPD deficiency and 5-FU sensitivity. Using a dpyd-1 knockout and CRISPR-generated ciao-1 variants that mirror patient-derived variants (p.Trp184Cys, p.His193Tyr, and p.Arg65Trp), we provide the first in vivo evidence that pathogenic variants in CIA complex components can lead to DPD deficiency and, consequently, heightened 5-FU toxicity. Our findings highlight the critical role of CIAO1 in DPD function and 5-FU tolerance, expanding the genetic landscape of DPD deficiency and offering a robust platform for functional evaluation of pathogenic variants.
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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".