Functional recovery of AQP2 recessive mutations through hetero‐oligomerization with wild‐type counterpart (1133.2)
Bibliographic record
Abstract
Mutations in Aquaporin‐2 (AQP2) induce nephrogenic diabetes insipidus (NDI), a water reabsorption defect of the kidney challenging water homeostasis. While the accepted NDI model claims that recessive (rec) mutations are misfolded and monomeric by nature, the partial activity (Pf= 15‐25% of wt‐AQP2) found with some mutations (D150E, V24A) challenges this notion, and even suggest the presence for mixed wt/rec heteromers in heterozygotes. We have tested this hypothesis in Xenopus oocytes and showed that not only do wt/rec associate (co‐IP assays), but activity of the rec‐AQP2 mutant is shown to be mostly restored (63‐100% of wt‐AQP2) in the process. Also, using bidirectional vectors for dual transfection in cell lines, we find a recovery of targeting for rec‐AQP2 when in presence of wt‐AQP2. Finally, the negative results found when analyzing the strictly monomeric R187C mutant support the notion that the functional recovery of (at least some) rec‐AQP2 mutants is secondary to wt/rec heteromerization. In conclusion, we show that recessive mutations may be functionally recovered through wt/rec oligomerization, contributing to the overall activity in heterozygotes, a notion which could be relevant to all homomeric proteins.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".