Human V-ATPase a2 P405L Mutation Results in Cutis Laxa by Affecting V-ATPase Assembly and/or Stability
Bibliographic record
Abstract
Cutis Laxa is a genetic disorder in which a patient’s skin becomes loose and inelastic. The autosomal recessive variant of this disorder has been linked to a genetic mutation in vacuolar-type H+-ATPase (V-ATPase). This enzyme contains a cytosolic domain, responsible for hydrolyzing ATP, and a membrane-bound domain that actively transports protons across intracellular and plasma membranes. Proton pumping regulates housekeeping functions inside the cell, resorption of bone, and acidification of urine. A human missense mutation in one of the V-ATPase subunits (a2 P405L) that causes Cutis Laxa was recreated in the yeast V-ATPase to elucidate why a single amino acid change could affect enzyme activity. The mutation recreated in the yeast V-ATPase disrupted activity based on the inability of yeast to acidify their vacuoles. The membrane domain of the mutant V-ATPase was correctly assembled and targeted to the yeast vacuole but the cytosolic domain was not attached explaining why the vacuoles were not acidic. These results suggest that the loss-of-function mutation present in cutis laxa leads to decreased V-ATPase stability and/or assembly. Further experiments will be designed to assess if the mutation results in a conformational defect, and if so, therapeutics assisting in protein folding can be explored. Such therapeutics not only hold promise for cutis laxa, but also for other V-ATPase genetic diseases such as osteopetrosis, distal renal tubular acidosis and male sterility.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".