Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3
Bibliographic record
Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS.
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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".