Impact of disease-causing missense mutations on the structure and function of PHEX
Bibliographic record
Abstract
X-linked hypophosphatemia (XLH), the most prevalent form of inherited rickets in humans, is caused by mutations in the PHEX gene, which encodes a protein with high homology to the M13 family of type-II integral membrane zinc metallopeptidases. We created an online mutation database, PHEXdb (http://data.mch.mcgill.ca/phexdb), to catalogue PHEX mutations identified in XLH patients, and found that missense mutations account for 22% of the 157 mutations reported to date. We also undertook to examine the effects of eight missense mutations (C85R, D237G, Y317F, G579R, G579V, S711R, A720T, and F731Y) on synthesis, glycosylation, cellular trafficking, and catalytic activity of the recombinant proteins using several approaches. The wild-type protein was resistant to endoglycosidase H (endo H), indicating that it is fully glycosylated. In addition, biotinylation and immunofluorescence studies revealed that the wild-type protein resides at the cell surface. The D237G, Y317F and F731Y mutant PHEX proteins were also endo H resistant and thus terminally glycosylated. In contrast, endo H digestion demonstrated that C85R, G579R, G579V, S711R and A720T were not terminally glycosylated. Furthermore, immunofluorescence showed that C85R, G579R and S711R were sequestered in the endoplasmic reticulum (ER). A secreted form of wild-type and mutant PHEX (secPHEX) proteins was generated to examine catalytic activity, using a synthetic fluorogenic peptide substrate. For this purpose, rescue of ER-trapped mutant proteins was attempted by growing transfected cells at 26°C. Low temperature was able to rescue three of the five trapped mutant proteins (G579V, S711R and A720T). Residual catalytic activity was observed with four mutant proteins (D237G, Y317F, A720T and F731Y) relative to the wild-type. However, the rescued S711R mutant was devoid of catalytic activity. Finally, limited proteolysis with trypsin and endoproteinase Glu-c revealed that the mutations D237G and F731Y induce conform
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 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 | 0.000 |
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".