Copper-dependent trafficking of Wilson disease mutant ATP7B proteins
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Bibliographic record
Abstract
We have previously developed a functional assay in yeast for the copper transporter, ATP7B, defective in Wilson disease (WND). Analysis of WND variant ATP7B proteins revealed that several were able to completely, or nearly completely, complement a mutant yeast strain in which the ATP7B ortholog CCC2 was disrupted, indicating that these ATP7B proteins retained copper transport activity. We analyzed the intracellular localization of these active WND ATP7B variant proteins using transient transfection of Chinese hamster ovary cells and triple-label immunofluorescence microscopy, as a second possible aspect of defective function. Two ATP7B variants, Asp765Asn and Leu776Val, which have normal copper transport activity in yeast, retained partial normal Golgi network localization, but were predominantly mislocalized throughout the cell. Asp765Asn and Leu776Val proteins were capable of only partial copper-dependent redistribution. WND variant protein Arg778Leu, which has defective function in yeast, was extensively mislocalized, presumably to the endoplasmic reticulum. ATP7B variant proteins Gly943Ser, which has nearly normal function in yeast, and CysProCys/Ser (mutation of the conserved CysProCys motif to SerProSer), inactive in yeast, were localized normally but were unable to redistribute in response to copper. Localization data from this study, combined with functional data from our yeast studies, provide a biochemical mechanism that can explain in part the variable biochemical features of WND, in particular the normal holo-ceruloplasmin levels observed in some patients. Our data have direct implications for WND diagnosis, indicating that decreased serum ceruloplasmin concentration is not likely to be observed with certain genetic variants of WND.
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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 it