Molecular Determinants of Heritable Vitamin E Deficiency
Bibliographic record
Abstract
Tocopherol transfer protein (TTP) is a key regulator of vitamin E homeostasis. TTP is presumed to function by transporting the hydrophobic vitamin between cellular compartments, thus facilitating its secretion to the extracellular space. Indeed, recombinant TTP demonstrates marked ability to facilitate tocopherol transfer between lipid bilayers. We report the biochemical characterization of six missense mutations TTP(1) that are found in human AVED patients. We expressed the H101Q, A120T, R192H, R59W, E141K, and R221W TTP mutants in Escherichia coli, and purified the proteins to homogeneity. We then characterized TTP and its mutant counterparts with respect to their affinity for RRR-alpha-tocopherol and to their ability to catalyze tocopherol transfer between membranes. We observe the R59W, E141K, and R221W mutations, associated with the severe, early-onset version of AVED, are impaired in tocopherol binding and transfer activity. Surprisingly, despite the profound clinical effect of the R59W, E141K, and R221W mutations in vivo, their impact on TTP activity in vitro is quite benign (2-3-fold reduction in transfer kinetics). Furthermore, mutations associated with milder forms of the AVED disease, while causing pronounced perturbations in tocopherol homeostasis in vivo, are remarkably similar to the wild-type protein in the tocopherol transfer assays in vitro. Our data indicate that tocopherol transfer activity in vitro does not properly recapitulate the physiological functions of TTP. These findings suggest the possibility that the AVED syndrome may not arise from an inability of TTP to bind or to transfer alpha tocopherol, but rather from defects in other activities of the protein.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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 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".