Pathogenicity of two <i>COQ7</i> mutations and responses to 2,4‐dihydroxybenzoate bypass treatment
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Bibliographic record
Abstract
Primary ubiquinone (co-enzyme Q) deficiency results in a wide range of clinical features due to mitochondrial dysfunction. Here, we analyse and characterize two mutations in the ubiquinone biosynthetic gene COQ7. One mutation from the only previously identified patient (V141E), and one (L111P) from a 6-year-old girl who presents with spasticity and bilateral sensorineural hearing loss. We used patient fibroblast cell lines and a heterologous expression system to show that both mutations lead to loss of protein stability and decreased levels of ubiquinone that correlate with the severity of mitochondrial dysfunction. The severity of L111P is enhanced by the particular COQ7 polymorphism (T103M) that the patient carries, but not by a mitochondrial DNA mutation (A1555G) that is also present in the patient and that has been linked to aminoglycoside-dependent hearing loss. We analysed treatment with the unnatural biosynthesis precursor 2,4-dihydroxybenzoate (DHB), which can restore ubiquinone synthesis in cells completely lacking the enzymatic activity of COQ7. We find that the treatment is not beneficial for every COQ7 mutation and its outcome depends on the extent of enzyme activity loss.
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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