The thermolabile variant 677C?T can further reduce activity when expressed in CIS with severe mutations for human methylenetetrahydrofolate reductase
Bibliographic record
Abstract
Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for homocysteine remethylation to methionine. Severe MTHFR deficiency is associated with hyperhomocysteinemia and homocystinuria. These patients show a wide variety of neurological and vascular symptoms, with variable age of onset. Residual enzyme activity is usually less than 20% of control values, and correlates reasonably well with age of onset of symptoms. A milder deficiency of MTHFR, with 30%-50% residual enzyme activity and increased enzyme thermolability, has been described as a risk factor for vascular disease and for neural tube defects. In earlier work, we isolated the human cDNA for MTHFR, and reported 14 mutations in severe MTHFR deficiency, as well as a common 677C-->T missense mutation (Ala-->Val) that encodes the thermolabile MTHFR. This variant has also been observed in some patients with severe MTHFR deficiency, in cis with their severe mutations. We report here the in vitro expression of seven severe MTHFR mutations in a bacterial expression system; six of these were expressed in cis with the Val allele to mimic the situation in the patients. We show that three of these constructs have significantly reduced enzyme activity (<10% of control); the presence of the thermolabile variant in these patients in cis is unlikely to affect enzyme function since activity is already low. One mutation causes a dramatic increase in activity when it is expressed in cis with the Ala allele, but is associated with extreme lability when in cis with the Val allele. Three mutations cause moderate decreases in enzyme activity, with a further decrease in activity when they are in cis with the Val allele. We hypothesize that deleterious mutations which alter stability may be compromised to a greater degree when the thermolabile variant is present on the same allele.
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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 | 0.001 | 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) | 0.001 | 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".