Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria
Bibliographic record
Abstract
The methylmalonic acidurias are metabolic disorders resulting from deficient methylmalonyl-CoA mutase activity, a vitamin B(12)-dependent enzyme. We have cloned the gene for the cblB complementation group caused by deficient activity of a cob(I)alamin adenosyltransferase. This was accomplished by searching bacterial genomes for genes in close proximity to the methylmalonyl-CoA mutase gene that might encode a protein with the properties of an adenosyltransferase. A candidate was identified in the Archaeoglobus fulgidus genome and was used to probe the human genome database. It yielded a gene on chromosome 12q24 that encodes a predicted protein of 250 amino acids with 45% similarity to PduO in Salmonella enterica, a characterized cob(I)alamin adenosyltransferase. A northern blot revealed an RNA species of 1.1 kb predominating in liver and skeletal muscle. The gene was evaluated for deleterious mutations in cblB patient cell lines. Several mutations were identified including a 5 bp deletion (5del572gggcc576), two splice site mutations (IVS2-1G>T, IVS3-1G>A), andt several point mutations (A135T, R186W, R191W and E193K). Two additional amino acid substitutions (R19Q and M239K) were found in several patient cell lines but were found to be common polymorphisms (36% and 46%) in control alleles. The R186W mutation, which we suggest is disease-linked, is present in four of the six patient cell lines examined (homoallelic in two) and in 4 of 240 alleles in control samples. These data confirm that the identified gene, MMAB, corresponds to the cblB complementation group and has the appearance of a cob(I)alamin adenosyltransferase, as predicted from biochemical data.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".