A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia
Bibliographic record
Abstract
Mutations in the mitochondrial aminoacyl-tRNA synthetases (ARSs) are associated with a strikingly broad range of clinical phenotypes, the molecular basis for which remains obscure. Here, we report a novel missense mutation (c.137G>A, p.Gly46Asp) in the catalytic domain of YARS2, which codes for the mitochondrial tyrosyl-tRNA synthetase, in a subject with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). YARS2 was undetectable by immunoblot analysis in subject myoblasts, resulting in a generalized mitochondrial translation defect. Retroviral expression of a wild-type YARS2 complementary DNA completely rescued the translation defect. We previously demonstrated that the respiratory chain defect in this subject was only present in fully differentiated muscle, and we show here that this likely reflects an increased requirement for YARS2 as muscle cells differentiate. An additional, heterozygous mutation was detected in TRMU/MTU1, a gene encoding the mitochondrial 2-thiouridylase. Although subject myoblasts and myotubes contained half the normal levels of TRMU, thiolation of mitochondrial tRNAs was normal. YARS2 eluted as part of high-molecular-weight complexes of ∼250 kDa and 1 MDa by gel filtration. This study confirms mutations in YARS2 as a cause of MLASA and shows that, like some of the cytoplasmic ARSs, mitochondrial ARSs occur in high-molecular-weight complexes.
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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 | 0.000 | 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 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".