A Mitochondrial Translation Defect Identified by Whole-Exome Sequencing Expands the Phenotypic Spectrum for<i>MARS2</i>
Bibliographic record
Abstract
The mitochondrial genome encodes 13 proteins of the Electron Transport Chain. This genome requires nuclear-encoded proteins for its maintenance, replication, transcription and translation. A growing list of disorders ranging from ovarian dysgenesis, pulmonary hypertension and neurodegeneration have been found to result from mutations in mitochondrial aminoacyl-tRNA synthetases required for mitochondrial translation. Complex duplications of the MARS2 locus have previously been reported in French Canadian individuals with autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL) (Bayat et al., PLOS Biology 10(3): e1001288, 2012). Webb et al. (Hum Mutat 36:587–592, 2015) now report missense mutations in the MARS2 gene through whole exome sequencing of two siblings with a severe earlier onset “ARSAL-like” condition, suggestive of a phenotypic expansion for MARS2. Besides the neurologic features, the siblings display a marked pectus carinatum, dysmorphic features and growth failure. Interestingly, they lack ataxic features although they are younger than ARSAL patients. The clinical feature of growth failure, besides being related to low levels of growth hormone, may also be related to lower overall proliferation rates, similar to what was reported by Bayat et al. in studies of MARS2 mutant flies and ARSAL patient cell lines. Importantly, the authors demonstrate mutations in both siblings and rule out other candidates through exome filtering and mtDNA analysis. Further supporting the role of defective mitochondrial translation, they demonstrate Complex I and IV dysfunction in patient fibroblasts and find reduced protein levels of NDUFB8 and COXII, defects that they can rescue with MARS2 expression. This study expands the phenotype related to MARS2, demonstrates distinct phenotypes resulting from point mutations vs. the previously reported complex duplications, and underscores the importance of mitochondrial tRNA synthetases as key candidate genes for a range of phenotypes.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".