Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1
Bibliographic record
Abstract
SCO1 is a nuclear-encoded protein with roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. It remains unclear, however, why mutations in this ubiquitously expressed gene product cause distinct, tissue-specific forms of disease that primarily affect heart, liver or brain function. To gain a better understanding of the clinical heterogeneity observed across SCO1 pedigrees, we deleted Sco1 in the murine brain and observed a severe COX deficiency in the absence of altered tissue copper content that was tied to early, neonatal lethality. We therefore transitioned to whole body knockin mice expressing allelic variants of SCO1 that are pathogenic in humans to more accurately reflect the patient condition and avoid the lethality associated with tissue-specific Sco1 knockout. Sco1M277V mice exhibited the most severe COX deficiency in their brain, modeling the pathophysiological consequences of the p.Met294Val variant in humans and supporting the idea that the primary role of SCO1 in this tissue is to promote COX assembly. Phenotyping of Sco1G115S, Sco1P157L and Sco1M277V mice nonetheless emphasized that the heart generally displayed the most severe, combined COX and copper deficiency, with Sco1G115S and Sco1P157L hearts developing a dilated cardiomyopathy that was accompanied by significant depletion of their mitochondrial copper pool. Taken together, our findings suggest that in an isogenic context the heart is the most susceptible organ to loss of SCO1 function, and that single nucleotide polymorphisms at modifier loci in an outbred population likely contribute to the clinical heterogeneity observed across SCO1 pedigrees.
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 | 0.000 |
| 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 | 0.001 |
| Research integrity | 0.000 | 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".