Targeted loss of the ATR-X syndrome protein in the limb mesenchyme of mice causes brachydactyly
Bibliographic record
Abstract
ATR-X syndrome is a rare genetic disorder caused by mutations in the ATRX gene. Affected individuals are cognitively impaired and display a variety of developmental abnormalities, including skeletal deformities. To investigate the function of ATRX during skeletal development, we selectively deleted the gene in the developing forelimb mesenchyme of mice. The absence of ATRX in the limb mesenchyme resulted in shorter digits, or brachydactyly, a defect also observed in a subset of ATR-X patients. This phenotype persisted until adulthood, causing reduced grip strength and altered gait in mutant mice. Examination of the embryonic ATRX-null forelimbs revealed a significant increase in apoptotic cell death, which could explain the reduced digit length. In addition, staining for the DNA damage markers γ-histone 2A family member X (γ-H2AX) and 53BP1 demonstrated a significant increase in the number of cells with DNA damage in the embryonic ATRX-null forepaw. Strikingly, only one large bright DNA damage event was observed per nucleus in proliferating cells. These large γ-H2AX foci were located in close proximity to the nuclear lamina and remained largely unresolved after cell differentiation. In addition, ATRX-depleted forelimb mesenchymal cells did not exhibit hypersensitivity to DNA fork-stalling compounds, suggesting that the nature as well as the response to DNA damage incurred by loss of ATRX in the developing limb fundamentally differs from other tissues. Our data suggest that DNA damage-induced apoptosis is a novel cellular mechanism underlying brachydactyly that might be relevant to additional skeletal syndromes.
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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) | 0.002 | 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".