Disruption of ADNP-KDM1A-GTF2I complex drives neural differentiation imbalance in Helsmoortel-Van der Aa syndrome
Bibliographic record
Abstract
ABSTRACT Mutations in ADNP (Activity-Dependent Neuroprotective Protein) are among the most frequent monogenic causes of autism spectrum disorder (ASD) and lead to Helsmoortel-Van der Aa syndrome (HVDAS). Yet how ADNP dysfunction leads to HVDAS is unclear. We employed patient-derived induced pluripotent stem cells, cortical organoids and ADNP KO human neural stem cells (hNSCs) to clarify the cellular and molecular mechanism of HVDAS onset. We purified an ADNP-KDM1A-GTF2I (AKG) protein complex from hNSCs and show that it targets transposable elements (TEs) to repress nearby gene transcription. Upon ADNP KO, KDM1A binding is lost at promoters targeted by AKG, pointing to ADNP as the anchoring subunit of the AKG complex. HVDAS cortical organoids show impaired progenitor proliferation and accelerated neuronal differentiation, coupled with a sustained upregulation of neurogenesis transcriptional programs, including key transcription factors normally repressed by AKG. This work suggests that the AKG complex acts as the relevant ADNP unit in the molecular onset of HVDAS.
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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) | 0.000 | 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 | 0.001 |
| 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".