AGAP1-associated endolysosomal trafficking abnormalities link gene–environment interactions in neurodevelopmental disorders
Bibliographic record
Abstract
AGAP1 is an Arf1 GTPase-activating protein that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report three new cases in which individuals had microdeletion variants in AGAP1. The affected individuals had intellectual disability (3/3), autism (3/3), dystonia with axial hypotonia (1/3), abnormalities of brain maturation (1/3), growth impairment (2/3) and facial dysmorphism (2/3). We investigated mechanisms potentially underlying AGAP1 variant-mediated neurodevelopmental impairments using the Drosophila ortholog CenG1a. We discovered reduced axon terminal size, increased neuronal endosome abundance and elevated autophagy compared to those in controls. Given potential incomplete penetrance, we assessed gene-environment interactions. We found basal elevation in the phosphorylation of the integrated stress-response protein eIF2α (or eIF2A) and inability to further increase eIF2α phosphorylation with subsequent cytotoxic stressors. CenG1a-mutant flies had increased lethality from exposure to environmental insults. We propose a model wherein disruption of AGAP1 function impairs endolysosomal trafficking, chronically activating the integrated stress response and leaving AGAP1-deficient cells susceptible to a variety of second-hit cytotoxic stressors. This model may have broader applicability beyond AGAP1 in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders.
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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".