ArticleDisease models & mechanisms2023
AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in neurodevelopmental disorders.
Article in Disease models & mechanisms, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 8 citations in OpenAlex.
- AGAP1 and noncanonical GDP binding regulate triple-negative breast cancer development.Cellular and molecular life sciences : CMLS · 2026Article
- The effect of human-specific genetic variants on neuronal spinogenesis.Frontiers in genetics · 2026Review
- Parkinson's disease-associated alterations in DNA methylation and hydroxymethylation in human brain.NPJ Parkinson's disease · 2025Article
- Recessive genomic and phenotypic variation in consanguineous families with cerebral palsy.medRxiv : the preprint server for health sciences · 2025Article
- Dysfunctional β-cell longevity in diabetes relies on energy conservation and positive epistasis.Life science alliance · 2024Article
- Genetics and Traumatic Brain Injury: Findings from an Exome-Based Study of a 50-Patient Case Series.Current issues in molecular biology · 2024Article
- Review
- eIF2α phosphorylation evokes dystonia-like movements with D2-receptor and cholinergic origin and abnormal neuronal connectivity.bioRxiv : the preprint server for biology · 2024Article
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10 authors at 5 institutions in 4 countries.
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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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