AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in neurodevelopmental disorders

Sara A Lewis, Somayeh Bakhtiari, Jacob Forstrom, Allan Bayat, Frédéric Bilan, Gwenaël Le Guyader, Ebba Alkhunaizi, Hilary Vernon, Sergio R. Padilla-Lopez, Michael C Kruer*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
Article numberdmm049838
JournalDisease Models & Mechanisms
Volume16
Issue number9
Number of pages11
ISSN1754-8403
DOIs
Publication statusPublished - 26. Sept 2023

Keywords

  • Humans
  • Gene-Environment Interaction
  • Endosomes
  • Intellectual Disability/genetics
  • GTPase-Activating Proteins

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