{"doi":"10.1101/2023.01.31.526497","title":"AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in a neurodevelopmental disorder","abstract":"Abstract AGAP1 is an Arf1 GAP that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report 3 new individuals with microdeletion variants in AGAP1 . Affected individuals have 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 neurodevelopmental impairments using the Drosophila ortholog, CenG1a . We discovered reduced axon terminal size, increased neuronal endosome abundance, and elevated autophagy at baseline. Given potential incomplete penetrance, we assessed gene-environment interactions. We found basal elevation in phosphorylation of the integrated stress-response protein eIF2α and inability to further increase eIF2α-P with subsequent cytotoxic stressors. CenG1a -mutant flies have 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. Summary statement We describe 3 additional patients with heterozygous AGAP1 deletion variants and use a loss of function Drosophila model to identify defects in synaptic morphology with increased endosomal sequestration, chronic autophagy induction, basal activation of eIF2α-P, and sensitivity to environmental stressors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395752,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":327686,"name":"Somayeh Bakhtiari","orcid":null,"position":1,"is_corresponding":false},{"id":1090892,"name":"Jacob Forstrom","orcid":null,"position":2,"is_corresponding":false},{"id":323114,"name":"Allan Bayat","orcid":"0000-0003-4986-8006","position":3,"is_corresponding":false},{"id":463265,"name":"Frédéric Bilan","orcid":"0000-0001-8589-6018","position":4,"is_corresponding":false},{"id":585672,"name":"Gwenaël Le Guyader","orcid":"0000-0003-2847-8121","position":5,"is_corresponding":false},{"id":695249,"name":"Ebba Alkhunaizi","orcid":"0000-0002-9026-7002","position":6,"is_corresponding":false},{"id":378032,"name":"Hilary J. Vernon","orcid":"0000-0001-9940-9866","position":7,"is_corresponding":false},{"id":465619,"name":"Sergio Padilla‐Lopez","orcid":"0009-0009-9354-3402","position":8,"is_corresponding":false},{"id":326371,"name":"Michael C. Kruer","orcid":"0000-0002-1373-7891","position":9,"is_corresponding":false},{"id":465602,"name":"Sara A. Lewis","orcid":"0000-0003-2560-1681","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:22.857556Z","pmid":"36778426","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}