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 modelmay have broader applicability beyond AGAP1 in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | dmm049838 |
| Tidsskrift | DMM Disease Models and Mechanisms |
| Vol/bind | 16 |
| Udgave nummer | 9 |
| ISSN | 1754-8403 |
| DOI | |
| Status | Udgivet - 2023 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:These studies were supported by the National Institutes of Health grant R01NS106298 awarded to M.C.K. Open access funding provided by the National Institutes of Health. Deposited in PMC for immediate release.
Funding Information:
We appreciate the participation by patients and their families for these studies. We acknowledge F. Nowlen and J. Liu for assistance with fly rearing and survival monitoring and A. Musmacker for western blotting. We thank Kurt Gusin, director of the Biomedical Imaging Core at the University of Arizona College of Medicine - Phoenix, for providing microscopy services and Jody Nyboer, director of the University of Arizona Bio5 media facility, for providing Drosophila food. Stocks obtained from the Bloomington Drosophila Stock Center (NIH, P40OD018537) were used in this study. The monoclonal antibodies, developed by S. Munro and C. Goodman were obtained from the Developmental Studies Hybridoma Bank, created by the National Institute of Child Health and Human Development of the NIH and maintained at the University of Iowa, Department of Biology, Iowa City, IA, USA. Biomedical Imaging Core microscopy facilities at the University of Arizona College of Medicine Phoenix were used in these studies. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from https://deciphergenomics.org/about/stats. Funding for the DECIPHER project was provided by Wellcome (grant number WT223718/Z/21/Z).
Publisher Copyright:
© 2023. Published by The Company of Biologists Ltd.