Complete disruption of autism-susceptibility genes by gene editing predominantly reduces functional connectivity of isogenic human neurons
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Abstract
Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.
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Recent efforts have been initiated to systematize phenotyping of model systems and apply a standard battery of assays to gene mutations on a single isogenic background.
“Recent efforts have been initiated to systematize the phenotyping of model systems and to apply a standard battery of assays to gene mutations on a single isogenic background (Deneault et al., 2018) and https://bit.ly/2Tc0lQ4).”
From Getting to the cores of autism (2019) · cites this paper as Deneault et al., 2018
In a systematic screen of ten ASD susceptibility genes using CRISPR/Cas9 iPSC lines and isogenic controls, patch-clamp recordings detected reduced EPSPs in a subset including ATRX, AFF2, KCNQ2, SCN2A, and ASTN2.
“In a systematic screen of ten ASD susceptibility genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1) using CRISPR/Cas9-created iPSC lines and isogenic controls (Deneault et al., 2018), patch-clamp recordings detected reduced excitatory postsynaptic potentials (EPSPs) in a subset of gene models including ATRX, AFF2, KCNQ2, SCN2A, and ASTN2.”
From Getting to the cores of autism (2019) · cites this paper as Deneault et al., 2018
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- Authors
- Deneault, E., White, S. H., Rodrigues, D. C., Ross, P. J., Faheem, M., Zaslavsky, K., Wang, Z., Alexandrova, R., Pellecchia, G., Wei, W., Piekna, A., Kaur, G., Howe, J. L., Kwan, V., Thiruvahindrapuram, B., Walker, S., Lionel, A. C., Pasceri, P., Merico, D., Yuen, R. K. C., Singh, K. K., Ellis, J., & Scherer, S. W.
- Affiliations
- McMaster University (CA)
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- Corresponding author
- Singh, Karun K.
- Ellis, James
- Scherer, Stephen W.
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 11
- Issue
- 5
- Pages
- 1211-1225
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC6235011
- OpenAlex
- W2949852486
- Cited by
- 145
- References
- 60
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 9 · 2023: 25 · 2022: 21 · 2021: 22 · 2020: 27 · 2019: 13
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-02-12)
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IslandScholar (University of Prince Edward Island) (submittedVersion, cc-by-nc-nd)
- Funders
- Centre for Applied Genomics
- Canadian Institutes of Health Research (FDN 143295, XGG-125818, EPS-129129, 148814)
- Canadian Institute for Advanced Research
- McLaughlin Centre
- Canada Foundation for Innovation
- Ontario Research Fund (GL2-01-013)
- Autism Speaks
- Hospital for Sick Children
- Ontario Brain Institute
- Natural Sciences and Engineering Research Council
- Scottish Rite Charitable Foundation
- NIH (4R33MH087908)
- Province of Ontario Neurodevelopmental Disorders
- Fonds de Recherche en Santé du Québec
- Fragile X Research Foundation
- International Rett Syndrome Foundation
- Ontario Stem Cell Initiative
- Ontario Ministry of Research & Innovation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- autism spectrum disorder, autism susceptibility genes, functional connectivity, excitatory postsynaptic currents, spontaneous synaptic activity, KCNQ2, SCN2A, ATRX, ASTN2, CHD8, CACNA1C, anosmin-1
- MeSH terms
- Gene Editing, Autistic Disorder, Cell Line, Electrodes, Humans, Neurons, Phenotype, Mutagenesis, Insertional, Genetic Predisposition to Disease, Gene Knockout Techniques, Induced Pluripotent Stem Cells, HEK293 Cells
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