Journal
STEM CELL REPORTS
Volume 11, Issue 5, Pages 1211-1225Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.10.003
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Funding
- Centre for Applied Genomics, Canada
- Canadian Institutes of Health Research (CIHR), Canada
- Canadian Institute for Advanced Research (CIFAR), Canada
- McLaughlin Centre, Canada
- Canada Foundation for Innovation (CFI), Canada
- Ontario Research Fund (ORF)
- Autism Speaks, United States
- Hospital for Sick Children, Canada
- CIHR [FDN 143295, XGG-125818, 148814, EPS-129129]
- CFI-John R. Evans Leaders Fund (JELF)/ORF
- Ontario Brain Institute (OBI), Canada
- Natural Sciences and Engineering Research Council (NSERC), Canada
- Scottish Rite Charitable Foundation
- NIH, United States [4R33MH087908]
- Province of Ontario Neurodevelopmental Disorders (POND) from OBI
- Banting Post-Doctoral Fellowship
- Fonds de Recherche en Sante du Quebec (FRQS) Post-Doctoral Fellowship
- Fragile X Research Foundation of Canada
- International Rett Syndrome Foundation, United States
- Ontario Stem Cell Initiative Fellowship
- Ontario Ministry of Research & Innovation Fellowship
- CIHR Canada Vanier Graduate Scholarship
- ORF [GL2-01-013]
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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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