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Complete Disruption of Autism-Susceptibility Genes by Gene-Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons [article]

Eric Deneault, Sean H White, Deivid C Rodrigues, Joel Ross, Muhammad Faheem, Kirill Zaslavsky, Zhuozhi Wang, Roumiana Alexandrova, Giovanna Pellecchia, Wei Wei, Alina Piekna, Gaganjot Kaur (+10 others)
2018 bioRxiv   pre-print

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https://web.archive.org/web/20200325220139/https://www.biorxiv.org/content/biorxiv/early/2018/06/11/344234.full.pdf

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Autism Spectrum Disorder is phenotypically and genetically heterogeneous, but genomic analyses have identified candidate susceptibility genes. 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 10 ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NEUROG2)-directed differentiation of iPSCs allowed
more » ... oduction of cortical excitatory neurons, and mutant proteins were not detectable. RNAseq 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 post-synaptic 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.
doi:10.1101/344234 fatcat:dm6iquivpzbkdkhjmmhsb33o24
Citation

Eric Deneault, Sean H White, Deivid C Rodrigues, Joel Ross, Muhammad Faheem, Kirill Zaslavsky, Zhuozhi Wang, Roumiana Alexandrova, Giovanna Pellecchia, Wei Wei, Alina Piekna, Gaganjot Kaur, Jennifer L Howe, Vickie Kwan, Bhooma Thiruvahindrapuram, Susan Walker, Peter Pasceri, Daniele Merico, Ryan KC Yuen, Karun K Singh, James Ellis, Stephen W Scherer. "Complete Disruption of Autism-Susceptibility Genes by Gene-Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons." bioRxiv (2018)