PLX032016

GSE107878: Disruption of Autism Spectrum Disorder-Susceptibility Genes Predominantly Reduces Functional Connectivity of Isogenic Human Neurons

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Autism Spectrum Disorder (ASD) 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 production of cortical excitatory neurons, and mutant proteins were not detectable. 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 inAFF2/FMR2-,ASTN2-,ATRX-,KCNQ2- andSCN2A-null neurons. RNAseq revealed convergence of several neuronal networks. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity. SOURCE: Stephen,W,Scherer (stephen.scherer@sickkids.ca) - The Hospital for Sick Children