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| Status |
Public on Nov 01, 2018 |
| Title |
Disruption of Autism Spectrum Disorder-Susceptibility Genes Predominantly Reduces Functional Connectivity of Isogenic Human Neurons |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2- and SCN2A-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.
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| Overall design |
RNAseq profile of 1 control sample and 10 isogenic knokout human induced pluripotent stem cells (iPSCs) samples with 2-4 replicates per sample, as well as their corresponding 28-day old differentiated glutamatergic neuron samples with 3-5 replicates per sample.
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| Contributor(s) |
Deneault E, White SH, Rodrigues DC, Ross PJ, Faheem M, Zaslavsky K, Wang Z, Alexandrova R, Pellecchia G, Wei W, Piekna A, Kaur G, Howe JL, Kwan V, Thiruvahindrapuram B, Walker S, Pasceri P, Merico D, Yuen RK, Singh KK, Ellis J, Scherer SW |
| Citation(s) |
30392976, 36635662 |
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| Submission date |
Dec 09, 2017 |
| Last update date |
Jan 25, 2023 |
| Contact name |
Stephen W Scherer |
| E-mail(s) |
[email protected]
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| Organization name |
The Hospital for Sick Children
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| Department |
Genetics and Genomic Biology
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| Street address |
686 Bay Street
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| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5G 0A4 |
| Country |
Canada |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (86)
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| Relations |
| BioProject |
PRJNA422099 |
| SRA |
SRP126560 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE107878_RAW.tar |
9.1 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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