IPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity
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ABSTRACT: PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to play roles in the endosomal pathway and nucleus, but how the p.R203W variant affects developing neurons is not fully understood. In this study we differentiated stem cells towards 2D and 3D neuronal models to investigate the impact of the PACS1 syndrome-causing variant on neurodevelopment. While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons in cortical organoids exhibited impaired expression of genes involved in synaptic signaling processes. The single-cell RNA sequencing data from dorsal cortical organoids after 40 and 88 days of differentiation can be found here. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased inter-spike interval. These findings demonstrate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncover putative electrophysiological underpinnings of disease.
ORGANISM(S): Homo sapiens
PROVIDER: GSE250386 | GEO | 2023/12/22
REPOSITORIES: GEO
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