| Autor: |
Lauren Rylaarsdam, Jennifer Rakotomamonjy, Eleanor Pope, Alicia Guemez-Gamboa |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.05.13.491892 |
| Popis: |
PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and craniofacial abnormalities resulting from ade novop.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 plays roles in the endosomal pathway and nucleus, but little is known about how this variant affects developing neurons and patients have few therapeutic options. Here, we used stem cellderived models to show that PACS1(+/R203W)neurons have impaired expression of genes enriched for synaptic signaling processes. We assessed the functional impact of this differential expression and find that PACS1(+/R203W)neurons have a striking prolongation of network burst duration resulting from an increased inter-spike interval. These results suggest that an aberrant regulation of ionic flux affecting spike frequency underlies the neurological phenotypes experienced by patients. This work is the first to investigate the impact of the PACS1 p.R203W variant on developing neural tissue, revealing electrophysiological mechanisms of disease and putative targets for pharmacological intervention. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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