A gain-of-function recurrent missense variant leads to a GABAergic/glutamatergic imbalance in a forebrain organoid model of PACS1 syndrome

Rylaarsdam, L.; Guemez-Gamboa, A.

doi:10.1101/2022.05.13.491892

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bioRxiv · 10.1101/2022.05.13.491892

A gain-of-function recurrent missense variant leads to a GABAergic/glutamatergic imbalance in a forebrain organoid model of PACS1 syndrome

Rylaarsdam, L.·Guemez-Gamboa, A.

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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 understood, leaving patients with few therapeutic options. Here we differentiated stem cells towards various neuronal models to investigate the impact of the PACS1 syndrome-causing variant on cortical development. While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes strongly enriched for synaptic signaling processes. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a strikingly prolonged neuronal network burst duration mediated by an increased inter-spike interval. This work is the first to investigate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncovers putative electrophysiological underpinnings of disease along with candidate targets for pharmacological intervention.

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Rylaarsdam, L., Guemez-Gamboa, A.. 2022-05-13. A gain-of-function recurrent missense variant leads to a GABAergic/glutamatergic imbalance in a forebrain organoid model of PACS1 syndrome. https://doi.org/10.1101/2022.05.13.491892

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