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DTSTART;TZID=America/Chicago:20260612T120000
DTEND;TZID=America/Chicago:20260612T130000
DTSTAMP:20260613T144020Z
SUMMARY:"PACS1 syndrome causative variant diverges from loss-of-function model in iNeuron"
UID:642802@northwestern.edu
TZID:America/Chicago
DESCRIPTION:Annika Schroder\, PhD candidate\, Guemez-Gamboa Lab\, Department of Neuroscience  PACS1 syndrome is a neurodevelopmental disorder hallmarked by craniofacial dysmorphisms and intellectual disability. Patients with PACS1 syndrome have a single de novo missense mutation at c.607C>T of the Phosphofurin acidic cluster sorting 1 (Pacs1) gene\, which causes an Arginine to Tryptophan substitution in the peptide (p.R203W). While PACS1 function remains understudied\, it is annotated as a multifunctional sorting protein with roles in both cytoplasmic and nuclear transport. We previously showed that PACS1+/R203W forebrain organoids develop mature glutamatergic neurons with impaired expression of synaptic signaling genes when compared to isogenic controls. Additionally\, PACS1+/R203W iNeurons (iNs) have prolonged network bursts\, which has implications for circuit formation. While these results highlight the impact of p.R203W in the broader context of neural development\, the mechanism by which p.R203W operates on a cellular level remains unclear. We can begin to understand more about disease pathogenesis and potential targets for therapeutics by determining if p.R203W operates via a loss-of-function\, gain-of-function\, or dominant-negative mechanism. Here we used control (PACS1+/+)\, pathogenic (PACS1+/R203W)\, and null (PACS1-/-) iNs to address if p.R203W operates via a loss-of-function mechanism. Our findings indicate that complete loss of PACS1 in iNs does not substantially alter neuronal electrophysiological properties or proteomic landscape\, potentially due to compensation by redundant proteins. In contrast\, introduction of p.R203W into iNs produces aberrant phenotypes\, suggesting that it acts through either a gain-of-function or dominant-negative mechanism rather than a loss-of-function.
LOCATION:Ward Building\, 5-230\, 303 E. Chicago Avenue\, Chicago\, IL 60611
TRANSP:OPAQUE
URL:https://planitpurple.northwestern.edu/event/642802
CREATED:20260609T050000Z
STATUS:CONFIRMED
LAST-MODIFIED:20260609T050000Z
PRIORITY:0
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