PACS1 syndrome variant alters proteomic landscape of developing cortical organoids

ABSTRACT: Several large-scale genetic studies investigating the cause of neurodevelopmental disorders (NDDs) have been conducted, leading to the identification of hundreds of risk genes. However, our understanding of the mechanisms by which the observed genetic variants act has lagged, limiting translation of genetic findings into clinical treatments. In recent years, patient-derived brain organoids have been increasingly used to model NDDs and identify pathogenic mechanisms. While most of these studies evaluate the mechanisms by which NDD risk genes and pathogenic variants affect the transcriptome, studies considering the proteome are limited. Here, we examine the effect of the pathogenic variant PACS1 p.R203W, causative of PACS1 Syndrome, on the proteomic landscape of brain organoids and compared it to our previously generated transcriptomic dataset. Although we observed low overlap between transcripts and proteins with altered expression and phosphorylation, most resulting dysregulated processes converged. The proteomic data not only reinforced the importance of these developmental processes for p.R203W pathogenesis, but also detected dysregulated processes not previously identified by the transcriptomic analysis. Key dysregulated transcripts and proteins observed in PACS1(+/R203W) organoids have been classified as NDD-causative and ASD-risk genes. Interestingly, the core neurodevelopmental features of PACS1 syndrome like intellectual disability, delayed speech, and epilepsy were enriched in all levels of regulation, while the facial and muscular abnormalities were enriched exclusively in the proteome and phosphoproteome. Our results highlight that proteomic analyses not only enhance our understanding of general NDD mechanisms by complementing transcriptomic studies, but also uncovering additional targets, and therefore facilitating therapy development.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Neurodevelopmental Disorder With Or Without Autism Or Seizures

SUBMITTER: Matthew MacDonald  

LAB HEAD: Matthew MacDonald

PROVIDER: PXD080130 | Pride | 2026-08-07

REPOSITORIES: Pride