# Identifying potential therapeutics using an animal model for PACS1 syndrome

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $157,945

## Abstract

Project Summary
PACS1 Syndrome is a de novo neurogenetic disorder affecting young children,
characterized by distinct dysmorphic facial features, intellectual disability and
developmental delays. In all cases identified throughout the world, individuals have the
same exact amino acid substitution, p.R203W, in a highly conserved position of the
PACS1 protein. PACS1 (Phosphofurin Acidic Cluster Sorting Protein 1) was first
identified by its interaction with the proprotein convertase furin, and subsequent studies
have revealed its role in secretary pathway, particularly the trans-Golgi network. PACS1
is conserved in all animals, and humans express an additional ortholog, PACS2. All
PACS proteins contain multiple functional domains including the furin-binding region, in
which the PACS1 syndrome variant resides. Currently, most understanding of PACS1
function is from cultured cells. A key question that must be addressed is how R203W
changes PACS1 function and results in syndrome symptoms. The nematode C.
elegans is a tractable model for studying human disease genes. A single C.
elegans pacs-1 gene encodes a protein that shares all conserved domains, and the
furin-binding region is especially well conserved between C. elegans and humans (45%
identical/70% similar) with the disease variant site, R203, denoted as R116 in C.
elegans. Here, we have generated a cePACS-1(R116W) model, using genome-editing.
Additionally, using drugs to probe neuronal function, we found that pacs-1(R116W)
animals are resistant to the paralyzing effect of the choline esterase inhibitor aldicarb.
Consistent with its neuronal function, we also found that endogenous PACS-1 is
expressed in the nervous system. Our C. elegans pacs-1(R116W) provides the first
germline-expressed model of PACS1 syndrome. In this R03 application, we propose to
complete a chemical compound screen, using the LOPAC chemical library, for
behavioral effects on our cePACS1 model. We will then test top candidate hits using
additional cell biology and functional assays. The project goal is within the feasibility
and guideline of R03 application. The outcome will be informative for the development
of designer-strategies in treatment of PACS1 syndrome, and also aid further
characterization of physiological mechanisms underlying PACS1 syndrome.

## Key facts

- **NIH application ID:** 10195626
- **Project number:** 1R03NS121487-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Dana T Byrd
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $157,945
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195626

## Citation

> US National Institutes of Health, RePORTER application 10195626, Identifying potential therapeutics using an animal model for PACS1 syndrome (1R03NS121487-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10195626. Licensed CC0.

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