# Use of novel methods to study the biochemical mechanisms of ACTG2 mutations in visceral myopathy

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $2,500

## Abstract

Project Summary
The goal of this proposal is to study the mechanisms by which mutations in gamma smooth muscle actin
(ACTG2) cause visceral myopathy by building upon newly developed methods to purify wildtype and mutant
ACTG2 proteins. Visceral myopathies are life-threatening diseases characterized by weakness of smooth
muscle in the bowel, bladder and uterus. Visceral smooth muscle weakness causes abdominal distension,
vomiting, urination difficulties, abdominal pain and malnutrition. Current treatments of visceral myopathy,
including surgical bowel resection and intravenous nutrition, are directed at symptoms and do not target
underling disease mechanisms. Despite current treatments, people suffering from visceral myopathy are
hospitalized for a significant portion of their life, undergo multiple invasive surgeries and often die in childhood.
Approximately half of patients with visceral myopathy have heterozygous mutations in ACTG2. Actin is a highly
conserved protein that forms contractile filaments with myosin in muscle tissue. The mechanisms by which
ACTG2 mutations cause visceral myopathy are currently unknown. One major obstacle to studying ACTG2
mutations is the lack of methods for producing recombinant actin that is pure and has proper post-translational
modifications. This work builds on recent unpublished advances to purify recombinant wildtype and mutant
ACTG2 proteins for in vitro biochemical characterization and involves optimization of novel purification methods
to study a representative set of uncharacterized ACTG2 variants associated with visceral myopathy. Studies will
use purified wildtype and mutant ACTG2 proteins in multiple in vitro assays to characterize the effects of ACTG2
mutations on 1) actin polymerization and filament stability, 2) interaction with relevant actin-binding proteins that
regulate ACTG2 dynamics in vivo, and 3) the ability of smooth muscle myosin to generate force on ACTG2
filaments. In addition, this work will determine if heterozygous ACTG2 mutations exert dominant negative effects
on wildtype ACTG2 via assays with mixtures of wildtype and mutant proteins. The ultimate goal of this work is to
determine the biochemical mechanisms through which ACTG2 mutations cause disease. This work is needed
to develop mechanism-based treatments to improve the life expectancy and quality of life for individuals suffering
from visceral myopathy. Studies are performed in the laboratories of Dr. Robert Heuckeroth, Dr. Roberto
Dominguez and Dr. Michael Ostap who have established a close collaboration to study ACTG2. Dr. Dominguez
is an actin structure and biochemistry expert. Dr. Ostap is an expert on myosin interactions with actin. Dr.
Heuckeroth is an expert on bowel motility disorders including visceral myopathy and cares for children with
ACTG2 mutations. This work is enhanced by parallel studies of these same ACTG2 mutations in cultured smooth
muscle cells, stem cells converted to smooth muscle, and (soon) an ACTG2 mu...

## Key facts

- **NIH application ID:** 10533420
- **Project number:** 3F31DK127610-02S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rachel Ceron
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,500
- **Award type:** 3
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533420

## Citation

> US National Institutes of Health, RePORTER application 10533420, Use of novel methods to study the biochemical mechanisms of ACTG2 mutations in visceral myopathy (3F31DK127610-02S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10533420. Licensed CC0.

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