# Role of ACTG2 Mutations in Visceral Myopathy

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2020 · $32,585

## Abstract

Project Summary: Myopathic chronic intestinal pseudo-obstruction (CIPO) and Megacystis Microcolon
Intestinal Hypoperistalsis Syndrome (MMIHS) are life-threatening bowel motility disorders characterized by
visceral (bowel, bladder, and uterine) smooth muscle weakness. Symptoms include bowel and bladder
distension, abdominal pain, vomiting, constipation, and growth failure. Many people with CIPO and MMIHS need
intravenous nutrition at least intermittently and affected individuals often have repeated surgery and spend
months in the hospital. Current therapy is largely ineffective so some people with CIPO or MMIHS undergo small
bowel transplantation. None of the medical therapies address underlying disease mechanisms and no current
therapy makes bowel smooth muscle stronger. Furthermore, molecular mechanisms causing visceral muscle
weakness are barely investigated. Within the past few years, it was discovered that heterozygous point mutations
in gamma smooth muscle actin (actin, gamma 2; ACTG2), the predominant actin isoform in visceral smooth
muscle, occur in almost half of people with CIPO and MMIHS. This work is focused on the most commonly
identified ACTG2 mutation (arginine 257 to cysteine, R257C). The goal is to determine how this mutation affects
actin cytoskeletal structure, actin dynamics, and force generation by smooth muscle cells. Studies will also test
the hypothesis that ACTG2 R257C alters smooth muscle differentiation. The model system employs human
intestinal smooth muscle cells and a novel paradigm for converting human pluripotent stem cells to visceral
smooth muscle-like cells. Diverse experimental approaches will be employed including live cell imaging using
actin filament binding proteins, live cell imaging of fluorescently tagged actin, actin cytoskeleton analysis in fixed
cells, electron microscopy of the actin cytoskeleton, traction force microscopy to measure contractile strength of
smooth muscle cells, and several molecular methods to assess relevant mRNA and protein levels in cultured
visceral smooth muscle. These studies should define how ACTG2 R257C causes devastating smooth muscle
weakness and may lead to novel mechanism-based treatment strategies. In particular, in vitro defects that define
the underlying pathophysiology of ACTG2 mutations, will provide a platform for high-throughput drug screening
to discover new treatments for CIPO/MMIHS.

## Key facts

- **NIH application ID:** 9904604
- **Project number:** 5F30DK118827-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sohaib Khalid Hashmi
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,585
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904604

## Citation

> US National Institutes of Health, RePORTER application 9904604, Role of ACTG2 Mutations in Visceral Myopathy (5F30DK118827-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904604. Licensed CC0.

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