# Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome

## TL;DR

A mouse model with an ACTA2 mutation shows gut motility issues, providing insights into a rare syndrome affecting smooth muscle function.

## Contribution

The study introduces a mouse model of MSMDS to investigate gastrointestinal dysfunction caused by ACTA2 mutations.

## Key findings

- ACTA2 R179H mice show cecal and colonic dilatation and disrupted motor complexes.
- Transcriptomic analysis reveals actin cytoskeleton-related gene changes in smooth muscle cells.
- Impaired gut motility is linked to smooth muscle dysfunction, not enteric nervous system changes.

## Abstract

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

ACTA2 mutation-driven intestinal dysmotility is linked to disrupted smooth muscle function, highlighting pathways for therapeutic strategies to restore motility in multisystemic smooth muscle dysfunction syndrome.