Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle...

Area of Science:

• Genetics and Molecular Biology
• Gastroenterology
• Pathology

Background:

• Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) is a rare genetic disorder linked to ACTA2 gene mutations.
• While cardiovascular issues are prominent, gastrointestinal (GI) dysmotility significantly affects patient quality of life.
• The R179H variant in ACTA2 disrupts actin filament stability, impacting smooth muscle function.

Purpose of the Study:

• To investigate the structural, functional, and cellular underpinnings of gut dysmotility in MSMDS.
• To characterize the ACTA2 R179H mouse model for studying GI pathology in MSMDS.
• To explore potential therapeutic targets for restoring intestinal motility.

Main Methods:

• Clinical data review from 24 MSMDS patients.
• Phenotypic analysis of the ACTA2 R179H mouse model, including gut transit studies and ex vivo contractility assessments.
• Transcriptomic analysis of smooth muscle cells and immune profiling.

Main Results:

• MSMDS patients frequently experience severe gut dysmotility, with 75% needing medication for constipation.
• ACTA2 mutant mice exhibit colonic dilation, reduced intestinal length, disrupted motor complexes, and delayed transit.
• Smooth muscle cells show altered actin cytoskeleton gene expression and increased lymphocytic infiltration, without affecting the enteric nervous system.

Conclusions:

• The ACTA2 R179H mouse is a valid model for studying GI dysmotility in MSMDS.
• Smooth muscle dysfunction, driven by actin cytoskeletal abnormalities, is central to gut motility issues in MSMDS.
• This research provides a basis for developing therapies targeting smooth muscle actin disruptions to treat intestinal dysmotility.