ACTG2 – Visceral Myopathy 1

Visceral Myopathy 1 is a life-threatening smooth muscle disorder characterized by impaired bladder and intestinal contractility, manifesting as megacystis, microcolon, and chronic intestinal pseudo-obstruction. Heterozygous variants in the ACTG2 gene, encoding γ-smooth muscle actin, underlie this autosomal dominant condition, with both de novo and familial inheritance patterns and recurrent involvement of arginine codons.

Genetic evidence for ACTG2 includes over 103 patients from 14 publications, harboring predominantly heterozygous missense variants at conserved residues. Six de novo occurrences and segregation in a single large pedigree of seven affected relatives support dominant inheritance (PMID:35149643; PMID:22960657). Recurrent variants include c.769C>T (p.Arg257Cys) and c.532C>T (p.Arg178Cys), with additional alleles at p.Arg148 and p.Arg40.

Functional assays demonstrate that R257C and other missense mutants disrupt ACTG2 polymerization, reduce filament bundling, and impair smooth muscle cell contractility in vitro (PMID:26647307). Knock-in mouse models of Actg2R257C recapitulate bladder distension, intestinal hypomotility, prolonged GI transit, and defective actin dynamics in smooth muscle cells (PMID:36264152).

Mechanistic studies reveal that different mutants variably affect filament stability, interaction with actin-binding proteins, and susceptibility to myosin-mediated fragmentation. For example, R40C impairs filament nucleation, R178C undergoes premature degradation, and R257C destabilizes filaments, correlating with phenotype severity (PMID:38820162).

Limited histopathological findings, such as non-specific light microscopic features in most patients, highlight the importance of molecular testing even when intestinal biopsies are inconclusive (PMID:35695198).

Integration of extensive genetic, segregation, and experimental data meets ClinGen criteria for a Definitive gene–disease relationship. Key take-home: ACTG2 sequencing should be incorporated into diagnostic panels for smooth muscle myopathies to guide prognosis, genetic counseling, and potential future therapies.

References

• Journal of pediatric gastroenterology and nutrition • 2022 • Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature. PMID:35695198
• Gastroenterology • 2012 • Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy PMID:22960657
• Human molecular genetics • 2016 • ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome. PMID:26647307
• Neurogastroenterology and motility • 2023 • Heterozygous Actg2R257C mice mimic the phenotype of megacystis microcolon intestinal hypoperistalsis syndrome. PMID:36264152
• Science advances • 2024 • Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy. PMID:38820162
• Molecular genetics & genomic medicine • 2021 • Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction. PMID:35149643

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