ACTG2 – Familial visceral myopathy

Familial visceral myopathy (FVM) is a rare autosomal dominant disorder characterized by severe gastrointestinal dysmotility, including chronic intestinal pseudo-obstruction, abdominal distension, and peritonitis. FVM has been linked to heterozygous missense variants in ACTG2, which encodes enteric smooth muscle actin γ-2.

Genetic evidence supports a strong gene–disease association. In one pedigree, a heterozygous ACTG2 c.442C>A (p.Arg148Ser) variant segregated with disease in seven affected members (PMID:22960657). A second family with 11 affected relatives harbored a c.806_807delinsAA (p.Gly269Glu) variant (PMID:25782675), and a sporadic index patient carried the same Arg148Ser change (PMID:24777424). Together these three families encompass 19 probands with autosomal dominant inheritance and robust segregation.

The variant spectrum in FVM is dominated by missense substitutions at conserved residues of ACTG2, particularly Arg148, Arg178, and Gly269, each predicted to disrupt actin filament dynamics critical for smooth muscle contractility.

Functional studies demonstrate a dominant-negative mechanism. Expression of ACTG2(p.Arg148Ser) in sarcoma cell lines resulted in reduced incorporation into actin filaments, abnormal intracellular inclusions, and impaired contractility compared with wild-type controls (PMID:22960657).

These genetic and experimental findings converge to establish that heterozygous ACTG2 missense variants cause autosomal dominant FVM by impairing smooth muscle actin polymerization and contraction. The combination of segregation across 19 affected individuals and concordant functional data warrants a Strong clinical validity classification.

Key take-home: ACTG2 genetic testing should be offered to patients with familial visceral myopathy to confirm diagnosis, inform prognosis, and guide management, potentially avoiding unnecessary surgical interventions.

References

• Gastroenterology • 2012 • Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy PMID:22960657
• Endoscopy • 2014 • Familial visceral myopathy diagnosed by exome sequencing of a patient with chronic intestinal pseudo-obstruction. PMID:24777424
• European journal of human genetics: EJHG • 2015 • Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution. PMID:25782675

Evidence Based Scoring (AI generated)