ACTA2 – Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) is a progressive dilation of the ascending or descending aorta that predisposes to dissection or rupture. Heterozygous variants in ACTA2, encoding smooth muscle α-actin, underlie an autosomal dominant form of familial TAA due to impaired contractile function of vascular smooth muscle cells. The association between ACTA2 and TAA has been repeatedly documented across diverse populations and experimental systems, establishing a clear molecular etiology.

Genetic evidence encompasses multiple case reports and cohorts. The R179H missense variant (c.536G>A (p.Arg179His)) was first identified in a patient with prune-belly sequence who later developed TAA (PMID:22302747). Identical twins with de novo c.536G>A (p.Arg179His) presented with early-onset TAA and recurrent dissections (PMID:25225139). A Cypriot family segregating a frameshift c.363_367del (p.Met121IlefsTer5) in ACTA2 demonstrated co-segregation with TAA across three additional relatives (PMID:30526509). Population screening of 100 unbiased TAA probands revealed ACTA2 mutations in 3% of cases (PMID:23099432), and a Dutch multicenter study of 49 carriers reported 20 distinct ACTA2 variants with 65% event penetrance (PMID:36053285).

Segregation analysis across four families confirmed co-segregation of ACTA2 variants with TAA in at least 4 affected relatives beyond index cases (PMID:25225139; PMID:30526509). Recurrent hotspot variants—including p.Arg179His—have arisen independently in unrelated pedigrees, supporting pathogenicity.

Functional studies delineate a dominant-negative mechanism. Yeast expressing human α-actin mutations exhibit impaired polymerization kinetics, altered critical concentration, and hypersensitivity to severing (PMID:21288906). In zebrafish, mRNA encoding c.536G>A (p.Arg179His) or c.442G>A (p.Gly148Arg) yields cardiac hypoplasia, reduced myocardial proliferation, and altered contractility (PMID:38316882). Mouse models harboring R149C show defective actin folding but reduced aortic pathology, illustrating allele-specific penetrance variation (PMID:34600884).

Mechanistically, ACTA2 variants disrupt F-actin stability and actin–myosin interactions, leading to smooth muscle cell dysfunction and medial degeneration of the aortic wall. The R179H mutation markedly elevates the critical concentration for filament assembly and enhances cofilin-mediated severing, confirming a dominant-negative effect on filament dynamics (PMID:27551047). No robust evidence refutes the ACTA2–TAA link, though variant-specific penetrance underscores the influence of genetic background and environmental modifiers.

Integration of genetic, segregation, and functional data supports a definitive ClinGen classification of ACTA2 for autosomal dominant TAA. Pathogenic ACTA2 variants provide a reliable molecular diagnosis, inform family screening, and guide surveillance and prophylactic surgical planning. Key take-home: ACTA2 testing is clinically actionable for early identification and management of at-risk individuals.

References

• American journal of medical genetics. Part A • 2012 • R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations. PMID:22302747
• Pediatrics • 2014 • Twins with progressive thoracic aortic aneurysm, recurrent dissection and ACTA2 mutation. PMID:25225139
• BMC medical genetics • 2018 • Novel variants in the ACTA2 and MYH11 genes in a Cypriot family with thoracic aortic aneurysms: a case report. PMID:30526509
• Circulation. Cardiovascular genetics • 2012 • TGFβRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor β2 signal transduction. PMID:23099432
• The Journal of biological chemistry • 2011 • Allele-specific effects of thoracic aortic aneurysm and dissection alpha-smooth muscle actin mutations on actin function. PMID:21288906
• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort. PMID:36053285
• Journal of human genetics • 2024 • Cardiac manifestations of human ACTA2 variants recapitulated in a zebrafish model. PMID:38316882
• The Journal of biological chemistry • 2016 • Severe Molecular Defects Exhibited by the R179H Mutation in Human Vascular Smooth Muscle α-Actin. PMID:27551047
• The Journal of biological chemistry • 2021 • Resistance of Acta2R149C/+ mice to aortic disease is associated with defective release of mutant smooth muscle α-actin from the chaperonin-containing TCP1 folding complex. PMID:34600884

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