ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Variants in ACTA2 have been observed in individuals with several potentially related phenotypes: thoracic aortic aneurysms and dissections (TAAD); Moyamoya disease; and multisystemic smooth muscle dysfunction syndrome (see OMIM 102620 for additional information). All reported variants in ACTA2 to date are missense variants. Additional information is needed to determine the mechanism by which variants in ACTA2 result in disease, though a few publications (PMIDs: 17994018 (see below for additional details), GeneReviews NBK1120) suggest that variants result in TAAD by a dominant negative mechanism. PMID 17994018 discusses that mutations in ACTA2 gene result in Thoracic aortic aneurysms and dissections (TAAD) . Authors describe a family with autosomal dominant TAAD and a missense mutation in ACTA2. Sequencing of the ACTA2 gene in 97 unrealted TAAD families identified an additional 14 families with mutations. All mutations segregated with TAAD and were absent in 192 controls. Structural analyses and immunofluorescence of ACTA2 filaments in aorticsmooth muscle cells dervived from patients with heterozygous ACTA2 mutations showed that the mutations perturb ACTA2 filament assembly and stability. Furthermore , aortic tissue from ACTA2 mutation patients showed typical findings of medial degredation of the aorta. Based on the findings, authors suggest ACTA2 mutations cause a dominant negative pathogenesis. To date only heterozygous missese mutations have been described in the ACTA2 gene (PMID 26034244,19409525,25207230). PMID 26153720 authors showed the the R258C ACTA2 mutation is less stable and more susceptible to severing by cofilin cleavage when compared to WT. Also smooth muscle myosin moves R258C filaments slower than WTand the slowing is exacerbated by smooth muscle tropomyosin. Overall many of the observed defects are not due to direct interaction with mutant but allosterically effects multiple regions of the monomer. Additional PMID:11053242

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity