Review of source material:
ClinGen:
https://search.clinicalgenome.org/kb/gene-validity/8249
ClinGen Evidence for Haploinsufficiency 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
Literature review:
Guo et al. (2007) PMID 17994018 showed that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections. Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrated that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction.
The penetrance of TAAD in individuals with ACTA2 mutations was low (0.48) and did not increase with age, differing from the pattern for other identified loci and genes for familial TAAD, which have a higher, age-related penetrance.
Omim https://www.omim.org/entry/102620
"...Several different missense mutations, including two recurrent mutations found in unrelated families, have been identified. In the family in which the disease was mapped, the mutation in ACTA2 (R149C) segregates invariantly with a skin rash caused by dermal capillary and small artery occlusion referred to as livedo reticularis. Other features associated in a subset of families with ACTA2 mutations include iris flocculi, PDA, and BAV...The majority of affected individuals presented with acute type A dissections or type B dissections, and 16 of 24 deaths occured due to type A dissections.
the missense ACTA2 mutations identified in familial TAAD are predicted to alter the dynamics of actin assembly into filaments, by either disrupting the actin-actin interaction sites or interfering with ATP hydrolysis. Analysis of SMCs explanted from patients heterozygous for ACTA2 mutations demonstrated reduced ACTA2-containing fibers and therefore confirmed that ACTA2 missense mutations disrupt actin fiber assembly or stability..."
Milewicz D et al. 2008 PMID: 18544034
"All missense mutations in ACTA2 reported here affect highly conserved amino acids and result in a deleterious alteration of the 2nd subdomain surface, a domain important for the conformational change of actin upon the exchange of ADP for ATP, in its turn important in filament assembly dynamics [20]. A dominant negative mechanism with reduced assembly and incomplete and disorganized actin filament assembly was previously suggested for ACTA2 mutations [10]. The current study demonstrates for the first time that TAAD may also result from premature truncating mutations in ACTA2. However, both nonsense mutations are predicted to escape nonsense mediated decay and could as such still exert a dominant negative effect. This confirms the hypothesis formulated by Guo et al, who suggest that mutations resulting in true null alleles are inherited only with a recessive transmission pattern"
Renard M et al. 2013 May 10 (PMID:21937134)
Syndromic HTAD. ACTA2 missense pathogenic variants that specifically disrupt the arginine 179 residue cause multisystem smooth-muscle dysfunction syndrome in which dysfunction of smooth muscle cells leads to severe and highly penetrant vascular diseases, pulmonary hypertension, and loss of proper smooth muscle cell contraction in other organs [Guo et al 2009, Milewicz et al 2010, Munot et al 2012].
Nonsyndromic HTAD. ACTA2 pathogenic variants, the most frequent cause of nonsyndromic familial HTAD, account for 12%-21% of cases [Guo et al 2007, Morisaki et al 2009, Disabella et al 2011, Renard et al 2013].
Thoracic aortic aneurysms are typically fusiform and initially involve the aortic root, extending into the ascending aorta and aortic arch. Descending and abdominal aortic aneurysms are less common. Penetrance for TAAD is reduced: the lifetime risk of an aortic event (aortic dissection or aneurysm repair) is 76% at age 85 years.
TAAD cosegregating with premature coronary artery disease, ischemic stroke, and moyamoya disease have been observed in families with ACTA2 pathogenic variants, more frequently in patients with mutation of the R258, R118, and R149 residues [Guo et al 2009].
Gene reviews https://www.ncbi.nlm.nih.gov/books/NBK1120/
Inheritance:
Autosomal dominant
(optional) modifiers: incomplete penetrance
Allelic requirement:
Monoallelic_aut
(optional) modifiers
Disease associated variant consequences:
Altered gene product structure
Narrative summary of molecular mechanisms:
The majority of pathogenic variants are missense variants. There is a report of two nonsense variants but they are predicted to escape NMD. The molecular mechanism is not completely understood but it is suggested disease results from a dominant negative mechanism. One proposed mechanism is an altered gene product alters the dynamics of actin assembly into filaments, by either disrupting the actin-actin interaction sites or interfering with ATP hydrolysis. Specific subsets of ACTA2 variants appear to be associated with different presentations for example TAAD cosegregating with premature coronary artery disease, ischemic stroke, and moyamoya disease has been observed more frequently in patients with mutations of the R258, R118, and R149 residues. ACTA2 missense variants that specifically disrupt the arginine 179 residue cause multisystem smooth-muscle dysfunction syndrome.
List variant classes in this gene proven to cause this disease:
- Missense
- Stop_gained predicted to escape NMD
List potential novel variant classes based on predicted functional consequence:
- Splice acceptor variant predicted to escape NMD
- Splice donor variant
- Splice donor variant predicted to escape NMD
- Frameshift predicted to escape NMD
- Stop_lost
- In frame deletion
- In frame insertion