Alternative titles; symbols
HGNC Approved Gene Symbol: ACTA2
SNOMEDCT: 782724001;
Cytogenetic location: 10q23.31 Genomic coordinates (GRCh38) : 10:88,935,074-88,991,337 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.31 | Aortic aneurysm, familial thoracic 6 | 611788 | Autosomal dominant | 3 |
| Moyamoya disease 5 | 614042 | 3 | ||
| Smooth muscle dysfunction syndrome | 613834 | Autosomal dominant | 3 |
Smooth muscle aortic alpha-actin (ACTA2) is 1 of 6 different actin isoforms that have been identified in vertebrates and that share similar amino acid sequences and are well conserved in evolution. Other actins include skeletal muscle (ACTA1; 102610), cardiac muscle (ACTC1; 102540) , smooth muscle enteric (ACTG2; 102545), and cytoplasmic beta (ACTB; 102630) and gamma (ACTG1; 102560) (summary by Vandekerckhove and Weber, 1979).
Ueyama et al. (1984) isolated and characterized the ACTA2 gene, encoding smooth muscle aortic actin. The gene has a transition point mutation in position 309, substituting thymine for cytosine.
Ueyama et al. (1984) found that the ACTA2 gene contains at least 9 exons.
Ueyama et al. (1990) assigned the ACTSA gene to chromosome 10 by Southern blot analysis of DNAs from 18 rodent-human somatic cell hybrids. Regional mapping by in situ hybridization localized the gene to chromosome 10q22-q24.
By FISH analysis, Ueyama et al. (1995) localized the ACTA2 gene to chromosome 10q23.3.
Kumar et al. (2003) developed transgenic mice expressing a reporter construct driven by the rat Actsa promoter. Mutation of 1 or both E boxes within the promoter significantly reduced expression of the reporter gene. Mouse fibroblasts cotransfected with the reporter plasmid and various transcription factors revealed that serum response factor (SRF; 600589), class I bHLH proteins, such as E12 (147141), HEB (600480), and E2-2 (602272), and the bHLH inhibitors ID (see ID1; 600349) and TWIST (601622) are likely important regulators of smooth muscle cell differentiation.
Aortic Aneurysm, Familial Thoracic 6
The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin, encoded by ACTA2, and the beta-myosin heavy chain, encoded by the MYH11 gene (160745). Guo et al. (2007) showed that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (AAT6; 611788). 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. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial thoracic aortic aneurysm, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta. Since mutations in 2 components of the SMC contractile unit, ACTA2 and MYH11, cause familial thoracic aortic aneurysm with dissection (TAAD), Guo et al. (2007) raised the possibility that mutations in other components of the SMC contractile unit may be responsible for a portion of the 80% of familial TAAD yet to be explained.
Guo et al. (2007) found that 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. Despite the young age of death of some family members, the Kaplan-Meier survival curve of the ACTA2 cohort estimated a median survival of 67 years, suggesting that the disease is less deadly than Loeys-Dietz syndrome (609192) and similar to treated Marfan syndrome (MFS; 154700).
In 40 German probands with thoracic aortic aneurysms, 21 of whom had clinical features suggestive of Marfan syndrome, but all of whom were negative for mutation in the FBN1 (134797) and TGFBR2 (190182) genes, Hoffjan et al. (2011) sequenced the ACTA2 gene and identified heterozygous mutations in 3 patients (see, e.g., 102620.0005 and 102620.0006). None of the 21 individuals with features suggestive of MFS were found to carry a mutation in ACTA2. Among the remaining 19 patients, there were no differences between the 3 patients with ACTA2 mutations and the nonmutated patients. The authors also noted that there was no history of premature stroke or coronary artery disease in the mutation-positive families.
Aortic Aneurysm and/or Moyamoya Disease
Guo et al. (2009) studied 20 families with 127 members harboring heterozygous ACTA2 mutations and phenotyped them for premature vascular disease, defined as an age of onset less than 55 years in men and less than 60 years in women. Family members aged 21 years and older were included, along with members who presented with vascular diseases at younger ages. Thoracic aortic aneurysm had been reported in 14 of these 20 families by Guo et al. (2007). The 6 additional families with ACTA2 mutations all carried missense mutations. None of these missense mutations was identified in 192 ethnically matched controls. Thoracic aortic aneurysm was the primary vascular disease in ACTA2 mutation carriers (76 individuals); 26 individuals had premature onset of coronary artery disease, and 15 had ischemic strokes. Fifteen individuals had more than 1 vascular disease, and none of the family members without an ACTA2 mutation had any of these early-onset vascular diseases. One family had more mutation carriers with premature coronary artery disease than with aortic disease. In 3 families with an ACTA2 mutation altering the arginine-258 residue (arg258 to cys, 102620.0003, arg258 to his, 102620.0002), 10 of 14 mutation carriers had aortic disease and 7 had onset of strokes at ages ranging from 5 to 46 years. Five of the 7 acute strokes had been classified as moyamoya disease (MYMY5; 614042); 2 others had fusiform cerebral aneurysms.
Shimojima and Yamamoto (2009) analyzed all coding exons of the ACTA2 gene in 53 Japanese patients with moyamoya disease but found no mutations. Noting that the diagnosis of moyamoya disease in the patients studied by Guo et al. (2009) was unclear, Shimojima and Yamamoto (2009) concluded that ACTA2 is not a major disease-causing gene for moyamoya disease in Japanese patients.
Roder et al. (2011) identified a heterozygous mutation in the ACTA2 gene (R179H; 102620.0004) in 1 of 39 unrelated patients of European descent with moyamoya disease who had no family history of the disorder. No other previously described ACTA2 mutations associated with moyamoya disease (Guo et al., 2009) were found in this cohort.
Smooth Muscle Dysfunction Syndrome
Milewicz et al. (2010) identified 7 unrelated patients with the same de novo missense mutation in the ACTA2 gene (R179H; 102620.0004) who presented with a multisystemic smooth muscle dysfunction syndrome (SMDYS; 613834), including vasculopathy, congenital mydriasis, patent ductus arteriosus, and thoracic aortic aneurysm.
In 3 unrelated females with SMDYS, including 1 of the patients (patient E) reported by Milewicz et al. (2010), Yetman et al. (2015) identified heterozygosity for the R179H mutation in the ACTA2 gene. All 3 presented with an aneurysmal patent ductus arteriosus, leading the authors to suggest that all infants with ductal aneurysms be tested for ACTA2 mutations.
From a cohort of 7 patients with visceral myopathy phenotypes, Moreno et al. (2016) identified a 2.75-year-old Brazilian girl (patient 7) with SMYDS who was heterozygous for an R179C mutation in the ACTA2 gene (102620.0008).
Regalado et al. (2018) reviewed 33 patients with SMDYS, including the patients reported by Milewicz et al. (2010), all of whom had an alteration at the R179 position of ACTA2 (see 102620.0004; 102620.0007-102620.0009).
In a large family in which thoracic aortic aneurysm with dissection segregated with reduced penetrance (AAT6; 611788), Guo et al. (2007) found a heterozygous 492C-T transition in exon 5 of the ACTA2 gene that caused an arg149-to-cys (R149C) amino acid substitution. In further studies, 4 additional families with the ACTA2 mutation were found; however, each family had a unique haplotype, implying that the mutations arose de novo in multiple families. Livedo reticularis and iris flocculi were found together or separately in some of these families.
Guo et al. (2009) analyzed 45 individuals with the R149C mutation and found that, in addition to the already established predisposition to TAAD, this mutation led to coronary artery disease (24 mutation carriers with TAAD, 12 with coronary artery disease).
In a family of European descent with hereditary thoracic aortic aneurysm with dissection (AAT6; 611788), Guo et al. (2007) identified an 820G-A transition in exon 7 of the ACTA2 gene, resulting in an arg258-to-his (R258H) substitution. One individual in the family had patent ductus arteriosus.
Guo et al. (2009) analyzed 15 individuals carrying a missense mutation at arg258 and found that, in addition to the already established predisposition to TAAD, mutation at this position was associated with stroke (10 individuals with TAAD, 7 with stroke). In 1 family with the R258H mutation, 3 affected individuals had a phenotype consistent with moyamoya disease-5 (MYMY5; 614042). Two of these 3 patients had strokes at ages 44 and 46 years, respectively, and also had thoracic aortic aneurysm with dissection; the third had isolated moyamoya disease with stroke at age 16 years. The findings indicated that ACTA2 mutations can cause a spectrum of vascular diseases, even within a single family.
In 2 families of European descent with hereditary thoracic aortic aneurysm with dissection (AAT6; 611788), Guo et al. (2007) identified an 819C-T transition in exon 7 of the ACTA2 gene, resulting in an arg258-to-cys (R258C) substitution. All 5 mutation carriers in 1 family had patent ductus arteriosus.
Guo et al. (2009) analyzed 15 individuals carrying a missense mutation at arg258 and found that, in addition to the already established predisposition to TAAD, mutation at this position was associated with stroke (10 individuals with TAAD, 7 with stroke). The authors identified a high risk of early-onset strokes in family members carrying the R258C mutation. In 1 family with the R258C mutation, 2 members had a phenotype consistent with moyamoya disease-5 (614042), with strokes at ages 39 and 5 years, respectively. The older patient had thoracic aneurysm with dissection at age 32 years, whereas the stroke was fatal in the younger patient. The findings indicated that ACTA2 mutations can cause a spectrum of vascular diseases, even within a single family.
Smooth Muscle Dysfunction Syndrome
In 7 unrelated patients of northern European descent with smooth muscle dysfunction syndrome (SMDYS; 613834), Milewicz et al. (2010) identified heterozygosity for a de novo arg179-to-his (R179H) substitution in the ACTA2 gene. The mutation was not identified in parents' DNA samples, confirming the de novo status in 5 patients. Three of the patients had previously been reported (Ades et al., 1999, Khan et al., 2004, and Lemire et al., 2004, respectively).
Brodsky et al. (2014) identified the R179H mutation in a 9-year-old boy diagnosed with congenital mydriasis and prune belly syndrome with megacystis, bilateral hydroureter, and hydronephrosis requiring surgical correction. On echocardiography at age 9 years, he had severe dilatation of the aortic root and mid-ascending aorta. MRI showed massive dilatation of the intracranial arteries and tortuosity of the distal cerebral vasculature.
In 3 unrelated females with SMDYS, including 1 of the patients (patient E) reported by Milewicz et al. (2010), Yetman et al. (2015) identified heterozygosity for the R179H mutation in the ACTA2 gene. All 3 presented with an aneurysmal patent ductus arteriosus, leading the authors to suggest that all infants with ductal aneurysms be tested for ACTA2 mutations.
In a review of the clinical history and outcomes of 33 patients with SMDYS, Regalado et al. (2018) found that 24 of the patients were heterozygous for the R179H mutation.
Moyamoya Disease 5
Roder et al. (2011) identified a heterozygous R179H mutation in 1 of 39 patients of European origin with moyamoya disease-5 (MYMY5; 614042) and no family history of the disorder. The patient was a girl who had a stroke at age 3 years, but she had no other abnormalities, particularly none of those described by Milewicz et al. (2010).
In a 3-generation German family with autosomal dominant thoracic aortic aneurysm (AAT6; 611788), Hoffjan et al. (2011) identified heterozygosity for a c.115C-T transition in exon 2 of the ACTA2 gene, resulting in an arg39-to-cys (R39C) substitution at a highly conserved residue adjacent to the DNAse-I-binding loop within subdomain 2. The mutation segregated with disease in the family and was not found in 192 control chromosomes or in the GenBank dbSNP library. The vascular phenotype was variable in this family, ranging from mild aortic dilation and insufficiency in a 44-year-old woman to overt aortic aneurysm extending from the ascending to the abdominal aorta in a 25-year-old man. None of the affected individuals showed syndromic features, and there was no history of premature stroke or coronary artery disease. Hoffjan et al. (2011) noted that although a different mutation at the R39 residue, R39H, had been associated with type A dissections in 2 families and with type B dissections in another family (Guo et al., 2009), dissections were not observed in the family with the R39C mutation.
In a German woman who presented with acute aortic dissection at 37 years of age, Hoffjan et al. (2011) identified heterozygosity for a c.145A-G transition in exon 3 of the ACTA2 gene, resulting in a met49-to-val (M49V) substitution at a highly conserved residue in the DNAse-I-binding loop within subdomain 2. The mutation was not found in 192 control chromosomes or in the GenBank dbSNP library. The patient's brother had died at 29 years of age from acute aortic dissection, and her mother, who suffered from slowly progressive spastic paraplegia over 20 years and cancer, died suddenly at 69 years of age in association with a massive drop in blood pressure.
In a review of the clinical history and outcomes of 33 patients with smooth muscle dysfunction syndrome (SMDYS; 613834), Regalado et al. (2018) found 1 patient who was heterozygous for an arg179-to-leu (R179L) substitution in ACTA2.
In a 2.75-year-old Brazilian girl (patient 7) with smooth muscle dysfunction syndrome (SMDYS; 613834), Moreno et al. (2016) identified heterozygosity for a c.535C-T transition in the ACTA2 gene, resulting in an arg179-to-cys (R179C). The mutation was not found in her unaffected mother; DNA was unavailable from the father.
In a review of the clinical history and outcomes of 33 patients with SMDYS, Regalado et al. (2018) found 7 patients who were heterozygous for the R179C substitution in ACTA2.
In a review of the clinical history and outcomes of 33 patients with smooth muscle dysfunction syndrome (SMDYS; 613834), Regalado et al. (2018) found 1 patient who was heterozygous for an arg179-to-ser (R179S) substitution in ACTA2.
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Lemire, B. D., Buncic, J. R., Kennedy, S. J., Dyack, S. J., Teebi, A. S. Congenital mydriasis, patent ductus arteriosus, and congenital cystic lung disease: new syndromic spectrum? Am. J. Med. Genet. 131A: 318-319, 2004. [PubMed: 15472996] [Full Text: https://doi.org/10.1002/ajmg.a.30341]
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