Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease

Guo, Dong; Papke, Christina L.; Tran-Fadulu, Van; Regalado, Ellen S.; Avidan, Nili; Johnson, Ralph J.; Kim, Dong H.; Pannu, Hariyadarshi; Willing, Marcia; Sparks, Elizabeth; Pyeritz, Reed E.; Singh, Michael; Dalman, Ronald L.; Grotta, James C.; Marian, Ali J.; Boerwinkle, Eric; Frazier, Lorraine; LeMaire, Scott A.; Coselli, Joseph S.; Estrera, Anthony L.; Safi, Hazim J.; Veeraraghavan, Sudha; Muzny, Donna M.; Wheeler, David A.; Willerson, James T.; Yu, Robert; Shete, Sanjay; Scherer, Steven E.; Raman, C.S.; Buja, L. Maximilian; Milewicz, Dianna M.

doi:10.1016/j.ajhg.2009.04.007

Cited by 492 publications

(453 citation statements)

References 32 publications

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“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Mariscalco

Debiec

Elefteriades

et al. 2018

JAHA

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BackgroundNonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not the current standard of care in NS‐TADs. We sought to determine the incidence of aortic diseases, the predictive accuracy of available screening tests, and the effectiveness of screening programs in relatives of patients affected by NS‐TADs.Methods and ResultsA systematic literature search on PubMed/MEDLINE, Embase, and the Cochrane Library was conducted from inception to the end of December 2017. The search was supplemented with the Online Mendelian Inheritance in Man database. A total of 53 studies were included, and a total of 2696 NS‐TAD relatives were screened. Screening was genetic in 49% of studies, followed by imaging techniques in 11% and a combination of the 2 in 40%. Newly affected individuals were identified in 33%, 24%, and 15% of first‐, second‐, and third‐degree relatives, respectively. Familial NS‐TADs were primarily attributed to single‐gene mutations, expressed in an autosomal dominant pattern with incomplete penetrance. Specific gene mutations were observed in 25% of the screened families. Disease subtype and genetic mutations stratified patients with respect to age of presentation, aneurysmal location, and aortic diameter before dissection. Relatives of patients with sporadic NS‐TADs were also found to be affected. No studies evaluated the predictive accuracy of imaging or genetic screening tests, or the clinical or cost‐effectiveness of an NS‐TAD screening program.ConclusionsFirst‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs.

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Section: Discussionmentioning

confidence: 99%

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Mariscalco

Debiec

Elefteriades

et al. 2018

JAHA

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“…However, only COL4A1 mutations have been identified after linkage in large pedigrees. 3 One of the reasons could be the difficulty to recruit large families with similarly affected patients, because of phenotypic variability or reduced penetrance of COL4A2 mutations, similarly to other causes of stroke and aneurysm, 35 which makes linkage analysis quite difficult.…”

Section: Pathogenesis Of Col4a2 Mutationsmentioning

confidence: 99%

COL4A2 mutation associated with familial porencephaly and small-vessel disease

et al. 2012

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Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 3206delC fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.

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“…This goes along with the fact that the mutations described so far were also almost exclusively missense mutations, except for one splice site mutation resulting in skipping of exon 6. 2,6,17 The three mutations presented in this work add to the single mutations previously reported for exons 2, 3 and 8 (Table 1) and therefore underpin the role of the N-and C-terminal portions of actin. Collectively, the genetic findings in the published cohorts suggest that routine genetic testing in TAAD should address all coding exons of ACTA2.…”

Section: Genetic Epidemiology Of Taad Linked To Acta2mentioning

confidence: 99%

“…4 Similar to the situation found in hypertrophic and dilated cardiomyopathy, mutations of the vascular isoforms of actin and myosin are thought to disturb SMC contractile function, thereby triggering profound remodelling of the vessel wall, followed by an increase in aortic stiffness and, ultimately, aortic dilation and dissection. 2,3,5,6 It is worth noting that MYH11 mutations appear to be rare (only five mutations reported so far) and have been exclusively found in patients displaying a syndrome comprising of TAAD and patent ductus arteriosus, a common congenital cardiovascular malformation. 7 In contrast, ACTA2 mutations were found to be responsible for approximately 14% of familial TAAD and are believed to interfere with the normal assembly of actin filaments.…”

Section: Introductionmentioning

confidence: 99%

“…5 It has been claimed that in addition to TAAD, ACTA2 mutations predispose patients to a variety of vascular diseases including premature coronary artery disease (CAD) and premature ischaemic strokes. 6 In order to further explore the role of ACTA2 variations in the pathogenesis of TAAD, we sequenced the coding regions of this gene in 40 unrelated German patients with TAAD who had previously tested negative for mutations in the FBN1 and TGFBR2 genes.…”

Section: Introductionmentioning

confidence: 99%

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Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections

Hoffjan¹,

Waldmüller²,

Blankenfeldt³

et al. 2011

Eur J Hum Genet

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Mutations in the gene encoding smooth muscle cell alpha actin (ACTA2) have recently been shown to cause familial thoracic aortic aneurysms leading to type A dissections (TAAD) and predispose to premature stroke and coronary artery disease. In order to further explore the role of ACTA2 variations in the pathogenesis of TAAD, we sequenced the coding regions of this gene in 40 unrelated German patients with TAAD (with (n¼21) or without (n¼19) clinical features suggestive of Marfan syndrome). All patients had previously tested negative for mutations in the FBN1 and TGFBR2 genes. We identified three novel ACTA2 mutations and mapped them on a three-dimensional model of actin. Two mutations affect residues within (M49V) or adjacent to (R39C), the DNAse-I-binding loop within subdomain 2 of alpha actin. They were observed in families with recurrent aortic aneurysm (R39C) or aortic dissection (M49V). The third mutation causes an exchange in the vicinity of the ATP-binding site (G304R) in a patient thought to have isolated TAAD. None of the affected individuals had clinical features typical for Marfan syndrome, and no case of premature stroke or coronary artery disease was reported from the affected families. In conclusion, we underscore the role of ACTA2 mutations in nonsyndromic TAAD and suggest that ACTA2 should be included in the genes routinely investigated for syndromic and nonsyndromic TAAD. Detailed clinical investigations of additional families are warranted to further explore the full range of phenotypic signs associated with the three novel mutations described here.

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Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease

Cited by 492 publications

References 32 publications

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

COL4A2 mutation associated with familial porencephaly and small-vessel disease

Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections

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