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Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2)

Published on Feb 15, 2011in Heart 5.42
· DOI :10.1136/hrt.2010.204388
Eliana Disabella6
Estimated H-index: 6
,
Maurizia Grasso31
Estimated H-index: 31
+ 9 AuthorsEloisa Arbustini56
Estimated H-index: 56
Abstract
Objective To evaluate the prevalence and phenotype of smooth muscle alpha-actin ( ACTA2 ) mutations in non-syndromic thoracic aortic aneurysms and dissections (TAAD). Design Observational study of ACTA2 mutations in TAAD. Setting Centre for Inherited Cardiovascular Diseases. Patients A consecutive series of 100 patients with TAAD. Exclusion criteria included genetically confirmed Marfan syndrome, Loeys–Dietz type 2, familial bicuspid aortic valve and Ehlers–Danlos type IV syndromes. Interventions Multidisciplinary clinical and imaging evaluation, genetic counselling and testing of ACTA2 , and family screening. Main outcome measures Prevalence of ACTA2 mutations and corresponding phenotypes. Results TAAD was familial in 43 cases and sporadic in 57 cases. Five mutations in the familial TAAD group (12%) were identified that were absent in controls. The known p.Arg149Cys and the novel p.Asp82Glu, p.Glu243Lys and p.Val45Leu mutations affected evolutionarily conserved residues. The IVS4+1G>A mutation was novel. Of 14 affected relatives, 13 were carriers of the mutation identified in the corresponding proband while one deceased relative had no genetic test. Type A dissection was the first manifestation of aortic aneurysm in four probands and occurred unexpectedly in five relatives. The aortic aneurysm was age dependent and absent in mutated children. Of nine patients who had acute dissection, five died following surgery. At dissection, the size of the aortic aneurysm ranged from 40 mm to 95 mm. Extravascular, ocular, skeletal, nervous and pulmonary traits were variably associated with TAAD, with iris flocculi being most common. Conclusions Timely diagnosis of TAAD in the probands, genetic counselling and family screening identify predisposed relatives and prevent catastrophic aortic dissections.
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  • Citations (39)
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References19
Newest
Published on Apr 1, 2010in Nature Methods 26.92
Ivan Adzhubei15
Estimated H-index: 15
(Harvard University),
Steffen Schmidt27
Estimated H-index: 27
(MPG: Max Planck Society)
+ 5 AuthorsShamil R. Sunyaev64
Estimated H-index: 64
(Harvard University)
To the Editor: Applications of rapidly advancing sequencing technologies exacerbate the need to interpret individual sequence variants. Sequencing of phenotyped clinical subjects will soon become a method of choice in studies of the genetic causes of Mendelian and complex diseases. New exon capture techniques will direct sequencing efforts towards the most informative and easily interpretable protein-coding fraction of the genome. Thus, the demand for computational predictions of the impact of p...
6,578 Citations Source Cite
Published on Mar 1, 2010in Journal of the American College of Cardiology 16.83
John A. Elefteriades54
Estimated H-index: 54
(Yale University),
Emily A. Farkas6
Estimated H-index: 6
(SLU: Saint Louis University)
This paper addresses clinical controversies and uncertainties regarding thoracic aortic aneurysm and its treatment. 1) Estimating true aortic size is confounded by obliquity, asymmetry, and noncorresponding sites: both echocardiography and computed tomography/magnetic resonance imaging are necessary for complete assessment. 2) Epidemiology of thoracic aortic aneurysm. There has been a bona fide increase in incidence of aortic aneurysm making aneurysm disease the 18th most common cause of death. ...
337 Citations Source Cite
Published on Oct 1, 2009in Human Mutation 5.36
Hiroko Morisaki23
Estimated H-index: 23
,
Koichi Akutsu14
Estimated H-index: 14
+ 11 AuthorsKenji Minatoya26
Estimated H-index: 26
Approximately 20% of aortic aneurysm and/or dissection (AAD) cases result from inherited disorders, including several systemic and syndromatic connective-tissue disorders, such as Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome, which are caused by mutations in the FBN1, COL3A1, and TGFBR1 and TGFBR2 genes, respectively. Nonsyndromatic AAD also has a familial background, and mutations of the ACTA2 gene were recently shown to cause familial AAD. In the present study, we conducte...
59 Citations Source Cite
Published on May 1, 2009in American Journal of Human Genetics 8.86
Dongchuan Guo32
Estimated H-index: 32
(University of Texas Health Science Center at Houston),
Christina L. Papke9
Estimated H-index: 9
(University of Texas Health Science Center at Houston)
+ 28 AuthorsElizabeth Sparks21
Estimated H-index: 21
(Harvard University)
The vascular smooth muscle cell (SMC)-specific isoform of α-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including p...
295 Citations Source Cite
Published on Sep 1, 2008in Annual Review of Genomics and Human Genetics 8.68
Dianna M. Milewicz56
Estimated H-index: 56
(University of Texas at Austin),
Dongchuan Guo32
Estimated H-index: 32
(University of Texas at Austin)
+ 5 AuthorsHariyadarshi Pannu18
Estimated H-index: 18
(University of Texas at Austin)
Thoracic aortic aneurysms leading to type A dissections (TAAD) can be inherited in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When TAAD occurs in the absence of syndromic features, it is inherited in an autosomal dominant manner with decreased penetrance and variable expression, the disease is referred to as familial TAAD. Familial TAAD exhibits significant clinical and genetic heterogeneity. The first genes identified to cause TAAD were...
258 Citations Source Cite
Published on Jan 1, 2008in Current Problems in Cardiology 4.19
Naser M. Ammash31
Estimated H-index: 31
,
Thoralf M. Sundt92
Estimated H-index: 92
,
Heidi M. Connolly55
Estimated H-index: 55
Abstract Marfan syndrome (MFS) is the most common inherited disorder of connective tissue that affects multiple organ systems. This autosomal-dominant condition has an incidence of 2-3 per 10,000 individuals. Although genetic testing is available, the diagnosis is still primarily made using the Ghent criteria. Early identification and appropriate management is critical for patients with MFS who are prone to the life-threatening cardiovascular complications of aortic dissection and rupture. Advan...
115 Citations Source Cite
Published on Dec 1, 2007in Nature Genetics 27.13
Dongchuan Guo32
Estimated H-index: 32
(University of Texas Health Science Center at Houston),
Hariyadarshi Pannu18
Estimated H-index: 18
(University of Texas Health Science Center at Houston)
+ 22 AuthorsElizabeth Sparks21
Estimated H-index: 21
(OSU: Ohio State University)
Mutations in smooth muscle α-actin ( ACTA2 ) lead to thoracic aortic aneurysms and dissections
527 Citations Source Cite
Published on Aug 24, 2006in The New England Journal of Medicine 79.26
Bart Loeys56
Estimated H-index: 56
(UGent: Ghent University),
Ulrike Schwarze30
Estimated H-index: 30
(UW: University of Washington)
+ 18 AuthorsSylvie Manouvrier18
Estimated H-index: 18
(Lille University of Science and Technology)
Background The Loeys–Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor β receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). Methods We undertook the clinical and molecular characterization of 52 affected familie...
1,034 Citations Source Cite
Published on Mar 6, 2006in Nucleic Acids Research 11.56
Ewy Mathé18
Estimated H-index: 18
(IARC: International Agency for Research on Cancer),
Magali Olivier33
Estimated H-index: 33
(IARC: International Agency for Research on Cancer)
+ 3 AuthorsSean V. Tavtigian55
Estimated H-index: 55
(IARC: International Agency for Research on Cancer)
Prediction of the biological effect of missense substitutions has become important because they are often observed in known or candidate disease susceptibility genes. In this paper, we carried out a 3-step analysis of 1514 missense substitutions in the DNA-binding domain (DBD) of TP53, the most frequently mutated gene in human cancers. First, we calculated two types of conservation scores based on a TP53 multiple sequence alignment (MSA) for each substitution: (i) Grantham Variation (GV), which ...
221 Citations Source Cite
Published on Mar 1, 2006in Nature Genetics 27.13
Limin Zhu5
Estimated H-index: 5
,
Roger Vranckx24
Estimated H-index: 24
+ 11 AuthorsFrançois Brunotte28
Estimated H-index: 28
Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus
405 Citations Source Cite
Cited By39
Newest
Adam J. Brownstein4
Estimated H-index: 4
(Yale University),
Bulat A. Ziganshin14
Estimated H-index: 14
(Yale University),
John A. Elefteriades54
Estimated H-index: 54
(Yale University)
Thoracic aortic aneurysm (TAA), a typically silent but frequently lethal disease, is strongly influenced by underlying genetics. Approximately 30 genes have been associated with syndromic and non-syndromic familial thoracic aortic aneurysm and dissection (TAAD) to date. An estimated 30% of patients with non-syndromic familial TAAD, which is typically inherited in an autosomal dominant manner, have a mutation in one of these genes. The underlying genetic mutation helps predict patients’ clinical ...
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Published on Apr 1, 2019in British Journal of Ophthalmology 3.38
Kenneth J. Taubenslag1
Estimated H-index: 1
(University of Pittsburgh),
Hannah L. Scanga3
Estimated H-index: 3
(University of Pittsburgh)
+ 5 AuthorsKen K. Nischal26
Estimated H-index: 26
(University of Pittsburgh)
Background Central cysts of the iris pigment epithelium, or iris flocculi, are frequently reported in the literature in association with thoracic aortic aneurysm and dissection due to smooth muscle alpha-actin 2 ( ACTA2 ) mutations. Children with ACTA2 mutations may also present with congenital mydriasis. We report our experience regarding the frequency of ACTA2 mutation in children with the above iris anomalies. Methods This is a retrospective, consecutive case series of all children presenting...
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Published on Jan 1, 2019in Genetics in Medicine 9.94
Stephanie Wallace3
Estimated H-index: 3
(University of Texas Health Science Center at Houston),
Ellen S. Regalado24
Estimated H-index: 24
(University of Texas Health Science Center at Houston)
+ 17 AuthorsCatherine Boileau55
Estimated H-index: 55
(Paris Diderot University)
Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm rep...
2 Citations Source Cite
Published on Dec 1, 2018in BMC Medical Genetics 1.91
Anna Keravnou4
Estimated H-index: 4
(The Cyprus Institute of Neurology and Genetics),
Evy Bashiardes6
Estimated H-index: 6
(The Cyprus Institute of Neurology and Genetics)
+ 3 AuthorsMarios A. Cariolou18
Estimated H-index: 18
(The Cyprus Institute of Neurology and Genetics)
Background Thoracic aortic aneurysm (TAA) and/or thoracic aortic aneurysm and dissection (TAAD) is characterized by a considerable risk of morbidity and mortality of affected individuals. It is inherited in an autosomal dominant pattern and the 20% of patients with non-syndromic TAA have a positive family history. To date, the genetic basis of Cypriot patients with TAA has not been investigated. The purpose of this case report is to determine underlying genetic cause in this Cypriot family with ...
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Published on Jun 1, 2018in European Journal of Preventive Cardiology 4.54
Davide Carino2
Estimated H-index: 2
(Yale University),
Andrea Agostinelli11
Estimated H-index: 11
(University of Parma)
+ 3 AuthorsFrancesco Nicolini19
Estimated H-index: 19
(University of Parma)
Although much has been learned about disease of the thoracic aorta, most diagnosis of thoracic aortic aneurysm (TAA) is still incidental. The importance of the genetic aspects in thoracic aortic disease is overwhelming, and today different mutations which cause TAA or alter its natural history have been discovered. Technological advance has made available testing which detects genetic mutations linked to TAA. This article analyses the genetic aspects of TAA and describes the possible role of gen...
1 Citations Source Cite
Published on Dec 1, 2017in Scientific Reports 4.12
Miaoxian Fang1
Estimated H-index: 1
(Academy of Medical Sciences, United Kingdom),
Changjiang Yu1
Estimated H-index: 1
(Academy of Medical Sciences, United Kingdom)
+ 5 AuthorsRuixin Fan1
Estimated H-index: 1
(Academy of Medical Sciences, United Kingdom)
Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide. Up to 40% of TAAD are hereditary with complex heterogeneous genetic backgrounds. Recently, next-generation sequencing (NGS) has been successfully applied to identify genetic variants in an efficient and cost-effective manner. In our study, NGS coupled with DNA target-capture array was used to screen 11 known causative genes of TAAD in 70 patients from Southern China. All the identifi...
3 Citations Source Cite
Published on Nov 1, 2017in Interactive Cardiovascular and Thoracic Surgery 1.76
Giada Tortora4
Estimated H-index: 4
(UNIBO: University of Bologna),
Anita Wischmeijer14
Estimated H-index: 14
(UNIBO: University of Bologna)
+ 10 AuthorsOrnella Leone30
Estimated H-index: 30
(UNIBO: University of Bologna)
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Published on Sep 1, 2017in Survey of Ophthalmology 3.76
Ilias Georgalas19
Estimated H-index: 19
(UoA: National and Kapodistrian University of Athens),
Petros Petrou9
Estimated H-index: 9
(UoA: National and Kapodistrian University of Athens)
+ 3 AuthorsMenelaos Kanakis3
Estimated H-index: 3
(UoA: National and Kapodistrian University of Athens)
Abstract Iris cysts, both primary and secondary, are a diagnostic and treatment challenge. Primary cysts arise either from the iris pigment epithelium or the iris stroma. Posterior pigment epithelial cysts are subdivided according to their location as central, midzonal, and peripheral. Iris stromal cysts are classified either as congenital or acquired. Free-floating cysts are usually dislodged pigment epithelial cysts. Secondary cysts are classified according to the underlying cause as implantat...
1 Citations Source Cite
Published on Aug 10, 2017in Frontiers in Physiology 3.39
Azra Alajbegovic5
Estimated H-index: 5
(Lund University),
Johan Holmberg20
Estimated H-index: 20
(Lund University),
Sebastian Albinsson20
Estimated H-index: 20
(Lund University)
Aortic aneurysms are defined as an irreversible increase in arterial diameter by more than 50% relative to the normal vessel diameter. The incidence of aneurysm rupture is about 10 in 100 000 persons per year and ruptured arterial aneurysms inevitably results in serious complications, which are fatal in about 40% of cases. There is also a hereditary component of the disease and dilation of the ascending thoracic aorta is often associated with congenital heart disease such as bicuspid aortic valv...
3 Citations Source Cite
Published on Feb 3, 2017in Circulation Research 15.21
Amelia K Boehme8
Estimated H-index: 8
(Columbia University),
Charles C. Esenwa4
Estimated H-index: 4
(Columbia University),
Mitchell S.V. Elkind63
Estimated H-index: 63
(Columbia University)
Stroke is a heterogeneous syndrome, and determining risk factors and treatment depends on the specific pathogenesis of stroke. Risk factors for stroke can be categorized as modifiable and nonmodifiable. Age, sex, and race/ethnicity are nonmodifiable risk factors for both ischemic and hemorrhagic stroke, while hypertension, smoking, diet, and physical inactivity are among some of the more commonly reported modifiable risk factors. More recently described risk factors and triggers of stroke includ...
51 Citations Source Cite