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Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2)
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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  • References (19)
  • Cited By (39)
  • References (19)
  • Cited By (39)
John A. Elefteriades53
Estimated H-index: 53
(Yale University),
Emily A. Farkas6
Estimated H-index: 6
(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. ...
323 Citations Download PDF Cite
2006 in Nature Genetics [IF: 27.13]
Limin Zhu4
Estimated H-index: 4
(French Institute of Health and Medical Research),
Roger Vranckx23
Estimated H-index: 23
(French Institute of Health and Medical Research),
Philippe Khau Van Kien13
Estimated H-index: 13
(University of Burgundy)
... more
Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus
391 Citations Source Cite
Sergey M. Vorobiev13
Estimated H-index: 13
(Yeshiva University),
B Strokopytov1
Estimated H-index: 1
(Yeshiva University),
David G. Drubin78
Estimated H-index: 78
(University of California, Berkeley)
... more
The structures of Saccharomyces cerevisiae, Dictyostelium, and Caenorhabditis elegans actin bound to gelsolin segment-1 have been solved and refined at resolutions between 1.9 and 1.75 Å. These structures reveal several features relevant to the ATP hydrolytic mechanism, including identification of the nucleophilic water and the roles of Gln-137 and His-161 in positioning and activating the catalytic water, respectively. The involvement of these residues in the catalytic mechanism is consistent w...
117 Citations Download PDF Cite
Naser M. Ammash30
Estimated H-index: 30
,
Thoralf M. Sundt90
Estimated H-index: 90
,
Heidi M. Connolly53
Estimated H-index: 53
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
2001 in Science [IF: 41.06]
Ludovic R. Otterbein4
Estimated H-index: 4
(Boston Biomedical Research Institute),
Philip Graceffa22
Estimated H-index: 22
(Boston Biomedical Research Institute),
Roberto Dominguez36
Estimated H-index: 36
(Boston Biomedical Research Institute)
The dynamics and polarity of actin filaments are controlled by a conformational change coupled to the hydrolysis of adenosine 5′-triphosphate (ATP) by a mechanism that remains to be elucidated. Actin modified to block polymerization was crystallized in the adenosine 5′-diphosphate (ADP) state, and the structure was solved to 1.54 angstrom resolution. Compared with previous ATP-actin structures from complexes with deoxyribonuclease I, profilin, and gelsolin, monomeric ADP-actin is characterized b...
403 Citations Download PDF Cite
2007 in Nature Genetics [IF: 27.13]
Dong Chuan Guo32
Estimated H-index: 32
(University of Texas Health Science Center at Houston),
Hariyadarshi Pannu17
Estimated H-index: 17
(University of Texas Health Science Center at Houston),
Van Tran-Fadulu11
Estimated H-index: 11
(University of Texas Health Science Center at Houston)
... more
Mutations in smooth muscle α-actin ( ACTA2 ) lead to thoracic aortic aneurysms and dissections
508 Citations Download PDF Cite
2003 in Nature [IF: 41.58]
Kenneth C. Holmes41
Estimated H-index: 41
(Max Planck Society),
Isabel Angert3
Estimated H-index: 3
(Max Planck Society),
F. Jon Kull21
Estimated H-index: 21
(Max Planck Society)
... more
Muscle contraction involves the cyclic interaction of the myosin cross-bridges with the actin filament, which is coupled to steps in the hydrolysis of ATP'. While bound to actin each cross-bridge undergoes a conformational change, often referred to as the power stroke 2 , which moves the actin filament past the myosin filaments; this is associated with the release of the products of ATP hydrolysis and a stronger binding of myosin to actin. The association of a new ATP molecule weakens the bindin...
308 Citations Download PDF Cite
Bart Loeys54
Estimated H-index: 54
(Ghent University),
Ulrike Schwarze30
Estimated H-index: 30
(University of Washington),
Tammy Holm9
Estimated H-index: 9
(Johns Hopkins University)
... more
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...
1,004 Citations Download PDF Cite
2010 in Nature Methods [IF: 26.92]
Ivan Adzhubei14
Estimated H-index: 14
(Harvard University),
Steffen Schmidt27
Estimated H-index: 27
(Max Planck Society),
Leonid Peshkin28
Estimated H-index: 28
(Harvard University)
... more
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...
6,149 Citations Source Cite
Dominique P. Germain2
Estimated H-index: 2
,
Yessica Herrera-Guzman2
Estimated H-index: 2
Abstract Vascular Ehlers–Danlos syndrome, also known as Ehlers–Danlos syndrome type IV, is a life-threatening inherited disorder of connective tissue, resulting from mutations in the COL3A1 gene coding for type III procollagen. Vascular EDS causes severe fragility of connective tissues with arterial and gastrointestinal rupture, and complications of surgical and radiological interventions. As for many rare orphan diseases, delay in diagnosis is common, even when the clinical features are typical...
107 Citations Source Cite
  • References (19)
  • Cited By (39)
Yskert von Kodolitsch25
Estimated H-index: 25
,
Peter N. Robinson53
Estimated H-index: 53
(Charité),
Jürgen Berger26
Estimated H-index: 26
In western countries, thoracic aortic aneurysms and dissections (TAAD) are a common cause of death. Among patients with TAAD, 9 % have Marfan syndrome, and another 19 % exhibit a family history of TAAD which is unrelated to Marfan syndrome. Patients with heritable TAAD usually develop aortic rupture or dissection at an age under 40 years. Before the evolution of open-heart surgery, affected persons died from aortic dissection or rupture at young age. Currently, Marfan patients and most other ind...
8 Citations Source Cite
2015 in Pediatrics [IF: 2.16]
Anji T. Yetman10
Estimated H-index: 10
,
Lois J. Starr7
Estimated H-index: 7
(University of Nebraska Medical Center),
Steven B. Bleyl18
Estimated H-index: 18
(University of Utah)
... more
Mutations in the gene ACTA2 are a recognized cause of aortic aneurysms with aortic dissection in adulthood. Recently, a specific mutation (Arg179His) in this gene has been associated with multisystem smooth muscle dysfunction presenting in childhood. We describe 3 patients with an R179H mutation, all of whom presented with an aneurysmal patent ductus arteriosus. Detailed information on the rate of aortic disease progression throughout childhood is provided. Death or need for ascending aortic rep...
7 Citations Download PDF Cite
A. Léonard , P. De Potter2
Estimated H-index: 2
Free-floating iris pigment epithelial cysts in the vitreous are very rare. We report the case of a partially pigmented cyst found on routine examination in the vitreous of a 51-year-old asymptomatic patient. Usually, non-pigmented cysts are derived from the hyaloid system. Pigmented cysts, however, are derived from the iris pigment epithelium. When they are not dislodged, these cysts can be confused with iris melanoma or primary stromal cysts. Treatment is usually unnecessary, unless they become...
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Sai Win2
Estimated H-index: 2
(University of New South Wales),
Richard T. Parker1
Estimated H-index: 1
,
Janice Jy Ku1
Estimated H-index: 1
(University of New South Wales)
... more
1 Citations Source Cite
Pawel Pomianowski3
Estimated H-index: 3
(Yale University),
John A. Elefteriades53
Estimated H-index: 53
(Yale University)
Genetic studies over the past several decades have helped to better elucidate the genomics and inheritance of thoracic aortic diseases. Seminal work from various researchers have identified several genetic factors and mutations that predispose to aortic aneurysms, which will aid in better screening and early intervention, resulting in better clinical outcomes. Syndromic aneurysms have been associated with Marfan syndrome, Loeys-Dietz syndrome, aneurysm osteoarthritis syndrome, arterial tortuosit...
45 Citations Download PDF Cite
2015 in Heart [IF: 5.42]
Ilse Luyckx3
Estimated H-index: 3
(University of Antwerp),
Bart Loeys54
Estimated H-index: 54
(University of Antwerp)
### Learning objectives Curriculum topic : Disease of the aorta and trauma to the aorta and heart Aortic aneurysm/dissection is a common cause of cardiovascular morbidity and mortality in the Western world. In general, two forms have been recognised: abdominal aortic aneurysm/dissection (AAAD) and thoracic aortic aneurysm/dissection (TAAD). Although some genetic predisposition for abdominal aneurysm has been recognised, major risk factors include male sex, age, smoking, hypercholesterolaemia and...
9 Citations Download PDF Cite
Nada Abdulkareem4
Estimated H-index: 4
(St George's Hospital),
Philipp Skroblin8
Estimated H-index: 8
(King's College London),
Marjan Jahangiri29
Estimated H-index: 29
(St George's Hospital)
... more
Aortic aneurysm is a deceptively indolent disease that can cause severe complications such as aortic rupture and dissection. In the normal aorta, vascular smooth muscle cells within the medial layer produce and sustain the extracellular matrix (ECM) that provides structural support but also retains soluble growth factors and regulates their distribution. Although the ECM is an obvious target to identify molecular processes leading to structural failure within the vessel wall, an in-depth proteom...
7 Citations Download PDF Cite
2012 in Brain [IF: 10.85]
P. Munot4
Estimated H-index: 4
(Great Ormond Street Hospital),
Dawn E. Saunders23
Estimated H-index: 23
(Great Ormond Street Hospital),
Dianna M. Milewicz56
Estimated H-index: 56
(University of Texas at Austin)
... more
Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus...
53 Citations Source Cite
Gisela Teixido-Tura12
Estimated H-index: 12
,
Irene Valenzuela2
Estimated H-index: 2
,
Laura Gutiérrez2
Estimated H-index: 2
... more
Source Cite

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