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Mutations in smooth muscle α-actin ( ACTA2 ) lead to thoracic aortic aneurysms and dissections

Published on Dec 1, 2007in Nature Genetics25.455
· DOI :10.1038/ng.2007.6
Dongchuan Guo33
Estimated H-index: 33
(University of Texas Health Science Center at Houston),
Hariyadarshi Pannu18
Estimated H-index: 18
(University of Texas Health Science Center at Houston)
+ 22 AuthorsDianna M. Milewicz58
Estimated H-index: 58
(University of Texas Health Science Center at Houston)
Abstract
Mutations in smooth muscle α-actin ( ACTA2 ) lead to thoracic aortic aneurysms and dissections
  • References (30)
  • Citations (539)
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References30
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#1Hariyadarshi Pannu (University of Texas Health Science Center at Houston)H-Index: 18
#2Van Tran-Fadulu (University of Texas Health Science Center at Houston)H-Index: 12
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
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Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in 20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11). On sequencing MYH11 in 93 families with TAAD alone a...
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#1Kristen J. Nowak (UWA: University of Western Australia)H-Index: 26
#2Caroline A. Sewry (Imperial College London)H-Index: 61
Last. Nigel G. Laing (UWA: University of Western Australia)H-Index: 61
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Objective To investigate seven congenital myopathy patients from six families: one French Gypsy, one Spanish Gypsy, four British Pakistanis, and one British Indian. Three patients required mechanical ventilation from birth, five died before 22 months, one is ventilator-dependent, but one, at 30 months, is sitting with minimal support. All parents were unaffected. Methods The α-skeletal muscle actin gene (ACTA1) was sequenced. Available muscle biopsies were investigated by standard histological a...
70 CitationsSource
#1Hariyadarshi Pannu (University of Texas Health Science Center at Houston)H-Index: 18
#2Nili Avidan (University of Texas Health Science Center at Houston)H-Index: 22
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
view all 4 authors...
: Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) have long been known to occur in association with a genetic syndrome such as Marfan syndrome (MFS). More recently, TAAD has also been demonstrated to occur as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified TAAD loci at 5q13-14 (TAAD1), 11q23 (FAA1), 3p24-25 (TAAD2), and 16p12.2-13.13. The genet...
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#1Bart Loeys (UGent: Ghent University)H-Index: 56
#2Ulrike Schwarze (UW: University of Washington)H-Index: 30
Last. Harry C. Dietz (Johns Hopkins University)H-Index: 90
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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...
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#1Limin ZhuH-Index: 5
#2Roger Vranckx (French Institute of Health and Medical Research)H-Index: 24
Last. Xavier JeunemaitreH-Index: 69
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Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus
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#1Rumin He (University of Texas at Austin)H-Index: 2
#2Dongchuan Guo (University of Texas at Austin)H-Index: 33
Last. Dianna M. Milewicz (University of Texas at Austin)H-Index: 58
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Objective The histopathologic abnormality underlying ascending aortic aneurysm and dissection is medial degeneration, a lesion that is described as the noninflammatory loss of smooth muscle cells and elastic fibers. This study sought to determine whether inflammatory cells are present in medial degeneration and assess any possible contribution of these cells to apoptosis of smooth muscle cells. Methods Aortic specimens were obtained from patients undergoing prophylactic surgical repair of an asc...
161 CitationsSource
#1Jil C. Tardiff (Albert Einstein College of Medicine)H-Index: 25
Hypertrophic Cardiomyopathy (HCM) is a relatively common primary cardiac disorder defined as the presence of a hypertrophied left ventricle in the absence of any other diagnosed etiology. HCM is the most common cause of sudden cardiac death in young people which often occurs without precedent symptoms. The overall clinical phenotype of patients with HCM is broad, ranging from a complete lack of cardiovascular symptoms to exertional dyspnea, chest pain, and sudden death, often due to arrhythmias....
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▪ Abstract Cardiomyopathies are primary disorders of cardiac muscle associated with abnormalities of cardiac wall thickness, chamber size, contraction, relaxation, conduction, and rhythm. They are a major cause of morbidity and mortality at all ages and, like acquired forms of cardiovascular disease, often result in heart failure. Over the past two decades, molecular genetic studies of humans and analyses of model organisms have made remarkable progress in defining the pathogenesis of cardiomyop...
260 CitationsSource
#1Hariyadarshi Pannu (University of Texas Health Science Center at Houston)H-Index: 18
#2Van Tran Fadulu (University of Texas Health Science Center at Houston)H-Index: 3
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
view all 14 authors...
Background— A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24–25, we sequenced the gene for transforming growth factor-β receptor type II (TGFBR2) to determine whether mutations in this gene resulted in familial TAAD. Methods and Results— We sequenced a...
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#1Brian J. Poindexter (TMC: Texas Medical Center)H-Index: 18
Objective: The aim of this study was visualization and localization of the human antimicrobials human beta defensins 1, 2, and 3, neutrophil defensin alpha (human neutrophil peptide), and the cathelicidin LL-37 in normal and burned skin, and determination of the cell types in which these antimicrobials were localized. Methods: Tissue sections were probed with antimicrobial antibodies, tagged with fluorescently labeled secondary antibodies, and subjected to fluorescence deconvolution microscopy a...
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Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients’ survival. This improved survival has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased ...
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Abstract Purpose Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease, of which genetic abnormalities are considered as important risk factors. The present research aims at identifying causal variants in Chinese patients with sporadic non-syndromic type A TAAD (ATAAD). Materials and Methods Whole exome sequencing (WES) was performed on 73 sporadic Chinese patients with ATAAD, 30 TAAD associated genes were curated for bioinformatic analyses. Clinical differences were compa...
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The aortic wall is composed of highly dynamic cell populations and extracellular matrix. In response to changes in the biomechanical environment, aortic cells and extracellular matrix modulate thei...
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BACKGROUND: Congenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (alpha-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal a...
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Aortic aneurysm is a permanent focal dilation of the aorta. It is usually an asymptomatic disease, but can lead to sudden death due to aortic rupture. Aortic aneurysm-related mortalities are estima...
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Mutations in ACTA2, encoding smooth muscle α-actin, are a frequent cause of heritable thoracic aortic aneurysm and dissections. These mutations are associated with impaired vascular smooth muscle c...
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Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed inc...
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