Aneurysm Syndromes Caused by Mutations in the TGF-β Receptor

Loeys, Bart; Schwarze, Ulrike; Holm, Tammy M.; Callewaert, Bert; Thomas, George H.; Pannu, Hariyadarshi; Backer, Julie De; Oswald, Gretchen; Symoens, Sofie; Manouvrier, Sylvie; Roberts, Amy; Faravelli, Francesca; Greco, M. Alba; Pyeritz, Reed E.; Milewicz, Dianna M.; Coucke, Paul; Cameron, Duke E.; Braverman, Alan C.; Byers, Peter H.; Paepe, Anne M. De; Dietz, Harry C.

doi:10.1056/nejmoa055695

Cited by 1,465 publications

(632 citation statements)

References 13 publications

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“…Typical Loeys-Dietz syndrome is characterized by a mutation in either TβRI or TβRII [91]. The molecular mechanism of Loeys-Dietz syndrome is complex and poorly understood; although mutations in TβR are inactivating its function, they lead paradoxically to overactive TGF-β signaling, as measured by accumulation of phosphorylated Smad2 in the nucleus and expression levels of connective-tissue growth factor [92].…”

Section: Marfan Syndrome and Loeys-dietz Syndrome (Mfs And Lds)mentioning

confidence: 99%

TGF-β signaling in vascular biology and dysfunction

2008

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Transforming growth factor (TGF)-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our understanding of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.

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Section: Marfan Syndrome and Loeys-dietz Syndrome (Mfs And Lds)mentioning

confidence: 99%

TGF-β signaling in vascular biology and dysfunction

2008

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“…Recently, a pleiotropic condition of adults that shows autosomal recessive inheritance was described. 6 Patients have marked tortuosity of the aorta and its branches, and there is a predisposition to dissection. They also have telangiectases of the cheeks, lax skin, high palate, and joint laxity.…”

Section: Familial Arterial Tortuosity Syndromementioning

confidence: 99%

“…PYERITZ | Marfanoid evaluation ACMG prACtiCe Guidelines associated with mutations in TGFBR1 and TGFBR2, 6 in some of which both the aorta and its major branches dissect in the absence of much, if any, dilatation. Thus, the echocardiogram is an essential test whenever any of these conditions is considered seriously and whenever concerns about modulating physical activity are raised.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the adolescent or adult with some features of Marfan syndrome

Pyeritz

2012

Genetics in Medicine

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“…The enlargement of the aorta can extend proximally till the aortic valve resulting in, aortic insufficiency. Individuals with Marfan's syndrome can also have instable valve apparatus that result in the falling of the mitral valve into the left atrium during a systole causing a condition known as mitral valve prolapse [18][19][20][21][22][23]. …”

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confidence: 99%

Heart, Aorta and Aortic Valve Development and Cardiovascular Malformations

Mohamed¹

2017

Hum Genet Embryol

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IntroductionIn vertebrates, the heart is the first organ to develop and takes shape during the third week of embryogenesis. The earliest evidence of a heart structure can be identified beginning from day 15 of pregnancy. Stem cells in the anterior-lateral mesoderm become specific cardiac precursor cells and align in a horseshoe shape. In the third week of pregnancy these heart precursor cells that are previously arranged in bilateral symmetrical manner move medially to unite and form a single primitive heart tube. This straight heart tube consists of an inner cell layer (endocardium), an outer cell layer (myocardium), and the extracellular matrix (ECM) separating the other two layers also known as the heart jelly.The developmental stage that follows is a right-hand rotation of the heart leading to the first left-right non-symmetry in the embryo. Because of this rotation, the segments of the heart tube that later form the atria are positioned above the segment that forms the ventricles. The atria, ventricles, and truncus arteriosus originate through local extensions of the heart tube during heart loop shaping. Simultaneously, the ECM within the outflow tract and the future atrioventricular channel expand to form so-called endocardial cushions. Heart-tube segmentation into atria, ventricles, and the outflow tract is accomplished by these cushions. By further growth and additional fusions, they form septum-and valve-structure precursors, separating the developing ventricles from each other.During the sixth and seventh week of pregnancy, the heart and the common outflow tract (truncus arteriosus) are chambered by the septa to divide into four distinct ventricles, the aorta, and the pulmonary artery. This results in the formation of a separate pulmonary and systemic circulation. The aorta and its respective segments originate from diverse embryonic structures. The ascending part of the aorta, the aorta ascenders is formed by the division of the truncus arteriosus as described above; however, the aortic arch and supra-aortic vessels originate from the third and fourth branchial arch arteries. The fivecomplete branchial arch artery pairs are also designated as aortic arches and originate from the truncus arteriosus, connecting it with the right and left dorsal aorta, which are also a part of the embryonic circulation. When the heart develops into the heart tube, valve morphogenesis also begins. The ECM in regions around the outflow tracts and between the atria and ventricles expand to form endocardial cushions, contributing to the formation of all four heart valves. During the next few days interactions between diverse endocardial and myocardial signals occur, which are of crucial importance for the transition remodeling of the endothelium and the mesenchyme. Following this transformation, mesenchymal cells proliferate and support further swelling of the endocardial cushions. In addition, myocardial cells infiltrate the edges of the endocardial cushions now containing mesenchymal cells [1][2][3][4][5].In the truncus ar...

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Aneurysm Syndromes Caused by Mutations in the TGF-β Receptor

Cited by 1,465 publications

References 13 publications

TGF-β signaling in vascular biology and dysfunction

TGF-β signaling in vascular biology and dysfunction

Evaluation of the adolescent or adult with some features of Marfan syndrome

Heart, Aorta and Aortic Valve Development and Cardiovascular Malformations

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