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Aneurysm Syndromes Caused by Mutations in the TGF-β Receptor

Published on Aug 24, 2006in The New England Journal of Medicine 70.67
· DOI :10.1056/NEJMoa055695
Bart Loeys56
Estimated H-index: 56
(UGent: Ghent University),
Ulrike Schwarze30
Estimated H-index: 30
(UW: University of Washington)
+ 18 AuthorsHarry C. Dietz86
Estimated H-index: 86
(Johns Hopkins University)
Cite
Abstract
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 families. Forty probands presented with typical manifestations of the Loeys–Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers–Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers–Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys–Dietz syndrome. Results We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys–Dietz syndrome (type I) and in 12 probands presenting ...
  • References (13)
  • Citations (1034)
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References13
Newest
Published on Apr 7, 2006in Science 41.04
Jennifer Habashi11
Estimated H-index: 11
,
Daniel P. Judge39
Estimated H-index: 39
+ 17 AuthorsCarla Calvi7
Estimated H-index: 7
(Johns Hopkins University)
Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor–β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β–neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, lo...
Published on Jan 1, 2006in European Journal of Human Genetics 3.65
Eliana Disabella6
Estimated H-index: 6
,
Maurizia Grasso31
Estimated H-index: 31
+ 12 AuthorsLuca Lanzarini18
Estimated H-index: 18
Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects
Published on Dec 1, 2005in The Lancet 59.10
Daniel P. Judge39
Estimated H-index: 39
(Johns Hopkins University),
Harry C. Dietz86
Estimated H-index: 86
(Johns Hopkins University)
Summary Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mou...
Published on Jul 18, 2005in Circulation 23.05
Hariyadarshi Pannu18
Estimated H-index: 18
(University of Texas Health Science Center at Houston),
Van Tran Fadulu3
Estimated H-index: 3
(University of Texas Health Science Center at Houston)
+ 11 AuthorsHazim J. Safi60
Estimated H-index: 60
(University of Texas Health Science Center at Houston)
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...
Published on Jul 1, 2005in Journal of Vascular Surgery 3.24
Gustavo S. Oderich34
Estimated H-index: 34
(Mayo Clinic),
Jean M. Panneton40
Estimated H-index: 40
(EVMS: Eastern Virginia Medical School)
+ 6 AuthorsPeter A. Gaines Frcp Frcr84
Estimated H-index: 84
(Mayo Clinic)
Purpose Ehlers-Danlos syndrome type IV (EDS-IV) results from abnormal procollagen III synthesis and leads to arterial, intestinal, and uterine rupture. The purpose of this study was to review the spectrum, management, and clinical outcome of EDS-IV patients. Methods We retrospectively reviewed the clinical data of 31 patients (15 male and 16 female) with a clinical diagnosis of EDS-IV treated over a 30-year period (1971 to 2001). Biochemical confirmation was obtained in 24 patients, and mutation...
Published on Mar 1, 2005in Nature Genetics 25.45
Bart Loeys56
Estimated H-index: 56
(Johns Hopkins University),
Junji Chen1
Estimated H-index: 1
(Johns Hopkins University)
+ 21 AuthorsNeda Sharifi2
Estimated H-index: 2
(Johns Hopkins University)
We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor β receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFβ signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetic...
Published on Aug 1, 2004in Nature Genetics 25.45
Takeshi Mizuguchi21
Estimated H-index: 21
,
Gwenaëlle Collod-Béroud27
Estimated H-index: 27
(Necker-Enfants Malades Hospital)
+ 20 AuthorsHiroko Morisaki23
Estimated H-index: 23
Marfan syndrome (MFS) is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton, and cardiovascular systems and associated with defects in the fibrillin gene (FBN1) at 15q21.1 1. We previously mapped the second locus for MFS (MFS type 2, MFS2, OMIM *154705), at 3p24.2-p25 in a large French family (MS1)2. Identification of a 3p24.1 chromosomal breakpoint disrupting the TGF-beta receptor 2 gene (TGFBR2) in a Japanese MFS patient led us to consider TGFBR2 as the MSF2 gen...
Published on Jul 1, 2003in Circulation 23.05
Sumera N. Hasham7
Estimated H-index: 7
(University of Texas Health Science Center at Houston),
Marcia C. Willing36
Estimated H-index: 36
(UI: University of Iowa)
+ 6 AuthorsDianna M. Milewicz56
Estimated H-index: 56
(University of Texas Health Science Center at Houston)
Background— Familial thoracic aortic aneurysms and dissections (TAAD) occur as part of known syndromes such as Marfan syndrome but can also be inherited in families in an autosomal dominant manner as an isolated condition. Previous studies have mapped genes causing nonsyndromic familial TAAD to 5q13–15 (TAAD1) and 11q23.2-q24 (FAA1). Further genetic heterogeneity for the condition was evident by the presence of TAAD in some families not linked to these known loci. Methods and Results— A 4-genera...
Published on Jan 15, 2001in Cancer Research 8.38
Chris D. Lücke1
Estimated H-index: 1
(University of Cambridge),
Anna Philpott32
Estimated H-index: 32
(University of Cambridge)
+ 4 AuthorsRobin Hesketh12
Estimated H-index: 12
(University of Cambridge)
Members of the transforming growth factor β (TGF-β) family are potent inhibitors of the growth of many epithelial cell types. Trans -membrane signaling by TGF-β occurs via a complex of the serine/threonine kinases TGF-β type 1 receptor and TGF-β type 2 receptor (TGFBR2), and inactivating mutations in the latter have recently been detected in some primary tumors and in several types of tumor-derived cell lines. The most common mutations that have been identified in TGFBR2 are frameshifts in a rep...
Published on Dec 1, 1997in American Journal of Human Genetics 9.92
Ulrike Schwarze30
Estimated H-index: 30
(UW: University of Washington),
Jayne A. Goldstein2
Estimated H-index: 2
(UW: University of Washington),
Peter H. Byers69
Estimated H-index: 69
(UW: University of Washington)
Summary Ehlers-Danlos syndrome (EDS) type IV results from mutations in the COL3A1 gene, which encodes the constituent chains of type III procollagen. We have identified, in 33 unrelated individuals or families with EDS type IV, mutations that affect splicing, of which 30 are point mutations at splice junctions and 3 are small deletions that remove splice-junction sequences and partial exon sequences. Except for one point mutation at a donor site, which leads to partial intron inclusion, and a si...
Cited By1034
Newest
Published on Jan 18, 2019in Human genome variation
Hironori Hara5
Estimated H-index: 5
(UTokyo: University of Tokyo),
Norifumi Takeda13
Estimated H-index: 13
(UTokyo: University of Tokyo)
+ 6 AuthorsIssei Komuro88
Estimated H-index: 88
(UTokyo: University of Tokyo)
Loeys–Dietz syndrome (LDS) is caused by variants of transforming growth factor-β (TGF-β)-related genes and is characterized by aortic aneurysm and dissection. We report an LDS patient with a de novo missense variant of TGFBR1 [c.1126A>G, p.(Lys376Glu)] in which active TGF-β signaling was observed in the aorta, despite the in vitro demonstration that the loss-of-function mutation lies within the serine/threonine kinase domain. The mechanism underlying this TGF-β paradox in LDS aortopathy should b...
Published in Scientific Reports 4.01
Valeriana Cesarini3
Estimated H-index: 3
(Sapienza University of Rome),
C Pisano1
Estimated H-index: 1
(Sapienza University of Rome)
+ -3 AuthorsSusanna Dolci35
Estimated H-index: 35
(Sapienza University of Rome)
Aneurysms and dissections affecting thoracic aorta are associated with smooth muscle cell (SMC) dysfunction. NO/cGMP signaling pathway in smooth muscle cells has been shown to be affected in sporadic thoracic aortic aneurysms. We analyzed the mRNA levels of PDE5, a cGMP-hydrolyzing enzyme highly expressed in aortic SMCs, that regulates arterious vascular tone by lowering cGMP levels. We found that aortic tissue obtained from Marfan, tricuspid and bicuspid thoracic aneurysms expressed lower level...
Published on Jul 1, 2019in World Neurosurgery 1.72
Pavlos Texakalidis5
Estimated H-index: 5
(Emory University),
Ahmad Sweid (Thomas Jefferson University Hospital)+ 5 AuthorsPascal Jabbour43
Estimated H-index: 43
(Thomas Jefferson University Hospital)
Abstract Cerebral Aneurysms (CAs) are characterized by a pathological wall structure with internal elastic lamina and media disruption which leads to focal weakened pouches of the arterial wall. The prevalence of unruptured CAs is estimated to be 2-5% in the general population. During the past few decades, the pathophysiological mechanisms behind the formation, growth and rupture of CAs have been the focus of numerous research studies. In this review, the inflammatory pathways, genetics and risk...
Published on Apr 1, 2019in Journal of Cardiology 2.29
Norifumi Takeda13
Estimated H-index: 13
(UTokyo: University of Tokyo),
Norifumi Takeda9
Estimated H-index: 9
(UTokyo: University of Tokyo),
Issei Komuro88
Estimated H-index: 88
(UTokyo: University of Tokyo)
Abstract Recent advances in DNA sequencing technology have identified several causative genes for hereditary thoracic aortic aneurysms and dissections (TAADs), including Marfan syndrome (MFS), Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial non-syndromic TAADs. Syndromic TAADs are typically caused by pathogenic variants in the transforming growth factor-β signal and extracellular matrix-related genes (e.g. FBN1 , TGFBR1 , TGFBR2 , SMAD3 , TGFB2 , and COL3A1 ). On the other ha...
Published on Jul 1, 2019in Neurosurgical Focus 2.89
Nardin Samuel10
Estimated H-index: 10
(U of T: University of Toronto),
Ivan Radovanovic3
Estimated H-index: 3
(U of T: University of Toronto)
Published on Apr 1, 2019in American Journal of Cardiology 2.84
Amir Solomonica5
Estimated H-index: 5
,
Amir Solomonica1
Estimated H-index: 1
(London Health Sciences Centre)
+ 1 AuthorsShahar Lavi19
Estimated H-index: 19
Spontaneous coronary artery dissection (SCAD) is a cause of about 4% of acute coronary syndrome. The pathophysiology of SCAD is not yet fully understood. Loeys-Dietz syndrome is a connective tissue disorder characterized by aortic aneurysms, arterial tortuosity, and aortic dissections. It is caused by mutations in the genes affecting the transforming growth factor β pathway. We describe a family with a SMAD3 gene mutation and Loeys-Dietz syndrome presenting with recurrent SCAD episodes.
Published on Jul 1, 2019in Journal of Cardiovascular Surgery 1.06
Giovanni Tinelli7
Estimated H-index: 7
,
Marco Ferraresi + 6 AuthorsStéphan Haulon33
Estimated H-index: 33
Published on Feb 26, 2019in European Journal of Human Genetics 3.65
Xue-Yan Duan1
Estimated H-index: 1
(University of Texas Health Science Center at Houston),
Dongchuan Guo32
Estimated H-index: 32
(University of Texas Health Science Center at Houston)
+ 9 AuthorsDeborah A. Nickerson90
Estimated H-index: 90
(UW: University of Washington)
SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c.290G>T, p.(Arg97Leu), not present in population databases and predicted to be damaging to protein function, was identified in a family with thoracic aortic disease and no evid...
Published on Jul 1, 2019in Journal of Molecular and Cellular Cardiology 5.05
Stephanie W. Tobin1
Estimated H-index: 1
(UHN: University Health Network),
Faisal J. Alibhai1
Estimated H-index: 1
(UHN: University Health Network)
+ 13 AuthorsLaura C. Tumiati22
Estimated H-index: 22
(U of T: University of Toronto)
Abstract Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles...
Published on Jun 15, 2019in Obstetric Medicine
Katharine E. Thomas (University of Oxford), Jennifer Hogan1
Estimated H-index: 1
+ 3 AuthorsCharlotte J Frise4
Estimated H-index: 4
(University of Oxford)
Loeys–Dietz syndrome is a recently described condition which causes cardiovascular, craniofacial, neurocognitive and skeletal abnormalities due to mutations in components of the transforming growth...