Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function

Hubmacher, Dirk; Apte, Suneel S.

doi:10.1007/s00018-011-0780-9

Cited by 83 publications

(74 citation statements)

References 97 publications

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“…Mutations in ADAMTS10 and fi brillin-1 genes cause Weill-Marchesani syndrome [8]. One feature, lens ectopy is common to both syndromes, while several features of Weil-Marchesani syndrome are the opposite of those that typical to MFS including brachydactyly, small stature and stiff joints [9].…”

Section: Marfan Syndrome From a Novel Point Of Viewmentioning

confidence: 99%

The role of transforming growth factor-beta in Marfan syndrome

Benke

Ágg²,

Szilveszter³

et al. 2013

Cardiol J

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The starting point, in Marfan syndrome (MFS) appears to be the mutation of fi brillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact on the tissue homeostasis of microfi brils, and elastic fi bers. We also investigate current data on the extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Together these factors, by the destruction of the connective tissue fi bers, may play an important role in the development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for

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Section: Marfan Syndrome From a Novel Point Of Viewmentioning

confidence: 99%

The role of transforming growth factor-beta in Marfan syndrome

Benke

Ágg²,

Szilveszter³

et al. 2013

Cardiol J

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“…Recent studies suggest that mutations in several adamts and adamtsl genes cause a family of human genetic disorders that are phenotypically similar to some fibrillinopathies (defects in fibrillin function; reviewed in Hubmacher & Apte (2011);Le Goff & Cormier-Daire (2011)). These include Weill-Marchesani syndrome 1 caused by mutations in adamts10, a Weill-Marchesani-like syndrome caused by mutations in adamts17, geleophysic dysplasia 1 caused by mutations in adamtsl2 and an isolated ectopis lentis caused by mutations in adamtsl4.…”

Section: Other Adamts(l)smentioning

confidence: 99%

“…Clinical symptoms of these diseases vary from short stature, joint stiffness and thick skin to eye defects such as glaucoma and displacement of the lens. Deficiencies in the cardiac valves were also found in some cases, but it is not known if they are related to cardiac NC development (Hubmacher & Apte, 2011;Le Goff & Cormier-Daire, 2011).…”

Section: Other Adamts(l)smentioning

confidence: 99%

“…Fibrillins form microfibrils, which also contain the latent transforming growth factor beta (TGF-b)-binding proteins (LTBPs), thereby sequestering TGF-b in the ECM. Phenotypes caused by fibrillin mutations have been attributed to dysregulated TGF-b signaling (Hubmacher & Apte, 2011;Neptune et al, 2003). Interestingly, ADAMTSL2 was found to interact with LTBP1, and hyperactive TGF-b signaling was observed in fibroblasts taken from geleophysic dysplasia patients with mutations in adamtsl2 (Le Goff et al, 2008).…”

Section: Other Adamts(l)smentioning

confidence: 99%

“…Interestingly, ADAMTSL2 was found to interact with LTBP1, and hyperactive TGF-b signaling was observed in fibroblasts taken from geleophysic dysplasia patients with mutations in adamtsl2 (Le Goff et al, 2008). It has also been shown that most ADAMTSLs, including ADAMTSL2, can bind to fibrillin-1 (Hubmacher & Apte, 2011;Sengle et al, 2012). In addition, ADAMTS10 was reported to bind and cleave fibrillin-1, but it is not clear if this cleavage activity is relevant to ADAMTS10 function in vivo (Kutz et al, 2011).…”

Section: Other Adamts(l)smentioning

confidence: 99%

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Extracellular metalloproteinases in neural crest development and craniofacial morphogenesis

Christian

Bahudhanapati

Wei

2013

Critical Reviews in Biochemistry and Molecular Biology

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The neural crest (NC) is a population of migratory stem/progenitor cells that is found in early vertebrate embryos. NC cells are induced during gastrulation, and later migrate to multiple destinations and contribute to many types of cells and tissues, such as craniofacial structures, cardiac tissues, pigment cells and the peripheral nervous system. Recently, accumulating evidence suggests that many extracellular metalloproteinases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs), play important roles in various stages of NC development. Interference with metalloproteinase functions often causes defects in craniofacial structures, as well as in other cells and tissues that are contributed by NC cells, in humans and other vertebrates. In this review, we summarize the current state of the field concerning the roles of these three families of metalloproteinases in NC development and related tissue morphogenesis, with a special emphasis on craniofacial morphogenesis. KeywordsA disintegrin and metalloproteinase, ADAMs with thrombospondin motifs, ADAMTSlike, epithelial to mesenchymal transition, extracellular matrix, matrix metalloproteinase, tissue inhibitors of metalloproteinase History

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Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

et al. 2022

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ImportanceThe emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD.ObjectiveTo identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features.Design, Setting, and ParticipantsWhole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy.Main Outcomes and MeasuresBurden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD.ResultsThis study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10−4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10−4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10−3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10−3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD.Conclusions and RelevanceIn this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.

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Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function

Cited by 83 publications

References 97 publications

The role of transforming growth factor-beta in Marfan syndrome

The role of transforming growth factor-beta in Marfan syndrome

Extracellular metalloproteinases in neural crest development and craniofacial morphogenesis

Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

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