Marfan syndrome in the third Millennium

Collod‐Béroud, Gwenaëlle; Boileau, Cathérine

doi:10.1038/sj.ejhg.5200876

Cited by 65 publications

(36 citation statements)

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“…In man, mutations in the fibrillin-1 gene are causative for Marfan syndrome, an autosomal disorder affecting the cardiovascular, skeletal, and ocular system. 20,22,24 To date, over 500 fibrillin-1 mutations have been identified. 57 Mutations are found throughout the gene and result in a reduced Aberrant fibrillin-1 in emphysematous lung AA Robbesom et al fibrillin-1 synthesis, a delayed secretion, and thus an impaired fibrillin-1 deposition into the matrix.…”

Section: Discussionmentioning

confidence: 99%

“…In man, developmental emphysema has been noticed in patients with Marfan syndrome, an autosomal disorder caused by mutations in the gene encoding fibrillin-1. [19][20][21][22][23][24][25][26][27] In mice, disruption of the fibrillin-1 gene results in developmental emphysema. The tight skin mouse, characterized by tandem duplication of 30-40 kb in the gene encoding fibrillin-1, develops emphysematous lesions that are in many ways similar to those observed in humans.…”

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Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

et al. 2008

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Parenchymal destruction, airspace enlargement, and loss of elasticity are hallmarks of pulmonary emphysema. Although the basic mechanism is unknown, there is a consensus that malfunctioning of the extracellular matrix is a major contributor to the pathogenesis of emphysema. In this study, we analyzed the expression of the elastic fiber protein fibrillin-1 in a large number (n ¼ 69) of human lung specimens with early-onset emphysema. Specimens were morphologically characterized by the Destructive Index, the Mean Linear Intercept, and the Panel Grading. We observed a strong correlation (Po0.001) of aberrant fibrillin-1 staining with the degree of destruction of lung parenchyma (r ¼ 0.71), airspace enlargement (r ¼ 0.47), and emphysema-related morphological abnormalities (r ¼ 0.69). There were no obvious correlations with age and smoking behavior. Staining for three other extracellular matrix components (type I collagen, type IV collagen, and laminin) was not affected. The aberrant fibrillin-1 staining observed in this study is similar to that observed in Marfan syndrome, a syndrome caused by mutations in the gene encoding fibrillin-1. Strikingly, emphysema is noticed in a number of Marfan patients. This, together with the notion that disruption of the fibrillin-1 gene in mice results in emphysematous lesions, makes fibrillin-1 a strong candidate to be involved in the etiology and pathogenesis of emphysema.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

et al. 2008

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“…However, genotype-phenotype correlations have been slow to emerge. To date, more than 500 mutations have been identified in this gene in patients with MFS and related diseases (Collod-Béroud & Boileau, 2002). The R2726W mutation in the FBN1 gene results in the substitution of tryptophan for arginine at nucleotide 8,176 (Milewicz et al 1995).…”

Section: Introductionmentioning

confidence: 99%

The FBN1 (R2726W) mutation is not fully penetrant

Buoni¹,

Zannolli²,

Macucci³

et al. 2004

Annals of Human Genetics

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SummaryThe R2726W mutation in the fibrillin 1 (FBN1, Marfan syndrome) gene segregates with isolated skeletal features of Marfan syndrome and/or high stature. Here we report a family in which two out of four individuals, an 18-year-old son and his mother, a 41-year-old woman, had the R2726W mutation of FBN1. Both family members carrying the mutation were of average height. The son had a Marfan-like phenotype, but his mother did not. The FBN1 R2776W mutation, which is associated with skeletal features of Marfan syndrome, appears incompletely penetrant. Consequently, genetic counselling in the presence of this mutation is difficult.

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“…54,55 Clinical features of the Marfan syndrome, such as malfunction of the mitral valve and dilatation/dissection of the aorta, are often manifested in adulthood. 10,55 In an accepted model of Marfan syndrome, mutant mice homozygous for a partial loss-of-function allele die of aortic dissection and rupture 2 weeks after they are born, recapitulating the vascular phenotype of the Marfan syndrome. 56 In this study, the morpholino knockdown approach was used in zebrafish to determine the loss-of-function consequence for the fibrillin-1 gene in embryonic development.…”

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Functional analysis of zebrafish microfibril-associated glycoprotein-1 (Magp1) in vivo reveals roles for microfibrils in vascular development and function

Chen

Larson

Ekker

2006

Blood

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Mutations in fibrillin-1 (FBN1) result in Marfan syndrome, demonstrating a critical requirement for microfibrils in vessel structure and function. However, the identity and function of many microfibrilassociated molecules essential for vascular development and function have yet to be characterized. In our morpholinobased screen for members of the secretome required for vascular development, we identified a key player in microfibril formation in zebrafish embryogenesis. Microfibril-associated glycoprotein-1 (MAGP1) is a conserved protein found in mammalian and zebrafish microfibrils. Expression of magp1 mRNA is detected in microfibril-producing cells. Analysis of a functional Magp1-mRFP fusion protein reveals localization along the midline and in the vasculature during embryogenesis. Underexpression and overexpression analyses demonstrate that specific Magp1 protein levels are critical for vascular development. Integrin function is compromised in magp1 morphant embryos, suggesting that reduced integrin-matrix interaction is the main mechanism for the vascular defects in magp1 morphants. We further show that IntroductionExtensive studies have shown that proper vascular development requires complex interactions among hematopoietic cells, endothelial cells, and supporting cells such as smooth muscle cells. [1][2][3][4] Advances have been made in elucidating the role of extracellular matrix (ECM) components, such as the integrins, the laminins, and the proteoglycans, in modulating the behaviors of endothelial cells and vascular smooth muscle cells, among them migration, contractility, proliferation, and apoptosis. [5][6][7][8] However, increasing evidence suggests that the structural elements of ECM components are also critical players in orchestrating proper vascular morphogenesis and function. For example, fibrillin-1 is a component of the microfibrils, which represent a major fibrillar network in the connective tissues within the cardiovascular system. 9 Dissecting aortic aneurysm is a major vascular abnormality of Marfan syndrome, a clinical entity associated with mutations in the fibrillin-1 gene (FBN1). 10 The idea that fibrillin-1 is more than a structural protein has been substantiated by studies demonstrating fibrillin-1 participation in TGF-␤ signaling in lung development and mitral valve disease. 11,12 Fibrillin-1 has also been implicated in vascular matrix remodeling by modulating the release of matrix metalloproteases in patients with bicuspid aortic valve malformations. 13 In spite of the increasing evidence that has begun to shed light on the diverse roles played by some major structural elements of the ECM in vascular morphogenesis and function, many molecular players that render the dynamic role of the ECM in vascular biology remain to be identified.Microfibrils represent 1 critical component in the ECM of the cardiovascular system and are present in the elastic fibers of the vessel wall. Elastic fibers, which are composed of an elastin core surrounded by microfibrils, lend elasticity and resilience...

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Marfan syndrome in the third Millennium

Cited by 65 publications

References 57 publications

Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

The FBN1 (R2726W) mutation is not fully penetrant

Functional analysis of zebrafish microfibril-associated glycoprotein-1 (Magp1) in vivo reveals roles for microfibrils in vascular development and function

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