Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

Robinson, Peter N.; Booms, Patrick; Katzke, Stefanie; Ladewig, Markus S.; Neumann, Luitgard M.; Palz, Monika; Pregla, Reinhard; Tiecke, Frank; Rosenberg, Thomas

doi:10.1002/humu.10113

Cited by 165 publications

(115 citation statements)

References 56 publications

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“…4 In the majority of patients with classical MFS, a mutation in the FBN1 gene can be identified with, so far, more than 550 different FBN1 mutations being reported that are spread throughout the gene and mostly unique for each family. 5,6 The MFS is known as an autosomal-dominant disorder (MIM 154700) and several studies in human and mice have, for a long time, favored a dominant-negative model for the pathogenesis of MFS. 7 However, recently, based on mice studies a role for a haplo-insuffiency model has been raised, 8 including the hypothesis that abnormal fibrillin or reduced levels of fibrillin may lead to an excess of TGF-b activity.…”

Section: Introductionmentioning

confidence: 99%

Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome

et al. 2007

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Section: Introductionmentioning

confidence: 99%

Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome

et al. 2007

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“…They have a widespread distribution in nonelastin and elastincontaining tissues, such as the ciliary zonules, blood vessels, lung, and skin, and they act as a lattice for elastin deposition during elastic fiber formation. Mutations in the fibrillin-1 (FBN1) gene cause the connective-tissue disease Marfan syndrome, which is associated with severe cardiovascular, ocular, and skeletal defects (4).…”

mentioning

confidence: 99%

Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility

Baldock

Siegler²,

Bax

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Fibrillin-1 is a 330-kDa multidomain extracellular matrix protein that polymerizes to form 57-nm periodic microfibrils, which are essential for all tissue elasticity. Fibrillin-1 is a member of the calcium-binding EGF repeat family and has served as a prototype for structural analyses. Nevertheless, both the detailed structure of fibrillin-1 and its organization within microfibrils are poorly understood because of the complexity of the molecule and the resistance of EGF arrays to crystallization. Here, we have used small-angle x-ray scattering and light scattering to analyze the solution structure of human fibrillin-1 and to produce ab initio structures of overlapping fragments covering 90% of the molecule. Rather than exhibiting a uniform rod shape as current models predict, the scattering data revealed a nonlinear conformation of calcium-binding EGF arrays in solution. This finding has major implications for the structures of the many other EGF-containing extracellular matrix and membrane proteins. The scattering data also highlighted a very compact, globular region of the fibrillin-1 molecule, which contains the integrin and heparan sulfate-binding sites. This finding was confirmed by calculating a 3D reconstruction of this region using electron microscopy and single-particle image analysis. Together, these data have enabled the generation of an improved model for microfibril organization and a previously undescribed mechanism for microfibril extensibility.elastic fibers ͉ fibrillin microfibrils ͉ solution x-ray scattering

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“…4 Second, the broad spectrum of type 1 fibrillinopathies, as well as the wide clinical heterogeneity among individuals and families affected with the same mutation, result in a challenging phenotypic-genotypic correlation. 8,9 Furthermore, extensive phenotypic overlapping is observed in the general population, with high prevalence of MVP or skeletal marfanoid disorders 10,11 and so-called MM conditions. 12,13,14 Finally, whereas this latter group shares $1 clinical features with Marfan syndrome, patients may differ in their clinical evolution and prognosis, showing a low risk of aortic/coronary dilation or dissection.…”

Section: Discussionmentioning

confidence: 99%

Chest Pain in Children With Suspected Type I Fibrillinopathy: A Case Report

et al. 2015

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Chest pain is the second most common reason for referral to a pediatric cardiologist, because cardiovascular-related disorders are a major concern for children and their families when seeking medical attention. On the rare occasions when pediatric chest pain is a result of severe heart disease, it is usually associated with well-known cardiovascular risk factors such as fibrillinopathies. Type 1 fibrillinopathies are heritable disorders caused by mutations in the fibrillin genes that lead to a broad spectrum of connective tissue phenotypes ranging from Marfan syndrome, at the most severe end, to patients displaying mild marfanoid features, or milder Marfan (MM). We report the case of an adolescent patient with MM and suspected acute coronary syndrome, with chest pain and electrocardiographic changes suggestive of myocardial ischemia. Despite the low risk of coronary or aortic dissection/aneurysm in MM, these possibilities should be tested. Once they are ruled out, mitral valve prolapse should be considered as the main cause of chest pain with ischemic-like changes in the inferior electrocardiogram leads. We emphasize that clinical and echocardiographic follow-up over years is warranted in the pediatric population to ensure that the aortic root does not show progressive dilatation or a tendency to dissect. Finally, genotyping is clinically indicated for early and complete diagnosis in patients with MM as well as de novo Marfan syndrome to take advantage of educational and clinical programs for young carriers of the mutation.

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Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

Cited by 165 publications

References 56 publications

Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome

Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome

Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility

Chest Pain in Children With Suspected Type I Fibrillinopathy: A Case Report

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