Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome

Pereira, Lygia V.; D’Alessio, Marina; Ramirez, Francesco; Lynch, Jodi; Sykes, Bryan; Pangilinan, Theresa; Bonadio, Jeffrey

doi:10.1093/hmg/2.7.961

Cited by 349 publications

(316 citation statements)

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“…3B) or fibrillin-1 polypeptide (not shown) used as the immobilized ligand. The specificity of this interaction is confirmed by its sensitivity to the presence of 10 mM EDTA (not shown), and also by the inhibition with synthetic GRGDS and IRPRGDNGD peptides or with recombinant fragment Numbers in brackets refer to the numbering of amino acids according to [6]. Due to an unexpected recombination event, fragment rF6trunc was found to contain a C-terminal 40-amino acid extension derived from the major capsid protein VP1 of the SV40 virus.…”

Section: Resultsmentioning

confidence: 81%

“…So far two members of this family, fibrillin-1 [3][4][5][6] and fibrillin-2 [4,7], have been described as products of different genes. These proteins share a common organization of domains consisting mostly of calcium-binding EGF-like repeats and novel motifs containing 8 cysteines, which are also found in the family of TGF-13 binding proteins [3,5,8].…”

Section: Introductionmentioning

confidence: 99%

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Cell adhesion and integrin binding to recombinant human fibrillin‐1

et al. 1996

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Fibrillin-1 is a major constituent of tissue microfibrfls that occur in most connective tissues, either in close association with or independent of elastin. To test possible cell-adhesive functions of this protein, we used recombinant human fibrlllin-1 polypeptides produced in a mammalian expression system in cell attachment and solid-phase integrin binding assays. necessitates the use of buffers containing denaturing agents and cannot separate fibrillin-1 and fibrillin-2 [18], we chose to use recombinant human fibrillin-1 polypeptides for a study of possible cell-adhesive functions. These human fibrillin-1 peptides were produced in a mammalian expression system and purified under non-denaturing conditions [19]. Extensive characterization indicated correct folding [19]. Using an experimental approach already applied to characterize cell-adhesive and integrin-binding functions of fibulins [20], laminin [21] and collagen VI [22], we demonstrate the ability of cells to adhere to fibrillin-1 via an RGD motif located in the fourth 8-cysteine domain. In addition we identify integrin aV[33 as a major cellular receptor for this site.

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Section: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Cell adhesion and integrin binding to recombinant human fibrillin‐1

et al. 1996

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“…4 The coding sequence of the FBN1 gene is spread over 65 coding exons, and contains 43 calcium binding (cb) epidermal growth factor-like (EGF) modules. 5,6 Private mutations have been identified over the entire length of the gene with no phenotypic association or apparent clustering in any specific region, with the exception of the severe neonatal form of the syndrome associated with mutations located between exons 24 and 32. 7 -11 The detection of a mutation, thus long, difficult and costly, cannot be offered to all suspected Marfan patients even in countries, in which state funding is available for wide molecular diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene

et al. 2009

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Mutations identified in the fibrillin-1 (FBN1) gene have been associated with Marfan syndrome (MFS). Molecular analysis of the gene is classically performed in probands with MFS to offer diagnosis for at-risk relatives and in children highly suspected of MFS. However, FBN1 gene mutations are found in an ill-defined group of diseases termed 'type I fibrillinopathies', which are associated with an increased risk of aortic dilatation and dissection. Thus, there is growing awareness of the need to identify these non-MFS probands, for which FBN1 gene screening should be performed. To answer this need we compiled the molecular data obtained from the screening of the FBN1 gene in 586 probands, which had been addressed to our laboratory for molecular diagnosis. In this group, the efficacy of FBN1 gene screening was high in classical MFS probands (72.5%,), low (58%) in those referred for incomplete MFS and only slight (14.3%) for patients referred as possible MFS. Using recursive partitioning, we found that the best predictor of the identification of a mutation in the FBN1 gene was the presence of features in at least three organ systems, combining one major, and various minor criteria. We also show that our original recommendation of two systems involved with at least one with major criterion represents the minimal criteria because in probands not meeting these criteria, the yield of mutation identification drastically falls. This recommendation should help clinicians and biologists in identifying probands with a high probability of carrying a FBN1 gene mutation, and thus optimize biological resources.

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“…2 MFS is caused by mutations in the gene for fibrillin-1 (FBN1). FBN1 contains 65 exons spanning 200 kb genomic DNA on chromosome 15q21.1 3,4 and codes for fibrillin-1, a 320 kD glycoprotein that is a main component of the extracellular microfibrils. Fibrillin-1 contains 47 motifs with homology to the human epidermal growth factor (EGF); 43 of these also contain a consensus sequence for calcium binding (cbEGF).…”

Section: Introductionmentioning

confidence: 99%