Disease relevance of FBN1

• Exon 24 in fibrillin lies in the region of the molecule where mutations produce the most severe phenotypes associated with Marfan syndrome (fibrillin-1) and congenital contractural arachnodactyly (fibrillin-2) [1].
• New fibrillin 1 gene mutations have been identified in patients with Marfan syndrome, the neonatal form of Marfan syndrome, and ectopia lentis [2].

High impact information on FBN1

• The supramolecular organization of fibrillin-rich microfibrils [3].
• Comparison of colloidal gold and antibody binding sites in untensioned microfibrils and those extended in vitro, and immunofluorescence studies of fibrillin deposition in cell layers, indicate conformation changes and intramolecular folding [3].
• Microfibrils are ubiquitous fibrillin-rich polymers that are thought to provide long-range elasticity to extracellular matrices, including the zonular filaments of mammalian eyes [4].
• Monoclonal antibodies to fibrillin 1 (MP340), a component of elastin-associated microfibrils, were used to screen cDNA libraries made from bovine nuchal ligament mRNA [5].
• It is possible that these mutations alter the ability of fibrillin to bind MAGP-1, which may contribute to the severity of the disease [1].

Biological context of FBN1

• The bovine fibrillin sequence contains the same number and type of motifs as the human FBN1 sequence, including the same number of putative calcium binding sites [6].
• Linkage mapping of FBN1 to bovine chromosome 10 [7].
• In developing bovine aorta, fibrillin mRNA levels again paralleled tropoelastin expression although, compared to ligament, elastin synthesis began at an earlier fetal age in this tissue [8].
• The coordinate upregulation of fibrillin-1 and fibrillin-2 expression with the onset of tropoelastin production is consistent with a role in elastic fiber assembly [8].
• Each of the above antibodies gave a tissue distribution identical to that of anti-MAGP antibodies, and thus MP340 and MP78 also were identified with the 12-nm microfibrils of nonelastic tissues [9].

Anatomical context of FBN1

• In cases of vascular calcification, the decreased expression of TE, FBN1, and LO may be partially responsible for decreased vascular elasticity and also for the decreased formation of new elastic fibers [10].
• The recent characterization of multiple fibrillin genes raises the question of whether each of the fibrillin proteins is a component of elastic fiber microfibrils and whether their expression during development of elastic tissues is consistent with a function associated with elastogenesis [8].
• RESULTS: Both MAGP and FBN1 are expressed by the urothelium and are found in association with the underlying basement membrane, as visualized by their co-localization with type IV collagen [11].
• In contrast, adhesion of auricular chondroblasts to fibrillin-1 was only partially inhibited by these reagents, suggesting that some cell types recognize a second, non-RGD binding site within the fibrillin molecule [12].
• Fibroblast attachment to fibrillin-1 was sensitive to inhibition by antibodies to the alphavbeta3 receptor and by peptides encoding the RGD sequence in fibrillin-1 and the second RGD sequence in fibrillin-2 [12].

Associations of FBN1 with chemical compounds

• Poly(A+) ribonucleic acid was isolated from cultured urothelial cells and subjected to Northern analysis using specific complementary deoxyribonucleic acid probes for MAGP and FBN1 [11].
• MP340 was shown to absorb out completely the microfibrillar immunoreactivity of anti-(reductive guanidine hydrochloride extract) antibodies, indicating that MP340 was (a) the major microfibrillar constituent in these extracts and (b) the second unidentified microfibrillar antigen described previously [9].
• Cyanogen bromide peptide mapping indicated that MAGP was structurally related to MP340 [9].
• Role of Ca(2+) for the mechanical properties of fibrillin [13].
• These experiments indicate that chondroitin sulphate proteoglycans associate with fibrillin and contribute to microfibril assembly [14].

Other interactions of FBN1

• Although the relative increase in expression of both fibrillins was equivalent, the basal level of fibrillin-1 expression was greater than fibrillin-2 [8].
• TE, FBN1, and LO mRNA levels, assessed by reverse transcription-polymerase chain reaction, were also decreased by exposure to 10 mM beta-GP [10].
• Immunoelectron microscopy confirmed that MAGP-2 was specifically associated with fibrillin-containing microfibrils in nuchal ligament, dermis, adventitia of aorta, glomerular mesangium and perimysium [15].
• It is postulated that MAGP and MP78 are constituents of MP340 which in turn is the subunit of which the 12-nm microfibrils are composed [9].
• The pattern of fibrillin deposition correlates with microfibril-associated glycoprotein 1 (MAGP-1) expression in cultured blood and lymphatic endothelial cells [16].

Analytical, diagnostic and therapeutic context of FBN1

• As determined by Western blot analysis, 10 mM of beta-GP time-dependently decreased TE and FBN1 protein levels [10].
• The following aspects will be described in this review: the structure and function of fibrillin-1; the fibrillin proteins; mutations in the FBN1 gene and pathogenic mechanisms; animal models [17].
• Therefore, we have used low dose electron microscopy and single particle image analysis to study the structure of fibrillin microfibrils [18].
• We have employed atomic force microscopy to investigate substrate dependent morphologies of two biochemically distinct native supramolecular assemblies: fibrillin and type-VI collagen microfibrils [19].
• Scanning transmission electron microscopy mass analysis of fibrillin-containing microfibrils from foetal elastic tissues [20].

References