Disease relevance of Fbn1

• The Tight skin (Tsk) mutation is a duplication of the mouse fibrillin 1 (Fbn1) gene that results in a larger (418 kD) than normal (350 kD) protein; Tsk/+ mice display increased connective tissue, bone overgrowth, and lung emphysema [1].
• We investigated whether tsk-Fbn1 might cause dermal fibrosis by affecting Fbn1 and associated extracellular matrices [2].
• Fbn1-/- mice died soon after birth from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse [3].
• Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils [4].
• Further, our results also show that in mice deficient in mature B cells inheriting the defective Fbn-1 gene, development of cutaneous hyperplasia is not abrogated [5].

Psychiatry related information on Fbn1

• Mouse lemurs remained torpid between 1.7-8.9 h with a daily mean of 3.4 h, and their Tsk s fell to a minimum of 18.8 degrees C. Mean home ranges of mouse lemurs which remained normothermic were similar in the rainy and dry season [6].

High impact information on Fbn1

• Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes [4].
• To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome [4].
• The vascular phenotype of MFS results from mutations in fibrillin-1 (FBN1), the major constituent of extracellular microfibrils [7].
• Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome [7].
• Here we report a gene-targetting experiment in mice that indicates that fibrillin-1 microfibrils are predominantly engaged in tissue homeostasis rather than elastic matrix assembly [7].

Chemical compound and disease context of Fbn1

• The Marfan syndrome (MFS) is a connective tissue disorder inherited as an autosomal dominant trait and caused by mutations in the gene encoding fibrillin, a 350-kD glycoprotein that multimerizes to form extracellular microfibrils [8].
• To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR) [9].
• METHODS: Frozen sections of conjunctiva from 6 patients with Marfan syndrome with ectopia lentis and from 15 age-matched control subjects were stained with mouse antihuman fibrillin-1 antibody, using an avidin biotin immunoperoxidase technique [10].

Biological context of Fbn1

• We now demonstrate that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript [11].
• However, virtually all Fbn1-/-;Fbn2-/- embryos and about half of the Fbn1+/-;Fbn2-/- embryos died in utero and displayed a significantly more severe vascular phenotype than Fbn1-/- mice [3].
• To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation [3].
• Of mice and Marfan: genetic linkage analyses of the fibrillin genes, Fbn1 and Fbn2, in the mouse genome [12].
• Tsk/Tsk cells produce only mutated fibrillin-1 which arises from mRNA containing an in-frame duplication of exons 17-40 [13].

Anatomical context of Fbn1

• Consistent with a specialized function of fibrillin-2, electron microscopy visualized ultrastructurally different microfibrils in Fbn1 null compared with control cell cultures [3].
• METHODS: An in vitro model of the TSK mouse was created by conditionally expressing tsk-Fbn1 in mouse embryonic fibroblasts (MEFs) [2].
• Immunoprecipitation of MAGP-2 from transfected COS-7 cells resulted in the coprecipitation of fibrillin [14].
• Tsk/Tsk, Tsk/+ and +/+ mouse embryonic fibroblast cell lines were used [13].
• Accordingly, we propose that fibrillin-1 provides mostly force-bearing structural support, whereas fibrillin-2 predominantly regulates the early process of elastic fiber assembly [15].

Associations of Fbn1 with chemical compounds

• TGF-beta1 binding protein-like modules of fibrillin-1 and -2 mediate integrin-dependent cell adhesion [16].
• Serum creatine kinase activity was significantly elevated in both mdx and mdx/Tsk double-mutant mice over normal controls [17].
• Fibrillin-1 and -2 contain heparin-binding sites important for matrix deposition and that support cell attachment [18].
• DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition [9].
• Activation and interaction with protein kinase C of a cytoplasmic tyrosine kinase, Itk/Tsk/Emt, on Fc epsilon RI cross-linking on mast cells [19].

Enzymatic interactions of Fbn1

• We found that loss of fibrillin-1 deposition promotes the production of intracellular reactive oxygen species and abnormal accumulation of phosphorylated TGF-beta-activated kinase 1 and p38 MAPK, in addition to increasing the levels of endogenous phospho-Smad2 [20].

Regulatory relationships of Fbn1

• Fibrillin-1 contributes to the regulated activation of the cytokine TGF-beta, and enhanced signaling is a consequence of fibrillin-1 deficiency [21].
• Our results indicate a novel role for decorin and biglycan during pressure-induced renal injury by stimulating fibrillin-1 expression [22].
• Further, fibrillin-1 significantly promoted spreading and focal contact formation detected by immunostaining for vinculin [23].
• The storage compliance of Mov-13 and control skin were similar and were greater than Tsk (p<0.001) [24].

Other interactions of Fbn1

• Moreover, MEF cells expressing tsk-Fbn1 showed increased MAGP-2 matrix [2].
• Restriction fragment length polymorphisms (RFLPs) between the progenitors of an interspecific backcross involving AEJ/Gn and Mus spretus mice were used to establish the segregation patterns of the murine homologs, Fbn1 and Fbn2, in the backcross progeny [12].
• The results position Fbn1 between the B2m and Illa genes on mouse Chromosome (Chr) 2 and establish its candidacy for the Tight skin (Tsk) mutation [12].
• Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen [2].
• Resultant mdx/Tsk double-mutant mice were then examined functionally, biochemically, and histologically [17].

Analytical, diagnostic and therapeutic context of Fbn1

• Real-time PCR using cDNA or Northern analyses using RNA were performed for Fbn1 and Types I, III and V collagens [13].
• Double immunofluorescence studies demonstrate colocalization of fibrillin-1, the major backbone component of microfibrils, with perlecan in fibroblast cultures as well as in dermal and ocular tissues [25].
• Coculture experiments using human epithelial cells and mouse fibroblasts implicated the cells themselves in the assembly of fibrillin [26].
• We then sublocalized the fibrillin genes to bands 2F (Fbn-1) and 18D-E1 (Fbn-2) by fluorescence in situ hybridization [27].
• RNA analysis, PCR analysis and sequence determination of the mutant gene showed that the Fbn-1 gene polymorphism is due to intragenic duplication of a segment of the gene coding for 3.0 Kb of mRNA sequence (10 Kb of the genome) [5].

References