Disease relevance of FBLN5

• Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa [1].
• The phenotypic abnormalities recently observed in a fibulin-5 knockout mouse model are reminiscent of human AR cutis laxa type I. Both share cutis laxa, lung emphysema and arterial involvement [1].
• FBLN-5 overexpression also augmented the tumorigenicity of human HT1080 fibrosarcoma cells by increasing their DNA synthesis, migration toward fibronectin, and invasion through synthetic basement membranes [2].
• Missense variations in the fibulin 5 gene and age-related macular degeneration [3].
• Mutations in major structural components of elastic fibres, especially elastin, fibrillins and fibulin-5, cause severe, often life-threatening, heritable connective tissue diseases such as Marfan syndrome, supravalvular aortic stenosis and cutis laxa [4].

Psychiatry related information on FBLN5

• Forty-three students were randomized to Dance for Health and 38 to usual physical activity [5].
• The groups targeted topics such as smoking cessation, improving diet, reducing stress through yoga, meditation, tai chi chuan, ROM (Range of Motion) Dance, aerobics, and a variety of other activities [6].

High impact information on FBLN5

• These data suggest that fibulin-5 could be a novel therapeutic target for elastic fiber regeneration [7].
• Deposition of fibulin-5 on microfibrils promotes coacervation and alignment of tropoelastins on microfibrils, and also facilitates cross-linking of tropoelastin by tethering lysyl oxidase-like 1, 2, and 4 enzymes [7].
• Elsewhere, frameshift mutations in the elastin gene have been reported in three families with autosomal dominant inheritance, and a family with autosomal recessive cutis laxa was recently reported to have a homozygous missense mutation in the fibulin-5 gene [8].
• Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene [8].
• The larger transcript contains an internal duplication of 483 nucleotides, which resulted in the synthesis and secretion of a mutant fibulin-5 protein with four additional tandem calcium-binding epidermal growth factor-like motifs [8].

Biological context of FBLN5

• TGF-beta markedly increased FBLN5 promoter activity in transient transfection assays [9].
• The transcription start site of the human FBLN5 gene was localized at 221 nucleotides upstream of the translation start site by using primer extension, Northern blots, and functional analysis of transcriptional activity in reporter plasmids containing 5'-flanking regions [9].
• Fibulin-5 gene expression in human lung fibroblasts is regulated by TGF-beta and phosphatidylinositol 3-kinase activity [9].
• It further demonstrates that FBLN5 mutations can be associated with different phenotypes of ARMD (not limited to the previously described cuticular drusen type) [10].
• We also correlated the FBLN5 genotype with the ARMD phenotype [10].

Anatomical context of FBLN5

• We demonstrated that the interaction of ELN and FBLN5 alleles results in elastic fibers susceptible to inflammatory destruction [11].
• In addition, LY-294002 markedly and proportionally decreased FBLN5 promoter activity in transient transfection analyses with TGF-beta-treated or untreated lung fibroblasts [9].
• We report that fibulin-5 protein potently induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils [7].
• Unlike its proliferative response in fibroblasts, FBLN-5 overexpression in mink lung Mv1Lu epithelial cells resulted in an antiproliferative response, reducing their DNA synthesis and cyclin A expression [2].
• The gene regulation in endothelial cells by follicular fluid could be confirmed by RT-PCR for gro-beta, angiopoietin-2, elastin, fibulin-5, and E-selectin [12].

Associations of FBLN5 with chemical compounds

• The addition of morphine, methionine-enkephalin, or UP50, 488H which preferentially bind mu-, delta-, and kappa-opiate receptors, respectively, did not decrease basal irGnRH release from cultured human placental cells [13].
• Fibulin-5 is an extracellular matrix glycoprotein that participates in elastogenesis [14].
• Finally, the ability of FBLN-5 to antagonize angiogenic processes was determined to be independent of its integrin-binding RGD motif [15].

Physical interactions of FBLN5

• Fibulin-5 interacts with fibrillin-1 molecules and microfibrils [16].
• Fibulin-5 binding to endothelial cell (EC) surface integrins may effect cell proliferation and cell attachment to extracellular matrix (ECM) or to artificial surfaces [17].

Regulatory relationships of FBLN5

• These results may suggest that the fibulin-5 gene induction is directly or indirectly regulated by tropoelastin gene expression and plays a role in the accumulation of elastic fibers within matrices [18].

Other interactions of FBLN5

• Furthermore, S227P mutant fibulin-5 also showed impaired association with fibrillin-1 microfibrils [19].
• Histological analysis of skin sections from a cutis laxa patient with a homozygous S227P mutation showed a lack of fibulin-5 in the extracellular matrix and a concomitant disorganization of dermal elastic fibers [19].
• UVB irradiation reduced fibulin-5, fibulin-2 and elastin markedly, moderately and weakly, respectively, compared with levels in control nontreated skin [20].
• Fibulin-5 (also known as DANCE) is an elastin-binding protein that is thought to play a role in elastogenesis [18].
• We show here that TGF-beta stimulates FBLN-5 expression in endothelial cells, and that this response was inhibited by coadministration of the proangiogenic factor, VEGF [15].

Analytical, diagnostic and therapeutic context of FBLN5

• Notably, recombinant fibulin-5 protein induced elastogenesis even in serum-free conditions, although elastogenesis in cell culture has been believed to be serum-dependent [7].
• Pulse-chase immunoprecipitation experiments indicated that S227P mutant fibulin-5 was synthesized and secreted by skin fibroblasts at a reduced rate when compared with the wild-type protein [19].
• In this study, we examined whether thoracic aortic dissection (TAD) is associated with abnormal fibulin-5 expression [21].
• Assignment of fibulin-5 (FBLN5) to human chromosome 14q31 by in situ hybridization and radiation hybrid mapping [22].
• DESIGN: Dance and injury history; physical examinations of back, lower extremities, and ligamentous laxity; and radiographs of lower extremity joints were performed in retired dancers [23].

References