Fbn1 gene

The FBN1 gene (Fibrillin1) comprises about 230 kb and 65 exons and is located on chromosome 15 (gene locus 15q21.1). The FBN1 gene encodes the protein, profibrillin-1, which is proteolytically cleaved at the C-terminus by a convertase. Fibrillin-1 is an ubiquitous extracellular matrix molecule that binds latent growth factor complexes.

Fibrillin is the main component of microfibrils. Fibrillin is an unusually cysteine-rich glycoprotein. Phylogenetically, fibrillin appeared about 800 to 1,000 million years ago and thus about 500 million years earlier than elastin, which is only found in vertebrates. Fibrillin (fibrillin -1 and -2) is a 350 kDa, ubiquitously expressed, extracellular, unusually cysteine-rich glycoprotein. It is secreted by fibroblasts into the extracellular matrix where it organizes itself into microfibrils (fibrin microfibrils, FMF). These enter into a close structural and functional bond with the amorphous elastin, which, as in the case of elastic fibres, envelops them like a sheath.

Microfibrils also occur as elastin-free fibers, e.g. in the skin as so-called oxytalan fibers in the dermo-epidermal junction zone of the papillary dermis. This fine-structured fibre system can be well represented by elastic staining. Furthermore, elastin-free fibres are found in the hyaline cartilage and in the zonula fibres of the eye lens.

Four forms of fibrillins have been described so far. Profibrillin has a molecular weight of about 350 kilodaltons. 47 protein modules are very similar to epidermal growth factor (EGF); most of them can bind calcium. Control of the bioavailability of the growth factor TGF-β is important for tissue formation and homeostasis. The deposition of the latent TGF-β complex (LLC) in the extracellular matrix is caused by fibrillin microfibrils. The protein LTBP-1 (Latent TGFβ-binding protein 1) in the complex interacts with fibronectin during fibrillogenesis. Fibrillins also participate in the structural maintenance of the extracellular matrix by binding to BMP7-like growth factors.

So far, more than 1500 different mutations have been identified, including mutations responsible for Marfan syndrome.

• Mutations in the FBN1 gene lead to numerous phenotypically different clinical pictures:
• Pathogenic germline mutation(s), dysplasia, acromic ORPHA:969
• Disease causing germline mutation(s) Ectopia lentis, isolated ORPHA:1885
• Pathogenic germline mutation/s Familial thoracic aortic aneurysm and aortic dissection ORPHA:91387
• Disease-causing germline mutation(s), geophysical ORPHA:2623
• Disease-causing germline mutation(s) Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy ORPHA:300382
• Pathogenic germline mutation(s) Marfan syndrome, neonatal ORPHA:284979
• Pathogenic germline mutation(s) Marfan syndrome type 1 ORPHA:284963
• Pathogenic germline mutation(s) Stiff-skin syndrome ORPHA:2833
• Disease-causing germline mutation(s) Weill-Marchesani syndrome ORPHA:3449

Several mouse models mutations in the fibrillin gene FBN1 have been developed as useful for the study of scleroderma-like diseases. Fibrillin-1 is known to play an important role in the correction of elastic fiber formation. Furthermore, fibrillin-1 can partially control the availability of TGF-β via confirmed interactions with TGF-β-binding proteins 1 and 4 (Khatri S et al. 2019).

1. Khatri S et al (2019) Autoantibodies in Morphea: An Update. Front Immunol 10:1487.