Fibrillin-1

FBN1 is a 230-kb gene with 65 coding exons that encode a 2,871-amino-acid long proprotein called profibrillin which is proteolytically cleaved near its C-terminus by the enzyme furin convertase to give fibrillin-1, a member of the fibrillin family, and the 140-amino-acid long protein hormone asprosin. == Structure ==

The sequence of fibrillin-1 includes 47 six-cysteine EGF-like domains, 7 eight-cysteine domains homologous with latent TGF-beta binding protein, and a proline-rich region. == Function ==

Fetal cardiovascular development The FBN-1 gene is involved in a variety of embryonic developmental programs. The microfibrils that are made from fibrillin-1 contribute to both elastic and non-elastic structures. The formation of the elastic fibers in the heart valves and the aorta require the involvement of both FBN-1 and FBN-2. It has been shown that both FBN-1 and FBN-2, along with the other components of elastic fibers, are expressed in the embryonic semilunar valves as early as 4 weeks of gestation. These molecules interact to form the elastic fibers in the ventricularis layer of the semilunar valves. Fibrillin-1 and fibrillin-2 are also crucial for the development of elastic fibers in the aorta. While expression of fibrillin-2 decreases significantly after fetal development, the expression of fibrillin-1 continues into adulthood. This supports the idea that fibrilin-2 dictates the development of early elastic fibers, while fibrillin-1 provides the structural support of mature elastic fibers. == Clinical significance ==

Mutations in the FBN1 gene are associated with Marfan syndrome and its variant Marfanoid–progeroid–lipodystrophy syndrome, autosomal dominant Weill–Marchesani syndrome, isolated ectopia lentis, MASS phenotype, and Shprintzen–Goldberg syndrome. Mutations in FBN1 and FBN2 are associated with adolescent idiopathic scoliosis. Clinical symptoms of MFS such as aortic root dilation, pulmonary emphysema, atrioventricular valve changes and skeletal muscle myopathy are induced by altered TGF-β activation and signalling. Fibrillin-1 is a large cysteine rich-glycoprotein approximately 350 kDa mainly composed of tandemly repeating domains of epidermal growth factor (EGF)-like modules. These domains are homologous to calcium binding epidermal growth factor module (cbEGF-like motifs) and of distinct 8-cysteine modules to make up elastic and non-elastic tissue. Elastogenesis is a biological process where microfibrils and elastic fibres are self-assembled via organised deposition by several macromolecules. Mutations can include: • Missense mutations caused by single base substitutions such as cysteine or those associated with calcium binding in Fibrillin-1. These loci tend to have genes that are involved in vascular function. Marfan syndrome Marfan syndrome (MFS) is an autosomal dominant disorder that affects the connective tissues of bodily systems such as the eyes, cardiovascular system, skeletal system, skin, pulmonary system and the dura. MFS affects approximately 1 in 5,000 individuals. MFS is not an easily diagnosed pathology with a scoring system called the Ghent nosology table used, rather than a single molecule test. To diagnose MFS individuals that have no previous family history, two criteria must be met. Firstly, two different major organ systems must be affected, and secondly, a third organ system must be involved. MFS has a large hereditary component, with 80% of cases being inherited. The skin epidermis is thin and flattened, and the upper protective skin layer is decreased in thickness. These symptoms are responsible for cobweblike skin appearances in patients with MFS. The fragility of the connective tissue usually results in aortic aneurysms due to the wall having the inability to withstand intraluminal pressure. Defects in fibrillin-1 results in elevated TGF-β levels that directly correlate to MFS. SLC then binds extracellularly to latent TGF-β binding protein (LTBP) forming a large latent complex (LLC), which includes an active cytokine. The LLC attaches to the microfibrils of Fibrillin-1 via LTBP, allowing the preservation of inactive TGF-β [6]. TGF-β can only be activated through a series of regulated mechanisms; maintaining correct functioning in embryonic development. This phosphorylation can cause failures such as an aortic aneurysm and prolapsed valves. Clinical symptoms of MFS such as aortic root dilation, pulmonary emphysema, atrioventricular valve changes and skeletal muscle myopathy are induced by altered TGF-β activation and signalling. Aortic specific symptoms are closely related to excessive TGF-β signalling in the aortic root wall. TGF-β antagonism via systemic administration of TGF-β neutralising antibody (NAb) averted the development of aortic pathologies associated with MDS, more specifically changes in the aortic wall and progressive aortic dilation. Antagonism of TGF-β also further reduced MFS symptoms where it helped muscle regeneration, architecture and strength, pulmonary alveolar septation and mitral valve morphology. LLC that fails to be removed from the ECM is more vulnerable to be activated in a protease-dependent or independent manner. MMP2 and MMP9 are select TGF-β activators and ligands and are found in higher levels in the tissues of patients affected with MFS. TGF-β in its complex and free-form can leach into the circulation due to the mutated ECM sequestration and increased LLC activation. Losartan Losartan is an angiotensin II type 1 (AT1) receptor blocker known to antagonise TGF-β signalling via inhibiting the expression and activation of TGF-β. Losartan can work independently or with β-blocker therapy to reduce rate of change in the aortic root diameter of MFS pathology. == See also ==