Microfibril-associated Disorders

Extracellular microfibrils are found in most organ systems and are abundant in ocular, cardiovascular, and skeletal tissues. Microfibrils always provide the outer mantle of elastic fibers where they play a crucial role in the biogenesis and homeostasis of these fibers. Microfibrils are also found in the absence of elastin in many tissues including the ciliary zonules in the eye. Microfibrils are supramolecular protein complexes composed of >20 different components with fibrillins being the most important building blocks. The fibrillin family of proteins consists of 3 highly homologous large proteins (∼350 kDa), fibrillin-1, fibrillin-2, and fibrillin-3, all encoded by different genes.1 Fibrillin-1 has been identified as one of the components of the lenticular exfoliation material.2 Mutations in fibrillins cause various connective tissue disorders known as fibrillinopathies. Fibrillin-1 mutations have been identified to cause Marfan syndrome, dominant Weill-Marchesani syndrome, geleophysic dysplasia, acromicric dysplasia, stiff skin syndrome, isolated ectopia lentis, kyphoscoliosis, familial arachnodactyly, familial thoracic ascending aortic aneurysms and dissections, and the “MASS” phenotype.3 Fibrillin-1 has been also implicated in the pathogenesis of homocystinuria and systemic sclerosis.4,5 Fibrillin-2 mutations lead to congenital contractural arachnodactyly also known as Beals-Hecht syndrome.6 It is not clear at present whether fibrillin-3 has a role in human disease. Marfan syndrome occurs with an estimated prevalence of 2 to 3 in 10,000 individuals, whereas other fibrillinopathies are rare.7 Clinical symptoms in Marfan syndrome develop in the cardiovascular, skeletal, and ocular systems, including progressive dilatation of the aortic root, dissection and rupture of the aortic wall, mitral valve prolapse, arachnodactyly, dolichostenomelia, loose joints, and scoliosis. Clinical complications in the eye include ectopia lentis, myopia, retinal detachment, and glaucoma. More than 1000 mutations in the gene for fibrillin-1 have been identified in individuals with Marfan syndrome, and a few in individuals with other fibrillinopathies (Fig. 1). The mutations leading to Marfan syndrome affect virtually every single protein domain in fibrillin-1. Mutations in the center of fibrillin-1 frequently result in a very severe phenotype with a high probability of ascending aortic dilatations. A common feature of Marfan syndrome and other fibrillinopathies is a high degree of interfamilial and intrafamilial variability, suggesting that modifier genes or environmental factors play a role in the progression of the disease.FIGURE 1: Schematic representation of fibrillin-1 in relation to human disease. Some mutations leading to Marfan syndrome are indicated by black vertical bars above and below the protein model. Protein domains harboring mutations that lead to other fibrillinopathies (dominant Weill-Marchesani syndrome, acromelic dysplasias, and stiff skin syndrome) are indicated by horizontal bars.Homocysteine is one example of a potential modifier. Homocystinuria, caused by deficiencies in cystathionine-β-synthase, and Marfan syndrome are both characterized by several overlapping clinical symptoms such as ectopia lentis, long bone overgrowth, and scoliosis.8 Elevated homocysteine has profound effects on the structure and function of fibrillin-1.9,10 In these studies, elevated homocysteine chemically modified fibrillin-1, increased its susceptibility to proteolysis, and altered its properties to interact with itself or with other matrix proteins. Elevated homocysteine was also reported in individuals with exfoliation syndrome.11 Given the chemical ability of homocysteine to modify fibrillin-1 and alter its function, it is possible that fibrillin-1 homocysteinylation contributes to the development and aggregation of exfoliation material. Other fibrillinopathies caused by mutations in only 1 or a few domains of fibrillin-1 are characterized by different clinical symptoms compared with Marfan syndrome. Autosomal dominant Weill-Marchesani syndrome, for example, is characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including myopia, microspherophakia, ectopia lentis, glaucoma, and cataract.12 Individuals with autosomal dominant geleophysic dysplasia typically present with a short stature, small hands and feet, thick skin, progressive contractures of the joints, glaucoma, strabismus, but typically lack ectopia lentis. Some of these clinical features represent the opposite spectrum of that associated with Marfan syndrome. The current pressing question in the field is how mutations in the same protein, fibrillin-1, can lead to fundamentally different clinical manifestations. In recent years it was demonstrated that fibrillins and microfibrils are involved in matrix deposition and activation of growth factors of the TGF-β superfamily, including TGF-β and bone morphogenetic proteins (BMPs).13 These growth factors regulate a broad array of developmental and homeostatic processes, and are involved in the pathobiology of a variety of tissues. The mammalian TGF-β1, TGF-β2, and TGF-β3 are synthesized as a complex with the latency-associated protein (LAP). Latent TGF-β1 was found to be associated with exfoliation material.14 Most cell lines secrete TGF-β as large latent complexes (LL-TGF-β) consisting of the LAP-TGF-β covalently bound to latent TGF-β binding protein (LTBP)-1, LTBP-3, and LTBP-4, but not LTBP-2.15 Fibrillins and fibrillin-containing microfibrils can indirectly sequester TGF-β through their interactions with LTBP-1 and LTBP-4.16 In addition, LTBPs interact with fibronectin fibers in the extracellular matrix.17 LTBP-1 is a major component of the exfoliation material.14 Normal TGF-β activation in LL-TGF-β can, for example, occur through binding to various cell surface integrins, interactions with thrombospondin-1, and proteolytic events mediated by plasmin and matrix metalloproteinases.18 A model proposes that the association of LTBPs with microfibrils and the simultaneous interactions with fibronectin fibers is necessary to stabilize the LL-TGF-β in the matrix. Mutant fibrillin-1 in microfibrils may destabilize the LL-TGF-β complex and facilitate the activation of TGF-β, but the precise mechanism is unknown. In contrast to TGF-β, some BMPs are targeted directly to microfibrils through interaction of their prodomain with fibrillins.19 Whether or not abnormal BMP signaling is involved in disease progression of fibrillinopathies is unknown. It is possible that TGF-β and BMP deregulation may affect the generation and deposition of the exfoliation material.

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