Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders

The extracellular microfibril, 10-14 nm in diameter, performs a number of functions, including serving as the scaffolding for deposition of tropoelastin to form elastic fibers. A variety of proteins compose the structure of microfibrils, the most prominent of which are the two fibrillins. Fibrillin-1 is encoded by FBN1 on human chromosome 15q21 and fibrillin-2 is encoded by FBN2 on 5q23. Each fibrillin monomer contains a large number of epidermal growth factor-like motifs, most capable of binding calcium ions, and a few motifs resembling the binding protein for transforming growth factor β. In vitro polymerization of fibrillin monomers produces 'beads on a string' structures that look on electron microscopy much like microfibrils purified from the extracellular matrices of a variety of tissues. Mutations in FBN1 produce Marfan syndrome, a pleiotropic autosomal dominant connective tissue disorder with prominent manifestations in the skeleton, eye and cardiovascular system. A number of conditions related to Marfan syndrome are also due to FBN1 mutations. Contractural arachnodactyly is due to mutations in FBN2. In this paper we review the published mutations in these genes, preliminary results of genotype-phenotype correlations, and speculations regarding molecular pathogenesis.