THE FIBRILLIN-MARFAN SYNDROME CONNECTION

A few years ago no one would have suspected that the well-known disord er of connective tissue, Marfan syndrome, could be caused by mutations in a recently discovered extracellular component, fibrillin. Likewise , nobody would have predicted that fibrillin represents a small family of proteins that are associated with several phenotypically overlappi ng disorders. The fibrillins are integral constituents of the non-coll agenous microfibrils, with an average diameter of 10 nm. These aggrega tes are distributed in the extracellular matrix of virtually every tis sue. Microfibrillar bundles provide the external coating to elastin in elastic fibers, and serve an anchoring function in non-elastic tissue s. At higher resolution, individual microfibrils have a ''beads-on-a-s tring'' appearance resulting from the head-to-tail polymerization of m ultiple fibrillin aggregates. Structurally, fibrillin contains a serie s of repeated sequences homologous to the epidermal growth factor calc ium-binding motif. Characterization of fibrillin mutations in Marfan s yndrome patients, together with the elucidation of the structure of th e fibrillin proteins, have provided new insights, and raised new quest ions, about the function of the 10 nm microfibrils. For example, it is possible that the fibrillins, in addition to serving a structural fun ction, might also be involved in regulating cellular activities and mo rphogenetic programs. It is fitting that the long search for the Marfa n syndrome gene has brought a novel group of proteins to the forefront of extracellular matrix biology.