Microfibrils: a cornerstone of extracellular matrix and a key to understand Marfan syndrome.

The extracellular matrix is made of collagen, reticular, elastic and oxytalan fibers, amorphous ground substance and adhesive proteins playing a structural role, such as fibronectin; the basement membrane is a specialized matrix compartment which adheres to non-connective tissues and is continuous with the remaining matrix thanks to reticular fibers, anchoring fibrils, collagen VI filaments and oxytalan fibers. Microfibrils are constituents of elastic and oxytalan fibers that confer mechanical stability and limited elasticity to tissues, contribute to growth factor regulation, and play a role in tissue development and homeostasis. The microfibril core is made of the glycoprotein fibrillin, of which three types are known. Other concurring molecules are microfibril associated proteins (MFAPs) and microfibril associated glycoproteins (MAGPs); they, and other peripheral molecules, contribute to link microfibrils to elastin, to other extracellular matrix components and to cells. Fibrillinopathies are genetic disorders due to mutations in fibrillin genes (FBN). The most frequent is Marfan syndrome, caused by mutations in FBN-1 and involving primarily the cardiovascular, skeletal, ocular and central nervous systems. Several mutations have been identified, which lead to alteration or reduction in the secretion or assembly of fibrillin molecules and to increased microfibril proteolysis. Marfan related disorders are associated with alterations of TGF-beta signaling that interfere with extracellular matrix formation. Understanding the pathogenesis of Marfan and related syndromes requires advances in the physiology of the extracellular matrix and in turn can cast light on the roles of microfibrils and of extracellular matrix in general in organ formation and function.