Marfan Syndrome - Pathogenesis

Pathogenesis

Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15, which encodes the glycoprotein fibrillin-1, a component of the extracellular matrix. Fibrillin-1 protein is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors. Elastin fibers are found throughout the body, but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye; consequently, these areas are among the worst affected.

A transgenic mouse has been created carrying a single copy of a mutant fibrillin-1, a mutation similar to that found in the human gene known to cause Marfan syndrome. This mouse strain recapitulates many of the features of the human disease and promises to provide insights into the pathogenesis of the disease. Reducing the level of normal fibrillin 1 causes a Marfan-related disease in mice.

Transforming growth factor beta (TGFβ) plays an important role in Marfan syndrome. Fibrillin-1 directly binds a latent form of TGFβ, keeping it sequestered and unable to exert its biological activity. The simplest model of Marfan syndrome suggests reduced levels of fibrillin-1 allow TGFβ levels to rise due to inadequate sequestration. Although it is not proven how elevated TGFβ levels are responsible for the specific pathology seen with the disease, an inflammatory reaction releasing proteases that slowly degrade the elastin fibers and other components of the extracellular matrix is known to occur. The importance of the TGFβ pathway was confirmed with the discovery of the similar Loeys-Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGFβ. Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two pathologies.