What is the genetic defect in Marfan Syndrome, and how does it contribute to the clinical manifestations?
MFS is caused by mutations in the fibrillin-1 gene on chromosome 15. Over 3000 mutations of this gene have been reported. The predominant inheritance pattern is AD, although 25% of cases are due to sporadic mutations. Fibrillin-1 is produced by fibroblasts and forms a scaffold for the deposition of elastin. In addition to being a connective protein important in structural support for tissues, the fibrillin-1 protein also binds transforming growth factor β (TGF-β). Researchers now believe that the mutated fibrillin-1 cannot bind TGF-β resulting in excessive accumulation of TGF-β. Excess TGF-β can have deleterious effects on vascular smooth muscle development and the integrity of the ECM by binding to its receptor and upregulating TGF-β responsive genes such as those that regulate the production of matrix metalloproteinases. The excess matrix metalloproteinases can interfere with tissue development and weaken the tissue. Therefore, organs that contain a lot of fibrillin-1 and elastin are most likely to be involved in MFS including the elastic walls of arteries (especially aorta), heart valves, zonula fibers of the eye, ligaments, skin, and lung parenchyma.
