Fibrillin is encoded by the FBN1 gene, which maps to chromosomal locus 15q21. Mutations in FBN1 are found in all patients with Marfan syndrome. More than 1800 distinct causative mutations in the very large FBN1 gene have been found, a level of complexity that complicates diagnosis by DNA sequencing. As a result, the diagnosis is mainly based on clinical findings. Because heterozygotes have clinical symptoms, it is thought that the mutant fibrillin protein may act as a dominant negative, preventing the assembly of normal microfibrils. The prevalence of Marfan syndrome is estimated to be 1 in 5000. Approximately 70% to 85% of cases are familial, and the rest are sporadic, arising from de novo FBN1 mutations in the germ cells of parents.
Although many of the abnormalities in Marfan syndrome can be explained on the basis of structural failure of connective tissues, some, such as overgrowth of bones, are difficult to relate to simple loss of fibrillin. It is now evident that loss of microfibrils gives rise to abnormal and excessive activation of transforming growth factor-β (TGF-β), because normal microfibrils sequester TGF-β, thereby controlling the bioavailability of this cytokine.
Excessive TGF-β signaling has deleterious effects on vascular smooth muscle development and the integrity of extracellular matrix. In support of this hypothesis, mutations in the TGF-β type II receptor give rise to a related syndrome, called Marfan syndrome type 2 (MFS2). Furthermore, patients with germline mutations in one isoform of TGF-β, called TGF-β3, present with an inherited predisposition to aortic aneurysm and other cardiovascular manifestations similar to those found in “classic” Marfan patients (see later). Of note, angiotensin receptor blockers, which inhibit the activity of TGF-β, improve aortic and cardiac function in mouse models of Marfan syndrome. Prevention of cardiovascular disease entails the use of beta-aderenergic blocking agents, which lower blood pressure, as well as angiotensin receptor inhibitors, which not only lower blood pressure but also interfere with TGF-β activity.