Fibrillins are the major components of microfibrils in the extracellular matrix 
of elastic and non-elastic tissues. They are multi-domain proteins, containing 
primarily calcium binding epidermal growth factor-like (cbEGF) domains and 
8-cysteine/transforming growth factor-beta binding protein-like (TB) domains. 
Mutations in the fibrillin-1 gene give rise to Marfan syndrome, a connective 
tissue disorder with clinical complications in the cardiovascular, skeletal, 
ocular and other organ systems. Here, we review the consequences of engineered 
Marfan syndrome mutations in fibrillin-1 at the protein, cellular and organismal 
levels. Representative point mutations associated with Marfan syndrome in 
affected individuals have been introduced and analyzed in recombinant 
fibrillin-1 fragments. Those mutations affect fibrillin-1 on a structural and 
functional level. Mutations which impair folding of cbEGF domains can affect 
protein trafficking. Protein folding disrupted by some mutations can lead to 
defective secretion in mutant fibrillin-1 fragments, whereas fragments with 
other Marfan mutations are secreted normally. Many Marfan mutations render 
fibrillin-1 more susceptible to proteolysis. There is also evidence that some 
mutations affect heparin binding. Few mutations have been further analyzed in 
mouse models. An extensively studied mouse model of Marfan syndrome expresses 
mouse fibrillin-1 with a missense mutation (p.C1039G). The mice display similar 
characteristics to human patients with Marfan syndrome. Overall, the analyses of 
engineered mutations leading to Marfan syndrome provide important insights into 
the pathogenic molecular mechanisms exerted by mutated fibrillin-1.