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Mutat Res Rev Mutat Res. 2015 Jul-Sep;765:7-18. doi: 10.1016/j.mrrev.2015.04.002. Epub 2015 May 5.

Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels.

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Faculty of Medicine, McGill University, Montreal, Canada. Electronic address:
Faculty of Medicine, McGill University, Montreal, Canada; Faculty of Dentistry, McGill University, Montreal, Canada. Electronic address:


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.


Fibrillin; Genotype–phenotype correlations; Marfan syndrome; Microfibrils; Molecular pathogenesis; Mutations

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