In vivo studies of mutant fibrillin-1 microfibrils. J Biol Chem 2010 Aug 06;285(32):24943-55
Date
06/10/2010Pubmed ID
20529844Pubmed Central ID
PMC2915730DOI
10.1074/jbc.M110.130021Scopus ID
2-s2.0-77955297956 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
In humans, mutations in fibrillin-1 result in a variety of genetic disorders with distinct clinical phenotypes. While most of the known mutations in fibrillin-1 cause Marfan syndrome, a number of other mutations lead to clinical features unrelated to Marfan syndrome. Pathogenesis of Marfan syndrome is currently thought to be driven by mechanisms due to haploinsufficiency of wild-type fibrillin-1. However, haploinsufficiency-driven mechanisms cannot explain the distinct phenotypes found in other fibrillinopathies. To test the hypothesis that mutations in fibrillin-1 cause disorders through primary effects on microfibril structure, two different mutations were generated in Fbn1 in mice. One mutation leads to a truncated fibrillin-1 molecule that is tagged with green fluorescent protein, allowing visualization of mutant fibrillin-1 incorporated into microfibrils. In heterozygosity, these mutant mice demonstrate progressive fragmentation of the aortic elastic lamellae and also display fragmentation of microfibrils in other tissues. Fibrillin-2 epitopes are also progressively revealed in these mice, suggesting that fibrillin-2 immunoreactivity can serve as a marker for microfibril degradation. In contrast, a second mutation (in-frame deletion of the first hybrid domain) in fibrillin-1 results in stable microfibrils, demonstrating that fibrillin-1 molecules are not required to be in perfect register for microfibril structure and function and that the first hybrid domain is dispensable for microfibril assembly. Taken together, these results suggest that perturbation of microfibril structure may underlie one of the major features of the Marfan syndrome: fragmentation of aortic elastic lamellae.
Author List
Charbonneau NL, Carlson EJ, Tufa S, Sengle G, Manalo EC, Carlberg VM, Ramirez F, Keene DR, Sakai LYAuthor
Valerie M. Carlberg MD Associate Professor in the Dermatology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAnimals
Extracellular Matrix
Fibrillin-1
Fibrillin-2
Fibrillins
Gene Deletion
Genotype
Humans
Marfan Syndrome
Mice
Mice, Transgenic
Microfibrils
Microfilament Proteins
Microscopy, Electron
Models, Genetic
Mutation
