In Vivo Studies of Mutant Fibrillin-1 Microfibrils

• DOI: 10.1074/jbc.m110.130021
• Publication Date: 2010-06-08T00:47:50Z
• Authors: Noe L. Charbonneau; Eric J. Carlson; Sara Tufa; Gerhard Sengle; Elise C. Manalo; Valerie M. Carlberg; Francesco Ramirez; Douglas R. Keene; Lynn Y. Sakai
• Keywords: Fibrillin; Microfibril; Haploinsufficiency; Cutis laxa

In humans, mutations in fibrillin-1 result a variety of genetic disorders with distinct clinical phenotypes. While most the known cause Marfan syndrome, number other lead to features unrelated syndrome. Pathogenesis syndrome is currently thought be driven by mechanisms due haploinsufficiency wild-type fibrillin-1. However, haploinsufficiency-driven cannot explain phenotypes found fibrillinopathies. To test hypothesis that through primary effects on microfibril structure, two different were generated Fbn1 mice. One mutation leads truncated molecule tagged green fluorescent protein, allowing visualization mutant incorporated into microfibrils. heterozygosity, these mice demonstrate progressive fragmentation aortic elastic lamellae and also display microfibrils tissues. Fibrillin-2 epitopes are progressively revealed mice, suggesting fibrillin-2 immunoreactivity can serve as marker for degradation. contrast, second (in-frame deletion first hybrid domain) results stable microfibrils, demonstrating molecules not required perfect register structure function domain dispensable assembly. Taken together, suggest perturbation may underlie one major syndrome: lamellae.