Characterization of mutated protein encoded by partially duplicated fibrillin-1 gene in tight skin (TSK) mice

Fibrillin-1 (Fbn-1) is a ubiquitous protein present in the extracellular matrix of various organs and it is a major component of microfibrils embedded in the core of elastic fibers. In humans, mutations or deletions of the Fbn- 1 gene are associated with several genetic disease. In addition, several microsatellite alleles near Fbn-1 gene were found associated with diffuse scleroderma. In TSK/+mice, which develop a scleroderma-like syndrome, the Fbn-1 gene exhibits an inframe duplication of exons 17-40. In this study, we report that the synthesis and secretion of wild-type Fbn-1 in TSK/+ is higher than that of the mutated Fbn-1 protein excluding the possibility that TSK genetic defect is due to a loss of the wild-type allele. We also demonstrate for the first time that TGF-β, which plays a crucial role in skin fibrosis, binds to both wild-type Fbn-1 and mutated Fbn-1. The amount of bound TGF-β was higher in mutated than wild-type Fbn-1 and appears related to the number of TGF-β binding motifs.