- Mice carrying the tight skin mutation (Tsk) have thickened skin and visceral fibrosis. The accumulation of extensive genetic analysis in the principal investigator's laboratory resulted in the recent demonstration of a mutation in the fibrillin gene (fbn-1). This mutation causes an in- frame duplication of a region of the gene and results in the expression of a larger fibrillin molecule (450 v 330 kDa). The larger fibrillin protein is secreted into the extracellular matrix in an amount approximately equal to that of the normal protein. In collaboration with Dr. Kielty the principal investigator has demonstrated that the increased size of fibrillin is seen as an increase in intersubunit distance in fibrillin isolated from tissue of Tsk mice. It might be expected that the increased collagen deposition in these mice occurs in response to altered mechanical properties of the matrix resulting from a disruption in components of the elastin-associated matrix. However the principal investigator has some evidence that collagen synthesis is increased in fibroblasts isolated from embryos homozygous for the mutation and to a lesser extent in fibroblasts from embryos heterozygous for the mutation. The principal investigator hypothesizes that the duplication seen in this gene is responsible for the increased collagen synthesis and has focused on two elements of the gene that are duplicated, a putative TGF-binding domain and an RGD sequence.
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