Sorsby Fundus Dystrophy-Related Mutation in Tissue Inhibitor of Metalloproteinases-3 Impairs Regulation of Its Expression in Mouse Fibroblasts

Abstract

Mutations in the C-terminal domain of tissue inhibitor of metalloproteinases-3 (TIMP-3) are linked with Sorsby fundus dystrophy (autosomal dominant retinal dystrophy). Experiments on timp-3 gene knock-out and knock-in mice, carriers of dystrophy-linked Timp-3S156C mutation, showed that expression of mutant Timp-3S156C, in contrast to the normal one, is not regulated by phorbol-myristate-12-acetate and is retained at a high level in a medium without FCS. The mutant protein is not transported into the nucleus, while fibroblasts expressing it survive without FCS and other growth factors. It is hypothesized that normal Timp-3 is involved in the regulation of expression of its own timp-3 gene and, probably, other genes associated with growth and proliferation. The absence of this characteristic in mutant Timp-3S156C is presumably responsible for its accumulation in the extracellular matrix.