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Sorsby's fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies.

A Novel TIMP-3 Mutation Reveals a Common Molecular Phenotype in Sorsby's Fundus Dystrophy