Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy.

Objective: To determine the molecular basis of a retinopathy previously described as dominant macular subretinal neovascularization with peripheral retinal degeneration.

Methods: The TIMP3 gene was analyzed in family members, and 4 mutation-positive patients were studied using psychophysics and electroretinography.

Results: Cosegregating with disease in the family was a single base pair change in the TIMP3 gene, altering a conserved tyrosine to cysteine at amino acid position 172 (Y172C). There was psychophysical and electroretinographic evidence of rod dysfunction greater than cone dysfunction. Dark adaptometry showed abnormalities with regional retinal variation in degree.

Conclusions: The Y172C mutation in the TIMP3 gene is another cause of Sorsby fundus dystrophy. The expression of this form of the disease, as in other C-terminal TIMP3 mutations, is speculated to be secondary to mutant TIMP-3, causing a decreased turnover of the extracellular matrix.

Clinical Relevance: The molecular clarification of inherited retinal degeneration involving abnormal extracellular matrix turnover in and around Bruch's membrane should provide clues to the pathogenesis of not only these particular diseases but also forms of age-related macular degeneration.