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Samuel G. Jacobson, MD, PhD; Artur V. Cideciyan, PhD; Jean Bennett, MD, PhD; Ronald M. Kingsley, MD; Val C. Sheffield, MD, PhD; Edwin M. Stone, MD, PhD

Arch Ophthalmol. 2002;120:376-379.

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.

From the Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia (Drs Jacobson, Cideciyan, and Bennett); Department of Ophthalmology, University of Oklahoma Health Sciences Center, Dean A. McGee Eye Institute, Oklahoma City (Dr Kingsley); and Departments of Ophthalmology (Dr Stone) and Pediatrics and the Howard Hughes Medical Institute (Dr Sheffield), University of Iowa College of Medicine, Iowa City.

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