TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy

PURPOSE. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP-3) gene have previously been identified in patients with Sorsby's fundus dyst rophy (SFD). We evaluated the ocular distribution of TIMP-3 and other extra cellular constituents in SFD. METHODS. The eyes of an SFD donor with a confirmed TIMP-3 mutation were exa mined using histologic techniques demonstrating connective tissue, calcium, and lipid. Immunohistochemical analyses were performed using antibodies ag ainst TIMP-3, collagen type IV, V, and VI, laminin, fibronectin, elastin, a nd fibrillin. Electron microscopy also was used. RESULTS. A subretinal pigment epithelium (sub-RPE) deposit similar to that previously described was seen. A morphologically similar but different depo sit was present internal to the nonpigmented ciliary epithelium (NPCE). Bot h deposits contained collagens, elastin, glycosaminoglycans, lipids, and ca lcium. Immunolabeling of TIMP-3 was found in the basement membrane of the N PCE, Bruch's membrane, and choroidal vessels in normal control subjects. In SFD, immunolabeling of TIMP-3 also was present in the sub-RPE deposit and in the inner portion of the ciliary body deposit. TIMP-3 immunoreactivity w as more extensive in the SFD eye. The pattern of elastin immunoreactivity w as remarkably similar to that of TIMP-3. Electron microscopy revealed a mor phologically altered elastic layer of the Bruch's membrane. CONCLUSIONS. Sub-RPE TIMP-3 immunoreactivity appears more extensive in SFD than in control subjects. There is also a correspondence between TIMP-3 and elastin immunoreactivies, which invites speculation as to a Link between t he SFD TIMP-3 mutation and altered elastin processing. The accumulation of abnormal material in SFD is more widespread than previously reported. In vi ew of this, SFD might be better termed Sorsby's ocular epitheliopathy.