Sorsby fundus dystrophy: Insights from the past and looking to the future

Abstract

Sorsby fundus dystrophy (SFD), an autosomal dominant, fully penetrant, degenerative disease of the macula, is manifested by symptoms of night blindness or sudden loss of visual acuity, usually in the third to fourth decades of life due to choroidal neovascularization (CNV). SFD is caused by specific mutations in the Tissue Inhibitor of Metalloproteinase-3, (TIMP3) gene. The predominant histo-pathological feature in the eyes of patients with SFD are confluent 20-30 m thick, amorphous deposits found between the basement membrane of the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane. SFD is a rare disease but it has generated significant interest because it closely resembles the exudative or "wet" form of the more common age-related macular degeneration (AMD). In addition, in both SFD and AMD donor eyes, sub-retinal deposits have been shown to accumulate TIMP3 protein. Understanding the molecular functions of wild-type and mutant TIMP3 will provide significant insights into the patho-physiology of SFD and perhaps AMD. This review summarizes the current knowledge on TIMP3 and how mutations in TIMP3 cause SFD to provide insights into how we can study this disease going forward. Findings from these studies could have potential therapeutic implications for both SFD and AMD.

Figure 1:

Schematic illustration of the TIMP3 protein displaying mutations that cause autosomal dominant Sorsby fundus dystrophy. Each amino acid residue of the mature protein is shown by a black filled circle. The twelve cysteine residues predicted to form six disulphide bonds are indicated in blue. Mutations leading to an unpaired cysteine are shown in red, the three missense mutations leading to amino acid exchanges other than cysteines are depicted in green. An asterisk indicates the splice mutation. The figure has been modified from Figure 10 in Gliem et al., 2015, copyright holder: Association for Research in Vision and Ophthalmology

Figure 2:

hiPSC-RPE as a tool to study SFD pathophysiology. A) Representative images showing patient-derived fibroblasts p.(Ser204Cys), hiPSCs and consequent differentiation of hiPSCs to obtain hiPSC-RPE monolayer. (B) Immunocytochemical and Western blotting analyses showing robust expression of TIMP3 in the basement membrane/ECM underlying control hiPSC-RPE cultures. Of note, the bottom panel shows the presence of TIMP3 bands consistent with unglycosylated, glycosylated and dimer forms of TIMP3 in ECM extracted from hiPSC-RPE cultures derived from three distinct control hiPSC lines. (C) Representative Immunoflurosecence labeling showing presence of APOE and TIMP3 positive drusen-like deposits underlying control vs. SFD hiPSC-RPE monolayer.