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G. J. Wistow, K. Wyatt, S. Mishra, R. Fariss, J.-Y. Tsai; Interaction of Complement Factor H and EFEMP1/Fibulin3 in Age Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2477.
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To examine the basis for tissue-targeting in age-related macular degeneration (AMD).
A yeast 2-hybrid (Y2H) library was constructed from aged human retinal pigment epithelium (RPE)/choroid and screened with bait constructs from the seventh domain of complement factor H (CFH). A specific interacting partner was verified and co-localization in vivo was indentified by immunofluorescence (IF).
A common sequence variant (Y402H) in the seventh domain of CFH is associated with increased risk for AMD, a major cause of blindness in aging populations. Y2H screening of aged human RPE/choroid showed that CFH domain 7 binds the C-terminal region of fibulin3/EFEMP1 (Fib3). Fib3 is mutated in Malattia leventinese/Doyne honeycomb retinal dystrophy, an inherited macular degeneration, and is also expressed abnormally in macular RPE in AMD. While both common variants of CFH bound Fib3, the increased risk variant (H402) had significantly higher affinity. IF labeling of a human donor eye with AMD showed tight co-localization of CFH and Fib3 in ‘soft’ drusen (deposits basal to the RPE that are associated with development of AMD) but not in the more common ‘hard’ drusen or in normal retina.
Direct interaction between Fib3 and CFH at the RPE/choroid interface may be a key step in formation of soft drusen and the cascade of events which leads to vision loss in AMD. This interaction connects systemic and tissue-specific features of AMD risk and suggests a potential new target for therapeutic intervention.
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