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D. S. Roh, Y. Du, A. R. Robinson, M. L. Gabriele, L. J. Niedernhofer, J. L. Funderburgh; Corneal Endothelial Changes in DNA Repair-Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4290.
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The accumulation of unrepaired DNA damage is known to cause degenerative changes in numerous tissues that correlate significantly to changes that occur spontaneously with aging. Our previous study (IOVS 2008;49:4837-43) demonstrated the accumulation of DNA damage in corneal endothelial (CE) cells treated in vitro with the genotoxic mitomycin-C, used in refractive surgery. This led us to study the effects of DNA damage on CE in vivo. Using mice genetically modified to express reduced levels of Ercc1-XPF (Ercc1-/Δ), a DNA endonuclease required for nucleotide excision repair of bulky monoadducts and the repair of interstrand crosslinks, we sought to identify long term changes in the CE resulting from the accumulation of DNA damage.
The changes in the Ercc1-/Δ mice CE were similar to those of the wild type "old" mice examined. Ercc1-/Δ mice displayed decreased CE cell density, increased CE cell pleomorphism and polymegathism, and the presence of guttae-like excrescences relative to controls. 3-D reconstructions demonstrated that the guttae-like excrescences projected into the anterior chamber originating from the CE monolayer. Significant increases in corneal thickness or opacity based on our imaging were not observed.
DNA repair deficiency accelerates the degeneration of CE cells in vivo. Despite these degenerative changes, the CE in Ercc1-/Δ mice appears to be able to maintain the proper hydration balance of the cornea. These results support the conclusion that DNA damage may play a causal role in the degeneration of CE.
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