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Adam Hedberg-Buenz, Tryphena Cuffy, Colleen M. McDowell, Michael G. Anderson; Molecular Mechanisms Underlying the Iris Transillumination Defects of Exfoliative Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2412.
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Exfoliation syndrome (XFS) is the most commonly identified cause of secondary open-angle glaucoma. C57BL/6J mice with the Lystbg-J mutation recapitulate many aspects of XFS, including a unique pattern of iris transillumination defects referred to as "Marcel-TID." Because Marcel-TID can be readily identified in mice, studies of this phenotype offer an opportunity to examine molecular pathways contributing to XFS. The purpose of the current experiments was to identify and test the role of additional genes contributing to XFS by performing phenotype- and candidate-driven screens for genes influencing Marcel-TID in mice.
Marcel-TID were assayed by slit lamp photography. Defect severities were quantified, averaged among mice of the same genotype, and experimental and control cohorts tested for potential differences using Student’s t-test. In a phenotype-driven approach, two inbred strains of mice carrying the Lystbg-J mutation were utilized in a screen for genetic modifiers. Mapping crosses were then performed. In a candidate-driven approach, gene expression profiling was performed to identify potentially contributing pathways and the role of individual genes was tested by examining mice with targeted mutations of candidates.
From the phenotype-driven approach, slit lamp analysis indicated that the Lystbg-J phenotype is more severe on the DBA/2J vs. C57BL/6J genetic background. Genetic crosses mapped this modifier to the Tyrp1b mutation present in DBA/2J mice. Subsequent studies found that the Tyrp1b mutation likely influences the Marcel-TID phenotype by influencing levels of lipid hydroperoxides in the iris. From the candidate-driven approach, microarray analysis identified 460 statistically significant changes in gene expression between Lystbg-J mutant and control mice. In specifically testing individual candidates, no Marcel-TID phenotypes were detected in cohorts of mice with conditional disruption of Cdh1 in neuroepithelial tissues or targeted mutation of Mmp12.
These results identify Tyrp1 as a modifier of Lystbg-J-mediated iris phenotypes and suggest oxidative damage to lipid membranes contributes to XFS pathophysiology. A large number of expression changes were detected in comparative transcriptional profiling; ongoing experiments continue to test the extent these candidates, and others, may impact XFS phenotypes.
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