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C. M. Trantow, M. G. Anderson; Utilizing B6-Lystbg-J Mice to Extend Genetic Pathways of Exfoliation Syndrome. Invest. Ophthalmol. Vis. Sci. 2009;50(13):892.
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© ARVO (1962-2015); The Authors (2016-present)
Exfoliation syndrome (XFS) is a common age-related disorder primarily recognized by the pathological accumulations of a fibrillar exfoliative material in the anterior chamber of the eye. Human eyes with XFS exhibit a striking pattern of Marcel-like iris transillumination defects. The same pattern is recapitulated in mice containing the Lystbg-J mutation. The goal of these experiments was to capitalize on this resource by using mice to begin studying the molecular pathways of XFS.
B6-Lystbg-J mice were identified from a screen of coat color variants assayed by slit-lamp exam. B6-Lystbg-J mice and age-matched C57BL/6J control mice were subsequently analyzed by clinical, histological, and physiological assays.
The iris transillumination defect in both human XFS patients and B6-Lystbg-J mice correlates to an unusual "saw-tooth" morphology of the iris pigment epithelium. At all ages clinically examined, B6-Lystbg-J mice exhibited significant iris defects (n= 30 eyes at 1-2 mo, 36 eyes at 3-6 mo, 106 eyes at 7-27 mo). Similar to human XFS, B6-Lystbg-J mice produce an exfoliative-like material and exhibit pronounced pigment dispersion. B6-Lystbg-J mice also produce accumulations of PAS-positive and anti-fibrillin-1 positive material, which contribute to occlusion of the irideocorneal angle. We have found the molecular basis of the bg-J mutation is a result of a three base pair deletion in the WD40 encoding region of the Lyst gene. Previously it has been shown that the LYST WD40 domain interacts with CSNK2B. We confirmed this interaction with a GST-pulldown experiment. Interestingly, LYSTbg-J completely disrupts the interaction with CSNK2B. CSNK2B function in regulating E-cadherin and β-catenin binding is subsequently disrupted.
These results lead to a working hypothesis that aspects of the XFS phenotype involve LYST and CSNK2B pathways, likely influencing cell-cell adherens junctions. Our results suggest that LYST, or a component of the LYST genetic pathway, are excellent candidates for contributing to human XFS and represent a valuable resource for studying the disease pathway.
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