Mutation of Lyst in Mice Recapitulates Aspects of Human Exfoliation Syndrome

Abstract

Purpose:: Currently, all forms of glaucoma are treated by reducing IOP. However, in secondary forms of glaucoma there are identifiable clinical features preceding IOP elevation that if better understood, could ultimately allow additional early intervention strategies. One approach for studying these features is to utilize mice. We have performed a phenotype-driven screen for new mouse models relevant to secondary forms of glaucoma and identified a previously unrecognized phenotype in Lyst mutant mice that strikingly resembles aspects of human exfoliation syndrome. Here, we present a phenotypic characterization of this strain and our initial mechanistic studies of the pathways underlying this phenotype.

Methods:: B6.Lyst^bg-J mice were identified from a screen of coat color variants initially assayed by slit-lamp exam. Cohorts of B6.Lyst^bg-J mice and age-matched B6 control mice were subsequently analyzed by a variety of clinical, histological, and physiological assays.

Results:: The realization that Lyst mutant mice resemble human exfoliation syndrome was driven by our observation that both share a very striking iris transillumination defect. The pattern of this defect correlates to an unusual "saw-tooth" morphology of the IPE. In order to begin addressing the extent to which Lyst mutant mice might resemble additional aspects of human exfoliation syndrome, aging cohorts of mice were analyzed. Lyst mutant mice exhibit pronounced pigment dispersion and sporadic accumulations of a PAS-positive fibrillar material which both contribute to occlusion of the irideocorneal angle. On the B6 genetic background, IOP does not become elevated and mice maintain healthy optic nerves. In order to test whether pathways involving pigmentation play a role in this phenotype, we performed a genetic epistasis experiment comparing pigmented versus albino Lyst mutant mice. Albinism completely rescues the iris phenotype of these mice. Combined, these results lead to a working hypothesis that aspects of the exfoliation syndrome phenotype may involve the oxidative stress associated with melanogenesis.

Conclusions:: Exfoliation syndrome is a common age-related disease of worldwide significance. Lyst mutant mice represent the first animal model that models any aspect of this disease. Our results suggest that LYST, or a component of the LYST genetic pathway, are excellent candidates for contributing to human glaucoma. Equally important, Lyst mutant mice represent a valuable resource for unraveling the pathways contributing to this disease.

Keywords: aging • iris • gene screening