Genetic pathways of Lyst and exfoliation syndrome

Human eyes with exfoliation syndrome (XFS) exhibit a distinctive pattern of iris transillumination defects that are recapitulated in Lyst mutant mice carrying the beige allele. Here I present the identification and characterization of the B6-Lyst mouse model of XFS, modifiers of Lyst mediated ocular phenotypes, mechanisms of intraocular pressure (IOP) pathology related to circadian rhythms, and mechanisms of iris transillumination defects in the B6-Lyst mice. Clinical and histological analysis shows that the B6-Lyst mice have multiple similarities to human XFS including: iris transillumination defects, production of an exfoliative-like material, and pronounced pigment dispersion. Despite these insults, Lyst mutation does not cause increased IOP or optic nerve damage within the context of a C57BL/6J genetic background. However, defects in the circadian rhythm regulation of IOP were identified. Sequence analysis identifies that the beige mutation is predicted to delete a single isoleucine from the WD40 domain of the LYST protein. I identified CSNK2B as a binding partner of LYST and showed that LYST completely disrupts the interaction. 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. Epistasis experiments were used to test for genetic modifiers of Lyst, which demonstrated that albino Lyst mutant mice exhibited complete rescue of Lyst-dependent iris phenotypes. In a genetic background-driven approach, a DBA/2J strain of congenic mice was created. The DBA/2J background, which harbors multiple mutations influencing melanosomal-proteins, enhanced Lyst dependent iris phenotypes. Thus, both experimental approaches implicated melanosomes, a potential source of oxidative stress,