Functional Analysis of Novel Genes in Eye Development and Vision

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Age-related macular degeneration (AMD) is a major cause of vision loss. We have shown that dry AMD is associated with specific deposits of complement factor H and fibulin 3 within domains rich in cholesterol basal to the RPE. Mass spectroscopy has been used to identify further components of complexes that are implicated in formation of protein depositions in AMD. A cell-culture model for stress-related processes in AMD shows that specific stress of RPE-derived cells causes gene expression changes for pathways important in AMD, particularly up-regulation of cholesterol synthesis and transport and decrease in intracellular free zinc. Retbindin is a novel protein of retinal photoreceptors. A knockout mouse model shows progressive deficits in visual response and age-related defects in the outer retina that have some striking similarities to some forms of age-related macular degeneration and to glaucoma. This model is under evaluation, along with other mouse models from our collaborators. We are also completing work on KLPH and Lengsin, two novel genes that have roles in lens function and transparency and are candidates for age-related cataract. We have completed work on an extensive collaborative study of a targeted deletion model for a miRNA cluster that has an important role in maturation of sensory neurons, including photoreceptors and auditory hair cells. The deletion has aspects of ciliopathies and provides a possible mouse model for Ushers-like disease. A manuscript is almost complete.