Functional Analysis of Novel Genes in Eye Development and Vision

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1: AMD and complement factor H (CFH). Common sequence variants of CFH have major roles in determining susceptibility to age-related macular degeneration (AMD). We have identified potentially important targets for CFH binding in human RPE/choroid. These results have been confirmed by immunofluorescence localization of multiple donor eyes and by using native and recombinant protein binding experiments and have been correlated with genotype for disease-risk variants of CFH. Protein complexes also appear to be associated with domains rich in cholesterol, another factor implicated in AMD. Mass spectroscopy has been used to identify further components of complexes that are implicated in formation of protein depositions in AMD. This has potential for drug-design to intervene in the progression of AMD. A cell-culture model for stress-related processes in AMD is also being investigated and shows that stressed RPE-derived cells up regulated genes for pathways important in AMD. 2: A miRNA cluster with high expression in eye and ear has been deleted in mouse, producing a new model of hearing and vision deficit. This has been examined in detail and provides evidence for involvement of miRNAs in maturation of photoreceptors, particularly of cone cells, and in other sensory neurons. 3: Retbindin is a novel protein of the retina. We have shown that retbindin is essentially specific for photoreceptors and that the human gene has separate cone and rod cell promoters. A transgenic mouse model shows suggests that retbindin has a role in control of retinoid and carotenoid levels in the retina. A knockout mouse has been created; it shows no defects in normal eye development and function but reveals age-related deficits in visual response