The studies proposed in this application will expand our understanding of lens biology through functional analysis of causal mutations liable for cataractogenesis. This proposal employs two specific aims to accomplish the proposed goals. In the first aim, we will identify genes that harbor cataract causing mutations using a combination of traditional genetics tools and a more recent exon capture technique coupled with next generation sequencing. Our methodology represents a powerful paradigm to unveil mutations that trigger cataractogenesis. In the second aim, we will expand on our recent discovery, that loss of function mutations in the novel autophagy component FYCO1 cause cataract, by elucidating its physiological significance in lens development and maintenance of lens transparency and examining the possible role of autophagy in cataractogenesis. Establishment of autophagy as an essential pathway for the maintenance of lens transparency will not only advance our knowledge of lens function, it will truly reveal a new paradigm in the field of lens biology that will provide a basis for multiple new and important lens studies.
This application will investigate the functional significance of causal mutations associated with congenital cataracts and their potential role in the development and/or maintenance of the human lens transparency. Successful execution of this proposal will lead to development of better treatments and therapeutic approaches for a debilitating disorder that is the principal cause of visual impairment in children worldwide and is responsible for about one third of cases of blindness in infants.