Molecular Basis of Human Visual System Disorders

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DESCRIPTION (provided by applicant): Abstract The goal of this project is to identify novel genes involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes whose mutations cause Retinitis Pigmentosa (RP), one of the most common forms of inherited retinal degeneration that affects an estimated 100,000 people in the United States alone, will be identified by combining whole exome sequencing with genetic mapping. Mutations in known RP genes account for about 50% of all cases in the European population, suggesting that many additional RP genes remain to be identified. To identify additional RP disease genes, we have collected more than 500 patient families with autosomal recessive RP (arRP) from around the world. Screen for mutations in known arRP disease genes suggests that about 300 of these families are likely to carry mutations in novel RP disease genes. Therefore, this collection represents a well characterized, rich resource for identifying new genes that can cause RP. In this proposal, we will identify the underlying mutations in these patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies. Our Specific Aims are to: 1. Whole exome sequencing of RP families to identify novel RP disease genes 2. Confirmation and discovery of novel RP genes by screening a 1300-patient cohort 3. Phenotype genotype analysis of RP families and continued enrollment Discovery of novel RP genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in RP disease genes also cause other retinal dystrophies, isolation of additional RP disease genes will provide important insights into the molecular mechanisms underlying both RP and retinal dystrophies in general.