The goal of this project is to better understand underlying disease mechanisms of 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. To accomplish this, functional studies will be performed for REEP6, a novel RP disease gene that is recently identified. In parallel, additional genes associated with RP will be identified by further characterizing a large cohort of 1,500 RP patients we have recruited during last funding cycle. Through establishing and follow up functional studies of mice model for these newly RP associated disease gene, we expect to gain new insights of disease mechanisms as well as lay the foundation for developing new diagnosis and treatment methods. Mutations in known RP genes account for about 60% 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 1,500 patient families from around the world. Screen for mutations in known arRP disease genes suggests that about 600 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. Indeed, whole exome sequencing of a subset of these 600 proband have led the discovery of ten novel disease genes, including the recently identified REEP6 gene. In this proposal, we plan to identify the underlying mutations the remaining proband and newly recruited patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies. In parallel, we will conduct functional studies of the newly establish Reep6 knock out and knock in mice to reveal novel interesting underlying disease mechanisms.
Our Specific Aims are to:
Specific Aim 1. Characterize the mechanism of action of the novel RP disease gene REEP6 Specific Aim 2. Identify and characterize novel RP candidate disease genes Specific Aim 3. Investigate noncoding mutations in RP patients Discovery and characterization 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, functional studies of additional RP disease genes will provide important insights into the molecular mechanisms underlying both RP and retinal dystrophies in general.
Description The goal of this research project is to identify and perform functional studies of novel genes that are involved in Retinitis Pigmentosa (RP). As one of the most common forms of inherited retinal degeneration that affects an estimated 100,000 people in the United States alone. Due to the genetic and clinical heterogeneity of the disease, identifying and understanding the molecular basis of the disease is the essential first step for accurate diagnosis as well as developing new treatment methods for the disease.
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