Molecular Basis of Human Visual System Disorders

描述（由申请人提供）： 本项目的目标是鉴定与人类视网膜疾病有关的新基因， 国家眼科研究所的优先事项。为了实现这一目标，其突变导致视网膜色素变性（RP）的其他基因，这是遗传性视网膜变性的最常见形式之一，仅在美国就影响了估计100，000人，将通过将全外显子组测序与遗传图谱相结合来确定。已知RP基因的突变占欧洲人群所有病例的约50%，这表明许多其他RP基因仍有待鉴定。为了鉴定其他RP疾病基因，我们从世界各地收集了500多个常染色体隐性遗传RP（arRP）患者家族。在已知的arRP疾病基因突变的筛选表明，约300这些家庭可能携带新的RP疾病基因突变。因此，这个集合代表了一个很好的特点，丰富的资源，用于确定新的基因，可以导致RP。在这个建议中，我们将使用全外显子组测序，生物信息学，统计学和功能研究的组合来确定这些患者中的潜在突变。我们的具体目标是：1。RP家族的全外显子组测序以鉴定新的RP疾病基因2.通过筛选1300名患者队列确认和发现新的RP基因3. RP家族的表型基因型分析和继续招募新RP基因的发现将有助于新诊断工具和治疗方法的发展。此外，由于RP疾病基因的突变也会导致其他视网膜营养不良，额外的RP疾病基因的分离将提供重要的见解RP和视网膜营养不良的分子机制。

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.