Molecular Basis of Human Visual System Disorders

描述(由申请人提供)： 摘要该项目的目标是识别与人类视网膜疾病有关的新基因。 国家眼科研究所声明的优先事项。为了实现这一目标，将通过结合整个外显子组测序和基因图谱来识别更多其突变导致视网膜色素变性(RP)的基因。RP是遗传性视网膜变性的最常见形式之一，仅在美国就有大约10万人受到影响。已知的RP基因突变约占欧洲人群所有病例的50%，这表明还有许多额外的RP基因仍有待鉴定。为了确定更多的RP疾病基因，我们从世界各地收集了500多个常染色体隐性RP(Arrp)患者家族。对已知的arrp病基因突变的筛查表明，这些家庭中约有300个可能携带新的rp病基因突变。因此，这个收集代表了一个很好的特征，丰富的资源，以确定新的基因，可以引起反转。在这项建议中，我们将结合整个外显子组测序、生物信息学、统计学和功能研究来确定这些患者的潜在突变。我们的具体目标是：1.对RP家系进行全外显子组测序，以发现新的RP病基因；2.通过对1300例患者队列的筛选，确认和发现新的RP基因；3.RP家系的表型分析和新的RP基因的发现将有助于开发新的诊断工具和治疗方法。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，分离其他RP疾病基因将为了解RP和视网膜营养不良的分子机制提供重要的见解。

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.