Molecular Basis of Hereditary Retinal Degenerations

摘要 在本申请中提出的研究的目标是提高我们对 通过鉴定与隐性RD相关的其他基因， 确定潜在的分子机制。据估计，已知的基因有助于 大约30%的隐性RD病例。这里提出的研究将测试 假设剩余的RD基因的鉴定将有助于理解 这些疾病的潜在机制。 近亲繁殖和近亲结婚的人群最适合 识别与隐性视网膜疾病相关的基因。遗传的分子基础 来自巴基斯坦、印度和墨西哥的近亲繁殖人群的视网膜疾病并不好， 研究了初步分析表明，新的基因参与导致RD， 这些人口。 在本申请中，研究集中于通过以下方法鉴定隐性RD的新基因： 分析了来自印度、巴基斯坦、墨西哥和美国的近亲家庭， 了解退化的潜在机制使用外显子组捕获和 测序已被证明是有效的，在确定基因突变引起遗传性 条件在一组近亲家庭中与隐性RD相关的基因将被检测。 通过分析外显子组序列鉴定。本申请中提出的研究将 进行了以下具体目标：（1）筛选先证者的突变，在已知的RD 通过使用基因分型阵列和/或通过分析外显子组中的变体，（2）鉴定新的 通过分析受影响和未受影响的基因的外显子组序列， RD家系成员;（3）了解疾病的潜在机制 通过确定新的RD基因的功能，我们将识别和评估其作用， 编码蛋白质上的突变。 这些新的RD基因可能有助于理解RD的分子病理学， 有助于提高我们对先前确定的RD基因的作用的理解， 对于视网膜正常功能至关重要的途径。这些研究的结果将有助于 为患者提供具体的诊断和治疗， 目标是开发治疗方法，以减缓这些疾病的进展，延迟其发作，或 对待他们。

Abstract The goal of the studies proposed in this application is to enhance our understanding of retinal degeneration (RD) by identifying additional genes associated with recessive RD and determining the underlying molecular mechanisms. Known genes are estimated to contribute to approximately 30% of cases of recessive RD. The studies proposed here will test the hypothesis that identification of remaining genes for RD will assist in understanding the mechanisms underlying these diseases. Populations with high inbreeding and consanguineous marriages are best suited for identifying genes associated with recessive retinal conditions. The molecular basis of hereditary retinal diseases in inbred populations from Pakistan, India, and Mexico has not been well studied. Preliminary analyses have indicated the involvement of new genes in causing RD in these populations. In this application, studies are focused on identifying new genes for recessive RD by analyzing consanguineous families from India, Pakistan, Mexico, and the United States and understanding the mechanisms underlying degeneration. Studies using exome capture and sequencing have been proven to be efficient in identifying gene mutations causing hereditary conditions. Genes associated with recessive RD in a cohort of consanguineous families will be identified by analyzing the exome sequence. The studies proposed in this application will be carried out with the following specific aims: (1) to screen probands for mutations in known RD genes by using genotyping arrays and/or by analyzing variants in the exome, (2) to identify new genes involved in causing RD by analyzing the exome sequence of affected and unaffected members of pedigrees with RD, and (3) to understand the mechanisms underlying the disease process by determining the function of novel RD genes we will identify and evaluating the effect of mutations on the encoded protein. These new RD genes may assist in understanding the molecular pathology of RD and help in improving our understanding of the role of previously identified RD genes and the pathways critical for normal function of the retina. The outcome of these studies will assist in providing specific diagnoses and prognoses to patients and in identifying specific therapeutic targets to develop therapies to slow the progression of these conditions, delay their onset, or treat them.