Molecular Basis of Hereditary Retinal Degenerations

描述（由申请人提供）： 本申请中提出的研究的目标是通过鉴定与隐性RD相关的其他基因并确定潜在的分子机制来增强我们对视网膜变性（RD）的理解。据估计，已知基因导致约30%的隐性RD病例。这里提出的研究将测试这一假设，即剩余的基因识别RD将有助于了解这些疾病的机制。 近亲繁殖和近亲结婚率高的人群最适合鉴定与隐性视网膜疾病相关的基因。遗传性视网膜疾病的分子基础在巴基斯坦，印度和墨西哥的近亲繁殖人口还没有得到很好的研究。初步分析表明，在这些人群中引起RD的新基因的参与。 在该应用中，研究的重点是通过分析来自印度、巴基斯坦、墨西哥和美国的近亲家庭并了解退化的机制来识别隐性RD的新基因。使用外显子组捕获和测序的研究已被证明在鉴定引起遗传性疾病的基因突变方面是有效的。将通过分析外显子组序列来鉴定一组近亲家庭中与隐性RD相关的基因。本申请中提议的研究将按照以下具体目标进行：（1）通过使用基因分型阵列和/或通过分析外显子组中的变体来筛选已知RD基因中突变的先证者，（2）通过分析患有RD的家系中受影响和未受影响成员的外显子组序列来鉴定参与引起RD的新基因，以及（3）通过确定新的RD基因的功能来理解疾病过程的潜在机制，我们将鉴定和评估突变对编码蛋白的影响。 这些新的RD基因可能有助于理解RD的分子病理学，并有助于提高我们对先前确定的RD基因的作用和视网膜正常功能的关键途径的理解。这些研究的结果将有助于为患者提供特定的诊断和治疗，并确定特定的治疗靶点，以开发治疗方法来减缓这些疾病的进展，延迟其发作或治疗它们。 公共卫生相关性： 叙述：在本申请中，我们提出鉴定引起隐性视网膜变性的新基因，并了解疾病病理学的潜在机制。这些研究将有助于提供具体的诊断，诊断和开发这些疾病的治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Narrative: In this application we propose to identify new genes causing recessive retinal degeneration and understand the mechanism underlying the disease pathology. These studies will help in providing specific diagnoses, prognoses and in developing therapies for these conditions.