Interdisciplinary approach to retinal disease gene identification

国家眼科研究所声明的一项主要研究重点是“识别与视网膜有关的基因 虽然已经发现了许多导致视网膜退化的基因， 许多仍有待确认，以及识别额外视网膜变性的新方法 基因是需要的。该项目的目标是识别导致人类视网膜病变的基因。 变性，特别是导致一种名为Bardet的光感受器退化综合症的基因- Biedl综合征(BBS)以及常染色体隐性遗传性视网膜色素变性(ARRP)。BBS是一种基因上的 到目前为止，已经确定了11个基因的异质性疾病，并且有很强的 有证据表明，还有多个额外的基因有待发现。同样，已知的ARRP基因也解释了 对于不到所有病例的一半，这一发现表明许多视网膜疾病基因仍然存在 被发现了。在历史上，疾病基因的识别一直依赖于基因图谱和位置 使用受影响的大家庭进行克隆。许多疾病缺乏大家庭，因此有必要使用 另类战略。在这个应用中，我们建议使用单核苷酸多态(SNP) 对小血缘家系进行基因分型以确定组合纯合子候选区域 利用比较基因组数据和新的眼睛基因表达数据来鉴定BBS基因。我们呈现的是 初步数据显示了这一方法的有效性。此外，我们还将使用一种新型的高成本 筛选ARRP患者候选基因突变的有效策略。除疾病基因外 ，我们建议进一步开发和验证视网膜疾病的功能分析方法 使用斑马鱼模型系统的候选基因。功能分析是功能分析中的重要一步。 确认候选基因是视网膜疾病的原因。开发、验证和利用 验证疾病原因的高通量分析是确定疾病病因的总体目标的重要组成部分 新的视网膜疾病基因。

A major stated research priority of the National Eye Institute is "to identify the genes involved in retinal degenerative diseases". Although numerous genes causing retinal degeneration have been discovered, many remain to be identified, and novel approaches to the identification of additional retinal degeneration genes are needed. The goal of this project is the identification of genes that cause human retinal degeneration, specifically genes causing a syndromic form of photoreceptor degeneration known as Bardet- Biedl syndrome (BBS), as well as autosomal recessive retinitis pigmentosa (ARRP). BBS is a genetically heterogeneous disorder for which eleven genes have been identified to date, and for which there is strong evidence that multiple additional genes remain to be discovered. Similarly, the known ARRP genes account for less than half of all cases, a finding that indicates that numerous retinal disease genes remain to be discovered. Historically, the identification of disease genes has relied on genetic mapping and positional cloning using large affected families. The lack of large families for many diseases makes it necessary to use alternative strategies. In this application, we propose to use single nucleotide polymorphism (SNP) genotyping of small consanguineous families to identify candidate regions of homozygosity in combination with comparative genomic data and novel eye gene expression data to identify BBS genes. We present preliminary data showing the effectiveness of this approach. In addition, we will use a novel highly cost effective strategy to screen candidate genes for mutations in ARRP patients. In addition to disease gene discovery, we propose to further develop and validate methods for the functional analysis of retinal disease candidate genes using the zebrafish model system. Analysis of function is an important step in the verification of candidate genes as a cause of retinal diseases. The development, validation and utilization of a high throughput assay to verify disease causation is an important component of the overall goal to identify new retinal disease genes.