Interdisciplinary approach to retinal disease gene identification

描述(由申请人提供)：国家眼科研究所声明的一个主要研究重点是“识别与视网膜退行性疾病有关的基因”。虽然已经发现了许多导致视网膜变性的基因，但仍有许多基因有待鉴定，还需要新的方法来鉴定更多的视网膜变性基因。该项目的目标是识别导致人类视网膜退化的基因，特别是导致一种名为Bardet-Biedl综合征(BBS)的光感受器退化综合征的基因，以及常染色体隐性遗传性视网膜色素变性(ARRP)。BBS是一种遗传异质性疾病，到目前为止已经确定了11个基因，有强有力的证据表明，还有更多的基因有待发现。同样，已知的ARRP基因占所有病例的不到一半，这一发现表明仍有许多视网膜疾病基因有待发现。从历史上看，疾病基因的识别依赖于利用大的受影响家庭的基因图谱和位置克隆。由于许多疾病缺乏大家庭，因此有必要使用替代策略。在这一应用中，我们建议使用小血缘家庭的单核苷酸多态性(SNP)基因分型来确定候选纯合子区域，并结合比较基因组数据和新的眼睛基因表达数据来确定BBS基因。我们给出的初步数据显示了这种方法的有效性。此外，我们将使用一种新的高成本效益的策略来筛选ARRP患者的候选基因突变。除了疾病基因的发现，我们还建议进一步开发和验证使用斑马鱼模型系统进行视网膜疾病候选基因功能分析的方法。功能分析是验证候选基因是否为视网膜疾病的原因的重要步骤。开发、验证和利用高通量检测来验证疾病的病因是识别新的视网膜疾病基因的总体目标的重要组成部分。

DESCRIPTION (provided by applicant): 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.