Interdisciplinary approach to retinal disease gene identification

描述（由申请人提供）：国家眼科研究所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，并且需要新的方法来鉴定其他视网膜变性基因。该项目的目标是鉴定引起人类视网膜变性的基因，特别是引起称为Bardet-Biedl综合征（BBS）的感光细胞变性的综合征形式以及常染色体隐性视网膜色素变性（ARRP）的基因。BBS是一种遗传异质性疾病，迄今为止已鉴定出11个基因，并且有强有力的证据表明仍有多个其他基因有待发现。同样，已知的ARRP基因占所有病例的不到一半，这一发现表明许多视网膜疾病基因仍有待发现。从历史上看，疾病基因的鉴定依赖于使用大的受影响家族的遗传作图和定位克隆。由于许多疾病缺乏大家庭，因此有必要使用替代战略。在本申请中，我们建议使用单核苷酸多态性（SNP）基因分型的小血缘家庭，以确定候选区域的纯合性结合比较基因组数据和新的眼睛基因表达数据，以确定BBS基因。我们目前的初步数据显示这种方法的有效性。此外，我们将使用一种新的高成本效益的策略来筛选候选基因突变的ARRP患者。除了疾病基因的发现，我们建议进一步开发和验证方法的视网膜疾病候选基因的功能分析使用斑马鱼模型系统。功能分析是验证候选基因作为视网膜疾病病因的重要步骤。开发、验证和利用高通量测定来验证疾病病因是鉴定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.