Interdisciplinary approach to retinal disease gene identification

视网膜疾病基因鉴定的跨学科方法

• 批准号: 7860547
• 负责人: Val C. Sheffield
• 金额: $ 57.01万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860547
• 关键词: Accounting; Affect; Bardet-Biedl Syndrome; Biological Models; Candidate Disease Gene; Chromosome Mapping; Complement; Data; Degenerative Disorder; Development; Disease; Effectiveness; Etiology; Eye; Family; Gene Expression; Gene Mutation; Genes; Genetic; Genotype; Goals; Human; Methods; Mutation; National Eye Institute; Patients; Positioning Attribute; Research Priority; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Screening procedure; Single Nucleotide Polymorphism; Validation; Zebrafish; comparative genomics; cost; cost effective; gene discovery; high throughput screening; insight; interdisciplinary approach; novel; novel strategies; photoreceptor degeneration; positional cloning

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.

描述（由申请人提供）：国家眼科研究所的一个主要陈述的研究优先级是“确定与视网膜退行性疾病有关的基因”。尽管已经发现了许多引起视网膜变性的基因，但仍有许多鉴定，并且需要鉴定其他视网膜变性基因的新方法。该项目的目的是鉴定引起人类视网膜变性的基因，特别是引起综合症形式的光感受器变性的基因，称为Bardet-biedl综合征（BBS），以及常染色体隐性视网膜炎色素（ARRP）。 BBS是一种遗传性异质性疾病，迄今为止已经确定了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基因不到所有病例的一半，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，疾病基因的鉴定一直依赖于使用大型家庭的遗传图和位置克隆。缺乏许多疾病的大家庭，因此有必要使用替代策略。在此应用中，我们建议将小亲属家族的单核苷酸多态性（SNP）基因分型与比较基因组数据和新颖的眼科基因表达数据结合使用，以鉴定纯合性的候选区域以识别BBS基因。我们介绍了该方法有效性的初步数据。此外，我们将使用一种新型的高度成本效益策略来筛选ARRP患者突变的候选基因。除了疾病基因的发现外，我们还建议使用斑马鱼模型系统进一步开发和验证视网膜疾病候选基因的功能分析的方法。功能分析是验证候选基因作为视网膜疾病的原因的重要步骤。高通量测定法以验证疾病因果关系的开发，验证和利用是鉴定新的视网膜疾病基因的总体目标的重要组成部分。