Genetic Modifier of the Retinoschisis Gene

视网膜劈裂基因的遗传修饰

• 批准号: 7388134
• 负责人: AKIHIRO IKEDA
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388134
• 关键词: Affect; Alleles; Binding; Binding Proteins; Candidate Disease Gene; Cell Adhesion; Cell surface; Cell-Cell Adhesion; Collagen; Collagen Type II; Defect; Disease; Electroretinography; Ethylnitrosourea; Genes; Genetic; Goals; Human; Individual; Inherited; Lead; Life; Localized; Macular degeneration; Maps; Mediating; Mediator of activation protein; Molecular; Molecular Genetics; Morus; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Orthologous Gene; Pathway interactions; Phenotype; Play; Property; Proteins; Research Personnel; Resolution; Retina; Retinal; Retinal Diseases; Retinoschisis; Role; Staging; Structure; Synapses; Testing; Transcript; Vision; X-Linked Retinoschisis; base; disease-causing mutation; gene function; mutant; positional cloning; synaptic function

PROVIDED. Our studies are specifically focused on understanding the molecular mechanisms causing human retinal diseases associated with synaptic functional and structural defects. X-linked retinoschisis (XLRS) is a common inherited macular degenerative disease caused by mutations in the RS1 gene. In humans, affected individuals show a significant loss in central vision at early stages of life with a splitting of the inner layers of the retina, and a loss in the b-wave of the electroretinogram (ERG). Loss of the b-wave indicates functional abnormalities in the synaptic interactions. Although RS1 function is predicted to be associated with cell adhesion, molecular pathways underlying the disease and the normal function of RS1 are largely unknown. We recently identified a new allele of the mutation in the RS1 mouse ortholog, Rs1h,in 44TNJ mice created by ENU mutagenesis. Synaptic abnormalities as well as severe cell adhesion and retinal laminar structure defects in mutant mice have been observed. In the course of positional cloning, we also identified a single major modifier locus that changes the schisis phenotype and laminar structure abnormality. The goal of this project is to understand the molecular pathway through which the RS1 gene functions using mouse molecular genetic approaches. Our hypothesis is that RS1H maintains the functional and structural integrity of the retinal layers, including the synaptic function, through its role in cell adhesion, which is regulated by genetically and physically interacting factors. In this proposal, our main focus is to identify and characterize the modifier of the Rs1h1 (Mori) gene. In Aim 1,we will conduct positional cloning to identify the Mori gene. In Aim 2, we will test interaction between RS1H and candidates for RS1H binding proteins. Further, we will test the effect of the modifier gene on phenotypes caused by a mutation in Rs1hand a candidate RS1H binding molecule. '

假如。 我们的研究特别侧重于了解导致人类 与突触功能和结构缺陷相关的视网膜疾病。 X连锁视网膜劈裂症 (XLRS) 是一种常见的遗传性黄斑变性疾病，由 RS1 突变引起 基因。在人类中，受影响的个体在生命的早期阶段表现出中央视力的显着丧失 视网膜内层分裂，视网膜电图 b 波丢失 （尔格）。 b 波丢失表明突触相互作用的功能异常。虽然 RS1 功能预计与细胞粘附、细胞粘附的分子途径有关 疾病和 RS1 的正常功能很大程度上未知。我们最近发现了一个新的等位基因 ENU 诱变产生的 44TNJ 小鼠中 RS1 小鼠直系同源物 Rs1h 的突变。 突触异常以及严重的细胞粘附和视网膜层状结构缺陷 已经观察到突变小鼠。在定位克隆的过程中，我们还鉴定出了一个 改变分裂表型和层状结构异常的主要修饰基因座。这 该项目的目标是了解 RS1 基因发挥作用的分子途径 使用小鼠分子遗传学方法。我们的假设是 RS1H 维持功能 视网膜层的结构完整性，包括突触功能，通过其在细胞中的作用 粘附力，受遗传和物理相互作用因素的调节。在这个提案中，我们的 主要重点是识别和表征 Rs1h1 (Mori) 基因的修饰因子。在目标 1 中，我们将 进行定位克隆以鉴定 Mori 基因。在目标 2 中，我们将测试之间的交互 RS1H 和 RS1H 结合蛋白的候选者。接下来我们来测试一下修改器的效果 由Rs1突变引起的表型基因和候选RS1H结合分子。 '