Genetic Modifier of the Retinoschisis Gene

视网膜劈裂基因的遗传修饰

• 批准号: 7189834
• 负责人: AKIHIRO IKEDA
• 金额: $ 31.87万
• 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/7189834
• 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

DESCRIPTION (provided by applicant): 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 Rs1h 1 (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 Rs1h and a candidate RS1H binding molecule.

描述(申请人提供)：我们的研究重点是了解与突触、功能和结构缺陷相关的导致人类视网膜疾病的分子机制。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基因突变引起。在人类中，受影响的个体在生命的早期阶段表现出严重的中央视力丧失，视网膜内层分裂，视网膜电信号(ERG)的b波丢失。B波的丢失表明突触相互作用的功能异常。虽然RS1的功能被预测与细胞黏附有关，但疾病的分子途径和RS1的正常功能在很大程度上是未知的。我们最近在由ENU突变产生的44TNJ小鼠中发现了RS1小鼠同源突变的一个新的等位基因Rs1h。突触异常以及严重的细胞粘连和视网膜板层结构缺陷已在突变小鼠中观察到。在定位克隆的过程中，我们还发现了一个改变裂隙表型和板层结构异常的主修饰基因座。这个项目的目标是利用小鼠分子遗传学方法了解RS1基因发挥作用的分子途径。我们的假设是，RS1H通过其在细胞黏附中的作用来维持视网膜层的功能和结构的完整性，包括突触功能，这是由遗传和物理相互作用的因素调节的。在这项建议中，我们的主要重点是鉴定和表征Rs1h1(Mori)基因的修饰。在目标1中，我们将进行定位克隆来鉴定Mori基因。在目标2中，我们将测试RS1H与RS1H结合蛋白候选之间的相互作用。进一步，我们将测试修饰基因对Rs1h和候选RS1H结合分子突变引起的表型的影响。