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（由申请人提供）：我们的研究特别侧重于了解导致与突触功能和结构缺陷相关的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早期阶段表现出中央视力的显着丧失，伴有视网膜内层的分裂，以及视网膜电图（ERG）b波的丧失。 b 波丢失表明突触相互作用的功能异常。尽管预计 RS1 功能与细胞粘附有关，但疾病背后的分子途径和 RS1 的正常功能在很大程度上尚不清楚。我们最近在 ENU 诱变产生的 44TNJ 小鼠中发现了 RS1 小鼠直系同源基因 Rs1h 突变的新等位基因。在突变小鼠中观察到突触异常以及严重的细胞粘附和视网膜层状结构缺陷。在定位克隆过程中，我们还鉴定了一个改变分裂表型和层状结构异常的单一主要修饰基因座。该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 通过其在细胞粘附中的作用维持视网膜层的功能和结构完整性，包括突触功能，细胞粘附受到遗传和物理相互作用因素的调节。在本提案中，我们的主要重点是识别和表征 Rs1h 1 (Mori) 基因的修饰符。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 与候选 RS1H 结合蛋白之间的相互作用。此外，我们将测试修饰基因对 Rs1h 突变和候选 RS1H 结合分子引起的表型的影响。