Genetic Modifier of the Retinoschisis Gene

描述（由申请人提供）：我们的研究特别关注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的早期阶段显示出中心视力的显著丧失，视网膜内层分裂，以及视网膜电图（ERG）的b波损失。b波的缺失表明突触相互作用的功能异常。虽然RS1功能被预测与细胞粘附相关，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44TNJ小鼠中鉴定了一个新的RS1小鼠直系同源基因Rs1h突变等位基因，该突变由ENU诱变产生。在突变小鼠中已经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。在定位克隆的过程中，我们还确定了一个单一的主要修饰基因座，改变裂表型和层状结构异常。该项目的目标是通过小鼠分子遗传学方法了解RS1基因功能的分子途径。我们的假设是，RS1H保持视网膜层的功能和结构的完整性，包括突触功能，通过其在细胞粘附中的作用，这是由遗传和物理相互作用的因素。在这个建议中，我们的主要重点是确定和表征的Rs1h 1（森）基因的修饰。在目的1中，我们将进行位置克隆以鉴定Mori基因。在目标2中，我们将测试RS1H与RS1H结合蛋白的候选物之间的相互作用。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。

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.