Genetic Modifier of the Retinoschisis Gene

描述（由申请人提供）：我们的研究特别专注于了解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连锁视网膜裂（XLRS）是一种常见的遗传性黄斑退行性疾病，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明显的中央视力丧失，视网膜内层分裂，视网膜电图（ERG）的b波丧失。b波的缺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粘附有关，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。我们最近在通过ENU诱变产生的44TNJ小鼠中发现了RS1小鼠同源基因Rs1h突变的一个新的等位基因。在突变小鼠中观察到突触异常以及严重的细胞粘连和视网膜层状结构缺陷。在定位克隆过程中，我们还发现了一个改变裂裂表型和层状结构异常的主要修饰位点。该项目的目标是利用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，这是由遗传和物理相互作用的因素调节的。在这项提议中，我们的主要重点是鉴定和表征rs11 （Mori）基因的修饰子。在Aim 1中，我们将进行定位克隆来鉴定Mori基因。在Aim 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和候选Rs1h结合分子突变引起的表型的影响。

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.