Genetic Modifier of the Retinoschisis Gene

提供了 我们的研究主要集中在理解人类疾病的分子机制上。 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 （XLRS）是一种常见的遗传性黄斑退行性疾病，由RS 1突变引起 基因在人类中，受影响的个体在生命的早期阶段显示出中央视力的显著丧失 视网膜内层分裂，视网膜电图b波缺失 （ERG）。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，细胞粘附的分子途径是细胞粘附的基础。 疾病和RS1的正常功能在很大程度上是未知的。我们最近发现了一种新的等位基因 通过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，我们还发现了一个单一的 改变裂表型和层状结构异常的主要修饰基因座。的 本项目的目标是了解RS1基因发挥功能的分子途径 使用小鼠分子遗传学方法。我们的假设是RS 1 H维持了功能 和结构完整性的视网膜层，包括突触功能，通过其在细胞中的作用， 粘附，这是由遗传和物理相互作用的因素调节。在本建议中，我们的 主要焦点是鉴定和表征Rs1h1（Mori）基因的修饰物。在目标1中，我们 进行定位克隆，鉴定Mori基因。在目标2中，我们将测试 RS1H和RS1H结合蛋白的候选物。此外，我们将测试修改器的效果 Rs1突变引起的表型上的Rs1H基因和候选的Rs1H结合分子。 '

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. '