Cataractogenesis, Connexin Mutants, and Genetic Modifiers

项目摘要 易患遗传变异和终生代谢和环境压力可损害透镜 体内平衡并导致与年龄相关的白内障。对遗传和 白内障形成的环境病因阻碍了非手术方法的发展 有效延缓或预防老年性白内障。几十年的研究已经导致了 许多导致遗传性白内障的基因突变的鉴定。然而， 在寻找影响严重性和/或发生的遗传修饰剂方面取得了很大进展， 白内障识别任何白内障的遗传修饰将是重要的理解 白内障形成的病理进展，并开发一种替代的非手术 目前无法预防或延迟年龄相关性白内障的治疗。该项目旨在 利用小鼠遗传学方法鉴定抑制核性白内障形成的遗传修饰剂， 模型透镜连接蛋白基因突变导致人类和小鼠白内障。以前的研究 已经证明，不同近交系的遗传背景影响严重程度， 由连接蛋白突变引起的核性白内障。使用一种新颖的策略， 数量性状基因座（QTL）的全基因组谱系分析， 来自近交系的同源对应物和来自候选基因的SNP的鉴定， 我们已经从遗传学上剖析了连接蛋白基因敲除小鼠的核性白内障的复杂特征。 我们已经确定了一个核性白内障的半显性抑制基因，它位于200万例白内障患者中。 7号染色体上的碱基对间隔。这种基因修饰剂的存在阻止了致密的 连接蛋白突变小鼠的核性白内障。在搜索了 编码区和测量透镜表达的一系列基因在这个区间，我们有 筛选出5个候选基因。该项目的主要目标是确定哪个候选基因 作为半显性抑制基因发挥作用，并研究其预防的分子基础 核性白内障此外，我们将继续确定其他新的遗传修饰剂， 抑制白内障形成。这些信息对于制定新战略非常重要， 有效预防或延缓核性白内障，约占年龄相关性白内障的三分之一。 白内障

Project Summary Predisposed genetic variance and life-long metabolic and environmental stresses can impair lens homeostasis and contribute to age-related cataracts. Inadequate knowledge about genetic and environmental etiology of cataractogenesis hinders the development of non-surgical approaches to effectively delay or prevent age-related cataracts. Decades of studies have led to the identification of many gene mutations that cause hereditary cataracts. However, there has not been much progress in finding genetic modifiers that influence the severity and/or occurrence of cataracts. Identification of any cataractous genetic modifiers will be important for understanding the pathological progression of cataract formation and for developing an alternative non-surgical treatment that is currently unavailable to prevent or delay age-related cataracts. This project aims to identify the genetic modifiers that suppress nuclear cataract formation by using mouse genetic models. Lens connexin gene mutations cause cataracts in humans and in mice. Previous studies have demonstrated that the genetic background of different inbred strains influences the severity of nuclear cataracts caused by connexin mutations. Using a novel strategy, a combination of a genome-wide linage analysis of quantitative trait loci (QTLs), chromosome substitution by homologous counterparts from inbred strains and identification of SNPs from candidate genes, we have genetically dissected the complex traits for nuclear cataracts in connexin knockout mice. We have identified a semi-dominant suppressor of nuclear cataracts that located in a 2 million base pair interval on chromosome 7. The presence of this genetic modifier prevents dense nuclear cataracts in connexin mutant mice. After searching the polymorphic differences in the coding region and measuring the lens expression of a list of genes in this interval, we have selected 5 candidate genes. The primary goal of this project is to determine which candidate gene functions as a semi-dominant suppressor and to investigate the molecular basis for the prevention of nuclear cataracts. Moreover, we will continue to identify additional new genetic modifiers that suppress cataractogenesis. The information will be important for developing a new strategy to effectively prevent or delay nuclear cataracts, which account for about one-third of age-related cataracts.