GENETIC STUDIES OF AUTOSOMAL DOMINANT CATARACTS

这项提议的长期目标是鉴定基因。 常染色体显性遗传性先天性白内障是主要原因 儿童失明。因为研究这方面的局限性 人类的眼部疾病，我们建议首先关注 小鼠，以便定位和表征涉及的候选基因 在白内障的形成中。一旦确定，老鼠的白内障基因就可以 用于通过杂交分离同源人类基因 小鼠基因抗人晶状体cdna文库。曾经的同源人类 基因已经被表征，它们的正常结构即DNA序列， 可以与常染色体个体的基因结构进行比较 显性白内障。白内障中含有突变的候选基因 患者会指出，这种异常基因是导致 白内障。然后基因治疗可以在同源小鼠身上进行评估。 我们最初研究的目的是预防白内障的模型 在胚胎期形成的。 作为这些长期目标的起点，我们建议专注于 5例导致常染色体的独立分离突变的研究 小鼠显性先天性白内障。首先，我们计划将每个 利用微卫星标记将异常基因定位到各自的染色体上。 其次，我们将研究每种白内障突变的组织病理学。 在显影镜头上。最后，要独立确定其他 分离小鼠的白内障突变，我们将进行广泛的等位基因 检测8个新的白内障突变。

The long term objective of this proposal is the identification of genes responsible for autosomal dominant congenital cataracts, a leading cause of blindness in children. Because of the limitations of studying this ocular disorder in humans, we propose to first devote our attention to mice in order to localize and characterize the candidate genes involved in cataractogenesis. Once identified, the mouse cataract genes can then be utilized to isolate the homologous human genes by hybridizing the mouse genes against a human lens cDNA library. Once the homologous human genes have been characterized, their normal structure i.e., DNA sequence, can be compared to the gene structured in individuals with autosomal dominant cataracts. A candidate gene harboring a mutation in a cataract patient would indicate that this abnormal gene is responsible for the cataract. Gene therapy could then be evaluated in the homologous mouse model which we originally studied for the purpose of preventing cataract formation during the embryonic period. As a starting point for these long term objectives, we propose to focus our studies on 5 independently segregating mutations causing autosomal dominant congenital cataracts in mice. First, we plan to map each abnormal gene to its respective chromosome by microsatellite markers. Second, we will investigate the histopathology of each cataract mutation on the developing lens. Finally, to identify additional independently segregating cataract mutations in mice we will conduct extensive allelism testing of 8 new cataract mutations.