GENETIC STUDIES OF AUTOSOMAL DOMINANT CATARACTS

这项建议的长期目标是鉴定基因 导致常染色体显性遗传性先天性白内障， 失明的儿童。 由于研究的局限性， 在人类的眼部疾病，我们建议首先把我们的注意力放在 小鼠，以定位和表征所涉及的候选基因 在白内障形成中。 一旦确定，小鼠白内障基因就可以 通过杂交， 小鼠基因与人透镜cDNA文库的比较。 一旦同源的人类 基因已经被表征，它们的正常结构，即，DNA序列， 可以与常染色体异常个体中的基因结构进行比较， 显性白内障 白内障中携带突变的候选基因 患者会指出，这种异常基因是负责 白内障 然后可以在同源小鼠中评估基因治疗 我们最初研究的预防白内障的模型 在胚胎期形成。 作为这些长期目标的起点，我们建议重点 我们对5个独立分离的常染色体突变进行了研究， 小鼠显性先天性白内障。 首先，我们计划绘制每一个 通过微卫星标记将异常基因定位到相应的染色体上。 其次，我们将调查每一个白内障突变的组织病理学 在显影透镜上。 最后，独立地确定额外的 在小鼠中分离白内障突变， 检测8种新的白内障突变。

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.