Genetic determinants of cataract

描述(申请人提供)：白内障是导致视力丧失的主要原因(占全球失明的45%)，也是眼科手术最常见的原因。我们研究的一个长期目标是绘制、识别和表征常见的和新的白内障遗传决定因素。在这项建议的具体目标1中，将利用微卫星标记和DNA扩增/测序技术进行遗传连锁分析，以定位和鉴定圣路易斯人群中四个或更多常染色体显性遗传白内障家系的遗传突变。在具体目标2中，将使用DNA扩增和测序技术来表征与常染色体显性遗传白内障相关的基因的核苷酸变异的性质、模式和频率。在具体目标3中，将使用连锁不平衡分析和DNA扩增/测序技术来检测遗传性白内障和年龄相关性白内障的基因之间的关联。在具体目标4中，将使用DNA表达方法、分析生化技术和分子细胞生物学技术来表征分别与染色体21q和22q连锁的常染色体显性白内障相关的αA晶体蛋白和βB1晶体蛋白基因突变的功能后果。这些研究的结果将导致：1.了解白内障发病机制的分子基础；2.针对潜在缺陷的基于DNA的白内障诊断和治疗方法的设计；3.更好地评估白内障的环境风险因素，从而使遗传易感的个人能够选择推迟甚至预防白内障发病的生活方式。

DESCRIPTION (provided by applicant): Cataract is the leading cause of vision loss (accounting for ~45% of blindness worldwide) and represents the most common reason for eye surgery. A long-term goal of our research is to map, identify and characterize common and novel genetic determinants of cataract. In Specific Aim 1 of this proposal, genetic linkage analysis with microsatellite markers and DNA amplification/sequencing techniques will be used to map and identify genetic mutations underlying autosomal dominant cataract in four or more pedigrees from the St. Louis population. In Specific Aim 2, DNA amplification and sequencing techniques will be used to characterize the nature, pattern and frequency of nucleotide variation in genes linked with autosomal dominant cataract. In Specific Aim 3, linkage disequilibrium analysis and DNA amplification/sequencing techniques will be used to test for association between genes for hereditary cataract and age-related cataract. In Specific Aim 4, DNA expression methods, analytical biochemical techniques and molecular cell biology techniques will be used to characterize the functional consequences of mutations in the genes for alphaA-crystallin and betaB1-crystallin that are associated with autosomal dominant cataract linked to chromosomes 21q and 22q, respectively. Results from these studies will lead to 1. A molecular basis for understanding the pathogenetic mechanisms of cataract development, 2. The design of DNA-based diagnostics and therapeutics for cataract that are targeted to the underlying defects and 3. Better evaluation of environmental risk factors for cataract, thereby enabling genetically susceptible individuals to choose a lifestyle that delays or even prevents cataract onset.