Genetic determinants of cataract

描述（由申请人提供）：白内障是视力丧失的主要原因（占全球失明的约45%），是眼科手术的最常见原因。我们研究的一个长期目标是绘制、鉴定和表征白内障的常见和新的遗传决定因素。在本提案的具体目标1中，将使用微卫星标记和DNA扩增/测序技术进行遗传连锁分析，以在圣路易斯人群的四个或更多家系中绘制和鉴定常染色体显性白内障的遗传突变。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白内障相关的基因中核苷酸变异的性质、模式和频率。在特定目标3中，将使用连锁不平衡分析和DNA扩增/测序技术来测试遗传性白内障和年龄相关性白内障基因之间的关联。在具体目标4中，将使用DNA表达方法、分析生物化学技术和分子细胞生物学技术来表征分别与染色体21 q和22 q相关的常染色体显性白内障相关的α A-晶状体蛋白和β B1-晶状体蛋白基因突变的功能后果。这些研究的结果将导致1。为理解白内障发病机制提供分子基础。设计基于DNA的白内障诊断和治疗方法，针对潜在的缺陷和3。更好地评估白内障的环境风险因素，从而使遗传易感个体能够选择延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.