MOLECULAR SCREENING METHODS FOR DIFFERENT TYPES OF GLAUCOMA

青光眼是一组遗传性眼部疾病，占美国和全球所有失明的3%。 近年来，已经确定了7个青光眼位点的染色体位置（其中5个由我们确定，2个由其他小组确定）。 此外，我们和另一个小组最近描述了两个独立基因的第一次突变，即编码细胞色素P4501 B1（CYP 1B 1）和小梁网诱导的糖皮质激素反应蛋白（TIGR）的基因，分别在原发性先天性青光眼和原发性开角型青光眼的家族中分离。 从那时起，这两种基因在这两种类型青光眼病因学中的作用已被其他研究人员和其他人群证实。 迄今为止，我们已经在原发性先天性青光眼的家族性和散发性病例中发现了16个新的CYP 1B 1突变，在原发性开角型青光眼家族中发现了6个新的TIGR突变。 鉴于这些发现，我们相信现在可以使用这些分子方法在青光眼的不可逆视神经损伤发生之前识别这些疾病的风险。 因此，本项目的具体目标是：1）识别、确定和临床检查从康涅狄格州眼科实践中招募的大样本青光眼患者（N = 500）; 2）从这些个体获得血液或口腔组织样本，并提取和储存DNA;（3）系统地从这些患者的DNA中筛选已知在青光眼中具有病因学意义的两个基因，CYP 1B 1和TIGR; 4）从这些患者的DNA中筛选随后被鉴定为在青光眼中具有病因学意义的其他基因中的突变;和5）将突变类型（基因型）与受影响受试者的临床数据（表型）相关联。 GCRC将有助于这些个体的识别、确定和临床检查;样本收集和处理;以及突变筛查，这是基于我们实验室和活跃在这一快速发展的研究领域的其他研究者的实验室正在进行的工作。

Glaucoma represents a group of inherited eye disorders that collectively accounts for 3% of all blindness in the US and worldwide. In recent years, the chromosomal locations of seven glaucoma loci have been identified (five of which were identified by us and two by other groups). Further, we and another group recently described the first mutations in two independent genes, namely that encoding Cytochrome P4501B1 (CYP1B1) and the Trabecular Meshwork -Induced Glucocorticoid Response protein (TIGR), in families segregating for primary congenital and primary open angle types of glaucoma, respectively. Since then, the role of these two genes in the etiology of these two types of glaucoma has been confirmed by other investigators and in other populations. To date, we have identified 16 novel CYP1B1 mutations in familial and sporadic cases with primary congenital glaucoma and six new TIGR mutations in families with primary open angle glaucoma. Given these findings, we believe it is now feasible to use these molecular methods to identify subjects at risk for these conditions before the irreversible optic nerve damage of glaucoma has occurred. Therefore, the specific aims of this project are: 1) To identify, ascertain, and clinically examine a large sample of glaucoma patients (N = 500) recruited from ophthalmology practices in Connecticut; 2) To obtain blood or buccal tissue samples from these individuals and to extract and bank the DNA; 3) To systematically screen DNA from these patients for the two genes, CYP1B1 and TIGR, which are known to be of etiologic significance in glaucoma; 4) To screen DNA from these patients for mutations in other genes that are subsequently identified as being of etiologic significance in glaucoma; and 5) To correlate the type of mutation (genotype) with the clinical data (phenotype) in affected subjects. The GCRC will be instrumental in the identification, ascertainment and clinical examination of these individuals; in sample collection and processing; and in mutation screening, which is based upon ongoing work in our laboratory and the laboratories of other investigators who are active in this rapidly- developing area of research.