MOLECULAR SCREENING METHODS FOR DIFFERENT TYPES OF GLAUCOMA

青光眼是一组遗传性眼病，占美国和世界范围内所有失明的3%。近年来，已确定了7个青光眼基因座的染色体位置(其中5个由我们鉴定，2个由其他研究小组鉴定)。此外，我们和另一个小组最近描述了两个独立基因的首次突变，即编码细胞色素P4501B1(CYP1B1)和小梁网络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系中。从那时起，这两个基因在这两种类型青光眼的病因中的作用已经被其他研究人员和其他人群证实。到目前为止，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CYP1B1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，我们认为，在青光眼发生不可逆视神经损害之前，使用这些分子方法来识别这些疾病的风险受试者现在是可行的。因此，该项目的具体目标是：1)识别、确定和临床检查从康涅狄格州眼科诊所招募的大样本青光眼患者(N=500)；2)从这些人身上获取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中筛选两个基因--CYP1B1和TIGR，这两个基因已知对青光眼有病因学意义；4)从这些患者的DNA中筛选其他基因的突变，这些基因后来被确定为青光眼的病因意义；5)研究突变类型(基因型)与临床资料(表型)之间的关系。GCRC将在这些人的识别、确定和临床检查；样本收集和处理；以及突变筛查方面发挥作用，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人员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.