青光眼表现为明显的临床和遗传异质性。前期工作中，我们通过对一个原发性开角型青光眼(POAG)大家系GCM-005进行全基因组SNP扫描和连锁分析，将该家系的致病基因定位于染色体13q32.1-32.3，属于新的POAG致病基因座，暂时命名为GLC1R。本项目拟在此基础上，选择与GLC1R紧密连锁区间及其上、下游含较高遗传信息量的微卫星标记对GCM-005家系进行连锁分析和单体型构建，进一步验证该新的POAG致病基因座；然后，采用外显子组(Exome)测序技术筛查候选致病基因及其变异位点，以及采用常规DNA测序鉴定致病基因及其突变位点。一旦发现新的致病基因及其突变位点，则在我们收集的其它POAG家系和散发病例进行该致病基因突变筛查；最后，根据致病基因的结构和功能特点，在体外培养细胞和转基因小鼠体内对致病基因的表达/定位及生物学功能进行分析，探讨突变型与表型的关系，阐明其致病的分子机制。

Glaucoma is a clinically and genetically heterogeneous disease, and it is the second hightest cause of blindness globally. In our previous work, a linkage analysis of a larger Chinese family GCM-005 with primary open angle glaucoma (POAG) was performed using genome-wide single nucleotide polymorphism (SNP) array. A novel POAG locus, temporarily named GLC1R, was obtained and located on chromosome 13q32.1-32.3. Based on the above results, we will futher confirmed the disease locus GLC1R by linkage analysis and haplotype analysis of GCM-005 family using the more genetic information of microsatellite markers, which located on or near GLC1R locus. And then we will screen the candidate genes and their variants through exome sequencing technology. The disease causing-gene was further confirmed in available other family members as well as in other POAG families and 100 normal unrelated controls by bidirectional DNA sequencing. Finally, according to the known characteristics (structure and function) of the diseas causing-gene, We will further research the relationship between gentype and phenotype through the expression, location and biological function of the pathogenic gene in cell culture in vitro and in transgenic mice in vivo, for explanation of the molecular mechanism of the disease causing-gene in POAG.