Genetics of Adult-Onset Primary Open-Angle Glaucoma

描述（由申请人提供）：我们的长期目标是成功干预原发性开角型青光眼（POAG）的进展，POAG是世界上致盲的主要原因之一。早期发现和治疗POAG已被证明是防止继发性失明的最成功方法之一。POAG的原因有很多，包括环境和遗传因素。几种形式的POAG已被证明是由特定的基因缺陷引起的。我们实验室正在进行GLC1C和GLC1F POAG基因的鉴定。希腊北部的伊庇鲁斯（Epirus）是一个孤立的小口袋，它可能是鉴定POAG GLC1C基因的重要关键。Epirus的一个大家庭有超过12个POAG患者携带GLC1C基因。我们认为GLC1C是该地区主要的POAG基因，这是基于过去两个世纪以来该种群与外界种群很少或没有相互作用的隔离。如果是这样，单倍型分析的Epirian家族和个体与POAG，将确定一个创始染色体，并应大大减少GLC1C区域的大小，以寻找POAG基因。类似的策略将用于分析美国和澳大利亚的POAG家族，这些家族显示出与GLC1C或GLC1F相关的积极证据。GLC1C和GLC1F创始人单倍型的鉴定可作为检测携带GLC1C或GLC1F基因的POAG个体的筛选工具。虽然筛选工具很重要，但GLC1C和GLC1F基因的鉴定是我们的最终目标。通过单倍型分析对GLC1C和GLC1F区域内的候选基因进行突变分析将是本提案的主要目标。本提案的最后一个目标是分析我们的希腊和美国POAG家族和随机POAG个体中已知POAG基因MYOC和OPTN的突变。GLC1C和GLC1F POAG基因的鉴定和表征将为POAG导致的失明的治疗和/或预防研究指明新的途径。

DESCRIPTION (provided by applicant): Our long-term objective is to successfully intervene in the progression of primary open-angle glaucoma (POAG), one of the leading causes of blindness in the world. Early detection of POAG and treatment has proven to be one of the most successful ways to stop blindness from ensuing. The causes of POAG are numerous involving both environmental and genetic determinants. Several forms of POAG have been shown to result from a specific gene defect. Our lab is pursuing the identification of the GLC1C and GLC1F POAG genes. A small isolated pocket of Northern Greece, Epirus, may hold an important key to identifying the POAG GLC1C gene. A large family from Epirus with over 12 individuals with POAG carries the GLC1C gene. We propose that GLC1C is the major POAG gene in this region based on the isolation of the population with little or no interaction with outside populations over the last two centuries. If so, haplotype analysis of Epirian families and individuals with POAG, will identify a founder chromosome and should dramatically reduce the size of the GLC1C region to be searched for the POAG gene. A similar strategy will be used to analyze US and Australian POAG families that show positive evidence for linkage to GLC1C or GLC1F. Identification of a GLC1C and a GLC1F founder haplotype could be used as a screening tool for detecting POAG individuals carrying either the GLC1C or GLC1F gene. While screening tools are important, identification of the GLC1C and GLC1F genes is our ultimate goal. Mutational analysis of candidate genes contained within the GLC1C and GLC1F regions refined by haplotype analysis will be a major goal of this proposal, The last aim of this proposal will be to analyze our Greek and US POAG families and random POAG individuals for mutations in the known POAG genes, MYOC and OPTN. Identification and characterization of the GLC1C and GLC1F POAG genes will point the way to new avenues for research for treatment and/or prevention of blindness resulting from POAG.