Gene Discovery in Primary Congenital Glaucoma

摘要 原发性先天性青光眼(PCG)是一种常染色体隐性遗传，典型的严重形式的青光眼 在孩提时代就有礼物。青光眼的特点是高眼压，导致青光眼。 与眼球增大相关的视神经病变。GLC3A、B、C和D四个遗传基因座 已被鉴定，其中两个基因座的致病基因已被报道。细胞色素P450 亚家族I多肽1(CyP1B1)位于GLC3A基因座，该基因的突变可解释 在美国高加索人口中，大约10%-20%的受影响个人。潜移默化 生长因子β结合蛋白2(LTBP2)基因位于GLC3D基因座，在小鼠中发生突变。 巴基斯坦和吉普赛人家庭的数量，但该基因的变异还没有在其他人群中发现。 最后，肌红蛋白(Myocin，MYOC)和细胞色素PYP1B1基因的突变共同作用被认为与PCG有关 加拿大家庭。这些基因只占美国PCG病例的10%-20%，而基因 大多数PCG病例的病因尚不清楚。 我们建议通过对75个基因中每个基因的每个编码外显子进行测序来发现导致PCG的突变 包含PCG患者的家庭。这一过程被称为完整外显子组测序，快速和 高效地提供了存在于个人基因组中的所有有害突变的完整清单。这 这项技术已经被用来识别包括米勒在内的许多不同疾病的致病突变 综合征、非症状性听力损失和先天性氯化物腹泻。整个外显子组测序是 非常适合于常染色体隐性遗传病(如PCG)突变的鉴定。 我们假设大多数致病突变是纯合子突变或复合杂合子突变。 错义突变或终止密码子。突变也有可能扰乱基因调控。 区域，如启动子或剪接位点，或将由复制或缺失(拷贝数变体)组成。 我们将对PCG数据集的其余部分进行筛查，以确定所有具有致病突变的个体 考虑到吉恩。然后，确认的突变将在两个独立的PCG数据集中复制。这些 研究将为开发多种类型青光眼的新疗法铺平道路。

ABSTRACT Primary Congenital Glaucoma (PCG) is an autosomal recessive, typically severe form of glaucoma that presents in early childhood. PCG is characterized by high intraocular pressure, leading to glaucomatous optic neuropathy associated with enlargement of the ocular globe. Four genetic loci-GLC3A, B, C and D- have been identified and the causative genes in two of these loci have been reported. Cytochrome P450 subfamily I polypeptide 1 (CYP1B1), is located within the GLC3A locus, and mutations in this gene account for approximately 10-20% of affected individuals in the US Caucasian population. The latent transforming growth factor beta binding protein 2 (LTBP2) gene, located within the GLC3D locus, is mutated in a small number of Pakistani and gypsy families, but variants in this gene have not been found in other populations. Finally, mutations in myocilin (MYOC) and CYP1B1 acting together have been implicated PCG in a large Canadian family. These genes account for only 10-20% of the PCG cases in the US, with the genetic etiology of the majority of PCG cases remaining unexplained. We propose to find mutations that cause PCG by sequencing every coding exon of every gene in 75 families containing individuals with PCG. This process, called whole exome sequencing, rapidly and efficiently provides a complete inventory of all deleterious mutations present in an individual's genome. This technique has been used to identify causative mutations for many different diseases including Miller syndrome, non-syndromic hearing loss, and congenital chloride diarrhea. Whole exome sequencing is ideally suited to the identification of mutations in autosomal recessive diseases such as PCG. We hypothesize that most causative mutations will be homozygous or compound heterozygous rare missense mutations or stop codons. It is also possible that mutations will be disrupt gene regulatory regions such as promoters or splice sites, or will consist of duplications or deletions (copy number variants). We will screen the remainder of our PCG dataset to identify all individuals with causative mutations in any given gene. Confirmed mutations will then be replicated in two independent PCG datasets. These investigations will pave the way for the development of new treatments for multiple types of glaucoma.