Gene Discovery in Primary Congenital Glaucoma

原发性先天性青光眼的基因发现

• 批准号: 8562510
• 负责人: Robert RAND ALLINGHAM
• 金额: $ 47.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562510
• 关键词: Accounting; Affect; Age of Onset; Appointment; Architecture; Binding Proteins; Birth; Blindness; Blood; Blood specimen; CYP1B1 gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Childhood; Chloride Ion; Chlorides; Clinical Data; Clinical Treatment; Code; Complex; Cytochrome P450; DNA; Data; Data Set; Databases; Development; Diagnosis; Diarrhea; Dideoxy Chain Termination DNA Sequencing; Disease; Equipment and supply inventories; Exons; Family; Family Sizes; Family member; Funding; Future; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genome; Glaucoma; Gypsies; Individual; Informatics; Investigation; LTBP2 gene; Lead; Life; Light; Methods; Missense Mutation; Mutate; Mutation; Nucleic Acid Regulatory Sequences; Participant; Patients; Physiologic Intraocular Pressure; Population; Primary Open Angle Glaucoma; Process; RNA Splicing; Recruitment Activity; Regulatory Element; Relative (related person); Reporting; Sampling; Severities; Signal Transduction; Site; Splice-Site Mutation; Syndrome; Techniques; Terminator Codon; Time; Tissues; Trabecular meshwork structure; Transforming Growth Factor beta; Variant; Work; affection; base; comparative genomic hybridization; early childhood; exome; exome sequencing; eye center; family structure; follow-up; gene discovery; genetic linkage analysis; genetic pedigree; hearing impairment; high intraocular pressure; improved; in vitro Assay; myocilin; novel; optic nerve disorder; polypeptide; primary congenital glaucoma; promoter; public health relevance; response; segregation

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.

抽象的 原发性先天青光眼（PCG）是一种常染色体隐性，通常是严重的青光眼形式 幼儿时期的礼物。 PCG的特征是高眼压，导致青光眼 与眼球的扩大有关的视神经病变。四个遗传基因座-GLC3A，B，C和D- 已经鉴定出并报道了其中两个基因座的因果基因。细胞色素P450 亚家族I多肽1（CYP1B1）位于GLC3A基因座内，该基因计算中的突变 在美国高加索人口中，大约有10-20％的受影响的个体。潜在的转化 生长因子β结合蛋白2（LTBP2）基因，位于GLC3D基因座内的基因，在小型中被突变 巴基斯坦和吉普赛家族的数量，但在其他人群中尚未发现该基因的变体。 最后，肌动蛋白（Myoc）和CYP1B1一起起作用的突变已与PCG有关 加拿大家庭。这些基因仅占美国PCG病例的10-20％ 大多数PCG病例的病因仍然无法解释。 我们建议通过对75中每个基因的每个编码外显子进行测序来找到引起PCG的突变 含有PCG的个体的家庭。这个过程，称为整个外显子组测序，快速和 有效地提供了个人基因组中所有有害突变的完整清单。这 技术已被用来识别许多不同疾病在内的病因突变 综合征，非综合性听力损失和先天性氯化腹泻。整个外显子组测序是 非常适合鉴定常染色体隐性疾病（例如PCG）突变。 我们假设大多数病因突变将是纯合或复合杂合稀有的 错义突变或停止密码子。突变也可能破坏基因调节 诸如启动子或剪接站点之类的区域，或将由重复或删除（复制号变体）组成。 我们将筛选剩余的PCG数据集，以识别所有具有因果突变的人 给定基因。然后，确认的突变将在两个独立的PCG数据集中复制。这些 调查将为多种类型的青光眼开发新疗法铺平道路。