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.

摘要 原发性先天性青光眼（PCG）是一种常染色体隐性遗传的，典型的严重青光眼， 在童年早期的礼物。PCG的特点是高眼压，导致昏迷 与眼球地球仪增大有关的视神经病。4个遗传位点-GLC 3A、B、C和D- 已被确定，并在这些基因座中的两个致病基因已被报道。细胞色素P450 亚家族I多肽1（CYP 1B 1）位于GLC 3A基因座内，该基因的突变导致 在美国高加索人群中，约有10-20%的受影响个体。潜在转化 生长因子β结合蛋白2（LTBP 2）基因，位于GLC 3D基因座内，在一个小的突变， 巴基斯坦人和吉普赛人的家庭，但在其他人群中尚未发现这种基因的变异。 最后，myocilin（MYOC）和CYP 1B 1共同作用的突变与PCG有关， 加拿大家庭。在美国，这些基因仅占PCG病例的10-20%， 大多数PCG病例的病因仍无法解释。 我们建议通过对75个样本中每个基因的每个编码外显子进行测序来找到导致PCG的突变。 有PCG患者的家庭。这一过程被称为全外显子组测序， 有效地提供了个体基因组中存在的所有有害突变的完整清单。这 该技术已被用于鉴定许多不同疾病的致病突变，包括米勒病 综合征、非综合征性听力损失和先天性氯化物腹泻。全外显子组测序是 理想地适合于鉴定常染色体隐性遗传疾病如PCG中的突变。 我们假设大多数致病突变是纯合子或复合杂合子， 错义突变或终止密码子。突变也有可能破坏基因调控， 区域，例如启动子或剪接位点，或者将由重复或缺失（拷贝数变体）组成。 我们将筛选PCG数据集的其余部分，以确定在任何基因组中具有致病突变的所有个体。 因为基因。然后将在两个独立的PCG数据集中复制确认的突变。这些 研究将为开发多种类型青光眼的新疗法铺平道路。