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Gene Discovery in Primary Congenital Glaucoma

原发性先天性青光眼的基因发现

基本信息

批准号：
8925892
负责人：
Robert RAND ALLINGHAM
金额：
$ 37.01万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925892
关键词：
Accounting Affect Age of Onset Appointment Architecture Binding Proteins Birth Blindness Blood Blood specimen CYP1B1 gene Candidate Disease Gene Caucasians Childhood Chloride Ion Chlorides Clinical Data Clinical Treatment Code Complex Copy Number Polymorphism 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 Health Individual Informatics Investigation LTBP2 gene Lead Life Light Mendelian disorder 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 response segregation

项目摘要

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：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出现在儿童早期。PCG的特点是高眼压，导致青光眼性视神经病变并伴有眼球增大。目前已鉴定出GLC3A、B、C和D四个遗传基因座，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，该基因突变约占美国高加索人群患病个体的10%-20%。潜伏的转化生长因子β结合蛋白2(LTBP2)基因位于GLC3D基因座，在少数巴基斯坦人和吉普赛人家系中发生突变，但在其他人群中未发现该基因的变异。最后，肌红素(MYOC)和CYP1B1的突变共同作用被认为与一个加拿大大家庭的PCG有关。这些基因只占美国PCG病例的10%-20%，大多数PCG病例的遗传病因尚不清楚。我们建议通过对75个包含PCG患者的家庭中每个基因的每个编码外显子进行测序来寻找导致PCG的突变。这一过程被称为完整外显子组测序，快速有效地提供了一个人基因组中存在的所有有害突变的完整清单。这项技术已被用于鉴定许多不同疾病的致病突变，包括米勒综合征、非综合征性听力损失和先天性氯化物腹泻。整个外显子组测序非常适合于常染色体隐性遗传病(如PCG)中突变的鉴定。我们假设大多数致病突变将是纯合子或复合杂合性罕见错义突变或停止密码子。突变也有可能破坏基因调控区域，如启动子或剪接位点，或由复制或缺失(拷贝数变体)组成。我们将筛选PCG数据集的其余部分，以识别任何给定基因中具有致病突变的所有个体。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。