Recessive Ocular Phenotypes from Murine ENU Mutagenesis

小鼠 ENU 突变导致的隐性眼部表型

• 批准号: 6778197
• 负责人: DAVID W STOCKTON
• 金额: $ 15.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778197
• 关键词: autosomal recessive trait; disease /disorder model; gene mutation; genetic models; genetic screening; genetically modified animals; genotype; laboratory mouse; model design /development; nitrosourea; phenotype; retina disorder; site directed mutagenesis

DESCRIPTION (provided by applicant): There has never been a large-scale effort to identify recessive mouse alleles for ocular disease even though much of human monogenic eye disease is recessively inherited. For example, greater than 49% of monogenic human retinal disease loci are recessive, while less than one third are dominant, 15% X-linked, and 4% mitochondrial. The critical importance of animal models at this point in time is underscored by the recent successes with gene therapy using a natural RPE65 deficient animal model for Leber Congenital Amaurosis. Having multiple alleles with variable penetrance and/or modes of inheritance will also be indispensable for dissecting the more common ophthalmic diseases with multifactorial genetic and environmental causes. Additionally, understanding the genetic bases of human eye disease holds the truest promise for prevention, treatment, and rehabilitation. Through the use of genome wide mouse mutagenesis and phenotype-driven approaches, both new models of known genes and novel genes can be identified. If in loci previously mutated, the point mutations induced by N-ethyI-N-nitrosourea (ENU) will provide new alleles to improve our understanding of the genotype-phenotype relationship as well as genomes for gene therapy trials that are otherwise un-manipulated. If in a novel locus, the mutation will expand the repertoire of candidate genes and/or model animals for eye disease. The Texas Medical Center Mouse Mutagenesis Center for Developmental Defects is currently generating a large number of mutant mice that undergo a number of phenotypic screens but none for ophthalmologic abnormalities. The mutagenesis center also has an infrastructure established to report phenotypic information prior to publication and provide mutant animals for the research community through the Internet. This proposal aims to add ophthalmologic screening for recessive eye phenotypes for the mutant mice already being generated. Abnormal phenotypes will be documented, made available to the vision research community, selected phenotypes will be genetically mapped, and have their mutations identified. Layering recessive ophthalmic phenotype identification and the means to map and identify the mutations onto the existing system will leverage the animals already being produced to accelerate eye research by providing new eye disease model animals for further study by the scientific community.

描述（由申请人提供）：尽管许多人类单基因眼病是隐性遗传的，但从未进行过大规模的努力来鉴定眼病的隐性小鼠等位基因。例如，大于49%的单基因人类视网膜疾病基因座是隐性的，而小于三分之一是显性的，15%是X连锁的，并且4%是线粒体的。 动物模型的关键重要性，在这个时间点上强调了最近的成功与基因治疗使用天然RPE 65缺陷的动物模型的Leber先天性黑蒙。 具有可变等位基因和/或遗传模式的多个等位基因对于解剖具有多因素遗传和环境原因的更常见的眼科疾病也是必不可少的。 此外，了解人类眼病的遗传基础对预防、治疗和康复有着最真实的希望。通过使用全基因组小鼠诱变和表型驱动的方法，可以鉴定已知基因和新基因的新模型。 如果在先前突变的基因座中，由N-乙基-N-亚硝基脲（ENU）诱导的点突变将提供新的等位基因，以提高我们对基因型-表型关系以及基因组的理解，以用于基因治疗试验，否则未被操纵。 如果在一个新的基因座，突变将扩大候选基因和/或模型动物的剧目眼病。德克萨斯州医学中心发育缺陷小鼠突变中心目前正在产生大量的突变小鼠，这些小鼠经历了许多表型筛选，但没有眼科异常。 诱变中心还建立了一个基础设施，用于在出版前报告表型信息，并通过互联网为研究界提供突变动物。该建议旨在为已经产生的突变小鼠增加隐性眼表型的眼科筛查。异常表型将被记录，提供给视觉研究界，选定的表型将被遗传映射，并确定其突变。分层隐性眼科表型鉴定以及将突变映射和鉴定到现有系统上的方法将利用已经生产的动物，通过提供新的眼病模型动物供科学界进一步研究来加速眼科研究。