Recessive Ocular Phenotypes from Murine ENU Mutagenesis

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，但从来没有大规模的努力来确定眼病的隐性小鼠等位基因。例如，超过49%的单基因人类视网膜疾病基因座是隐性的，而不到三分之一是显性的，15%是X连锁的，4%是线粒体的。最近利用天然RPE65缺陷动物模型对Leber先天性巨结肠症进行基因治疗的成功，突显了动物模型在这个时间点上的关键重要性。具有不同外显率和/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、治疗和康复具有最大的希望。通过使用全基因组小鼠突变和表型驱动的方法，既可以识别已知基因的新模型，也可以识别新基因。如果在先前突变的基因座上，由N-乙基-N-亚硝脲(ENU)引起的点突变将为我们提供新的等位基因，以提高我们对基因-表型关系的理解，并为基因治疗试验提供基因组，否则这些试验是不可操作的。如果在一个新的基因座上，这种突变将扩大候选基因和/或眼病模型动物的保留范围。德克萨斯医学中心老鼠发育缺陷突变中心目前正在产生大量突变小鼠，这些突变小鼠经历了一些表型筛查，但没有一只是眼科异常。突变中心还建立了一个基础设施，以便在发表前报告表型信息，并通过互联网为研究界提供突变动物。这项建议旨在为已经产生的突变小鼠增加隐性眼部表型的眼科筛查。异常表型将被记录下来，提供给视觉研究社区，选定的表型将被遗传作图，并识别它们的突变。分层隐性眼部表型鉴定以及将突变映射和识别到现有系统的方法将利用已生产的动物，通过提供新的眼病模型动物供科学界进一步研究，从而加快眼睛研究。

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.