Recessive Ocular Phenotypes from Murine ENU Mutagenesis

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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.