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D.B. Gould, F.C. Phalan, I.M. Cosma, A. Snow, R.T. Libby, R.S. Smith, S.W. M. John; Influence of Genetic Context on a Novel Mutation With Pleiotropic Phenotypes Including Ocular Dysgenesis, Glaucoma and Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3555.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:To understand the genetics of ocular disease and identify new mouse models, we performed a random mutagenesis screen. Here we describe the pleiotropic effects of a novel mouse mutation and the importance of genetic context in determining the phenotype. Methods: We examined mice from an EMS mutagenesis screen for ocular phenotypes. Mutant mice were used for positional cloning to identify the mutated gene. Phenotypic characterization included clinical, histological and physiological assessment of anterior and posterior ocular structures in both young mice and mice aged for two years. Results: We have identified a novel mutation in procollagen type IV alpha 1, (Col4a1). To determine how genetic context interacts with the mutation to alter the phenotype, we bred the mutation onto different genetic backgrounds. On one genetic background, mutation of Col4a1 causes severe anterior segment dysgenesis including obstruction of the iridocorneal angle. Intraocular pressures of mutant mice are often high. These mice also have optic nerve hypoplasia. The developmental defects are genetic context dependent and are not present on all backgrounds. For example, on a second genetic background, some mutant mice have elevated intraocular pressure and optic nerve damage consistent with glaucoma. On this background, the mice do not have obvious anterior segment dysgenesis and may more closely model open angle glaucoma. Interestingly, Col4a1 mutant mice also develop hallmarks of age–related macular degeneration including geographic atrophy, and photoreceptor cell degeneration. Conclusions: We have identified a novel mutation in Col4a1 with pleitropic ocular phenotypes. The phenotypes caused by a single mutation can include features of anterior segment dysgenesis, glaucoma or age related macular degeneration depending on genetic context. This work clearly demonstrates the profound modifying influence of mulitple genetic factors on ocular disease and provides models to understand the complex genetic interactions involved.
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