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D.B. Gould, R.T. Libby, C. Phalan, R.S. Smith, S.W. M. John; Mice With a Col4a1 Mutation Have Phenotypes Relevant to Human Age–Related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5914.
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© ARVO (1962-2015); The Authors (2016-present)
Age related macular degeneration (AMD) is a leading cause of blindness. Recent work suggests a role for complement and immunity in AMD pathogenesis, however, other pathogenic processes are clearly important. Our purpose is to further understand AMD pathogenesis by using mouse models. We hypothesized that mice with a mutation of type IV collagen alpha 1 (Col4a1) may have abnormalities of the retinal pigmented epithelium (RPE), Bruch's membrane or choriodal vasculature that might lead to AMD–relevant phenotypes. Furthermore, because AMD is multi–factorial, we hypothesized that the phenotypes might be modified by genetic context.
Col4a1 mutant mice were aged to ≥18 months and analyzed for hallmarks of AMD at various ages. Analyses included fundus examination, fluorescein angiography, light microscopy and electron microscopy. To evaluate the role of genetic context, we analyzed aged mutant mice from three different strain backgrounds.
Mice with a dominant mutation in Col4a1 develop phenotypes consistent with human AMD. In vivo analysis revealed progressive geographic atrophy, window defects and choroidal neo–vascularization (CNV). Histological analysis revealed photoreceptor cell loss, retinal pigmented epithelium atrophy, disruptions of Bruch's membrane and CNV. Importantly, the presence and severity of these phenotypes is dependent on genetic context.
Our data demonstrates that mutations in Col4a1 can induce phenotypes that are relevant to AMD. This supports evaluation of COL4A1 and other basement membrane components in human AMD patients. These experiments characterize a new mouse model for investigating genetic and pathogenic mechanisms underlying AMD relevant phenotypes. The strong effect of genetic context on the mouse phenotypes offers an opportunity to identify other modifying genes. Ultimately, such studies may contribute to a better understanding of the multi–factorial interactions that predispose to AMD and its component phenotypes.
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