Anatomy and Neuroscience - Research Publications

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Author: Fletcher, Erica × Author: Jobling, Andrew × Subject: cone photoreceptors ×

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    A Naturally Occurring Mouse Model of Achromatopsia: Characterization of the Mutation in Cone Transducin and Subsequent Retinal Phenotype
    Jobling, AI ; Vessey, KA ; Waugh, M ; Mills, SA ; Fletcher, EL (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2013-05)
    PURPOSE: This work investigates a novel, naturally occurring mouse model of achromatopsia. The specific missense mutation within the Gnat2 gene was identified and the subsequent retinal phenotype characterized. METHODS: The Gnat2 sequence was amplified using PCR from BALB/c and Gnat2(c.518A>G) retinae and the product sequenced. Retinal function was assessed at 3, 6, 9, and 12 months using the electroretinogram. Transducin and opsin expression were assessed at 3 and 12 months using immunohistochemistry and quantitative PCR. Retinal remodeling and Müller cell gliosis were investigated using immunocytochemistry. RESULTS: An A to G missense mutation at position 518 of the Gnat2 gene was identified that resulted in an aspartic acid to glycine substitution. Gnat2(c.518A>G) animals showed no cone response, while the rod response was normal except for a decrease in the photoreceptor response at 12 months (a-wave, -14%). Gnat2(c.518A>G) retinal sections showed no transducin immunolabeling; however, protein was detected via Western blot. Gnat2 gene expression was only decreased at 12 months of age (-27%). There was reduced cone number at 12 months (-27%) and M-opsin showed evidence of mislocalization. Displaced photoreceptor terminals and altered horizontal cell, cone/rod bipolar cell morphology were evident at 3 months, becoming more extensive at 12 months with the emergence of Müller cell gliosis. CONCLUSIONS: The Gnat2(c.518A>G) mouse contains a missense mutation that results in no cone function due to a misfolding of transducin. Cone photoreceptors also show signs of opsin mislocalization, retinal remodeling and degeneration. This naturally occurring model shows all the hallmark signs of achromatopsia.