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      Genetically engineered large animal model for studying cone photoreceptor survival and degeneration in retinitis pigmentosa.

      Nature biotechnology

      Animals, Animals, Genetically Modified, Blotting, Southern, Disease Models, Animal, Electroretinography, Embryo Transfer, Gene Expression Regulation, genetics, Genetic Engineering, Microscopy, Electron, Molecular Sequence Data, Phenotype, Polymerase Chain Reaction, Retina, pathology, physiopathology, ultrastructure, Retinal Cone Photoreceptor Cells, Retinal Degeneration, Retinitis Pigmentosa, Rhodopsin, chemistry, Swine, embryology, Transgenes

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          Abstract

          Patients with retinitis pigmentosa (RP) typically develop night blindness early in life due to loss of rod photoreceptors. The remaining cone photoreceptors are the mainstay of their vision; however, over years or decades, these cones slowly degenerate, leading to blindness. We created transgenic pigs that express a mutated rhodopsin gene (Pro347Leu). Like RP patients with the same mutation, these pigs have early and severe rod loss; initially their cones are relatively spared, but these surviving cones slowly degenerate. By age 20 months, there is only a single layer of morphologically abnormal cones and the cone electroretinogram is markedly reduced. Given the strong similarities in phenotype to that of RP patients, these transgenic pigs will provide a large animal model for study of the protracted phase of cone degeneration found in RP and for preclinical treatment trials.

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          Most cited references 33

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          [19] Rapid and efficient site-specific mutagenesis without phenotypic selection

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            Retinopathy induced in mice by targeted disruption of the rhodopsin gene.

            Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and pigmentary deposits. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho-/- mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.
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              A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors.

              1. We have undertaken a theoretical analysis of the steps contributing to the phototransduction cascade in vertebrate photoreceptors. We have explicitly considered only the activation steps, i.e. we have not dealt with the inactivation reactions. 2. From the theoretical analysis we conclude that a single photoisomerization leads to activation of the phosphodiesterase (PDE) with a time course which approximates a delayed ramp; the delay is contributed by several short first-order delay stages. 3. We derive a method for extracting the time course of PDE activation from the measured electrical response, and we apply this method to recordings of the photoresponse from salamander rods. The results confirm the prediction that the time course of PDE activation is a delayed ramp, with slope proportional to light intensity; the initial delay is about 10-20 ms. 4. We derive approximate analytical solutions for the electrical response of the photoreceptor to light, both for bright flashes (isotropic conditions) and for single photons (involving longitudinal diffusion of cyclic GMP in the outer segment). The response to a brief flash is predicted to follow a delayed Gaussian function of time, i.e. after an initial short delay the response should begin rising in proportion to t2. Further, the response-intensity relation is predicted to obey an exponential saturation. 5. These predictions are compared with experiment, and it is shown that the rising phase of the flash response is accurately described over a very wide range of intensities. We conclude that the model provides a comprehensive description of the activation steps of phototransduction at a molecular level.
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                Author and article information

                Journal
                9335046
                10.1038/nbt1097-965

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