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Daniela Klein, Alexandra Mendes-Madeira, Birgit Lorenz, Fabienne Rolling, Silke Haverkamp, Knut Stieger; Early S Cone Loss And L/m Cone Opsin Delocalization In The Canine Model Of Rpe65 Deficiency. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6439. doi: https://doi.org/.
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Mutations in the RPE65 gene are associated with early onset severe retinal dystrophy or Leber congenital amaurosis, a rare form of blindness in humans that is characterized by severe visual impairment within the first years of life and legal blindness before the second decade of life. The Swedish Briard dog is a naturally occurring animal model for this disease with a null mutaion in the RPE65 gene, which has been extensively used for the development of gene therapy applications. Morphological studies in mice and functional studies in humans indicate early S cone function loss, while L/M cones remain initially functional. The aim of this study was to examine the cone photorector morphology in RPE65 -/- dogs in the course of the disease in order to further elucidate the underlying pathology.
Retinae from 11 dogs (n=22) were used in this study, two unaffected and 9 affected animals. Age varied between 5 months and 6.5 years. Eyes were processed to obtain either cryosections or flatmount preparations. Antibodies against the cone opsins (S-opsin, LM-opsin) and a nonspecific cone marker (Penut agglutinin) were used. Quantifications were done on flatmount preparations using imageJ cell counter software.
Opsin delocalisation was observed at two years of age in L/M and S cones. Especially L/M cone opsin delocalized into the inner segment and nuclear region. In retinae from affected dogs, the total number of S cones was already lower at two years of age, and further decreased progressively. Overall, at all time points cones in the periphery were more affected than in the central retina.
Early S cone loss in the canine retina corresponds well with related studies in mice and humans. Furthermore, early L/M cone opsin delocalization also indicates functional impairments in L/M cones at young ages. These observations are of high interest with regard to current gene therapy studies, both in humans and large animal models.
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