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Y. Ishiba, N. Mori, S. Kubota, A. Kobayashi, T. Higashide, M.J. McLaren, G. Inana; Changes in Retinal Synaptic Proteins in the Knock–Out Model of HRG4 (UNC119) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4581.
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© ARVO (1962-2015); The Authors (2016-present)
HRG4 (UNC119) is a novel photoreceptor synaptic protein we have isolated by a differential cloning approach. A truncation mutation of HRG4 causes late–onset cone–rod dystrophy in a patient, and a transgenic (TG) model expressing the identical mutation develops late–onset retinal degeneration, just as in the patient. Analysis of retinal synaptic proteins in a 13 month TG demonstrated a decrease in some peripheral synaptic vesicle (SV) membrane proteins and an increase in some synaptoplasmic and pre–synaptic membrane proteins. A knock–out (KO) model of HRG4 has been constructed in which a progressive retinal degeneration was observed with an earlier onset and a more severe end–stage degeneration than the TG. Retinal synaptic proteins were analyzed in the KO model to begin to investigate the pathogenic mechanism in this model.
Retinal proteins were isolated from 5, 10, 15, and 20 months KO and subjected to western blot analysis with antibodies for Synaptotagmin, Synaptobrevin, Synaptogyrin, Rab3, Rabphilin3A, and Syntaxin.
For peripheral SV membrane proteins, interestingly, an increase in Rab3 was observed, but a slight decrease in Synaptotagmin and Synaptobrevin was observed starting at 10 months. The SV integral membrane protein Synaptogyrin showed a moderate increase through 10 months, then a decrease. The pre–synaptic membrane protein Syntaxin showed an increase starting at 5 months.
Some of the changes in the synaptic proteins in the KO, such as Synaptotagmin, Rabphilin3A, and Syntaxin, were similar to that in the TG, while others were different, reflecting the differences in the mechanism of pathogenesis in the two models. This KO model should be very useful for elucidation of the function and pathogenic mechanism of HRG4.
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