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BD Perkins, JE Dowling; Identification of Dominant Mutations Causing Night Blindness in Adult Zebrafish . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3660.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: More than 24 different inherited retinal diseases have been classified in humans. More than 130 different disease-causing loci are known and more than 70 genes have been cloned. Animal models for many of these diseases do not exist and other disease-causing mutations have likely not been identified. To further our understanding of the genetic basis for retinal disease, we conduced a genetic screen to identify dominantly inherited mutations that cause night blindness in zebrafish. Methods: Approximately 1100 mutagenized F1 zebrafish were screened for night blindness using a behavioral assay previously developed in our laboratory (Li and Dowling, 1997, PNAS). Night blind mutants were outcrossed to wild type fish to generate F2 families. Behavioral testing was performed on adult F2 fish to identify families carrying a dominant mutation leading to night blindness. Electroretinographic (ERG) and histological analyses were done to localize the effects of the mutation to the outer or inner retina and to identify those families exhibiting retinal degeneration. Results: Of the 1100 F1 fish screened, 13 exhibited a night blindness phenotype with visual thresholds at least two orders of magnitude higher than wild type. Of these, 10 F2 families were generated and in 5 families between 40-50% of the adult progeny showed elevated visual thresholds, indicating the presence of a dominant mutation. Histological data indicated that two families, H2184 and H2298, showed some degree of retinal degeneration but two additional families, H2148 and H2186, did not show significant signs of retinal degeneration. ERG thresholds from H2148 mutants were similar to wild type, implying a defect downstream of the outer retina. ERG thresholds from H2298 mutants were lower than wild type, consistent with loss of outer retinal function. Conclusion: By performing a genetic screen based upon a simple behavioral test, we have identified five mutations that lead to night blindness in zebrafish. Of these, whereas two show clear retinal degeneration, at least one appears to have a defect more proximal than the outer nuclear layer. Further analysis of these mutations will enhance our understanding of inherited retinal degeneration and other retinal disease in humans.
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