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NB Haider, PM Nishina; Identification of Modifiers for Retinal Degeneration 7 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):834.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:To identify genes that interact with the rd7 mutation by suppressing the rd7 phenotype in order to define the pathway in which NR2E3 functions. Methods: DNA was collected from three independent F2 intercrosses: (Cast/EiJxB6.Cg-rd7/rd7)F1, (AKRxB6.Cg-rd7/rd7)F1, and (NODxB6.Cg-rd7/rd7)F1. F2 mice were phenotyped at 8 and 20 weeks and tissue from suppressed animals was collected at 20 weeks. Mice were genotyped using primers flanking the Nr2e3 deletion found in rd7 mice to identify those homozygous for rd7. Suppressed mice were those that were genotypically homozygous for the rd7 mutation but phenotypically normal. DNA from the F2 Cast/rd7 intercross was used in a genome wide screen. Primers were chosen at approximately 30 cM intervals and PCR was performed under standard conditions. Results:Over 300 F2 mice have been phenotyped from each cross. Approximately 31% of NODxB6.Cg-rd7/rd7, 29% of Cast/EiJxB6.Cg-rd7/rd7, and 40% of AKRxB6.Cg-rd7/rd7 mice homozygous for rd7 were suppressed. Mice were considered suppressed if they showed no rd7 retinal spotting at 8 weeks, and only faint retinal spotting at 20 weeks. Histologically, retinas from suppressed mice revealed complete suppression of the retinal dysplasia characterized by whorls in the outer nuclear layer. Furthermore, immunohistochemistry of suppressed mice revealed they do not have an increase in cone photoreceptor cells seen in rd7 retinas. A genome wide scan of 75 F2 rd7/rd7 mice from the Cast/EiJxB6.Cg-rd7/rd7 intercross identified a major locus on chromosome1 associated with the CAST allele that was able to suppress the rd7 phenotype. Conclusion:Modifiers for the rd7 retinal phenotype have been observed in 3 independent backgrounds. Complete restoration of retinal morphology in the suppressed mice suggests these genes are able to restore or compensate for Nr2e3 function in the retina. The restoration of rd7 retinal morphology is significant as the primary defect in rd7mice is retinal dysplasia that in turn causes degeneration of the photoreceptor cells. The identification of these modifier genes at the molecular level will help define the pathway in which Nr2e3 functions.
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