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NM McNally, PF Kenna, D Rancourt, T Ahmed, A Stitt, W Colledge, B O'Neill, M Humphries, P Humphries, GJ Farrar; Retinopathy Induced in Mice by Targeted Single Base Deletion at Codon 307 of the rds-Peripherin Gene . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3665.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To generate a mouse model of human autosomal dominant Retinitis Pigmentosa due to a single base pair deletion at codon 307 in the rds-Peripherin gene. Methods: A single base pair at codon 307 of the murine rds-Peripherin gene was deleted by gene targeting. Mice heterozygous and homozygous for the Δ;307 mutation were assessed by Ganzfeld electroretinography and histopathological examination of retinal sections at 2, 6, 10 and 12 month time points and compared with similarly aged naturally occurring null mutant rds-/- mice and rds+/- mice. Results: The frameshift brought about in the mouse genome by the 1bp deletion at codon 307 is predicted to result in alteration of the last 40 amino acids of the carboxy-terminus of the protein and the addition of an extra 11 amino acids. In both heterozygous and homozygous mice, the induced retinopathy appears to be more rapid than that of the rds+/- or rds-/- mice, the bulk of the outer nuclear layer (ONL) of the retina being lost in heterozygotes at 10 months, while in homozygotes, almost complete loss of the ONL occurs by 4 months of age. In rds-/- animals 3 to 4 rows of nuclei remain in the ONL at 4 months of age. Electroretinography shows no recordable rod and cone photoreceptor function in mice homozygous for the Δ;307 mutation by 4 months of age. These data suggest that the mutation displays a dominant negative phenotype in combination with that due to haploinsufficiency Conclusion: Mutations within the rds-Peripherin gene, encoding a structural component of photoreceptors, represent a prevalent cause of the inherited degenerative disease of the retina, Retinitis Pigmentosa (RP), in humans. This murine model of an autosomal dominant form of human RP should be of value in the development and validation of therapeutic strategies designed to amend dominant mutations within the human rds-Peripherin gene.
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