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S. M. Conley, S. J. Fliesler, M. I. Naash; Retinal Degeneration in Mice With I-255/256 Deletion Mutation in Opsin Gene: Gene Dosage vs. Transgene Effects. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4511.
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© ARVO (1962-2015); The Authors (2016-present)
Deletion of isoleucine at codon 255/256 of the human opsin gene is associated with early onset autosomal dominant retinitis pigmentosa ( ADRP). Previously, we showed that mice heterozygous for this mutation (I255+/-) are blind and do not form photoreceptor outer segments (OSs). However, it is unclear whether this is due to the mutation per se or to opsin over-expression. Here, we characterized the mutation phenotype on normal (WT), hemizygous (Rhod+/-), and null (RKO) opsin backgrounds, to distinguish gene dosage vs. transgene effects.
Mice containing a 3bp opsin gene deletion at codon 255/256 and the full-length opsin promoter region were generated as described previously (Penn et al., IOVS 41:4007, 2000). Retinal morphology and ultrastructure were assessed in I255+/+/WT, I255+/-/Rhod+/- and I255+/-/RKO mice, particularly with regard to OS structure, outer nuclear layer (ONL) thickness, and outer limiting membrane (OLM) formation. Visual function was assessed by electroretinography (ERG).
At postnatal day 5 (P5), retinal morphology in I255+/+/WT mice was comparable to that in I255+/-/Rhod+/- and WT mice. However, by P10, I255+/+/WT retinas started to degenerate and, by P15, there were 0-1 rows of ONL nuclei, no OLM, and no OSs. Retinal degeneration in I255+/-/Rhod+/- mice was much slower: at P10, although lacking OSs, the ONL and OLM appeared normal. By P21, neither I255+/+/WT nor I255+/-/Rhod+/- mice exhibited appreciable ERG function.
Opsin expression level is a significant factor in the rate of retinal degeneration in I255 mutant mice. However, the mutation alone can cause a severe dominant retinal degeneration. Further studies using I255+/-/RKO+/- mice are ongoing to assess the mechanisms of cell death underlying this retinal degeneration.
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