A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse

Abstract

The rd7 mouse, an animal model for hereditary retinal degeneration, has some characteristics similar to human flecked retinal disorders. Here we report the identification of a deletion in a photoreceptor-specific nuclear receptor (mPNR) mRNA that is responsible for hereditary retinal dysplasia and degeneration in the rd7 mouse. mPNR was isolated from a pool of photoreceptorspecific cDNAs originally created by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas. Localization of the gene corresponding to mPNR to mouse Chr 9 near the rd7 locus made it a candidate for the site of the rd7 mutation. Northern analysis of total RNA isolated from rd7 mouse retinas revealed no detectable signal after hybridization with the mPNR cDNA probe. However, with reverse transcription-PCR, we were able to amplify different fragments of mPNR from rd7 retinal RNA and to sequence them directly. We found a 380-nt deletion in the coding region of the rd7 mPNR message that creates a frame shift and produces a premature stop codon. This deletion accounts for more than 32% of the normal protein and eliminates a portion of the DNA-binding domain. In addition, it may result in the rapid degradation of the rd7 mPNR message by the nonsense-mediated decay pathway, preventing the synthesis of the corresponding protein. Our findings demonstrate that mPNR expression is critical for the normal development and function of the photoreceptor cells.

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

“…At P16, shortly after eye opening at P14, white retinal spots were present over the entire retina [Haider et al, 2001]. The number of retinal spots decreased by 5 months of age and completely disappeared by 16 months [Akhmedov et al, 2000]. This was consistent with the disappearance of rosettes, suggesting an association of white spots with rosettes.…”

“…Consistent with the recessive mode of inheritance of human ESCS, GFS and CRPD, heterozygote mice were normal, and a slow, but progressive degeneration of both the rod and cone systems was only observed in rd7/rd7 mice [Akhmedov et al, 2000;Haider et al, 2001]. Starting at P12, the presence of waves, whorls, and rosettes was observed in the outer nuclear layer of the retina [Haider et al, 2001].…”

“…The retinal degeneration 7 (rd7) mouse is a spontaneous null mutation of the Nr2e3 gene by L1 retrotransposon insertion, and has been instrumental to determine in vivo the essential role of NR2E3 in proper photoreceptor cell fate determination, differentiation, and maintenance [Akhmedov et al, 2000;Chen et al, 2006]. Consistent with the recessive mode of inheritance of human ESCS, GFS and CRPD, heterozygote mice were normal, and a slow, but progressive degeneration of both the rod and cone systems was only observed in rd7/rd7 mice [Akhmedov et al, 2000;Haider et al, 2001].…”

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

“…Similar to ESCS in humans, the rd7 retina has excess cones that express mostly S-cone opsin (Haider et al, 2001). Rod and cone function measured by electroretinography (ERG) is near normal in young adults but significantly declines in older mice as a result of degeneration of both rods and cones (Akhmedov et al, 2000;Ueno et al, 2005;Haider et al, 2006). These phenotypes of human ESCS and rd7 mice support a role for Nr2e3 in rod/cone development by demonstrating how its mutations lead to disease.…”

“…Genetic analysis revealed that these mice carry a homozygous 380-bp deletion in the coding region of the Nr2e3 cDNA (Akhmedov et al, 2000;Haider et al, 2001), due to mRNA splicing defects resulting from an L1-retrotransposon insertion (Chen et al, 2006). This leads to a frame-shift with a premature termination.…”