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Published on: November 19, 2011
A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse
N B Akhmedov1, N I Piriev, B Chang
1Jules Stein Eye Institute, University of California School of Medicine, Los Angeles, CA 90095-7000, USA.
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 photoreceptor-specific 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.
Insights
A deletion in the photoreceptor-specific nuclear receptor (mPNR) mRNA causes hereditary retinal degeneration in rd7 mice, mimicking human retinal disorders. This finding highlights mPNR
Area of Science:
- Genetics
- Molecular Biology
- Ophthalmology
Background:
- The rd7 mouse is an animal model exhibiting hereditary retinal degeneration with similarities to human flecked retinal disorders.
- Photoreceptor-specific nuclear receptor (mPNR) is a gene crucial for retinal development.
Purpose of the Study:
- To identify the genetic cause of hereditary retinal dysplasia and degeneration in the rd7 mouse.
- To investigate the role of mPNR in photoreceptor cell development and function.
Main Methods:
- Subtractive hybridization to isolate photoreceptor-specific cDNAs.
- Gene mapping to localize the mPNR gene near the rd7 locus.
- Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) to detect mPNR mRNA.
- Direct sequencing of amplified mPNR fragments.
Main Results:
- A 380-nucleotide deletion was identified in the coding region of the mPNR mRNA in rd7 mouse retinas.
- This deletion causes a frameshift, premature stop codon, and loss of a significant portion of the DNA-binding domain.
- The mutation may lead to rapid degradation of the mPNR mRNA via nonsense-mediated decay, preventing protein synthesis.
- No detectable mPNR signal was observed in rd7 retinas via Northern blot.
Conclusions:
- The identified deletion in mPNR mRNA is responsible for hereditary retinal dysplasia and degeneration in rd7 mice.
- mPNR expression is essential for the normal development and function of photoreceptor cells.
- This study provides a molecular basis for understanding rd7 mouse retinal disease and its relevance to human retinal disorders.
