Human Molecular Genetics Advance Access published online on September 18, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn295
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Titles: Age-related retinal degeneration (arrd1) in a novel mouse model due to a nonsense mutation in the Mdm1 gene
1 The Jackson Laboratory, Bar Harbor, Maine 04609 2 W.K. Kellogg Eye Center, The University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105 3 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106 4 University of Wisconsin-Madison, Dept. Ophthalmology and Visual Sciences, Madison, WI 53705
* Corresponding author: Radha Ayyagari ( Email: rayyagari{at}ucsd.edu). Present Address: Jacobs Retina Center, Rm 206, Shiley Eye Center, University of California San Diego, 9415 Campus Point Drive, La Jolla, CA, 92093-0946., Phone: 858-534-0929, Fax: 858-534-8293
Received July 2, 2008; Revised August 25, 2008; Accepted September 9, 2008
We observed that a naturally occurring mouse strain developed age-related retinal degeneration (arrd1). These mice had normal fundi, ERGs and retinal histology at 6 months of age; vessel attenuation, RPE atrophy, and pigmentary abnormalities at 14 months, which progressed to complete loss of photoreceptors and extinguished ERG by 22 months. Genetic analysis revealed that the retinal degeneration in arrd1 segregates in an autosomal recessive manner and the disease gene localizes to mouse Chromosome 10. A positional candidate cloning approach detected a nonsense mutation in the mouse double minute-1 gene (Mdm1), which results in the truncation of the putative protein from 718 amino acids to 398. We have identified a novel transcript of the Mdm1 gene, which is the predominant transcript in the retina. The Mdm1 transcript is localized to the nuclear layers of neural retina. Expression of Mdm1 in the retina increases steadily from post-natal day 30 to one year, and a high level of Mdm1 is subsequently maintained. The Mdm1 transcript was found to be significantly depleted in the retina of arrd1 mice and the transcript was observed to degrade by nonsense-mediated decay. These results indicate that depletion of the Mdm1 transcript may underlie the mechanism leading to late-onset progressive retinal degeneration in arrd1 mice. Analysis of a cohort of patients with age-related macular degeneration (AMD) wherein the susceptibility locus maps to chromosome 12q, a region bearing the human ortholog to MDM1, did not reveal association between human MDM1 and AMD.
These authors contributed equally to this work Sequences submitted to the GenBank: GI: 1064299, and GI: 1064301