PMID:18805803

Citation	Chang, B, Mandal, MN, Chavali, VR, Hawes, NL, Khan, NW, Hurd, RE, Smith, RS, Davisson, ML, Kopplin, L, Klein, BE, Klein, R, Iyengar, SK, Heckenlively, JR and Ayyagari, R (2008) Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene. Hum. Mol. Genet. 17:3929-41
Abstract	We observed that a naturally occurring mouse strain developed age-related retinal degeneration (arrd2). These mice had normal fundi, electroretinograms (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 arrd2 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 1 year, and a high level of Mdm1 are subsequently maintained. The Mdm1 transcript was found to be significantly depleted in the retina of arrd2 mice and the transcript was observed to degrade by nonsense-mediated decay. These results indicate that the depletion of the Mdm1 transcript may underlie the mechanism leading to late-onset progressive retinal degeneration in arrd2 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.
Links	PubMed PMC2638579 Online version:10.1093/hmg/ddn295
Keywords	Aging/genetics; Animals; Codon, Nonsense/genetics; Electroretinography; Female; Gene Deletion; Humans; Male; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-mdm2/genetics; Retina/metabolism; Retina/pathology; Retinal Degeneration/genetics; Retinal Degeneration/pathology; Sequence Analysis, DNA
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:MDM1		GO:0106083: nuclear membrane protein complex	ECO:0000177: genomic context evidence		C		Figure 3. Mdm1 mutation in arrd2. (A) Linkage cross-data: 73 inter-cross progeny from the (arrd2/C57BL/6J)F1 (arrd2/C57BL/6J)F1 was phenotyped for histological phenotype and genotyped for the indicated microsatellite markers. Black boxes represent haplotypes for arrd2-derived alleles and white boxes represent haplotypes for C57BL/6J-derived alleles.	complete

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