RGD Reference Report - Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene. - Rat Genome Database

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Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene.

Authors: 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  Ayyagari, R 
Citation: Chang B, etal., Hum Mol Genet. 2008 Dec 15;17(24):3929-41. doi: 10.1093/hmg/ddn295. Epub 2008 Sep 18.
RGD ID: 10412062
Pubmed: PMID:18805803   (View Abstract at PubMed)
PMCID: PMC2638579   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddn295   (Journal Full-text)

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.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
MDM1HumanKuhnt-Junius degeneration  ISOMdm1 (Mus musculus)DNA more ...RGD 
Mdm1RatKuhnt-Junius degeneration  ISOMdm1 (Mus musculus)DNA more ...RGD 
Mdm1MouseKuhnt-Junius degeneration  IAGP DNA more ...RGD 


Genes (Rattus norvegicus)
Mdm1  (Mdm1 nuclear protein)

Genes (Mus musculus)
Mdm1  (MDM1 nuclear protein)

Genes (Homo sapiens)
MDM1  (Mdm1 nuclear protein)

Gene MDM2 MDM2 proto-oncogene Homo sapiens
Gene Mdm2 transformed mouse 3T3 cell double minute 2 Mus musculus
Gene Mdm2 MDM2 proto-oncogene Rattus norvegicus