Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene
Open accessAbstract
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.
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The location of MDM1 on chromosome 12q has previously been reported to be an AMD susceptibility locus.
“though this location has previously been reported to be an AMD susceptibility locus”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Chang et al., 2008
Analysis of a cohort of AMD patients with the human ortholog of MDM1 on chromosome 12q did not reveal an association between MDM1 and AMD.
“Analysis of a cohort of AMD patients with the human ortholog of MDM1 on chromosome 12q did not reveal an association between MDM1 and AMD”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Chang et al., 2008
A murine model of naturally occurring, severe, late-onset, age-related retinal degeneration (arrd2) has a nonsense mutation in the Mdm1 gene on mouse chromosome 10 that is inherited in an autosomal recessive manner.
“A murine model of a naturally occurring, severe, late-onset, age-related, retinal degeneration (arrd2) has been identified to have a nonsense mutation in the Mdm1 gene on mouse chromosome 10 that is inherited in an autosomal recessive manner”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Chang et al., 2008
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Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Ramkumar, H. L., Zhang, J., & Chan, C.-C. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.02.002 · Cited by 163 · see citing works
- Authors
- Chang, B., Mandal, M. N. A., Chavali, V. R. M., Hawes, N. L., Khan, N. W., Hurd, R. E., Smith, R. S., Davisson, M. L., Kopplin, L., Klein, B. E. K., Klein, R., Iyengar, S. K., Heckenlively, J. R., & Ayyagari, R.
- Affiliations
- Jackson Laboratory (US)
- University of Michigan (US)
- Case Western Reserve University (US)
- Corresponding author
- Ayyagari, Radha
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-18
- Volume
- 17
- Issue
- 24
- Pages
- 3929-3941
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2638579
- OpenAlex
- W2142098760
- Cited by
- 30
- References
- 39
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 5 · 2012: 2
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health (5r03ey013438-02)
- National Eye Institute (U10 EY06594, T32-EY07157, EY 015810, EY 13198, R01EY007758, U10EY006594, EY015286, EY10605, R01EY015286, EY07758, R01EY010605, EY 13438, R01EY013198, R01EY015810, T32EY007157)
- National Cancer Institute (#CA34196, P-30 CA43703, P30CA043703, P30CA034196)
- National Institute of General Medical Sciences (T32GM007250)
- National Center for Research Resources (RR-03655, P41RR003655, P40RR001183, RR 01183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related retinal degeneration, nonsense mutation, photoreceptor degeneration, retinal pigment epithelium atrophy, nonsense-mediated mRNA decay, retinal gene expression, autosomal recessive inheritance, age-related macular degeneration, mouse chromosome 10
- MeSH terms
- Aging, Animals, Electroretinography, Female, Humans, Male, Mice, Inbred C57BL, Retina, Retinal Degeneration, Gene Deletion, Sequence Analysis, DNA, Codon, Nonsense, Mice, Proto-Oncogene Proteins c-mdm2
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