Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
Open accessAbstract
Significance: Accumulation of lipofuscin in the retinal pigment epithelium precedes retinal degenerations and dystrophies responsible for blindness-causing retinal diseases. The mechanism behind lipofuscin formation in the retina or in any tissue is poorly understood. Here we show in mice that the dimerization of vitamin A is responsible for triggering the formation of more than 50% of ocular lipofuscin. Replacing three hydrogen atoms on vitamin A with deuterium inhibits vitamin A dimerization, resulting in reduced lipofuscin and transcriptional normalization of genes associated with inflammation without compromising retinal function. Thus, vitamin A deuterated at the carbon 20 position provides a clinically amiable tool to prevent vitamin A dimerization in humans to assess whether impeding such dimerization might prevent retinal degenerations such as Stargardt disease and age-related macular degeneration.
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Provision of vitamin A deuterated at the carbon 20 position impedes the dimerization rate of vitamin A.
“Alternative approach that does not compromise retinal function has been the provision of vitamin A deuterated at the carbon 20 position, which impedes the dimerization rate of vitamin A [105,106,107].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [105]
Cites
Allikmets, R., Singh, N., Sun, H., Shroyer, N. F., Hutchinson, A., Chidambaram, A., Gerrard, B., Baird, L., Stauffer, D., Peiffer, A., et al. (1997) · Nature Genetics · doi:10.1038/ng0397-236 · Cited by 1,435 · cited 1× · see citing works
“The condition results from mutations in the ATPbinding cassette, subfamily A, member 4 (ABCA4) gene (1), which encodes a transmembrane flippase localized in photoreceptor outer segments.”
BackgroundBrunk, U. T., & Terman, A. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00959-0 · Cited by 919 · see citing works
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., & Travis, G. H. (1999) · Cell · doi:10.1016/s0092-8674(00)80602-9 · Cited by 881 · cited 2× · see citing works
“Similar to humans, Abca4 knockout (Abca4) mice exhibit increased rates of vitamin A dimerization and lipofuscin accumulation compared with their wild-type counterparts (17, 18).”
BackgroundABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer
Quazi, F., Lenevich, S., & Molday, R. S. (2012) · Nature Communications · doi:10.1038/ncomms1927 · Cited by 276 · see citing works
Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X., Sieving, P. A., & Travis, G. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0737855100 · Cited by 227 · see citing works
Radu, R. A., Yuan, Q., Hu, J., Peng, J. H., Lloyd, M., Nusinowitz, S., Bok, D., & Travis, G. H. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-1470 · Cited by 188 · see citing works
Simple and Complex ABCR: Genetic Predisposition to Retinal Disease
Allikmets, R. (2000) · The American Journal of Human Genetics · doi:10.1086/303100 · Cited by 128 · cited 4× · see citing works
“For example, complement proteins such as C3 (30), CFB (31), and CFP (32), all dysregulated here in the mutant animals, are found in histologic specimens of AMD eyes, whereas variants of several genes encoding complement proteins are associated with a modulated risk to develop AMD.”
BackgroundInfluentialKaufman, Y., Ma, L., & Washington, I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178640 · Cited by 78 · cited 2× · see citing works
“Administration of C20-D3-vitamin A has been shown to inhibit vitamin A dimerization (19).”
BackgroundSelf-citationCukras, C., Gaasterland, T., Lee, P., Gudiseva, H. V., Chavali, V. R. M., Pullakhandam, R., Maranhao, B., Edsall, L., Soares, S., Reddy, G. B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050205 · Cited by 65 · see citing works
Total rod ERG suppression with high dose compassionate Fenretinide usage
Marmor, M. F., Jain, A., & Moshfeghi, D. (2008) · Documenta Ophthalmologica · doi:10.1007/s10633-008-9132-y · Cited by 18 · see citing works
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- Authors
- Charbel Issa, P., Barnard, A. R., Herrmann, P., Washington, I., & MacLaren, R. E.
- Affiliations
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford and Oxford Eye Hospital, OX3 9DU, Oxford, United Kingdom;
- University of Oxford (GB)
- University of Bonn (DE)
- Columbia University Irving Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-23
- Volume
- 112
- Issue
- 27
- Pages
- 8415-8420
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4500285
- OpenAlex
- W1595068158
- Cited by
- 124
- References
- 10
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 2 · 2023: 7 · 2022: 14 · 2021: 12 · 2020: 19 · 2019: 8 · 2018: 14 · 2017: 15 · 2016: 7 · 2015: 3
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- The European Commission FP7, Marie Curie Intra-European Fellowship (237238)
- Wellcome Trust (086868/Z/08/Z)
- Office of Extramural Research, National Institutes of Health (1R01EY021207, 5P30EY019007)
- Medical Research Council (MR/K007629/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- Stargardt disease, ABCA4, A2E, lipofuscin accumulation, retinal pigment epithelium, retinal inflammation, retinopathy, knockout mice, blindness prevention
- MeSH terms
- Stargardt Disease, Animals, Deuterium, Electroretinography, Lipofuscin, Macular Degeneration, Phenotype, Retina, Vitamin A, Vitamins, Treatment Outcome, Mice, Knockout, ATP-Binding Cassette Transporters, Dimerization, Microscopy, Electron, Transmission, Retinal Pigment Epithelium, Mice, 129 Strain
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