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A. McMahon, I. A. Butovich, S. N. Jackson, X. Liu, M. Klein, D. G. Birch, A. Woods, W. Kedzierski; Generation of Homozygous Stargardt-3 Mice Which Completely Lack Retinal Polyunsaturated C28-C36 Fatty Acids. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3661.
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Stargardt disease-3 (STGD3), a juvenile dominant macular degeneration, is caused by mutations in elongase of very long chain fatty acid-4 (ELOVL4), the only mammalian enzyme known to synthesize C28-C40 fatty acids. Heterozygous Stgd3 mice, a genetic model of the human pathology, show very early, selective reduction by a half of C28-C36 acyl phosphatidylcholine (PC) levels in the retina. This pathology is later followed by increased lipofuscin accumulation and reduced vision. To fully comprehend the retinal function of these PCs, homozygous Stgd3 mice which completely lack these retinal lipids are needed. Unfortunately, such mutant mice die shortly after birth due to a skin permeability barrier defect caused by absence of epidermal C28-C40 fatty acid synthesis.
To restore the synthesis of C28-C40 fatty acids in the epidermis and a functional skin barrier, we generated transgenic (Tg)/ homozygous Stgd3 mice which express a wt Elovl4 transgene under control of an epidermis-specific involucrin promoter.
The Tg/homozygous Stgd3 mice, we generated, express Tg mRNA in the skin but not in the eyecups. In these mice the transgene expression (a) reinstates synthesis of C28-C40 fatty acids to the epidermis, (b) restores skin barrier function and (c) rescues the neonatal lethality of homozygous Stgd3 pups. The mice remain viable for at least one month, a time at which they have mature retinas. Retinal lipid analysis in these mice verifies the predicted complete absence of C28-C36 acyl PCs.
Our Tg/homozygous Stgd3 mice will be utilized in future studies to (a) identify retinal functions for polyunsaturated C28-C36 fatty acids and (b) test treatments for the retinal C28-C36 fatty acid deficiency, an early selective change seen in our mouse model of the human pathology.
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