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W. Kedzierski, X. Liu, M. Klein, S. N. Jackson, I. Butovich, D. Birch, A. Woods, A. McMahon; Abnormal Retinal Morphology and Function in Homozygous Stargardt-3 Mice Which Completely Lack Polyunsaturated C28-C36 Fatty Acids in the Mature Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2939.
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Stargardt disease-3 (STGD3), a juvenile dominant macular dystrophy, is caused by mutations in elongase of very long chain fatty acid-4 (ELOVL4). Previously generated heterozygous Stgd3 mice, which carry a human pathogenic 5-bp deletion in the mouse Elovl4 gene, demonstrate an early, selective, ca. 50% reduction in retinal levels of C28-C36 acyl phosphatidylcholines (PCs). These lipids are significant components of photoreceptor outer segment membranes in wt mice. Homozygous Stgd3 mice die shortly after birth due to a skin permeability barrier defect which is caused by the absence of epidermal C28-C40 fatty acids. The goal of the current studies is to identify retinal pathological changes in mature, viable homozygous Stgd3 mice where skin barrier function is rescued by epidermal expression of a wt Elovl4 transgene.
One-month-old transgenic (Tg)/homozygous Stgd3 mice were used for studies of (a) retinal lipids using mass spectrometry, (b) retinal morphology using light and electron microscopy, and (c) visual functions using electroretinography.
Tg/homozygous Stgd3 mice completely lack C28-C36 acyl PCs in the retina. Despite this, the retinas demonstrate a fully developed and well organized multilayer structure. Although the photoreceptor outer segments retain normal structure, the organization of distal disks appears to be disrupted. The retinal pigmented epithelium shows more pronounced changes with a significantly increased number of melanosomes and altered morphology in pigmented granules. In the complete absence of C28-C36 acyl PCs, both rod and cone functions are reduced by at least 50% at the 1-month of age.
C28-C36 acyl PCs are not required for formation of the retinal multilayer structure. Their complete absence induces, however, pathological changes in photoreceptor outer segments and retinal pigmented epithelium, and impairs vision. Such changes are already seen in 1-month-old mice. These results strengthen our previously published hypothesis that metabolic- and/or diet-mediated deficiency of retinal polyunsaturated C28-C36 fatty acids may contribute to the etiology of human macular diseases.
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