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Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids

Agbaga, Martin-Paul, Brush, Richard S., Mandal, Md Nawajes A., Henry, Kimberly, Elliott, Michael H., Anderson, Robert E.
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.35 pp. 12843-12848
biosynthesis, brain, cardiomyocytes, cell death, epithelium, exons, genes, humans, juveniles, long chain polyunsaturated fatty acids, macular degeneration, mice, mutation, patients, phenotype, photoreceptors, polyunsaturated fatty acids, rats, retina, saturated fatty acids, spermatozoa, very long chain fatty acids, vision
Stargardt-like macular dystrophy (STGD3) is a dominantly inherited juvenile macular degeneration that eventually leads to loss of vision. Three independent mutations causing STGD3 have been identified in exon six of a gene named Elongation of very long chain fatty acids 4 (ELOVL4). The ELOVL4 protein was predicted to be involved in fatty acid elongation, although evidence for this and the specific step(s) it may catalyze have remained elusive. Here, using a gain-of-function approach, we provide direct and compelling evidence that ELOVL4 is required for the synthesis of C28 and C30 saturated fatty acids (VLC-FA) and of C28-C38 very long chain polyunsaturated fatty acids (VLC-PUFA), the latter being uniquely expressed in retina, sperm, and brain. Rat neonatal cardiomyocytes and a human retinal epithelium cell line (ARPE-19) were transduced with recombinant adenovirus type 5 carrying mouse Elovl4 and supplemented with 24:0, 20:5n3, or 22:5n3. The 24:0 was elongated to 28:0 and 30:0; 20:5n3 and 22:5n3 were elongated to a series of C28-C38 PUFA. Because retinal degeneration is the only known phenotype in STGD3 disease, we propose that reduced VLC-PUFA in the retinas of these patients may be the cause of photoreceptor cell death.