Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids.
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.
Agbaga
Martin-Paul
MP
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
Brush
Richard S
RS
Mandal
Md Nawajes A
MN
Henry
Kimberly
K
Elliott
Michael H
MH
Anderson
Robert E
RE
D000818:Animals; D002460:Cell Line; D005136:Eye Proteins / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis*; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D019076:Transgenes
C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D005231:Fatty Acids, Unsaturated; D008565:Membrane Proteins