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

Martin Paul Agbaga, Richard S. Brush, Nawajes Mandal, Kimberly Henry, Michael H. Elliott, Robert E. Anderson

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12843-12848
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number35
DOIs
StatePublished - Sep 2 2008
Externally publishedYes

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Macular Degeneration
Fatty Acids
Unsaturated Fatty Acids
Retina
Photoreceptor Cells
Retinal Degeneration
Proteins
Cardiac Myocytes
Adenoviridae
Spermatozoa
Exons
Cell Death
Epithelium
Phenotype
Cell Line
Mutation
Brain
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. / Agbaga, Martin Paul; Brush, Richard S.; Mandal, Nawajes; Henry, Kimberly; Elliott, Michael H.; Anderson, Robert E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 35, 02.09.2008, p. 12843-12848.

Research output: Contribution to journalArticle

Agbaga, Martin Paul ; Brush, Richard S. ; Mandal, Nawajes ; Henry, Kimberly ; Elliott, Michael H. ; Anderson, Robert E. / Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 35. pp. 12843-12848.
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