Abstract
Stargardt-like macular dystrophy-3 (STGD3) is a juvenile-onset disease caused by mutations in ELOVL4 (elongation of very long fatty acids-4). This gene product catalyzes the elongation of long chain saturated and polyunsaturated fatty acids (LC-FAs and LC-PUFAs) into very long chain FAs and PUFAs (VLC-FAs and VLC-PUFAs). These mutations cause a frame shift in the ELOVL4 transcript, introducing a premature stop codon that results in the translation of a truncated protein that has lost a C-terminus endoplasmic reticulum (ER) retention/retrieval signal. The truncated protein is not targeted to the ER, the site of very long-chain PUFA (VLC-PUFA; 28–40 carbons) synthesis. Expression of the ELOVL4 gene is limited mainly to the brain, testis, skin, and photoreceptor cells of the retina. While the skin and brain contain very long chain saturated fatty acids (VLC-FAs), the other tissues expressing ELOVL4 contain VLC-PUFAs, with sperm and the retina having the highest levels. This review focuses on the current information available concerning the role of VLC-PUFAs in the retina.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Agbaga M-P, Brush RS, Mandal MNA et al (2008) Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci U S A 105:12843–12848
Anne McMahon IAB, Nathan L Mata, Martin Klein, Robert Ritter III, James Richardson, David G Birch, Albert O Edwards, Wojciech Kedzierski (2007) Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4. Mol Vis 13:258–272
Aveldano MI (1988) Phospholipid species containing long and very long polyenoic fatty acids remain with rhodopsin after hexane extraction of photoreceptor membranes. Biochemistry 27:1229–1239
Aveldano MI (1992) Long and very long polyunsaturated fatty acids of retina and spermatozoa: the whole complement of polyenoic fatty acid series. Adv Exp Med Biol 318:231–242
Aveldaño MI, Sprecher H (1987) Very long chain (C24 to C36) polyenoic fatty acids of the n-3 and n-6 series in dipolyunsaturated phosphatidylcholines from bovine retina. J Biol Chem 262:1180–1186
Barabas P, Liu A, Xing W et al (2013) Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration. Proc Natl Acad Sci U S A 110:5181–5186
Bennett LD, Hopiavuori BR, Brush RS et al (2014a) Examination of VLC-PUFA-deficient photoreceptor terminals. Invest Ophthalmol Vis Sci 55(7):4063–72
Bennett LD, Brush RS, Chan MD et al (2014b) Effect of reduced retinal VLC-PUFA on rod and cone photoreceptors. Invest Ophthalmol Vis Sci 55(5):3150–3157
Bernstein PS, Tammur J, Singh N et al (2001) Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci 42:3331–3336
Edwards AO, Miedziak A, Vrabec T et al (1999) Autosomal dominant Stargardt-like macular dystrophy: I. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14. Am J Ophthalmol 127:426–435
Edwards AO, Donoso LA, Ritter R 3rd (2001) A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family. Invest Ophthalmol Vis Sci 42:2652–2663
Harkewicz R, Du H, Tong Z et al (2012) Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem 287:11469–11480
Le YZ, Zheng L, Zheng W et al (2006) Mouse opsin promoter-directed Cre recombinase expression in transgenic mice. Mol Vis 12:389–398
Li W, Chen Y, Cameron DJ et al (2007) Elovl4 haploinsufficiency does not induce early onset retinal degeneration in mice. Vis Res 47:714–722
Marchette LD, Sherry DM, Brush RS et al (2014) Very long chain polyunsaturated fatty acids and rod cell structure and function. Adv Exp Med Biol 801:637–645
McMahon A, Butovich IA, Kedzierski W (2011) Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice. J Lipid Res 52:1128–1138
Raz-Prag D, Ayyagari R, Fariss RN et al (2006) Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. Invest Ophthalmol Vis Sci 47:3603–3611
Rotstein NP, Aveldano MI (1988) Synthesis of very long chain (up to 36 carbon) tetra, penta and hexaenoic fatty acids in retina. Biochem J 249:191–200
Rowan S, Cepko CL (2004) Genetic analysis of the homeodomain transcription factor Chx10 in the retina using a novel multifunctional BAC transgenic mouse reporter. Dev Biol 271:388–402
Vasireddy V, Jablonski MM, Mandal MNA et al (2006) Elovl4 5-bp–deletion knock-in mice develop progressive photoreceptor degeneration. Invest Ophthalmol Vis Sci 47:4558–4568
Zhang K, Kniazeva M, Han M et al (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27:89–93
Acknowledgments
This work was supported by NIH Grants EY00871, EY04149, EY12190, EY21725 and RR17703; Foundation Fighting Blindness, and Research to Prevent Blindness.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this paper
Cite this paper
Bennett, L., Anderson, R. (2016). Current Progress in Deciphering Importance of VLC-PUFA in the Retina. In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_20
Download citation
DOI: https://doi.org/10.1007/978-3-319-17121-0_20
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-17120-3
Online ISBN: 978-3-319-17121-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)