Stargardt-like macular dystrophy (STGD3, MIM 600110) is an autosomal dominant form of juvenile macular degeneration characterized by decreased visual acuity, macular atrophy, and extensive flecks. Using a positional cloning approach, we identified ELOVL4 as the causal disease gene responsible for Stargardt-like macular dystrophy (STGD3, MIM 600110). ELOVL4 encodes a protein with sequence and structural similarities to the ELO family of proteins. The ELO family of proteins is involved in the elongation of long chain fatty acids (LCFA), suggesting that ELOVL4 may have a similar function. The long term objectives of this proposal are to characterize the biochemical properties of ELOVL4 and to elucidate molecular mechanism leading to macular degeneration due to ELOVL4 mutations in humans. ELOVL4 proteins are strongly conserved throughout vertebrate species. The exact enzymatic function of ELOVL4 and the pathogenic mechanisms by which mutant ELOVL4 causes macular degeneration are unclear. Our central hypothesis is that ELOVL4 is a key enzyme in a biosynthetic pathway that produces very long chain fatty acids which play an essential role in retina development and function. Guided by this hypothesis, we propose to define ELOVL4 function through a comprehensive analysis of fatty acid composition in vitro and in vivo, and to examine retinal development and pathogenesis in ELOVL4 transgenic, knockin, and knockout mice. To further understand ELOVL4 functions and pathogenic mechanisms giving rise to macular degeneration we will address the following specific aims:
Specific Aim 1 : To determine the enzymatic function of ELOVL4 Specific Aim 2: To determine the role of ELOVL4 in retinal development and pathology Specific Aim 3: To examine RPE dysfunction in ELOVL4 mutant transgenic mice Stargardt macular dystrophy is the most common juvenile macular degeneration and shares many important clinical and histopathological similarities with AMD including an abnormal accumulation of lipofuscin in the RPE, atrophy of the RPE and overlying photoreceptor cells, and loss of central vision. ELOVL4 is the first gene involved in the biosynthesis of long chain fatty acids implicated in any form of macular degeneration. The proposed study should lead to new insights into lipid metabolism in photoreceptor cells and reveal a novel pathway in the pathogenesis of macular degeneration. Our study should also provide insights into the formation of lipofuscin and provide new avenues for treatments for Stargardt macular dystrophy and AMD.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of California San Diego
Schools of Medicine
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Skowronska-Krawczyk, Dorota; Zhao, Ling; Zhu, Jie et al. (2015) P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma. Mol Cell 59:931-40
Loomis, Stephanie J; Kang, Jae H; Weinreb, Robert N et al. (2014) Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss. Ophthalmology 121:508-16
Du, Hongjun; Sun, Xufang; Guma, Monica et al. (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci U S A 110:2377-82
Ouyang, Hong; Zhuo, Yehong; Zhang, Kang (2013) WNT signaling in stem cell differentiation and tumor formation. J Clin Invest 123:1422-4
Hannum, Gregory; Guinney, Justin; Zhao, Ling et al. (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359-367
Luo, Jing; Zhao, Ling; Chen, Aaron Yun et al. (2013) TCF7L2 variation and proliferative diabetic retinopathy. Diabetes 62:2613-7
Wiggs, Janey L; Hauser, Michael A; Abdrabou, Wael et al. (2013) The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables. J Glaucoma 22:517-25
Harkewicz, Richard; Du, Hongjun; Tong, Zongzhong et al. (2012) Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem 287:11469-80
Du, H; Grob, S R; Zhao, L et al. (2012) Myotonia congenita with strabismus in a large family with a mutation in the SCN4A gene. Eye (Lond) 26:1039-43
Carbone, Mary Anna; Chen, Yuhong; Hughes, Guy A et al. (2011) Genes of the unfolded protein response pathway harbor risk alleles for primary open angle glaucoma. PLoS One 6:e20649

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