ELOVL4 and Retinal Disease

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DESCRIPTION (provided by applicant): The long-term objectives of this application are to characterize the biochemical properties of ELOVL4, the protein product of the ELOVL4 gene, and to elucidate the underlying molecular mechanism responsible for macular degeneration. Using a positional cloning approach, we identified a disease gene called ELO VL4, which is responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3) and autosomal dominant macular dystrophy (adMD). STGD3 and adMD are two related forms of inherited macular degeneration characterized by decreased visual acuity, macular atrophy, and fundus flecks. We identified a single five base-pair deletion in the coding region of ELOVL4 in all affected members of four independent STGD3 families and one adMD family. The deletion generates a frame-shift mutation and results in loss of 51 amino acids at the C-terminus, including a putative di-lysine ER targeting signal. ELOVL4 demonstrated cone and rod photoreceptor-specific expression in the eye and encoded a putative transmembrane protein with similarities to the ELO family of proteins involved in elongation of very long-chain fatty acids. Three specific aims are designed to test the underlying hypothesis: that ELOVL4 is crucial for the biosynthesis of long-chain polyunsaturated fatty acids in the photoreceptor cells and that the disease phenotype of STGD3 and adMD is a result of a deletion mutation of ELOVL4. The specific aims are (1) Localization of normal and mutant forms of ELOVL4; (2) Characterization of biochemical functions of ELOVL4; (3) Characterization of ELOVL4 function in vivo using transgenic and knock-out mice. Stargardt's 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 photoreceptor 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 may also provide insights into the formation of lipofuscin.