ELOVL4 and Retinal Disease

描述（由申请人提供）：本项目的长期目标 应用的目的是表征HPVL 4的生化性质， 蛋白质产物，并阐明潜在的分子生物学机制。 导致黄斑变性的机制。使用定位克隆 通过这种方法，我们确定了一种名为ELO VL 4的疾病基因， Stargardt样黄斑营养不良（STGD 3）的常染色体显性形式，和 常染色体显性黄斑营养不良（adMD）。STGD 3和adMD是两个相关的 以视力下降为特征的遗传性黄斑变性 视力、黄斑萎缩和眼底软化。我们确认了一个五人组 在所有受影响的成员中， 四个独立的STGD 3家族和一个adMD家族。删除会生成一个 移码突变并导致C-末端51个氨基酸的缺失， 包括推定的二赖氨酸ER靶向信号。VL 4演示锥 和视杆细胞光感受器特异性表达，并编码一个假定的 与涉及的ELO蛋白家族相似的跨膜蛋白 在延长极长链脂肪酸方面。 设计了三个具体目标来检验基本假设： 对于长链多不饱和脂肪酸的生物合成至关重要， 光感受器细胞，STGD 3和adMD的疾病表型是一种 这是一个由HPVL 4的缺失突变引起的结果。 具体目标是（1）定位正常和突变形式的BCLVL 4; (2)BCLVL 4的生物化学功能的表征;（3）表征 使用转基因和基因敲除小鼠， Stargardt黄斑营养不良是最常见的青少年黄斑变性 与AMD有许多重要的临床和组织病理学相似之处 包括RPE中脂褐素的异常积累、RPE的萎缩 以及感光细胞的覆盖，以及中心视觉的丧失。VL 4是一个 参与长链脂肪酸生物合成的第一个基因， 任何形式的光感受器退化。拟议的研究将导致新的 深入了解感光细胞中的脂质代谢，并揭示了一种新的 黄斑变性的发病机制。我们的研究还可以提供 对脂褐素形成的深入了解。

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.