ELOVL4 and Retinal Disease

描述(由申请人提供)：这项计划的长期目标 应用于表征ELOVL4的生化性质， ELOVL4基因的蛋白产物，并阐明其潜在的分子 黄斑变性的机制。使用位置克隆 方法，我们确定了一种名为ELO VL4的疾病基因，它负责 一种常染色体显性的Stargardt样黄斑营养不良(STGD3)和 常染色体显性遗传性黄斑营养不良(ADMD)。STGD3和ADMD是两个相关的疾病 以视力下降为特征的遗传性黄斑变性 视力、黄斑萎缩和眼底斑点。我们只确认了五个人 所有受影响的成员中ELOVL4编码区的碱基对缺失 四个独立的STGD3家族和一个ADMD家族。删除操作将生成一个 移码突变，并导致C末端51个氨基酸的丢失， 包括假定的双赖氨酸ER靶向信号。ELOVL4演示锥体 和杆状感光器在眼睛中的特异表达，并编码了一个假定的 与涉及的ELO蛋白家族相似的跨膜蛋白 在超长链脂肪酸的延伸中。 设计了三个具体的目标来检验潜在的假设：ELOVL4 是长链多不饱和脂肪酸生物合成的关键 STGD3和ADMD的疾病表型是一种 ELOVL4基因缺失突变的结果。 具体目标是(1)ELOVL4的正常和突变形式的定位； (2)ELOVL4的生化功能鉴定；(3)鉴定 利用转基因和基因敲除小鼠研究ELOVL4在体内的功能。 Stargardt黄斑营养不良是最常见的青少年黄斑变性 并与AMD有许多重要的临床和组织病理学相似之处 包括RPE中脂褐素的异常积聚，RPE的萎缩 和覆盖的光感受器细胞，以及中央视力丧失。ELOVL4是 第一个参与长链脂肪酸生物合成的基因 任何形式的光感受器退化。拟议的研究应导致新的 对感光细胞脂代谢的洞察并揭示了一种新的 黄斑变性的发病机制。我们的研究也可能提供 对脂褐素形成的洞察。

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.