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首页> 外文期刊>Genomics >Atrophic macular degeneration mutations in ELOVL4 result in the intracellular misrouting of the protein.
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Atrophic macular degeneration mutations in ELOVL4 result in the intracellular misrouting of the protein.

机译：ELOVL4的萎缩性黄斑变性突变导致蛋白质的细胞内错误转移。

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Elongation of very long chain fatty acids 4 (ELOVL4) is a novel member of the ELO family of genes that are involved in fatty acid metabolism. ELOVL4 encodes a putative transmembrane protein of 314 amino acids that carries a possible endoplasmic reticulum (ER) retention/retrieval signal (KXKXX) at the C-terminus. Two distinct mutations, a 5-bp deletion and a complex mutation from the same region in exon 6 of this gene, have been reported so far and are associated with autosomal dominant atrophic macular degeneration (adMD/STGD3). Both of these deletions could result in C-terminal truncation and loss of the ER retention signal in the mutant protein. We expressed the wild-type and mutant proteins in COS-7 and CHO cells to study the intracellular distribution of ELOVL4 and to identify possible implications of the above mutations in its localization. Immunofluorescence analysis of these proteins along with organelle marker antibodies revealed predominant ER localization for wild-type ELOVL4. Targeted deletion of the dilysine motif at the C-terminus of the protein resulted in the loss of ER localization. Immunoelectron microscopy and immunofluorescence analysis revealed a similar ER localization pattern for the protein in human photoreceptors. These data indicate that ELOVL4 is an ER-resident protein, which supports its suggested function in fatty acid elongation. We also demonstrate that the localization of both mutant proteins was dramatically changed from an ER to a Golgi distribution. Our observations suggest that the consequences of defective protein trafficking could underlie the molecular mechanism associated with degeneration of the macula in the patients with adMD/STGD3.
机译：超长链脂肪酸4（ELOVL4）的延伸是涉及脂肪酸代谢的ELO基因家族的新成员。 ELOVL4编码一个314个氨基酸的推定跨膜蛋白，该蛋白在C端带有可能的内质网（ER）保留/检索信号（KXKXX）。迄今为止，已经报道了该基因第6外显子同一区域的两个不同突变，即5bp缺失和一个复杂突变，与常染色体显性萎缩性黄斑变性（adMD / STGD3）有关。这两个缺失都可能导致C端截短和突变蛋白中ER保留信号的丢失。我们在COS-7和CHO细胞中表达了野生型和突变蛋白，以研究ELOVL4的细胞内分布并确定上述突变在其定位中的可能含义。这些蛋白质与细胞器标记抗体的免疫荧光分析表明，野生型ELOVL4的主要ER定位。在蛋白质的C端靶向删除赖氨酸基序会导致ER定位丢失。免疫电子显微镜和免疫荧光分析揭示了人类感光细胞中蛋白质的类似ER定位模式。这些数据表明ELOVL4是一种ER驻留蛋白，支持其在脂肪酸延伸中的建议功能。我们还证明，两个突变蛋白的定位从ER到高尔基体分布都发生了巨大变化。我们的观察结果表明，有缺陷的蛋白质运输的后果可能是adMD / STGD3患者黄斑变性相关的分子机制的基础。

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