Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis?
Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis?
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DOI：
10.1167/iovs.17-22962
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发表时间：
2018-02-01
影响因子：
4.4
通讯作者：
Sidoti，Antonina
中科院分区：
文献类型：
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作者：
Donato，Luigi;Scimone，Concetta;Sidoti，Antonina
目的：Stargardt病（STGD）是遗传性青少年黄斑变性最常见的形式。它是作为常染色体隐性遗传性状（STGD 1）遗传的，尽管STGD 3和STGD 4是作为常染色体显性遗传模式遗传的。STGD 3是由编码极长链脂肪酸延长酶的极长链脂肪酸样4（VL 4）基因的延长突变引起的。突变导致截短的Elovl 4，缺乏跨膜蛋白在内质网中保留所必需的二赖氨酸基序。STGD的发生是由于极长链多不饱和脂肪酸（VLC-PUFA）的合成改变。我们的工作研究了ELOVL 4基因启动子区中两个变体的作用，c.- 236 C> T（rs 240307）和c.-方法：采用双荧光素酶报告基因（Dual-Luciferase Reporter）分析方法，检测rs62407622和rs 240307突变体对STGD患者CD 34 + VL 4表达的影响，结果：rs62407622和rs 240307突变体分别使STGD患者CD 34 + VL 4表达降低14%和18%。一个非常强大的基因表达下降是由这两种变体的共存所造成的。结论：由于两种变体的组合，注册了一个高度降低活性的TLRVL 4启动子。VL 4酶活性的降低可能导致VLC-PUFA的缺乏，VLC-PUFA是杆功能和寿命的必需组分，其是STGD的发病机制中涉及的参数之一。
Purpose: Stargardt disease (STGD) is the most common form of inherited juvenile macular degeneration. It is inherited as autosomal recessive trait (STGD1), although STGD3 and STGD4 are inherited as autosomal dominant inheritance pattern. STGD3 is caused by mutations in the elongation of very long-chain fatty acids-like 4 (ELOVL4) gene encoding for a very long-chain fatty acid elongase. Mutations lead to a truncated Elovl4, lacking of a dilysine motif necessary for retention of transmembrane proteins in the endoplasmic reticulum. STGD occurs due to altered synthesis of very long-chain polyunsaturated fatty acids (VLC-PUFA). Our work investigates the role of two variants in the ELOVL4 gene promoter region, c.-236 C> T (rs240307) and c.-90 G> C (rs62407622), identified in a patient with STGD in transconfiguration.Methods: Their effects on ELOVL4 expression were examined by Dual-Luciferase Reporter assay.Results: rs62407622 and rs240307 variants caused 14% and 18% of expression reduction, respectively, compared with wild-type promoter. A very strong decreased gene expression was caused by coexistence of both variants.Conclusions: A highly reduced activity of the ELOVL4 promoter was registered due to combination of two variants. Decrease of ELOVL4 enzymatic activity could lead to a deficiency of VLC-PUFA, essential components for rods function and longevity, which are among the parameters involved in the etiopathogenesis of STGD.