Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.
Department of Cutting-Edge Medicine and Therapies, Biomolecular Strategies and Neuroscience, Section of Neuroscience-Applied Molecular Genetics and Predictive Medicine, Istituto Euro Mediterraneo di Scienza e Tecnologia (I.E.ME.S.T.), Palermo, Italy.
Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):843-857. doi: 10.1167/iovs.17-22962.
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.
Their effects on ELOVL4 expression were examined by Dual-Luciferase Reporter assay.
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.
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.
斯塔加特病（STGD）是最常见的遗传性青少年黄斑变性形式。它作为常染色体隐性遗传特征（STGD1）遗传，尽管 STGD3 和 STGD4 作为常染色体显性遗传模式遗传。STGD3 是由伸长非常长链脂肪酸样 4（ELOVL4）基因中的突变引起的，该基因编码非常长链脂肪酸延长酶。突变导致 Elovl4 截断，缺乏内质网中跨膜蛋白保留所必需的二赖氨酸基序。STGD 是由于非常长链多不饱和脂肪酸（VLC-PUFA）的合成改变引起的。我们的工作研究了 ELOVL4 基因启动子区域中的两个变体 c.-236 C>T（rs240307）和 c.-90 G>C（rs62407622）的作用，这些变体在一位 STGD 患者中以反式构型被鉴定出来。
通过双荧光素酶报告基因检测法检测它们对 ELOVL4 表达的影响。
与野生型启动子相比，rs62407622 和 rs240307 变体分别导致表达减少 14%和 18%。两种变体共存导致基因表达非常强烈的降低。
由于两种变体的组合，ELOVL4 启动子的活性受到高度抑制。ELOVL4 酶活性的降低可能导致 VLC-PUFA 缺乏，VLC-PUFA 是杆状细胞功能和寿命所必需的重要成分，这是 STGD 发病机制涉及的参数之一。
