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Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome.
Journal of Endocrinological Investigation ( IF 5.4 ) Pub Date : 2020-03-26 , DOI: 10.1007/s40618-020-01228-2
K Batjargal 1, 2 , T Tajima 1 , E F Jimbo 1 , T Yamagata 1
Affiliation  

Purpose

Wolfram syndrome (WS) is a rare disorder caused by mutations in WFS1 that is characterized by diabetes mellitus, optic atrophy, sensorineural deafness, diabetes insipidus, and neurodegeneration. This disease is usually inherited as an autosomal recessive trait, but an autosomal dominant form has been reported. WFS1 encodes a transmembrane protein, which is a maintenance component of endoplasmic homeostasis. These dominant mutations were thought to increase endoplasmic reticulum (ER) stress. Recent studies suggest that 4-phenylbutyrate (PBA) and valproate (VPA) reduce ER stress. The objective of this study was to analyze the effect of PBA and VPA on dominant WFS1 mutants in vitro.

Methods

We determined whether dominant WFS1 mutants (p.His313Tyr, p.Trp314Arg, p.Asp325_Ile328del, p.Glu809Lys, and p.Glu864Lys) have the dominant negative effect using a luciferase assay of ER stress response element marker as ER stress. Moreover, the rescue of cell apoptosis induced by dominant WFS1 mutants following treatment with PBA or VPA was determined by quantitative real-time PCR of C/EBP homologous protein (CHOP) mRNA expression.

Results

These mutants showed the dominant negative effect on the wild-type WFS1. In addition, the levels of ER stress and CHOP mRNA were significantly elevated by all dominant WFS1 mutants. After treatment with PBA or VPA, ER stress and cell apoptosis were reduced in each mutant.

Conclusions

PBA and VPA could reduce the ER stress and cell apoptosis caused by dominant WFS1 mutants.



中文翻译:

4-苯基丁酸酯和丙戊酸酯对Wolfram综合征WFS1基因显性突变的影响。

目的

Wolfram综合征(WS)是由WFS1突变引起的罕见疾病,其特征是糖尿病,视神经萎缩,感觉神经性耳聋,尿崩症和神经变性。该疾病通常被遗传为常染色体隐性遗传,但是据报道常染色体显性遗传。WFS1编码跨膜蛋白,它是内质稳态的维持成分。这些显性突变被认为会增加内质网(ER)压力。最近的研究表明,4-苯基丁酸酯(PBA)和丙戊酸酯(VPA)可以降低内质网应激。本研究的目的是分析体外PBA和VPA对显性WFS1突变体的影响

方法

我们使用萤光素酶测定法将ER应激反应元件标记作为ER应激,确定了显性WFS1突变体(p.His313​​Tyr,p.Trp314Arg,p.Asp325_Ile328del,p.Glu809Lys和p.Glu864Lys)是否具有显性负效应。此外,通过定量实时PCR检测C / EBP同源蛋白(CHOP)mRNA表达,确定了在用PBA或VPA处理后,由显性WFS1突变体诱导的细胞凋亡的挽救。

结果

这些突变体显示出对野生型WFS1的显性负作用。此外,所有显性WFS1突变体均显着提高了ER应激和CHOP mRNA的水平。用PBA或VPA处理后,每个突变体的ER压力和细胞凋亡均降低。

结论

PBA和VPA可以减少由显性WFS1突变体引起的内质网应激和细胞凋亡。

更新日期:2020-03-26
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