4-苯丁酸和丙戊酸对 WFS1 基因显性突变的影响在 WFS 综合征。

Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome.

机构信息

Department of Pediatrics, Graduate School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.

Department of Pediatrics, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.

出版信息

J Endocrinol Invest. 2020 Sep;43(9):1317-1325. doi: 10.1007/s40618-020-01228-2. Epub 2020 Mar 26.

DOI:10.1007/s40618-020-01228-2

PMID:32219690

Abstract

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.

摘要

目的

Wolfram 综合征（WS）是一种由 WFS1 基因突变引起的罕见疾病，其特征为糖尿病、视神经萎缩、感音神经性聋、尿崩症和神经退行性变。这种疾病通常以常染色体隐性遗传方式遗传，但也有报道称存在常染色体显性遗传形式。WFS1 编码一种跨膜蛋白，是内质网稳态的维持成分。这些显性突变被认为会增加内质网（ER）应激。最近的研究表明，4-苯基丁酸（PBA）和丙戊酸（VPA）可减轻 ER 应激。本研究的目的是分析 PBA 和 VPA 对体外显性 WFS1 突变体的影响。

方法

我们通过 ER 应激反应元件标记物的荧光素酶测定来确定显性 WFS1 突变体（p.His313Tyr、p.Trp314Arg、p.Asp325_Ile328del、p.Glu809Lys 和 p.Glu864Lys）是否具有显性负效应。此外，通过 C/EBP 同源蛋白（CHOP）mRNA 表达的定量实时 PCR 测定，确定 PBA 或 VPA 处理后，显性 WFS1 突变体诱导的细胞凋亡是否得到挽救。