Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA 6009, Australia.
Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA 6150, Australia.
Biomolecules. 2023 Sep 4;13(9):1346. doi: 10.3390/biom13091346.
Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000-30,000 people are affected by WFS worldwide, and, on average, patients suffering from WFS die at 30 years of age, usually from central respiratory failure caused by massive brain atrophy. The more prevalent of the two kinds of WFS is WFS1, which is a monogenic disease and caused by the loss of the gene, whereas WFS2, which is more uncommon, is caused by mutations in the gene. Currently, there is no treatment for WFS1 to increase the life expectancy of patients, and the treatments available do not significantly improve their quality of life. Understanding the genetics and the molecular mechanisms of WFS1 is essential to finding a cure. The inability of conventional medications to treat WFS1 points to the need for innovative strategies that must address the fundamental cause: the deletion of the gene that leads to the profound ER stress and disturbances in proteostasis. An important approach here is to understand the mechanism of the cell degeneration after the deletion of the gene and to describe the differences in these mechanisms for the different tissues. The studies so far have indicated that remarkable clinical heterogeneity is caused by the variable vulnerability caused by mutations, and these differences cannot be attributed solely to the positions of mutations in the gene. The present review gives a broader overview of the results from genomic studies on the WFS1 mouse model.
沃尔夫拉赫综合征（Wolfram syndrome，WFS）是一种罕见的常染色体隐性神经遗传疾病，会影响多个器官系统。其特征为尿崩症、糖尿病、视神经萎缩和耳聋，因此也被称为 DIDMOAD。全球约有 15000-30000 人受到 WFS 的影响，而患有 WFS 的患者的平均死亡年龄为 30 岁，通常死于由于大脑严重萎缩导致的中枢性呼吸衰竭。两种 WFS 中较为普遍的是 WFS1，它是一种单基因疾病，由 基因缺失引起，而较为罕见的 WFS2 则由 基因突变引起。目前，没有治疗 WFS1 的方法可以增加患者的预期寿命，而现有的治疗方法并不能显著提高他们的生活质量。了解 WFS1 的遗传学和分子机制对于找到治疗方法至关重要。由于传统药物无法治疗 WFS1，因此必须采用创新策略来解决根本原因：即缺失 基因导致的严重内质网应激和蛋白质稳态紊乱。一个重要的方法是了解 基因缺失后细胞退化的机制，并描述不同组织中这些机制的差异。迄今为止的研究表明，由于 基因突变导致的可变易感性引起了显著的临床异质性，而这些差异不能仅仅归因于 基因中突变的位置。本综述更全面地概述了 WFS1 小鼠模型的基因组研究结果。
