Fischer Tom T, Ehrlich Barbara E
Department of Pharmacology, Yale University, New Haven, CT-06520, USA.
Institute of Pharmacology, University of Heidelberg, Germany.
Curr Opin Physiol. 2020 Oct;17:115-123. doi: 10.1016/j.cophys.2020.07.009. Epub 2020 Jul 15.
Wolfram syndrome (WS) is a rare, progressive disorder characterized by childhood-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and neurodegeneration. Currently, there is no effective treatment for WS, and patients typically die between 30 and 40 years of age. WS is primarily caused by autosomal recessive mutations in the () gene (OMIM 222300), which encodes for wolframin (WFS1). This disorder is therefore a valuable monogenic model for prevalent diseases, particularly diabetes mellitus and neurodegeneration. Whereas reduced survival and secretion are known cellular impairments causing WS, the underlying molecular pathways and the physiological function of WFS1 remain incompletely described. Here, we characterize WFS1 as a regulator of intracellular calcium homeostasis, review our current understanding of the disease mechanism of WS, and discuss candidate treatment approaches. These insights will facilitate identification of new therapeutic strategies not only for WS but also for diabetes mellitus and neurodegeneration.
沃夫勒姆综合征（WS）是一种罕见的进行性疾病，其特征为儿童期发病的糖尿病、视神经萎缩、听力丧失、尿崩症和神经退行性变。目前，尚无针对WS的有效治疗方法，患者通常在30至40岁之间死亡。WS主要由（）基因（OMIM 222300）的常染色体隐性突变引起，该基因编码沃尔弗蛋白（WFS1）。因此，这种疾病是常见疾病，特别是糖尿病和神经退行性变的一个有价值的单基因模型。虽然已知生存和分泌减少是导致WS的细胞损伤，但WFS1的潜在分子途径和生理功能仍未完全阐明。在这里，我们将WFS1表征为细胞内钙稳态的调节因子，回顾我们目前对WS疾病机制的理解，并讨论候选治疗方法。这些见解将不仅有助于识别针对WS的新治疗策略，也有助于识别针对糖尿病和神经退行性变的新治疗策略。
