Wolfram Syndrome: a Monogenic Model to Study Diabetes Mellitus and Neurodegeneration

Abstract

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 Wolfram syndrome 1 (WFS1) 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.

Keywords: Orphan disease; WFS1; ibudilast; intracellular calcium signaling; neurodevelopment; pancreatic β-cells.

Figure 1:

Overview of Wolfram syndrome pathology. (A) Clinical presentation. Symptoms most frequently observed in Wolfram syndrome patients are listed with labels indicating affected organs (schematic, list not exhaustive). The characteristic “DIDMOAD”-phenotype is shown in bold. (B-C) These two subpanels illustrate the pathomechanism of WS, focusing on pancreatic β-cells because diabetes mellitus is the first diagnosed symptom in WS and has been most frequently studied. (B) Cellular dysfunction due to the loss of WFS1 in the endocrine pancreas (Islet of Langerhans) is characterized by decreased insulin secretion and increased loss of β-cells. (C) Molecular impairments due to the loss of WFS1 are characterized by disrupted intracellular Ca2+ homeostasis, ER stress, and reduced mitochondrial functionality – resulting in reduced secretion, enhanced apoptosis, and reduced survival. Disruption of intracellular Ca2+ homeostasis, including elevation of resting free cytosolic Ca2+ [Ca2+]_cyto and impaired ER-Ca2+ release into the cytosol and mitochondria, appears as a likely underlying cause for WS pathology.