8.A.57 The Wolfram Syndrome or Wolframin (Wolframin) Family
Wolfram syndrome is an autosomal recessive disorder in humans characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein with 890 aas and 10 putative TMSs that is involved in the regulation of the unfolded protein response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production and regulation of insulin biosynthesis and secretion. A reduced and delayed rise in cytosolic free Ca2+ concentration and diminished [ATP] occurs in response to elevated glucose concentrations in WFS1-depleted MIN6 cells (Zatyka et al. 2015). Moreover, sarco(endo)plasmic reticulum ATPase (SERCA; TC# 3.A.3.2.7)) expression was elevated in several WFS1-depleted cell models and primary islets (Takei et al. 2006). Interaction between WFS1 and SERCA by co-immunoprecipitation was demonstrated (Takei et al. 2006). These results reveal a role for WFS1 in the negative regulation of SERCA and provide insight into the function of WFS1 in calcium homeostasis. Additionally, WFS1 positively regulates the stability of V-ATPase subunits ATP6V1A and ATP1B1 by preventing their degradation through an unknown proteasome-independent mechanism (Gharanei et al. 2013).
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 is a maintenance component of endoplasmic homeostasis, and dominant mutations were thought to increase endoplasmic reticulum (ER) stress. 4-Phenylbutyrate (PBA) and valproate (VPA) reduce ER stress. Batjargal et al. 2020 determined that dominant WFS1 mutants have effects on ER stress. The rescue of cell apoptosis induced by dominant WFS1 mutants following treatment with PBA or VPA was significantly elevated by all dominant WFS1 mutants. After treatment with PBA or VPA, ER stress and cell apoptosis were reduced in each mutant.