A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome

Background Wolfram syndrome ( WS ) is a disorder characterized by the association of insulin‐dependent diabetes mellitus ( DM ), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum ( ER ). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as “ ER stress”. This is attenuated by the unfolded protein response ( UPR ), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11‐month‐old Japanese female WS patient with insulin‐dependent DM , congenital cataract and severe bilateral hearing loss. Objective Analyze the WFS1 and functional consequence of the patient WFS1 in vitro. Results The patient WFS1 contained a heterozygous 4 amino acid in‐frame deletion (p.N325_I328del). Her mutant WFS1 increased GRP78 and ATF6α promoter activities in the absence of thapsigargin, indicating constitutive ER stress and nuclear factor of activated T‐cell reporter activity, reflecting elevated cytosolic Ca 2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca 2+ transport ATPase 2b ( SERCA2b ) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca 2+ homeostasis, decreased SERCA2b expression might affect ER Ca 2+ efflux, causing cell apoptosis. Conclusion A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca 2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM .