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

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Title: A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome
Other Titles: Constitutive ER stress and Wolfram syndrome
Authors: Morikawa, Shuntaro Browse this author
Tajima, Toshihiro Browse this author →KAKEN DB
Nakamura, Akie Browse this author
Ishizu, Katsura Browse this author
Ariga, Tadashi Browse this author →KAKEN DB
Keywords: calcium
endoplasmic reticulum
ER stress
WFS1
Wolfram syndrome
Issue Date: Dec-2017
Publisher: John Wiley & Sons
Journal Title: Pediatric diabetes
Volume: 18
Issue: 8
Start Page: 934
End Page: 941
Publisher DOI: 10.1111/pedi.12513
PMID: 28271591
Abstract: 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 Ca2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca2+ transport ATPase 2b (SERCA2b) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca2+ homeostasis, decreased SERCA2b expression might affect ER Ca2+ efflux, causing cell apoptosis. Conclusion: A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM.
Rights: This is the peer reviewed version of the following article: Morikawa S, Tajima T, Nakamura A, Ishizu K, Ariga T. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome, Pediatr Diabetes, 2017;18:934–941, which has been published in final form at https://doi.org/10.1111/pedi.12513. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Type: article (author version)
URI: http://hdl.handle.net/2115/72083
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 有賀 正

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