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

Morikawa, Shuntaro; Tajima, Toshihiro; Nakamura, Akie; Ishizu, Katsura; Ariga, Tadashi

doi:10.1111/pedi.12513

Cited by 34 publications

(26 citation statements)

References 21 publications

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“…Morikawa et al have found a de novo heterozygous 4 aa inframe deletion (p.N325_I328del) in an 11-month-old Japanese female WS patient with insulin-dependent DM, congenital cataract, and severe bilateral hearing loss (55). Although cataract is not typical of WS1, other cases associated with WFS1 heterozygous mutations have been described (56).…”

Section: Molecular Biology Physiology and Pathophysiology Of Ws1mentioning

confidence: 99%

Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease

et al. 2018

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Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and other abnormalities. WS1 usually results in death before the age of 50 years. The pathogenesis of WS1 is ascribed to mutations of human WFS1 gene on chromosome 4p encoding a transmembrane protein called wolframin which has physiological functions in membrane trafficking, secretion, processing, and/or regulation of ER calcium homeostasis. Different types of WFS1 mutations have been identified, and some of these have been associated with a dominant, severe type of WS.

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Section: Molecular Biology Physiology and Pathophysiology Of Ws1mentioning

confidence: 99%

Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease

et al. 2018

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“…Since SERCA2b is expressed in MAMs and is a well-known effector of ER Ca 2+ uptake 150 , Wfs1 may be a novel MAM physiological effector essential for Ca 2+ homeostasis. In contrast, Morikawa et al 151 described a reduced mRNA level of SERCA2b in HEK-293 cells transfected with mutant WFS1 cDNA compared to HEK-293 cells transfected with wild-type WFS1 cDNA. This elevation of [Ca 2+ ] cyto is associated with an increase of the mRNA level of CCAAT-enhancer-binding protein homologous protein, leading to ER stress-induced cell apoptosis 152 .…”

Section: Is Mams' Dysfunction Playing a Role In Ws1 Pathology?mentioning

confidence: 84%

Wolfram syndrome: MAMs’ connection?

Delprat

Maurice²,

Delettre

2018

Cell Death Dis

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Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca2+ transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed “mitochondria-associated ER membranes” (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.

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“…Silencing of Wfs1 by specific shRNA in neurons also induced increased expression of these factors but only to a moderate extent. ER stress caused by Wfs1 deficiency was implicated also in the disruption of β-cell function (Morikawa et al, 2017; Ohta et al, 2017). Wfs1 was also suggested to participate in calcium handling: silencing of Wfs1 by specific shRNA in neurons resulted in depression of calcium transients and of Ca 2+ release from the ER (Cagalinec et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Calcium Signaling and Contractility in Cardiac Myocyte of Wolframin Deficient Rats

et al. 2019

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Wolframin (Wfs1) is a membrane protein of the sarco/endoplasmic reticulum. Wfs1 mutations are responsible for the Wolfram syndrome, characterized by diabetic and neurological symptoms. Although Wfs1 is expressed in cardiac muscle, its role in this tissue is not clear. We have characterized the effect of invalidation of Wfs1 on calcium signaling-related processes in isolated ventricular myocytes of exon5-Wfs1 deficient rats (Wfs1-e5/-e5) before the onset of overt disease. Calcium transients and contraction were measured in field-stimulated isolated myocytes using confocal microscopy with calcium indicator fluo-3 AM and sarcomere length detection. Calcium currents and their calcium release-dependent inactivation were characterized in whole-cell patch-clamp experiments. At 4 months, Wfs1-e5/-e5 animals were euglycemic, and echocardiographic examination revealed fully compensated cardiac function. In field-stimulated isolated ventricular myocytes, both the amplitude and the duration of contraction of Wfs1-e5/-e5 animals were elevated relative to control Wfs1+/+ littermates. Increased contractility of myocytes resulted largely from prolonged cytosolic calcium transients. Neither the amplitude of calcium currents nor their voltage dependence of activation differed between the two groups. Calcium currents in Wfs1-e5/-e5 myocytes showed a larger extent of inactivation by short voltage prepulses applied to selectively induce calcium release-dependent inactivation of calcium current. Neither the calcium content of the sarcoplasmic reticulum, measured by application of 20 mmol/l caffeine, nor the expression of SERCA2, determined from Western blots, differed significantly in myocytes of Wfs1-e5/-e5 animals compared to control ones. These experiments point to increased duration of calcium release in ventricular myocytes of Wfs1-e5/-e5 animals. We speculate that the lack of functional wolframin might cause changes leading to upregulation of RyR2 channels resulting in prolongation of channel openings and/or a delay in termination of calcium release.

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

Abstract: A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM.

Cited by 34 publications

References 21 publications

Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease

Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease

Wolfram syndrome: MAMs’ connection?

Calcium Signaling and Contractility in Cardiac Myocyte of Wolframin Deficient Rats

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