Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

Xavier, Jean; Bourvis, Nadège; Tanet, Antoine; Ramos, Tatiana Loaeza; Marey, Isabelle; Cohen, David; Consoli, Angèle

doi:10.1089/cap.2015.0241

Cited by 8 publications

(5 citation statements)

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“…Wolfram syndrome patients may develop psychiatric disorders (56), such as bipolar disorder, schizophrenia, anxiety, and depression (57)(58)(59). Surprisingly, changes in NCS1 abundance provoke similar symptoms in human and mice (60,61).…”

Section: Discussionmentioning

confidence: 99%

ER-mitochondria cross-talk is regulated by the Ca ²⁺ sensor NCS1 and is impaired in Wolfram syndrome

et al. 2018

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Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3R) to promote Ca2+ transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca2+ exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca2+ transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

ER-mitochondria cross-talk is regulated by the Ca ²⁺ sensor NCS1 and is impaired in Wolfram syndrome

et al. 2018

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“…Deafness and DI are present in 46 and 29% of the patients, respectively ( 4 ). Other symptoms could include urinary disorders, pons atrophy, ataxia ( 4 , 5 ), and psychiatric disorders, including bipolar disorder ( 6 ), schizophrenia ( 7 ), suicide ( 8 ), or mania ( 9 ). To date, no treatment is available, and most of the affected patients die prematurely.…”

Section: Introductionmentioning

confidence: 99%

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

et al. 2022

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The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein’s stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.

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“…Specifically, p.Ala684Val had a higher in silico impact based on Combined Annotation Dependent Depletion (CADD) ( https://cadd.gs.washington.edu/ ) and Rare Exome Variant Ensemble Learner (REVEL) ( https://sites.google.com/site/revelgenomics/ ) algorithms, with scores of 28.8 and 0.891, respectively. Functional research has established the pathogenicity of the p.Ala684Val variant [ 19 ] and alternative variant (p.Ala684Thr) with corresponding residues [ 39 , 40 ]. Co-segregation analysis confirmed that the two variants segregated as de novo trait in three unrelated families (Fig.…”

Section: Resultsmentioning

confidence: 99%

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

Lim

Lee

et al. 2023

BMC Med Genomics

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Background Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. Methods We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1–NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. Results One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7–9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. Conclusions We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

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Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

Abstract: Given the complexity of WS, this case suggests that the possible association between WS and BD should not only be merely limited to a possible statistical association with WFS1 polymorphism but also to developmental, cognitive, and endocrine risk factors for BD.

Cited by 8 publications

References 49 publications

ER-mitochondria cross-talk is regulated by the Ca ²⁺ sensor NCS1 and is impaired in Wolfram syndrome

ER-mitochondria cross-talk is regulated by the Ca ²⁺ sensor NCS1 and is impaired in Wolfram syndrome

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

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Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

Abstract: Given the complexity of WS, this case suggests that the possible association between WS and BD should not only be merely limited to a possible statistical association with WFS1 polymorphism but also to developmental, cognitive, and endocrine risk factors for BD.

Cited by 8 publications

References 49 publications

ER-mitochondria cross-talk is regulated by the Ca 2+ sensor NCS1 and is impaired in Wolfram syndrome

ER-mitochondria cross-talk is regulated by the Ca 2+ sensor NCS1 and is impaired in Wolfram syndrome

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

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ER-mitochondria cross-talk is regulated by the Ca ²⁺ sensor NCS1 and is impaired in Wolfram syndrome

ER-mitochondria cross-talk is regulated by the Ca ²⁺ sensor NCS1 and is impaired in Wolfram syndrome