A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions

Rouzier, Cécile; Moore, David; Delorme, Cécile; Lacas‐Gervais, Sandra; Ait-El-Mkadem, Samira; Fragaki, Konstantina; Burté, Florence; Serre, Valérie; Bannwarth, Sylvie; Chaussenot, Annabelle; Catala, Martin; Yu‐Wai‐Man, Patrick; Paquis‐Flucklinger, Véronique

doi:10.1093/hmg/ddx130

Cited by 29 publications

(20 citation statements)

References 42 publications

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“…This elevated [Ca 2+ ] er might be responsible for the degeneration of β-cells and neurons since ER Ca 2+ overload increases the cell susceptibility to apoptosis 77 , 132 . Similar results were obtained in fibroblasts from WS2 patients 133 . In addition, the number of ER–mitochondrial contacts was increased in patient fibroblasts compared to controls, as visualized using transmission electron microscopy (TEM).…”

Section: Could Ws2 Also Be a Mam-related Pathology?supporting

confidence: 86%

“…In addition, the number of ER–mitochondrial contacts was increased in patient fibroblasts compared to controls, as visualized using transmission electron microscopy (TEM). This observation was confirmed in living cell by analyzing the colocalization between ER, using the GFP Sec61b marker, and mitochondria, using MitoTracker 133 . Finally, even if no ultrastructural abnormalities could be observed in mitochondria preparations from patients, both the average length and volume of mitochondrial fragments were increased in fibroblasts from patients.…”

Section: Could Ws2 Also Be a Mam-related Pathology?mentioning

confidence: 61%

“…Finally, even if no ultrastructural abnormalities could be observed in mitochondria preparations from patients, both the average length and volume of mitochondrial fragments were increased in fibroblasts from patients. The more fused and elongated mitochondrial network was associated, in a galactose medium used to force cells to rely predominantly on OXPHOS for ATP production, with a respiratory chain defect in complexes I and II of the mitochondrial respiratory chain 133 .

Fig.…”

Section: Could Ws2 Also Be a Mam-related Pathology?mentioning

confidence: 99%

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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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Section: Could Ws2 Also Be a Mam-related Pathology?supporting

confidence: 86%

Section: Could Ws2 Also Be a Mam-related Pathology?mentioning

confidence: 61%

Fig.…”

Section: Could Ws2 Also Be a Mam-related Pathology?mentioning

confidence: 99%

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Wolfram syndrome: MAMs’ connection?

Delprat

Maurice²,

Delettre

2018

Cell Death Dis

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“…CISD2 is a rare causative gene and autosomal-recessive mutations in CISD2 is the pathogeny of WFS2. So far, very limited mutations have been reported in this gene (Table 3) [17–20]. In our study, patient 1 was homozygous for the frame-shift mutation c.272_273del in CISD2 , due to the parental consanguinity.…”

Section: Discussionmentioning

confidence: 54%

“…CISD2 , CDGSH iron-sulfur domain-containing protein 2, located on chromosome 4q22–24, encodes endoplasmic reticulum intermembrane small protein (ERISP) [19]. Although the biological functions of CISD2 still remain incompletely defined, some studies show that it has a similar role with WFS1 in maintaining the homeostasis of Ca 2+ and ER and the cross-talk between ER and mitochondria [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Novel mutations and the ophthalmologic characters in Chinese patients with Wolfram Syndrome

Zhang

Kong

et al. 2019

Orphanet J Rare Dis

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Background Wolfram Syndrome (WFS) is a rare autosomal recessive neurodegenerative disease which has a wide spectrum of manifestations including diabetes insipidus, diabetes mellitus, optic atrophy and deafness. WFS1 and CISD2 are two main causing genes of WFS. The aim of this study was to illustrate the ophthalmologic manifestations and determine the genotype of Chinese WFS patients. Results Completed ophthalmic examinations and family investigations were performed on 4 clinically diagnosed WFS patients from 4 unrelated families. Genetic testing was done by the next generation sequencing of candidate genes. One patient carried a homozygous mutation (c.272_273del) in CISD2 , two patients carried compound heterozygous mutations (c.1618 T > G + c.2020G > A and c.1048 T > A + c.2020G > A) in WFS1 , and one patient carried a heterozygous mutation (c.937C > T) in WFS1 . Three of them were novel mutations. Conclusions Our study indicated WFS in Chinese is a neurodegenerative disease with both wide spectrum of clinical features and genetic heterogeneity. We found three novel mutations in WFS patients, and to our best knowledge, this is the first report of Chinese WFS patient with mutation in CISD2 . Electronic supplementary material The online version of this article (10.1186/s13023-019-1161-y) contains supplementary material, which is available to authorized users.

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A framework for pathway knowledge driven prioritization in genome‐wide association studies

Biswas

Pal

Majumder

et al. 2020

Genetic Epidemiology

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Many variants with low frequencies or with low to modest effects likely remain unidentified in genome‐wide association studies (GWAS) because of stringent genome‐wide thresholds for detection. To improve the power of detection, variant prioritization based on their functional annotations and epigenetic landmarks has been used successfully. Here, we propose a novel method of prioritization of a GWAS by exploiting gene‐level knowledge (e.g., annotations to pathways and ontologies) and show that it further improves power. Often, disease associated variants are found near genes that are coinvolved in specific biological pathways relevant to disease process. Utilization of this knowledge to conduct a prioritized scan increases the power to detect loci that map to genes clustered in a few specific pathways. We have developed a computationally scalable framework based on penalized logistic regression (termed GKnowMTest—Genomic Knowledge‐guided Multiplte Testing) to enable a prioritized pathway‐guided GWAS scan with a very large number of gene‐level annotations. We demonstrate that the proposed strategy improves overall power and maintains the Type 1 error globally. Our method works on genome‐wide summary level data and a user‐specified list of pathways (e.g., those extracted from large pathway databases without reference to biology of a specific disease). It automatically reweights the input p values by incorporating the pathway enrichments as “adaptively learned” from the data using a cross‐validation technique to avoid overfitting. We used whole‐genome simulations and some publicly available GWAS data sets to illustrate the application of our method. The GKnowMTest framework has been implemented as a user‐friendly open‐source R package.

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A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions

Cited by 29 publications

References 42 publications

Wolfram syndrome: MAMs’ connection?

Wolfram syndrome: MAMs’ connection?

Novel mutations and the ophthalmologic characters in Chinese patients with Wolfram Syndrome

A framework for pathway knowledge driven prioritization in genome‐wide association studies

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