A Novel Unstable Mutation in Mitochondrial DNA Responsible for Maternally Inherited Diabetes and Deafness

Bannwarth, Sylvie; Abbassi, Meriame; Valéro, René; Fragaki, Konstantina; Dubois, Nicole; Vialettes, B.; Paquis‐Flucklinger, Véronique

doi:10.2337/dc11-1012

Cited by 13 publications

(6 citation statements)

References 14 publications

(18 reference statements)

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“…The results showed that no pathogenic mutations were found in the non-coding region of WFS1 gene of the patient and his families (Table 3 ). In addition, we screened mitochondrial mutations of m.3337G > A and m.3243A > G, which were associated with WS and maternally inherited diabetes and deafness (MIDD), respectively [ 15 , 16 ]. Both mutations were not found in the patient and his families (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1

Gong

Xiong

et al. 2021

BMC Endocr Disord

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Background Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Mutations in Wolfram syndrome 1 (WFS1) gene may cause dysregulated endoplasmic reticulum (ER)-stress and cell apoptosis, contributing to WS symptoms. The aim of this study was to identify the molecular etiology of a case of WS and to explore the functional consequence of the mutant WFS1 gene in vitro. Methods A 27 years-old Chinese man was diagnosed as wolfram syndrome type 1 based on clinical data and laboratory data. DNA sequencing of WFS1 gene and mitochondrial m.3337G > A, m.3243A > G mutations were performed in the patient and his 4 family members. Functional analysis was performed to assessed the in vitro effect of the newly identified mutant. ER stress were evaluated by ER stress response element (ERSE)-luciferase assay. Cell apoptosis were performed by CCK-8, TUNEL staining and flow cytometric analysis. Results A novel heterozygous 10-base deletion (c. 2067_2076 del10, p.W690fsX706) was identified in the patient. In vitro studies showed that mutant p.W690fsX706 increased ERSE reporter activity in the presence or absence of thapsigargin instead of wild type WFS1. Knockdown of WFS1 activated the unfolded protein response (UPR) pathway and increased the cell apoptosis, which could not be restored by transfection with WFS1 mutant (p.W690fsX706) comparable to the wild type WFS1. Conclusions A novel heterozygous mutation of WFS1 detected in the patient resulted in loss-of-function of wolframin, thereby inducing dysregulated ER stress signaling and cell apoptosis. These findings increase the spectrum of WFS1 gene mutations and broaden our insights into the roles of mutant WFS1 in the pathogenesis of WS.

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Section: Resultsmentioning

confidence: 99%

A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1

Gong

Xiong

et al. 2021

BMC Endocr Disord

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“…In fact, the phenotype of a pathogenic mtDNA mutation, or the severity of an mtDNA mutation that may not be pathological in some cases, could be influenced by the mitochondrial DNA haplogroup [38] . In addition, the genetic instability of mtDNA heteroplasmic mutations in the patient's somatic tissues [39] , or the nuclear background, by nuclear modifiers, may also play a role in determining mtDNA mutation pathogenicity [40] .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes in Children: Seek and You Will Find It

et al. 2012

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Maternally Inherited Diabetes and Deafness (MIDD) is a rare form of diabetes due to defects in mitochondrial DNA (mtDNA). 3243 A>G is the mutation most frequently associated with this condition, but other mtDNA variants have been linked with a diabetic phenotype suggestive of MIDD. From 1989 to 2009, we clinically diagnosed mitochondrial diabetes in 11 diabetic children. Diagnosis was based on the presence of one or more of the following criteria: 1) maculopathy; 2) hearing impairment; 3) maternal heritability of diabetes/impaired fasting glucose and/or hearing impairment and/or maculopathy in three consecutive generations (or in two generations if 2 or 3 members of a family were affected). We sequenced the mtDNA in the 11 probands, in their mothers and in 80 controls. We identified 33 diabetes-suspected mutations, 1/33 was 3243A>G. Most patients (91%) and their mothers had mutations in complex I and/or IV of the respiratory chain. We measured the activity of these two enzymes and found that they were less active in mutated patients and their mothers than in the healthy control pool. The prevalence of hearing loss (36% vs 75–98%) and macular dystrophy (54% vs 86%) was lower in our mitochondrial diabetic adolescents than reported in adults. Moreover, we found a hitherto unknown association between mitochondrial diabetes and celiac disease. In conclusion, mitochondrial diabetes should be considered a complex syndrome with several phenotypic variants. Moreover, deafness is not an essential component of the disease in children. The whole mtDNA should be screened because the 3243A>G variant is not as frequent in children as in adults. In fact, 91% of our patients were mutated in the complex I and/or IV genes. The enzymatic assay may be a useful tool with which to confirm the pathogenic significance of detected variants.

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“…In many (but not all, Noll et al, 1990) cell types, the bulk of ATP is produced by OXPHOS in mitochondria. Since mtDNA encodes components for four out of five mitochondrial respiratory complexes, it is not surprising that mutations in mtDNA have been associated with various human pathologies, such as mitochondrial diseases (Schapira, 2012; Ylikallio & Suomalainen, 2012; Zheng et al, 2012), diabetes (Bannwarth et al, 2011; Maassen et al, 2005; Supale et al, 2012), cancer (Wallace, 2012; Yu, 2012), neurodegenerative disorders (Milone, 2012), and many others. Therefore, understanding cellular mechanisms for the maintenance of mtDNA integrity is of utmost importance as it can provide targets for clinical interventions aimed at the prevention and treatment of human diseases.…”

Section: Introductionmentioning

confidence: 99%

The efficiency of the translesion synthesis across abasic sites by mitochondrial DNA polymerase is low in mitochondria of 3T3 cells

Kozhukhar

Spadafora

Fayzulin

et al. 2015

Mitochondrial DNA Part A

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Translesion synthesis by specialized DNA polymerases is an important strategy for mitigating DNA damage that cannot be otherwise repaired either due to the chemical nature of the lesion. Apurinic/Apyrimidinic (abasic, AP) sites represent a block to both transcription and replication, and are normally repaired by the base excision repair (BER) pathway. However, when the number of abasic sites exceeds BER capacity, mitochondrial DNA is targeted for degradation. Here, we used two uracil-N-glycosylase (UNG1) mutants, Y147A or N204D, to generate AP sites directly in the mtDNA of NIH3T3 cells in vivo at sites normally occupied by T or C residues, respectively, and to study repair of these lesions in their native context. We conclude that mitochondrial DNA polymerase γ (Pol γ) is capable of translesion synthesis across AP sites in mitochondria of the NIH3T3 cells, and obeys the A-rule. However, in our system, base excision repair (BER) and mtDNA degradation occur more frequently than translesion bypass of AP sites.

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A Novel Unstable Mutation in Mitochondrial DNA Responsible for Maternally Inherited Diabetes and Deafness

Cited by 13 publications

References 14 publications

A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1

A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1

Mitochondrial Diabetes in Children: Seek and You Will Find It

The efficiency of the translesion synthesis across abasic sites by mitochondrial DNA polymerase is low in mitochondria of 3T3 cells

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