The mitochondrial genome in Wolfram syndrome

Barrett, Timothy; Scott-Brown, Martin; Seller, A; Bednarz, Amy L.; Poulton, Kelvin; Poulton, Joanna

doi:10.1136/jmg.37.6.463

Cited by 42 publications

(23 citation statements)

References 28 publications

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“…Notably, Bundey et al (1992) described a WFS patient having morphologically and biochemical abnormal mitochondria in the muscle biopsy; this finding indicated that a mitochondrial defect may be involved in the pathogenesis of WFS. However, other clinical studies revealed no evidence supporting the hypothesis of mitochondrial deficiency (Hofmann et al 1997;Barrett et al 2000). This controversy seems to have been resolved by the identification of different causative genes for WFS, and this hypothesis is supported by the mouse works carried out in this study.…”

Section: Discussionsupporting

confidence: 68%

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Chen¹,

Kao²,

Chen³

et al. 2009

Genes Dev.

249

260

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CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondriamediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.[Keywords: Cisd2; Wolfram syndrome 2; autophagy; knockout mice; mitochondria; premature aging] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionsupporting

confidence: 68%

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Chen¹,

Kao²,

Chen³

et al. 2009

Genes Dev.

249

260

View full text Add to dashboard Cite

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“…Contradictory results have been reported in several studies [Barrett et al, 2000;Bundey et al, 1992]. The hypothesis of a mitochondrial origin of the disease was ruled out in 1998 after the cloning of a responsible nuclear Wolfram syndrome 1 (WFS1) gene [Inoue et al, 1998;Strom et al, 1998].…”

Section: Introductionmentioning

confidence: 61%

Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay

et al. 2003

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Communicated by Paolo FortinaWolfram syndrome (WS) is a recessively inherited mendelian form of diabetes and neurodegeneration also known by the acronym DIDMOAD from the major clinical features, including diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Affected individuals may also show renal tract abnormalities as well as multiple neurological and psychiatric symptoms. The causative gene for WS (WFS1) encoding wolframin maps to chromosome 4p16.1 and consists of eight exons, spanning 33.44 Kb of genomic DNA. In this study we report on the mutational analysis of the WFS1 coding region in 19 Italian WS patients and 25 relatives, using a DHPLC-based protocol. A total of 19 different mutations in WFS1 were found in 18 of 19 patients (95%). All these mutations, except one, are novel, preferentially located in WFS1 exon 8, and include deletions, insertions, duplications, and nonsense and missense changes. In particular, a 16 base-pair deletion in WFS1 codon 454 was detected in five different unrelated nuclear families, being the most prevalent alteration in this Italian group. Nine neutral changes and polymorphisms were also identified. Overall, this study represents the molecular characterization of the largest cohort of Italian WS patients and carriers studied so far, and increases the number of identified WFS1 allelic variants worldwide. Hum Mutat 21:622-629,

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“…Most patients carry mutations in the WFS1 gene; a second form of WS is caused by a homozygous mutation in a recently identified zinc-finger protein, Endoplasmatic Reticulum Intermembrane Small protein (ERIS) encoded by the WFS2 gene, mapping to 4q22-q25 [4][5][6][7]. Defects in mitochondrial DNA were reported in some sporadic cases, but the mitochondrial genome was not found to be systematically involved in the disease [8][9][10][11]. Mutations reported in the WFS1 gene give rise to two distinct phenotypes: autosomal recessive WS and autosomal dominant low-frequency sensorineural hearing loss (AD LFSNHL) [5,12].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Wsf1 Mutations in a Sicilian Child with Wolfram Syndrome

Pizzolanti¹

2014

J Genet Syndr Gene Ther

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Wolfram Syndrome (WS) is a rare hereditary disease with autosomal recessive inheritance with incomplete penetrance. It is characterized by diabetes mellitus associated with progressive optic atrophy. The diagnosis is essentially clinical and mutation analysis is used to confirm the diagnosis. In the present study we describe the clinical and molecular features of a diabetic child carrying two novel WFS1 mutations. The Sicilian proband and his non-affected family were studied. Ophthalmologic examination included: visual acuity determination and funduscopy, optical coherent tomography, retinal fluorangiography, perimetry and electroretinogram. Molecular methods: automatic sequencing of PCR amplified WFS1 gene fragments and qRT-PCR analysis of WFS1 transcripts. 3 WSF1 mutations have been identified in the proband. One allele carries 2 paternally inherited mutations (c.1332 C>G and c.1631C>G) in exon-8, never annotated before, in heterozygosis with one "de novo" classic mutation (c.505 G>A) in exon-5. In addition, we report an unexpected molecular feature: higher WFS1 mRNA levels in the proband compared to the father. Milan, Italy) following manifacturer's instructions. A neuroblastoma cell line (LAN5) used as a positive control. WFS1 expression was analysed by real-time quantitative RT-PCR (qRT-PCR) in individual samples and WFS1 mRNA levels were quantified in comparison to β-actin mRNA expression. WFS1 PCR primers were purchased from Quiagen (Quantitect Primer Hs_WFS1_1_SG QT00082663) the amplicon size was 117 bp (Suppl. Figure 1); β-actin primers were obtained from RealTimePrimers.com (Elkins Park, PA, USA) with the following sequences: F 5'-GGACTTCGAGCAAGAGATGG-3'; R 5'-AGCACTGTGTTGGCGTACAG-3'; the amplicon size was 234 bp. All reactions were performed using the LightCycler 1.0 (Roche Diagnostics GMbH, Germany). Briefly, 2 g of total RNA was retrotranscribed using the ImProm-II™ Reverse Transcription System (Promega, Milan, Italy). Each RNA was combined with 1l of oligo16dT (Promega Milan, Italy) and thermally denatured at 70°C for 5 minutes and then chilled on ice. As a final step, the template-oligodT combination was added to the reaction mix (4 l ImProm-II™ 1X Reaction Buffer, 1l ImProm-II™ Reverse Transcriptase, 3.2 l Magnesium Chloride 3 mM, 1 l dNTPs mix 10 mM and 1 l Recombinant RNasin Ribonuclease Inhibitor 1u/l) and nuclease-free water was added to 20 l of final volume on ice. Following an initial annealing at 25°C for 5 minutes, the reaction was incubated at 42°C for one hour. In order to heat-inactivate the ImProm-II Reverse Transcriptase the reaction mix was finally incubated at 70°C for 15 minutes. Journal of Genetic Syndromes & Gene TherapyReal-time PCR was performed using 2 l of cDNA diluited 1:5, plus 10 l of Quantitech master mix (Qiagen), 2 l of Quantitect Primer Hs_WFS1_1_SG or β-actin primers, and nuclease-free water to 20 l of final volume. A standard reference curve was performed in parallel using RNAs extracted from LAN5 cell line serially 1:2 diluited starting from 100 ng reaction...

show abstract

The mitochondrial genome in Wolfram syndrome

Cited by 42 publications

References 28 publications

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay

Identification of Novel Wsf1 Mutations in a Sicilian Child with Wolfram Syndrome

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