A novel mitochondrial DNA m.7507A&gt;G mutation is only pathogenic at high levels of heteroplasmy

McCann, Beverly Jo; Tuppen, Helen A.L.; Küsters, Benno; Lammens, Martin; Smeitink, Jan A.M.; Taylor, Robert W.; Rodenburg, Richard J.; Wortmann, Saskia B.

doi:10.1016/j.nmd.2014.11.002

Cited by 9 publications

(6 citation statements)

References 17 publications

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“…The first pathogenic mtDNA mutations were reported in 1988 (41,97); since then, an increasing number of mtDNA mutations associated with a wide variety of clinical symptoms have been identified in patients with mitochondrial disease. To date, more than 260 different pathogenic mutations have been characterized [see MITOMAP (59)], and the number continues to rise (52,64). These mutations can be classified into three types: point mutations in protein-coding genes, point mutations in genes involved in protein synthesis (tRNA or rRNA genes), and mtDNA rearrangements, including mtDNA deletions and insertions.…”

Section: Mitochondrial Dna Diseasementioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

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242

198

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Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.

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Section: Mitochondrial Dna Diseasementioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

Self Cite

242

198

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“…However, another report published that ethidium bromide‐mediated depletion of mtDNA led to an increase in mitochondrial mass even though it decreased the mtDNA content (Nacarelli et al, ). This difference may be attributed to the use of different subpopulations of cells with dissimilar or even diverse mtDNA heteroplasmy (McCann et al, ; Zhang et al, ). Furthermore, in mtDNA‐related diseases, there is large clinical diversity due to the characteristics of mtDNA, such as copy number and percentage mtDNA heteroplasmy (McCann et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Failure to maintain quality and contents of mtDNA may be associated with mutation in the nuclear and mitochondrial genome (Michel et al, 2012). Due to this, cells with subpopulations having dissimilar or even diverse mtDNA heteroplasmy render large clinical diversities (McCann et al, 2015;Zhang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Low abundance of mitochondrial DNA changes mitochondrial status and renders cells resistant to serum starvation and sodium nitroprusside insult

Lee

Heo

Jeong

et al. 2015

Cell Biology International

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Mutation or depletion of mitochondrial DNA (mtDNA) can cause severe mitochondrial malfunction, originating from the mitochondrion itself, or from the crosstalk between nuclei and mitochondria. However, the changes that would occur if the amount of mtDNA is diminished are less known. Thus, we generated rat myoblast H9c2 cells containing lower amounts of mtDNA via ethidium bromide and uridine supplementation. After confirming the depletion of mtDNA by quantitative PCR and gel electrophoresis analysis, we investigated the changes in mitochondrial physical parameters by using flow cytometry. We also evaluated the resistance of these cells to serum starvation and sodium nitroprusside. H9c2 cells with diminished mtDNA contents showed decreased mitochondrial membrane potential, mass, free calcium, and zinc ion contents as compared to naïve H9c2 cells. Furthermore, cytosolic and mitochondrial reactive oxygen species levels were significantly higher in mtDNA-lowered H9c2 cells than in the naïve cells. Although the oxygen consumption rate and cell proliferation were decreased, mtDNA-lowered H9c2 cells were more resistant to serum deprivation and nitroprusside insults than the naïve H9c2 cells. Taken together, we conclude that the low abundance of mtDNA cause changes in cellular status, such as changes in reactive oxygen species, calcium, and zinc ion levels inducing resistance to stress.

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“…Furthermore, we proposed that the mtDNA point mutations in the present study might result from a process where a normal mtDNA was gradually mutated by a mutated mtDNA in cells/tissues. When the mtDNA mutations reached to a certain level, the mutated cells might become cancerous (McCann et al 2015;Stefano and Kream 2016).…”

Section: Discussionmentioning

confidence: 99%

Investigation of frequent somatic mutations of MTND5 gene in gastric cancer cell lines and tissues

Xing

Cui

et al. 2018

Mitochondrial DNA Part B

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The present study investigated the single nucleotide variants (SNVs) in mitochondrial DNA (mtDNA) of 13 paired gastric cancer tissue samples and seven gastric cancer cell lines using direct sequencing analysis of the MTND5 region. Results showed that nuclear mitochondrial pseudogenes (NUMTs) and mitochondrial copy number affected the detection of the SNV frequency in gastric cancer tissue and cell line samples using high-throughput sequencing technique. The heteroplasmic point mutation C12474T and G12835A happened in AGS and BGC823 cell lines, respectively. A total of seven SNVs were found in three paired gastric cancer tissue samples, including five heteroplasmic point mutations (A12406G, C12705T, T12882C, G12501A, and A12584G) and two homoplasmic point mutations (G12561A and C13590T). Gastric cancer tissue sample 16 exhibited the highest SNVs frequency with four SNVs (np 12406, np 12705, np 12882, and np 12501), whereas no SNVs or SNPs were detected in the tissue sample 4. SNP 12705 turned out to be an SNV in gastric cancer tissue sample 16. SNV 12338 detected by exome sequencing approach appeared to be an SNP in this study.

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A novel mitochondrial DNA m.7507A>G mutation is only pathogenic at high levels of heteroplasmy

Cited by 9 publications

References 17 publications

Recent Advances in Mitochondrial Disease

Recent Advances in Mitochondrial Disease

Low abundance of mitochondrial DNA changes mitochondrial status and renders cells resistant to serum starvation and sodium nitroprusside insult

Investigation of frequent somatic mutations of MTND5 gene in gastric cancer cell lines and tissues

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