Inherited Mitochondrial Diseases of DNA Replication*

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Annual Review of Medicine (Impact Factor: 12.93). 02/2008; 59(1):131-46. DOI: 10.1146/
Source: PubMed


Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.

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Available from: William C Copeland, Dec 20, 2013
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    • "While individual deletions have little effect on mtDNA stability, loss of both genes leads to frequent and rapid mtDNA depletion [53]. In humans, mitochondrial genetic diseases linked with nuclear genes affect replication of mtDNA either directly at the replication fork or by nucleotide supply [54]. In view of RECQ4's possible role during replication, it is not surprising that symptoms associated with deficiency in some of these genes (POLG, TWINKLE) show similarity to those of subsets of RTS patients, including mental retardation associated with atrophy of the brain [55] [56] [57]. "
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    ABSTRACT: The RECQ4 protein belongs to the RecQ helicase family, which plays crucial roles in genome maintenance. Mutations in the RECQ4 gene are associated with three insidious hereditary disorders: Rothmund-Thomson, Baller-Gerold, and RAPADILINO syndromes. These syndromes are characterized by growth deficiency, radial ray defects, red rashes, and higher predisposition to malignancy, especially osteosarcomas. Within the RecQ family, RECQ4 is the least characterized, and its role in DNA replication and repair remains unknown. We have identified several DNA binding sites within RECQ4. Two are located at the N-terminus and one is located within the conserved helicase domain. N-terminal domains probably cooperate with one another and promote the strong annealing activity of RECQ4. Surprisingly, the region spanning 322-400aa shows a very high affinity for branched DNA substrates, especially Holliday junctions. This study demonstrates biochemical activities of RECQ4 that could be involved in genome maintenance and suggest its possible role in processing replication and recombination intermediates. Copyright © 2015 Elsevier B.V. All rights reserved.
    DNA Repair 02/2015; 30. DOI:10.1016/j.dnarep.2015.02.020 · 3.11 Impact Factor
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    • "Nuclear genes encode the other 1000–1500 proteins imported into the mitochondria (Calvo et al., 2006). If any of these proteins get defective it can lead to mitochondrial DNA (mtDNA) mutations followed by a mitochondrial dysfunction and disease (Copeland, 2008; Figure 1). "
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    ABSTRACT: Abstract Mitochondrion is a cellular organelle that is present in most of the cells and is responsible for producing energy for the cell. Mitochondria have their own double-stranded DNA genome which is distinct from nuclear genome. The replication, recombination and repair of mtDNA are achieved by DNA polymerase-gamma which is encoded by POLG gene. Mutation in the mtDNA or POLG gene might lead to mitochondrial dysfunction and disease. Several mutations and polymorphisms in these regions have been associated to mitochondrial disorders. Nuceloside and nucelotide reverse transcriptase inhibitors (NRTIs) that form the basis of AIDS therapy have significantly increased the survival rate of HIV-infected individuals predisposing them to other side effects. One of the most common side effects of NRTI usage is mitochondrial toxicity leading to several mitochondrial disorders. Mutations in mtDNA have also been associated to the use of specific NRTIs leading to specific mitochondrial disorders. This review briefly summarizes the advances in mtDNA mutations and NRTI-caused mitochondrial toxicity and mutations.
    Mitochondrial DNA 09/2014; DOI:10.3109/19401736.2014.958728 · 1.21 Impact Factor
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    • "However, a large proportion of patients harbour multiple mitochondrial DNA deletions in skeletal muscle which accumulate throughout life and cause the disorder (Zeviani et al., 1989; Moslemi et al., 1996). Several nuclear-encoded mitochondrial genes have been shown to cause these secondary defects of mitochondrial DNA (Copeland, 2008), but the underlying nuclear gene defect is not known in $50% of cases. Defining the molecular aetiology of this group will have direct implications for clinical management and genetic counselling , and also lead to novel mechanistic insights. "
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    ABSTRACT: Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.
    Brain 04/2014; 137(5). DOI:10.1093/brain/awu060 · 9.20 Impact Factor
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