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.

Download full-text


Available from: William C Copeland, Dec 20, 2013
  • Source
    • "In addition to direct mutations in mtDNA, mtDNA dysfunction can also be caused by mutations in nDNA (Figure 1). MtDNA-related nuclear genes that cause disease mainly affect mtDNA replication and copy number maintenance, and they fall into two categories: those that directly affect the mtDNA replication fork and mutations in genes that are involved in the supply of nucleotides for mtDNA replication (such as mitochondrial thymidine kinase TK2, the deoxyguanosine kinase dGK, and adenine nucleotide transporter ANT1) (Copeland, 2008). The effects of these mutations are sometimes called secondary mtDNA defects. "

    Turkish Journal of Biology 08/2015; 39:840-855. DOI:10.3906/biy-1505-20 · 1.34 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
Show more