Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease
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Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2) or the biosynthesis pathways of deoxyribonucleoside 5'-triphosphates for mtDNA synthesis. However, in many of these disorders, the underlying genetic defect has yet to be discovered. Here, we identify homozygous nonsense and missense mutations in the orphan gene C20orf72 in three families with a mitochondrial syndrome characterized by external ophthalmoplegia, emaciation and respiratory failure. Muscle biopsies showed mtDNA depletion and multiple mtDNA deletions. C20orf72, hereafter MGME1 (mitochondrial genome maintenance exonuclease 1), encodes a mitochondrial RecB-type exonuclease belonging to the PD-(D/E)XK nuclease superfamily. We show that MGME1 cleaves single-stranded DNA and processes DNA flap substrates. Fibroblasts from affected individuals do not repopulate after chemically induced mtDNA depletion. They also accumulate intermediates of stalled replication and show increased levels of 7S DNA, as do MGME1-depleted cells. Thus, we show that MGME1-mediated mtDNA processing is essential for mitochondrial genome maintenance.
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Three different families presenting with PEO, skeletal muscle wasting/weakness, emaciation and respiratory distress bear MGME1 mutations.
“Three different families presenting with PEO, skeletal muscle wasting/weakness, emaciation and respiratory distress bear MGME1 mutations (Kornblum et al., 2013).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Kornblum et al., 2013
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- Authors
- Kornblum, C., Nicholls, T. J., Haack, T. B., Schöler, S., Peeva, V., Danhauser, K., Hallmann, K., Zsurka, G., Rorbach, J., Iuso, A., Wieland, T., Sciacco, M., Ronchi, D., Comi, G. P., Moggio, M., Quinzii, C. M., DiMauro, S., Calvo, S. E., Mootha, V. K., Klopstock, T., Strom, T. M., Meitinger, T., Minczuk, M., Kunz, W. S., & Prokisch, H.
- Affiliations
- University of Bonn (DE)
- MRC Mitochondrial Biology Unit (GB)
- Helmholtz Munich (DE)
- University of Milan (IT)
- Columbia University Irving Medical Center (US)
- Broad Institute (US)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Minczuk, Michal
- Kunz, Wolfram S
- ORCID
- Kornblum, Cornelia
- Nicholls, Thomas J
- Haack, Tobias B
- Peeva, Viktoriya
- Danhauser, Katharina
- Zsurka, Gábor
- Rorbach, Joanna
- Iuso, Arcangela
- Wieland, Thomas
- Sciacco, Monica
- Ronchi, Dario
- Comi, Giacomo P
- Moggio, Maurizio
- Quinzii, Catarina M
- Calvo, Sarah E
- Mootha, Vamsi K
- Klopstock, Thomas
- Meitinger, Thomas
- Minczuk, Michal
- Kunz, Wolfram S
- Prokisch, Holger
- Venue
- Nature Genetics
- Published
- 2013-01-13
- Volume
- 45
- Issue
- 2
- Pages
- 214-219
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3678843
- OpenAlex
- W2091701724
- Cited by
- 232
- References
- 33
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 15 · 2023: 14 · 2022: 15 · 2021: 16 · 2020: 16 · 2019: 26 · 2018: 12 · 2017: 22 · 2016: 24 · 2015: 16 · 2014: 20 · 2013: 15
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM077465, GM097136, R01GM097136, R01GM077465)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23HD065871)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial DNA replication, mitochondrial DNA maintenance, single-stranded DNA cleavage, mitochondrial DNA deletions, mtDNA depletion, external ophthalmoplegia, respiratory failure
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cloning, Molecular, DNA Replication, DNA, Mitochondrial, Exodeoxyribonucleases, HeLa Cells, Humans, Models, Molecular, Molecular Sequence Data, Sequence Analysis, DNA, DNA Primers, Codon, Nonsense, Mitochondrial Diseases, Gene Components
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