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Loss-of-function Mutations In MGME1 Impair MtDNA Replication And Cause Multisystemic Mitochondrial Disease

C. Kornblum, T. Nicholls, T. Haack, S. Schoeler, V. Peeva, K. Danhauser, K. Hallmann, G. Zsurka, J. Rorbach, A. Iuso, T. Wieland, M. Sciacco, D. Ronchi, G. Comi, M. Moggio, C. Quinzii, S. Dimauro, S. Calvo, V. Mootha, T. Klopstock, T. Strom, T. Meitinger, M. Minczuk, W. Kunz, H. Prokisch
Published 2013 · Medicine, Biology

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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.
This paper references
10.1128/MCB.01834-08
Human Dna2 Is a Nuclear and Mitochondrial DNA Maintenance Protein
Julien P. Duxin (2009)
10.1093/NAR/28.18.3417
SURVEY AND SUMMARY: holliday junction resolvases and related nucleases: identification of new families, phyletic distribution and evolutionary trajectories.
L. Aravind (2000)
10.1007/978-1-59745-365-3_16
Analysis of replicating mitochondrial DNA by two-dimensional agarose gel electrophoresis.
A. Reyes (2007)
10.1038/90058
Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria
J. N. Spelbrink (2001)
10.1093/nar/gkm215
Expression of catalytic mutants of the mtDNA helicase Twinkle and polymerase POLG causes distinct replication stalling phenotypes
S. Wanrooij (2007)
10.1093/nar/gkr470
PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria
J. Rorbach (2011)
10.1126/scitranslmed.3003310
Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing
S. Calvo (2012)
10.1016/j.molcel.2008.11.007
DNA2 resolves expanding flap in mitochondrial base excision repair.
W. Copeland (2008)
10.1016/j.molcel.2008.09.024
Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates.
L. Zheng (2008)
10.1016/j.jmb.2010.02.029
Mammalian mitochondrial DNA replication intermediates are essentially duplex but contain extensive tracts of RNA/DNA hybrid.
J. Pohjoismäki (2010)
10.1093/NAR/30.9.2004
Release of replication termination controls mitochondrial DNA copy number after depletion with 2',3'-dideoxycytidine.
T. Brown (2002)
10.1086/430843
Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion.
O. Elpeleg (2005)
10.1128/MCB.00457-08
Removal of Oxidative DNA Damage via FEN1-Dependent Long-Patch Base Excision Repair in Human Cell Mitochondria
P. Liu (2008)
10.1097/NEN.0b013e3181839b2d
Clonally Expanded Mitochondrial DNA Mutations in Epileptic Individuals With Mutated DNA Polymerase &ggr;
G. Zsurka (2008)
10.1136/jmedgenet-2012-100846
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing
T. Haack (2012)
10.1038/ng2040
Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion
A. Bourdon (2007)
10.1016/j.cell.2008.06.016
A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology
D. J. Pagliarini (2008)
University of Cologne; 1:40,000 dilution), Histone H4 (Abcam, ab10158; 1:5,000 dilution), GAPDH (Abcam, ab9482; 1:1,000 dilution) and TOM20
Tfam r
10.1074/jbc.M110.215715
APOPTOSIS INDUCED BY PERSISTENT SINGLE-STRAND BREAKS IN THE MITOCHONDRIAL GENOME: CRITICAL ROLE OF EXOG (5’ EXO/ENDONUCLEASE) IN THEIR REPAIR
Anne W. Tann (2011)
10.1126/SCIENCE.289.5480.782
Role of adenine nucleotide translocator 1 in mtDNA maintenance.
J. Kaukonen (2000)
10.1038/ng1765
MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion
A. Spinazzola (2006)
10.1038/nature02988
Crystal structure of RecBCD enzyme reveals a machine for processing DNA breaks
M. Singleton (2004)
10.1038/ng746
The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA
H. Mandel (2001)
10.1126/SCIENCE.283.5402.689
Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.
I. Nishino (1999)
10.1007/s12033-008-9100-5
MitoP2: An Integrative Tool for the Analysis of the Mitochondrial Proteome
M. Elstner (2008)
10.1086/519222
Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion.
E. Ostergaard (2007)
10.1101/gr.107524.110
The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
A. McKenna (2010)
10.1016/S0092-8674(00)80688-1
Coupled Leading- and Lagging-Strand Synthesis of Mammalian Mitochondrial DNA
I. Holt (2000)
10.1016/j.bbadis.2010.11.012
POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts.
J. D. Stewart (2011)
10.1093/nar/gks382
Sequence, structure and functional diversity of PD-(D/E)XK phosphodiesterase superfamily
Kamil Steczkiewicz (2012)
10.1038/90034
Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions
G. Goethem (2001)
10.1016/j.ymgme.2011.03.004
Cellular rescue-assay aids verification of causative DNA-variants in mitochondrial complex I deficiency.
K. Danhauser (2011)
10.1086/504303
Mutant POLG2 Disrupts DNA Polymerase γ Subunits and Causes Progressive External Ophthalmoplegia
M. Longley (2006)
10.1038/ng751
Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy
Ann Saada (2001)



This paper is referenced by
10.1016/j.arr.2016.04.006
Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases
Karen L. DeBalsi (2017)
10.1093/nar/gkz241
A unique exonuclease ExoG cleaves between RNA and DNA in mitochondrial DNA replication
Chyuan-Chuan Wu (2019)
Generating mammalian mitochondrial disease models with mitochondrial DNA mutations
Johanna H K Kauppila (2018)
10.1016/j.bbadis.2017.02.017
Mitochondrial DNA maintenance defects.
A. El-Hattab (2017)
10.1001/jamaneurol.2014.1753
Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28.
G. Gorman (2015)
Proteomics of lipid accumulation and DGAT inhibition in HepG2 liver carcinoma cells
Bhumika Bhatt-Wessel (2017)
10.1007/978-3-030-05517-2_12
Mitochondrial Depletion Syndromes
S. Parikh (2019)
10.1038/nrneurol.2013.126
The clinical maze of mitochondrial neurology
S. Dimauro (2013)
Clinical and genetic studies in paediatric mitochondrial disease
Yng Wedatilake (2017)
10.3390/ijms18071562
DNA2—An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein?
E. Pawlowska (2017)
10.1016/j.ajhg.2016.05.027
Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy.
Robert Kopajtich (2016)
10.1016/bs.enz.2019.08.004
Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response.
Linlin Zhao (2019)
10.1038/s41467-018-03552-x
Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria
S. Matic (2018)
10.1101/280339
Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery
Bruno Giotti (2018)
10.1186/s12993-018-0135-x
Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion
Noémi Ágnes Varga (2018)
10.1016/j.biochi.2013.09.017
To be or not to be a nucleoid protein: a comparison of mass-spectrometry based approaches in the identification of potential mtDNA-nucleoid associated proteins.
F. Hensen (2014)
10.1002/jimd.12104
Recent advances in understanding the molecular genetic basis of mitochondrial disease
Kyle Thompson (2019)
10.1093/bib/bbx038
Next-generation sequencing data analysis
Christian T. K.-H. Stadtländer (2018)
10.3389/fgene.2019.00576
Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions
Lidia Carreño-Gago (2019)
10.1096/fj.201801591R
Increased dNTP pools rescue mtDNA depletion in human POLG‐deficient fibroblasts
C. Blázquez-Bermejo (2019)
10.1093/nar/gku797
The CRISPR-associated Cas4 protein Pcal_0546 from Pyrobaculum calidifontis contains a [2Fe-2S] cluster: crystal structure and nuclease activity
Sofia Lemak (2014)
10.1016/B978-0-12-800877-5.00022-X
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
Michio Hirano (2016)
10.1172/jci128514
SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.
V. Del Dotto (2019)
10.20944/PREPRINTS201706.0059.V1
Pathology of Adult and Paediatric Mitochondrial Myopathies
Rahul Phadke (2017)
Probing the Mammalian Mitochondrial Nucleoid
Nina K. Rajala (2015)
10.1016/j.neurol.2014.03.007
An overview of neurological and neuromuscular signs in mitochondrial diseases.
A. Chaussenot (2014)
10.1177/0883073814537380
Defects of Mitochondrial DNA Replication
W. Copeland (2014)
10.1155/2013/293893
Mitochondrial Fusion Proteins and Human Diseases
M. Ranieri (2013)
10.1016/B978-0-12-417044-5.00041-X
Chapter 41 – Mitochondrial Encephalomyopathies
D. C. Vivo (2015)
10.1007/978-3-030-27371-2
Genetic Causes of Cardiac Disease
J. Erdmann (2019)
10.1016/j.envpol.2019.113266
Air pollution and placental mitochondrial DNA copy number: Mechanistic insights and epidemiological challenges.
Zhen Li (2019)
10.1002/bies.201800102
Known Unknowns of Mammalian Mitochondrial DNA Maintenance
Jaakko L. O. Pohjoismäki (2018)
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