Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease
Michal Minczuk, Wolfram Kunz and colleagues report that loss-of-function mutations in MGME1 impair mitochondrial DNA replication and cause a multisystemic mitochondrial disease. Their functional studies show that MGME1 encodes a RecB-type exonuclease that cleaves single-stranded DNA and processes DN...
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| Published in | Nature genetics Vol. 45; no. 2; pp. 214 - 219 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.02.2013
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1061-4036 1546-1718 1546-1718 |
| DOI | 10.1038/ng.2501 |
Cover
| Abstract | Michal Minczuk, Wolfram Kunz and colleagues report that loss-of-function mutations in
MGME1
impair mitochondrial DNA replication and cause a multisystemic mitochondrial disease. Their functional studies show that
MGME1
encodes a RecB-type exonuclease that cleaves single-stranded DNA and processes DNA flap substrates.
Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (
POLG
,
POLG2
and
C10orf2
)
1
,
2
,
3
or the biosynthesis pathways of deoxyribonucleoside 5′-triphosphates for mtDNA synthesis
4
,
5
,
6
,
7
,
8
,
9
,
10
,
11
. 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. |
|---|---|
| AbstractList | 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. [PUBLICATION ABSTRACT] Michal Minczuk, Wolfram Kunz and colleagues report that loss-of-function mutations in MGME1 impair mitochondrial DNA replication and cause a multisystemic mitochondrial disease. Their functional studies show that MGME1 encodes a RecB-type exonuclease that cleaves single-stranded DNA and processes DNA flap substrates. Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery ( POLG , POLG2 and C10orf2 ) 1 , 2 , 3 or the biosynthesis pathways of deoxyribonucleoside 5′-triphosphates for mtDNA synthesis 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . 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. 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. 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.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. Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2) (1-3) or the biosynthesis pathways of deoxyribonucleoside 5'-triphosphates for mtDNA synthesis (4-11). 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. |
| Audience | Academic |
| Author | Quinzii, Catarina M Kornblum, Cornelia Zsurka, Gábor Minczuk, Michal Kunz, Wolfram S Comi, Giacomo P Meitinger, Thomas Iuso, Arcangela Ronchi, Dario Schöler, Susanne Strom, Tim M Mootha, Vamsi K Nicholls, Thomas J Rorbach, Joanna Moggio, Maurizio Wieland, Thomas Peeva, Viktoriya Hallmann, Kerstin Klopstock, Thomas Danhauser, Katharina Haack, Tobias B Calvo, Sarah E Prokisch, Holger DiMauro, Salvatore Sciacco, Monica |
| Author_xml | – sequence: 1 givenname: Cornelia surname: Kornblum fullname: Kornblum, Cornelia organization: Department of Neurology, University of Bonn Medical Center – sequence: 2 givenname: Thomas J surname: Nicholls fullname: Nicholls, Thomas J organization: Medical Research Council (MRC) Mitochondrial Biology Unit – sequence: 3 givenname: Tobias B surname: Haack fullname: Haack, Tobias B organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health – sequence: 4 givenname: Susanne surname: Schöler fullname: Schöler, Susanne organization: Department of Epileptology, University of Bonn Medical Center, Life and Brain Center, University of Bonn Medical Center – sequence: 5 givenname: Viktoriya surname: Peeva fullname: Peeva, Viktoriya organization: Department of Epileptology, University of Bonn Medical Center, Life and Brain Center, University of Bonn Medical Center – sequence: 6 givenname: Katharina surname: Danhauser fullname: Danhauser, Katharina organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health – sequence: 7 givenname: Kerstin surname: Hallmann fullname: Hallmann, Kerstin organization: Department of Epileptology, University of Bonn Medical Center, Life and Brain Center, University of Bonn Medical Center – sequence: 8 givenname: Gábor surname: Zsurka fullname: Zsurka, Gábor organization: Department of Epileptology, University of Bonn Medical Center, Life and Brain Center, University of Bonn Medical Center – sequence: 9 givenname: Joanna surname: Rorbach fullname: Rorbach, Joanna organization: Medical Research Council (MRC) Mitochondrial Biology Unit – sequence: 10 givenname: Arcangela surname: Iuso fullname: Iuso, Arcangela organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health – sequence: 11 givenname: Thomas surname: Wieland fullname: Wieland, Thomas organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health – sequence: 12 givenname: Monica surname: Sciacco fullname: Sciacco, Monica organization: Neuromuscular Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda, Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan – sequence: 13 givenname: Dario surname: Ronchi fullname: Ronchi, Dario organization: Neurology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan – sequence: 14 givenname: Giacomo P surname: Comi fullname: Comi, Giacomo P organization: Neurology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan – sequence: 15 givenname: Maurizio surname: Moggio fullname: Moggio, Maurizio organization: Neuromuscular Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda, Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan – sequence: 16 givenname: Catarina M surname: Quinzii fullname: Quinzii, Catarina M organization: Department of Neurology, Columbia University Medical Center – sequence: 17 givenname: Salvatore surname: DiMauro fullname: DiMauro, Salvatore organization: Department of Neurology, Columbia University Medical Center – sequence: 18 givenname: Sarah E surname: Calvo fullname: Calvo, Sarah E organization: Department of Molecular Biology and Medicine, Massachusetts General Hospital, Department of Systems Biology, Harvard Medical School, Broad Institute – sequence: 19 givenname: Vamsi K surname: Mootha fullname: Mootha, Vamsi K organization: Department of Molecular Biology and Medicine, Massachusetts General Hospital, Department of Systems Biology, Harvard Medical School, Broad Institute – sequence: 20 givenname: Thomas surname: Klopstock fullname: Klopstock, Thomas organization: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität München – sequence: 21 givenname: Tim M surname: Strom fullname: Strom, Tim M organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health – sequence: 22 givenname: Thomas surname: Meitinger fullname: Meitinger, Thomas organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health – sequence: 23 givenname: Michal surname: Minczuk fullname: Minczuk, Michal email: michal.minczuk@mrc-mbu.cam.ac.uk organization: Medical Research Council (MRC) Mitochondrial Biology Unit – sequence: 24 givenname: Wolfram S surname: Kunz fullname: Kunz, Wolfram S email: wolfram.kunz@ukb.uni-bonn.de organization: Department of Epileptology, University of Bonn Medical Center, Life and Brain Center, University of Bonn Medical Center – sequence: 25 givenname: Holger surname: Prokisch fullname: Prokisch, Holger organization: Institute of Human Genetics, Technische Universität München and Helmholtz Zentrum München–German Research Center for Environmental Health |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23313956$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Springer Nature America, Inc. 2013 COPYRIGHT 2013 Nature Publishing Group Copyright Nature Publishing Group Feb 2013 |
| Copyright_xml | – notice: Springer Nature America, Inc. 2013 – notice: COPYRIGHT 2013 Nature Publishing Group – notice: Copyright Nature Publishing Group Feb 2013 |
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| DOI | 10.1038/ng.2501 |
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| Snippet | Michal Minczuk, Wolfram Kunz and colleagues report that loss-of-function mutations in
MGME1
impair mitochondrial DNA replication and cause a multisystemic... Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2) or... Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2)... |
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| SubjectTerms | 631/208/726/2129 631/208/737 631/337/151 692/699/317 Abnormalities Agriculture Amino Acid Sequence Animal Genetics and Genomics Base Sequence Biomedicine Biosynthesis Cancer Research Cloning, Molecular Codon, Nonsense - genetics DNA Primers - genetics DNA Replication - genetics DNA, Mitochondrial - genetics Enzymes Exodeoxyribonucleases - genetics Gene Components Gene Function Gene mutations Health aspects HeLa Cells Human Genetics Humans letter Mitochondrial diseases Mitochondrial Diseases - enzymology Mitochondrial Diseases - genetics Mitochondrial DNA Models, Molecular Molecular Sequence Data Mutation Physiological aspects Proteins Risk factors Sequence Analysis, DNA |
| Title | Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease |
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