Document Detail

Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.
MedLine Citation:
PMID:  23313956     Owner:  NLM     Status:  MEDLINE    
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.
Cornelia Kornblum; Thomas J Nicholls; Tobias B Haack; Susanne Schöler; Viktoriya Peeva; Katharina Danhauser; Kerstin Hallmann; Gábor Zsurka; Joanna Rorbach; Arcangela Iuso; Thomas Wieland; Monica Sciacco; Dario Ronchi; Giacomo P Comi; Maurizio Moggio; Catarina M Quinzii; Salvatore DiMauro; Sarah E Calvo; Vamsi K Mootha; Thomas Klopstock; Tim M Strom; Thomas Meitinger; Michal Minczuk; Wolfram S Kunz; Holger Prokisch
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-13
Journal Detail:
Title:  Nature genetics     Volume:  45     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-29     Completed Date:  2013-03-26     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  214-9     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Base Sequence
Cloning, Molecular
Codon, Nonsense / genetics
DNA Primers / genetics
DNA Replication / genetics*
DNA, Mitochondrial / genetics*
Exodeoxyribonucleases / genetics*
Gene Components
HeLa Cells
Mitochondrial Diseases / enzymology,  genetics*
Models, Molecular*
Molecular Sequence Data
Sequence Analysis, DNA
Grant Support
C.37//Telethon; C.46//Telethon; GM077465/GM/NIGMS NIH HHS; GM097136/GM/NIGMS NIH HHS; GTB07001//Telethon; GTF01001//Telethon; GTF02008//Telethon; GUP09004//Telethon; K23 HD065871/HD/NICHD NIH HHS; MC_U105697135//Medical Research Council; R01 GM077465/GM/NIGMS NIH HHS; R01 GM097136/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Codon, Nonsense; 0/DNA Primers; 0/DNA, Mitochondrial; EC 3.1.-/Exodeoxyribonucleases; EC 3.1.-/MGME1 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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