Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.

TitleLoss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsKornblum, C, Nicholls, TJ, Haack, TB, Schöler, S, Peeva, V, Danhauser, K, Hallmann, K, Zsurka, G, Rorbach, J, Iuso, A, Wieland, T, Sciacco, M, Ronchi, D, Comi, GP, Moggio, M, Quinzii, CM, DiMauro, S, Calvo, SE, Mootha, VK, Klopstock, T, Strom, TM, Meitinger, T, Minczuk, M, Kunz, WS, Prokisch, H
JournalNat Genet
Date Published2013 Feb
KeywordsAmino Acid Sequence, Base Sequence, Cloning, Molecular, Codon, Nonsense, DNA Primers, DNA Replication, DNA, Mitochondrial, Exodeoxyribonucleases, Gene Components, HeLa Cells, Humans, Mitochondrial Diseases, Models, Molecular, Molecular Sequence Data, Sequence Analysis, DNA

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.

Alternate JournalNat. Genet.
Citation Key10.1038/ng.2501
PubMed ID23313956
PubMed Central IDPMC3678843
Grant ListC.37 / / Telethon / Italy
R01 GM097136 / GM / NIGMS NIH HHS / United States
C.46 / / Telethon / Italy
GTF01001 / / Telethon / Italy
GM097136 / GM / NIGMS NIH HHS / United States
GUP09004 / / Telethon / Italy
GTB07001 / / Telethon / Italy
K23 HD065871 / HD / NICHD NIH HHS / United States
MC_U105697135 / / Medical Research Council / United Kingdom
GTF02008 / / Telethon / Italy
GM077465 / GM / NIGMS NIH HHS / United States
R01 GM077465 / GM / NIGMS NIH HHS / United States