title: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.
abstract: 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.
authors: Department of Neurology, University of Bonn Medical Center, Bonn, Germany.
authors: Cornelia
authors: C
authors: Kornblum
authors: Thomas J
authors: TJ
authors: Nicholls
authors: Tobias B
authors: TB
authors: Haack
authors: Susanne
authors: S
authors: Schöler
authors: Viktoriya
authors: V
authors: Peeva
authors: Katharina
authors: K
authors: Danhauser
authors: Kerstin
authors: K
authors: Hallmann
authors: Gábor
authors: G
authors: Zsurka
authors: Joanna
authors: J
authors: Rorbach
authors: Arcangela
authors: A
authors: Iuso
authors: Thomas
authors: T
authors: Wieland
authors: Monica
authors: M
authors: Sciacco
authors: Dario
authors: D
authors: Ronchi
authors: Giacomo P
authors: GP
authors: Comi
authors: Maurizio
authors: M
authors: Moggio
authors: Catarina M
authors: CM
authors: Quinzii
authors: Salvatore
authors: S
authors: DiMauro
authors: Sarah E
authors: SE
authors: Calvo
authors: Vamsi K
authors: VK
authors: Mootha
authors: Thomas
authors: T
authors: Klopstock
authors: Tim M
authors: TM
authors: Strom
authors: Thomas
authors: T
authors: Meitinger
authors: Michal
authors: M
authors: Minczuk
authors: Wolfram S
authors: WS
authors: Kunz
authors: Holger
authors: H
authors: Prokisch
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D018389:Codon, Nonsense / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000235:genetics*; D040461:Gene Components; D006367:HeLa Cells; D006801:Humans; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; D004272:DNA, Mitochondrial; D005090:Exodeoxyribonucleases; C579164:MGME1 protein, human