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

• Published in: Nature genetics Vol. 45; no. 2; pp. 214 - 219
• Main Authors: Kornblum, Cornelia, Nicholls, Thomas J, Haack, Tobias B, Schöler, Susanne, Peeva, Viktoriya, Danhauser, Katharina, Hallmann, Kerstin, Zsurka, Gábor, Rorbach, Joanna, Iuso, Arcangela, Wieland, Thomas, Sciacco, Monica, Ronchi, Dario, Comi, Giacomo P, Moggio, Maurizio, Quinzii, Catarina M, DiMauro, Salvatore, Calvo, Sarah E, Mootha, Vamsi K, Klopstock, Thomas, Strom, Tim M, Meitinger, Thomas, Minczuk, Michal, Kunz, Wolfram S, Prokisch, Holger
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2013; Nature Publishing Group
• Subjects: 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; Germany
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2501

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.