MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion
Top Cited Papers
- 2 April 2006
- journal article
- letter
- Published by Springer Nature in Nature Genetics
- Vol. 38 (5) , 570-575
- https://doi.org/10.1038/ng1765
Abstract
The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17−/− mice.Keywords
This publication has 32 references indexed in Scilit:
- NEW DEVELOPMENTS IN MITOCHONDRIAL ASSEMBLYAnnual Review of Cell and Developmental Biology, 2004
- SYM1 Is the Stress-Induced Saccharomyces cerevisiae Ortholog of the Mammalian Kidney Disease Gene Mpv17 and Is Required for Ethanol Metabolism and Tolerance during Heat ShockEukaryotic Cell, 2004
- The Protein Import Machinery of MitochondriaJournal of Biological Chemistry, 2004
- Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stabilityHuman Molecular Genetics, 2004
- Ethylmalonic Encephalopathy Is Caused by Mutations in ETHE1, a Gene Encoding a Mitochondrial Matrix ProteinAmerican Journal of Human Genetics, 2004
- Insertion of Hydrophobic Membrane Proteins into the Inner Mitochondrial Membrane—A Guided TourJournal of Molecular Biology, 2003
- Structure of the Signal Sequences for Two Mitochondrial Matrix Proteins That Are Not Proteolytically Processed upon ImportBiochemistry, 1994
- Transgenic mouse model of kidney disease: Insertional inactivation of ubiquitously expressed gene leads to nephrotic syndromeCell, 1990
- Site-directed mutagenesis by overlap extension using the polymerase chain reactionGene, 1989
- Mitochondrial DNA from yeast “petite” mutants: Specific changes of buoyant density corresponding to different cytoplasmic mutationsBiochemical and Biophysical Research Communications, 1966