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MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion

Nat Genet. 2006 May;38(5):570-5. doi: 10.1038/ng1765. Epub 2006 Apr 2.

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 hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. 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. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Chromosomes, Human, Pair 2
  • Cloning, Molecular
  • DNA, Mitochondrial / genetics*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Intracellular Membranes / metabolism*
  • Liver Diseases / genetics*
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Mice
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Syndrome

Substances

  • DNA, Mitochondrial
  • MPV17L protein, human
  • Membrane Proteins