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.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Spinazzola A,Viscomi C,Fernandez-Vizarra E,Carrara F,D'Adamo P,Calvo S,Marsano RM,Donnini C,Weiher H,Strisciuglio P,Parini R,Sarzi E,Chan A,DiMauro S,Rötig A,Gasparini P,Ferrero I,Mootha VK,Tiranti V,Zeviani Mdoi
10.1038/ng1765keywords:
subject
Has Abstractpub_date
2006-05-01 00:00:00pages
570-5issue
5eissn
1061-4036issn
1546-1718pii
ng1765journal_volume
38pub_type
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