MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.
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.
Spinazzola
Antonella
A
Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute C. Besta, Milan 20126, Italy.
Viscomi
Carlo
C
Fernandez-Vizarra
Erika
E
Carrara
Franco
F
D'Adamo
Pio
P
Calvo
Sarah
S
Marsano
René Massimiliano
RM
Donnini
Claudia
C
Weiher
Hans
H
Strisciuglio
Pietro
P
Parini
Rossella
R
Sarzi
Emmanuelle
E
Chan
Alicia
A
DiMauro
Salvatore
S
Rötig
Agnes
A
Gasparini
Paolo
P
Ferrero
Iliana
I
Mootha
Vamsi K
VK
Tiranti
Valeria
V
Zeviani
Massimo
M
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002889:Chromosomes, Human, Pair 2; D003001:Cloning, Molecular; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D013577:Syndrome
D004272:DNA, Mitochondrial; C511128:MPV17L protein, human; D008565:Membrane Proteins