Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency.

TitleMutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency.
Publication TypeJournal Article
Year of Publication2014
AuthorsMelchionda, L, Haack, TB, Hardy, S, Abbink, TEM, Fernandez-Vizarra, E, Lamantea, E, Marchet, S, Morandi, L, Moggio, M, Carrozzo, R, Torraco, A, Diodato, D, Strom, TM, Meitinger, T, Tekturk, P, Yapici, Z, Al-Murshedi, F, Stevens, R, Rodenburg, RJ, Lamperti, C, Ardissone, A, Moroni, I, Uziel, G, Prokisch, H, Taylor, RW, Bertini, E, van der Knaap, MS, Ghezzi, D, Zeviani, M
JournalAm J Hum Genet
Date Published2014 Sep 04
KeywordsAdolescent, Adult, Apoptosis Regulatory Proteins, Cells, Cultured, Child, Child, Preschool, Cytochrome-c Oxidase Deficiency, Electron Transport Complex IV, Female, Fibroblasts, Humans, Infant, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Mitochondria, Mitochondrial Proteins, Mutation, Myoblasts

Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined. Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein. We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2014.08.003
PubMed ID25175347
PubMed Central IDPMC4157140
Grant ListGGP11011 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom
MR/K000608/1 / / Medical Research Council / United Kingdom
322424 / / European Research Council / International
GTB12001 / / Telethon / Italy
G0601943 / / Medical Research Council / United Kingdom