TY - JOUR
T1 - Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency
AU - Melchionda, Laura
AU - Haack, Tobias B.
AU - Hardy, Steven
AU - Abbink, Truus E.M.
AU - Fernandez-Vizarra, Erika
AU - Lamantea, Eleonora
AU - Marchet, Silvia
AU - Morandi, Lucia
AU - Moggio, Maurizio
AU - Carrozzo, Rosalba
AU - Torraco, Alessandra
AU - Diodato, Daria
AU - Strom, Tim M.
AU - Meitinger, Thomas
AU - Tekturk, Pinar
AU - Yapici, Zuhal
AU - Al-Murshedi, Fathiya
AU - Stevens, Rene
AU - Rodenburg, Richard J.
AU - Lamperti, Costanza
AU - Ardissone, Anna
AU - Moroni, Isabella
AU - Uziel, Graziella
AU - Prokisch, Holger
AU - Taylor, Robert W.
AU - Bertini, Enrico
AU - Van Der Knaap, Marjo S.
AU - Ghezzi, Daniele
AU - Zeviani, Massimo
N1 - Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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..
AB - 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..
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U2 - 10.1016/j.ajhg.2014.08.003
DO - 10.1016/j.ajhg.2014.08.003
M3 - Article
C2 - 25175347
AN - SCOPUS:84908254396
SN - 0002-9297
VL - 95
SP - 315
EP - 325
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -