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Mutations in APOPT1, Encoding a Mitochondria! Protein, Cause Cavitating Leukoencephalopathy with Cytochrome c Oxidase Deficiency

Lookup NU author(s): Dr Steven Hardy, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Melchionda 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

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2014

Volume: 95

Issue: 3

Pages: 315-325

Print publication date: 04/09/2014

Online publication date: 28/08/2014

Acceptance date: 08/08/2014

Date deposited: 13/11/2014

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2014.08.003


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Funder referenceFunder name
German Federal Ministry of Education and Research (BMBF) - German Center for Diabetes Research (DZD e.V.)
Lily Foundation
Pierfranco and Luisa Mariani Foundation of Italy
UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service
Italian Association of Mitochondrial Disease Patients and Families (Mitocon)
01GM1113CGerman Network for Mitochondrial Disorders (mitoNET)
01GM1207E-Rare project GENOMIT, Medical Research Council, UK
0315494ASystems Biology of Metabotypes (SysMBo)
096919/Z/11/ZWellcome Trust Strategic Award
91211005Dutch Organisation for Scientific Research (ZonMw, TOP)
FWF I 920-B13E-Rare project GENOMIT, Medical Research Council, UK
FP7-322424European Research Council (ERC)
GPP10005Fondazione Telethon
GR2010-2316392Italian Ministry of Health
GTB12001JTelethon Network of Genetic Biobanks
G0601943MRC Centre for Neuromuscular Diseases
GGP11011Fondazione Telethon
HA-215Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society
RF-INN-2007-634163Italian Ministry of Health