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

Am J Hum Genet. 2014 Sep 4;95(3):315-25. doi: 10.1016/j.ajhg.2014.08.003.

Laura Melchionda ¹, Tobias B Haack ², Steven Hardy ³, Truus E M Abbink ⁴, Erika Fernandez-Vizarra ⁵, Eleonora Lamantea ¹, Silvia Marchet ¹, Lucia Morandi ⁶, Maurizio Moggio ⁷, Rosalba Carrozzo ⁸, Alessandra Torraco ⁸, Daria Diodato ⁹, Tim M Strom ², Thomas Meitinger ², Pinar Tekturk ¹⁰, Zuhal Yapici ¹⁰, Fathiya Al-Murshedi ¹¹, René Stevens ¹², Richard J Rodenburg ¹³, Costanza Lamperti ¹, Anna Ardissone ¹⁴, Isabella Moroni ¹⁴, Graziella Uziel ¹⁴, Holger Prokisch ², Robert W Taylor ³, Enrico Bertini ⁸, Marjo S van der Knaap ⁴, Daniele Ghezzi ¹⁵, Massimo Zeviani ¹⁶

Affiliations

1 Unit of Molecular Neurogenetics, Foundation IRCCS Institute of Neurology Besta, 20126 Milan, Italy.
2 Institute of Human Genetics, Technische Universität München, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
3 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
4 Departments of Child Neurology and Functional Genomics, Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
5 MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK.
6 Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Institute of Neurology Besta, 20133 Milan, Italy.
7 Neuromuscular Unit, Department of Neurology, Centro Dino Ferrari, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
8 Unit of Neuromuscular Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, 00165 Rome, Italy.
9 Unit of Molecular Neurogenetics, Foundation IRCCS Institute of Neurology Besta, 20126 Milan, Italy; Unit of Neuromuscular Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, 00165 Rome, Italy.
10 Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34098 Istanbul, Turkey.
11 Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat 123, Oman.
12 Department of Paediatrics, CHC Clinique de l'Espérance at Liège, Liège 4000, Belgium.
13 Nijmegen Center for Mitochondrial Disorders, Laboratory for Genetic, Endocrine, and Metabolic Disorders, Department of Pediatrics, Radboud University Medical Center, 9101 Nijmegen, the Netherlands.
14 Department of Child Neurology, Foundation IRCCS Institute of Neurology Besta, 20133 Milan, Italy.
15 Unit of Molecular Neurogenetics, Foundation IRCCS Institute of Neurology Besta, 20126 Milan, Italy. Electronic address: [email protected].
16 Unit of Molecular Neurogenetics, Foundation IRCCS Institute of Neurology Besta, 20126 Milan, Italy; MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK. Electronic address: [email protected].

PMID: 25175347 DOI: 10.1016/j.ajhg.2014.08.003

Abstract

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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