title: Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.
abstract: The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits. Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor. PET117 has not been identified as a mitochondrial disease gene before. Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients, and indicating a pivotal role of this protein in the proper functioning of complex IV. Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this. This case presentation thus implicates mutations in PET117 as a novel cause of mitochondrial disease.
authors.affiliation: Department of Pediatrics, 774 Translational Metabolic Laboratory (TML), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Renkema
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Visser
authors.affiliation: Department of Pediatrics, 774 Translational Metabolic Laboratory (TML), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.|Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-University, Duesseldorf, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Baertling
authors.affiliation: Department of Pediatrics, 774 Translational Metabolic Laboratory (TML), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: L T
authors.initials: LT
authors.lastname: Wintjes
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
authors.forename: V M
authors.initials: VM
authors.lastname: Wolters
authors.affiliation: Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Montfrans
authors.affiliation: Department of Radiology, University Medical Center, Utrecht, The Netherlands.
authors.forename: G A P
authors.initials: GAP
authors.lastname: de Kort
authors.affiliation: Department of Pathology, University Medical Center, Utrecht, The Netherlands.
authors.forename: P G J
authors.initials: PGJ
authors.lastname: Nikkels
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: van Hasselt
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
authors.forename: S N
authors.initials: SN
authors.lastname: van der Crabben
authors.affiliation: Department of Pediatrics, 774 Translational Metabolic Laboratory (TML), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. richard.rodenburg@radboudumc.nl.
authors.forename: R J T
authors.initials: RJT
authors.lastname: Rodenburg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D002675:Child, Preschool; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008526:Medulla Oblongata / Q000473:pathology*; D009154:Mutation; D010085:Oxidative Phosphorylation; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C413044:KAT14 protein, human