title: COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency.
abstract: Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.
authors: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide - Consejo Superior de Investigaciones Científicas - Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras, 41013 Sevilla, Spain.
authors: Gloria
authors: G
authors: Brea-Calvo
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Tobias B
authors: TB
authors: Haack
authors: Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors: Daniela
authors: D
authors: Karall
authors: Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
authors: Akira
authors: A
authors: Ohtake
authors: Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy.
authors: Federica
authors: F
authors: Invernizzi
authors: Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carettere Scientifico, 00165 Rome, Italy.
authors: Rosalba
authors: R
authors: Carrozzo
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Laura
authors: L
authors: Kremer
authors: Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy.
authors: Sabrina
authors: S
authors: Dusi
authors: Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors: Christine
authors: C
authors: Fauth
authors: Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors: Sabine
authors: S
authors: Scholl-Bürgi
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Elisabeth
authors: E
authors: Graf
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Uwe
authors: U
authors: Ahting
authors: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy.
authors: Nicoletta
authors: N
authors: Resta
authors: Neonatology and Neonatal Intensive Care Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy.
authors: Nicola
authors: N
authors: Laforgia
authors: Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carettere Scientifico, 00165 Rome, Italy.
authors: Daniela
authors: D
authors: Verrigni
authors: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan; Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
authors: Yasushi
authors: Y
authors: Okazaki
authors: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
authors: Masakazu
authors: M
authors: Kohda
authors: Unit of Metabolism, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carettere Scientifico, 00165 Rome, Italy.
authors: Diego
authors: D
authors: Martinelli
authors: Department of Pediatrics, Klinikum Reutlingen, 72764 Reutlingen, Germany.
authors: Peter
authors: P
authors: Freisinger
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Tim M
authors: TM
authors: Strom
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Thomas
authors: T
authors: Meitinger
authors: Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy.
authors: Costanza
authors: C
authors: Lamperti
authors: Walter Mackenzie Health Sciences Centre, 8440 112 Street NW, Edmonton, AB T6G 2B7, Canada.
authors: Atilano
authors: A
authors: Lacson
authors: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide - Consejo Superior de Investigaciones Científicas - Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras, 41013 Sevilla, Spain.
authors: Placido
authors: P
authors: Navas
authors: Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
authors: Johannes A
authors: JA
authors: Mayr
authors: Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carettere Scientifico, 00165 Rome, Italy.
authors: Enrico
authors: E
authors: Bertini
authors: Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan; Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors: Kei
authors: K
authors: Murayama
authors: Mitochondrial Biology Unit, Medical Research Council, Hills Road, Cambridge CB2 0XY, UK.
authors: Massimo
authors: M
authors: Zeviani
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany. Electronic address: prokisch@helmholtz-muenchen.de.
authors: Holger
authors: H
authors: Prokisch
authors: Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy. Electronic address: dghezzi@istituto-besta.it.
authors: Daniele
authors: D
authors: Ghezzi
mesh_terms: D000595:Amino Acid Sequence; D001259:Ataxia / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D040461:Gene Components; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018908:Muscle Weakness / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012441:Saccharomyces cerevisiae; D017422:Sequence Analysis, DNA; D014451:Ubiquinone / Q000172:deficiency* / Q000235:genetics
chemical_list: C529610:COQ4 protein, human; D024101:Mitochondrial Proteins; D014451:Ubiquinone