2. Academic Validation
  3. COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency

COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency

  • Am J Hum Genet. 2015 Feb 5;96(2):309-17. doi: 10.1016/j.ajhg.2014.12.023.
Gloria Brea-Calvo 1,  Tobias B Haack 2,  Daniela Karall 3,  Akira Ohtake 4,  Federica Invernizzi 5,  Rosalba Carrozzo 6,  Laura Kremer 2,  Sabrina Dusi 5,  Christine Fauth 7,  Sabine Scholl-Bürgi 3,  Elisabeth Graf 2,  Uwe Ahting 2,  Nicoletta Resta 8,  Nicola Laforgia 9,  Daniela Verrigni 6,  Yasushi Okazaki 10,  Masakazu Kohda 11,  Diego Martinelli 12,  Peter Freisinger 13,  Tim M Strom 2,  Thomas Meitinger 2,  Costanza Lamperti 5,  Atilano Lacson 14,  Placido Navas 1,  Johannes A Mayr 15,  Enrico Bertini 6,  Kei Murayama 16,  Massimo Zeviani 17,  Holger Prokisch 18,  Daniele Ghezzi 19
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 4 Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
  • 5 Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy.
  • 6 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.
  • 7 Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 8 Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy.
  • 9 Neonatology and Neonatal Intensive Care Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy.
  • 10 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.
  • 11 Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
  • 12 Unit of Metabolism, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carettere Scientifico, 00165 Rome, Italy.
  • 13 Department of Pediatrics, Klinikum Reutlingen, 72764 Reutlingen, Germany.
  • 14 Walter Mackenzie Health Sciences Centre, 8440 112 Street NW, Edmonton, AB T6G 2B7, Canada.
  • 15 Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
  • 16 Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan; Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
  • 17 Mitochondrial Biology Unit, Medical Research Council, Hills Road, Cambridge CB2 0XY, UK.
  • 18 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: [email protected].
  • 19 Unit of Molecular Neurogenetics, Foundation of the Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carettere Scientifico, 20126 Milan, Italy. Electronic address: [email protected].
PMID: 25658047 DOI: 10.1016/j.ajhg.2014.12.023
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.

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