Affordable Access

deepdyve-link
Publisher Website

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.

Authors
  • Wortmann, Saskia B1, 2, 3
  • Timal, Sharita4, 5
  • Venselaar, Hanka6
  • Wintjes, Liesbeth T4
  • Kopajtich, Robert2
  • Feichtinger, René G1
  • Onnekink, Carla7, 8
  • Mühlmeister, Mareike4
  • Brandt, Ulrich4
  • Smeitink, Jan A4
  • Veltman, Joris A9, 10
  • Sperl, Wolfgang1
  • Lefeber, Dirk5
  • Pruijn, Ger7, 8
  • Stojanovic, Vesna11, 12
  • Freisinger, Peter13
  • V Spronsen, Francjan14
  • Derks, Terry Gj14
  • Veenstra-Knol, Hermine E15
  • Mayr, Johannes A1
  • And 4 more
  • 1 Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria. , (Austria)
  • 2 Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany. , (Germany)
  • 3 Institute of Human Genetics, Technische Universität München, Munich, Germany. , (Germany)
  • 4 Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 5 Department of Neurology, Donders Center for Brain, Cognition, and Behavior, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 6 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 7 Department of Biomolecular Chemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. , (Netherlands)
  • 8 Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 9 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. , (Netherlands)
  • 10 Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom. , (United Kingdom)
  • 11 School of Medicine, University of Novi Sad, Novi Sad, Serbia. , (Serbia)
  • 12 Institute for Child and Youth Health Care of Vojvodina, Intensive Care Unit, Novi Sad, Serbia. , (Serbia)
  • 13 Children's Hospital, Klinikum am Steinenberg, Reutlingen, Germany. , (Germany)
  • 14 Division of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center of Groningen, Groningen, the Netherlands. , (Netherlands)
  • 15 Department of Genetics, University of Groningen, University Medical Center of Groningen, Groningen, the Netherlands. , (Netherlands)
  • 16 INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France. , (France)
  • 17 Department of Pediatrics, Division of Neuromuscular and Neurometabolic Diseases, McMaster University Medical Center, Hamilton, Ontario, Canada. , (Canada)
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2017
Volume
38
Issue
12
Pages
1786–1795
Identifiers
DOI: 10.1002/humu.23340
PMID: 28905505
Source
Medline
Keywords
License
Unknown

Abstract

Mitochondrial protein synthesis involves an intricate interplay between mitochondrial DNA encoded RNAs and nuclear DNA encoded proteins, such as ribosomal proteins and aminoacyl-tRNA synthases. Eukaryotic cells contain 17 mitochondria-specific aminoacyl-tRNA synthases. WARS2 encodes mitochondrial tryptophanyl-tRNA synthase (mtTrpRS), a homodimeric class Ic enzyme (mitochondrial tryptophan-tRNA ligase; EC 6.1.1.2). Here, we report six individuals from five families presenting with either severe neonatal onset lactic acidosis, encephalomyopathy and early death or a later onset, more attenuated course of disease with predominating intellectual disability. Respiratory chain enzymes were usually normal in muscle and fibroblasts, while a severe combined respiratory chain deficiency was found in the liver of a severely affected individual. Exome sequencing revealed rare biallelic variants in WARS2 in all affected individuals. An increase of uncharged mitochondrial tRNATrp and a decrease of mtTrpRS protein content were found in fibroblasts of affected individuals. We hereby define the clinical, neuroradiological, and metabolic phenotype of WARS2 defects. This confidently implicates that mutations in WARS2 cause mitochondrial disease with a broad spectrum of clinical presentation.

Report this publication

Statistics

Seen <100 times