title: Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.
abstract: BACKGROUND
  Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy.
  
  
  RESULTS
  We identified a proband with an epileptic encephalopathy, complex movement disorder and a combined mitochondrial respiratory chain enzyme deficiency. The child presented with neurological regression, complex movement disorder and intractable seizures. A combined deficiency of mitochondrial complexes I, III and IV was noted in liver tissue, along with increased mitochondrial DNA content in skeletal muscle. Incomplete assembly of complex V, using blue native polyacrylamide gel electrophoretic analysis and complex I, using western blotting, suggested a disorder of mitochondrial transcription or translation. Exome sequencing identified compound heterozygous mutations in CARS2, a mitochondrial aminoacyl-tRNA synthetase. Both mutations affect highly conserved amino acids located within the functional ligase domain of the cysteinyl-tRNA synthase. A specific decrease in the amount of charged mt-tRNA(Cys) was detected in patient fibroblasts compared with controls. Retroviral transfection of the wild-type CARS2 into patient skin fibroblasts led to the correction of the incomplete assembly of complex V, providing functional evidence for the role of CARS2 mutations in disease aetiology.
  
  
  CONCLUSIONS
  Our findings indicate that mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy.
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Curtis R
authors: CR
authors: Coughlin
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA Department of Pediatrics, Section of Clinical Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Gunter H
authors: GH
authors: Scharer
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Marisa W
authors: MW
authors: Friederich
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Hung-Chun
authors: http://orcid.org/0000-0002-4980-8508
authors: HC
authors: Yu
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Elizabeth A
authors: EA
authors: Geiger
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Geralyn
authors: G
authors: Creadon-Swindell
authors: Department of Pediatrics, Section of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Abigail E
authors: AE
authors: Collins
authors: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
authors: Arnaud V
authors: AV
authors: Vanlander
authors: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
authors: Rudy Van
authors: RV
authors: Coster
authors: MRC Mitochondrial Biology Unit, Cambridge, UK.
authors: Christopher A
authors: CA
authors: Powell
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Michael A
authors: MA
authors: Swanson
authors: MRC Mitochondrial Biology Unit, Cambridge, UK.
authors: Michal
authors: M
authors: Minczuk
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Johan L K
authors: JL
authors: Van Hove
authors: Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Tamim H
authors: TH
authors: Shaikh
mesh_terms: D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D049148:Aminoacylation; D001927:Brain Diseases / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics*; D059472:Exome; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D012343:RNA, Transfer / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D012343:RNA, Transfer; D000604:Amino Acyl-tRNA Synthetases; C000595892:CARS2 protein, human
keywords: Alpers syndrome; CARS2; aminoacyl-tRNA synthetases; exome sequencing; mitochondrial translation