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Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder
  1. Curtis R Coughlin II1,
  2. Gunter H Scharer1,2,3,
  3. Marisa W Friederich1,
  4. Hung-Chun Yu1,
  5. Elizabeth A Geiger1,
  6. Geralyn Creadon-Swindell1,
  7. Abigail E Collins4,
  8. Arnaud V Vanlander5,
  9. Rudy Van Coster5,
  10. Christopher A Powell6,
  11. Michael A Swanson1,
  12. Michal Minczuk6,
  13. Johan L K Van Hove1,
  14. Tamim H Shaikh1,2
  1. 1Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA
  2. 2Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA
  3. 3Department of Pediatrics, Section of Clinical Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  4. 4Department of Pediatrics, Section of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA
  5. 5Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
  6. 6MRC Mitochondrial Biology Unit, Cambridge, UK
  1. Correspondence to Dr Tamim H Shaikh, Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA; tamim.shaikh{at}


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.

Methods and 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-tRNACys 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.

  • Alpers syndrome
  • exome sequencing
  • CARS2
  • mitochondrial translation
  • aminoacyl-tRNA synthetases

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