Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.

TitleMutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.
Publication TypeJournal Article
Year of Publication2015
AuthorsCoughlin, CR, Scharer, GH, Friederich, MW, Yu, H-C, Geiger, EA, Creadon-Swindell, G, Collins, AE, Vanlander, AV, Van Coster, R, Powell, CA, Swanson, MA, Minczuk, M, Van Hove, JLK, Shaikh, TH
JournalJ Med Genet
Date Published2015 Aug
KeywordsAmino Acid Sequence, Amino Acyl-tRNA Synthetases, Aminoacylation, Brain Diseases, Child, DNA Mutational Analysis, Epilepsy, Exome, Humans, Male, Molecular Sequence Data, RNA, Transfer, Sequence Alignment

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-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.

Alternate JournalJ. Med. Genet.
Citation Key10.1136/jmedgenet-2015-103049
PubMed ID25787132
Grant ListMC_U105697135 / / Medical Research Council / United Kingdom
DK062453 / DK / NIDDK NIH HHS / United States
GM081519 / GM / NIGMS NIH HHS / United States