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FEBS Lett. 2018 Mar;592(5):703-717. doi: 10.1002/1873-3468.12962. Epub 2018 Feb 1.

The role of tRNA synthetases in neurological and neuromuscular disorders.

Author information

1
Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA-encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl-tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot-Marie-Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT-causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

KEYWORDS:

Charcot-Marie-Tooth disease; aminoacyl-tRNA synthetases; cytosolic and mitochondrial translation

PMID:
29288497
PMCID:
PMC5873386
DOI:
10.1002/1873-3468.12962
[Indexed for MEDLINE]
Free PMC Article

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