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, 592 (5), 703-717

The Role of tRNA Synthetases in Neurological and Neuromuscular Disorders


The Role of tRNA Synthetases in Neurological and Neuromuscular Disorders

Veronika Boczonadi et al. FEBS Lett.


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.


Figure 1
Figure 1
Clinical variability of diseases caused by ARSs mutations. (A) Tissues commonly affected by mutations in cytosolic, bifunctional and mitochondrial ARS genes. (B) Common neurological presentations reported in cytosolic, bifunctional and mitochondrial ARS genes, with peripheral neuropathy highlighted. Solid line indicates dominant mode of inheritance, dashed line indicates recessive mode of inheritance. References: AARS 33, 48, 50, 96, DARS 97,HARS 27, IARS 37, 40 MARS 45, 98, RARS 99, SARS 18, WARS 30, ARS 28, 39, QARS 34, GARS 7, 29, 71, KARS 38, AARS2 10, 67, CARS2 12, DARS2 8, EARS2 9, FARS2 13, 100, HARS2 21, IARS2 101, 102, LARS2 22, MARS2 11, 19, NARS2 20, 103, 104, PARS2 14, 103, RARS2 17, 105, SARS 2 24, TARS2 15, VARS2 15, 16, WARS2 18, 106, YARS2 23, 107.
Figure 2
Figure 2
Possible pathological pathways of axonal degeneration in tRNA synthetase mutations.

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