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Page 62 Franz et al. J Transl Genet Genom 2020;4:50-70 I https://doi.org/10.20517/jtgg.2020.13

cerebral atrophy, neonatal choleastasis, muscular hypotension, infantile hepatopathy and hypomyelination to
speech disorders and aggressive behavior. Finally, it should be mentioned that the non-canonical functions of
ARSs could also be responsible for the wide phenotypic spectra that can be observed in the diseases related
to their mal- or dysfunction.

Mitochondrial ARSs
Human mitochondrial ARSs (mt-ARSs) are essential for the synthesis of 17 mt-DNA-encoded proteins,
which are all subunits of the respiratory chain complexes. Therefore, they are involved in the generation of
the major source of cellular energy, i.e., ATP. Like cytosolic ARSs, all mt-ARSs are encoded by nuclear genes,
which are, however, different from those coding for the cytosolic ARSs. Three ARS genes encode enzymes
that are active in both mitochondria and cytosol: glycyl-tRNA synthetase (GARS), lysyl-tRNA synthetase
(KARS), and glutaminyl-tRNA synthetase (QARS). Only QARS, however, has so far been found to be
associated with an ID phenotype [Table 1B]. The first correlation between an mt-ARS mutation and a human
disorder was published in 2007 by Scheper et al. [222] , who found autosomal recessive mutations in the DARS2
gene in individuals suffering from leukoencephalopathy with brain stem and spinal cord involvement and
lactate elevation (LBSL). Since then, numerous other pathogenic mutations in mt-ARSs have been described,
so that to date, at least 17 out of the 19 mt-ARSs genes have been implicated in human genetic disorders
[35]
involving damage to the central nervous system .

It is noteworthy at this point that in 2017, Moulinier et al. [223] introduced MiSynPat, an integrated knowledge
base that links clinical, genetic, and structural data for disease-causing mutations in human mt-ARSs.
According to the authors, this tool provides a “comprehensive knowledge base together with an ergonomic
Web server designed to organize and access all pertinent information (sequences, multiple sequence
alignments, structures, disease descriptions, mutation characteristics, original literature) (http://misynpat.
org/misynpat/AboutMisynpat.rvt last accessed 2020-01-09).

Mutations in at least six mt-ARS genes (Table 1B - aminoacylation, including QARS) are involved in the
etiology of ID. All of these lead to a syndromic phenotype. Mutations in NARS2 and PARS2, for example,
cause Alpers syndrome, and homozygous RARS2 defects lead to pontocerebellar hypoplasia, which is
characterized by not only overall delayed development, impaired brain development, movement problems
and ID but also progressive atrophy, particularly of the pons and cerebellum. WARS2 mutation carriers show
a phenotype that is very similar to patients with mutations in cytosolic SARS (Table 1B - aminoacylation).
Other than that seen for ct-ARSs, there are no clearly prominent recurrent motives in homozygous or
compound heterozygous carriers of mt-ARS mutations (Table 1B - aminoacylation) with the possible
exception of seizures that are observed with a notably increased frequency (NARS2, PARS2 and QARS).

CONCLUSION
The literature compilation we present here makes a compelling case for an important if not pivotal role of
a fully functional tRNA complement for the development and maintenance of higher cognitive functions.
Interestingly, disease-causing ARSs mutations often only result in a reduction of enzyme activity without
causing complete inhibition [158,224,225] . This points to the sensitivity of cognitive features towards even slight
disturbances in this basic cellular process.

In addition, there is much evidence that tRNA molecules assume possibly unknown biological functions
[17]
in eukaryotes, which have not yet been fully elucidated but could be influenced by disruption of tRNA
function. This opens up a myriad of further possibilities for tRNA involvement in the formation of cognitive
features and underlines the importance of further research in this field.