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Franz et al. J Transl Genet Genom 2020;4:50-70 I https://doi.org/10.20517/jtgg.2020.13 Page 53

associated protein folding defects [23,27-29] . Defects in tRNA modifications, which sometimes only represent
[30]
a single atom, can trigger serious neurodegenerative diseases . For example, if tRNA molecules lack only
a single chemical group, protein biosynthesis can stop at innumerable sites in the mRNA (reviewed in
[31]
Torres et al. 2014). The result is an increase in protein aggregates that the cells can no longer remove.
Nerve cells in particular are very sensitive to such aggregates, as is well known from Alzheimer’s and
[27]
Parkinson’s diseases . Moreover, ribosome profiling experiments have shown that ribosomes in cells with
[27]
defects in tRNAs take longer to read certain sections of the mRNA . The fact that protein biosynthesis does
not occur at a constant rate plays a major role in this context, because changes in protein synthesis rate can
[32]
influence protein conformation, as proteins take on their active form at the same time as they are produced .

Another important function in protein biosynthesis is performed by the ARSs. These enzymes are essential
for translation, since they catalyze the binding of the proteinogenic amino acids to their respective associated
tRNAs to form aminoacylated tRNAs.

There are 37 ARSs known - 17 occur only in the cytoplasm, 17 are mitochondria-specific, and three encode
[33]
bifunctional proteins that charge tRNAs in both compartments . It is known that mutations in genes
coding for ARSs play an important role in many human inherited diseases, both with recessive and dominant
inheritance patterns. In homozygous carriers, recessive mutations in ARSs often cause early-onset disorders
with a severe course, not only affecting nerve cells but also impairing the function of many other tissues.
A total of 31 of the 37 human ARSs have been linked to a genetic phenotype. These range from later-onset
peripheral neuropathy to severe multi-system development syndromes [34-36] with ID.

In the following sections, we will first give an overview of tRNA modifiers that have been found to play a
role in the etiology of hereditary forms of cognitive impairment, focusing on the major tRNA sites targeted
by these enzymes. Subsequently, we will introduce the ID-associated ARSs known to date, based on their
cytosolic or mitochondrial occurrence.

TRNA MODIFICATION AND ID
A list of currently known tRNA modifiers, which have been associated with ID, is given in Table 1 (see Part A).

The tRNA schematic in Figure 2 gives an overview over the main target nucleotides of tRNA modifiers
involved in the etiology of ID, showing that there are 4 main sites that are of particular importance for
human cognition: the C-arm (anticodon arm), V-arm (variable arm), D-arm (dihydrouridine-arm) and
T-arm (ribothymidine arm).

Anticodon arm
The anticodon arm of a tRNA molecule contains the anticodon site and is the most heavily modified part of
the tRNA molecule.

Currently, six different ID proteins catalyzing tRNA modifications in this tRNA region have been identified.
These include the following enzymes.

FTSJ1
FTSJ1 (filamentous temperature-sensitive J, E. coli homolog 1) is an X-linked tRNA 2’-O-methyltransferase
that catalyzes ribose methylation at tRNA positions 32 and 34. The homologous gene was originally isolated
from an E. coli in 1991 [178] , and the crystal structure with the methyl donor S-adenosyl-methionine was later
solved [179] .

Yeast has been the model of choice for investigations concerning FTSJ1 as human FTSJ1 is able to
complement yeast Trm7 growth defects [180] . In yeast, two different interaction partners have been identified