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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 61
1
A lack of m G modification in yeast has been shown to play a role in tRNA stability and translation
9
terminating efficiency [212,213] . In human tRNA , which has an adenine at position 9, a lack of methylation
Lys
prevented the tRNA to be folded into the cloverleaf form [214] . However, how exactly the lack of methylation is
connected to the variety of symptoms is still not fully understood and continues to be the subject of ongoing
research.

T-arm
PUS10
So far, no modifications on the T-arm of tRNAs have been shown to cause ID specifically. While
microduplications or -deletions of the 2p16.1p15 locus, which contains the pseudouridine synthase 10 gene
(PUS10) among several other genes, have been linked to ID and developmental and speech delay [215-217] , there
is growing evidence that in these cases, BCL11A is the cause for ID [218,219] . Still, it cannot be ruled out that
PUS10, which pseudouridinylates tRNAs at positions 54 and 55, contributes to the phenotype, but clinical
cases with PUS10-specific mutations linked to ID have not yet been described so far.

ARSS AND ID
Cytoplasmic ARSs
The main task of ARSs is to transfer and bind amino acids to the appropriate tRNA molecules. The charged
tRNAs are then used by the ribosomes to carry out protein synthesis. Their availability therefore plays an
essential role in the regulatory processes of cell functions [220] . All ARSs are ubiquitously expressed and highly
conserved. There is one ARS enzyme for each amino acid to facilitate binding with the appropriate tRNA. Of
[33]
the 37 known ARS genes, 17 encode purely cytoplasmic enzymes . Like mitochondrial ARSs (mt-ARSs), all
cytosolic ARSs (ct-ARSs) are encoded by nuclear genes. They are complemented by three ARSs that function
in both the cytoplasm and mitochondria to match the full complement of amino acids. It has already been
mentioned that biallelic mutations in 31 ARS genes lead to serious recessive, early onset diseases, ranging
from later-onset peripheral neuropathy to severe multi-system development syndromes. Here, however, we
will focus only on ARSs, which have been found to play a role in the etiology of diseases associated with ID
[Table 1, see Part B].

In VARS, for example, Friedman et al. [140] found different biallelic mutations in several families, leading
to a very heterogeneous symptomatic picture including, developmental delay, epileptic encephalopathy
and primary or progressive microcephaly. Another interesting case is the glutaminyl-tRNA synthetase
gene (QARS). This gene encodes both the cytosolic as well as the mitochondrial QARS and shows a strong
level of expression in the brain of the developing fetus. A very often found missense mutation (V476I) in
QARS was shown to cause a reduction in its aminoacylation activity [148] . Mutations in QARS have severe
consequences in affected individuals including not only ID but also progressive microcephaly, cerebral
cerebellar atrophy and seizures that are difficult to treat. Altogether 11 patients have so far been described
with QARS mutations [147,149,151,221] , all of whom consistently show a severe so-called global development delay
but none reaching any significant milestone. An initially normal occipito-frontal circumference (OFC)
quickly and clearly changed to postnatal microcephaly. Various degrees of severity of ID from mild to severe
were described in several case studies [Table 1B]. In addition to other serious symptoms, the condition is
ultimately fatal for a large proportion of patients [148] . These examples shows the breadth and variability of the
phenotypic spectrum associated with ARS mutations.

There are, however, recurrent motives among the features accompanying ARS-dependent ID, such as
microcephaly, which is observed in carriers of mutations in AARS, RARS, DARS, LARS, MARS, YARS,
QARS, SARS, VARS and WARS2 [Table 1B]. An association with the occurrence of seizures (AARS, DARS,
LARS, SARS, VARS, QARS, NARS2, PARS2 and WARS2) and hypotonia (AARS, DARS, LARS, MARS, YARS
and IARS) is also frequently observed. Less common features among affected individuals range from ataxia,