Page 22 - Read Online

Page 60 Franz et al. J Transl Genet Genom 2020;4:50-70 I https://doi.org/10.20517/jtgg.2020.13

I tRNAs have shorter variable arms (between 4-5 nucleotides) than class II tRNAs (> 10 nucleotides) [206,207] .
The variable arm functions as a stabilizer of the tertiary structure as well as in the specific recognition of the
ARS. So far, two modifications of nucleotides in the variable arm by two different genes have been linked to
ID.

NSUN2
NSUN2 (Nop2/Sun RNA methyltransferase family member 2) is one of three cytosine-5 tRNA methyltransferases
and is responsible for methylating tRNAs that carry a cytosine at positon 48 or 49. There have been several
reports linking mutations in the NSUN2 gene to ID [46,49,51,208] . Two reports observed a Dubowitz-like
syndrome in patients [46,51] . Other common symptoms described include microcephaly, facial dysmorphism
and growth retardation.

The likely molecular mechanism in NSUN2-deficient cells is increased angiogenin-induced fragmentation
[55]
of tRNA which inhibits protein translation . Methylation of cytosine at the variable loop in healthy cells
protects tRNAs from binding to angiogenin.

WDR4
WDR4 (WD repeat domain 4) encodes the noncatalytic subunit of the tRNA (guanine-N7-)-methyltransferase
7
[62]
which is necessary for the 7-methylguanosine modification (m G) at position 46 . It has been described to
cause primordial dwarfism, a phenotypically diverse syndrome with several subtypes, characterized by ID
as well as pre- and postnatal growth deficiency [58,62,63] . More recently, WDR4 deficiency has also been linked
[57]
to the Galloway-Mowat syndrome . WDR4 knockouts result in a complete loss of m G modification in
7
tRNAs and consequently to disturbed codon recognition and ribosome stalling. It has also been shown that
[60]
depletion of WDR4 in mice impairs the neural lineage differentiation capacity in mESCs .
D-arm
The D-arm of tRNAs is located between the anticodon and acceptor arms. It is of variable length, but
the modification of the D-loop nucleotides is highly conserved in all kingdoms. Its function is mainly
the stabilization of tRNA structure through tertiary interaction with the T-arm, but it is also involved in
aminoacyl tRNA synthase recognition. Defects in two tRNA methyltransferases that modify different
positions in the D-arm have been shown to cause ID.

TRMT1
The TRMT1 (TRNA methyltransferase 1) gene encodes for a tRNA methyltransferase that dimethylates G at
position 26 in the D-arm of most tRNAs. It was first connected to non-syndromic ID in a deep sequencing-
[67]
based screen for novel genes for cognitive disorders in 2011 . More recent reports confirm this finding
and describe facial dysmorphism, general developmental delay and in some cases muscle weakness and
spasticity as TRMT1-specific symptoms in patients [64,65,70] . Apart from decreased protein translation and cell
proliferation, TRMT1-deficient cells show disturbed redox homeostasis and hypersensitivity to oxidative
[69]
reagents, which might explain some of the neurological defects observed . The causative mechanism at the
2
tRNA level is still unclear; however, loss of m G could affect tRNA structure or stability [209,210] or modulate
2
translation activity [211] .
TRMT10A
TRMT10A (TRNA methyltransferase 10A) is a tRNA methyltransferase that is responsible for methylating
the G at position 9 of tRNAs (m1G9). A missing, shortened or otherwise non-functioning TRMT10A gene
[86]
causes ID, microcephaly and general developmental delay . Interestingly, some reports describe early-onset
diabetes or hypoglycemia in patients with mutations in the gene [86,88,91,92] .