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Page 58 Franz et al. J Transl Genet Genom 2020;4:50-70 I https://doi.org/10.20517/jtgg.2020.13

CTU2
CTU2 (cytosolic thiouridylase 2) is also a highly conserved gene that was first identified in yeast and found
necessary for tRNA thiolation in yeast, C. elegans and even plants [102,104,191] . In these organisms, CTU1
and CTU2 homologs form a complex that catalyzes tRNA thiolation of wobble uridine. Inactivation of
the complex leads to loss of thiolation at the tRNA wobble uridine and abnormal phenotypes [102,104,191] .
Interestingly, proteins involved in thiolation of the uridine wobble base are also important for the altered
protein synthesis driven by the BRAF V600E oncogene transformation in melanomas, and melanomas depend
on these tRNA-modifying proteins for survival [103] .

The first human CTU2 mutations were reported in three families from Saudi Arabia and two families from
the United Arab Emirates, and they were all homozygous for the same haplotype and splice site mutation
(c.873G>A, Thr247AlafsTer21). The affected individuals presented with dysmorphic faces, renal agenesis,
ambiguous genitalia, polydactyly and lissencephaly, and the authors suggested the acronym DREAM-PL for
this syndromic form of ID [105,107] .

Five more patients with the DREAM-PL phenotype were recently reported, all showing a reduced ratio of
thiolated wobble uridine to unmodified wobble uridine [106] .

KEOPS
KEOPS (kinase, endopeptidase and other proteins of small size) and the KEOPS complex were originally
identified in yeast as a complex involved in telomere capping and elongation [192] . In 2010, yeast KEOPS was
6
6
found to be necessary for N -threonyl-carbamoyl-adenosine modification of yeast tRNA adenosine (t A),
which is present at position 37 in all tRNAs that pair with ANN codons [193] . Although telomere regulation
[66]
6
seems to be independent of t A modifications , yeast cells lacking t A modifications show severe growth
6
defects.
The human and yeast KEOPS complex each consist of four homologous subunits (OSGEP, TP53RK, TPRKB,
LAGE3 and kae1, Bud32, Cgi121, Pcc1, respectively), and mutations were found in genes encoding any of
[83]
the four subunits in Galloway-Mowat syndrome (GAMOS, MIM#251300) patients . These patients were all
affected by early-onset nephrotic syndrome, primary microcephaly, developmental delay and propensity for
[83]
seizures of which most patients died in early childhood . None of the patients carried truncating mutations
[83]
on both alleles .
Due to the multiple functions involving the KEOPS complex it is difficult to determine the effect of a
6
missing t A modification on the patient phenotype. However, as overlapping phenotypes are observed in
patients with WDR4 mutations, missing t6A modifications are likely to contribute to the observed GAMOS
[82]
phenotype .

ELP2 and ELP4
The Elongator protein complex (ELP) is composed of six highly conserved subunits (ELP1-6) and, as the
name suggests, was initially thought to promote elongation of transcription. Recently, it was discovered
5 2
that its primary role is to modify the uridine at position 34 of tRNAs (mcm s U) [194,195] . Mutations in two of
the Elongator subunits have been linked to ID. Missense mutations in the ELP2 gene have been identified
in three families with ID [67,93] . Microdeletions in the ELP4 gene have been linked to ID and speech delay,
although deletion of part of the regulatory regions of PAX6 may contribute to the phenotype [99,100] . Previously,
mutations in the ELP4 gene have been implicated in Rolandic epilepsy [101] . It is now accepted that the diverse
disease phenotypes caused by defects in Elongator are likely due to hypomodified tRNAs, but it remains
to be seen whether rescue experiments with elevated tRNA levels prevent the phenotypes in multicellular
organisms [97,98] .