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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 57

Yeast is a good model for molecular investigations into tRNA modifications, but far from identical to
the human situation. For example, yeast Trm7 methylates tRNAs encoding phenylalanine, leucine and
tryptophan whereas human FTSJ1 methylates tRNAs encoding phenylalanine, asparagine, glutamine, alanine
and methionine [181] .

In ID patients, protein-truncating mutations have been reported in 5 families [37,41,183] , and a missense change
has also been found in patients with non-syndromic ID [180] . In addition, duplication or microdeletions
involving FTSJ1 and other ID genes were also found in ID families [184-187] . Recently, a mouse model for FTSJ1
deficiency was reported. In combination with a mild ID phenotype, these mice presented with additional
phenotypic features, some of which were also found in affected humans upon reexamination of patients who
[40]
were previously considered to have a non-syndromic phenotype .

ADAT3
ADAT3 (adenosine deaminase TRNA specific 3) is part of an enzyme complex involved in inosine formation
through hydrolytic deamination of adenosine at the tRNA wobble position. This protein was also first
characterized in yeast and is specific for modification of the tRNA wobble position. In yeast, Adat3 complexes
[73]
with Adat2 to function as a deaminase, and the coding genes for both are essential for yeast viability . In
human cells, ADAT2 and 3 form a complex, localized in the nucleus that is required for inosine formation at
the tRNA precursor level [188] .

ID caused by ADAT3 mutations is inherited in an autosomal recessive manner and several consanguineous
families have been analyzed mainly in the Middle East. ADAT3 mutations were first identified in 24
[71]
individuals from eight consanguineous Arab ID families that all presented with ID and strabismus . The
missense change c.382G>A, V128M, is located in an ancient haplotype that is approximately 1600 years
[71]
old and considered to be the most common cause for autosomal recessive ID in Arabia . Other clinical
symptoms in ID patients with the V128M mutation apart from ID and strabismus were reported to include
[72]
growth failure, microcephaly and tone abnormality . The authors concluded that despite a distinct facial
profile, this syndrome should be considered also for ID patients from apparently non-consanguineous ID
[72]
families originating from Arabia . Recently, an 8-bp duplication in ADAT3 was found in a patient with mild
[75]
ID, microcephaly and hyperactivity but without strabismus .
In a patient cell line, it was recently shown that the ADAT3 mutation V128M indeed reduces adenosine
[74]
deaminase activity and inosine formation at the tRNA wobble position .

ALKBH8
ALKBH8 (alkylated DNA repair protein AlkB homolog 8) was originally investigated because it is expressed
[80]
in human cancers, including bladder cancer . Knockdown of ALKBH8 in cell lines has shown several
effects including reduced H O generation, induction of JNK- and p38-mediated apoptosis, phosphorylation
2
2
[80]
of the histone 2 variant H2AX and reduced gall bladder cancer growth . In a mouse model for ALKBH8
deficiency, Alkbh8 was identified as a methyltransferase necessary for 5-methoxycarbonylmethyluridine
5
5
(mcm u) formation of wobble uridine residues [189] . Generation of mcm u is required for ALKBH8
hydroxylation of wobble uridine to 5-methoxycarbonylhydroxymethyluridine in certain tRNAs [78,190] .
Although Alkbh8-deficient mice seemed normal, the authors observed aberrant modification of
selenocysteine-specific tRNA Sec[189] .
Recently, truncating ALKBH8 mutations were found in ID patients from two consanguineous families
with different mutations (c.1660C>T, p. Arg554Ter and c.1794delC, Trp599GlyfsTer19). tRNA from the
investigated patients showed complete loss of wobble uridine modifications. All seven investigated patients
had ID and showed global developmental delay. Out of the seven patients, only one affected sister did not
[79]
present with epilepsy .