tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

Abstract

Post-transcriptional tRNA modifications are numerous and require a large set of highly conserved enzymes in humans and other organisms. In yeast, the loss of many modifications is tolerated under unstressed conditions; one exception is the N-threonyl-carbamoyl-adenosine (tA) modification, loss of which causes a severe growth phenotype. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with global developmental delay, failure to thrive and a renal defect manifesting in proteinuria and hypomagnesemia. Using exome sequencing, the patients were found to be homozygous for the c.974G>A (p.(Arg325Gln)) variant of the KAE1 gene. KAE1 is a constituent of the KEOPS complex, a five-subunit complex that catalyzes the second biosynthetic step of tA in the cytosol. The yeast KAE1 allele carrying the equivalent mutation did not rescue the tA deficiency of the kae1Δ yeast strain as efficiently as the WT allele; furthermore, tA levels quantified by LC-MS/MS were lower in the kae1Δ strain which was complemented by the mutation than in the kae1Δ strain, which was complemented by the WT allele. We conclude that homozygosity for c.974G>A (p.(Arg325Gln)) in KAE1 likely exerts its pathogenic effect by perturbing tA synthesis, thereby interfering with global protein production. This is the first report of tA biosynthesis defect in human. KAE1 joins the growing list of cytoplasmic tRNA modification enzymes, all associated with severe neurological disorders.

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Several human diseases, including neurological disorders, have been linked to mutations in tRNA modification enzymes, and this topic has been the subject of recent comprehensive reviews (Bednářová et al, 2017; Torres et al, 2014). Recently, homozygous mutations in KAE1 (kinase-associated endopeptidase; OSGEP ), which plays a role in the biosynthesis of N 6 -threonylcarbamoyladenosine (t 6 A) modifications of tRNA, have been linked progressive cerebellar atrophy and leukodystrophy (Edvardson et al, 2017). This modification is present at nucleotide 37 in the anticodon stem loop of nearly all tRNAs decoding ANN (where N is any nucleotide) codons, and defects in t 6 A biosynthesis in yeast lead to leaky scanning bypass of start codons, as well as impaired reading frame maintenance (Thiaville et al, 2016).…”

Elongator Subunit 3 (Elp3) Is Required for Zebrafish Trunk Development

“…It is not clear whether these functions in which the complex is involved are consequences of impaired translation or are bona fide novel functions acquired during evolution. Something similar happens with the threonyl-carbamoyl transferase complex (TCTC, formerly known as EKC/KEOPS) as it is required for tRNA modification and also has been related with other functions [29,30]. Strong evidence in yeast support that the primary function of Elongator complex is tRNA modification, as mutation of Elp3 (Sin3p) in fission yeast leads to a severe reduction in the levels of mcm 5 s 2 U [31] and impaired growth could be reverted by the overexpression of two different tRNAs (tRNA Lys UUU and tRNA Leu UUG ), which are substrates for Elongator complex [32].…”

Role of RNA modifications in brain and behavior

“…90 Nonsyndromic X-linked mental retardation and intellectual disability can be caused by mutations in FtsJ methyltransferase homolog 1 ( FTSJ 1), 55,91 an enzyme that methylates tRNAs.…”

“…89 Recently, a mutation in kinase-associated endopeptidase (KAE1), part of the biosynthetic pathway that generates the tRNA N6-threonyl-carbamoyl-adenosine (t6A) modification, was associated with neurodegenerative disease. 90 Nonsyndromic X-linked mental retardation and intellectual disability can be caused by mutations in FtsJ methyltransferase homolog 1 (FTSJ1), 55,91 an enzyme that methylates tRNAs.…”