Published on May 1, 2017 in Eur J Hum Genet volume 25.
PubMed ID: 28272532
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(6)-threonyl-carbamoyl-adenosine (t(6)A) 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 t(6)A in the cytosol. The yeast KAE1 allele carrying the equivalent mutation did not rescue the t(6)A deficiency of the kae1Delta yeast strain as efficiently as the WT allele; furthermore, t(6)A levels quantified by LC-MS/MS were lower in the kae1Delta strain which was complemented by the mutation than in the kae1Delta 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 t(6)A synthesis, thereby interfering with global protein production. This is the first report of t(6)A biosynthesis defect in human. KAE1 joins the growing list of cytoplasmic tRNA modification enzymes, all associated with severe neurological disorders.