Here we demonstrate a requirement for CLP1 in human brain development. We identify four independent families carrying a founder p.R140H which impairs affinity for the TSEN complex, kinase activity in a recombinant assay, as well as function in vivo. Consistent with its role tRNA splicing, we find depleted mature tRNAs and excessive pre-tRNAs accumulating in patient-derived induced neurons (iNeurons). We demonstrate sensitivity of patient cells to oxidative-stress induced death exacerbated by the addition of unphosphorylated 3’-tRNA-exon halves and partially corrected with 5’-phospho- 3’-tRNA exon addition. In sum, we uncover an evolutionarily conserved requirement for CLP1 during vertebrate neurogenesis, and show CLP1 is necessary for tRNA maturation, the loss of which leads to stress-induced cell death.
