Distinct roles of the two Elongator subcomplexes during neurodevelopment

The highly conserved Elongator complex is a translational regulator and a subject of growing interest due to its critical role in neurodevelopment, neurological diseases and brain tumors. Clinically relevant mutations have been reported in the catalytic Elp123 subcomplex, while no mutation in the accessory subcomplex Elp456 have been described so far. Here, we identify pathogenic variants of ELP4 and ELP6 in patients with developmental delay, epilepsy as well as intellectual and motor impairment. We use single particle cryo-EM to determine the structures of human and murine Elp456 subcomplexes and reconstitute an active mouse Elongator comprising of all six subunits. We show that patient derived mutations in Elp456 affect the affinity for specific tRNA molecules and diminish the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modelling the mutations in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Altogether, our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity and neurological defects. Foremost, our data indicate distinct roles of the Elp123 and Elp456 subcomplexes for different tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.