Schaffer, Ashleigh E.Eggens, Veerle R. C.Caglayan, Ahmet OkayReuter, Miriam S.Scott, EricCoufal, Nicole G.Silhavy, Jennifer L.2024-02-232024-02-2320140092-86741097-4172https://doi.org/10.1016/j.cell.2014.03.049https://hdl.handle.net/20.500.12452/11690Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.eninfo:eu-repo/semantics/openAccess[Keyword Not Available]Article1573651663247668102-s2.0-84899581919Q1WOS:000335392100014Q110.1016/j.cell.2014.03.049