|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Schaffer, AE, Eggens, VR, Caglayan, AO, Reuter, MS, Scott, E, Coufal, NG, Silhavy, JL, Xue, Y, Kayserili, H, Yasuno, K, Rosti, RO, Abdellateef, M, Caglar, C, Kasher, PR, Cazemier, JL, Weterman, MA, Cantagrel, V, Cai, N, Zweier, C, Altunoglu, U, Satkin, NB, Aktar, F, Tuysuz, B, Yalcinkaya, C, Caksen, H, Bilguvar, K, Fu, XD, Trotta, CR, Gabriel, S, Reis, A, Gunel, M, Baas, F, Gleeson, JG|
Neurodegenerative 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.