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Cell DOI:10.1016/j.cell.2014.03.049

CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration.

Publication TypeJournal Article
Year of Publication2014
AuthorsSchaffer, 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
JournalCell
Volume157
Issue3
Pages651-63
Date Published2014/04/24
ISSN0092-8674
Abstract

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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)00478-4
DOI10.1016/j.cell.2014.03.049
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24766810?dopt=Abstract