You are here

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, VRC, Çağlayan, AOkay, Reuter, MS, Scott, E, Coufal, NG, Silhavy, JL, Xue, Y, Kayserili, H, Yasuno, K, Rosti, ROzgur, Abdellateef, M, Caglar, C, Kasher, PR, J Cazemier, L, Weterman, MA, Cantagrel, V, Cai, N, Zweier, C, Altunoglu, U, N Satkin, B, Aktar, F, Tuysuz, B, Yalcinkaya, C, Caksen, H, Bilguvar, K, Fu, X-D, Trotta, CR, Gabriel, S, Reis, A, Gunel, M, Baas, F, Gleeson, JG
JournalCell
Volume157
Issue3
Pages651-63
Date Published2014 Apr 24
ISSN1097-4172
KeywordsAnimals, Brain, Cerebellum, Cleavage And Polyadenylation Specificity Factor, Female, Humans, Male, Mice, Models, Molecular, Neurodegenerative Diseases, Nuclear Proteins, Pedigree, Phosphotransferases, RNA Splicing, RNA, Transfer, Saccharomyces cerevisiae, Transcription Factors, Zebrafish, Zebrafish Proteins
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

Alternate JournalCell
PubMed ID24766810
PubMed Central IDPMC4128918
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
P30NS047101 / NS / NINDS NIH HHS / United States
R01NS048453 / NS / NINDS NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54HG006504 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
RC2NS070477 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
P01HD070494 / HD / NICHD NIH HHS / United States
GM049369 / GM / NIGMS NIH HHS / United States
R01 GM049369 / GM / NIGMS NIH HHS / United States