CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration

Journal article


Publication Details

Author(s): Schaffer AE, Eggens VRC, Caglayan AO, Reuter M, 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
Journal: Cell
Publication year: 2014
Volume: 157
Journal issue: 3
Pages range: 651-63
ISSN: 0092-8674


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.


FAU Authors / FAU Editors

Reuter, Miriam Dr. med.
Humangenetisches Institut
Zweier, Christiane Prof. Dr.
Medizinische Fakultät


External institutions with authors

Diyarbakir State Hospital / Diyarbakır Devlet Hastanesi
Eli and Edythe L. Broad Institute of MIT and Harvard
Istanbul University / İstanbul Üniversitesi
Necmettin Erbakan Üniversitesi
PTC Therapeutics Inc.
University of Amsterdam
University of California, San Diego


How to cite

APA:
Schaffer, A.E., Eggens, V.R.C., Caglayan, A.O., Reuter, M., Scott, E., Coufal, N.G.,... Gleeson, J.G. (2014). CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell, 157(3), 651-63. https://dx.doi.org/10.1016/j.cell.2014.03.049

MLA:
Schaffer, Ashleigh E., et al. "CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration." Cell 157.3 (2014): 651-63.

BibTeX: 

Last updated on 2018-09-10 at 07:22