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

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 (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Cell Elsevier

Book Volume: 157

Pages Range: 651-63

Journal Issue: 3

DOI: 10.1016/j.cell.2014.03.049

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.

Authors with CRIS profile

Miriam Reuter Institute of Human Genetics Christiane Zweier Medizinische Fakultät André Wiesmann da Silva Reis Lehrstuhl für Humangenetik

Involved external institutions

University of California, San Diego US United States (USA) (US) University of Amsterdam NL Netherlands (NL) Yale University US United States (USA) (US) Istanbul University / İstanbul Üniversitesi TR Turkey (TR) Diyarbakir State Hospital / Diyarbakır Devlet Hastanesi TR Turkey (TR) Necmettin Erbakan Üniversitesi TR Turkey (TR) PTC Therapeutics Inc. US United States (USA) (US) Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US)

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.

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