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

Cell. 2014 Apr 24;157(3):651-63. doi: 10.1016/j.cell.2014.03.049.

Ashleigh E Schaffer ¹, Veerle R C Eggens ², Ahmet Okay Caglayan ³, Miriam S Reuter ⁴, Eric Scott ¹, Nicole G Coufal ¹, Jennifer L Silhavy ¹, Yuanchao Xue ⁵, Hulya Kayserili ⁶, Katsuhito Yasuno ³, Rasim Ozgur Rosti ¹, Mostafa Abdellateef ¹, Caner Caglar ³, Paul R Kasher ², J Leonie Cazemier ², Marian A Weterman ², Vincent Cantagrel ⁷, Na Cai ¹, Christiane Zweier ⁴, Umut Altunoglu ⁶, N Bilge Satkin ⁶, Fesih Aktar ⁸, Beyhan Tuysuz ⁹, Cengiz Yalcinkaya ¹⁰, Huseyin Caksen ¹¹, Kaya Bilguvar ³, Xiang-Dong Fu ⁵, Christopher R Trotta ¹², Stacey Gabriel ¹³, André Reis ⁴, Murat Gunel ³, Frank Baas ², Joseph G Gleeson ¹⁴

Affiliations

1 Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
2 Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
3 Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
4 Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
5 Cellular Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
7 Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Institut IMAGINE, INSERM U1163, Faculté Paris-Descartes, 75015 Paris, France.
8 Department of Pediatrics, Diyarbakir State Hospital, 21100 Diyarbakir, Turkey.
9 Department of Pediatric Genetics, Cerrahpaşa Medical School, Istanbul University, 34098 Istanbul, Turkey.
10 Department of Neurology, Division of Child Neurology, Cerrahpaşa Medical School, Istanbul University, 34098 Istanbul, Turkey.
11 Department of Pediatrics, Meram Medical School, Necmettin Erbakan University, 42080 Konya, Turkey.
12 PTC Therapeutics, South Plainfield, NJ 07080, USA.
13 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
14 Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jogleeson@ucsd.edu.

PMID: 24766810 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.

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