CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.
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.
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Ashleigh E
AE
Schaffer
Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
Veerle R C
VR
Eggens
Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Ahmet Okay
AO
Caglayan
Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
Miriam S
MS
Reuter
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Eric
E
Scott
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Nicole G
NG
Coufal
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Jennifer L
JL
Silhavy
Cellular Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Yuanchao
Y
Xue
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
Hulya
H
Kayserili
Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Katsuhito
K
Yasuno
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Rasim Ozgur
RO
Rosti
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Mostafa
M
Abdellateef
Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Caner
C
Caglar
Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
Paul R
PR
Kasher
Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
J Leonie
JL
Cazemier
Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
Marian A
MA
Weterman
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.
Vincent
V
Cantagrel
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Na
N
Cai
Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
Christiane
C
Zweier
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
Umut
U
Altunoglu
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
N Bilge
NB
Satkin
Department of Pediatrics, Diyarbakir State Hospital, 21100 Diyarbakir, Turkey.
Fesih
F
Aktar
Department of Pediatric Genetics, Cerrahpaşa Medical School, Istanbul University, 34098 Istanbul, Turkey.
Beyhan
B
Tuysuz
Department of Neurology, Division of Child Neurology, Cerrahpaşa Medical School, Istanbul University, 34098 Istanbul, Turkey.
Cengiz
C
Yalcinkaya
Department of Pediatrics, Meram Medical School, Necmettin Erbakan University, 42080 Konya, Turkey.
Huseyin
H
Caksen
Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Kaya
K
Bilguvar
Cellular Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Xiang-Dong
XD
Fu
PTC Therapeutics, South Plainfield, NJ 07080, USA.
Christopher R
CR
Trotta
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Stacey
S
Gabriel
Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
André
A
Reis
Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Murat
M
Gunel
Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
Frank
F
Baas
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jogleeson@ucsd.edu.
Joseph G
JG
Gleeson
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000254:growth & development* / Q000473:pathology*; D039223:Cleavage And Polyadenylation Specificity Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010770:Phosphotransferases / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D012343:RNA, Transfer / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D039223:Cleavage And Polyadenylation Specificity Factor; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D012343:RNA, Transfer; C520030:CLP1 protein, human; C000589203:CLP1 protein, zebrafish; D010770:Phosphotransferases