PUBLICATION
CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration
- Authors
- Schaffer, A.E., Eggens, V.R., Caglayan, A.O., Reuter, M.S., Scott, E., Coufal, N.G., Silhavy, J.L., Xue, Y., Kayserili, H., Yasuno, K., Rosti, R.O., Abdellateef, M., Caglar, C., Kasher, P.R., Cazemier, J.L., Weterman, M.A., Cantagrel, V., Cai, N., Zweier, C., Altunoglu, U., Satkin, N.B., Aktar, F., Tuysuz, B., Yalcinkaya, C., Caksen, H., Bilguvar, K., Fu, X.D., Trotta, C.R., Gabriel, S., Reis, A., Gunel, M., Baas, F., Gleeson, J.G.
- ID
- ZDB-PUB-140513-86
- Date
- 2014
- Source
- Cell 157: 651-63 (Journal)
- Registered Authors
- Baas, Frank, Kasher, Paul
- Keywords
- none
- MeSH Terms
-
- Animals
- Brain/metabolism
- Brain/pathology
- Cerebellum/growth & development*
- Cerebellum/pathology*
- Cleavage And Polyadenylation Specificity Factor/genetics
- Cleavage And Polyadenylation Specificity Factor/metabolism*
- Female
- Humans
- Male
- Mice
- Models, Molecular
- Neurodegenerative Diseases/genetics
- Neurodegenerative Diseases/pathology
- Nuclear Proteins/genetics*
- Nuclear Proteins/metabolism
- Pedigree
- Phosphotransferases/genetics*
- Phosphotransferases/metabolism
- RNA Splicing*
- RNA, Transfer/genetics*
- RNA, Transfer/metabolism
- Saccharomyces cerevisiae/metabolism
- Transcription Factors/genetics*
- Transcription Factors/metabolism
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 24766810 Full text @ Cell
Citation
Schaffer, A.E., Eggens, V.R., Caglayan, A.O., Reuter, M.S., Scott, E., Coufal, N.G., Silhavy, J.L., Xue, Y., Kayserili, H., Yasuno, K., Rosti, R.O., Abdellateef, M., Caglar, C., Kasher, P.R., Cazemier, J.L., Weterman, M.A., Cantagrel, V., Cai, N., Zweier, C., Altunoglu, U., Satkin, N.B., Aktar, F., Tuysuz, B., Yalcinkaya, C., Caksen, H., Bilguvar, K., Fu, X.D., Trotta, C.R., Gabriel, S., Reis, A., Gunel, M., Baas, F., Gleeson, J.G. (2014) CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration. Cell. 157:651-63.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping