CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration

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dc.contributor.authorSchaffer, Ashleigh E.
dc.contributor.authorEggens, Veerle R. C.
dc.contributor.authorCaglayan, Ahmet Okay
dc.contributor.authorReuter, Miriam S.
dc.contributor.authorScott, Eric
dc.contributor.authorCoufal, Nicole G.
dc.contributor.authorSilhavy, Jennifer L.
dc.date.accessioned2024-02-23T14:02:23Z
dc.date.available2024-02-23T14:02:23Z
dc.date.issued2014
dc.departmentNEÜen_US
dc.description.abstractNeurodegenerative 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.en_US
dc.description.sponsorshipNational Institutes of Health (NIH) [P01HD070494, R01NS048453, P30NS047101]; Broad Institute [U54HG003067, GM049369]; Yale Center for Mendelian Disorders [U54HG006504, RC2NS070477]; Gregory M. Kiez and Mehmet Kutman Foundation; French National Research Agency [ANRRVP13016KKA]en_US
dc.description.sponsorshipThis work was supported by the National Institutes of Health (NIH) (P01HD070494, R01NS048453, and P30NS047101 for imaging support to J.G.G., Broad Institute grant U54HG003067 to Eric Lander, GM049369 to X.-D.F., the Yale Center for Mendelian Disorders U54HG006504 to R. Lifton and M.G., RC2NS070477) and the Gregory M. Kiez and Mehmet Kutman Foundation to M.G. We acknowledge M. Gerstein, S. Mane, A.B. Ekici, and S. Uebe for sequencing support and analysis; the Yale Biomedical High Performance Computing Center for data analysis and storage; the Yale Program on Neurogenetics and the Yale Center for Human Genetics andGenomics; the Center for Inherited Disease Research for genotyping; and the Simons Foundation Autism Research Initiative. Consortium for Autosomal Recessive Intellectual Disability (CARID) supported patient ascertainment. We thank E.W.E. Verweij for zebrafish analysis, E. Cuppen and H. van Roekel for support with ENU Tilling, and ZF Health funding for tilling. A.E.S. is the recipient of an A. P. Gianinni Fellowship. V.C. was supported by the French National Research Agency (ANRRVP13016KKA). J.G.G. is an Investigator of the Howard Hughes Medical Institute. We thank patients and parents for participation and J. Lupski, J. Martinez, and S. Weitzer for communicating unpublished results and sharing reagents.en_US
dc.identifier.doi10.1016/j.cell.2014.03.049
dc.identifier.endpage663en_US
dc.identifier.issn0092-8674
dc.identifier.issn1097-4172
dc.identifier.issue3en_US
dc.identifier.pmid24766810en_US
dc.identifier.scopus2-s2.0-84899581919en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage651en_US
dc.identifier.urihttps://doi.org/10.1016/j.cell.2014.03.049
dc.identifier.urihttps://hdl.handle.net/20.500.12452/11690
dc.identifier.volume157en_US
dc.identifier.wosWOS:000335392100014en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofCellen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleCLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegenerationen_US
dc.typeArticleen_US

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