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CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.
Schaffer, Ashleigh E; Eggens, Veerle R C; Caglayan, Ahmet Okay; Reuter, Miriam S; Scott, Eric; Coufal, Nicole G; Silhavy, Jennifer L; Xue, Yuanchao; Kayserili, Hulya; Yasuno, Katsuhito; Rosti, Rasim Ozgur; Abdellateef, Mostafa; Caglar, Caner; Kasher, Paul R; Cazemier, J Leonie; Weterman, Marian A; Cantagrel, Vincent; Cai, Na; Zweier, Christiane; Altunoglu, Umut; Satkin, N Bilge; Aktar, Fesih; Tuysuz, Beyhan; Yalcinkaya, Cengiz; Caksen, Huseyin; Bilguvar, Kaya; Fu, Xiang-Dong; Trotta, Christopher R; Gabriel, Stacey; Reis, André; Gunel, Murat; Baas, Frank; Gleeson, Joseph G.
Afiliação
  • Schaffer AE; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Eggens VR; Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
  • Caglayan AO; Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Reuter MS; Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
  • Scott E; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Coufal NG; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Silhavy JL; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Xue Y; Cellular Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kayserili H; Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
  • Yasuno K; Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Rosti RO; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Abdellateef M; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Caglar C; Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Kasher PR; Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
  • Cazemier JL; Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
  • Weterman MA; Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
  • Cantagrel V; 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.
  • Cai N; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zweier C; Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
  • Altunoglu U; Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
  • Satkin NB; Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Fatih/Istanbul, Turkey.
  • Aktar F; Department of Pediatrics, Diyarbakir State Hospital, 21100 Diyarbakir, Turkey.
  • Tuysuz B; Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, 34098 Istanbul, Turkey.
  • Yalcinkaya C; Department of Neurology, Division of Child Neurology, Cerrahpasa Medical School, Istanbul University, 34098 Istanbul, Turkey.
  • Caksen H; Department of Pediatrics, Meram Medical School, Necmettin Erbakan University, 42080 Konya, Turkey.
  • Bilguvar K; Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Fu XD; Cellular Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Trotta CR; PTC Therapeutics, South Plainfield, NJ 07080, USA.
  • Gabriel S; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Reis A; Institute of Human Genetics, Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany.
  • Gunel M; Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • Baas F; Department of Genome Analysis, Academic Medical Center, Meibergdreef 9,1105AZ Amsterdam, the Netherlands.
  • Gleeson JG; Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jogleeson@ucsd.edu.
Cell ; 157(3): 651-63, 2014 Apr 24.
Article em En | MEDLINE | ID: mdl-24766810
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfotransferases / Fatores de Transcrição / RNA de Transferência / Proteínas Nucleares / Cerebelo / Splicing de RNA / Proteínas de Peixe-Zebra / Fator de Especificidade de Clivagem e Poliadenilação Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfotransferases / Fatores de Transcrição / RNA de Transferência / Proteínas Nucleares / Cerebelo / Splicing de RNA / Proteínas de Peixe-Zebra / Fator de Especificidade de Clivagem e Poliadenilação Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2014 Tipo de documento: Article