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


SCHAFFER A. E. , EGGENS V. R. C. , Caglayan A. O. , REUTER M. S. , SCOTT E., COUFAL N. G. , ...Daha Fazla

CELL, cilt.157, ss.651-663, 2014 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 157 Konu: 3
  • Basım Tarihi: 2014
  • Doi Numarası: 10.1016/j.cell.2014.03.049
  • Dergi Adı: CELL
  • Sayfa Sayıları: ss.651-663

Özet

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.