CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.

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.

journal_name

Cell

journal_title

Cell

authors

Schaffer AE,Eggens VR,Caglayan AO,Reuter MS,Scott E,Coufal NG,Silhavy JL,Xue Y,Kayserili H,Yasuno K,Rosti RO,Abdellateef M,Caglar C,Kasher PR,Cazemier JL,Weterman MA,Cantagrel V,Cai N,Zweier C,Altunoglu U,Satkin N

doi

10.1016/j.cell.2014.03.049

subject

Has Abstract

pub_date

2014-04-24 00:00:00

pages

651-63

issue

3

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(14)00478-4

journal_volume

157

pub_type

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