CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.
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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. |
Year of Publication | 2014
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Journal | Cell
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Volume | 157
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Issue | 3
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Pages | 651-63
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Date Published | 2014 Apr 24
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ISSN | 1097-4172
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URL | |
DOI | 10.1016/j.cell.2014.03.049
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PubMed ID | 24766810
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PubMed Central ID | PMC4128918
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Links | |
Grant list | U54 HG003067 / HG / NHGRI NIH HHS / United States
P30NS047101 / NS / NINDS NIH HHS / United States
R01NS048453 / NS / NINDS NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54HG006504 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
RC2NS070477 / NS / NINDS NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
P01HD070494 / HD / NICHD NIH HHS / United States
GM049369 / GM / NIGMS NIH HHS / United States
R01 GM049369 / GM / NIGMS NIH HHS / United States
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