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The Clp1 R140H mutation alters tRNA metabolism and mRNA 3' processing in mouse models of pontocerebellar hypoplasia.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Sep 28; Vol. 118 (39). - Publication Year :
- 2021
-
Abstract
- Homozygous mutation of the RNA kinase CLP1 (cleavage factor polyribonucleotide kinase subunit 1) causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the transfer RNA (tRNA) splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments up-regulated, and other fragments down-regulated. However, the spatiotemporal patterns of dysregulation do not correlate with pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on precursor messenger RNA (pre-mRNA) cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1 <superscript> R140H/- </superscript> spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes were also expressed at lower levels in the Clp1 <superscript> R140H/- </superscript> mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that impaired mRNA 3' processing may contribute to pathogenesis in PCH10.<br />Competing Interests: The authors declare no competing interest.<br /> (Copyright © 2021 the Author(s). Published by PNAS.)
- Subjects :
- Animals
Cerebellar Diseases genetics
Cerebellar Diseases metabolism
Disease Models, Animal
Female
Gene Expression Regulation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Neurodegenerative Diseases genetics
Neurodegenerative Diseases metabolism
RNA Precursors genetics
RNA Precursors metabolism
RNA, Messenger genetics
RNA, Transfer genetics
Cerebellar Diseases pathology
Neurodegenerative Diseases pathology
Polyadenylation
RNA Processing, Post-Transcriptional
RNA, Messenger metabolism
RNA, Transfer metabolism
RNA-Binding Proteins physiology
Transcription Factors physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 39
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 34548404
- Full Text :
- https://doi.org/10.1073/pnas.2110730118