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Germline AGO2 mutations impair RNA interference and human neurological development.
- Source :
-
Nature communications [Nat Commun] 2020 Nov 16; Vol. 11 (1), pp. 5797. Date of Electronic Publication: 2020 Nov 16. - Publication Year :
- 2020
-
Abstract
- ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
- Subjects :
- Adolescent
Animals
Argonaute Proteins chemistry
Child
Child, Preschool
Cluster Analysis
Dendrites metabolism
Fibroblasts metabolism
Gene Silencing
HEK293 Cells
Hippocampus pathology
Humans
Mice
Molecular Dynamics Simulation
Neurons metabolism
Phosphorylation
Protein Domains
RNA, Messenger genetics
RNA, Messenger metabolism
RNA, Small Interfering metabolism
RNA-Induced Silencing Complex metabolism
Rats
Transcriptome genetics
Argonaute Proteins genetics
Germ Cells metabolism
Mutation genetics
Nervous System growth & development
Nervous System metabolism
RNA Interference
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33199684
- Full Text :
- https://doi.org/10.1038/s41467-020-19572-5