Lessel, Davor and Zeitler, Daniela M. and Reijnders, Margot R. F. and Kazantsev, Andriy and Nia, Fatemeh Hassani and Bartholomaeus, Alexander and Martens, Victoria and Bruckmann, Astrid and Graus, Veronika and McConkie-Rosell, Allyn and McDonald, Marie and Lozic, Bernarda and Tan, Ee-Shien and Gerkes, Erica and Johannsen, Jessika and Denecke, Jonas and Telegrafi, Aida and Zonneveld-Huijssoon, Evelien and Lemmink, Henny H. and Cham, Breana W. M. and Kovacevic, Tanja and Ramsdell, Linda and Foss, Kimberly and Le Duc, Diana and Mitter, Diana and Syrbe, Steffen and Merkenschlager, Andreas and Sinnema, Margje and Panis, Bianca and Lazier, Joanna and Osmond, Matthew and Hartley, Taila and Mortreux, Jeremie and Busa, Tiffany and Missirian, Chantal and Prasun, Pankaj and Luettgen, Sabine and Mannucci, Ilaria and Lessel, Ivana and Schob, Claudia and Kindler, Stefan and Pappas, John and Rabin, Rachel and Willemsen, Marjolein and Gardeitchik, Thatjana and Loehner, Katharina and Rump, Patrick and Dias, Kerith-Rae and Evans, Carey-Anne and Andrews, Peter Ian and Roscioli, Tony and Brunner, Han G. and Chijiwa, Chieko and Lewis, M. E. Suzanne and Abou Jamra, Rami and Dyment, David A. and Boycott, Kym M. and Stegmann, Alexander P. A. and Kubisch, Christian and Tan, Ene-Choo and Mirzaa, Ghayda M. and McWalter, Kirsty and Kleefstra, Tjitske and Pfundt, Rolph and Ignatova, Zoya and Meister, Gunter and Kreienkamp, Hans-Juergen (2020) Germline AGO2 mutations impair RNA interference and human neurological development. NATURE COMMUNICATIONS, 11 (1): 5797. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)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. AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; INTELLECTUAL DISABILITY; ARGONAUTE PROTEINS; STRUCTURAL BASIS; MICRORNAS; GENE; PHOSPHORYLATION; RECOGNITION; CLEAVAGE; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie I > Prof. Dr. Gunter Meister |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 12:10 |
| Last Modified: | 08 Mar 2021 12:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43367 |
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