Germline AGO2 mutations impair RNA interference and human neurological development

D. Lessel*, D.M. Zeitler, M.R.F. Reijnders, A. Kazantsev, F.H. Nia, A. Bartholomaus, V. Martens, A. Bruckmann, V. Graus, A. McConkie-Rosell, M. McDonald, B. Lozic, E.S. Tan, E. Gerkes, J. Johannsen, J. Denecke, A. Telegrafi, E. Zonneveld-Huijssoon, H.H. Lemmink, B.W.M. ChamT. Kovacevic, L. Ramsdell, K. Foss, D. Le Duc, D. Mitter, S. Syrbe, A. Merkenschlager, M. Sinnema, B. Panis, J. Lazier, M. Osmond, T. Hartley, J. Mortreux, T. Busa, C. Missirian, P. Prasun, S. Luttgen, I. Mannucci, I. Lessel, C. Schob, S. Kindler, J. Pappas, R. Rabin, M. Willemsen, T. Gardeitchik, K. Lohner, P. Rump, K.R. Dias, C.A. Evans, P.I. Andrews, Hans-Jurgen Kreienkamp*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Web of Science)

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.
Original languageEnglish
Article number5797
Number of pages14
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 16 Nov 2020

Keywords

  • argonaute proteins
  • cleavage
  • crystal-structure
  • gene
  • intellectual disability
  • micrornas
  • molecular-dynamics
  • phosphorylation
  • recognition
  • structural basis
  • MOLECULAR-DYNAMICS
  • RECOGNITION
  • PHOSPHORYLATION
  • CRYSTAL-STRUCTURE
  • MICRORNAS
  • CLEAVAGE
  • INTELLECTUAL DISABILITY
  • GENE
  • STRUCTURAL BASIS
  • ARGONAUTE PROTEINS

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