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Journal Articles Nature Communications Year : 2020

Germline AGO2 mutations impair RNA interference and human neurological development

Davor Lessel
  • Function : Author
Daniela Zeitler
  • Function : Author
Margot Reijnders
  • Function : Author
Andriy Kazantsev
  • Function : Author
Fatemeh Hassani Nia
  • Function : Author
Alexander Bartholomäus
  • Function : Author
Victoria Martens
  • Function : Author
Astrid Bruckmann
Veronika Graus
  • Function : Author
Allyn Mcconkie-Rosell
  • Function : Author
Marie Mcdonald
  • Function : Author
Bernarda Lozic
  • Function : Author
Ee-Shien Tan
  • Function : Author
Erica Gerkes
  • Function : Author
Jessika Johannsen
  • Function : Author
Jonas Denecke
  • Function : Author
Aida Telegrafi
  • Function : Author
Evelien Zonneveld-Huijssoon
  • Function : Author
Henny Lemmink
  • Function : Author
Breana Cham
  • Function : Author
Tanja Kovacevic
  • Function : Author
Linda Ramsdell
  • Function : Author
Kimberly Foss
  • Function : Author
Diana Le Duc
  • Function : Author
Diana Mitter
  • Function : Author
Steffen Syrbe
  • Function : Author
Andreas Merkenschlager
  • Function : Author
Margje Sinnema
  • Function : Author
Bianca Panis
  • Function : Author
Joanna Lazier
  • Function : Author
Matthew Osmond
  • Function : Author
Taila Hartley
  • Function : Author
Pankaj Prasun
  • Function : Author
Sabine Lüttgen
  • Function : Author
Ilaria Mannucci
  • Function : Author
Ivana Lessel
  • Function : Author
Claudia Schob
  • Function : Author
Stefan Kindler
  • Function : Author
John Pappas
  • Function : Author
Rachel Rabin
  • Function : Author
Marjolein Willemsen
  • Function : Author
Thatjana Gardeitchik
  • Function : Author
Katharina Löhner
  • Function : Author
Patrick Rump
  • Function : Author
Kerith-Rae Dias
  • Function : Author
Carey-Anne Evans
  • Function : Author
Peter Ian Andrews
  • Function : Author
Tony Roscioli
  • Function : Author
Han Brunner
  • Function : Author
Chieko Chijiwa
  • Function : Author
M. Lewis
  • Function : Author
Rami Abou Jamra
  • Function : Author
David Dyment
  • Function : Author
Kym Boycott
  • Function : Author
Alexander Stegmann
  • Function : Author
Christian Kubisch
  • Function : Author
Ene-Choo Tan
  • Function : Author
Ghayda Mirzaa
  • Function : Author
Kirsty Mcwalter
Tjitske Kleefstra
  • Function : Author
Rolph Pfundt
  • Function : Author
Zoya Ignatova
  • Function : Author
Gunter Meister
  • Function : Author
Hans-Jürgen Kreienkamp
  • Function : Author

Abstract

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.

Dates and versions

hal-03222237 , version 1 (10-05-2021)

Identifiers

Cite

Davor Lessel, Daniela Zeitler, Margot Reijnders, Andriy Kazantsev, Fatemeh Hassani Nia, et al.. Germline AGO2 mutations impair RNA interference and human neurological development. Nature Communications, 2020, 11 (1), ⟨10.1038/s41467-020-19572-5⟩. ⟨hal-03222237⟩

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