Germline AGO2 mutations impair RNA interference and human neurological development

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


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.

Bibliographical data

Original languageEnglish
Publication statusPublished - 16.11.2020
PubMed 33199684