Germline AGO2 mutations impair RNA interference and human neurological development

Davor Lessel , Daniela Zeitler , Margot 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 Lemmink , Breana 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 (1, 2) , Tiffany Busa (1, 2) , Chantal Missirian (1, 2) , 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 Brunner , Chieko Chijiwa , M. Lewis , Rami Abou Jamra , David Dyment , Kym Boycott , Alexander Stegmann , Christian Kubisch , Ene-Choo Tan , Ghayda Mirzaa , Kirsty Mcwalter , Tjitske Kleefstra , Rolph Pfundt , Zoya Ignatova , Gunter Meister , Hans-Jürgen Kreienkamp

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Département de génétique médicale [Hôpital de la Timone - APHM]

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.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Human health and pathology

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⟩