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 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 and Hans-Jürgen Kreienkamp ()
Additional contact information
Davor Lessel: University Medical Center Hamburg-Eppendorf
Daniela M. Zeitler: University of Regensburg
Margot R. F. Reijnders: Radboud University Medical Center
Andriy Kazantsev: University of Hamburg
Fatemeh Hassani Nia: University Medical Center Hamburg-Eppendorf
Alexander Bartholomäus: University of Hamburg
Victoria Martens: University Medical Center Hamburg-Eppendorf
Astrid Bruckmann: University of Regensburg
Veronika Graus: University of Regensburg
Allyn McConkie-Rosell: Duke University
Marie McDonald: Duke University
Bernarda Lozic: University Hospital of Split
Ee-Shien Tan: KK Women’s & Children’s Hospital
Erica Gerkes: University of Groningen, University Medical Center Groningen
Jessika Johannsen: University Medical Center Eppendorf
Jonas Denecke: University Medical Center Eppendorf
Aida Telegrafi: GeneDx
Evelien Zonneveld-Huijssoon: University of Groningen, University Medical Center Groningen
Henny H. Lemmink: University of Groningen, University Medical Center Groningen
Breana W. M. Cham: KK Women’s & Children’s Hospital
Tanja Kovacevic: University Hospital of Split
Linda Ramsdell: Seattle Children’s Hospital
Kimberly Foss: Seattle Children’s Hospital
Diana Duc: University of Leipzig Hospitals and Clinics
Diana Mitter: University of Leipzig Hospitals and Clinics
Steffen Syrbe: University Hospital Heidelberg
Andreas Merkenschlager: University of Leipzig
Margje Sinnema: Maastricht University Medical Center
Bianca Panis: Zuyderland Medical Center
Joanna Lazier: Children’s Hospital of Eastern Ontario
Matthew Osmond: University of Ottawa
Taila Hartley: University of Ottawa
Jeremie Mortreux: CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM
Tiffany Busa: CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM
Chantal Missirian: CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM
Pankaj Prasun: Icahn School of Medicine at Mount Sinai
Sabine Lüttgen: University Medical Center Hamburg-Eppendorf
Ilaria Mannucci: University Medical Center Hamburg-Eppendorf
Ivana Lessel: University Medical Center Hamburg-Eppendorf
Claudia Schob: University Medical Center Hamburg-Eppendorf
Stefan Kindler: University Medical Center Hamburg-Eppendorf
John Pappas: New York University Grossman School of Medicine
Rachel Rabin: New York University Grossman School of Medicine
Marjolein Willemsen: Radboud University Medical Center
Thatjana Gardeitchik: Radboud University Medical Center
Katharina Löhner: University of Groningen, University Medical Center Groningen
Patrick Rump: University of Groningen, University Medical Center Groningen
Kerith-Rae Dias: University of New South Wales
Carey-Anne Evans: University of New South Wales
Peter Ian Andrews: Sydney Children’s Hospital
Tony Roscioli: University of New South Wales
Han G. Brunner: Radboud University Medical Center
Chieko Chijiwa: University of British Columbia
M. E. Suzanne Lewis: University of British Columbia
Rami Abou Jamra: University of Leipzig Hospitals and Clinics
David A. Dyment: Children’s Hospital of Eastern Ontario
Kym M. Boycott: Children’s Hospital of Eastern Ontario
Alexander P. A. Stegmann: Radboud University Medical Center
Christian Kubisch: University Medical Center Hamburg-Eppendorf
Ene-Choo Tan: Research Laboratory, KK Women’s & Children’s Hospital
Ghayda M. Mirzaa: Seattle Children’s Research Institute
Kirsty McWalter: GeneDx
Tjitske Kleefstra: Radboud University Medical Center
Rolph Pfundt: Radboud University Medical Center
Zoya Ignatova: University of Hamburg
Gunter Meister: University of Regensburg
Hans-Jürgen Kreienkamp: University Medical Center Hamburg-Eppendorf

Nature Communications, 2020, vol. 11, issue 1, 1-14

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.

Date: 2020
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DOI: 10.1038/s41467-020-19572-5

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