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Germline AGO2 mutations impair RNA interference and human neurological development

Author

Listed:
  • Davor Lessel

    (University Medical Center Hamburg-Eppendorf)

  • Daniela M. Zeitler

    (University of Regensburg)

  • Margot R. F. Reijnders

    (Radboud University Medical Center
    Maastricht University Medical Center)

  • Andriy Kazantsev

    (University of Hamburg)

  • Fatemeh Hassani Nia

    (University Medical Center Hamburg-Eppendorf)

  • Alexander Bartholomäus

    (University of Hamburg
    GFZ German Research Centre for Geosciences, Section Geomicrobiology)

  • 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
    University of Split School of Medicine)

  • 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
    Aix Marseille Univ, INSERM, MMG)

  • Tiffany Busa

    (CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM)

  • Chantal Missirian

    (CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM
    Aix Marseille Univ, INSERM, MMG)

  • 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
    NSW Health Pathology Randwick Genetics)

  • Carey-Anne Evans

    (University of New South Wales
    NSW Health Pathology Randwick Genetics)

  • Peter Ian Andrews

    (Sydney Children’s Hospital
    University of New South Wales)

  • Tony Roscioli

    (University of New South Wales
    Centre for Clinical Genetics, Sydney Children’s Hospital
    New South Wales Health Pathology Genomics Laboratory Randwick)

  • Han G. Brunner

    (Radboud University Medical Center
    Maastricht 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
    University of Ottawa)

  • Kym M. Boycott

    (Children’s Hospital of Eastern Ontario
    University of Ottawa)

  • Alexander P. A. Stegmann

    (Radboud University Medical Center
    Maastricht 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
    University of Washington
    Brotman Baty Institute for Precision Medicine)

  • Kirsty McWalter

    (GeneDx)

  • Tjitske Kleefstra

    (Radboud University Medical Center)

  • Rolph Pfundt

    (Radboud University Medical Center
    University of Groningen, University Medical Center Groningen)

  • Zoya Ignatova

    (University of Hamburg)

  • Gunter Meister

    (University of Regensburg)

  • Hans-Jürgen Kreienkamp

    (University Medical Center Hamburg-Eppendorf)

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.

Suggested Citation

  • Davor Lessel & Daniela M. Zeitler & Margot R. F. Reijnders & Andriy Kazantsev & Fatemeh Hassani Nia & Alexander Bartholomäus & Victoria Martens & Astrid Bruckmann & Veronika Graus & Allyn McConkie-Ros, 2020. "Germline AGO2 mutations impair RNA interference and human neurological development," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19572-5
    DOI: 10.1038/s41467-020-19572-5
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    Cited by:

    1. Aditya Kshirsagar & Svetlana Maslov Doroshev & Anna Gorelik & Tsviya Olender & Tamar Sapir & Daisuke Tsuboi & Irit Rosenhek-Goldian & Sergey Malitsky & Maxim Itkin & Amir Argoetti & Yael Mandel-Gutfre, 2023. "LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Carlos A. Vergani-Junior & Raíssa De P. Moro & Silas Pinto & Evandro A. De-Souza & Henrique Camara & Deisi L. Braga & Guilherme Tonon-da-Silva & Thiago L. Knittel & Gabriel P. Ruiz & Raissa G. Ludwig , 2024. "An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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