ArticleNature communications2020
Germline AGO2 mutations impair RNA interference and human neurological development.
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Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53citing papers in PubMed
5.3field-weighted citation impact, top 3% of its field
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Who cites it
53 citing papers in PubMed, 98 citations in OpenAlex.
- The clinical and molecular spectrum of AGO2-associated Lessel-Kreienkamp neurodevelopmental syndrome.Genome medicine · 2026Article
- Structural basis for RISC assembly of human Argonaute2.Molecular cell · 2026Article
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- Structural insights into disease-associated mutations in the microRNA processing machinery.Experimental & molecular medicine · 2026Review
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- The superpowers of imprinting control regions.Genome research · 2026Review
- The AGO2-ATOX1 axis exacerbates inflammation in a mouse sepsis model.Central-European journal of immunology · 2026Article
- Neurodevelopmental disorder-linked Argonaute mutations permit delayed RISC formation and unusual shortening of miRNAs by 3'→5' trimming.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome.Nucleic acids research · 2025Article
- Zebrafish in neurodevelopmental disorders studies: Genetic models and pathological involvement of microglia.Developmental medicine and child neurology · 2025Review
- The Life of MicroRNAs: Biogenesis, Function and Decay in Cancer.Biomolecules · 2025Review
- Structural and evolutionary determinants of Argonaute function.Nucleic acids research · 2025Article
- Centrosome‑, mitotic spindle‑ and cytokinetic bridge‑specific compartmentalization of AGO2 protein in human liver cells undergoing mitosis: Non‑canonical, RNAi‑dependent, control of local homeostasis.Molecular medicine reports · 2025Article
- Ribonucleases in Mendelian disease: Characterization and insight from model organisms.Genes & diseases · 2025Review
- Molecular dynamics simulations based siRNA design against GPR10 reveals stable RNAi therapeutics for hormone-dependent uterine fibroids.Scientific reports · 2025Article
- WAGO-1 is a sexually dimorphic Argonaute protein required for proper germ granule structure and gametogenesis.bioRxiv : the preprint server for biology · 2025Article
- Article
- Fine Regulation of MicroRNAs in Gene Regulatory Networks and Pathophysiology.International journal of molecular sciences · 2025Review
- DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.American journal of human genetics · 2025Article
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Authors and funding
67 authors at 20 institutions in 8 countries.
Davor LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. d.lessel@uke.de.ORCID 0000-0003-4496-244X
Daniela M ZeitlerRegensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
Margot R F ReijndersDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.ORCID 0000-0002-6379-7147
Andriy KazantsevInstitute of Biochemistry & Molecular Biology, University of Hamburg, Hamburg, Germany.ORCID 0000-0002-7587-9983
Fatemeh Hassani NiaInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.ORCID 0000-0002-5036-0317
Alexander BartholomäusInstitute of Biochemistry & Molecular Biology, University of Hamburg, Hamburg, Germany.ORCID 0000-0003-0970-7304
Victoria MartensInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Astrid BruckmannRegensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
Veronika GrausRegensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
Allyn McConkie-RosellDivision of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC, 27707, USA.
Marie McDonaldDivision of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC, 27707, USA.
Bernarda LozicUniversity Hospital of Split, Split, Croatia.
Ee-Shien TanGenetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore, Singapore.
Erica GerkesDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Jessika JohannsenDepartment of Pediatrics, University Medical Center Eppendorf, 20246, Hamburg, Germany.
Jonas DeneckeDepartment of Pediatrics, University Medical Center Eppendorf, 20246, Hamburg, Germany.
Aida TelegrafiGeneDx, Gaithersburg, MD, 20877, USA.
Evelien Zonneveld-HuijssoonDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.ORCID 0000-0002-9503-6297
Henny H LemminkDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.ORCID 0000-0002-2748-803X
Breana W M ChamGenetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore, Singapore.
Tanja KovacevicUniversity Hospital of Split, Split, Croatia.ORCID 0000-0003-4252-9415
Linda RamsdellDivision of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, 98105, USA.
Kimberly FossDivision of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, 98105, USA.
Diana Le DucInstitute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.ORCID 0000-0001-7289-2552
Diana MitterInstitute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Steffen SyrbeDepartment of General Paediatrics, Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Andreas MerkenschlagerDepartment of Neuropediatrics, University of Leipzig, Leipzig, Germany.ORCID 0000-0001-9959-2306
Margje SinnemaDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Bianca PanisDepartment of Pediatrics, Zuyderland Medical Center, Heerlen and Sittard, 6419, the Netherlands.
Joanna LazierDepartment of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Matthew OsmondChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
Taila HartleyChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
Jeremie MortreuxDépartement de Génétique Médicale, CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM, Marseille, France.ORCID 0000-0002-2914-1961
Tiffany BusaDépartement de Génétique Médicale, CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM, Marseille, France.
Chantal MissirianDépartement de Génétique Médicale, CHU Timone Enfants, Assistance Publique - Hôpitaux de Marseille AP-HM, Marseille, France.
Pankaj PrasunDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
Sabine LüttgenInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Ilaria MannucciInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.ORCID 0000-0002-5799-1859
Ivana LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Claudia SchobInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Stefan KindlerInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
John PappasDepartment of Pediatrics, New York University Grossman School of Medicine, New York, NY, 10016, USA.ORCID 0000-0001-5625-2598
Rachel RabinDepartment of Pediatrics, New York University Grossman School of Medicine, New York, NY, 10016, USA.
Marjolein WillemsenDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
Thatjana GardeitchikDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
Katharina LöhnerDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Patrick RumpDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.ORCID 0000-0003-4059-0247
Kerith-Rae DiasNeuroscience Research Australia (NeuRA), Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.ORCID 0000-0002-4707-8089
Carey-Anne EvansNeuroscience Research Australia (NeuRA), Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Peter Ian AndrewsDepartment of Neurology, Sydney Children's Hospital, Sydney, Australia.
Tony RoscioliNeuroscience Research Australia (NeuRA), Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Han G BrunnerDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
Chieko ChijiwaDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
M E Suzanne LewisDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.ORCID 0000-0002-1542-1399
David A DymentDepartment of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Kym M BoycottDepartment of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Alexander P A StegmannDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.ORCID 0000-0002-9736-7137
Christian KubischInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Ene-Choo TanResearch Laboratory, KK Women's & Children's Hospital, Singapore, Singapore.ORCID 0000-0001-5497-6058
Ghayda M MirzaaCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.ORCID 0000-0003-2648-7657
Kirsty McWalterGeneDx, Gaithersburg, MD, 20877, USA.ORCID 0000-0002-1654-9036
Tjitske KleefstraDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
Zoya IgnatovaInstitute of Biochemistry & Molecular Biology, University of Hamburg, Hamburg, Germany.
Gunter MeisterRegensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
Hans-Jürgen KreienkampInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. kreienkamp@uke.de.ORCID 0000-0002-8871-9970
Universität Hamburg · DERadboud University Nijmegen · NLUniversity Medical Center Groningen · NLUniversity of Ottawa · CAUniversity of Regensburg · DEKK Women's and Children's Hospital · SGUniversity Hospital Leipzig · DEDuke University · USInserm · FRNew South Wales Department of Health · AUNew York University · USSeattle Children's Hospital · USUniversity of British Columbia · CAUniversity of Split · HRUNSW Sydney · AUAssistance Publique Hôpitaux de Marseille · FRChildren's Hospital of Eastern Ontario · CAHeidelberg University · DEIcahn School of Medicine at Mount Sinai · USLeipzig University · DE
Funding
Genes and pathways underlying brain overgrowth and focal cortical malformationsK08NS092898 · NINDS · SEATTLE CHILDREN'S HOSPITAL · PI MIRZAA, GHAYDA · 2015 to 2019
$930kNINDS NIH HHS K08 NS092898
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.
Indexed as
RNA InterferenceAdolescentAnimalsArgonaute ProteinsChildChild, PreschoolCluster AnalysisDendritesFibroblastsGene SilencingGerm CellsHEK293 CellsHippocampusHumansMiceMolecular Dynamics SimulationAGO2 protein, humanArgonaute ProteinsRNA-Induced Silencing ComplexRNA, MessengerRNA, Small Interfering
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