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dc.contributor.authorDuan, Ye
dc.contributor.authorLi, Li
dc.contributor.authorPanzade, Ganesh Prabhakar
dc.contributor.authorPiton, Amélie
dc.contributor.authorZinovyeva, Anna
dc.contributor.authorAmbros, Victor R.
dc.date.accessioned2024-03-26T15:37:50Z
dc.date.available2024-03-26T15:37:50Z
dc.date.issued2024-02-27
dc.identifier.citationDuan Y, Li L, Panzade GP, Piton A, Zinovyeva A, Ambros V. Modeling neurodevelopmental disorder-associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1. Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2308255121. doi: 10.1073/pnas.2308255121. Epub 2024 Feb 27. PMID: 38412125; PMCID: PMC10927592.en_US
dc.identifier.eissn1091-6490
dc.identifier.doi10.1073/pnas.2308255121en_US
dc.identifier.pmid38412125
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53225
dc.description.abstractMicroRNAs (miRNA) associate with Argonaute (AGO) proteins and repress gene expression by base pairing to sequences in the 3' untranslated regions of target genes. De novo coding variants in the human AGO genes AGO1 and AGO2 cause neurodevelopmental disorders (NDD) with intellectual disability, referred to as Argonaute syndromes. Most of the altered amino acids are conserved between the miRNA-associated AGO in Homo sapiens and Caenorhabditis elegans, suggesting that the human mutations could disrupt conserved functions in miRNA biogenesis or activity. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homologous gene, alg-1. These alg-1 NDD mutations cause phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC (miRNA silencing complex) formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic, causing developmental and molecular phenotypes stronger than those of alg-1 null mutants, likely by sequestrating functional miRISC components into non-functional complexes. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or messenger RNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental AGO functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.en_US
dc.description.sponsorshipThis research was supported by funding from NIH grants R01GM088365, R01GM034028, R35GM131741 (V.R.A.), and R35GM124828 (A.Z.). Some C. elegans strains were provided by Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (P40OD010440).en_US
dc.language.isoenen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.relation.urlhttps://doi.org/10.1073/pnas.2308255121en_US
dc.rightsCopyright © 2024 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectArgonauteen_US
dc.subjectdisease modelingen_US
dc.subjectintellectual disabilityen_US
dc.subjectmicroRNAen_US
dc.subjectneurodevelopmental disorderen_US
dc.titleModeling neurodevelopmental disorder-associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1en_US
dc.typeJournal Articleen_US
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume121
dc.source.issue10
dc.source.beginpagee2308255121
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of America
refterms.dateFOA2024-03-26T15:37:51Z
dc.contributor.departmentProgram in Molecular Medicineen_US


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Copyright © 2024 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Except where otherwise noted, this item's license is described as Copyright © 2024 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).