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Although multiple patients have been identified, the underlying molecular basis for pathogenesis remains unclear. Here, we biochemically examined five AGO2 mutations (p.L192P, p.A367P, p.T357M, p.F182del, and p.G733R) linked to different clinical severities. Except for G733R, all AGO2 mutant proteins maintained a stable fold, capable of binding and using microRNA (miRNA) guides. Kinetic studies showed that the L192P, A367P, and T357M mutants have prolonged dwell times on target RNAs, indicating impaired target release. The L192P and A367P variants also display slow target RNA association kinetics. RNA Bind-n-Seq experiments showed that in vitro, the L192P, A367P, T357M, and F182\u0394 mutants are prone to mis-targeting. In cultured murine cortical neurons, the L192P mutant altered the miRNA complement associated with AGO2, altered guide strand selectivity, and increased the accumulation of 3\u2032 isomiRs, suggesting altered miRNA loading and increased miRNA 3\u2032 end exposure. In vivo, mice carrying the p.L192P variant, but not p.G733R, demonstrated strongly reduced breeding ability, altered cortical transcriptomes, and over-repression of miRNA targets. The combined results suggest patient mutations impact AGO2 targeting dynamics in a gain-of-function manner, leading to deregulation of the neuronal transcriptome and the observed neurodevelopmental anomalies.<\/jats:p>","DOI":"10.1093\/nar\/gkaf1002","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:25:33Z","timestamp":1760621133000},"source":"Crossref","is-referenced-by-count":3,"title":["Dysregulation of AGO2-miRNA dynamics underlies the <i>AGO2<\/i>-associated Lessel\u2013Kreienkamp syndrome"],"prefix":"10.1093","volume":"53","author":[{"given":"TingYu M","family":"Liu","sequence":"first","affiliation":[{"name":"The Scripps Research Institute Department of Integrative Structural and Computational Biology, , La Jolla , CA\u00a092037 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Tibbe","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf ,\u00a0 Hamburg\u00a020246 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Broder","family":"Engler","sequence":"additional","affiliation":[{"name":"Institute for Neuroimmunology and Multiple Sclerosis, at the Center for Molecular Neurobiology, University Medical Center , Hamburg-Eppendorf\u00a020251 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irm","family":"Hermans-Borgmeyer","sequence":"additional","affiliation":[{"name":"Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , Hamburg\u00a020251 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Borgmeyer","sequence":"additional","affiliation":[{"name":"Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , Hamburg\u00a020251 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin Robles","family":"de\u00a0Maruri","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Regensburg , Regensburg\u00a093053 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davor","family":"Lessel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf ,\u00a0 Hamburg\u00a020246 ,","place":["Germany"]},{"name":"Institute of Human Genetics, University of Regensburg , Regensburg\u00a093053 ,","place":["Germany"]},{"name":"Institute of Clinical Human Genetics, University Hospital Regensburg , Regensburg\u00a093053 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5112-0294","authenticated-orcid":false,"given":"Ian J","family":"MacRae","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute Department of Integrative Structural and Computational Biology, , La 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