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Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [RNA-Seq]

ABSTRACT: Mutations in human Argonaute genes, AGO1 and AGO2, are associated with neurodevelopmental disorders. Although multiple patients have been identified, the underlying molecular basis for pathogenesis remains unclear. Here, we performed an extensive investigation of five AGO2 mutations (p.L192P, p.A367P, p.T357M, p.F182del, and p.G733R) linked to different clinical severities.

ORGANISM(S): Mus musculus

PROVIDER: GSE294381 | GEO | 2025/10/03

REPOSITORIES: GEO

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Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [miRNA-Seq]

2025-10-03 | GSE294382 | GEO

Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [RNA-Seq, 2]

Project description:Mutations in human Argonaute genes, AGO1 and AGO2, are associated with neurodevelopmental disorders. 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 F182D 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' isomiRs, suggesting altered miRNA loading and increased miRNA 3' 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.

2025-10-03 | GSE308750 | GEO

Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome

Project description:Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome

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AGO2 mutations impair RNA interference and human neurological development

Project description:Argonaute-2 forms together with associated miRNAs the RNA induced silencing complex (RISC), which recognizes target mRNAs for translational silencing and degradation. Here, we identified thirteen heterozygous mutations in AGO2 in a cohort of 20 patients affected by mild to severe neurodevelopmental disorder. Each of the identified single amino acid mutations results in impaired shRNA-mediated silencing. Through biochemical and molecular dynamic analyses, we uncovered two mutation-specific functional consequences: one mutation (p.G733R) induces a loss-of-function, whereas the other exchanges lead to increased binding of AGO2 to mRNA targets. The latter is supported by decreased phosphorylation of a C-terminal cluster of serine residues known to be involved in mRNA target release, and by the increased formation of dendritic P-bodies in neurons. Our data highlight the complexity underlying AGO2 function, and underline the importance of tight gene expression regulation through the dynamic AGO2-RNA association for neuronal development.

2020-08-24 | GSE141099 | GEO

Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [miRNA-Seq]

Project description:Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [miRNA-Seq]

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Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [RNA-Seq]

Project description:Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [RNA-Seq]

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AGO2 protects Drosophila siRNAs and microRNAs from target-directed degradation, even in the absence of 2′-O-methylation

Project description:Target-directed degradation (TDD) of microRNAs (miRNAs) plays an important role in shaping miRNA abundances across bilateria. Some endogenous small interfering RNAs (siRNAs) of Drosophila cells have target sites resembling those that trigger miRNA TDD, raising the question as to whether they too might undergo such regulation. Here, we find that at least seven of these siRNAs are indeed sensitive to TDD when loaded into AGO1, the Argonaute paralog that preferentially associates with miRNAs. Despite this sensitivity when loaded into AGO1, these siRNAs are not detectably regulated by TDD because most molecules are loaded into AGO2, the Argonaute paralog that preferentially associates with siRNAs, and we find that siRNAs and miRNAs loaded into AGO2 are insensitive to TDD. One explanation for the protection of these small RNAs loaded into AGO2 is that these small RNAs are 2′-O-methylated at their 3′ termini. However, contrary to previous proposals, 2′-O-methylation does not protect these RNAs from TDD, which indicates that their protection is instead conferred by features of the AGO2 protein itself. Together, these observations clarify the requirements for regulation by TDD and revise our understanding of the role of 2′-O-methylation in small-RNA biology.

2021-01-05 | GSE163938 | GEO

LIS1 RNA binding orchestartes the mechanosensitive properties of embryonic stem cells in AGO2 dependent and independent ways.

Project description:LIS1 immunoprecipitation in nuclear and cytoplasmic fractions of LIS1 Floxed/-, OE and WT embryonic stem cells. To identify AGO2 dependent and independent interactions LIS1 was immunoprecipitated in AGO1-4 knockout and doxycycline induced AGO2 mouse embryonic stem cells.

2023-07-20 | PXD033150 | Pride

Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [RNA-Seq, 2]

Project description:Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel-Kreienkamp syndrome [RNA-Seq, 2]

| PRJNA1332650 | ENA

Ago1 vs Ago2-IP small RNA deep-sequencing with age in Drosophila

Project description:Drosophila miRNAs show distinct change in isoform distribution pattern with age. Some miRNAs show accumulation of the short isoforms, while other miRNAs show the accumulation of the long isoforms with age. The increase of the long isoforms of some miRNAs reflects increased 2'-O-methylated miRNA isoforms with age. The increase in 2'-O-methylated miRNA isoforms reflected increased Ago2-loading, but not Ago1-loading of specific miRNA isoforms with age. This raised a question on whether there is global shift in small RNA loading pattern between Ago1 and Ago2 with age. To investigate change in small RNA loading pattern between Ago1 and Ago2 with age, we performed small RNA deep-sequencing of Ago1 vs Ago2-IP small RNAs at 3d and 30d in Drosophila. This analysis revealed global increase of miRNA loading into Ago2, but not into Ago1 with age.

2014-01-01 | GSE52961 | GEO

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