AGO2 mutations impair RNA interference and human neurological development

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. Overall design: RNA sequencing and gene expression analysis of primary fibroblasts