RNA interference is a major mechanism for post-transcriptional regulation of gene expression. Precursors of microRNAs (miRNAs) are transcribed, processed into mature miRNAs and loaded onto Argonaute (AGO1-4) proteins to form the RNA-induced silencing complex (RISC). Each miRNA may recognize a set of target mRNAs by base pairing, which leads to translational silencing and mRNA degradation in cytoplasmic structures referred to as processing (P-) bodies. Biallelic loss of Ago2 leads to early embryonic lethality in mice exhibiting various development defects including anomalies of the central nervous system.
Therefore, accurate regulation of gene expression by the RNA interference pathway seems to be of utmost importance for proper development and maintenance of complex neural circuits. However, so far no genetic alterations in the gene encoding for AGO2 have been described which are associated with any human pathology. Thus, it still remains largely elusive how RNA interference, and especially domains of AGO2 or local sequences down to single amino acid residues, regulate human organismal development and function.
Here, scientists from University Medical Center Hamburg, demonstrate that germline AGO2 mutations affect human neurological development and provide molecular insight into how AGO2 dysfunction causes a human Mendelian disorder.
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.
They 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. They 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.
Their data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development. This research has been published on Nature in November 2020.
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