Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that mediate post-transcriptional gene silencing through a conserved pathway involving the sequential actions of DROSHA, DICER and Argonaute proteins. These RNA interference core components recognize and process precursor transcripts with structural precision to generate functional miRNA duplexes and guide-loaded Argonaute effector complexes. Recent genetic and structural studies have revealed disease-associated mutations in these proteins, particularly within their catalytic centers and RNA-binding interfaces, that impair miRNA biogenesis and contribute to human pathologies. Such mutations disrupt RNA cleavage fidelity, destabilize domain architecture or hinder small RNA loading, leading to cancers and developmental disorders, including Wilms tumor, DICER1 syndrome, myelodysplastic syndromes and Lessel-Kreienkamp syndrome. This Review highlights the structural basis of these pathogenic mutations and discusses how emerging insights from structural biology are shaping our understanding of RNA interference-related disease mechanisms and guiding potential therapeutic strategies.