miRNA biogenesis and inherited disorders: clinico-molecular insights

• Published in: Trends in genetics Vol. 39; no. 5; pp. 401 - 414
• Main Authors: Pelletier, Dylan, Rivera, Barbara, Fabian, Marc R., Foulkes, William D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2023
• Subjects: AGO1/2 syndrome; cancer predisposition; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; DGCR8 syndrome; DICER1 syndrome; Genome, Human; Genotype; Humans; MicroRNAs - genetics; miRNA biogenesis; neurodevelopmental disorder; Ribonuclease III - genetics; Ribonuclease III - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; DGCR8 syndrome; cancer predisposition; miRNA biogenesis; neurodevelopmental disorder; AGO1/2 syndrome; DICER1 syndrome
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2023.01.009

Over the past decade or so it has been found that germline pathogenic variants (GPVs) in microRNA (miRNA) processing genes cause Mendelian disorders that fall in the general categories of tumor-predisposing or neurodevelopment disorders (NDDs).Novel structural and functional studies looking at the roles of DICER1, DROSHA, and DiGeorge critical region 8 (DGCR8) in miRNA biogenesis, as well as the role of Argonaute (AGO) 1/2 in miRNA-induced silencing, have provided insight with respect to the impact of variants in these genes on miRNA-mediated gene silencing.GPVs in DGCR8 and DICER1 are both associated with thyroid nodular hyperplasia, while GPVs in both AGO1 and AGO2 are associated with NDDs.Noncanonical roles of AGO1/2 outside of forming the RNA-induced silencing complex have recently been described, while DICER1 has been shown to participate in DNA repair. MicroRNAs (miRNAs) play vital roles in the regulation of gene expression, a process known as miRNA-induced gene silencing. The human genome codes for many miRNAs, and their biogenesis relies on a handful of genes, including DROSHA, DGCR8, DICER1, and AGO1/2. Germline pathogenic variants (GPVs) in these genes cause at least three distinct genetic syndromes, with clinical manifestations that range from hyperplastic/neoplastic entities to neurodevelopmental disorders (NDDs). Over the past decade, DICER1 GPVs have been shown to lead to tumor predisposition. Moreover, recent findings have provided insight into the clinical consequences arising from GPVs in DGCR8, AGO1, and AGO2. Here we provide a timely update with respect to how GPVs in miRNA biogenesis genes alter miRNA biology and ultimately lead to their clinical manifestations.