New research by Profs. Lessel, Kreienkamp and MacRae helps us understand why AGO2 mutations lead to neurodevelopmental problems — it’s not just a broken gene, but a disrupted regulatory system. Understanding exactly how the mutation disrupts its normal function is crucial is an important step toward future therapies.
AGO2 (like AGO1) helps control how other genes are turned “on” or “off,” especially in the brain. When AGO2 doesn’t work properly, it can affect brain development, speech, movement, and learning in different ways.
What did the study look at?
Researchers studied how the AGO2 protein works together with tiny molecules called miRNAs. In healthy cells, AGO2 and miRNAs constantly attach and release from their targets in a balanced way — like a switch that keeps gene activity just right.
Even small disruptions of this rhythm cause downstream problems. With AGO2 mutations some RNAs that should be repressed may not be, or repression may become less precise
This results in widespread “noise” in gene activity, especially in brain cells.
Why does this matter?
AGO2 mutations cause developmental problems not because the gene is missing, but because it’s working in the wrong rhythm.
Different mutations affect the dynamics in different ways, which may help explain why some children are more mildly or more severely affected.
This new understanding could guide future research and treatments that aim to correct or stabilize these interactions.
There’s no direct treatment yet, but this research brings scientists closer to understanding the root cause. For now, supportive therapies — speech, physical, and occupational therapy — remain the best way to help children reach their potential.
References
For more details, you can read the full paper for free here.
Liu et al., Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel–Kreienkamp syndrome. Nucleic Acids Research. 2025; 53(19):gkaf1002