Targeting protein synthesis control regions may reduce seizures in genetic epilepsy
Targeting the control of protein synthesis in the KCNQ2 gene may serve as a potential disease-modifying strategy for patients with a genetic form of neonatal-onset epilepsy and impaired brain development, according to a Northwestern Medicine study published in the Proceedings of the National Academy of Sciences.
A recent Northwestern Medicine study, published in the Proceedings of the National Academy of Sciences, suggests that targeting the control of protein synthesis in the KCNQ2 gene could provide a disease-modifying treatment for neonatal-onset epilepsy and impaired brain development. Genetic variants of the KCNQ2 gene are linked to severe conditions that cause seizures during infancy, intellectual disability, developmental delays, and poor long-term neurological outcomes. However, no KCNQ2-targeted therapies currently exist to address these disorders.
Normally, KCNQ2, a brain potassium channel gene, acts as a brake on the nervous system by preventing overactive neurons from firing too much. In the case of neonatal-onset epilepsy caused by KCNQ2 variants, this braking system fails, leading to excessive neuronal activity and seizures. The study's researchers investigated the regulation of KCNQ2 protein synthesis, discovering a regulatory element called an upstream open reading frame (uORF) within the KCNQ2 gene.
The uORF can divert the cell's protein synthesis machinery away from the primary protein code, reducing the overall efficiency of producing the main protein.
By using DNA base editing to modify the KCNQ2 gene and inactivate the uORF in cultured cells, the scientists observed an increase in functional KCNQ2 protein production and potassium channel activity. This finding suggests that inactivating the uORF could be an effective therapeutic strategy to boost KCNQ2 protein levels in patients with KCNQ2 gene variants, potentially lowering the risk of seizures.
The researchers are now investigating whether inactivating the uORF in mice with KCNQ2 pathogenic variants yields similar results.
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