Aug 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123 34, pp.
e2610782123
· 0 citations· 82 references
Medicine
TL;DR
A single uORF in KCNQ2 is identified that is highly repressive of protein translation and it is demonstrated that mutations disabling the uORF start codon enhance synthesis of encoded potassium channels and weaken ribosome engagement at the uORF.
Abstract
Upstream open reading frames (uORFs) within the 5'-untranslated region (5'-UTR) of messenger RNA transcripts can regulate protein translation. Despite widespread prevalence within the human genome, they remain unidentified for many clinically relevant genes. A gene frequently associated with neonatal-onset epilepsy is KCNQ2, which encodes a neuronal voltage-gated potassium channel subunit that functions to dampen neuronal excitability. Heterozygous loss-of-function pathogenic KCNQ2 variants are known to cause a range of neurodevelopmental disorders and epileptic encephalopathies, but there remains an unmet clinical need for patients harboring these variants. We identified a single uORF in KCNQ2 that is highly repressive of protein translation and demonstrated that mutations disabling the uORF start codon enhance synthesis of encoded potassium channels. Additionally, we show that adenine base editing of the uORF start codon can weaken ribosome engagement at the uORF and enhance translation of the protein in a neuron-like cell line. This study establishes a previously underexplored regulatory feature for KCNQ2 and highlights the importance of understanding uORFs for clinically relevant genes, both for assessing disease risk and therapeutic potential.
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