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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:p>\n                    Upstream open reading frames (uORFs) within the 5\u2019-untranslated region (5\u2019-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\n                    <jats:italic toggle=\"yes\">KCNQ2<\/jats:italic>\n                    , which encodes a neuronal voltage-gated potassium channel subunit that functions to dampen neuronal excitability. Heterozygous loss-of-function pathogenic\n                    <jats:italic toggle=\"yes\">KCNQ2<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">KCNQ2<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">KCNQ2<\/jats:italic>\n                    and highlights the importance of understanding uORFs for clinically relevant genes, both for assessing disease risk and therapeutic potential.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2610782123","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:59:27Z","timestamp":1787075967000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7316-790X","authenticated-orcid":false,"given":"Dalton J.","family":"Huey","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Feinberg School of Medicine, Northwestern 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