{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T02:27:06Z","timestamp":1782440826678,"version":"3.54.5"},"reference-count":19,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS122887"],"award-info":[{"award-number":["R01 NS122887"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U54 NS108874"],"award-info":[{"award-number":["U54 NS108874"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To further clarify genotype:phenotype correlations associated with variants in <jats:italic>KCNC1<\/jats:italic> encoding the voltage\u2010gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in <jats:italic>KCNC1<\/jats:italic> associated with nonspecific developmental delay\/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole\u2010cell voltage clamp electrophysiological recording of wild\u2010type versus variants in a heterologous mammalian expression system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3\u2010expressing high frequency\u2010 firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical\u2010genetic syndrome within the spectrum of <jats:italic>KCNC1<\/jats:italic>\u2010related neurological disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51707","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T13:11:10Z","timestamp":1669295470000},"page":"111-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A <i>KCNC1<\/i>\u2010related neurological disorder due to gain of Kv3.1 function"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-3469","authenticated-orcid":false,"given":"Jerome","family":"Clatot","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy Neurogenetics Initiative The Children's Hospital of Philadelphia  Philadelphia Pennsylvania 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Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"The Epilepsy Neurogenetics Initiative The Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Neurology The University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Neuroscience The University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania 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