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The Arg320His variant, which occurs in the voltage\u2010sensing domain of the channel, causes a highly penetrant and specific form of progressive myoclonus epilepsy with severe ataxia, designated myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK).<jats:italic>KCNC1<\/jats:italic>encodes the voltage\u2010gated potassium channel K<jats:sub>V<\/jats:sub>3.1, a channel that is important for enabling high\u2010frequency firing in interneurons, raising the possibility that MEAK is associated with reduced interneuronal function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To determine how this variant triggers MEAK, we expressed K<jats:sub>V<\/jats:sub>3.1b<jats:sup>R320H<\/jats:sup>in cortical interneurons in vitro and investigated the effects on neuronal function and morphology. We also performed electrophysiological recordings of oocytes expressing K<jats:sub>V<\/jats:sub>3.1b to determine whether the mutation introduces gating pore currents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of the K<jats:sub>V<\/jats:sub>3.1b<jats:sup>R320H<\/jats:sup>variant profoundly reduced excitability of mature cortical interneurons, and cells expressing these channels were unable to support high\u2010frequency firing. The mutant channel also had an unexpected effect on morphology, severely impairing neurite development and interneuron viability, an effect that could not be rescued by blocking K<jats:sub>V<\/jats:sub>3 channels. Oocyte recordings confirmed that in the adult K<jats:sub>V<\/jats:sub>3.1b isoform, R320H confers a dominant negative loss\u2010of\u2010function effect by slowing channel activation, but does not introduce potentially toxic gating pore currents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Overall, our data suggest that, in addition to the regulation of high\u2010frequency firing, K<jats:sub>V<\/jats:sub>3.1 channels play a hitherto unrecognized role in neuronal development. MEAK may be described as a developmental dendritopathy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16867","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T18:30:15Z","timestamp":1616092215000},"page":"1256-1267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Progressive myoclonus epilepsy<i>KCNC1<\/i>variant causes a developmental dendritopathy"],"prefix":"10.1111","volume":"62","author":[{"given":"Jenna C.","family":"Carpenter","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy University College London Queen Square Institute of Neurology London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roope","family":"M\u00e4nnikk\u00f6","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases University College London Queen Square Institute of Neurology London 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