{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:50:34Z","timestamp":1791111034885,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Kv1.2 channels, encoded by the KCNA2 gene, are localized in the central and peripheral nervous system, where they regulate neuronal excitability. Recently, heterozygous mutations in KCNA2 have been associated with a spectrum of symptoms extending from epileptic encephalopathy, intellectual disability, and cerebellar ataxia. Patients are treated with a combination of antiepileptic drugs and 4-aminopyridine (4-AP) has been recently trialed in specific cases. We identified a novel variant in KCNA2, E236K, in a Serbian proband with non-progressive congenital ataxia and early onset epilepsy, treated with sodium valproate. To ascertain the pathogenicity of E236K mutation and to verify its sensitivity to 4-AP, we transfected HEK 293 cells with Kv1.2 WT or E236K cDNAs and recorded potassium currents through the whole-cell patch-clamp. In silico analysis supported the electrophysiological data. E236K channels showed voltage-dependent activation shifted towards negative potentials and slower kinetics of deactivation and activation compared with Kv1.2 WT. Heteromeric Kv1.2 WT+E236K channels, resembling the condition of the heterozygous patient, confirmed a mixed gain- and loss-of-function (GoF\/LoF) biophysical phenotype. 4-AP inhibited both Kv1.2 and E236K channels with similar potency. Homology modeling studies of mutant channels suggested a reduced interaction between the residue K236 in the S2 segment and the gating charges at S4. Overall, the biophysical phenotype of E236K channels correlates with the mild end of the clinical spectrum reported in patients with GoF\/LoF defects. The response to 4-AP corroborates existing evidence that KCNA2-disorders could benefit from variant-tailored therapeutic approaches, based on functional studies.<\/jats:p>","DOI":"10.3390\/ijms22189913","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T21:47:21Z","timestamp":1631656041000},"page":"9913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A Novel KCNA2 Variant in a Patient with Non-Progressive Congenital Ataxia and Epilepsy: Functional Characterization and Sensitivity to 4-Aminopyridine"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9140-5350","authenticated-orcid":false,"given":"Paola","family":"Imbrici","sequence":"first","affiliation":[{"name":"Department of Pharmacy\u2014Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-5125","authenticated-orcid":false,"given":"Elena","family":"Conte","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-2907","authenticated-orcid":false,"given":"Rikard","family":"Blunck","sequence":"additional","affiliation":[{"name":"Department of Physics, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"},{"name":"Department of Pharmacology and Physiology, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"},{"name":"CIRCA, Center for Interdisciplinary Research on Brain and Learning, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizia","family":"Stregapede","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Ges\u00f9, Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Liantonio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9083-7837","authenticated-orcid":false,"given":"Michele","family":"Tosi","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology and Psychiatry, University Hospital of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-6064","authenticated-orcid":false,"given":"Maria Cristina","family":"D\u2019Adamo","sequence":"additional","affiliation":[{"name":"Department of Physiology & Biochemistry, Faculty of Medicine, University of Malta, MSD 2080 Msida, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-7341","authenticated-orcid":false,"given":"Annamaria","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8582-1403","authenticated-orcid":false,"given":"Vesna","family":"Brankovic","sequence":"additional","affiliation":[{"name":"Clinic for Child Neurology and Psychiatry, Medical Faculty, University of Belgrade, 11 000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6367-1843","authenticated-orcid":false,"given":"Ginevra","family":"Zanni","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Ges\u00f9, Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.neuron.2014.12.042","article-title":"Subcellular localization of K+ channels in mammalian brain neurons: Remarkable precision in the midst of extraordinary complexity","volume":"85","author":"Trimmer","year":"2015","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1152\/physrev.00002.2008","article-title":"Localization and targeting of voltage-dependent ion channels in mammalian central neurons","volume":"88","author":"Vacher","year":"2008","journal-title":"Physiol. 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