{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:31:24Z","timestamp":1790206284274,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo Ordinario Ricerca Scientifica Uniba","award":["PJT-169160"],"award-info":[{"award-number":["PJT-169160"]}]},{"name":"Fondo Ordinario Ricerca Scientifica Uniba","award":["RGPIN-2017-06871"],"award-info":[{"award-number":["RGPIN-2017-06871"]}]},{"name":"Canadian Institutes for Health Research (CIHR)","award":["PJT-169160"],"award-info":[{"award-number":["PJT-169160"]}]},{"name":"Canadian Institutes for Health Research (CIHR)","award":["RGPIN-2017-06871"],"award-info":[{"award-number":["RGPIN-2017-06871"]}]},{"name":"Natural Sciences and Engineering Research Council (NSERC)","award":["PJT-169160"],"award-info":[{"award-number":["PJT-169160"]}]},{"name":"Natural Sciences and Engineering Research Council (NSERC)","award":["RGPIN-2017-06871"],"award-info":[{"award-number":["RGPIN-2017-06871"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype\u2013phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies.<\/jats:p>","DOI":"10.3390\/ijms23158079","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T12:53:45Z","timestamp":1658494425000},"page":"8079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia"],"prefix":"10.3390","volume":"23","author":[{"given":"Giorgia","family":"Dinoi","sequence":"first","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Morin","sequence":"additional","affiliation":[{"name":"Department of Physics, 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-5125","authenticated-orcid":false,"given":"Elena","family":"Conte","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagar","family":"Mor Shaked","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonietta","family":"Coppola","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, 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 Medicine and Surgery, LUM University, 70010 Casamassima, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly","family":"Elpeleg","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Liantonio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbar","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Clinic, Shamir Medical Center (Assaf Harofeh), Zerifin 7033001, Israel"}],"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-Drug 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":"CIRCA, Center for Interdisciplinary Research on Brain and Learning, 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0322-2640","authenticated-orcid":false,"given":"Angelo","family":"Russo","sequence":"additional","affiliation":[{"name":"Child Neurology Unit, IRCCS, Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9140-5350","authenticated-orcid":false,"given":"Paola","family":"Imbrici","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"D\u2019Adamo, M.C., Liantonio, A., Rolland, J.-F., Pessia, M., and Imbrici, P. 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