{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:57:26Z","timestamp":1791910646979,"version":"4.3.4"},"reference-count":113,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS100954"],"award-info":[{"award-number":["R01NS100954"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS099188"],"award-info":[{"award-number":["R01NS099188"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS129643"],"award-info":[{"award-number":["R01NS129643"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["953621"],"award-info":[{"award-number":["953621"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001454","name":"American Epilepsy Society predoctoral fellowship","doi-asserted-by":"publisher","award":["R01NS100954"],"award-info":[{"award-number":["R01NS100954"]}],"id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001454","name":"American Epilepsy Society predoctoral fellowship","doi-asserted-by":"publisher","award":["R01NS099188"],"award-info":[{"award-number":["R01NS099188"]}],"id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001454","name":"American Epilepsy Society predoctoral fellowship","doi-asserted-by":"publisher","award":["R01NS129643"],"award-info":[{"award-number":["R01NS129643"]}],"id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001454","name":"American Epilepsy Society predoctoral fellowship","doi-asserted-by":"publisher","award":["953621"],"award-info":[{"award-number":["953621"]}],"id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel \u03b1 subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype\u2013phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel\u2019s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype\u2013phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.<\/jats:p>","DOI":"10.3390\/ijms24108826","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T02:04:05Z","timestamp":1684289045000},"page":"8826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4405-3900","authenticated-orcid":false,"given":"Kelsey","family":"Paulhus","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8702-2349","authenticated-orcid":false,"given":"Edward","family":"Glasscock","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/ng1094-136","article-title":"Episodic Ataxia\/Myokymia Syndrome Is Associated with Point Mutations in the Human Potassium Channel Gene, KCNA1","volume":"8","author":"Browne","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Paulhus, K., Ammerman, L., and Glasscock, E. (2020). Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082802"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/ane.13522","article-title":"Effectiveness of Clinical Exome Sequencing in Adult Patients with Difficult-to-Diagnose Neurological Disorders","volume":"145","author":"Sainio","year":"2022","journal-title":"Acta Neurol. Scand."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/mdc3.12518","article-title":"Episodic Ataxia Type 1 (K-Channelopathy) Manifesting as Paroxysmal Nonkinesogenic Dyskinesia: Expanding the Phenotype","volume":"4","author":"Set","year":"2017","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.3389\/fneur.2022.975849","article-title":"Case Report: A Novel Loss-of-Function Pathogenic Variant in the KCNA1 Cytoplasmic N-Terminus Causing Carbamazepine-Responsive Type 1 Episodic Ataxia","volume":"13","author":"Manville","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_6","first-page":"1107","article-title":"Clinical, Genetic, Neurophysiological and Functional Study of New Mutations in Episodic Ataxia Type 1","volume":"84","author":"Tomlinson","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1093\/brain\/awx081","article-title":"A Panel Study on Patients with Dominant Cerebellar Ataxia Highlights the Frequency of Channelopathies","volume":"140","author":"Coutelier","year":"2017","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/mdc3.13381","article-title":"Interictal Headache, Pseudodystonia, and Persistent Ataxia in Episodic Ataxia Type 1 Due to a Novel KCNA1 Gene Mutation","volume":"9","author":"Bhattacharjee","year":"2022","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1093\/brain\/113.5.1361","article-title":"Familial Paroxysmal Kinesigenic Ataxia and Continuous Myokymia","volume":"113","author":"Brunt","year":"1990","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s004390050722","article-title":"Three Novel KCNA1 Mutations in Episodic Ataxia Type I Families","volume":"102","author":"Scheffer","year":"1998","journal-title":"Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1111\/j.1460-9568.2006.05186.x","article-title":"Episodic Ataxia Type 1 Mutations in the KCNA1 Gene Impair the Fast Inactivation Properties of the Human Potassium Channels Kv1.4-1.1\/Kv\u03b21.1 and Kv1.4-1.1\/Kv\u03b21.2","volume":"24","author":"Imbrici","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0022-510X(75)90191-4","article-title":"Hereditary Myokymia and Periodic Ataxia","volume":"25","author":"Griggs","year":"1975","journal-title":"J Neurol Sci"},{"key":"ref_13","first-page":"525","article-title":"Novel Phenotype Associated with a Mutation in the KCNA1(Kv1.1) Gene","volume":"5","author":"Servettini","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1093\/brain\/awu012","article-title":"Episodic Ataxia Type 1: Clinical Characterization, Quality of Life and Genotype-Phenotype Correlation","volume":"137","author":"Graves","year":"2014","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/ana.410400422","article-title":"Episodic Ataxia and A New Mutation of Myokymia Syndrome: Potassium Channel Gene Kvl. 1","volume":"40","author":"Comu","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s10048-006-0071-z","article-title":"Functional Analysis of a Novel Potassium Channel (KCNA1) Mutation in Hereditary Myokymia","volume":"8","author":"Chen","year":"2007","journal-title":"Neurogenetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s10048-015-0460-2","article-title":"Clinical Heterogeneity Associated with KCNA1 Mutations Include Cataplexy and Nonataxic Presentations","volume":"17","author":"Brownstein","year":"2016","journal-title":"Neurogenetics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1093\/brain\/122.5.817","article-title":"A Novel Mutation in the Human Voltage-Gated Potassium Channel Gene (Kv1.1) Associates with Episodic Ataxia Type 1 and Sometimes with Partial Epilepsy","volume":"122","author":"Zuberi","year":"1999","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/1531-8249(200010)48:4<647::AID-ANA12>3.0.CO;2-Q","article-title":"Clinical, Genetic, and Expression Studies of Mutations in the Potassium Channel Gene KCNA1 Reveal New Phenotypic Variability","volume":"48","author":"Eunson","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.braindev.2020.02.004","article-title":"Targeted Gene Panel Sequencing in Early Infantile Onset Developmental and Epileptic Encephalopathy","volume":"42","author":"Na","year":"2020","journal-title":"Brain Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3988\/jcn.2022.18.2.235","article-title":"A Novel KCNA1 Variant Manifesting as Persistent Limb Myokymia Without Episodic Ataxia","volume":"18","author":"Shin","year":"2022","journal-title":"J. Clin. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s10048-016-0486-0","article-title":"A Novel KCNA1 Mutation in a Family with Episodic Ataxia and Malignant Hyperthermia","volume":"17","author":"Mestre","year":"2016","journal-title":"Neurogenetics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/mus.20904","article-title":"Novel Mutation in KCNA1 Causes Episodic Ataxia with Paroxysmal Dyspnea","volume":"37","author":"Shook","year":"2008","journal-title":"Muscle Nerve"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/acn3.597","article-title":"Paroxysmal Motor Disorders: Expanding Phenotypes Lead to Coalescing Genotypes","volume":"5","author":"Zima","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1172\/JCI36948","article-title":"A Missense Mutation in the Kv1.1 Voltage-Gated Potassium Channel-Encoding Gene KCNA1 Is Linked to Human Autosomal Dominant Hypomagnesemia","volume":"119","author":"Glaudemans","year":"2009","journal-title":"J. Clin. Invest."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1074\/jbc.M109.041517","article-title":"Functional Analysis of the Kv1.1 N255D Mutation Associated with Autosomal Dominant Hypomagnesemia","volume":"285","author":"Glaudemans","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/hmg\/ddx430","article-title":"Familial Paroxysmal Kinesigenic Dyskinesia Is Associated with Mutations in the KCNA1 Gene","volume":"27","author":"Yin","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1111\/epi.17118","article-title":"Distinct Epilepsy Phenotypes and Response to Drugs in KCNA1 Gain- and Loss-of Function Variants","volume":"63","author":"Miceli","year":"2022","journal-title":"Epilepsia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e1434","DOI":"10.1002\/mgg3.1434","article-title":"Two Novel KCNA1 Variants Identified in Two Unrelated Chinese Families Affected by Episodic Ataxia Type 1 and Neurodevelopmental Disorders","volume":"8","author":"Yuan","year":"2020","journal-title":"Mol. Genet. Genomic. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.abb.2012.05.006","article-title":"Characterization of the Kv1.1 I262T and S342I Mutations Associated with Episodic Ataxia 1 with Distinct Phenotypes","volume":"524","author":"Zhu","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1055\/s-2004-817921","article-title":"Episodic Ataxia Type 1 with Distal Weakness: A Novel Manifestation of a Potassium Channelopathy","volume":"35","author":"Klein","year":"2004","journal-title":"Neuropediatrics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/mus.24242","article-title":"A Novel KCNA1 Mutation Causing Episodic Ataxia Type I","volume":"50","author":"Lassche","year":"2014","journal-title":"Muscle Nerve"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3988\/jcn.2021.17.2.333","article-title":"A Novel KCNA1 Mutation in an Episodic Ataxia Type 1 Patient with Asterixis and Falls","volume":"17","author":"Lee","year":"2021","journal-title":"J. Clin. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Imbrici, P., Accogli, A., Blunck, R., Altamura, C., Iacomino, M., D\u2019Adamo, M.C., Allegri, A., Pedemonte, M., Brolatti, N., and Vari, S. (2021). Musculoskeletal Features without Ataxia Associated with a Novel de Novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel. Biomedicines, 9.","DOI":"10.3390\/biomedicines9010075"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.mcn.2017.06.006","article-title":"A Novel KCNA1 Mutation in a Patient with Paroxysmal Ataxia, Myokymia, Painful Contractures and Metabolic Dysfunctions","volume":"83","author":"Imbrici","year":"2017","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"942","DOI":"10.4103\/aian.aian_235_22","article-title":"Cervical Dystonia with Cerebellar Ataxia in KCNA1 Mutation: A Phenotypic Expansion","volume":"25","author":"Mahale","year":"2022","journal-title":"Ann. Indian. Acad. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1002\/acn3.51742","article-title":"KCNA1 Gain-of-function Epileptic Encephalopathy Treated with 4-aminopyridine","volume":"10","author":"Takacs","year":"2023","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1212\/WNL.0b013e3181b87959","article-title":"A Patient with Episodic Ataxia and Paramyotonia Congenita Due to Mutations in KCNA1 and SCNA4","volume":"73","author":"Rajakulendran","year":"2009","journal-title":"Neurology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.1038\/s41598-017-03041-z","article-title":"A Channelopathy Mutation in the Voltage-Sensor Discloses Contributions of a Conserved Phenylalanine to Gating Properties of Kv1.1 Channels and Ataxia","volume":"7","author":"Hasan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s00415-006-0134-y","article-title":"Chronic Neuromyotonia as a Phenotypic Variation Associated with a New Mutation in the KCNA1 Gene","volume":"253","author":"Poujois","year":"2006","journal-title":"J. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1212\/WNL.0b013e3181ea9ee3","article-title":"Nongenetic Factors Influence Severity of Episodic Ataxia Type 1 in Monozygotic Twins","volume":"75","author":"Graves","year":"2010","journal-title":"Neurology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3389\/fneur.2018.00587","article-title":"Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I","volume":"9","author":"Karalok","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0014-5793(98)00814-X","article-title":"Characterization of Three Episodic Ataxia Mutations in the Human Kv1.1 Potassium Channel","volume":"431","author":"Zerr","year":"1998","journal-title":"FEBS J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1002\/mds.26737","article-title":"Dominant-Negative Mutation p.Arg324Thr in KCNA1 Impairs Kv1.1 Channel Function in Episodic Ataxia","volume":"31","author":"Scholl","year":"2016","journal-title":"Mov. Disord."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1136\/jnnp.59.4.400","article-title":"Hereditary Myokymia and Paroxysmal Ataxia Linked to Chromosome 12 Is Responsive to Acetazolamide","volume":"59","author":"Brunt","year":"1995","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/mds.28843","article-title":"Downbeat Nystagmus in Episodic Ataxia Type 1 Associated with a Novel KCNA1 Mutation","volume":"37","author":"Jorge","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1159\/000488954","article-title":"A de Novo KCNA1 Mutation in a Patient with Tetany and Hypomagnesemia","volume":"139","author":"Konrad","year":"2018","journal-title":"Nephron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/1098-1004(200010)16:4<374::AID-HUMU15>3.0.CO;2-4","article-title":"Identification of a Novel Missense Mutation L329I in the Episodic Ataxia Type 1 Gene KCNA1\u2014A Challenging Problem","volume":"16","author":"Knight","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ejhg.2016.146","article-title":"Clinical Exome Sequencing: Results from 2819 Samples Reflecting 1000 Families","volume":"25","author":"Trujillano","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1002\/humu.9295","article-title":"A Novel Mutation in KCNA1 Causes Episodic Ataxia without Myokymia","volume":"24","author":"Lee","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1136\/jmedgenet-2019-106373","article-title":"Complete Loss of KCNA1 Activity Causes Neonatal Epileptic Encephalopathy and Dyskinesia","volume":"57","author":"Verdura","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.3389\/fneur.2021.701351","article-title":"Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of KCNA1 in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of KCNA1- and SLC2A1-Related Disorders","volume":"12","author":"Kegele","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e6-12","DOI":"10.1111\/epi.12489","article-title":"High-Resolution Molecular Genomic Autopsy Reveals Complex Sudden Unexpected Death in Epilepsy Risk Profile","volume":"55","author":"Klassen","year":"2014","journal-title":"Epilepsia"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Dinoi, G., Morin, M., Conte, E., Mor Shaked, H., Coppola, M.A., D\u2019Adamo, M.C., Elpeleg, O., Liantonio, A., Hartmann, I., and De Luca, A. (2022). Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158079"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1002\/ajmg.a.38840","article-title":"De Novo KCNA1 Variants in the PVP Motif Cause Infantile Epileptic Encephalopathy and Cognitive Impairment Similar to Recurrent KCNA2 Variants","volume":"176","author":"Rogers","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.mayocp.2015.01.001","article-title":"Whole-Exome Sequencing as a Diagnostic Tool in a Family with Episodic Ataxia Type 1","volume":"90","author":"Tacik","year":"2015","journal-title":"Mayo Clin. Proc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/humu.23149","article-title":"Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes","volume":"38","author":"Parrini","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/mds.22467","article-title":"A Novel KCNA1 Mutation Associated with Global Delay and Persistent Cerebellar Dysfunction","volume":"24","author":"Demos","year":"2009","journal-title":"Mov. Disord."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.neuroscience.2008.09.022","article-title":"A Novel KCNA1 Mutation Identified in an Italian Family Affected by Episodic Ataxia Type 1","volume":"157","author":"Imbrici","year":"2008","journal-title":"Neuroscience"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"129","DOI":"10.14802\/jmd.16028","article-title":"Episodic Ataxias: Clinical and Genetic Features","volume":"9","author":"Choi","year":"2016","journal-title":"J. Mov. Disord."},{"key":"ref_61","first-page":"317","article-title":"New Insights into the Pathogenesis and Therapeutics of Episodic Ataxia Type 1","volume":"9","author":"Hasan","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"358","DOI":"10.3389\/fncel.2019.00358","article-title":"A Kinetic Map of the Homomeric Voltage-Gated Potassium Channel (Kv) Family","volume":"13","author":"Ranjan","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1021\/bi00173a001","article-title":"Antibodies Specific for Distinct Kv Subunits Unveil a Hetero-Oligomeric Basis for Subtypes of \u03b1-Dendrotoxin-Sensitive K+ Channels in Bovine Brain","volume":"33","author":"Scott","year":"1994","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/365075a0","article-title":"Heteromultimeric K+ Channels in Terminal and Juxtaparanodal Regions of Neurons","volume":"365","author":"Wang","year":"1993","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11084","DOI":"10.1021\/bi00160a018","article-title":"Oligomeric Properties of Alpha-Dendrotoxin-Sensitive Potassium Ion Channels Purified from Bovine Brain","volume":"31","author":"Parcej","year":"1992","journal-title":"Biochemistry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1152\/physrev.00020.2009","article-title":"Ancillary Subunits Associated With Voltage-Dependent K Channels","volume":"90","author":"Pongs","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1046\/j.1471-4159.1999.0730849.x","article-title":"Subunit Composition of Kv1 Channels in Human CNS","volume":"73","author":"Coleman","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1113\/jphysiol.2011.224212","article-title":"Voltage-Gated Potassium Channels and the Diversity of Electrical Signalling","volume":"590","author":"Jan","year":"2012","journal-title":"J. Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3389\/fncel.2015.00259","article-title":"Molecular Pathophysiology and Pharmacology of the Voltage-Sensing Module of Neuronal Ion Channels","volume":"9","author":"Miceli","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1152\/physrev.2000.80.2.555","article-title":"The Voltage Sensor in Voltage-Dependent Ion Channels","volume":"80","author":"Bezanilla","year":"2000","journal-title":"Physiol. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00232-014-9764-7","article-title":"Conformational Dynamics of Shaker-Type Kv1.1 Ion Channel in Open, Closed, and Two Mutated States","volume":"248","author":"Bhuyan","year":"2015","journal-title":"J. Membr. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/prot.20065","article-title":"A Set of Homology Models of Pore Loop Domain of Six Eukaryotic Voltage-Gated Potassium Channels Kv1.1-Kv1.6","volume":"55","author":"Liu","year":"2004","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1113\/jphysiol.2001.013242","article-title":"Variable K+ Channel Subunit Dysfunction in Inherited Mutations of KCNA1","volume":"538","author":"Rea","year":"2002","journal-title":"J. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"C496","DOI":"10.1152\/ajpcell.00464.2009","article-title":"Tetramerization Domain Mutations in KCNA5 Affect Channel Kinetics and Cause Abnormal Trafficking Patterns","volume":"298","author":"Burg","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nrm2376","article-title":"How Membrane Proteins Sense Voltage","volume":"9","author":"Bezanilla","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/epi.13306","article-title":"Epileptic Encephalopathy: Use and Misuse of a Clinically and Conceptually Important Concept","volume":"57","author":"Howell","year":"2016","journal-title":"Epilepsia"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11352","DOI":"10.1073\/pnas.1000142107","article-title":"Structure of the Full-Length Shaker Potassium Channel Kv1.2 by Normal-Mode-Based X-Ray Crystallographic Refinement","volume":"107","author":"Chen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng.3239","article-title":"De Novo Loss- or Gain-of-Function Mutations in KCNA2 Cause Epileptic Encephalopathy","volume":"47","author":"Syrbe","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1093\/brain\/awx184","article-title":"Clinical Spectrum and Genotype\u2013Phenotype Associations of KCNA2-Related Encephalopathies","volume":"140","author":"Masnada","year":"2017","journal-title":"Brain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"eaaz4957","DOI":"10.1126\/scitranslmed.aaz4957","article-title":"4-Aminopyridine Is a Promising Treatment Option for Patients with Gain-of-Function KCNA2 -Encephalopathy","volume":"13","author":"Hedrich","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1523\/JNEUROSCI.4423-14.2015","article-title":"Early-Onset Epileptic Encephalopathy Caused by Gain-of-Function Mutations in the Voltage Sensor of K v 7.2 and K v 7.3 Potassium Channel Subunits","volume":"35","author":"Miceli","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.1111\/epi.13601","article-title":"Infantile Spasms and Encephalopathy without Preceding Neonatal Seizures Caused by KCNQ2 R198Q, a Gain-of-Function Variant","volume":"58","author":"Millichap","year":"2017","journal-title":"Epilepsia"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/ana.25522","article-title":"Autism and Developmental Disability Caused by KCNQ3 Gain-of-function Variants","volume":"86","author":"Sands","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1177\/1073858418763752","article-title":"Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox","volume":"24","author":"Niday","year":"2018","journal-title":"Neuroscientist"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.1007\/s10072-020-04600-5","article-title":"West Syndrome: A Comprehensive Review","volume":"41","author":"Pavone","year":"2020","journal-title":"Neurol. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1126\/science.1185954","article-title":"A Gating Charge Transfer Center in Voltage Sensors","volume":"328","author":"Tao","year":"2010","journal-title":"Science"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6444","DOI":"10.1073\/pnas.1103397108","article-title":"Control of a Final Gating Charge Transition by a Hydrophobic Residue in the S2 Segment of a K \u00fe Channel Voltage Sensor","volume":"108","author":"Lacroix","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.bpj.2012.11.3827","article-title":"The Conserved Phenylalanine in the K+ Channel Voltage-Sensor Domain Creates a Barrier with Unidirectional Effects","volume":"104","author":"Schwaiger","year":"2013","journal-title":"Biophys. J."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Persson, A.-S., Klement, G., Almgren, M., Sahlholm, K., Nilsson, J., Petersson, S., \u00c5rhem, P., Schalling, M., and Lavebratt, C. (2005). A Truncated Kv1.1 Protein in the Brain of the Megencephaly Mouse: Expression and Interaction. BMC Neurosci., 6.","DOI":"10.1186\/1471-2202-6-65"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1111\/j.1460-9568.2003.03044.x","article-title":"Truncation of the Shaker-like Voltage-Gated Potassium Channel, Kv1.1, Causes Megencephaly","volume":"18","author":"Petersson","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3218","DOI":"10.1111\/j.1460-9568.2003.02994.x","article-title":"MRI and in Situ Hybridization Reveal Early Disturbances in Brain Size and Gene Expression in the Megencephalic (Mceph\/Mceph) Mouse","volume":"18","author":"Diez","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s003359900259","article-title":"Megencephaly: A New Mouse Mutation on Chromosome 6 That Causes Hypertrophy of the Brain","volume":"7","author":"Cook","year":"1996","journal-title":"Mamm. Genome"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/hmg\/11.3.331","article-title":"The Human Intronless Melanocortin 4-Receptor Gene Is NMD Insensitive","volume":"11","author":"Brocke","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1038\/nn1999","article-title":"Masking Epilepsy by Combining Two Epilepsy Genes","volume":"10","author":"Glasscock","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1523\/JNEUROSCI.3191-12.2013","article-title":"Tau Loss Attenuates Neuronal Network Hyperexcitability in Mouse and Drosophila Genetic Models of Epilepsy","volume":"33","author":"Holth","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1111\/epi.13960","article-title":"BAD Knockout Provides Metabolic Seizure Resistance in a Genetic Model of Epilepsy with Sudden Unexplained Death in Epilepsy","volume":"59","author":"Foley","year":"2018","journal-title":"Epilepsia"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1093\/hmg\/ddx104","article-title":"Scn2a Deletion Improves Survival and Brain-Heart Dynamics in the Kcna1-Null Mouse Model of Sudden Unexpected Death in Epilepsy (SUDEP)","volume":"26","author":"Mishra","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e125","DOI":"10.1111\/epi.17374","article-title":"Genetic Interaction between Scn8a and Potassium Channel Genes Kcna1 and Kcnq2","volume":"63","author":"Hill","year":"2022","journal-title":"Epilepsia"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"111696","DOI":"10.1016\/j.celrep.2022.111696","article-title":"Loss of Functional System X-c Uncouples Aberrant Postnatal Neurogenesis from Epileptogenesis in the Hippocampus of Kcna1-KO Mice","volume":"41","author":"Aloi","year":"2022","journal-title":"Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/S1474-4422(13)70214-X","article-title":"Incidence and Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS): A Retrospective Study","volume":"12","author":"Ryvlin","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"180","DOI":"10.5698\/1535-7511.17.3.180","article-title":"Practice Guideline Summary: Sudden Unexpected Death in Epilepsy Incidence Rates and Risk Factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society","volume":"17","author":"Harden","year":"2016","journal-title":"Epilepsy Curr."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1111\/epi.12666","article-title":"Sudden Unexpected Death in Epilepsy: Assessing the Public Health Burden","volume":"55","author":"Thurman","year":"2014","journal-title":"Epilepsia"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/S0896-6273(00)81018-1","article-title":"Deletion of the K(v)1.1 Potassium Channel Causes Epilepsy in Mice","volume":"20","author":"Smart","year":"1998","journal-title":"Neuron"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.nbd.2019.04.006","article-title":"Cardiorespiratory Profiling Reveals Primary Breathing Dysfunction in Kcna1-Null Mice: Implications for Sudden Unexpected Death in Epilepsy","volume":"127","author":"Dhaibar","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1523\/JNEUROSCI.5591-09.2010","article-title":"Kv1.1 Potassium Channel Deficiency Reveals Brain-Driven Cardiac Dysfunction as a Candidate Mechanism for Sudden Unexplained Death in Epilepsy","volume":"30","author":"Glasscock","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1111\/epi.12793","article-title":"The Kv1.1 Null Mouse, a Model of Sudden Unexpected Death in Epilepsy (SUDEP)","volume":"55","author":"Moore","year":"2014","journal-title":"Epilepsia"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e178","DOI":"10.1111\/epi.13444","article-title":"Ketogenic Diet Treatment Increases Longevity in Kcna1-Null Mice, a Model of Sudden Unexpected Death in Epilepsy","volume":"57","author":"Simeone","year":"2016","journal-title":"Epilepsia"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/epi.13971","article-title":"Respiratory Dysfunction Progresses with Age in Kcna1-Null Mice, a Model of Sudden Unexpected Death in Epilepsy","volume":"59","author":"Simeone","year":"2018","journal-title":"Epilepsia"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1109\/OJEMB.2020.3036544","article-title":"Directed Connectivity Analysis of the Neuro-Cardio- and Respiratory Systems Reveals Novel Biomarkers of Susceptibility to SUDEP","volume":"1","author":"Hutson","year":"2020","journal-title":"IEEE Open J. Eng. Med. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"103615","DOI":"10.1016\/j.mcn.2021.103615","article-title":"Kv1.1 Subunits Localize to Cardiorespiratory Brain Networks in Mice Where Their Absence Induces Astrogliosis and Microgliosis","volume":"113","author":"Dhaibar","year":"2021","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1001\/jama.2020.3911","article-title":"Nystagmus","volume":"325","author":"Kates","year":"2021","journal-title":"JAMA"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"27016","DOI":"10.1073\/pnas.2007965117","article-title":"Coupling Stabilizers Open K V 1-Type Potassium Channels","volume":"117","author":"Wallner","year":"2020","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1124\/jpet.119.264507","article-title":"Isoform-Selective KCNA1 Potassium Channel Openers Built from Glycine","volume":"373","author":"Manville","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8826\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:35:52Z","timestamp":1760124952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":113,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108826"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108826","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,16]]}}}