{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:57:04Z","timestamp":1788973024550,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"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>KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function KV4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19\/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the KV4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of KV4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19\/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. KV4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.<\/jats:p>","DOI":"10.3390\/ijms22094986","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T10:06:12Z","timestamp":1620381972000},"page":"4986","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19\/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6367-1843","authenticated-orcid":false,"given":"Ginevra","family":"Zanni","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, B. Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Tsung","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"},{"name":"Department of Neurology, School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei 112, Taiwan"},{"name":"Department of Neurology, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ssu-Ju","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"},{"name":"Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1065-2865","authenticated-orcid":false,"given":"Chih-Yung","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Capuano","sequence":"additional","affiliation":[{"name":"Unit of Neurology, B. Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Bosco","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, B. Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Sciences, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1554-9517","authenticated-orcid":false,"given":"Federica","family":"Graziola","sequence":"additional","affiliation":[{"name":"Unit of Neurology, B. Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-849X","authenticated-orcid":false,"given":"Emanuele","family":"Bellacchio","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8478-2799","authenticated-orcid":false,"given":"Serenella","family":"Servidei","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Universit\u00e0 Cattolica del S. Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A.Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-7008","authenticated-orcid":false,"given":"Guido","family":"Primiano","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Universit\u00e0 Cattolica del S. Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A.Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Wen","family":"Soong","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei 112, Taiwan"},{"name":"Department of Neurology, Shuang Ho Hospital, Taipei Neuroscience Institute, Taipei Medical University, New Taipei City 235, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-5704","authenticated-orcid":false,"given":"Chung-Jiuan","family":"Jeng","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1002\/ana.23700","article-title":"Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19","volume":"72","author":"Duarri","year":"2012","journal-title":"Ann. 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