{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:07:04Z","timestamp":1788941224853,"version":"build-2803163510"},"reference-count":21,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007632","name":"Changhua Christian Hospital","doi-asserted-by":"publisher","award":["113\u2010CCH\u2010IRP\u2010065"],"award-info":[{"award-number":["113\u2010CCH\u2010IRP\u2010065"]}],"id":[{"id":"10.13039\/501100007632","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 114\u20102320\u2010B\u2010A49\u2010032\u2010MY3"],"award-info":[{"award-number":["NSTC 114\u20102320\u2010B\u2010A49\u2010032\u2010MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010002","name":"Ministry of Education","doi-asserted-by":"publisher","award":["114 W032101"],"award-info":[{"award-number":["114 W032101"]}],"id":[{"id":"10.13039\/100010002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Spinocerebellar ataxia type 19\/22 (SCA19\/22) is a rare autosomal dominant neurodegenerative disorder caused by\n KCND3<\/jats:italic>\n variants encoding the K\n V<\/jats:sub>\n 4.3 potassium channel. While most pathogenic variants result in loss\u2010of\u2010function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity.\n <\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To elucidate the genetic cause and functional LOF mechanisms underlying severe early\u2010onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We evaluated twins presenting with early\u2010onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole\u2010exome sequencing (WES) identified a\n KCND3<\/jats:italic>\n c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression,\n Xenopus<\/jats:italic>\n oocyte electrophysiology, and structural homology modeling.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n WES identified a heterozygous de novo p.L368P variant in the \u201cTLGYG\u201d selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant\u2010negative effect on wild\u2010type K\n V<\/jats:sub>\n 4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Identifying the first pathogenic variant in the K\n V<\/jats:sub>\n 4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19\/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. \u00a9 2026 International Parkinson and Movement Disorder Society.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mds.70514","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T07:33:57Z","timestamp":1788939237000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selectivity Filter\n \n KCND3<\/i>\n <\/scp>\n Variant Causes Spinocerebellar Ataxia 19\/22 and\n \n K\n V<\/sub>\n 4\n <\/scp>\n .3 Functional Loss"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0117-0490","authenticated-orcid":false,"given":"Chia\u2010Ju","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Neurology Changhua Christian Hospital Changhua Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai\u2010Min","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine National Taiwan University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Ling","family":"Cheng","sequence":"additional","affiliation":[{"name":"Vascular and Genomic Center, Institute of ATP Changhua Christian Hospital Changhua Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang\u2010Heng","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, College of Medicine National Yang Ming Chiao Tung University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Tin","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, College of Medicine National Yang Ming Chiao Tung University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin\u2010Hung","family":"Pan","sequence":"additional","affiliation":[{"name":"Vascular and Genomic Center, Institute of ATP Changhua Christian Hospital Changhua Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Yung","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine National Taiwan University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung\u2010Jiuan","family":"Jeng","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, College of Medicine National Yang Ming Chiao Tung University Taipei Taiwan"},{"name":"Brain Research Center National Yang Ming Chiao Tung University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-9654","authenticated-orcid":false,"given":"Chin\u2010San","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology Changhua Christian Hospital Changhua Taiwan"},{"name":"Vascular and Genomic Center, Institute of ATP Changhua Christian Hospital Changhua Taiwan"},{"name":"Graduate Institute of Integrated Medicine China Medical University Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"11","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1002\/humu.23865","article-title":"Novel SCA19\/22\u2010associated KCND3 mutations disrupt human K(V) 4.3 protein biosynthesis and channel gating","volume":"40","author":"Hsiao CT","year":"2019","journal-title":"Hum 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