{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T21:34:48Z","timestamp":1768772088161,"version":"3.49.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["MOST 110\u20102320\u2010B\u2010A49A\u2010529\u2010MY3"],"award-info":[{"award-number":["MOST 110\u20102320\u2010B\u2010A49A\u2010529\u2010MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Spinocerebellar ataxia type 22 (SCA22) caused by\n                    <jats:italic>KCND3<\/jats:italic>\n                    mutations is an autosomal dominant disorder. We established a mouse model carrying the\n                    <jats:italic>Kcnd3<\/jats:italic>\n                    F227del mutation to study the molecular pathogenesis. Four findings were pinpointed. First, the heterozygous mice exhibited an early onset of defects in motor coordination and balance which mirror those of SCA22 patients. The degeneration and a minor loss of Purkinje cells, together with the concurrent presence of neuroinflammation, as well as the previous finding on electrophysiological changes, may all contribute to the development of the SCA22 ataxia phenotype in mice carrying the\n                    <jats:italic>Kcnd3<\/jats:italic>\n                    F227del mutant protein. Second, the mutant protein is retained by the endoplasmic reticulum and Golgi, leading to activation of the unfolded protein response and a severe trafficking defect that affects its membrane destination. Intriguingly, profound damage of the Golgi is the earliest manifestation. Third, analysis of the transcriptome revealed that the\n                    <jats:italic>Kcnd3<\/jats:italic>\n                    F227del mutation down\u2010regulates a panel of genes involved in the functioning of synapses and neurogenesis which are tightly linked to the functioning of Purkinje cells. Finally, no ataxia phenotypes were detectable in knockout mice carrying a loss\u2010of\u2010function\n                    <jats:italic>Kcnd3<\/jats:italic>\n                    mutation. Thus,\n                    <jats:italic>Kcnd3<\/jats:italic>\n                    F227del is a dominant\u2010negative mutation. This mouse model may serve as a preclinical model for exploring therapeutic strategies to treat patients. \u00a9 2024 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6368","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T23:49:17Z","timestamp":1732060157000},"page":"57-68","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A dominant negative\n                    <scp>\n                      <i>Kcnd3<\/i>\n                    <\/scp>\n                    F227del mutation in mice causes spinocerebellar ataxia type 22 (\n                    <scp>SCA22<\/scp>\n                    ) by impairing\n                    <scp>ER<\/scp>\n                    and Golgi functioning"],"prefix":"10.1002","volume":"265","author":[{"given":"Hao\u2010Chih","family":"Hung","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia\u2010Han","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan\u2010Chi","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"},{"name":"Department of Medical Research Taipei Veterans General Hospital  Taipei 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