{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:22:51Z","timestamp":1781227371560,"version":"3.54.1"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,5,3]],"date-time":"2020-05-03T00:00:00Z","timestamp":1588464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous myoclonus\u2010dystonia in a UK kindred with affected individuals in three generations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Known genetic causes of myoclonus\u2010dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole\u2010exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus\u2010dystonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The core phenotype consisted of childhood\u2010onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium\u2010activated channel subfamily N member 2 (<jats:italic>KCNN2<\/jats:italic>) [NM_021614:c.1112G&gt;A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen\u20102 and had an overall CADD score of 29.7.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>KCNN2<\/jats:italic>, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. <jats:italic>KCNN2<\/jats:italic> mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and <jats:italic>in\u2010silico<\/jats:italic> prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with <jats:italic>KCNN2<\/jats:italic> mutations being a plausible cause underlying myoclonus\u2010dystonia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.14228","type":"journal-article","created":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T15:04:34Z","timestamp":1585148674000},"page":"1471-1477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["KCNN2 mutation in autosomal\u2010dominant tremulous myoclonus\u2010dystonia"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4127-8554","authenticated-orcid":false,"given":"B.","family":"Balint","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London UK"},{"name":"Department of Neurology University Hospital Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Dementia Research Institute at UCL and Department of Neurodegenerative Diseases UCL Institute of Neurology London UK"},{"name":"Center for Neurodegenerative Science Van Andel Research Institute Grand Rapids MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Carmona","sequence":"additional","affiliation":[{"name":"Dementia Research Institute at UCL and Department of Neurodegenerative Diseases UCL Institute of Neurology London UK"},{"name":"Center for Neurodegenerative Science Van Andel Research Institute Grand Rapids MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Dehghani","sequence":"additional","affiliation":[{"name":"Dementia Research Institute at UCL and Department of Neurodegenerative Diseases UCL Institute of Neurology London UK"},{"name":"Center for Neurodegenerative Science Van Andel Research Institute Grand Rapids MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7103-5209","authenticated-orcid":false,"given":"A.","family":"Latorre","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London UK"},{"name":"Department of Human Neurosciences Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Cordivari","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurophysiology National Hospital for Neurology and Neurosurgery London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. P.","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Bras","sequence":"additional","affiliation":[{"name":"Dementia Research Institute at UCL and Department of Neurodegenerative Diseases UCL Institute of Neurology London UK"},{"name":"Center for Neurodegenerative Science Van Andel Research Institute Grand Rapids MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25475"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12650"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.04.008"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp698"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu314"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19695"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22376"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks539"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22426"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001562200"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1098"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M500279-MCP200"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-016-1258-1"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.205823"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2017.09.012"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-008-0136-2"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2001.0393"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12311-016-0825-6"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25035"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0000000000000754"}],"container-title":["European Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fene.14228","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.14228","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ene.14228","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.14228","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T02:09:11Z","timestamp":1693361351000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ene.14228"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,3]]},"references-count":27,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1111\/ene.14228"],"URL":"https:\/\/doi.org\/10.1111\/ene.14228","archive":["Portico"],"relation":{},"ISSN":["1351-5101","1468-1331"],"issn-type":[{"value":"1351-5101","type":"print"},{"value":"1468-1331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,3]]},"assertion":[{"value":"2019-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}