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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,3,17]]},"abstract":"<jats:p>\n                    Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene\n                    <jats:italic>KCNMA1<\/jats:italic>\n                    , encoding the \u03b1-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BK\n                    <jats:sub>G354S<\/jats:sub>\n                    ) in\n                    <jats:italic>KCNMA1<\/jats:italic>\n                    , in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BK\n                    <jats:sub>G354S<\/jats:sub>\n                    channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BK\n                    <jats:sub>G354S<\/jats:sub>\n                    cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BK\n                    <jats:sub>G354S<\/jats:sub>\n                    channel, but not the BK\n                    <jats:sub>WT<\/jats:sub>\n                    channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK\/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1920008117","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T20:15:31Z","timestamp":1583352931000},"page":"6023-6034","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":78,"title":["Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia"],"prefix":"10.1073","volume":"117","author":[{"given":"Xiaofei","family":"Du","sequence":"first","affiliation":[{"name":"Department of Neurology, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao L.","family":"Carvalho-de-Souza","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637;"},{"name":"Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cenfu","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy","family":"Carrasquel-Ursulaez","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencia de Valpara\u00ecso, Facultad de Ciencias, Universidad de Valparaiso, Valpara\u00edso 2340000, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yenisleidy","family":"Lorenzo","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencia de Valpara\u00ecso, Facultad de Ciencias, Universidad de Valparaiso, Valpara\u00edso 2340000, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naileth","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencia de Valpara\u00ecso, Facultad de Ciencias, Universidad de Valparaiso, Valpara\u00edso 2340000, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637;"},{"name":"Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Staisch","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Hain","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Petrossian","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Latorre","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencia de Valpara\u00ecso, Facultad de Ciencias, Universidad de Valparaiso, Valpara\u00edso 2340000, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Bezanilla","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 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