Abstract
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 KCNMA1, encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BKG354S) in KCNMA1, 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 BKG354S 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 BKG354S 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 BKG354S channel, but not the BKWT 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.
Original language | English (US) |
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Pages (from-to) | 6023-6034 |
Number of pages | 12 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 117 |
Issue number | 11 |
DOIs | |
State | Published - Mar 17 2020 |
Funding
ACKNOWLEDGMENTS. This work was supported by NIH Grants R01NS082788, R01NS094665, and R21NS094872-01 (to C.M.G.), and R01GM030376 and R21-EY027101 (to F.B.); by University of Chicago Big Vision Grant (to C.M.G.); and by Fondecyt Grants 1150273 and 1190203, and the US Air Force Office of Scientific Research under Award A9550-16-1-0384 (to R.L.). This work was also supported by Centro Interdisciplinario de Neurociencia de Valparaiso, a Millennium Institute supported by the Millennium Scientific Initiative of the Chilean Ministry of Economy, Development, and Tourism (P029-022-F). We thank Yimei Chen at the University of Chicago Electron Microscopy Core Facility for the sample preparation and imaging service. We thank Dr. Vytas Bindokas at the University of Chicago Microscopy Core Facility for the imaging service.
Keywords
- Ataxia
- Cerebellar degeneration
- KCNMA1
ASJC Scopus subject areas
- General