Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia

Xiaofei Du, Joao L. Carvalho-De-Souza, Cenfu Wei, Willy Carrasquel-Ursulaez, Yenisleidy Lorenzo, Naileth Gonzalez, Tomoya Kubota, Julia Staisch, Timothy Hain, Natalie Petrossian, Michael Xu, Ramon Latorre, Francisco Bezanilla, Christopher M. Gomez

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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 languageEnglish (US)
Pages (from-to)6023-6034
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 17 2020
Externally publishedYes


  • Ataxia
  • Cerebellar degeneration
  • KCNMA1

ASJC Scopus subject areas

  • General


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