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

Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6023-6034. doi: 10.1073/pnas.1920008117. Epub 2020 Mar 4.

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.

Keywords: KCNMA1; ataxia; cerebellar degeneration.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Animals
  • Animals, Newborn
  • Cell Line
  • Cerebellum / cytology
  • Cerebellum / pathology*
  • Chlorzoxazone / administration & dosage*
  • DNA Mutational Analysis
  • Dependovirus / genetics
  • Disease Models, Animal
  • Exome Sequencing
  • Female
  • Gene Knockdown Techniques
  • Genetic Vectors / genetics
  • Humans
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / antagonists & inhibitors
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism
  • Loss of Function Mutation
  • Mice
  • Mitochondria / pathology*
  • Oocytes
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Spinocerebellar Degenerations / diagnosis
  • Spinocerebellar Degenerations / drug therapy
  • Spinocerebellar Degenerations / genetics*
  • Spinocerebellar Degenerations / pathology
  • Transfection
  • Xenopus

Substances

  • KCNMA1 protein, human
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Recombinant Proteins
  • Chlorzoxazone

Associated data

  • Dryad/10.5061/dryad.1ns1rn8qk