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

Significance Genetic disruption of ion channels underlies several neurological diseases, suggesting that ionic disturbances are common neuronal stressors potentially amenable to therapies. The detailed intracellular pathways coupling ion channel mutations to neuronal damage are largely unknown. Here, we describe the finding of a single loss-of-function mutation in the BK channel in a young patient with progressive cerebellar degeneration. The mutant BK channel caused a profound dominant-negative effect on native channels, combined with reduced ion selectivity, leading to depolarization and depletion of mitochondria, and when delivered virally to mice, mimicked the disease. BK channel active drugs rescued the mutant cellular phenotype. These results point to the importance of mitochondrial ionic homeostasis in cerebellar disease and suggest therapeutic strategies. 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.