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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.

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