A Mutation Causing Reduced BK Channel Activity Leads to Cognitive Inpairment and Progressive Cerebellar Ataxia (P5.394)

Objective: Determine the functional consequences of a BK potassium channel mutation associated with cerebellar degeneration. Background: We described a 16 yo female with delayed milestones and ataxic gait since 18 months. She had cognitive delay, dysarthria, perioral dyskinesias, and nystagmus. MRI scan showed severe cerebellar atrophy. Exome sequencing revealed a de novo variant in one KCNMA1 gene predicting a G354S mutation in the BK channel α subunit. The only other reported BK channel mutation causes enhanced channel activity, epilepsy, and dyskinesias. Methods: Wild type and G354S mutant BK channel α subunits were expressed in cultured HEK293 cells using eukaryotic expression vectors and immuno-localized using anti-α subunit antibodies. Also, mRNAs encoding the WT and G354S mutant were injected into Xenopus oocytes for macroscopic voltage-activated K+ currrent recordings under voltage-clamp during standard step depolarization protocols. Results: There was no difference in cellular distribution between the WT and G354S mutant. In oocytes expressing the G354S mutant alone, macroscopic K+ currents were 11[percnt] of those detected in WT-expressing oocytes, and the kinetics of activation were signficantly slowed compared to WT. Co-injection of the WT and G354S mutant in equal amounts (imitating heterozygous condition) led to currents less than 35[percnt] of WT. K+ currents recorded from dual-injected oocytes showed slower activation than WT. Unitary single channels recordings showed circa 90[percnt] decrease in the G354S mutant channel conductance relative to WT Thus, co-injection of G354S mutant together with WT α subunit reduced the conductance and slowed activation of BK channels out of proportion to abundance of subunits. Conclusions: The BK channel mutant G354S has a dominant negative effect on channel function. Reduced BK channel activity and delayed activation lead to progressive cerebellar atrophy and ataxia, possibly through damaging delays in repolarization. Drugs that increase BK channel activity may be a rational approach for treating this disease.