Liang-Wang syndrome-associated variants in the BK potassium channel KCNMA1 disrupt channel trafficking and gating

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Liang-Wang syndrome is a neurodevelopmental syndrome characterized by developmental delay and intellectual disability with variable multi-organ abnormalities, and caused by pathogenic variants in KCNMA1 encoding the BK potassium channel. In this study, we identified and characterized three new KCNMA1 variants, including p.W268R, p.A664T and p.M578T, for their molecular mechanism underlying the pathogenesis of Liang-Wang syndrome using macroscopic and single-channel patch-clamping recordings. We also evaluated the effects of BK channel activator NS11021 on the three variants. The three variants act by a loss-of-function mechanism (LOF) as all significantly reduced the macroscopic BK current densities by shifting the G-V curves to more positive potentials, increasing activation time constants, and decreasing single channel open probability. However, the detailed mechanisms are different. Variant p.W268R reduced BK channel trafficking to membranes, and reduced calcium and magnesium sensitivity; p.A664T decreased single channel open dwell time, reduced calcium sensitivity, but increased magnesium sensitivity; p.M578T decreased single channel open dwell time, and reduced calcium and magnesium sensitivity. Notably, NS11021 reversed the electrophysiological abnormalities associated with three KCNMA1 variants. In conclusion, our results provide important input for genetic testing and counseling, and show that small molecule compound NS11021 reverses cellular abnormalities associated with three Liang-Wang syndrome variants, suggesting a candidate therapeutic strategy.