BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy

The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here we address this question by recording from single BK channels expressed for a heterozygous G375R mutation. Five different types of functional BK channels were observed: 3% were WT, 12% were homomeric mutant, and 85% were three different types of hybrid channels. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller loss-of-function in single channel conductance, with both becoming more pronounced as the number of mutant subunits per tetrameric channel increased. The molecular phenotype suggested codominance for the two homomeric channels and partial dominance for the hybrid channels. A model in which BK channels are randomly assembled from mutant and WT subunits, with each subunit contributing increments of activation and conductance, approximated the molecular phenotype of the heterozygous G375R mutation.