An epilepsy-associated K V 1.2 charge-transfer-center mutation impairs K V 1.2 and K V 1.4 trafficking

Significance A child with epilepsy has a previously unreported, heterozygous mutation inKCNA2 , the gene encoding KV 1.2 proteins. Four KV 1.2 assemble into a potassium-selective channel, a protein complex at the neuronal cell surface regulating electrical signaling. KV 1.2 subunits assemble with other KV 1-family members to form heterotetrameric channels, contributing to neuronal potassium-channel diversity. The most striking consequence of this mutation is preventing KV 1.2-subunit trafficking, i.e., their ability to reach the cell surface. Moreover, the mutation is dominant negative, as mutant subunits can assemble with wild-type KV 1.2 and KV 1.4, trapping them into nontrafficking heterotetramers and decreasing their functional expression. Thus, KV 1-family genes’ ability to form heterotetrameric channels is a double-edged sword, rendering KV 1-family members vulnerable to dominant-negative mutations in a single member gene.