Novel post-translational modification in voltage-gated potassium channel KCNQ2

KCNQ2 is a member of the voltage-gated potassium (Kv) channel family and regulates neuronal activity through potassium ion efflux. Pathogenic variants of KCNQ2 lead to aberrant neuronal activity and cause two types of epilepsy: self-limited familial neonatal epilepsy (SLFNE) and developmental and epileptic encephalopathies (DEE). However, how these pathogenic variants influence KCNQ2 expression remains unclear. Here we show a short isoform of mouse KCNQ2 (KCNQ2 ^S ), whose expression levels differed significantly across variants compared with wild type, whereas those of full-length KCNQ2 (KCNQ2 ^F ) remained unchanged. Of particular interest, two variants at residue Y284, Y284C and Y284D, which are associated with distinct clinical phenotypes—self-limited familial neonatal epilepsy (SLFNE) and developmental and epileptic encephalopathy (DEE), respectively—exerted opposite effects on the short isoform: Y284C increased the level of KCNQ2 ^S , whereas Y284D decreased it compared with the wild type. As KCNQ2 ^S was found to be localized in the plasma membrane, it is suggested that KCNQ2 ^S is a post-translational product resulting from a cleavage of full-length KCNQ2. This novel post-translational cleavage generating KCNQ2 ^S was observed in neuronal cells and appears to be evolutionarily conserved. Although the role of this post-translational modification in epilepsy remains unknown, it may be elucidated through future studies.