Pathogenic variants of KCNQ2 altered the amounts of novel post-translational cleavage fragments, with the Y284C and Y284D variants exerting opposite effects compared to wild type.
KCNQ2 undergoes a novel post-translational proteolytic cleavage, and the relative amounts of the resulting fragments vary among pathogenic variants associated with different epilepsy phenotypes.
KCNQ2 is a member of the voltage-gated potassium (Kv) channel family and regulates neuronal activity through potassium ion efflux. Pathogenic variants of KCNQ2 induce aberrant neuronal activity and cause two types of epilepsy: self-limited familial neonatal epilepsy (SLFNE) and developmental and epileptic encephalopathies (DEE). However, the molecular mechanism by which these pathogenic variants influence KCNQ2 expression remains unclear. Here, we show N-terminal and C-terminal fragments derived from mouse KCNQ2 (KCNQ2S−N and KCNQ2S−C, respectively), whose amounts differed significantly across variants compared with wild type, whereas those of full-length KCNQ2 (KCNQ2F) remained unchanged. Of particular interest, two variants at the same codon, 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 fragment: Y284C increased the amounts of both KCNQ2 fragments, whereas Y284D decreased it compared with the wild type. As both KCNQ2S−N and KCNQ2S−C were localized in the plasma membrane, both fragments were suggested to be post-translational products resulting from a cleavage of full-length KCNQ2. This novel post-translational cleavage 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.
Kimura et al. (Wed,) conducted a other in Epilepsy (SLFNE and DEE). KCNQ2 pathogenic variants (T274M, Y284C, Y284D, G290D, A306T) vs. Wild type KCNQ2 was evaluated on Amount of KCNQ2 post-translational cleavage fragments. Pathogenic variants of KCNQ2 altered the amounts of novel post-translational cleavage fragments, with the Y284C and Y284D variants exerting opposite effects compared to wild type.