Mislocalization of KCNQ2 Channels as a Pathogenic Mechanism in KCNQ2 Developmental and Epileptic Encephalopathy.

ABSTRACT: KCNQ2 potassium channel variants are linked to developmental and epileptic encephalopathy (DEE). However, the mechanisms by which pathogenic variants, especially those outside known hotspots, such as the S4-S5 linker, lead to disease remain unknown. Here, we examined the H228R variant, a pathogenic mutation in the S4-S5 linker associated with DEE. We tested whether H228R induces KCNQ2 channel mistargeting in addition to its biophysical effects, given recent evidence of impaired trafficking in KCNQ2 DEE variants. We confirmed the H228R variant as a loss-of-function (LOF) when expressed as a homomer and as a dominant-negative when coexpressed with wild-type (WT) KCNQ3. Surprisingly, it exhibited some gain-of-function effects when coexpressed with WT KCNQ2. To determine its cellular localizat

SUBMITTER: Springer K 

PROVIDER: S-EPMC12758638 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature