Mislocalization of KCNQ2 Channels as a Pathogenic Mechanism in KCNQ2 Developmental and Epileptic Encephalopathy.
Document Type
Article
Publication Date
1-21-2026
Original Citation
Springer K,
Soh H,
Paz Zavala R,
Varghese N,
Lutz C,
Zuberi A,
Jackson A,
Tzingounis A.
Mislocalization of KCNQ2 Channels as a Pathogenic Mechanism in KCNQ2 Developmental and Epileptic Encephalopathy. J Neurosci. 2026;46(3):e0947252025.
Keywords
JGM, Animals, KCNQ2 Potassium Channel, Mice, Female, Male, Humans, Hippocampus, Protein Transport, Mice, Inbred C57BL, Epilepsy, Mice, Transgenic, HEK293 Cells, Nerve Tissue Proteins
JAX Source
J Neurosci. 2026;46(3):e0947252025.
ISSN
1529-2401
PMID
41419331
DOI
https://doi.org/10.1523/JNEUROSCI.0947-25.2025
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 localization in vivo, we used male and female heterozygous