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Two distinct missense variants at the same residue, p.R213W and p.R213Q, are associated with SeLFNIE and EIDEE, respectively. This study aimed to elucidate the in vivo effects of these variants on brain development and neuronal excitability using two knock-in mouse models,\n                    <jats:italic>Kcnq2<\/jats:italic>\n                    <jats:sup>R213W\/+<\/jats:sup>\n                    and\n                    <jats:italic>Kcnq2<\/jats:italic>\n                    <jats:sup>R213Q\/+<\/jats:sup>\n                    . We assessed survival, seizure susceptibility, histological and molecular phenotypes, and electrophysiological properties in cortical and hippocampal neurons, and conducted RNA sequencing analyses of cortical tissue to identify transcriptional alterations.\n                    <jats:italic>Kcnq2<\/jats:italic>\n                    <jats:sup>R213Q\/+<\/jats:sup>\n                    mice exhibited tonic\u2013clonic seizures, shortened lifespan, delayed cortical neuron migration, abnormal elongation of the axon initial segment in cortical neurons, and dentate gyrus-specific gliosis. In contrast,\n                    <jats:italic>Kcnq2<\/jats:italic>\n                    <jats:sup>R213W\/+<\/jats:sup>\n                    mice showed a milder phenotype with transient seizures and largely preserved cortical function. RNA sequencing analyses revealed that p.R213Q selectively upregulated genes involved in endoplasmic reticulum stress and synaptic regulation, together with compensatory upregulation of potassium channel subunits. These findings demonstrate that the two\n                    <jats:italic>Kcnq2<\/jats:italic>\n                    variants lead to distinct neurodevelopmental phenotypes, attributable not only to differential impairment of the M-current but also to aberrant cortical development and stress response pathways. In particular, p.R213Q induces sustained cortical hyperexcitability and axon initial segment abnormalities, whereas p.R213W results in the milder phenotype. The established knock-in models provide powerful tools for elucidating disease mechanisms of EIDEE and SeLFNIE, and developing targeted therapies for\n                    <jats:italic>KCNQ2<\/jats:italic>\n                    -related epilepsies.\n                  <\/jats:p>","DOI":"10.1186\/s40478-026-02264-4","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:23:38Z","timestamp":1772029418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kcnq2 R213 knock-in mice reveal variant- and region-specific mechanisms underlying self-limited familial neonatal-infantile epilepsy and early infantile developmental and epileptic encephalopathy"],"prefix":"10.1186","volume":"14","author":[{"given":"Takuma","family":"Nishijo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanako","family":"Hamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reut","family":"Suliman-Lavie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Tabata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuko","family":"Iwamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagiv","family":"Shifman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koh-ichi","family":"Nagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"2264_CR1","doi-asserted-by":"publisher","first-page":"570588","DOI":"10.3389\/fphys.2020.570588","volume":"11","author":"N Dirkx","year":"2020","unstructured":"Dirkx N, Miceli F, Taglialatela M, Weckhuysen S (2020) The role of Kv7.2 in neurodevelopment: insights and gaps in our understanding. 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As to the animal experiments, we followed the fundamental guidelines for proper conduct of animal experiments and related activity in academic research institution under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology, Japan. All the protocols for animal handling and treatment were reviewed and approved by the animal care and use committee of Institute for Developmental Research, Aichi Developmental Disability Center (approval number: 2019\u2013013). All experiments were conducted in compliance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. All methods, data presentation and statistical analyses were carried out in accordance with the TOP (Transparency and Openness Promotion) guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"76"}}