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LQT2 is associated with arrhythmias, seizures, sudden cardiac death, and sudden unexpected death in epilepsy (SUDEP). The goal of the study is to develop a translational model that reproduces the neuro-cardiac electrical abnormalities and sudden death seen in people with LQT2.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We generated the first knock-in rabbit model of LQT2 (<jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup>), due to a 7 base-pair (7bp) deletion in the pore domain of the endogenous rabbit <jats:italic>Kcnh2<\/jats:italic> gene.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Mutant <jats:italic>Kcnh2<\/jats:italic> is expressed in the heart and brain and constitutes 11% of total <jats:italic>Kcnh2<\/jats:italic> in <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> rabbits. Total <jats:italic>Kcnh2<\/jats:italic>, WT <jats:italic>Kcnh2<\/jats:italic>, and WT K<jats:sub>v<\/jats:sub>11.1 expression is lower in <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> vs. WT rabbits. <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> rabbits exhibit prolonged cardiac ventricular repolarization (QT<jats:sub>c<\/jats:sub>, JT<jats:sub>ec<\/jats:sub>, JT<jats:sub>pc<\/jats:sub>). There is an increased prevalence of spontaneous epileptiform activity and clinical seizures in <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> (7 of 37 rabbits) vs. WT rabbits (1:68 rabbits, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.003). 18.9% of <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> vs. 1.5% of WT rabbits died suddenly and spontaneously (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.003). We recorded 2 spontaneous lethal events in <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> rabbits: (1) sudden cardiac death and (2) seizure-mediated sudden death due to generalized tonic-clonic seizures, post-ictal generalized EEG suppression, bradycardia, ECG-T-wave inversion, focal cardiac activity, and asystole\/death.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We developed the first genetic rabbit model of LQT2 that reproduces the cardiac and epileptic phenotypes seen in people with LQT2. <jats:italic>Kcnh2<\/jats:italic>\n              <jats:sup>(+\/7bp\u2212del)<\/jats:sup> rabbits provide a valuable tool for future mechanistic studies, development of neurotherapeutics, and cardiac-safety testing.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12967-025-06382-w","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T19:16:41Z","timestamp":1744744601000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Knock-in Kcnh2 rabbit model of long QT syndrome type-2, epilepsy, and sudden death"],"prefix":"10.1186","volume":"23","author":[{"given":"Veronica","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle T.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura G.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M.","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine R.","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Mohnkern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Gardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis T.","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie M.","family":"Ziobro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. 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