Singh Veronica, Wagner Kyle T, Williams Laura G, Ryan Justin M, Keller Katherine R, Mohnkern Jonathan D, Gardner Robert S, Dang Louis T, Ziobro Julie M, Wojcikiewicz Richard J H, Tucker Nathan R, Auerbach David S
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
J Transl Med. 2025 Apr 15;23(1):446. doi: 10.1186/s12967-025-06382-w.
Long QT Syndrome Type-2 (LQT2) is due to loss-of-function KCNH2 variants. KCNH2 encodes K11.1 that forms a delayed-rectifier potassium channel in the brain and heart. 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.
We generated the first knock-in rabbit model of LQT2 (Kcnh2), due to a 7 base-pair (7bp) deletion in the pore domain of the endogenous rabbit Kcnh2 gene.
Mutant Kcnh2 is expressed in the heart and brain and constitutes 11% of total Kcnh2 in Kcnh2 rabbits. Total Kcnh2, WT Kcnh2, and WT K11.1 expression is lower in Kcnh2 vs. WT rabbits. Kcnh2 rabbits exhibit prolonged cardiac ventricular repolarization (QT, JT, JT). There is an increased prevalence of spontaneous epileptiform activity and clinical seizures in Kcnh2 (7 of 37 rabbits) vs. WT rabbits (1:68 rabbits, p < 0.003). 18.9% of Kcnh2 vs. 1.5% of WT rabbits died suddenly and spontaneously (p < 0.003). We recorded 2 spontaneous lethal events in Kcnh2 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.
We developed the first genetic rabbit model of LQT2 that reproduces the cardiac and epileptic phenotypes seen in people with LQT2. Kcnh2 rabbits provide a valuable tool for future mechanistic studies, development of neurotherapeutics, and cardiac-safety testing.
2型长QT综合征（LQT2）是由功能丧失的KCNH2变异引起的。KCNH2编码K11.1，其在大脑和心脏中形成延迟整流钾通道。LQT2与心律失常、癫痫发作、心源性猝死以及癫痫中的意外猝死（SUDEP）相关。本研究的目的是建立一种转化模型，以再现LQT2患者中出现的神经心脏电异常和猝死情况。
由于内源性兔Kcnh2基因孔结构域中的7个碱基对（7bp）缺失，我们构建了首个LQT2（Kcnh2）基因敲入兔模型。
突变型Kcnh2在心脏和大脑中表达，占Kcnh2兔中总Kcnh2的11%。与野生型兔相比，Kcnh2兔中的总Kcnh2、野生型Kcnh2和野生型K11.1表达较低。Kcnh2兔表现出心脏心室复极化延长（QT、JT、JT）。与野生型兔（1/68只兔）相比，Kcnh2兔（37只兔中的7只）出现自发性癫痫样活动和临床癫痫发作的患病率增加（p < 0.003）。18.9%的Kcnh2兔与1.5%的野生型兔突然自发死亡（p < 0.003）。我们在Kcnh2兔中记录到2起自发性致死事件：（1）心源性猝死和（2）由于全身强直阵挛性发作、发作后全身脑电图抑制、心动过缓、心电图T波倒置、局灶性心脏活动以及心搏停止/死亡导致的癫痫介导的猝死。
我们建立了首个LQT2基因兔模型，该模型再现了LQT2患者中出现的心脏和癫痫表型。Kcnh2兔为未来的机制研究、神经治疗药物开发和心脏安全性测试提供了有价值的工具。
