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
bioRxiv. 2024 Dec 16:2024.12.11.627988. doi: 10.1101/2024.12.11.627988.
Long QT Syndrome Type-2 (LQT2) is due to loss-of-function variants. encodes K 11.1 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 ( ), due to a 7 base-pair (7bp) deletion in the pore domain of the endogenous rabbit gene.
Mutant is expressed in the heart and brain and constitutes 11% of total in rabbits. Total , WT , and WT K 11.1 expression is lower in vs. WT rabbits. rabbits exhibit prolonged cardiac ventricular repolarization (QT , JT , JT ). There is an increased prevalence of spontaneous epileptiform activity and clinical seizures in (7 of 37 rabbits) vs. WT rabbits (1:68 rabbits, <0.003). 18.9% of vs. 1.5% of WT rabbits died suddenly and spontaneously ( <0.003). We recorded 2 spontaneous lethal events in 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. rabbits provide a valuable tool for future mechanistic studies, development of neurotherapeutics, and cardiac-safety testing.
2型长QT综合征（LQT2）是由功能丧失变异引起的。它编码Kv11.1，该蛋白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）有关。本研究的目的是建立一个能重现LQT2患者神经心脏电异常和猝死情况的转化模型。
由于内源性兔Kv11.1基因孔道结构域中7个碱基对（7bp）的缺失，我们构建了首个LQT2基因敲入兔模型（Kv11.1KI）。
突变型Kv11.1在心脏和大脑中表达，占Kv11.1KI兔中Kv11.1总量的11%。与野生型兔相比，Kv11.1KI兔中Kv11.1总量、野生型Kv11.1及野生型Kv11.1的表达均较低。Kv11.1KI兔表现出心室复极延长（QTc、JTc、JTpeak）。与野生型兔（1/68只兔）相比，Kv11.1KI兔（37只兔中有7只）自发性癫痫样活动和临床癫痫发作的发生率增加（P<0.003）。18.9%的Kv11.1KI兔与1.5%的野生型兔突然自发死亡（P<0.003）。我们在Kv11.1KI兔中记录到2次自发致死事件：（1）心源性猝死；（2）由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。
我们构建了首个LQT2基因兔模型，该模型重现了LQT2患者的心脏和癫痫表型。Kv11.1KI兔为未来的机制研究、神经治疗药物开发以及心脏安全性测试提供了有价值的工具。
