Wong Jennifer C, Butler Kameryn M, Shapiro Lindsey, Thelin Jacquelyn T, Mattison Kari A, Garber Kathryn B, Goldenberg Paula C, Kubendran Shobana, Schaefer G Bradley, Escayg Andrew
Department of Human Genetics, Emory University, Atlanta, GA, United States.
Greenwood Genetic Center, Greenwood, SC, United States.
Front Pharmacol. 2021 Nov 17;12:748415. doi: 10.3389/fphar.2021.748415. eCollection 2021.
Numerous mutations have been identified, of which, the majority are missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.
已鉴定出众多突变，其中大多数是错义变体。大多数突变会导致癫痫性脑病；然而，有些与不太严重的表型相关。通过敲入人类错义突变产生的小鼠模型表现出癫痫发作和一系列行为异常。迄今为止，仅有少数具有框内缺失或插入的小鼠模型，值得注意的是，这些小鼠品系均未表现出癫痫易感性增加。在本研究中，我们报告了两个在结构域4的电压传感器（DIVS4）内携带重叠框内缺失的小鼠模型（ΔIRL / +和ΔVIR / +）的产生和特征。两个小鼠品系均表现出癫痫易感性增加和偶发的自发性癫痫发作。我们还描述了两名在DIV S5 - S6孔区域具有相同框内缺失的无关患者，突出了这类突变的临床相关性。
