The role of Kv?2 deletion in the neurological phenotype of 1p36 deletion syndrome

描述（由申请人提供）：1号染色体短臂远端消融（1p36缺失综合征）是人类最常见的终端缺失综合征之一，约5000例新生儿中有1例发生。1p36缺失综合征（1p36DS）患者表现出广泛的临床特征，包括生长迟缓、先天性心脏缺陷和颅面畸形。此外，患有1p36DS的个体具有相当严重的神经系统疾病：中度至重度智力迟钝和癫痫活动是常见的临床特征。尽管在缺失程度方面存在显著的可变性，但已经将几个基因定位到1p36区域，作为可能导致1p36DS神经表型的候选基因。其中一个编码钾通道辅助亚基Kv¿2的基因kcnab2最近被发现与1p36DS患者的癫痫有关。为了确定Kv¿2的缺失在多大程度上导致了1p36DS的神经表型，我们已经开始研究通过同源重组删除KCNAB2小鼠同源物的小鼠（Kv¿2 KO小鼠）。我们的初步实验显示Kv¿2 KO小鼠表现出海马依赖性学习/记忆障碍和自发性癫痫发作。这些神经异常发生在海马体内基础突触传递没有改变的情况下。在这个探索性/发展性应用中，我们寻求在这些研究的基础上进一步开发这种小鼠模型。具体目标1中概述的实验将进一步探讨Kv¿2 KO小鼠在另外两个海马体依赖的学习/记忆任务中：Morris水迷宫和Olton 8臂径向迷宫的学习/记忆障碍。在Specific Aim II中，将使用标准视频/脑电图方法来定义Kv¿2 KO小鼠自发癫痫发作的频率、严重程度和患病率。在特定目标III中，我们将确定Kv¿2的缺失在多大程度上改变了长期增强和内在神经元兴奋性。我们预计，从这项探索性/发展性研究中获得的结果不仅将为KCNAB2缺失对1p36 DS中观察到的神经表型的相对贡献提供重要见解，而且还将有助于阐明Kv¿2的神经元功能。1p36缺失综合征是一种染色体疾病，其中1号染色体的任何一个拷贝的短臂末端被删除。1p36患者表现出各种各样的症状，包括几种神经异常。该应用程序建议使用基因工程小鼠来检查删除已知在1p36缺失综合征中丢失的特定基因（KCNA2B）对神经系统的影响。

DESCRIPTION (provided by applicant): Ablation of the distal end of the short arm of chromosome 1 (1p36 deletion syndrome) is one of the most commonly occurring terminal deletion syndrome in humans, occurring in about 1 in 5000 newborns. Subjects with 1p36 deletion syndrome (1p36DS) exhibit a wide range of clinical features including growth delay, congenital heart defects and craniofacial dysmorphism. In addition, individuals with 1p36DS have rather profound neurological disorders: moderate to severe mental retardation and seizure activity are common clinical features. Although there is significant variability with regard to the extent of the deletion, several genes have been mapped to region 1p36 as candidate genes that may underlie the neurological phenotype in 1p36DS. One such gene-KCNAB2-which encodes the potassium channel auxiliary subunit Kv¿2, has recently been linked to epilepsy in patients with 1p36DS. To determine to what extent loss of Kv¿2 contributes to the neurological phenotype of 1p36DS we have begun to examine mice in which the mouse homologue of KCNAB2 has been deleted by homologous recombination (Kv¿2 KO mice). Our preliminary experiments reveal that the Kv¿2 KO mice exhibit hippocampal-dependent learning/memory impairments and spontaneous seizures. These neurological abnormalities occur in the absence of alterations in basal synaptic transmission within the hippocampus. In this Exploratory/Developmental application we seek to build upon these studies to further develop this mouse model. The experiments outlined in Specific Aim I will further explore the learning/memory impairments in the Kv¿2 KO mice in two additional hippocampal-dependent learning/memory tasks: the Morris water maze and the Olton 8-arm radial maze. In Specific Aim II standard video/EEG methodology will be utilized to define the frequency, severity and prevalence of the spontaneous seizures in the Kv¿2 KO mice. In Specific Aim III we will determine to what extent long-term potentiation and intrinsic neuronal excitability are altered by deletion of Kv¿2. We anticipate that the results obtained from this Exploratory/Developmental will not only provide important insights into the relative contribution of KCNAB2 deletion to the neurological phenotype observed in 1p36 DS but will also help to elucidate the neuronal function of Kv¿2. ject Narrative 1p36 deletion syndrome is a chromosome disorder in which the end of the short arm of either copy of chromosome 1 is deleted. Patients with 1p36 exhibit a wide variety of symptoms including several neurological abnormalities. This application proposes to use genetically engineered mice to examine the neurological impact of deleting a specific gene (KCNA2B) known to be lost in 1p36 deletion syndrome.