Combined Approach to Genetic Modifiers of Inherited Epilepsy

遗传性癫痫基因修饰的综合方法

• 批准号: 9021876
• 负责人: Jennifer A Kearney
• 金额: $ 20.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-03 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021876
• 关键词: Combined; Approach; Genetic; Modifiers; Inherited

DESCRIPTION (provided by applicant): Mutations in voltage-gated sodium channels have been associated with several types of human epilepsy, including Genetic (Generalized) Epilepsy with Febrile Seizure Plus (GEFS+) and Dravet Syndrome. Within these genetic epilepsies, there is variable penetrance and expressivity of the clinical phenotype, suggesting a role for genetic modifiers. We have developed mouse models with mutations in voltage-gated sodium channels and seizure-related phenotypes with different underlying mechanisms. Scn2aQ54 transgenic mice have a gain-of-function mutation that results in spontaneous, adult-onset partial motor seizures and models features of GEFS+. Heterozygous Scn1a+/- null mice are a model of Dravet Syndrome, a severe, infant-onset epilepsy with progressive worsening accompanied by psychomotor regression. A common feature of these mouse models is that epilepsy severity varies depending on the genetic strain background, suggesting that genetic modifiers influence the phenotype. Scn2aQ54 mice on the resistant C57BL/6J background have delayed onset, decreased severity and improved survival compared to the susceptible (C57BL/6J x SJL/J)F1 background. Conversely, the epilepsy phenotype of Scn1a+/- mice is more severe on the C57BL/6J background, while they have delayed onset and improved survival on the 129S6/SvEvTac strain background. Based on these observations, we hypothesize that multiple genetic modifiers act to influence penetrance and expressivity of the primary epilepsy mutation. Previously we mapped two modifier loci that are responsible for the strain difference in Scn2aQ54 mice: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. During the previous funding period we performed fine mapping and candidate gene analysis of the Moe1 region, identified the Moe2 modifier gene, and identified additional modifier loci that influence the Scn2aQ54 phenotype. We propose to continue our analysis of epilepsy modifiers using the Scn2aQ54 and Scn1a+/- mouse models. First, we will identify the responsible genes at Scn2aQ54 modifier loci. Next, we will determine the molecular basis of the Moe2 modifier effect. Finally, we will map genetic modifier loci in the Scn1a+/- mouse model and perform transcriptome analysis via RNA-seq for accelerated identification of candidate genes. The major goal of our studies is to identify and characterize modifier genes that influence epilepsy susceptibility and severity. These genes are likely to contribute to common epilepsy syndromes with more complex genetics. Identification of epilepsy modifier genes will provide insight into the basic biology of epileptogenesis and may identify novel therapeutic targets for the treatment of human patients.

描述（由申请人提供）：电压门控钠通道突变与几种类型的人类癫痫有关，包括遗传性（全局性）癫痫伴热性癫痫发作（GEFS+）和Dravet综合征。在这些遗传性癫痫中，临床表型的外显率和表达性是可变的，这表明遗传修饰剂的作用。我们开发了具有电压门控钠通道突变和具有不同潜在机制的癫痫相关表型的小鼠模型。Scn2aQ54转基因小鼠具有功能获得突变，可导致自发的，成人发病的部分运动癫痫发作，并具有GEFS+的模型特征。杂合子Scn1a+/-缺失小鼠是Dravet综合征的模型，Dravet综合征是一种严重的婴儿期癫痫，伴有精神运动性退化。这些小鼠模型的一个共同特征是癫痫的严重程度取决于遗传菌株背景，这表明遗传修饰因子影响表型。与易感（C57BL/6J x SJL/J）F1背景相比，耐药C57BL/6J背景的Scn2aQ54小鼠发病延迟，严重程度降低，生存率提高。相反，C57BL/6J背景下Scn1a+/-小鼠的癫痫表型更严重，而129S6/SvEvTac背景下Scn1a+/-小鼠的癫痫发作延迟，生存率提高。基于这些观察结果，我们假设多种遗传修饰因子影响原发性癫痫突变的外显率和表达性。之前，我们在Scn2aQ54小鼠中定位了两个负责品系差异的修饰位点：第11染色体上的Moe1（癫痫修饰因子1）和第19染色体上的Moe2。在之前的资助期内，我们对Moe1区域进行了精细定位和候选基因分析，鉴定了Moe2修饰基因，并鉴定了影响Scn2aQ54表型的其他修饰位点。我们建议使用Scn2aQ54和Scn1a+/-小鼠模型继续分析癫痫调节剂。首先，我们将确定Scn2aQ54修饰位点上的相关基因。接下来，我们将确定Moe2修饰剂效应的分子基础。最后，我们将在Scn1a+/-小鼠模型中绘制遗传修饰位点，并通过RNA-seq进行转录组分析，以加速候选基因的鉴定。我们研究的主要目的是鉴定和表征影响癫痫易感性和严重程度的修饰基因。这些基因很可能导致遗传更为复杂的常见癫痫综合征。鉴定癫痫修饰基因将提供对癫痫发生的基本生物学的深入了解，并可能为治疗人类患者确定新的治疗靶点。