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相关，包括遗传性（全身性）癫痫伴热性惊厥+（GEFS+）和Dravet综合征。在这些遗传性癫痫中，临床表型的表达率和表达率是可变的，这表明遗传修饰剂的作用。我们已经开发了具有电压门控钠通道突变和具有不同潜在机制的糖尿病相关表型的小鼠模型。Scn 2aQ 54转基因小鼠具有功能获得性突变，该突变导致自发性、成年发作的部分运动性癫痫发作并模拟GEFS+的特征。杂合Scn 1a +/- null小鼠是Dravet综合征的模型，Dravet综合征是一种严重的婴儿发作癫痫，伴有进行性恶化伴精神衰退。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品系背景，这表明遗传修饰剂影响表型。与易感（C57 BL/6 J x SJL/J）F1背景相比，耐药C57 BL/6 J背景下的Scn 2aQ 54小鼠具有延迟发作、降低严重程度和改善存活率。相反，Scn 1a +/-小鼠的癫痫表型在C57 BL/6 J背景下更严重，而它们在129 S6/SvEvTac品系背景下延迟发作并改善存活率。基于这些观察结果，我们假设多种遗传修饰剂影响原发性癫痫突变的表达率和表达率。以前，我们绘制了两个修饰基因座，负责在Scn 2aQ 54小鼠的应变差异：Moe 1（癫痫1的修饰）染色体11和Moe 2染色体19。在上一个资助期内，我们对Moe 1区域进行了精细定位和候选基因分析，确定了Moe 2修饰基因，并确定了影响Scn 2aQ 54表型的其他修饰基因座。我们建议继续使用Scn 2aQ 54和Scn 1a +/-小鼠模型分析癫痫调节剂。首先，我们将识别Scn 2aQ 54修饰基因座上的负责基因。接下来，我们将确定Moe 2改性剂效应的分子基础。最后，我们将在Scn 1a +/-小鼠模型中绘制遗传修饰基因座，并通过RNA-seq进行转录组分析，以加速候选基因的鉴定。我们研究的主要目标是识别和表征影响癫痫易感性和严重性的修饰基因。这些基因可能导致具有更复杂遗传学的常见癫痫综合征。癫痫修饰基因的鉴定将提供对癫痫发生的基础生物学的深入了解，并可能为人类患者的治疗确定新的治疗靶点。