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Genetic Modifiers of Childhood Epilepsy

儿童癫痫的基因修饰

基本信息

批准号：
8759567
负责人：
Jennifer A Kearney
金额：
$ 33.8万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759567
关键词：
Address Age-Months Backcrossings Candidate Disease Gene Childhood Chromosomes, Human, Pair 5 Clinical Code Cognitive Complex Congenic Strain DNA Data Set Development Developmental Delay Disorders Disease Progression Encephalopathies Epilepsy Etiology Event Exhibits Failure Febrile Convulsions Functional disorder Gene Expression Profile Genes Genetic Genetic Identity Goals Hippocampus (Brain)Human Individual Infant Interneurons Life Longevity Maps Modeling Molecular Mus Mutation Neurons Outcome Pathway interactions Patients Penetrance Phase Phenotype Predisposition Quantitative Trait Loci Reporting Resistance Resolution Risk SCN1A protein Seizures Severities Severity of illness Sodium Sodium Channel Syndrome Testing Transgenes Transgenic Organisms base clinical phenotype congenic density improved insight loss of function mutation mortality neurophysiology new therapeutic target novel therapeutics premature public health relevance resistant strain response simple febrile seizure transcriptome sequencing voltage

项目摘要

DESCRIPTION (provided by applicant): Mutations in voltage-gated sodium channels are responsible for several human epilepsies with varying degrees of clinical severity. Over 800 mutations in SCN1A, encoding the neuronal voltage-gated sodium channel Nav1.1, have been reported patients. SCN1A mutations are associated with epilepsy phenotypes on the genetic epilepsy with febrile seizures plus (GEFS+) spectrum. The GEFS+ spectrum ranges from simple febrile seizures on the mild end of the spectrum to Dravet syndrome on the severe end. Heterozygous loss-of-function mutations in SCN1A result in Dravet syndrome, an infant-onset epileptic encephalopathy characterized by a variety of seizure types, developmental delay and elevated mortality risk. A common feature of monogenic epilepsies is variable expressivity in individuals carrying the same mutation, suggesting that clinical severity is influenced by genetic modifiers. Mice with heterozygous deletion of Scn1a (Scn1a+/-) model a number of features of Dravet syndrome, including spontaneous seizures and increased mortality risk. Loss of Scn1a results in reduced sodium current in hippocampal GABAergic interneurons, which is predicted to increase excitability due to failure of inhibition. Phenotype severity in Scn1a+/- mice is strongly dependent on strain background. Scn1a+/- mice on the resistant 129 strain background (129.Scn1a+/-) have no overt phenotype and live a normal lifespan. In contrast, Scn1a+/- mice on a (129xB6)F1 strain background (F1.Scn1a+/-) exhibit spontaneous seizures and premature lethality, with 50% dying by 1 month of age. Based on the strain- dependent difference in phenotype, we hypothesize that genetic modifiers influence Scn1a+/- phenotype severity. We recently mapped several modifier loci that influence premature lethality of Scn1a+/- mice. In the current proposal, we will perform fine mapping and candidate gene analysis with the goal of identifying the responsible modifier genes. In addition to the strain-dependent differences in clinical severity, we also observed strain-dependent differences in hippocampal neuron sodium currents (INa). GABAergic interneurons isolated from the F1.Scn1a+/- mice exhibit decreased INa density compared to wildtype littermate controls. In contrast, INa density is preserved in GABAergic interneurons isolated from 129.Scn1a+/- and is no different from wildtype littermates. This suggests that interneurons from strain 129 compensate for the loss of Nav1.1, while F1 interneurons do not. Based on this observation, we hypothesize that there are strain differences in compensatory capacity in the context of Scn1a heterozygous deletion. We propose to perform RNA-seq analysis to characterize hippocampal transcriptome differences during the critical phase of phenotype onset in susceptible F1.Scn1a+/- and resistant 129.Scn1a+/- mice. The results of this analysis will suggest candidate modifier genes and pathways that influence phenotype severity in Scn1a+/- mice. Identification of Dravet syndrome modifier genes will provide insight into the pathophysiology of epilepsy and will suggest novel therapeutic strategies for the improved treatment of human patients.

描述（由申请人提供）：电压门控钠通道突变导致几种临床严重程度不同的人类癫痫。已报道患者中编码神经元电压门控钠通道Nav1.1的SCN 1A中有超过800个突变。SCN 1A突变与遗传性癫痫伴热性惊厥加重（GEFS+）谱上的癫痫表型相关。GEFS+范围从轻度的简单热性惊厥到严重的Dravet综合征。SCN 1A中的杂合性功能丧失突变导致Dravet综合征，这是一种婴儿发作的癫痫性脑病，其特征在于多种癫痫发作类型、发育迟缓和死亡风险升高。单基因癫痫的一个共同特征是携带相同突变的个体的可变表达性，这表明临床严重程度受遗传修饰剂的影响。Scn 1a杂合缺失（Scn 1a +/-）的小鼠模型具有Dravet综合征的许多特征，包括自发性癫痫发作和死亡风险增加。Scn 1a的缺失导致海马GABA能中间神经元中钠电流降低，这被预测会由于抑制失败而增加兴奋性。Scn 1a +/-小鼠中的表型严重程度强烈取决于应变背景。耐药129菌株背景下的Scn 1a +/-小鼠（129.Scn1a+/-）没有明显的表型，寿命正常。相比之下，（129 xB 6）F1品系背景（F1.Scn1a+/-）的Scn 1a +/-小鼠表现出自发性癫痫发作和过早致死，50%在1月龄时死亡。基于表型的菌株依赖性差异，我们假设遗传修饰剂影响Scn 1a +/-表型严重程度。我们最近绘制了几个修饰基因位点，影响Scn 1a +/-小鼠的过早致死率。在目前的建议中，我们将进行精细定位和候选基因分析，以确定负责的修饰基因的目标。除了临床严重程度的应变依赖性差异外，我们还观察到海马神经元钠电流（INa）的应变依赖性差异。与野生型同窝对照相比，从F1.Scn1a+/-小鼠中分离的GABA能中间神经元显示出降低的INa密度。相比之下，INa密度在从129.Scn1a+/-分离的GABA能中间神经元中保持，并且与野生型同窝仔没有区别。这表明来自菌株129的中间神经元补偿了Nav1.1的损失，而F1中间神经元没有。基于这一观察结果，我们假设，有应变的补偿能力的Scn 1a杂合性缺失的背景下的差异。我们建议进行RNA-seq分析，以表征易感F1.Scn1a+/-和耐药129.Scn1a+/-小鼠表型发作关键阶段的海马转录组差异。该分析的结果将提示影响Scn 1a +/-小鼠表型严重程度的候选修饰基因和途径。Dravet综合征修饰基因的鉴定将提供对癫痫病理生理学的深入了解，并将为人类患者的改善治疗提出新的治疗策略。