Genetic Modifiers of Childhood Epilepsy

儿童癫痫的基因修饰

• 批准号: 8914054
• 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
• 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/8914054
• 关键词: Address; Age-Months; Backcrossings; Candidate Disease Gene; Childhood; Chromosomes, Human, Pair 5; Clinical; Code; Complex; Congenic Strain; DNA; Data Set; Developmental Delay Disorders; Disease Progression; Encephalopathies; Epilepsy; Etiology; Event; Exhibits; Failure; Febrile Convulsions; Functional disorder; Gene Expression Profile; Genes; Genetic; Genetic Identity; Goals; Health; 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; cognitive development; congenic; density; improved; insight; loss of function mutation; mortality; neurophysiology; new therapeutic target; novel therapeutics; premature; resistant strain; response; simple febrile seizure; transcriptome sequencing; voltage

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是几种临床严重程度不同的人类癫痫的原因。据报道，编码神经元电压门控钠通道Nav1.1的SCN1A有超过800个突变。SCN1A突变与遗传性癫痫伴热性癫痫发作（GEFS+）谱上的癫痫表型相关。GEFS+的范围从轻度的单纯发热性癫痫发作到重度的德拉韦综合征。SCN1A的杂合子功能缺失突变可导致Dravet综合征，这是一种以多种癫痫发作类型、发育迟缓和死亡风险升高为特征的婴儿癫痫性脑病。单基因癫痫的一个共同特征是携带相同突变的个体表现不同，这表明临床严重程度受到基因修饰因子的影响。Scn1a杂合缺失（Scn1a+/-）的小鼠可以模拟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。Scn1a的缺失导致海马gaba能中间神经元的钠电流减少，预计由于抑制失败而增加兴奋性。Scn1a+/-小鼠的表型严重程度很强