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: 7813777
• 负责人: Jennifer A Kearney
• 金额: $ 29.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-25 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813777
• 关键词: Affect; Age-Months; Biology; Candidate Disease Gene; Cessation of life; Childhood; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 19; Clinical; Complex; Congenic Mice; Disease; Disease Progression; ENG gene; Elderly; Epilepsy; Epileptogenesis; Ethylnitrosourea; Exhibits; Family; Family member; Febrile Convulsions; Focal Seizure; Gene Targeting; Gene Transfer Techniques; Generalized Epilepsy; Genes; Genetic; Goals; Human; Incidence; Inherited; Knock-in Mouse; Life; Maps; Methods; Modeling; Mouse Strains; Mus; Mutagenesis; Mutant Strains Mice; Mutate; Mutation; Pathogenesis; Patients; Phenotype; Predisposition; Quantitative Trait Loci; Research Personnel; Resistance; Resolution; Seizures; Severities; Sodium Channel; Status Epilepticus; Syndrome; Temporal Lobe Epilepsy; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; clinical phenotype; congenic; embryonic stem cell; genome-wide; insight; mouse model; new therapeutic target; novel; positional cloning; premature; programs; voltage

DESCRIPTION (provided by applicant): Mutations in voltage-gated sodium channels have been implicated in some forms of human epilepsy, including the heterogeneous syndrome Generalized Epilepsy with Febrile Seizures Plus (GEFS+). Within GEFS+ families there is variable expressivity of the phenotype among family members with the same primary sodium channel mutations. The epilepsies seen in GEFS+ families with sodium channel mutations include almost all seizure types, ranging from only febrile seizures to temporal lobe epilepsy. This suggests that there are other factors that influence the clinical phenotype which may include genetic modifiers. Scn2a-Q54 transgenic mice have a mutation in the voltage-gated sodium channel Scn2a and are a model of inherited epilepsy. Consistent with the human patients, the clinical severity of the epilepsy in Q54 mice is influenced by the genetic background. Q54 mice on the resistant C57BL/6J background have delayed seizure onset, decreased severity, and increased survival compared to susceptible (SJL/J x C57BL/6J)F1 mice. This suggests that genetic modifiers underlie the susceptibility and severity of the phenotype. We have mapped two modifier loci that influence the seizure phenotype in Scn2a-Q54 mice. We will perform high resolution mapping of these loci and test positional candidate genes by BAC transgenesis. We will use genome-wide ENU mutagenesis to identify additional epilepsy modifier genes in a sensitized screen with severely affected Scn2a-Q54, Kcnq2 double mutant mice. Mutagenesis increases the pool of potential modifier genes and provides a complementary approach to QTL analysis which relies on existing variants between mouse strains. Finally, we are developing Scn1a knock-in mice carrying human epilepsy mutations and will test the effect of modifiers on these mice as they become available. The goal of this proposal is to identify modifier genes that influence the clinical course of epilepsy. Identification of epilepsy modifier genes will provide insight into the complex inheritance and pathogenesis of epilepsy, and suggest novel therapeutic targets for the treatment of human epilepsy.

描述(由申请人提供)：电压门控钠通道的突变与某些形式的人类癫痫有关，包括异质综合征全面性癫痫伴发热性癫痫发作加(GEFS+)。在GEFS+家族中，具有相同原发钠通道突变的家族成员的表型表达能力不同。在有钠通道突变的GEFS+家族中看到的癫痫包括几乎所有的癫痫类型，从只有发热性癫痫到颞叶癫痫。这表明还有其他因素影响临床表型，其中可能包括遗传修饰物。SCN2A-Q54转基因小鼠存在电压门控钠通道SCN2A突变，是遗传性癫痫的模型。与人类患者一致，Q54小鼠癫痫的临床严重程度受到遗传背景的影响。与易感(SJL/J x C57BL/6J)F1小鼠相比，抗性C57BL/6J背景下的Q54小鼠癫痫发作延迟，严重程度降低，存活率提高。这表明遗传修饰物是表型易感性和严重性的基础。我们已经定位了影响SCN2A-Q54小鼠癫痫表型的两个修饰基因座。我们将进行这些基因座的高分辨率定位，并通过BAC转基因检测位置候选基因。我们将使用全基因组ENU突变在严重影响SCN2A-Q54、KCNQ2双突变小鼠的致敏筛查中识别额外的癫痫修饰基因。突变增加了潜在修饰基因库，并为QTL分析提供了一种补充方法，这依赖于小鼠品系之间现有的变异。最后，我们正在开发携带人类癫痫突变的Scn1a基因敲除小鼠，并将在这些小鼠获得修饰剂时测试它们的效果。这项建议的目标是确定影响癫痫临床过程的修饰基因。癫痫修饰基因的发现将有助于深入了解癫痫的复杂遗传和发病机制，并为人类癫痫的治疗提供新的治疗靶点。