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: 7143273
• 负责人: Jennifer A Kearney
• 金额: $ 14.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143273
• 关键词: epilepsy; gene mutation; genes; genetics; human; phenotype; sodium channel

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，包括异质综合征全身性癫痫伴热性惊厥附加症（GEFS+）。在 GEFS+ 家族中，具有相同初级钠通道突变的家族成员之间的表型表达存在差异。具有钠通道突变的 GEFS+ 家族中出现的癫痫几乎包括所有癫痫类型，从单纯的热性惊厥到颞叶癫痫。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因素。 Scn2a-Q54 转基因小鼠的电压门控钠通道 Scn2a 发生突变，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，具有耐药性 C57BL/6J 背景的 Q54 小鼠癫痫发作延迟，严重程度降低，存活率提高。这表明遗传修饰因素是表型的易感性和严重程度的基础。我们绘制了影响 Scn2a-Q54 小鼠癫痫表型的两个修饰位点。我们将对这些基因座进行高分辨率作图，并通过 BAC 转基因测试位置候选基因。我们将使用全基因组 ENU 诱变，在对严重受影响的 Scn2a-Q54、Kcnq2 双突变小鼠的致敏筛选中鉴定其他癫痫修饰基因。诱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，该方法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 敲入小鼠，并将在这些小鼠上市后测试修饰剂对这些小鼠的影响。该提案的目标是确定影响癫痫临床病程的修饰基因。癫痫修饰基因的鉴定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出新的治疗靶点。