Combined Approach to Genetic Modifiers of Inherited 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，包括异质性综合征全身性癫痫伴热性惊厥+（GEFS+）。在GEFS+家族内，具有相同初级钠通道突变的家族成员之间的表型表达率存在差异。在钠通道突变的GEFS+家族中观察到的癫痫包括几乎所有的癫痫发作类型，从仅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。Scn 2a-Q54转基因小鼠在电压门控钠通道Scn 2a中具有突变，并且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 C57 BL/6 J）F1小鼠相比，耐药C57 BL/6 J背景下的Q54小鼠癫痫发作延迟，严重程度降低，存活率增加。这表明遗传修饰因素是表型易感性和严重性的基础。我们绘制了两个修饰基因座，影响Scn 2a-Q54小鼠癫痫发作表型。我们将对这些基因座进行高分辨率定位，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，以确定额外的癫痫修饰基因在致敏筛选严重影响Scn 2a-Q54，Kcnq 2双突变小鼠。诱变增加了潜在的修饰基因库，并提供了一种互补的方法来QTL分析，依赖于现有的小鼠品系之间的变异。最后，我们正在开发携带人类癫痫突变的Scn 1a基因敲入小鼠，并将在这些小鼠上测试修饰剂的效果。这项提案的目标是确定修饰基因，影响癫痫的临床过程。癫痫修饰基因的发现将为癫痫的复杂遗传和发病机制提供新的线索，并为癫痫的治疗提供新的靶点。

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.