Fine mapping of an epilepsy modifier gene on mouse Chromosome 19
Fine mapping of an epilepsy modifier gene on mouse Chromosome 19
复制标题
DOI：
10.1007/s00335-009-9193-6
复制
发表时间：
2009-06-01
期刊：
影响因子：
2.5
通讯作者：
Kearney, Jennifer A.
中科院分区：
文献类型：
--
作者：
Bergren, Sarah K.;Rutter, Elizabeth D.;Kearney, Jennifer A.
电压门控钠通道的突变与几种类型的人类癫痫有关。由钠通道突变引起的遗传性癫痫的共同特征是表达能力和外显性的变化，这表明遗传修饰物可能会影响临床严重程度。小鼠模型SCN2A(Q54)具有癫痫表型，原因是SCN2A突变导致持续性钠电流升高。SCN2A(Q54)小鼠的表型严重程度取决于遗传背景。同基因C57BL/6J.Q54小鼠与(C57BL/6J x SJL/J)F1.Q54小鼠相比，发作延迟，癫痫发作频率低。此前，我们发现了影响SCN2A(Q54)癫痫表型的两个修饰基因座：11号染色体上的Moe1(癫痫修饰基因1)和19号染色体上的Moe2。我们构建了区间特异的同源基因株，将Moe2在19号染色体上的位置进一步细化到5-Mb区域。对关键区间基因的测序和表达分析表明有两个可能的修饰物：(1)电压门控钾通道亚家族V，成员2(Kcnv2)；(2)与SWI/SNF相关、基质相关、肌动蛋白依赖的染色质调节蛋白，亚家族a，成员2(Smarca2)。基于Kcnv2在调节膜兴奋性方面的生物学作用，以及离子通道变体与癫痫发作之间的联系，Kcnv2是Moe2的一个强大的功能候选者。影响SCN2A(Q54)小鼠癫痫表型的修饰基因可能有助于钠通道突变的人类癫痫患者的不同表达和外显率。
Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a (Q54) has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a (Q54) mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J x SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a (Q54) epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a (Q54) mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.