Survey of the genetic modifier for Dravet syndrome

我们实验室研究了引入Scn1a基因R1407X突变的Nav1.1缺陷小鼠（C57BL/6J背景）作为Dravet综合征的模型小鼠（Ogiwara et al., J Neurosci 27: 5903- 5914,2007）。杂合子小鼠（Scn1a+/-）表现为自发性癫痫发作，其中约60%存活至成年。有趣的是，杂合小鼠的存活率取决于小鼠品系。猝死潜伏期的菌株依赖性表明，遗传背景在一个或多个基因座上携带显性修饰等位基因，这些基因座决定癫痫表型的严重程度。在本研究中，为了鉴定修饰基因，我们利用回交对MSM/Ms菌株进行了猝死表型的遗传定位。结果表明，两种修饰基因与癫痫致死亡有关。对猝死高度敏感的1^<st>修饰基因位于x染色体上。由于与MSM/Ms小鼠的回交提高了每代小鼠的存活率，我们估计MSM/Ms株的常染色体也具有2^<和>修饰基因，以抵抗癫痫症状。

As a model mouse for Dravet syndrome, the Nav1.1 deficient mouse(C57BL/6J background) that introduced R1407X mutation in the Scn1a gene has been investigated in our laboratory(Ogiwara et al., J Neurosci 27 : 5903-5914, 2007. Heterozygous mice(Scn1a+/-) exhibit spontaneous seizures, and approximately 60% of them survive to adulthood. Interestingly, this survivability of heterozygous mice depended on mouse strain. The strain dependency of latency of sudden death indicates that genetic background carries dominant modifier alleles at one or more loci that determine the severity of the epilepsy phenotype. In this study, to identify modifier genes, we performed genetic mapping of the sudden death phenotype using backcrossing to MSM/Ms strain. The results show 2 types of modifier genes involve in mortality induced by epilepsy. 1^<st> modifier gene that is highly sensitive to the sudden death is located on chromosome X. Because backcrossing with MSM/Ms mice increased survival rate in each generation, we estimated that the autosomes of MSM/Ms strain have 2^<nd> modifier gene(s) to resist symptoms of epilepsy also.