Hessel E V S, van Gassen K L I, Wolterink-Donselaar I G, Stienen P J, Fernandes C, Brakkee J H, Kas M J H, de Graan P N E
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
Genes Brain Behav. 2009 Mar;8(2):248-55. doi: 10.1111/j.1601-183X.2008.00466.x.
Febrile seizures (FS) are the most common seizure type in children and recurrent FS are a risk factor for developing temporal lobe epilepsy. Although the mechanisms underlying FS are largely unknown, recent family, twin and animal studies indicate that genetics are important in FS susceptibility. Here, a forward genetic strategy was used employing mouse chromosome substitution strains (CSS) to identify novel FS susceptibility quantitative trait loci (QTLs). FS were induced by exposure to warm air at postnatal day 14. Video electroencephalogram monitoring identified tonic-clonic convulsion onset, defined as febrile seizure latency (FSL), as a reliable phenotypic parameter to determine FS susceptibility. FSL was determined in both sexes of the host strain (C57BL/6J), the donor strain (A/J) and CSS. C57BL/6J mice were more susceptible to FS than A/J mice. Phenotypic screening of the CSS panel identified six strains(CSS1, -2, -6 -10, -13 and -X) carrying QTLs for FS susceptibility. CSS1, -10 and -13 were less susceptible (protective QTLs), whereas CSS2, -6 and -X were more susceptible (susceptibility QTLs) to FS than the C57BL/6J strain. Our data show that mouse FS susceptibility is determined by complex genetics, which is distinct from that for chemically induced seizures. This is the first dataset using CSS to screen for a seizure trait in mouse pups. It provides evidence for common FS susceptibility QTLs that serve as starting points to fine map FS susceptibility QTLs and to identify FS susceptibility genes. This will increase our understanding of human FS, working toward the identification of new therapeutic targets.
热性惊厥（FS）是儿童中最常见的惊厥类型，而复发性FS是发生颞叶癫痫的一个危险因素。尽管FS的潜在机制在很大程度上尚不清楚，但最近的家族、双胞胎和动物研究表明，遗传学在FS易感性中起重要作用。在此，采用正向遗传学策略，利用小鼠染色体置换系（CSS）来鉴定新的FS易感性数量性状基因座（QTL）。在出生后第14天通过暴露于暖空气诱导FS。视频脑电图监测确定强直阵挛性惊厥发作，定义为热性惊厥潜伏期（FSL），作为确定FS易感性的可靠表型参数。在宿主品系（C57BL/6J）、供体品系（A/J）和CSS的雌雄个体中均测定了FSL。C57BL/6J小鼠比A/J小鼠对FS更易感。对CSS组的表型筛选鉴定出六个携带FS易感性QTL的品系（CSS1、-2、-6、-10、-13和-X）。与C57BL/6J品系相比，CSS1、-10和-13对FS的易感性较低（保护性QTL），而CSS2、-6和-X对FS的易感性较高（易感性QTL）。我们的数据表明，小鼠FS易感性由复杂的遗传学决定，这与化学诱导惊厥的遗传学不同。这是第一个使用CSS筛选小鼠幼崽惊厥性状的数据集。它为常见的FS易感性QTL提供了证据，这些QTL可作为精细定位FS易感性QTL和鉴定FS易感基因的起点。这将增加我们对人类FS的理解，朝着鉴定新的治疗靶点努力。
