Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females
Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females
复制标题
DOI：
10.1093/brain/awp107
复制
发表时间：
2009-06-01
期刊：
影响因子：
14.5
通讯作者：
Golden, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Marsh, Eric;Fulp, Carl;Golden, Jeffrey A.
X-连锁aristaless-related homeobox基因（ARX）的突变与大脑结构异常以及多种神经认知缺陷有关。Arx缺陷小鼠的产生揭示了几个形态异常，类似于在患者和中间神经元迁移缺陷中观察到的，但围产期致死性排除了以后的表型分析。有趣的是，在具有各种ARX突变的患者中观察到的许多神经学表型可以部分归因于中间神经元功能障碍。为了直接测试这种可能性，产生携带floxed Arx等位基因的小鼠并与Dlx 5/6（CRE-IRES-GFP）（Dlx 5/6（CIG））小鼠杂交，从神经节隆起衍生的神经元（包括皮质中间神经元）中条件性地缺失Arx。我们现在报告，Arx（/y）; Dlx 5/6（CIG）（雄性）小鼠在生命早期就表现出多种癫痫发作类型，包括行为和脑电图上类似婴儿痉挛的癫痫发作，并通过发育表现出进化。因此，这代表了一种新的恶性形式的儿科癫痫的遗传模型，具有类似婴儿痉挛症的一些特征，由已知婴儿痉挛症基因的突变引起。出乎意料的是，大约一半携带单个突变Arx等位基因（Arx（/）; Dlx 5/6（CIG））的雌性小鼠也发生癫痫发作。我们还发现，一部分女性携带者有癫痫发作和神经认知缺陷。总之，我们已经确定了一个以前未被认识的患者群体，其神经功能缺损归因于我们的小鼠模型中重现的ARX突变。此外，我们表明，扰动的中间神经元亚群是一个重要的机制，在半合子男性和女性的发展癫痫的发病机制。鉴于婴儿痉挛症和相关疾病患者中ARX突变的频率，我们的数据揭示了进一步了解这些疾病发病机制的新模型。
Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6(CRE-IRES-GFP)(Dlx5/6(CIG)) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx(/y);Dlx5/6(CIG) (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx(/);Dlx5/6(CIG)) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.