Human Epilepsy Genetics - Neuronal Migration Disorders

项目摘要/摘要： 发育性脑畸形是影响许多重大神经系统疾病的核心 美国和世界各地的家庭。癫痫、特殊学习障碍和智力 残疾、脑性瘫痪和脑大小异常通常可归因于病理性畸形。 大脑皮层的。尽管癫痫和智力残疾等症状可能在 出于各种原因，我们将重点放在与皮质畸形相关的病例上 突出个体发育途径，可能由无数和稀有的孟德尔等位基因代表。 我们的实验室已经发现了数十个与这些疾病相关的基因，我们正在开始剖析 早期大脑皮层发育的机制。然而，我们知道还有更多的基因尚未被发现。 而这些目前尚未确定的基因将提供对大脑的更重要的洞察 发展和功能。 我们研究的目标是找出导致人类大脑异常的新的遗传因素 皮质发育。这是通过确定患有先天性脑畸形的家庭来实现的， 推测是由于遗传因素，并使用神经成像数据对病情进行分类，2]识别 包含导致畸形的突变的基因，以及描述这些基因的功能。我们 将重点放在中东，以确定家庭情况，在那里，家庭内婚姻和 庞大的家庭规模丰富了这一人群的罕见孟德尔疾病，并为研究提供了重要的力量 甚至非编码突变，这通常更难表征。已确定致病基因突变 当突变不是外显子时，使用全外显子测序或全基因组和RNA测序。这个 突变的基因在细胞系、斑马鱼和小鼠或雪貂模型中进一步表征，以阐明 它的功能。 新基因的发现，当突变时会导致大脑发育异常，影响 在几个方面影响人类健康。这些发现提供了对这些问题的分类和诊断的见解 通常可以迅速转化为临床实践的破坏性疾病，2]允许改善基因 为忧心忡忡的家庭提供咨询和测试，以及3]提供对潜在的 人类大脑发育中的分子过程，它可以告知潜在的未来的概念 治疗或干预。这些治疗可能不仅适用于我们特定的、通常得不到充分服务的患者 人群，但也更广泛地适用于受相对常见的 癫痫发作以及智力和运动障碍。因此，我们的研究工作是为了减轻 神经疾病对我们人类社会的影响，而且对我们人类社会具有重要的短期和长期影响。

Project Summary/Abstract: Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. Epilepsy, specific learning deficits and intellectual disabilities, cerebral palsy, and abnormalities of brain size can often be attributed to pathological malformations of the cerebral cortex. Although symptoms such as epilepsy and intellectual disabilities may appear broadly in the population for any number of reasons, our focus on those cases associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Our lab has uncovered dozens of genes associated with these conditions, and we are beginning to dissect the mechanisms underlying early cortical development. However, we know many more genes are yet to be discovered and these currently unidentified genes will provide even more important insight into brain development and function. The goal of our research is to identify novel genetic factors that result in abnormal human cerebral cortical development. This is achieved through 1] ascertaining families with congenital brain malformations, presumably due to inherited factors, and categorizing conditions using neuroimaging data, 2] identifying the genes that harbor mutations that cause the malformations, and 3] describing the function of these genes. We focus on the Middle East for ascertainment of families, where the prevalence of intra-familial marriage and large family size enriches this population for rare Mendelian disorders and offers significant power to study even noncoding mutations, which are typically more difficult to characterize. Causative mutations are identified using whole exome sequencing or whole genome and RNA sequencing when the mutation is not exonic. The mutated gene is further characterized in cell lines, zebrafish, and mouse or ferret models in order to elucidate its function. The discovery of new genes, which when mutated result in abnormal brain development, impacts human health in several ways. These discoveries 1] provide insight into classification and diagnosis of these often devastating conditions that can be quickly translated to clinical practice, 2] permit improved genetic counseling and testing for concerned families, and 3] offer an enhanced understanding of the underlying molecular processes of the developing human brain which can inform the conception of potential future therapies or interventions. These treatments may apply not only to our specific, often under-served, patient populations, but also more broadly to numerous patients impacted by the relatively common symptoms of seizures and intellectual and motor impairments. Hence, our research works to reduce the burden of neurologic disease on our human society and does so with important short and long-term implications.