The Role of ARX in Normal and Abnormal Brain Development

描述（由申请人提供）：大脑发育异常，包括智力迟钝和畸形，约占所有活产儿童的2%，癫痫约占0.5%，是已知最常见的儿童疾病之一。尽管频率如此之高，但最近只有极少数疾病的分子和细胞基础得到了阐明，而更多疾病的基础仍然未知。转录因子ARX的突变已经在几个患有早期儿童癫痫和智力低下的儿童中被描述，这些儿童有或没有相关的脑畸形。正如我们在第一个应用中所预测的那样，该基因的突变被证明是智力迟钝和婴儿癫痫的一个相对常见的原因，这是基于在这组儿童中已经明显存在的广泛的严重程度，以及在该基因中发现的四个聚丙氨酸束中至少两个的反复突变机制。ARX突变导致这一系列问题的发育机制尚不完全清楚，尽管新出现的数据涉及径向和非径向细胞迁移的干扰，这是正常大脑发育所需的两条途径。根据这项资助在人类和小鼠中产生的数据，产生了以下假设：(1)ARX突变的类型预测了半合子雄性和杂合子雌性的表型；(2)受感染的女性人和小鼠的表型与x失活相关；(3) poly-A通道扩大的Arx导致转录抑制缺陷，最终导致小鼠癫痫发作和智力迟钝。为了验证这些假设，研究人员提出了一系列实验，以发现大量具有候选表型的男性和女性患者的突变类型，并确定x失活状态。在本应用中，我们将重点阐明多聚a束突变导致神经表型的机制，并进一步了解Arx的下游靶点及其在正常和异常脑发育和功能中的作用。将分析不同ARX/ ARX突变的人和突变小鼠的表型，并将其相互比较，并与相关基因突变引起的重叠表型进行比较。这些研究有望进一步了解Arx在正常和异常发育中的作用，并有助于我们理解智力迟钝、癫痫和大脑结构异常等儿童常见疾病的发病机制。公共卫生相关性：癫痫和智力发育迟滞在许多儿童中同时存在，它们共同给美国卫生保健美元造成了重大的财政负担，估计为512亿美元（按2003年美元计算）。虽然美国所有儿童中有3-5%表现出癫痫和/或智力低下，但在大多数情况下，对这些疾病的潜在病因知之甚少。我们以前工作的数据和本次申请中提出的数据旨在了解一个基因ARX是如何通常导致儿童癫痫和智力迟钝的。最终，我们期望这些研究将导致他们的诊断，治疗和预防这些和相关的神经系统疾病的改进。

DESCRIPTION (provided by applicant): Developmental anomalies of the brain, including mental retardation and malformations, occur in approximately 2% of all live born children and epilepsy in about 0.5%, placing them among the most common known childhood disorders. Despite this high frequency, the molecular and cellular basis for only a very few disorders has been recently elucidated, while the basis of many more remains unknown. Mutations in the transcription factor ARX have been described in several children with early childhood epilepsy and mental retardation, both with and without associated brain malformations. As predicted in our first application, mutations of this gene prove to be a relatively common cause of mental retardation and infantile epilepsy based on the wide spectrum of severity already apparent in this group of children and a recurrent mechanism for mutation in at least two of the four polyalanine tracts found in the gene. The developmental mechanism by which ARX mutations result in this wide spectrum of problems is incompletely understood, although emerging data implicate disturbances in radial and nonradial cell migration, two pathways required for normal brain development. Based on data generated from this grant in humans and mice, the following hypotheses have been generated: (1) the type of ARX mutation predicts the phenotype in both hemizygous males and heterozygous females; (2) the phenotype in affected female humans and mice correlates with X-inactivation; and (3) Arx with an expanded poly-A tract results in defects in transcriptional repression, ultimate resulting in mice with seizures and mental retardation. To test these hypotheses, a series of experiments are proposed that will discover the mutation types in a large series of male and female patients with candidate phenotypes and determine X-inactivation status. In this application we will focus on elucidating the mechanism of a poly-A tract mutation in causing the neurologic phenotype, and in further understanding the downstream targets of Arx and their role in normal and abnormal brain development and function. The phenotypes in humans and mutant mice with different ARX/Arx mutations will be analyzed and compared to each other and to overlapping phenotypes caused by mutations of related genes. These studies are expected to provide a greater understanding of how Arx functions in normal and abnormal development, and will contribute to our understanding of the pathogenesis of such common disorders in children as mental retardation, epilepsy, and structural anomalies of the brain. PUBLIC HEALTH RELEVANCE: Epilepsy and mental retardation co-exist in many children and together extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Although 3-5% of all children in the United States exhibit epilepsy and/or mental retardation, the underlying pathogeneses for these disorders is poorly understood in most cases. The data from our previous work and from that proposed in this application seeks to understand how one gene, ARX, commonly causes childhood epilepsy and mental retardation. Ultimately we expect these studies will lead to improvements in their diagnosis, treatment, and prevention of these and related neurologic disorders.