The Role of ARX in Normal and Abnormal Brain Development

ARX 在正常和异常大脑发育中的作用

• 批准号: 8606909
• 负责人: Jeffrey A Golden
• 金额: $ 25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606909
• 关键词: Role; ARX; Normal; Abnormal; Brain

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.

描述（由申请人提供）：大脑发育异常，包括智力迟钝和畸形，发生在所有活产儿童的约2%中，癫痫发生在约0.5%中，将其置于最常见的已知儿童疾病中。尽管发病率很高，但最近仅阐明了极少数疾病的分子和细胞基础，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精神发育迟滞的儿童中被描述，无论是否有相关的脑畸形。正如我们在第一次申请中所预测的，该基因的突变被证明是智力迟钝和婴儿癫痫的相对常见的原因，这是基于在这组儿童中已经明显的广泛的严重性和在该基因中发现的四个多聚丙氨酸束中的至少两个中的突变的复发机制。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放射状和非放射状细胞迁移的干扰，这是正常大脑发育所需的两条途径。基于在人类和小鼠中从该授权产生的数据，已经产生了以下假设：（1）ARX突变的类型预测半合子雄性和杂合子雌性中的表型;（2）受影响的雌性人类和小鼠中的表型与X失活相关;（3）多聚腺苷酸束扩增的Arx基因导致转录抑制缺陷，最终导致小鼠癫痫发作和智力低下。为了验证这些假设，提出了一系列实验，将发现在一个大系列的男性和女性患者的候选表型的突变类型，并确定X-失活状态。在本申请中，我们将专注于阐明多聚A道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。将分析人类和具有不同ARX/Arx突变的突变小鼠的表型，并相互比较，并与相关基因突变引起的重叠表型进行比较。这些研究将有助于我们更好地了解Arx在正常和异常发育中的作用，并有助于我们了解儿童常见疾病如精神发育迟滞、癫痫和大脑结构异常的发病机制。公共卫生相关性：癫痫和智力迟钝在许多儿童中共存，共同给美国卫生保健带来了巨大的财政负担，估计为512亿美元（以2003年美元计算）。尽管美国所有儿童中有3-5%表现出癫痫和/或智力迟钝，但在大多数情况下，对这些疾病的潜在病因知之甚少。来自我们以前的工作和本申请中提出的数据试图了解一种基因ARX如何通常导致儿童癫痫和智力迟钝。最终，我们希望这些研究将导致这些和相关神经系统疾病的诊断，治疗和预防的改进。