The Role of ARX in Normal and Abnormal Brain Development

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%，癫痫约0.5%，使其成为已知的最常见的儿童疾病。尽管发病率很高，但一些潜在疾病的分子和细胞基础直到最近才得到阐明，而更多疾病的基础仍然未知。转录因子ARX的突变最近被描述在几个儿童早期癫痫和精神发育迟滞，无论是有或没有相关的脑畸形。我们预计，该基因的突变将被证明是一个相对常见的原因，精神发育迟滞和婴儿癫痫的基础上，广泛的严重程度已经明显在这组儿童和复发机制的突变，在至少两个四聚丙氨酸束中发现的基因。ARX突变导致这种广泛的发育问题的发育机制是 尽管新出现的数据暗示放射状和非放射状细胞迁移的干扰，但尚未完全理解，这是正常大脑发育所需的两种途径。基于人类和小鼠的初步数据，已经产生了以下假设：（1）ARX突变的类型预测了半合子男性和杂合子女性的表型;（2）Arx是新皮质投射神经元正常放射状细胞迁移所必需的。 （3）在某些婴儿癫痫和智力低下患者中观察到的Arx的5'聚丙氨酸扩增导致Arx在核中聚集，这导致Arx功能丧失或使蛋白质对脆弱神经元有毒。为了验证这些假设，提出了一系列实验，这些实验将在大量具有候选表型的男性和女性患者中发现突变类型。此外，将产生具有外显子2周围的LoxP位点的小鼠，允许在新皮质或神经节隆起中特异性缺失Arx。最后，将构建具有模拟人类常见的ARX突变的聚丙氨酸轨道扩增的小鼠。人类和突变小鼠的表型不同。将分析ARX/Arx突变， 相互比较以及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。

Developmental anomalies of the brain, including mental retardation and malformations, occur in approximately 2% of all liveborn children and epilepsy in about 0.5%, placing them among the most common childhood disorders known. Despite the high frequency, the molecular and cellular basis for some of the underlying disorders has been elucidated only recently, while the basis of many more remains unknown. Mutations in the transcription factor ARX have recently been described in several children with early childhood epilepsy and mental retardation, both with and without associated brain malformations. We anticipate that mutations of this gene will 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 developmental problems is incompletely understood, although emerging data implicate disturbances in radial and nonradial cell migration, two pathways required for normal brain development. Based on preliminary data from 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) Arx is necessary for normal radial cell migration of projection neurons from the neocortical ventricular zone, and for nonradial migration of inhibitory interneurons and development of the basal ganglia from the ganglionic eminence; and (3) 5' polyalanine expansions of Arx seen in some patients with infantile seizures and mental retardation cause Arx aggregation in the nucleus, which results in loss of Arx function or renders the protein toxic to vulnerable neurons. 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. In addition, a mouse will be generated with LoxP sites surrounding exon 2, allowing for the specific deletion of Arx in either the neocortex or the ganglionic eminence. Finally, mice with an expansion of a polyalanine track, mimicking a common human mutation of ARX will be constructed. 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.