The Role of ARX in Normal and Abnormal Brain Development

大脑发育异常，包括智力发育迟缓和畸形，在所有活着出生的儿童中约占2%，癫痫约占0.5%，使其成为已知的最常见的儿童疾病之一。尽管频率很高，但一些潜在疾病的分子和细胞基础直到最近才被阐明，而更多的基础仍然未知。最近，转录因子ARX的突变在几名患有儿童早期癫痫和智力低下的儿童中被描述出来，这些儿童既有也没有相关的脑畸形。我们预计，该基因的突变将被证明是一种相对常见的智力低下和婴儿癫痫的原因，因为在这组儿童中已经出现了广泛的严重性，并且该基因中发现的四条聚丙氨酸中至少有两条突变是一种反复发生的机制。ARX突变导致如此广泛的发育问题的发育机制是 尽管新出现的数据表明放射状和非放射状细胞迁移存在障碍，但尚不完全清楚，这两条途径是正常大脑发育所必需的。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对于来自新皮质的投射神经元的正常径向细胞迁移是必需的 (3)在一些婴儿癫痫和智力低下患者中可见Arx的5‘聚丙氨酸扩张导致Arx在细胞核内聚集，从而导致Arx功能丧失或使该蛋白对脆弱神经元产生毒性。为了验证这些假设，提出了一系列实验，以发现具有候选表型的一大系列男性和女性患者的突变类型。此外，将产生一只外显子2周围有loxP位点的小鼠，允许在新皮质或神经节隆起中特定缺失Arx。最后，将构建具有聚丙氨酸轨迹扩展的小鼠，模仿常见的人类ARX突变。人类和突变小鼠的表型不同。将分析ARX/ARX突变并 相互比较以及与相关基因突变引起的重叠表型进行比较。这些研究有望更好地了解ARX在正常和异常发育中的作用，并将有助于我们理解儿童常见疾病的发病机制，如智力低下、癫痫和脑结构异常。

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.