New strategies to identify the gene mutated in Aicardi syndrome

描述(申请人提供)：这个项目的最终目标是确定艾卡迪综合征的突变基因，艾卡迪综合征是一种罕见的神经发育障碍，几乎只影响女性，并与智力低下有关。它被认为是由从头开始的X连锁显性杂合突变引起的。受影响的女孩表现为典型的老茧发育不全、严重癫痫发作(婴儿痉挛)和脉络膜视网膜陷窝的三联症。其他缺陷，包括神经元迁移、视神经和其他器官系统的异常。这表明Aicardi综合征中突变的基因在正常发育过程中具有重要的复杂功能。表型的变异性比最初确定的更大，这可能部分是由于患者之间的X染色体失活(XCI)模式的差异。此外，具有最复杂表型的一小部分患者可能存在基因组缺失或重复，从而影响多个基因的功能。因为艾卡迪综合征的所有病例都是零星的，所以不可能用基因连锁来定位包含突变基因的基因座。对于这项研究项目，我们提出了三个具体目标，以寻求寻找艾卡迪综合征基因的其他新策略。在特定的目标1中，我们将更详细地描述这种表型，并研究大量患者DNA上的XCI模式，以进一步支持这种疾病的X连锁遗传。在特定目标2中，我们将使用基因组DNA微阵列上的比较基因组杂交来筛选患者DNA中的微缺失或复制。在第三个特定目标中，我们将对X染色体上的候选基因进行突变分析，这些候选基因将根据已知或推测的功能及其表达模式进行选择。为了选择这些基因，我们还将考虑在类似表型的条件下被破坏的分子途径，以及协调艾卡迪综合征最受影响的器官系统发育的途径。至于其他罕见的神经发育障碍，发现艾卡迪综合征基因不仅有助于这种疾病的诊断和治疗，还将增加对引导大脑、眼睛和其他受影响器官系统发育的分子途径的了解。了解这些生物学过程将有助于许多发育障碍的发现、诊断和治疗。这将改善儿童的健康。

DESCRIPTION (provided by applicant): The ultimate goal of this project is to identify the gene that is mutated in Aicardi syndrome, a rare neurodevelopment disorder that affects almost exclusively females and is associated with mental retardation. It is thought to be caused by de novo X-linked dominant heterozygous mutations. Affected girls present with a typical triad of agenesis of the corpus callosum, severe seizures (infantile spasms) and chorioretinal lacunae. Other defects, including abnormalities of neuronal migration, optic nerve and other organ systems are often present. This suggests that the gene mutated in Aicardi syndrome has important complex functions in normal development. There is more variability in the phenotype than was initially ascertained, which may in part result from differences in X chromosome inactivation (XCI) patterns between patients. In addition, a small subset of patients with the most complex phenotype may have a genomic deletion or duplication that affects the function of more than one gene. Because all cases of Aicardi syndrome are sporadic, genetic linkage to map the locus that harbors the mutated gene is not possible. For this research project we propose three specific aims to pursue other novel strategies to find the Aicardi syndrome gene. In specific aim 1, we will characterize the phenotype in more detail and study XCI patterns on a large number of patient DNAs to provide further support for the X-linked inheritance of the condition. In specific aim 2, we will use comparative genomic hybridization on genomic DNA micro arrays to screen for micro deletions or duplications in DNA from patients. In the third specific aim, we will perform mutation analysis of candidate genes on the X chromosome that will be selected based on their known or putative function and their expression pattern. To select these genes, we will also take into account the molecular pathways that are disrupted in conditions with similar phenotypes and the pathways that orchestrate the development of the organ systems most affected in Aicardi syndrome. As for other rare neurodevelopment disorders, finding the Aicardi syndrome gene will not only benefit diagnosis and treatment of this disorder, it will also increase knowledge on molecular pathways that guide development of the brain, eye and other affected organ systems. Understanding these biological processes will benefit discovery, diagnosis and treatment of many developmental disorders. This will improve the health of children.