New strategies to identify the gene mutated in Aicardi syndrome

识别艾卡迪综合征基因突变的新策略

• 批准号: 7210983
• 负责人: IGNATIA B VAN DEN VEYVER
• 金额: $ 22.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210983
• 关键词: Accounting; Affect; Aicardi' s syndrome; Animal Model; Biological Process; Brain; Candidate Disease Gene; Characteristics; Child health care; Chromosomes, Human, Pair 14; Clinical; Complex; Condition; Corpus Callosum; DNA; DNA Microarray Chip; DNA Microarray format; DNA Sequence Rearrangement; Defect; Development; Diagnosis; Disease; Eye; Female; Gene Mutation; Genes; Genetic; Genome; Genomics; Goals; Human Genetics; Infantile spasms; Karyotype; Knowledge; Link; Maps; Mental Retardation; Molecular; Mutate; Mutation; Mutation Analysis; Neurodevelopmental Disorder; Neurologic; Neurons; Numbers; Optic Nerve; Pathway interactions; Patients; Pattern; Phenotype; Research Project Grants; Seizures; Sister; Syndrome; System; Technology; Thinking; Triad Acrylic Resin; X Chromosome; X Inactivation; base; body system; comparative genomic hybridization; concept; developmental disease; genetic linkage; girls; improved; male; microdeletion; migration; neurodevelopment; novel strategies; positional cloning

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.

描述（由申请人提供）：该项目的最终目标是确定艾卡迪综合征中突变的基因，这是一种罕见的神经发育障碍，几乎只影响女性，并且与智力低下有关。它被认为是由新的X连锁显性杂合突变引起的。受影响的女孩出现典型的三联征：胼胝体发育不全、严重癫痫发作（婴儿痉挛）和脉络膜视网膜缺损。经常存在其他缺陷，包括神经元迁移、视神经和其他器官系统的异常。这表明艾卡迪综合征中的突变基因在正常发育中具有重要的复杂功能。表型的变异性比最初确定的要大，部分原因可能是患者之间 X 染色体失活 (XCI) 模式的差异造成的。此外，一小部分具有最复杂表型的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。由于所有艾卡迪综合征病例都是散发性的，因此不可能通过遗传联系来绘制包含突变基因的基因座图谱。对于这个研究项目，我们提出了三个具体目标，以寻求其他新策略来寻找艾卡迪综合征基因。在具体目标 1 中，我们将更详细地表征表型，并研究大量患者 DNA 的 XCI 模式，为该疾病的 X 连锁遗传提供进一步支持。在具体目标 2 中，我们将在基因组 DNA 微阵列上使用比较基因组杂交来筛选患者 DNA 中的微缺失或重复。在第三个具体目标中，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其已知或推定的功能及其表达模式进行选择。为了选择这些基因，我们还将考虑在具有相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中受影响最严重的器官系统发育的途径。至于其他罕见的神经发育障碍，找到艾卡迪综合征基因不仅有利于这种疾病的诊断和治疗，还将增加对指导大脑、眼睛和其他受影响器官系统发育的分子途径的了解。了解这些生物过程将有利于许多发育障碍的发现、诊断和治疗。这将改善儿童的健康。