GABRBeta3 Expression Variation and the Autism Spectrum

GABRBeta3 表达变异和自闭症谱系

• 批准号: 7197611
• 负责人: LAURA B HERZING
• 金额: $ 19.42万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197611
• 关键词: Address; Affect; Animals; Anterior; Anxiety; Autistic Disorder; Behavior; Behavioral; Behavioral Symptoms; Birth; Brain; Candidate Disease Gene; Characteristics; Chromosome abnormality; Chromosomes, Human, Pair 15; Cultured Cells; Defect; Development; Disease; Dominant Genes; Engineering; Etiology; Exhibits; Functional disorder; GABA Receptor; Gender; Gene Expression; Genes; Genetic Transcription; Individual; Intelligence; Knock-out; Knockout Mice; Language; Lead; Mediating; Mus; Mutation; Neonatal; Neurodevelopmental Disorder; Neurons; Parents; Pathway interactions; Patients; Phenotype; Pliability; Protein Isoforms; Proteins; RNA Interference; Relative (related person); Research Personnel; Role; Sampling; Seizures; Severities; Social Interaction; Socialization; Structure; Subgroup; Synapses; Technology; Testing; Transcript; Transcriptional Activation; Transgenic Animals; Up-Regulation; Variant; Western Blotting; autism spectrum disorder; autistic behaviour; brain size; embryonic stem cell; executive function; expression vector; frontal lobe; insight; interstitial; knock-down; knockout animal; neurodevelopment; programs; promoter; receptor; social; trait

DESCRIPTION (provided by applicant): Autism is a progressive neurodevelopment disorder defined primarily by abnormal behavioral features including deficits in social interactions, language dysfunction, and stereotypic behaviors, many of which reflect defects in higher-order (executive) functions. Numerous patients with autism show a relative enlargement of brain size, with anterior structures such as the frontal cortex most affected; also within the cortex, defects in minicolumn formation have been described. Linkage between autism and GABRB3, the dominant beta subunit of GABAA-receptors in differentiating cortical neurons, is enhanced using subgroups of patients exhibiting higher-level repetitive behaviors. By micro array, qRT-PCR and Western blot analysis, GABRB3 expression is decreased in brain samples from some individuals with autism spectrum disorders. However, GABAA-receptor mutations have not been identified in patients with autism. We suggest that the inability to identify non-synonymous mutations in autism may be because such mutations lead to a severe, early phenotype, as observed in Gabrb3-knockout mice. In contrast, heterozygous animals have only subtle defects, as a consequence of compensatory up regulation of Gabrb3 expression to 70-80% wild-type levels at birth. We propose that low GABRB3 expression during development may more accurately reflect phenotypic severities observed in autism. Furthermore, GABRB3 exhibits developmentally regulated, alternative promotor usage as well. As alteration of total or isoform-specific expression of many genes, including other GABAA-receptor subunits has considerable functional and phenotypic effect, we hypothesize that aberrant GABRB3 expression, including alterations in variant-specific or total expression, rather than mutation, underlies chromosome 15-associated autism. To further characterize the role of Gabrb3 transcription variation in development, and its contribution to the autism phenotype, we propose to: 1) Generate RNAi-mediated knock-down Gabrb3 mice; and 2) Characterize the phenotypic consequences of decreased total and variant-specific Gabrb3 expression. These analyses will define the role of variation of the autism candidate gene GABRB3 in neurodevelopment and in specific features of autism such as perseveration and social intelligence, which will lead to greater insight into the etiology and treatment of autism and autism spectrum disorders.

描述（由申请人提供）：自闭症是一种进行性神经发育障碍，主要由异常行为特征定义，包括社会互动缺陷、语言功能障碍和刻板行为，其中许多反映了高阶（执行）功能的缺陷。许多自闭症患者表现出大脑体积相对增大，额叶皮质等前部结构受到的影响最大;在皮质内，也描述了微柱形成的缺陷。自闭症和GABRB 3之间的联系，在分化皮层神经元中GABAA受体的主导β亚基，使用表现出较高水平的重复行为的患者亚组增强。通过微阵列，qRT-PCR和Western印迹分析，GABRB 3表达在一些自闭症谱系障碍个体的大脑样本中降低。然而，GABAA受体突变尚未在自闭症患者中发现。我们认为，无法识别自闭症中的非同义突变可能是因为此类突变会导致严重的早期表型，正如在Gabrb 3基因敲除小鼠中观察到的那样。相比之下，杂合子动物只有轻微的缺陷，这是出生时Gabrb 3表达补偿性上调至野生型水平的70-80%的结果。我们认为，低GABRB 3表达在发展过程中可能更准确地反映了自闭症中观察到的表型严重程度。此外，GABRB 3也表现出发育调节的替代启动子使用。由于许多基因（包括其他GABAA受体亚基）的总表达或亚型特异性表达的改变具有相当大的功能和表型效应，我们假设异常GABRB 3表达（包括变异特异性或总表达的改变，而不是突变）是15号染色体相关自闭症的基础。为了进一步表征Gabrb 3转录变异在发育中的作用及其对自闭症表型的贡献，我们提出：1）产生RNAi介导的敲低Gabrb 3小鼠;和2）表征总的和变体特异性Gabrb 3表达降低的表型后果。这些分析将定义自闭症候选基因GABRB 3的变异在神经发育以及自闭症的特定特征（例如持续行为和社交智力）中的作用，这将使人们更深入地了解自闭症和自闭症谱系障碍的病因和治疗。