GABRBeta3 Expression Variation and the Autism Spectrum

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，无法识别自闭症的非同义突变可能是因为这样的突变导致严重的，早期的表型，在Gabrb 3基因敲除小鼠中观察到。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。这些分析将确定自闭症候选基因GABRB 3变异在神经发育和自闭症的特定特征（如持续和社会智力）中的作用，这将导致对自闭症和自闭症谱系障碍的病因学和治疗有更深入的了解。

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.