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的相对增大，其中前部结构如额叶皮层受到的影响最大；在皮层内，也有描述过小柱形成缺陷。自闭症与GABRB3 （gabaa -受体分化皮质神经元的主要β亚基）之间的联系在表现出更高水平重复行为的患者亚组中得到增强。通过微阵列、qRT-PCR和Western blot分析，部分自闭症谱系障碍患者脑样品中GABRB3表达降低。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这些突变导致了严重的早期表型，正如在gabrb3敲除小鼠中观察到的那样。相比之下，杂合子动物只有细微的缺陷，这是出生时Gabrb3表达补偿性上调至70-80%野生型水平的结果。我们认为发育过程中GABRB3的低表达可能更准确地反映自闭症中观察到的表型严重程度。此外，GABRB3也表现出发育调控的、可替代的启动子使用。由于包括其他gabaa受体亚基在内的许多基因的总或同型特异性表达的改变具有相当大的功能和表型影响，我们假设异常的GABRB3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Gabrb3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)生成rnai介导的Gabrb3敲低小鼠；2)表征Gabrb3总表达和变异特异性表达降低的表型后果。这些分析将确定自闭症候选基因GABRB3的变异在神经发育和自闭症的特定特征（如毅力和社交智力）中的作用，这将有助于更深入地了解自闭症和自闭症谱系障碍的病因和治疗。

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.