Mouse model of Timothy syndrome recapitulates triad of autistic traits
Mouse model of Timothy syndrome recapitulates triad of autistic traits
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DOI：
10.1073/pnas.1112667108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Shamloo, Mehrdad
中科院分区：
文献类型：
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作者：
Bader, Patrick L.;Faizi, Mehrdad;Shamloo, Mehrdad
自闭症和自闭症谱系障碍（ASD）通常是由环境影响和多种基因改变共同引起的。在一些罕见的情况下，如蒂莫西综合征（TS），单个基因的特定突变足以在大多数患者中产生自闭症或ASD，这可能为了解自闭症的一般病因提供了潜在的见解。TS的两种变体（较轻的TS1和较严重的TS2）都是由交替剪接的外显子的错义突变引起的，这些突变导致Ca(V)1.2 l型钙通道中相同的G406R替换。我们产生了ts2样小鼠，但发现杂合（和纯合）动物无法存活。然而，允许保留倒置新霉素盒（TS2-neo）的杂合子TS2小鼠存活至成年期。我们将其存活归因于通过转录干扰降低G406R l型通道的表达，减弱突变型l型通道过度活跃的有害影响，并通过研究Ca(V)1.2敲除杂合子来解决基因剂量改变的潜在影响。在这里，我们展示了TS2-neo小鼠的彻底行为表型，利用这个独特的机会使用TS突变来模拟小鼠的ASD。在一般健康、活动和焦虑水平正常的情况下，TS2-neo小鼠表现出明显的限制性、重复性和持久性行为，改变了社会行为，改变了超声波发声，并在恐惧条件反射后增强了音调暗示和情境记忆。我们的研究结果表明，当TS突变通道的表达水平低到足以避免死亡时，它们足以引起多种不同的行为异常，这与ASD的核心方面一致。
Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.