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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mouse model of Timothy syndrome recapitulates triad of autistic traits
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Mouse model of Timothy syndrome recapitulates triad of autistic traits

机译：Timothy综合征的小鼠模型概括了自闭症的三合会

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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 Cav1.2 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 Cav1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyp-ing 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.
机译：自闭症和自闭症谱系障碍（ASD）通常源于环境影响和多种遗传改变的混合。在某些罕见的情况下，例如蒂莫西综合征（TS），单个基因中的特定突变可能足以在大多数患者中产生自闭症或ASD，从而有可能提供一般性的自闭症病因学见识。 TS的两个变体（较轻的TS1和较重的TS2）都来自交替剪接的外显子中的错义突变，这些突变导致Cav1.2 L型钙通道中的相同G406R替换。我们生成了TS2样小鼠，但发现杂合（和纯合）动物不可行。但是，允许保留反向新霉素盒（TS2-neo）的杂合TS2小鼠在成年后得以存活。我们将生存归因于通过转录干扰降低G406R L型通道的表达，钝化突变型L型通道过度活跃的有害影响，并通过研究Cav1.2敲除杂合子解决了基因剂量改变的潜在影响。在这里，我们介绍了TS2-neo小鼠的全面行为表型，利用了利用TS突变在小鼠中模拟ASD的独特机会。除了正常的总体健康，活动和焦虑程度，TS2-neo小鼠表现出明显的限制性，重复性和持久性行为，改变了社交行为，改变了超声发声，并在恐惧调节后增强了语调提示和背景记忆。我们的结果表明，当TS突变体通道的表达水平足够低以避免死亡时，与ASD的核心方面一致，它们足以引起多种不同的行为异常。

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