A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation.
A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation.
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一种新颖的条件敲入方法定义了 DYT1 肌张力障碍突变的分子和电路效应。
DOI：
10.1093/hmg/ddv355
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发表时间：
2015
影响因子：
3.5
通讯作者：
Dauer,WilliamT
中科院分区：
文献类型：
--
作者：
Weisheit,CorinneE;Dauer,WilliamT
DYT 1肌张力障碍是原发性肌张力障碍中最常见的遗传形式，是由TOR 1A基因显性突变引起的神经发育疾病。这种突变（“Δ E”）从编码的蛋白质torsinA中去除了一个谷氨酸。这种突变在分子和电路水平上的影响，以及其神经发育发作的原因，仍然不完全清楚。为了独特地解决疾病发病机制的关键问题，我们产生了一个条件性Tor 1a敲入等位基因，该等位基因在Cre重组后从野生型转化为DYT 1突变体（“诱导”ΔE：Tor 1ai-ΔE）。我们使用该模型进行基因剂量研究，探索ΔE突变在分子、神经病理学和生物体水平上的影响。这些分析表明ΔE-torsinA是一个亚型等位基因，没有证据表明任何功能获得性毒性。该模型的独特功能也使我们能够测试DYT 1肌张力障碍的回路水平假设，该假设预测DYT 1基因型（Tor 1a ΔE/+）在后脑结构内选择性表达将产生明显的肌张力障碍动物。与此预测相反，我们发现DYT 1基因型的这种解剖学特异性表达没有影响，这一发现对人类和小鼠扩散张量成像研究的解释具有重要意义。这些研究促进了对ΔE突变的分子效应的理解，挑战了表征疾病的电路功能障碍的当前概念，并建立了一个强大的工具，这将对未来的疾病病理生理学研究有价值。
DYT1 dystonia, the most common inherited form of primary dystonia, is a neurodevelopmental disease caused by a dominant mutation inTOR1A. This mutation (‘ΔE’) removes a single glutamic acid from the encoded protein, torsinA. The effects of this mutation, at the molecular and circuit levels, and the reasons for its neurodevelopmental onset, remain incompletely understood. To uniquely address key questions of disease pathogenesis, we generated a conditionalTor1aknock-in allele that is converted from wild-type to DYT1 mutant (‘induced’ ΔE:Tor1ai-ΔE), following Cre recombination. We used this model to perform a gene dosage study exploring the effects of the ΔE mutation at the molecular, neuropathological and organismal levels. These analyses demonstrated that ΔE-torsinA is a hypomorphic allele and showed no evidence for any gain-of-function toxic properties. The unique capabilities of this model also enabled us to test a circuit-level hypothesis of DYT1 dystonia, which predicts that expression of the DYT1 genotype (Tor1aΔE/+) selectively within hindbrain structures will produce an overtly dystonic animal. In contrast to this prediction, we find no effect of this anatomic-specific expression of the DYT1 genotype, a finding that has important implications for the interpretation of the human and mouse diffusion tensor-imaging studies upon which it is based. These studies advance understanding of the molecular effects of the ΔE mutation, challenge current concepts of the circuit dysfunction that characterize the disease and establish a powerful tool that will be valuable for future studies of disease pathophysiology.