Lack of neuropathy-related phenotypes in hint1 knockout mice.
Lack of neuropathy-related phenotypes in hint1 knockout mice.
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DOI：
10.1097/nen.0000000000000085
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发表时间：
2014-07
影响因子：
3.2
通讯作者：
Burgess RW
中科院分区：
文献类型：
--
作者：
Seburn KL;Morelli KH;Jordanova A;Burgess RW
编码组氨酸三核苷酸结合蛋白1 （HINT1）的基因HINT1的突变导致隐性遗传周围神经病变，主要涉及运动功能障碍，通常与神经肌强直有关，即由周围神经的过度兴奋性引起的肌肉收缩延长。由于这些突变被假设会导致功能丧失，我们分析了Hint1敲除小鼠作为疾病模型的相关性。缺乏Hint1的小鼠在外观和行为测试或运动表现上都是正常的，尽管它们在开阔的场地上比野生型（WT）小鼠移动得更慢，时间也更短。肌肉、神经肌肉连接处和朗维耶淋巴结在解剖学上是正常的，没有退行性变或再生的迹象。4月龄和13月龄时，周围神经轴突数量和髓鞘形成正常。4月龄时轴突比WT小鼠略小，但未引起传导速度降低，13月龄时轴突直径未见差异。使用肌电图，我们无法检测神经肌强直，即使使用超生理刺激和应激源，如降低温度或3,4二氨基吡啶来阻断钾通道。因此，我们得出结论，Hint1敲除小鼠可能有助于研究Hint1的生化活性，但这些小鼠不能为研究Hint1相关神经病和神经肌强直的基础提供疾病模型或手段。
Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that involves primarily motor dysfunction and is usually associated with neuromyotonia, i.e. prolonged muscle contraction resulting from hyperexcitability of the peripheral nerve. Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 were normal in appearance and in behavioral tests or motor performance, although they moved slower and for a smaller fraction of time than wild-type (WT) mice in an open field arena. Muscles, neuromuscular junctions, and nodes of Ranvier are anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at 4 and 13 months of age. Axons were slightly smaller than those in WT mice at 4 months of age, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. Using electromyography, we were unable to detect neuromyotonia, even using supra-physiological stimuli and stressors such as reduced temperature or 3,4 diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia.