A mouse model of AChR deficiency syndrome with a phenotype reflecting the human condition
A mouse model of AChR deficiency syndrome with a phenotype reflecting the human condition
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DOI：
10.1093/hmg/ddh320
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Beeson, D
中科院分区：
文献类型：
--
作者：
Cossins, J;Webster, R;Beeson, D
哺乳动物肌肉尼古丁乙酰胆碱受体（AChR）的两种亚型是由AChR五聚体中的epsilon（成人）亚基取代gamma（胎儿）亚基而产生的。成人AChR epsilon亚基基因的零突变是导致AChR缺乏症的最常见原因。这是一种神经肌肉传递障碍，其特征是终生存在非进行性疲劳性肌肉无力。与人类疾病相反，携带AChR epsilon-亚基零突变的小鼠在10至14周龄之间死亡。我们在AChR epsilon亚基敲除的背景下产生了组成性表达人类AChR γ亚基的转基因小鼠。这些小鼠的神经肌肉传递是由胎儿AChR介导的，它们能很好地活到成年，但表现出与人类AChR缺乏症惊人的相似之处。表现为疲劳性肌无力，微终板电位和终板电位降低，运动终板AChR数减少，终板形态改变。我们的研究结果说明了控制离子通道基因表达的物种差异如何影响疾病表型，表明成人AChR亚型的表达对长期生存不是必需的，并提示在AChR缺乏综合征患者中，上调γ -亚基可能是一种有益的治疗策略。
The two subtypes of mammalian muscle nicotinic acetylcholine receptors (AChR) are generated by the substitution of the epsilon (adult) subunit for the gamma (fetal) subunit within the AChR pentamer. Null mutations of the adult AChR epsilon-subunit gene are the most common cause of the AChR deficiency syndrome. This is a disorder of neuromuscular transmission characterized by non-progressive fatigable muscle weakness present throughout life. In contrast with the human disorder, mice with AChR epsilon-subunit null mutations die between 10 and 14 weeks of age. We generated transgenic mice that constitutively express the human AChR gamma-subunit in an AChR epsilon-subunit 'knock-out' background. These mice, in which neuromuscular transmission is mediated by fetal AChR, live well into adult life but show striking similarities to human AChR deficiency syndrome. They display fatigable muscle weakness, reduced miniature endplate potentials and endplate potentials, reduced motor endplate AChR number and altered endplate morphology. Our results illustrate how species differences in the control of ion-channel gene expression may affect disease phenotype, demonstrate that expression of adult AChR subtype is not essential for long-term survival, and suggest that in patients with AChR deficiency syndrome, up-regulation of the gamma-subunit could be a beneficial therapeutic strategy.