An active dominant mutation of Glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model
An active dominant mutation of Glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model
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DOI：
10.1016/j.neuron.2006.08.027
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发表时间：
2006-09-21
期刊：
影响因子：
16.2
通讯作者：
Burgess, Robert W.
中科院分区：
文献类型：
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作者：
Seburn, Kevin L.;Nangle, Leslie A.;Burgess, Robert W.
许多遗传性腓骨肌萎缩性侧索硬化周围神经病2D型（CMT2D）是由编码甘氨酰tRNA合成酶（GlyRS）的基因加尔斯中的显性点突变引起的。在这里，我们报告了一个显性突变加尔斯，导致神经病变的小鼠。重要的是，感觉和运动轴突都受到影响，并且显性表型不是由GlyRS氨酰化功能的丧失引起的。突变小鼠具有异常的神经肌肉接头形态和受损的传输，降低神经传导速度，和大直径外周轴突的损失，没有髓鞘形成缺陷。突变体GlyRS酶保留了氨酰化活性，并且由基因陷阱插入产生的功能丧失等位基因在小鼠中没有表现出显性表型。这些结果表明，CMT2D表型不是由典型GlyRS活性的降低和蛋白质合成的不稳定性引起的，而是由特异性影响外周神经元的突变型GlyRS的新致病作用引起的。
the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS). Here we report a dominant mutation in Gars that causes neuropathy in the mouse. Importantly, both sensory and motor axons are affected, and the dominant phenotype is not caused by a loss of the GlyRS aminoacylation function. Mutant mice have abnormal neuromuscular junction morphology and impaired transmission, reduced nerve conduction velocities, and a loss of large-diameter peripheral axons, without defects in myelination. The mutant GlyRS enzyme retains aminoacylation activity, and a loss-of-function allele, generated by a gene-trap insertion, shows no dominant phenotype in mice. These results indicate that the CMT2D phenotype is caused not by reduction of the canonical GlyRS activity and insufficiencies in protein synthesis, but instead by novel pathogenic roles for the mutant GlyRS that specifically affect peripheral neurons.