An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy
An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy
复制标题
DOI：
10.1242/dmm.002527
复制
发表时间：
2009-07-01
影响因子：
4.3
通讯作者：
Fisher, Elizabeth M. C.
中科院分区：
文献类型：
--
作者：
Achilli, Francesca;Bros-Facer, Virginie;Fisher, Elizabeth M. C.
glycyl-tRNA合成酶（GARS）的突变导致人类周围神经系统的运动和感觉轴突丧失，临床描述为charco - mare - tooth型2D或远端脊髓性肌萎缩型v。在这里，我们描述了一种新的小鼠突变体GARS (C201R)，其点突变导致GARS内的非保守替代。具有C3H遗传背景的杂合小鼠握力丧失，运动柔韧性下降，精细运动控制中断；这种相对温和的表型在C57BL/6基因背景下更为严重。纯合子突变体具有一系列高度有害的特征，包括运动困难和断奶前死亡。杂合动物周围神经轴突直径减小，神经传导减慢，有髓轴突恢复周期改变，神经支配缺损。对GARS水平的评估显示，与对照组相比，15日龄小鼠的蛋白质含量有所增加；然而，在3个月大的动物中没有观察到这种增加，这表明GARS功能在年幼的动物中可能更为重要。我们发现，在任何年龄，杂合子的酶活性都没有明显降低，但在纯合子小鼠中，与对照组相比，酶活性明显降低；因此，纯合子动物可能遭受部分功能丧失。本文描述的Gars（C201R）突变有助于我们理解tRNA合成酶突变的机制，tRNA合成酶是一种重要的、普遍表达的酶，可导致特定神经元组的轴突病。
Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars(C201R) mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.