Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy
Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy
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DOI：
10.1038/ng1727
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发表时间：
2006-02-01
期刊：
影响因子：
30.8
通讯作者：
Timmerman, V
中科院分区：
文献类型：
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作者：
Jordanova, A;Irobi, J;Timmerman, V
腓骨肌萎缩症（CMT）神经病是由脱髓鞘或轴突变性或两者的组合特征引起的周围神经系统的常见病症。我们先前将常染色体显性中间型CMT神经病C型（DI-CMTC）的基因座分配到染色体1 p34-p35。我们在三个不相关的DI-CMTC家族中发现了酪氨酸-tRNA合成酶（YARS）的两个杂合错义突变（G41 R和E196 K）和一个从头缺失（153 - 156 delVKQV）。生化实验和酵母中的遗传互补显示突变蛋白的氨酰化活性部分丧失，并且YARS或其酵母直向同源物TYS 1中的突变降低酵母生长。YARS定位于区分初级运动神经元和神经母细胞瘤培养物的轴突末端。这种特异性分布在表达突变YARS蛋白的细胞中显著降低。YARS是第二个发现参与CMT的氨酰-tRNA合成酶，从而将蛋白质合成复合物与神经变性联系起来。
Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion ( 153 - 156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.