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主导NARS1突变导致轴突Charcot-Marie-Tooth疾病扩展NARS1相关疾病

Danique Beijer^1,2,3, Sheila Marte⁴, Jiaxin C Li^5,6

¹Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, B-2610, Belgium.

Brain communications

|March 18, 2024

概括

阿斯巴拉基尼尔-tRNA合成酶 (NARS1) 基因中的致病变体会导致遗传的外围神经病变. 这项研究确定了与轴突Charcot-Marie-Tooth疾病相关的新NARS1变异,扩大了这种神经系统疾病的遗传基础.

科学领域:

遗传学是一个遗传学.
神经科学是一个神经科学.
分子生物学分子生物学

背景情况:

氨基酸-tRNA合成酶 (ARS) 基因对于蛋白质合成至关重要.
几种ARS基因中的致病变体与神经系统疾病有关,特别是遗传性外围神经病变.
阿斯帕拉基尼尔-tRNA合成酶 (NARS1) 变体与发育延迟,动脉缩和脱髓性神经病变有关,但与轴突Charcot-Marie-Tooth疾病无关.

研究的目的:

研究NARS1变异在遗传性外围神经病变中的作用.
为了识别和描述与轴突Charcot-Marie-Tooth疾病相关的新型NARS1变异.
使用体外和体外模型阐明已识别的NARS1变异的功能影响.

主要方法:

在患有遗传性外围神经病变的患者身上进行了exome测序.
在三个家族中发现了三种新型异质合体NARS1变异.
收集和分析了临床和电生理学数据.
用酵母补充试验和敲进小鼠模型来评估变异性病原性.

主要成果:

三种新的异质合体NARS1变体 (p.Met236del,p.Cys342Tyr和p.Ser461Phe) 与传感运动轴突神经病变现型共同分离.
酵母补充试验表明,这三种变体都有功能丧失效应.
对p.Ser461Phe的同卵性敲进小鼠模型也表现出功能丧失的特征.
NARS1被确定为第七个涉及主导轴突Charcot-Marie-Tooth疾病的ARS基因.

结论:

已识别的NARS1变异是致病的,并导致感官运动轴突神经病变.
NARS1与主导的轴突Charcot-Marie-Tooth疾病有关,扩大了与ARS相关的神经病变的范围.
所有二维ARS基因都应在查尔科-玛丽-图斯病的遗传评估中考虑.

关键词:

查尔科特玛丽牙病牙疾病这就是NARS1的意思.氨基酸-tRNA合成酶.亚斯帕拉基尼尔-tRNA合成酶轴突的感觉运动神经病变

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