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在肌缩性侧面硬化症中,CGG在LRP12中重复扩张

Kodai Kume¹, Takashi Kurashige², Keiko Muguruma³

¹Department of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

American journal of human genetics

|June 20, 2023

概括

在LRP12基因中CGG重复扩张会导致骨髓缩侧面硬化症 (ALS) 和眼节骨髓损伤 (OPDM). 具体的重复次数决定了ALS或OPDM是否发展,为神经退行性疾病提供了新的见解.

科学领域:

神经遗传学神经遗传学
分子神经学分子神经学
基因组医学是基因组医学.

背景情况:

肌缩侧面硬化 (ALS) 是一种进展性神经退行性疾病,主要影响运动神经元.
虽然C9orf72的重复扩张是已知的原因,但ALS病变的全谱仍然不完全理解.
第1型耳鼻腹肌病 (OPDM1) 与LRP12基因的重复扩张有关.

研究的目的:

调查LRP12重复扩张作为ALS的潜在原因的作用.
根据重复长度来区分LRP12重复扩展的表型影响.

主要方法:

在患有ALS的个体中识别和描述LRP12基因中CGG重复扩张.
在LRP12-ALS和LRP12-OPDM病例之间的重复长度和相关的分子病理 (TDP-43,RNA焦点,Muscleblind-like1聚合物) 的比较.
来自受影响个体的诱导多能干细胞衍生的运动神经元 (iPSMNs) 的分析.

主要成果:

在LRP12中发现了CGG重复扩张在ALS (LRP12-ALS) 的五个家庭和两个简单个体中,表现出61-100次重复.
在iPSMN中,LRP12-ALS病例显示了细胞质酸化TDP-43,这是ALS的一个关键病理标志.
与LRP12-OPDM相比,RNA焦点在LRP12-ALS组织中更为突出,而与Muscleblind类似的1聚合物则针对OPDM.
在LRP12中,耳鼻喉骨髓损伤 (OPDM) 病例通常呈现出100-200次重复.

结论:

在LRP12中CGG重复扩张是ALS和OPDM的致病因素.
在LRP12中CGG重复扩张的长度决定了由此产生的表型,在ALS和OPDM之间切换.
这些发现阐明了神经退行性和神经肌肉疾病中的重复长度依赖机制.

关键词:

这就是ALS.CGG重复扩张,重复扩张.在LRP12中使用LRP.在OPDM中,我们将进行OPDM.它们是RNA焦点.这些是iPSCs.运动神经元运动神经元 pTDP-43 的时间.疾病重复的疾病重复这是骨肌肉的骨架肌肉.

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