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在LRP12中扩展的CGG重复的翻译与眼关节骨髓损伤相关
Chengcheng Li1, Jil A Daw1, Sara K Pittman1
1Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
Acta neuropathologica communications
|March 6, 2026
概括
耳鼻鼻椎骨髓损伤 (OPDM) 与LRP12基因CGG重复扩张有关. 重复关联的非AUG (RAN) 翻译产生有毒的多糖氨酸,导致OPDM中的核内含和细胞损伤.
科学领域:
- 遗传学 遗传学 是一个
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
背景情况:
- 眼鼻位骨髓损伤 (OPDM) 呈现出垂死,眼睛衰竭,消化不良和远端虚弱.
- 病理学特征包括边缘真空孔和内核内含.
- 在几个基因中,OPDM与致病性CGG重复扩张有关,包括LRP12.
研究的目的:
- 研究LRP12基因中CGG重复扩张的翻译机制.
- 确定LRP12中是否发生重复依赖翻译,以及它是否导致有毒的多糖氨酸 (polyG) 产物.
主要方法:
- 在LRP12 5'UTR上下文中表达的正常和扩展的CGG重复,在三个读取中,在GFP的上游.
- 分析了polyG翻译启动和框架转移.
- 评估了与LRP12相关的polyG产品对细胞的影响,包括包含形成和核膜完整性.
- 检查了LRP12扩张载体诱导的多能干细胞 (iPSC) 衍生的神经管.
主要成果:
- LRP12 CGG重复的重复依赖翻译仅在甘氨酸读取框架中发生.
- 与其他重复性疾病不同,LRP12缺少用于polyG转换的近位AUG启动码子;相反,与重复相关的非AUG (RAN) 转换在氨酸框架中启动,并将 +1 转移到甘氨酸框架中.
- 与LRP12相关的polyG产品形成了对SQSTM1/ubiquitin阳性的核内含物,这些含物具有细胞毒性,并破坏了核层结构.
- 这些核内含物与在FMR1相关疾病中看到的细胞质内含物不同.
- 来自LRP12扩张载体的iPSC衍生的髓管显示了内核和周核入,表明患者的polyG表达.
结论:
- 这些发现提供了RAN转化和LRP12相关的OPDM病理学中的多G毒性的证据.
- 形成核多G包容和随后的细胞损伤是LRP12相关肌肉病变的关键机制.
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