C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease. BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes. Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G₄C₂ repeats generated from the single-copy C9–500 line show longer repeats result in earlier onset, increased disease penetrance, and increased levels of RNA foci and dipeptide RAN protein aggregates. These data demonstrate G₄C₂ repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.

中文翻译：

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重复长度增加了 C9orf72 ALS/FTD BAC 转基因小鼠的疾病外显率和严重程度

C9orf72 ALS/FTD 患者表现出显着的临床异质性，但重复扩增突变的复杂生物学限制了我们对该疾病的了解。BAC 转基因小鼠用于更好地了解C9orf72 ALS/FTD的分子机制和重复长度效应。这些小鼠的遗传分析表明 BAC 转基因而不是整合位点效应会导致 ALS/FTD 表型。在疾病晚期发现细胞增殖、炎症和神经元通路的转录组变化，而选择性剪接变化提供了随着疾病进展而恶化的早期分子标记。具有 800、500 或 50 G ₄ C ₂的小鼠等基因亚系从单拷贝 C9-500 细胞系产生的重复显示更长的重复导致更早的发病、增加的疾病外显率以及增加的 RNA 病灶和二肽 RAN 蛋白聚集体的水平。这些数据表明 G ₄ C ₂重复长度是疾病的一个重要驱动因素，并将替代剪接变化识别为C9orf72 ALS/FTD 的早期生物标志物。