The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms underlying C9orf72-related diseases and to identify potential disease modifiers, we performed an extensive RNA sequencing study. We included individuals for whom frontal cortex tissue was available: FTLD and FTLD/MND patients with (n = 34) or without (n = 44) an expanded C9orf72 repeat as well as control subjects (n = 24). In total, 6706 genes were differentially expressed between these groups (false discovery rate [FDR] < 0.05). The top gene was C9orf72 (FDR = 1.41E-14), which was roughly two-fold lower in C9orf72 expansion carriers than in (disease) controls. Co-expression analysis revealed groups of correlated genes (modules) that were enriched for processes such as protein folding, RNA splicing, synaptic signaling, metabolism, and Golgi vesicle transport. Within our cohort of C9orf72 expansion carriers, machine learning uncovered interesting candidates associated with clinico-pathological features, including age at onset (vascular endothelial growth factor A [VEGFA]), C9orf72 expansion size (cyclin dependent kinase like 1 [CDKL1]), DPR protein levels (eukaryotic elongation factor 2 kinase [EEF2K]), and survival after onset (small G protein signaling modulator 3 [SGSM3]). Given the fact that we detected a module involved in vesicular transport in addition to a GTPase activator (SGSM3) as a potential modifier, our findings seem to suggest that the presence of a C9orf72 repeat expansion might hamper vesicular transport and that genes affecting this process may modify the phenotype of C9orf72-linked diseases.

中文翻译：

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广泛的转录组研究强调了C9orf72扩展载体中囊泡运输的重要性。

在C9orf72-SMCR8复合亚基（C9orf72）中具有重复扩增的患者中观察到的大多数临床病理变异性仍无法解释。这种扩展代表额颞叶变性（FTLD）和运动神经元疾病（MND）的最常见遗传原因，导致C9orf72表达缺失以及RNA病灶和二肽重复（DPR）蛋白的生成。C9orf72蛋白本身在水泡运输中发挥作用，作为调节GTPases的鸟嘌呤核苷酸交换因子。为了进一步阐明与C9orf72相关疾病的潜在机制并确定潜在的疾病修饰因子，我们进行了广泛的RNA测序研究。我们纳入了具有额叶皮质组织的个体：FTLD和FTLD / MND患者（n = 34）或没有（n = 44）扩大的C9orf72重复序列以及对照组（n = 24）。这些组之间总共有6706个基因差异表达（假发现率[FDR] <0.05）。最高的基因是C9orf72（FDR = 1.41E-14），在C9orf72扩展载体中，其基因表达比在（疾病）对照中低约两倍。共表达分析揭示了一组相关基因（模块），这些基因在蛋白质折叠，RNA剪接，突触信号传导，代谢和高尔基囊泡转运等过程中富集了。在我们的C9orf72扩展载体队列中，机器学习发现了与临床病理特征相关的有趣候选物，包括发病年龄（血管内皮生长因子A [VEGFA]），C9orf72扩展大小（细胞周期蛋白依赖性激酶，如1 [CDKL1]），DPR蛋白水平（真核延伸因子2激酶[EEF2K]）和发病后的存活率（小G蛋白信号调节剂3 [SGSM3]）。考虑到我们检测到除了GTPase激活剂（SGSM3）以外还涉及水泡运输的模块作为潜在修饰因子的事实，我们的发现似乎表明C9orf72重复扩增的存在可能会阻碍水泡运输，并且影响这一过程的基因可能修饰与C9orf72相关的疾病的表型。