Dystonia due to pathogenic variants in the THAP1 gene (DYT-THAP1) shows variable expressivity and reduced penetrance of ~ 50%. Since THAP1 encodes a transcription factor, modifiers influencing this variability likely operate at the gene expression level. This study aimed to assess the transferability of differentially expressed genes (DEGs) in neuronal cells related to pathogenic variants in the THAP1 gene, which were previously identified by transcriptome analyses. For this, we performed quantitative (qPCR) and Digital PCR (dPCR) in cultured fibroblasts. RNA was extracted from THAP1 manifesting (MMCs) and non-manifesting mutation carriers (NMCs) as well as from healthy controls. The expression profiles of ten of 14 known neuronal DEGs demonstrated differences in fibroblasts between these three groups. This included transcription factors and targets (ATF4, CLN3, EIF2A, RRM1, YY1), genes involved in G protein-coupled receptor signaling (BDKRB2, LPAR1), and a gene linked to apoptosis and DNA replication/repair (CRADD), which all showed higher expression levels in MMCs and NMCs than in controls. Moreover, the analysis of genes linked to neurological disorders (STXBP1, TOR1A) unveiled differences in expression patterns between MMCs and controls. Notably, the genes CUEDC2, DRD4, ECH1, and SIX2 were not statistically significantly differentially expressed in fibroblast cultures. With > 70% of the tested genes being DEGs also in fibroblasts, fibroblasts seem to be a suitable model for DYT-THAP1 research despite some restrictions. Furthermore, at least some of these DEGs may potentially also serve as biomarkers of DYT-THAP1 and influence its penetrance and expressivity.

THAP1基因 (DYT-THAP1)致病性变异导致的肌张力障碍表现出可变的表达性和约 50% 的外显率降低。由于THAP1编码转录因子，影响这种变异性的修饰因子可能在基因表达水平上起作用。本研究旨在评估与THAP1基因致病变异相关的神经元细胞中差异表达基因 (DEG) 的可转移性，这些变异先前已通过转录组分析鉴定。为此，我们在培养的成纤维细胞中进行了定量 (qPCR) 和数字 PCR (dPCR)。从 THAP1 显性突变携带者 (MMC) 和非显性突变携带者 (NMC) 以及健康对照中提取 RNA。14 个已知神经元 DEG 中的 10 个的表达谱证明了这三组之间成纤维细胞的差异。这包括转录因子和靶标（ATF4、CLN3、EIF2A 、 RRM1 、 YY1）、参与 G 蛋白偶联受体信号传导的基因（BDKRB2 、 LPAR1）以及与细胞凋亡和 DNA 复制/修复相关的基因（CRADD）， MMC 和 NMC 中的表达水平高于对照。此外，对与神经系统疾病相关的基因（ STXBP1、TOR1A ）的分析揭示了 MMC 和对照之间表达模式的差异。值得注意的是，基因CUEDC2、DRD4、ECH1和SIX2在成纤维细胞培养物中没有统计学上显着的差异表达。由于 > 70% 的测试基因也是成纤维细胞中的 DEG，因此成纤维细胞似乎是 DYT-THAP1 研究的合适模型，尽管存在一些限制。此外，至少其中一些 DEG 也可能作为 DYT-THAP1 的生物标志物并影响其外显率和表达性。