DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Dystonia due to pathogenic variants in the THAP1 gene (DYT-THAP1) exhibits significant variability in expressivity and reduced penetrance.
• The THAP1 gene encodes a transcription factor, implying that gene expression modifiers likely influence DYT-THAP1's variable presentation.

Purpose of the Study:

• To evaluate the transferability of differentially expressed genes (DEGs) identified in neuronal cells to fibroblast models of DYT-THAP1.
• To investigate if fibroblasts can serve as a suitable model for studying gene expression changes associated with DYT-THAP1.

Main Methods:

• Quantitative PCR (qPCR) and Digital PCR (dPCR) were employed to analyze RNA extracted from fibroblasts.
• Fibroblast samples were obtained from individuals with manifesting mutations (MMCs), non-manifesting mutation carriers (NMCs), and healthy controls.

Main Results:

• Ten out of 14 previously identified neuronal DEGs showed significant expression differences in fibroblasts among the three groups.
• Genes related to transcription factors, G protein-coupled receptor signaling, and apoptosis/DNA repair exhibited higher expression in MMCs and NMCs compared to controls.
• Expression patterns of STXBP1 and TOR1A, genes linked to neurological disorders, differed between MMCs and controls.

Conclusions:

• Fibroblasts demonstrate a high transferability rate (>70%) of DEGs relevant to DYT-THAP1, supporting their utility as a research model.
• Certain DEGs identified in fibroblasts may serve as potential biomarkers for DYT-THAP1, potentially influencing its penetrance and expressivity.